PLACE N RETURN BOX To roman thi- chockom from you "coed.
O AVOID FINES Mum on or him dd. 60..

» r______—____________——————————-T
DATE DUE DATE DUE DATE DUE
i f E “ _ J* _
\LE’ L]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

REGIOSELECI'IVITY IN THE INTRAMOLECllAR CY CLOADDITION OF
DOUBLE BONDS TO TRIPLET BENZENES

By

Ahmad Emad-Eldin Madkour

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
Department of Chemistry

1996

ABSTRACT

REGIOSELECI'IVITY IN THE INTRAMOLECULAR CY CLOADDITION OF
DOUBLE BONDS TO TRIPLET BENZENES

By

Ahmad Emad-Eldin Madkour

The regioselectivity of the intramolecular [2+2] photocycloaddition of
meta-substituted para-butenoxyacetophenones was investigated. Several such
ketones were prepared and irradiated using ultraviolet light. Photoreactions were
generally followed by 1H NMR spectroscopy and stable products were isolated
using standard chromatography techniques.

Generally, electron-withdrawing meta-substituents direct the double bond
addition 100% onto the bond between the tether and the electron-withdrawing
group. The initially formed tricyclo[6.3.0.0]undeca-2,4-diene derivatives
isomerize thermally to their corresponding bicyclo[6.3.0]undec-l,3,5-trienes
which on further irradiation cyclize to cyclobutene derivatives. With meta-
methoxy and thiomethoxy derivatives, the initial bicyclooctatriene
photoproducts are favored over the corresponding triene derivatives in an
equilibrium mixture. Moreover, the opposite regioselectivity of addition is
observed. Meta-alkyl substitiuents show strong directing effect for the double
bond to add onto the bond between the tether and the substituent. Also, in a

competitive study, the double bond prefers to add towards the larger alkyl group.

The reaction is proposed to proceed via exciplex formation between the
electron-rich double bond and the electron deficient triplet benzene ring. Strong
electron-withdrawing substituents attract the double bond toward them during
exciplex formation whereas strong electron-donating groups slightly repel the
double bond. With alkyl substituents, which are weak electron-donors, steric
effects during both exciplex formation and addition of the triplet benzene to the
double bond play dominant roles in the selectivity. Substituents are also found to
have strong effects on both secondary photoreactions and thermal
rearrangements of the photoproducts.

The photochemistry of o-allyloxy-a,a,ot-trifluoroacetophenone was also
studied. Instead of photocyclization, 8-hydrogen abstraction occurs exclusively
to provide vinylbenzofuran derivatives. This behavior, which is similar to that of
the corresponding benzophenone but not the acetophenone, is explained in
terms of a captodative conjugative effect in the intermediate biradical formed by

hydrogen abstraction.

Acknowledgements

My sincere thanks are given to Professor Peter J. Wagner for his guidance
and sharing his knowledge through the course of this research. His insight and
encouragement are deeply appreciated.

I am also grateful to the National Science Foundation and the National
Institute of Health for the research assistantship administrated by Professor
Wagner. I would also like to thank the Chemistry Department at Michigan State
University for the use of its research facilities.

I also owe special thanks to many friends, specially in Wagner research
group. Their friendship and sense of humor made my stay at MSU enjoyable.

Most of all, I thank my wife, Amal, for her love support, encouragement
and patience. I am also grateful to my parents, brothers and parents-in-low and

brother-in-low for their continuous support.

iv

TABLE OF CONTENTS

INTRODUCTION

Triplet Phenyl Ketones

Addition of Triplet Phenylketones to Double Bonds
Photocycloaddition of Double Bonds to Benzenes

Addition of Triple Bonds to Arenes

Selectivity in Photocycloaddition of Singlet Benzenes to Olefrns
[2+2] Photocycloaddition to Enones and Dienones

Thermal and Photochemical Transformation of Photoproducts
1H NMR Data For Some Photoproducts

Conformational Analysis

RESULTS

Preparation of Acetophenones
Photocycloaddition and Identification of Photoproducts
Photochemistry of m-Amide-pBA
Photochemistry of m-CN-pBA
Photochemistry of m-OMe-pBA
Photochemistry of m-Me-pBA
Photochemistry of m-tBu-pBA
Photochemistry of m-Me-iPr-pBA
Photochemistry of m-Me—iPr-Mez-pBA
Photochemistry of m-Me—oBA
Photochemistry of m-SMe-pBA

11
16
17
19
22 I
31
37

38

41
48
51
55
58
66
75
82
85
88
90

Photochemistry of m-OMe-Me3-pBA 98

Photochemistry of m-Est-pBA 101
Photochemistry of m-CF3—pBA 103
Photochemistry of p-OMe-mBA 105
Photochemistry of p-Thio-AP 105
Photochemistry of p-NH-AP 107
Photochemistry of p-NAc-AP 108
Photochemistry of p-Ac-TB-Me 108
Photochemistry of o-Ac-TB-H 109
Photochemistry of o-BTFAc 110
Photochemistry of o-PTFAc 111
Computational Studies 121
a-Conforrnational Analysis 121
b-Rotational Barriers 135
c-I-leats of Formation 143
DISCUSSION 146
Regioselectivity 146
Overall Mechanism 147
Triplet-State and Exciplex Formation 147
Radical Addition . 158
Closure of Biradicals 160
Cyclohexadiene-Cyclooctatriene Equilibrium: 161
Temperature Effect on Cycloaddition Regioselectivity 164

Cyclobutene to Cyclooctatriene Rearrangement 165

vi

Regio- and Stereoselectivity of COT Cyclization 167

Thermal Chemistry of ACB's 171
Rearrangement of m-tBu-LCBa,anti 176
The Di-rt-Methane Rearrangement ' 177
Photochemistry of 4-(3-buten-l-mercapto)acetophenone 178
Photochemistry of Triple Bond Derivatives 181
Photochemistry of The Amino Derivatives 181
Photochemistry of o—Allyloxy Trifuoroacetophenone 182
EXPERIMENTAL 185
General Procedures . 185
Purification of Chemicals 18S
Irradiation Procedures 186
Preparation of Starting Ketones 187
Identification of Photoproducts 187
Computational Analysis 293
REFERENCES 295

Table 1:

Table 2:

Table 3:

Table 4:

Table 5:

Table 6:
Table7:

Table 8:
Table 9:

Table 10:
Table 11:
Table 12:
Table 13:
Table 14:
Table 15:
Table 16:
Table 17:
Table 18:
Table 19:
Table 20:

LIST OF TABLES

Rate and equilibrium constants for 7- and 8- substituted
cyclooctatrienes and their corresponding cyclohexadienes.
Selected chemical shifts and coupling constants of some 4-acetyl-
ll- oxabicyclo[6.3.0]undeca-l,3,5-triene (COT) derivatives
Selected chemical shifts and coupling constants of some 4-acety1-
l1-oxatricyclo[6.3.0.01’41undeca-2,5-diene (ACB) derivatives
Selected chemical shifts and coupling constants of some 4-acetyl-
1l-oxatricyclo[6.3.0.03'6]undeca-l,4-diene (LCB) derivatives
Selected chemical shifts and coupling constants of some 4-acetyl-
l1-oxa-tricyclo[6.3.0.01'6]undeca-2,4-diene (Cl-1D) derivatives
13c NMR chemical shifts (ppm) for Z-BTHF1 and BTHFz
1H NMR data for some subtituted linear cyclobutenes (LCmefi)
12,3 Coupling Constants for Some LCBs

Coupling Constants of m-Amide-COTs

Coupling Constants of m-CN-COTs

Coupling Constants of m-Me-COTS

Coupling Constants of m-Amide-ACBS

Coupling Constants of m-Me-ACBS

Coupling Constants of m-OMe-CHDa

Coupling Constants of m-CN-LCBs,mfi

Coupling Constants of m-CN-L.CBs,syn

Coupling Constants of m-Me-LCBSN‘ti

Coupling Constants of m-Me-LCBsgyn

Coupling Constants of m-SMe-LCBa,syn

Coupling Constants of m-SMe-LCBa,antj

23

32

33

34

35

115
119
120
122
123
124
125
126
127
128
129
130
131
132
133

Table 21:
Table 22:

Table 23:

Table 24:

Table 25:

Table 26:

Table 27:

Table 28:

Table 29:
Table 30 :

Coupling Constants of m-Me-o-LCB

Calculated rotational barrier around C—OEt bond for 5-acetyl-2-
ethoxy benzamide excited triplet state.

Calculated rotational barrier around C—OEt bond for 3-cyano-4-
ethoxy acetophenone excited triplet state.

Calculated rotational barrier around C—OEt bond for 4—ethoxy 3-
methyl acetophenone excited triplet state.

Calculated rotational barrier around C—OEt bond for 3-
t-butyl-4-ethoxy acetophenone excited triplet state.

Calculated rotational barrier around C—OEt bond for 4-ethoxy-3-
methoxy- acetophenone excited triplet state.

Calculated rotational barrier around C—OEt bond for 4-ethoxy-3-
mercaptomethyl acetophenone excited triplet state.

Calculated rotational banier around C—OEt bond for 4-ethoxy-3-
isopropyl-S-methyl acetophenone excited triplet state.

Calculated Heat of Formations For Some Compounds.

Charge Distribution for the Excited Singlet State of Some COT's

134

136

137

138

139

140

141

142

144
169

Figure 1:
Figure 2:
Figure 3:
Figure 4:

Figure 5:

Figure 6:

Figure 7:

Figure 8:
Figure 9:

Figure 10:
Figure 11:

Figure 12:

LIST OF FIGURES

1H NMR spectrum of m-Amide-COTS in methanol-d4

1H NMR spectrum of m-CN-LCBs,anti in chloroform-d.

1H NMR spectrum of m-OMe-CHDa in chloroform-d

1H NMR spectrum of a mixture of m-OMe—ACBa and m-OMe-
ACB; obtained by irradiation of m-OMe-pBA in benzene-d6 using
Pyrex-filtered light.

1H NMR spectrum of a mixture of m-OMe-CHDa and m-OMe-
COTS obtained by irradiation of m—OMe-pBA in benzene-d5 and
leaving the sample at room temperature.

1H NMR spectrum of a mixture of m-OMe-CHDa and m-OMe-
COTa in chloroform-d obtained by irradiation of m-OMe-pBA in
benzene.

1H NMR spectrum of a mixture of m-Me-ACBS and its
photorearrngement product after irradiation in benzene-d6 using
Pyrex-filtered light.

1H NMR spectrum of m-Me-COTS in benzene-d5.

1H NMR spectrum of a mixture of m-Me-ACBS and m-Me-
LCBmu obtained by irradiation of m-Me-pBA in warm benzene-
d5 at 365 nm.

1H NMR spectrum of m-tBu-LCBa,anfi in benzene-d5.

1H NMR spectrum of a mixture of m-tBu-LCB'g,anti and m-tBu-

LCngnu obtained by treatment of t-Bu-LCB'a,anti with PTSA in
benzene-d5.

1H NMR spectrum of m-Me—iPr-ACBS obtained by irradiation of
m-Me—iPr-COTS in benzene-d5 using Pyrex-filtered light.

53
57

6O

61

63

65

68
71

73
77

79

84

Figure 13: 1H NMR spectrum of rn-SMe-COTS in chloroform-d. 95
Figure 14: 1H NMR spectrum of equilibrium mixture of m-SMe-CHDa and m-

SMe-COTa in benzene-d5. 96
Figure 15: 1H NMR spectrum of rn-SMe-ACBa obtained by irradiation of a

mixture of rn-SMe-CHDa and m-SMe-COTa in benzene-d6 at 365

nm. 97
Figure 16: 1H NMR spectrum of a mixture of m-OMe-Me3COTs in benzene-

d5 100
Figure 17: 1H NMR spectrum of a mixture of Z-BTHF1 and E-BTHF1

obtained by irradiation of o-PTFAc in benzene-d5. 112
Figure 18: 1H NMR spectrum of a mixture of Z-BTHFl and E-BTHF1

obtained by irradiation of o-PTFAc in benzene-ddpyridine-ds

followed by removal of pyridine. 113
Figure 19: Best Geometry of m-Amide-COTS 122
Figure 20: Best Geometry of m-CN-COTS 123
Figure 21: Best Geometry of m-Me-COTS 124
Figure 22: Best Geometry of m-Amide-ACBS 125
Figure 23: Best Geometry of m-Me-ACBS 126
Figure 24: Best Geometry of m-OMe-CHDa 127
Figure 25: Best Geometry of m-CN-LCBs,anti 128
Figure 26: Best Geometry of m-CN-LCBsgyn (Not Formed) 130
Figure 27: Best Geometry of m-Me-LCBs,anti 131
Figure 28: Best Geometry of m-Me-LCBsfiyn (Not Formed) 132
Figure 29: Best Geometry of m-SMe-LCBuyn (Not Formed) 133
Figure 30: Best Geometry of m-SMe-LCBMmu 134
Figure 31: Best Geometry of m-Me-o-LCBs,anu 135

Figure 32:

Figure 33:

Figure 34:

Figure 35:

Figure 36:

Figure 37:

Figure 38:

Dihedral drive for rotation arround C—OEt bond for S-acetyl-Z-
ethoxy benzamide excited triplet state.

Dihedral drive for rotation arround C—OEt bond for 3-cyano-4-
ethoxy acetophenone excited triplet state.

Dihedral drive for rotation arround C—OEt bond for 4—ethoxy 3-
methyl acetophean excited triplet state.

Dihedral drive for rotation arround C—OEt bond for 3-t—butyl-4-
ethoxy acetophenone excited triplet state.

Dihedral drive for rotation arround C—OEt bond for 4-ethoxy-3-
methoxy acetophenone excited triplet state.

Dihedral drive for rotation arround C—OEt bond for 4—ethoxy-3-
mercaptomethyl acetophenone excited triplet state.

Dihedral drive for rotation arround C—OEt bond for 4-ethoxy-3-

isopropyl-S-methyl acetophenone excited triplet state.

153

154

154

155

155

156

156

Al

H

INTRODUCTION

One of the most studied functional groups in organic photochemistry is the
carbonyl group.1 Ketones absorb in the easily accessible longer wave length
region of the u.v. light and lead in many cases to efficient product formation. In
general the carbonyl group is one of the most reactive groups both in the ground
and excited states.2

On the other hand, aromatic compounds are among the most
thermodynamically stable compounds in the ground state. In most of their ground
state reactions the aromaticity is preserved. In the excited state, the aromatic ring
gains over 70 kcal/mol of excitation energy and becomes different in electronic

distribution leading in many cases to nonaromatic products.l

W

Phenyl ketones are known to have n,1t* lowest singlets with fast efficient
intersystem crossing (Rise-'10“ SCC'l, ¢isc= 1) to their triplet states.3'4 The lowest
triplet may be either n,rt* or rut“ depending mainly on the ring substituents. The
n,rt* transition is a result of excitation of a non-bonding electron to the rt“ orbital
of the carbonyl group and produces an alkoxy radical-er excited state.5'6'7 On
the other hand, Mt“ triplets shows little radical-like reactivity. This is because of
lack of strong spin localization on the carbonyl oxygen.8

Unsubstituted alkyl phenyl ketones have n,1t* lowest triplets. Their rt,1t*
triplets are about 2 kcal per mole higher in energy.9'w'll In general, electron-
donating (+R) substituents at any ring position lower rt,1t* and raise n,1t*

transition energies so that the 1t,1t* state is lowest in energy.11'12'13 Inductively

2

electron-withdrawing (-1) substituents lower n,rt* transition energies relative to
1t,1t* energiesm'n’12 On the other hand, para conjugatively electron-withdrawing
(-R) substituents lower 1t,rt* triplet energies so much more than n,rt* energies that
the lowest triplet becomes 1t,1t*. Meta (-R) substituents do not stabilize 1t,1t*

triplets enough to invert triplet levels.l4

lll'l' [I'IIEI HI ID llBl

Photochemical cycloaddition of alkenes to singlet benzenes has been
studied for four decades”:16 In 1987 Wagner and Nahm17 discovered a new
[2+2] photocycloaddition reaction. They found that double bonds add
intramolecularly to phenyl ketones with lowest 1t,1t* triplet states to produce
bicyclo[4.2.0]octa-2,4-dienes as initial photoproducts. The reaction proceeds
only if the double bond is tethered ortho or para to the keto group (Scheme 1).

The primary photoproduct contains a cyclohexadiene subunit which
opens thermally (disrotatory, following the Woodward-Hofman rule) to give all
cis cyclooctatriene. This absorbs light and causes one of its two diene units to
undergo a disrotatory cyclization to give the final cyclobutene product.18 The
cyclooctatriene was found to be in thermal equilibrium with the initial
photoproduct. This equilibrium is strongly affected by ring or side chain
substituents.19'20 In the case of no substituent the equilibrium favors the

cyclooctatriene.

3

0
O
o \_
GOP/a; 9:0 gas
0 A
0

 

 

 

o-Ac-CHD-Ou o-Ac-COT-On o-Ac-LCB-Ou
Ho Ji. Am .I 6
O O A O
p°AC'CIID'O ll P'AC'COT'Ol I p-AC'ACB '01 1
Scheme 1

The cyclobutenes were found to be thermally unstable. Upon heating they
opened to all cis cyclooctatrienes, a process that does not follow the Woodward-
Hoffman rule. It was proposed that the opening probably involves a biradical
intermediate and is facilitated by donor-acceptor weakening of the cyclobutane 0

bond (Scheme 2).18

o o - D
C. ___. ._.
OR OR
+0

OR

Scheme 2

4

Direct irradiation can cause [2+2] cycloaddition of double bonds to
substituted benzenes.”22 This is true only if there is a strong donor-acceptor
interaction between the double bond and the lowest excited singlet state of the
substituted benzenes. This means that an activated double bond is needed for the
ortho addition to occur from the excited singlet state otherwise meta addition will
predominate. For Nahm and Wagner's cycloaddition reaction, unactivated double
bonds give only ortho addition products.

It was proposed that Wagner's cycloaddition reaction occurs from the
triplet state since phenyl ketones undergo a very fast intersystem crossing (k ~
1011 3'1)4 with which no other reaction can compete. In addition, product
formation was quenched by the addition of triplet quenchers. The 1t,1t* state was
assumed to be responsible for this reaction since p-butenoxyacetophenone which
has lowest rut" triplet state gave the cycloadduct in much higher chemical and
quantum yield than p-(3-buten-l-oxy) benzophenone which has lowest n,1t*

triplet.17

\

\
O o _ 8+
“5-; —’ ‘8' nus
H30 —»*~ We «)1—
0
ex

/ mp1
0

   

Biradical
Scheme 3

5

Wagner and Sakamoto23 studied the triplet decay kinetics for the meta
substituted p-alkenoxyacetophenones over a wide temperature range. They
found that activation energies varied from 5.0 kcal/mol for a m-methoxy to 3.0
kcal/mo] for m—cyano whereas it was 4.3 kcal/mol for the m-methyl and 3.9
kcal/mol for the unsubstituted p-alkenoxyacetophenone. That electron-
withdrawing groups (CN) increase triplet reactivity whereas electron-donating
groups (OMe) suppress reactivity supports the originally proposed idea that the
electron rich double bond acts as an electron donor to the electron deficient
triplet benzene ring forming an exciplex.

Generally, it is hard to know what is the exact electronic charge and spin
density distribution of excited states. However, it can be predicted from reaction
products, kinetics, some spectroscopic analysis, and quantum mechanical

calculations. Paquette and co-workers24

reported several examples of
regiospecificity in the di-rt-methane rearrangements of benzonorbomadienes

substituted by electron donating or electron withdrawing groups. They have

 

 

wow/w 3th
._ _ I

WW—WTW

 

 

L. .-

 

 

 

Scheme 4

'nI;
I”

sitar

6

shown that cyano and acetyl substituents direct the rearrangement such that the
double bond bridges to the benzene ring ortho or para but not meta (Scheme 4).
This is in agreement with Wagner's25 and Hirota's26 findings that spin density in
triplet benzonitriles is highest ortho and para to the nitrile group (Scheme 5). This
situation can be extended to the rut?“ triplets of acetophenones.

 

 

 

 

If: 11’: ii
IC 0.90 C
© 0.12
<———>
0.034
0.93
Scheme 5

Wagner also pointed out that the benzonitrile triplet is essentially a 1,4
diradical.25 This was proved by analyzing the EPR spectra of triplet fluoro-
benzonitriles. Results showed that spin density on the carbon para to the cyano
group is close to unity and the bond between C1 and C2 (C6) to be nearly a single
bond, whereas those between C2, C3 and C5, C6 are nearly double bonds. This
strongly suggested that the most dominant valance bond structure for the
benzonitrile triplet state has a quinoidal structure. It was also proposed that the
rut“ triplets have charge transfer character with the ring being electron deficient
and the carbonyl electron rich.12

After exciplex formation, the radical- center para to the acetyl group adds
to the double bond to give a 1,4 biradical which will either close to the initial

photoproduct or cleave to give starting material (a mixture of cis and trans

7

olefms). Observation of cis—)trans isomerization supports the idea of a biradical
intermediate.17

The intermediacy of a 1,4 biradical was supported by studying the
photochemistry of AP-CP which has a cyclopropyl group at the double bond.27
Analysis showed that none of the products has the cyclopropyl ring intact. The
opening of the cyclopropyl ring verifies the existence of a biradical intermediate

(Scheme 6).27

is L%%%

AP-CP BR—CP Not Famed
. 70/ \070
O .
ACE/E I
0 O
BR-trans BR-cis
Scheme 6

Wagner and Alehashem28 studied several compounds in which the
unsaturated tether is anchored to the benzene ring with a methylene group. They
found that irradiation of the compounds below produced a mixture of two

isomeric cyclobutenes (Scheme 7).

 

R2 R
0+1“ 111.». 1 R1
O ——»‘“’ 0, , +
F39 x R2 >290nm - /x
F3C
R1=R2=H; X=O
R1=H; R2=Me; x=o
R2=H; R1=Me; x=o p-TFA-ACB-XroCrr p-TFA-LCB-XmCu
R1=R2=H; X=CH2
Scheme7

Wagner and Smart have demonstrated in another system that this reaction
can show a high degree of regioselectivetylg. Substituents ortho to the acetyl
group were found to direct the double bond towards them. Fluorine was found to

give 9% of the other isomer (Scheme 8).

O X 0 X
3' ‘JL. ”0 _hv_. C!
X Methanol O Methanol
O - O
.. ’ x: cm, Me, OMe
X“ F (9%) and F (91%)
Scheme 8

Wagner and Cheng20 studied the diastereoselectivity observed when a-
and p-butenoxyacetophenones undergo ’[2+2] photocycloadditions. They
always found R2 syn to the cyclobutene ring in compounds of type d. Also, in

every case R1 and R3 are trans to each other in the major products (Scheme 9).

\f

fig, iv? CY‘i ,. .r. ‘

0 O-u ODE: R2
R‘
a b c d

Scheme 9

Later, Wagner and McMahon29 reported that high diastereoselectivity can
be achieved in the cycloaddition reaction through the use of chiral auxiliaries.
They showed that by introducing a chiral amide group ortho to the tether, 90%

diastereoselectivity was obtained (Scheme 10).

 

 

 

 

 

 

Auxilairy (X) % de
OH 0
(2R,5R)-(-)-2,5-dimethylpyrrolidine 90
(7R)-(+)-camphorsultam 90
Scheme 10

In another system Wagner and Sakamoto30 found that irradiation of both
1-butenoxy-2-acetonaphthone and 2-butenoxy-1-acetonaphthone promoted
[2+2] cycloaddition from their triplet states. Sakamoto also looked at a few meta

substituents and found evidence for high regioselectivity (Scheme 11).

 

Scheme 11

Gilbert and coworkers31 found that 2'- and 4'- cyano substituted 4-
phenoxybut-l-ene undergo intramolecular ortho cycloaddition upon irradiation
at 2. = 254 nm and 3. 2 290 nm respectively. The formation of the cyclooctatriene
was quenched by 1,3 dienes whereas its intramolecular cyclization to

cyclobutene was not quenched (Scheme 12).

 

Onnnnnnn 0134”" It?
/ 4' at 254 nm

R 2' at >290 nm

R=2'CN R=CN, R': H
4'CN . R=H R'= CN

Scheme 12

11

Ell lll'l' [1211]! III!

The photochemistry of benzenes has been known for over forty years.
Following the discovery of the formation of fulvene after irradiation of benzene,
the intermolecular ortho photocycloaddition of olefins to benzene was
discovered”. In two independent studies in 1966 Wilzbach and Kaplan33 and
Bryce-Smith, Gilbert and Orger34 discovered the 1,3-(meta) photocycloaddition

/ v
254 nm ‘

of simple alkenes to benzene. In 1971 Morrison and coworkers35 studied the
intramolecular version of this reaction. Since then this area has been dramatically
developed leading to the application of this reaction in the synthesis of
polycyclic compounds.15

Since the discovery of arene-alkene photocycloaddition, many research
groups have studied this reaction either mechanistically or synthetically. Zupan
and coworkers36 found that irradiation of pentafluorophenyl-prop—2-enyl ether at
254 nm resulted in intramolecular [2+2] cycloaddition, forming 2,3,4,5,6-

pentafluoro—l ,8-epoximethano bicyclo[4.2.0]octa-2,4-diene (Scheme 13).

F F
F F O hv F $01}!
A 254 nm )F
F F CGH12 F F
Scheme 13

 

 

C1;

in 1

it

the:

 

12

Aoyama and coworkers37 demonstrated the first example of [2+2]
cycloaddition of styrenes to benzenes. They irradiated N-benzylstyryl-acetamide
in methanol using a low pressure mercury lamp and obtained a triCyclic product

which reverts to starting material upon heating or photolysis (Scheme 14).

 

 

 

Ph
I O hv
m»
hv or heat
0 ' _
R R=CH2Ph, Pr‘
Scheme 14

Cornelisse and coworkers38 found that irradiation of 2-methy1-6-(fluoro-
phenyl)hex-2-ene produced a [2+2] photocycloaddition product. The terminal
methyl groups are essential for the reaction to occur otherwise meta

cycloaddition products predominate (Scheme 15).

 

Scheme 15

o-Methyl and methoxy substituted 3-benzyloxyprop-2-enes were found
to undergo ortho [2+2] photocycloaddition as a minor pathway.39 The major
reaction was the meta photocycloaddition reaction to produce linear triqinane

derivatives (Scheme 16).

Sci.

112‘

.J

hi.

13

— ‘1 R R o
O hv, 254 nm
cyclohexane> + . .

 

R O
R=Me 1 I 12
R=OMe 1 : 2.5
Scheme 16

Gilbert and coworkers39 found that when 1-(l',2',3',4'-tetra-hydro-l'-
naphthyloxy)-3-methylbut-2-ene was irradiated at 254 nm, the major
photoproduct was a result of initial intramolecular 1,2 cycloaddition. The other

reactants shown below gave meta cycloaddition products only (Scheme 17).

254 nm
n
X=O, n=2, R=Me
X=CH2, n=2, R=H
X=O, n=2, R=H hv . .
X =0, “=1, R=H W meta cycloaddition products
X=O, n=l , R=Me

Scheme 17

On the other hand, Keese and coworkers40 found that irradiation of the
substituted 7-methoxyindanes shown below led to photoproducts which arise
from an ortho [2+2] cycloaddition reaction along with other meta cycloaddition

products (Scheme 18).

 

OMe
R \
meta cycloaddition
0. products
R=OH 1 3 1
R: 3.5 1 2.5

Scheme 18

The first example of intermolecular photocycloaddition reaction of simple
alkene to benzenes was reported in 1963.41 2-Methyl-2-butene was found to add
to benzonitrile when irradiated at 254 nm. The ortho cycloaddition product
formed was found to be photoreactive and reverted to starting materials upon

further irradiation (Scheme 19).

hv /
-———->
+ I 254 11111 g .

 

Scheme 19

Gilbert and coworkers42 found that 1,1-dimethoxyethylene and 2,3-
dihydro-1,4-dioxin add to benzene when irradiated at 254 nm affording the ortho
cycloaddition products (Scheme 20).

15

OMe

‘9 MeO /» h
TOMB “OMe
.+ 254nm O
f - O
+ [I j 254nm “: j
‘ 0

Scheme 20

It was also found that ethyl vinyl ether adds photochemically to both
ortho and para cyanoanisole to give ortho cycloaddition products.43 The reaction
was regioselective for the ortho isomer whereas the para isomer gave two

different regioisomers as the major products (Scheme 21).

 

 

CN
OEt NOEt OMe
IE: I m—sz’M 0‘ “ECO; 10:61:33
OMe e t
1.75 1 1.00
L J
Y
70%
@OMC OBI 0M6
CN + {I 254 nm ’C’f
Scheme 21

It should be mentioned that the ortho photocycloaddition of naphthalenes
is also known. The reaction proceed via kinetically well defined singlet

exciplexes.44 Wagner and Sakamoto30 reported the only example for the 1,2

16

photocycloaddition of double bonds to triplet naphthalenes whereas Dopp and

coworkers reported the 1,4 triplet cycloaddition reaction.45

lll'l' [1.]! ll!

Alkynes were found also to undergo the ortho photocycloaddition

46

reaction . The initial cycloadducts usually rearrange directly to

cyclooctatetraene products (Scheme 22).

 

 

 

R=R'= H
R=R'=COOMe
R=COOMe, R'=t=Bu

Scheme 22

The intramolecular version of this reaction is also known. Morrison and

coworkers" irradiated 6-phenyl-2-hexyne at 254 nm and observed the formation

©/\/\ IIV .
-—F
254 nm
OH
|. ——>
TMS 254 nm 0 .

OH
TMS

Scheme 23

f?

5??"

“
Nui

17

of cyclooctatetraene in very low quantum and chemical yields. Pirrung“8 found
that placement of trimethylsilyl group on the alkyne improved the reaction

efficiency (Scheme 23).
1' hurt -1 '11.1r -121!!! 1 .1_'..‘ i'i..'1‘ -1.“ 1

Double bonds can add to the excited singlet arene to give ortho— and/or
meta- adduct(s)15 (Scheme 24). The para addition process is limited to only a few
cases. The mode of the addition depends on the olefin as well as the substituents

on the benzene ring.

0+tjh—v»/

Scheme 24

 

 

 

 

Bryce-Smith49 reported that the ortho addition predominates if charge
transfer between the arene and the double bond is involved or if the ionization
potential difference between the arene and olefin is greater than 0.4 eV. On the
other hand, the meta photocycloaddition predominates if the ionization potential
difference is less than 0.4 eV.

50 suggested that the reaction proceeds via an

Morrison and Ferree
exciplex between the excited benzene ring and the double bond. Later Leismann
and Mattay51 observed exciplex emission during the photocycloaddition of
benzene to various olefins.

In a qualitative theoretical study based on orbital symmetry and frontier

molecular orbital analysis, Houk52 has provided explanation for the partitioning

17

of cyclooctatetraene in very low quantum and chemical yields. Pirrung48 found
that placement of trimethylsilyl group on the alkyne improved the reaction

efficiency (Scheme 23).
r' ails .I.1'..A .12019111 1'.‘ 3'1- '1' J 0 '1.

Double bonds can add to the excited singlet arene to give ortho- and/or
meta- adduct(s)15 (Scheme 24). The para addition process is limited to only a few
cases. The mode of the addition depends on the olefin as well as the substituents

on the benzene ring.

0+tfi—n»/

Scheme 24

 

 

 

 

Bryce-Smith49 reported that the ortho addition predominates if charge
transfer between the arene and the double bond is involved or if the ionization
potential difference between the arene and olefin is greater than 0.4 eV. On the
other hand, the meta photocycloaddition predominates if the ionization potential
difference is less than 0.4 eV.

50 suggested that the reaction proceeds via an

Morrison and Ferree
exciplex between the excited benzene ring and the double bond. Later Leismann
and Mattay51 observed exciplex emission during the photocycloaddition of
benzene to various olefins.

In a qualitative theoretical study based on orbital symmetry and frontier

molecular orbital analysis, Houk52 has provided explanation for the partitioning

18

between ortho-, meta-, and para cycloadditions. The benzene lowest excited
singlet 1B2“ can be represented as a combination between S—>A* and A-—>S*.
The ortho addition could be achieved by the interaction of the benzene A orbital
with the ethylene HOMO or the benzene A* orbital with the ethylene LUMO.
The meta addition is due to interaction between the benzene S with the ethylene
HOMO or the benzene A“ with the ethylene LUMO. The para addition is due to
the weak interaction of the ethylene HOMO with the benzene S*. This means
that the S—)A* transition will stabilize the meta complex more than the ortho,
while the A—)S* transition will stabilize the ortho only.

One well-known generalization about the reaction is that electron-
donating substituents on the benzene ring direct the olefin to add to the C2 and
C5 positions, whereas electron withdrawing groups direct the double bond to add
to the C2 and C4 positions (Scheme 25).

Scheme 25

The high selectivity was explained by proposing the formation of a dipolar

intermediate following the exciplex formation.21b This rationalization was

19

supported by semi-empirical calculations which shows that on the approach of
the olefin, the ring becomes polarized.53(Scheme 26)

R R R
1‘“ —»
Que. |R_. @355 R C.® R
R R NC R R
+ 14“» _. (:9 {DR
NC R NC R NC
Scheme26

 

One of the most widely used photochemical reactions in organic synthesis
is the [2+2] photocycloaddition of enones to alkenes. Since the reaction's
discovery54 in 1962, many research groups have explored its mechanism, which
has been the subject of some controversy.” Based on the regiochemistry of the
addition of enones to polar olefins, Corey, suggested that the enone excited state,
which has a polarity opposite to its ground state, would form an oriented 1t-
complex with the ground state of the olefin (Scheme 27).56 The excited state was
proposed to be an n,1t* triplet that adds to the olefin to form a biradical which

couples to products.

2O

.126161—61...

OMe
MeoJk DMe Meo JkeOM Meo

 

[oriented rt-complex] biradical cycloaddition product

0* o o 0
CN CN CN CN
M212 ~12. '—+

Scheme 27

Recent studies showed that there is no evidence to support Corey's
hypothesis of the oriented n-complex formation. Also the excited state

responsible for the reaction was found to be the 1t,1t* triplet not the n,rt* triplet.

Weedon and his group performed several experiments in which biradicals from

57.58 59 with olefins were

trapped using ste. The results showed that biradicals arising from both "favored

the reaction of cyclopentenone or cyolohexenone

and unfavored orientations" are formed in nearly 1 : 1 ratio (Scheme 28). In other

experiments he generated the biradicals independently and found that they
undergo reversion to starting materials to different extents.

hora t1orat ‘ Et‘J/OH

biradical ratio 1 : 1 1.2 t 1

 

product ratio 6 3.1 : 1 4. 3 ; 1
Scheme 28

2O

2126161~61

MeOJk OMe MeO AOMe

[oriented n-complex] biradical cycloaddition product

6:: tar—6 («61—6

Scheme 27

Recent studies showed that there is no evidence to support Corey's
hypothesis of the oriented n-complex formation. Also the excited state

responsible for the reaction was found to be the 1c,rt* triplet not the n,1t* triplet.

Weedon and his group performed several experiments in which biradicals from

57.58 59

the reaction of cyclopentenone with olefins were

trapped using ste. The results showed that biradicals arising from both "favored

or cyolohexenone

and unfavored orientations" are formed in nearly 1 : 1 ratio (Scheme 28). In other

experiments he generated the biradicals independently and found that they
undergo reversion to starting materials to different extents.

O O o 0
{)7 dz 0 ‘1. '
OEt OEt 5‘

biradical ratio 1 : 1 1.2 : 1

 

product ratio 31 : 1 4.3 ; 1
Scheme 28

21

Cross-conjugated cyclohexadienones are known to rearrange
photochemically and form bicyclo[3.l.0]hex-3-en-2-ones60 (type A photo-
rearrangement) (Scheme 29). The rearrangement was proposed to occur from the
n,1t* triplet followed by bonding between C3 and C4 to give a bicyclic molecule
which is still electronically excited. This step is followed by TI:* to n electron
demotion, affording the ground state of zwitterion which rearranges to the final

product.“62

 

Scheme 29

Schultz discovered that cross-conjugated cyclohexenone can undergo
both inter-63 and intra-molecular64 photocycloaddition to double bonds. The
addition of the double bond was found to be greatly regoiselective. When a
methoxy group was placed on C2 of the dienone, the olefin added to the
substituted double bond whereas the addition favored the unsubstituted double
bond if the methoxy group was at C3. On the other hand the addition was mainly
towards the methyl group for the C3-methoxy and C5-methyl substituted dienone
(Scheme 30). The author proposed that the reaction occurs from the 1t,1t* triplet
state. The reaction was proposed to have a biradical intermediate, since using a cis
or trans substituted olefin led to isomerization of the double bond in the

recovered starting material.

22

 

      

0
R3
hv (366 nm)
benzene
R1 R2
M602
R1=OMe;R2=R3=H R1=OMe;R2=R3=H 95%
R1=R3=H;R2=OMe 5%
R1=OMe;R2=Me;R3=H R1=OMe;R2=Me;R3=H 87%
R1=Me;R2=OMe;R3=H 13%
R1=R2=H;R3=OMC R1=R2=H,R3=OMC
Scheme 30

 

Cope“ was the first to observe that cycloocta—1,3,5-triene exits in
equilibrium with bicyclo[4.2.0]octa-2,4-diene. Later, it was found that
substituents greatly affect the equilibrium constant between the two isomers.
Substituents in the 7,8 positions of the cyclooctatriene system were found to shift
the equilibrium towards the bicyclic compound. The significant increase of Keq
for the trans— 7,8 disubstituted olefin-compared to the cis isomer is due to steric

effect of an endo group in the concavity of the cyclooctatriene tub66.

H

Hg

23

x k1 X
I :—
x' In x'

Table 1: Rate and equilibrium constants for 7— and 8- substituted
cyclooctatrienes and their corresponding cyclohexadienes.

Kaq k1(sec:'1) R61 6
at 60°C at 20°C

>19 66

* lief.

    

 

 

 

OAc L
H 4.16 66 OCH, >19 66
CH3 fOCIh
CH3
H CH1
.3 13.67 66 H 1.13 3,1x 10—6 66
CH3 for“
a CH,
CH; -
5 4 3.3 x 10-6 66 H 0.54 60 x 1045 as

 

 

CH;
$55 1.0 X10'3 66 {H
030°C) D

H
T—
CI
8
CI
2.33 1,1x1o-5 67 0.43 67—!
0 (RT) (RT)

.04 1.9x 10'7 66

 

 

 

 

 

 

 

 

 

 

 

 

24

mm68 found that 2,5-diphenylbicyclo[4.2.0]octa-2,4-diene exists in the
bicyclic form at room temperature to 100°C. This is due to the tendency of the
phenyl groups to conjugate with the almost planar cyclohexadiene moiety.
Streitwieserf’9 also found that 1,5-di-tert-butyl-l,3,5-cyclooctatriene exists

exclusively in the bicyclic form, and attributed this to a relaxation of steric

:0 ii

R1=H;R2=R3=Ph
R1=R3=I'BU;R2=H

compression (Scheme 31).

Scheme 31

On the other hand, Vogel70 found that conjugatively electron-
withdrawing substituents in the 1- or 1- and 6- position of the bicyclic compound
rearranges very easily to the eight-membered isomer. This is due to the substituent
conjugation with the triene system and to the unfavorable conformation of the

two neighboring cis-substituents in the four-membered ring (Scheme 32).

R
1?.2 R2
R1 :11; R2=C OOMe
R1 =R2= COOH
R1 =R2= C OOMC

Scheme 32

25

The previous results were confirmed by Takeda and coworkers71 who
found that the stabilization provided by conjugation with a single carbonyl

group is great enough to maintain the triene structure (Scheme 33).

R2 0 R2

R1 R1

R1: R2: H
R1=Me, R2: H
R1=H, R2: Me
R1: R2: Me

Scheme 33

 

Wagner and coworkersls'28 also found that 4-acetyl-11-
oxabicyclo[6.3.0]undeca—1,3,5-triene exists in the triene form whereas replacing
the ether oxygen with a methylene group reversed the equilibrium to favor the

corresponding diene component (Scheme 34).

 

Scheme 34

26

Irradiation of 1,3,5-cyclooctatriene in ether”, pentane73

or in the gas
phase74 led to the formation of a mixture of bicyclo[4.2.0]octa-2,7-diene and
tricyclol3.2.l.02'8]-3-octene. On the other hand irradiation of bicyclo[4.2.0]- oct-
2,4-diene led to the formation of a mixture of benzene, ethylene, and 1,3,5-

cyclooctatriene (Scheme 35).

CD L©+II+©

Scheme 35

 

Direct irradiation of cyano-benzocyclooctatrienes gave a mixture of two
possible cyano-2,3—benzobicyclo[4.2.0]octa-2,4,7-trienes arising from
electrocyclization of the two diene subunits of the reactant.75 The regioselectivity
of cyclization depended greatly on the position of the cyano group. It was also
found76 that direct irradiation of 6,7-dimethyl-benzocyclooctatn'enes gave only

one regioisomer (Scheme 36).

26

Irradiation of 1,3,5-cyclooctatriene in ether”, pentane73

or in the gas
phase74 led to the formation of a mixture of bicyclo[4.2.0]octa-2,7-diene and
tricyclo[3.2.1.02'81-3-octene. On the other hand irradiation of bicyclo[4.2.0]- oct-
2,4-diene led to the formation of a mixture of benzene, ethylene, and 1,3,5-

cyclooctatriene (Scheme 35 ).

LquO

Scheme 35

Direct irradiation of cyano—benzocyclooctatrienes gave a mixture of two
possible cyano-2,3-benzobicyclo[4.2.0]octa-2,4,7-trienes arising from
electrocyclization of the two diene subunits of the reactant.75 The regioselectivity
of cyclization depended greatly on the position of the cyano group. It was also
found76 that direct irradiation of 6,7-dimethyl-benzocyclooctatrienes gave only

one regioisomer (Scheme 36).

27

 

 

Direct. IN 2 310i»
Cyclohexane

   

Direg hv 2 3 um I
Cyclohexane

   

Scheme 36

27

 

 

 

 

CN
7 1
Direct, hv 2 310*
Cyclohexane
2.3 : 1
CN

 

Sensitization gave no products 1 3 1

CH3
, CH3
0 Dire hv 2 3 nm
‘\ Cyclohexane

Scheme 36

28

Wagner and Alehashem28 found several examples in which the
tricyclo[6.3.0.01'4]undeca-2,5-diene system was thermally transformed to the

tricyclo[6.3.O.O3'6]undeca-1,4-diene system at relatively low temperatures
(Scheme 37).

2 H =
100°C "
——> II x
toluene R3C /
2. 5 hrs H

R=F, H
X=C, 0

Scheme 37

 

Mulrai77 and Kimura78 found that 1-X-bicyclo[3.2.0]hepta-3,6-diene-2—one
can be converted thermally into 3-X-bicyclo[3.2.0]hepta-3,6-diene-2-one. They
suggested that these reactions proceed via the symmetry-allowed antara-antara

Cope rearrangement (Scheme 38).

X: OMe, NHCOR
Scheme 38

Baldwin and Kaplan79 pointed out that the Cope mechanism is rendered
highly unlikely by the fact that a molecule constrained to react this way, 3,7-
dideuteriobicyclol3.3.0]octa-2,6-diene, does not rearrange in 85 min at 450°C.
On the other hand, Baldwin found that deuterium-labeled bicyclo[4.2.0]octa-2,7-

diene rearranges to the other isomer (Scheme 39).

29

 

D D D
*2 3
D

var» >e——»::‘::;

Baldwin80 suggested that these rearrangements occurs through the
formation of the cis, trans, cis cyclic trienes via the thermally allowed conrotatory
opening of the cyclobutene ring. (This shows the importance of the cyclobutene

moiety for production of the postulated triene intermediate).81 The cyclic triene

1
”s“...

0/

Scheme 40

“‘11

i

30

will either revert to starting material or close on the other cis double bond to give
the rearranged bicyclic structure. Kinetic studies showed that the cyclic triene
rearranges to the bicyclic products which open thermally to all cis cyclooctatriene
(Scheme 40).

31

1W

In this work the regioselectivity for the [2+2] photocycloaddition reaction
was studied. The remote double bond can add either syn or anti to the substituent
ortho to the tether. Differentiation between the two modes of addition was done
by 1H NMR analysis. Thus, thorough understanding of the 1H NMR spectra of
similar systems is required. The following tables present key 1H NMR data of
some [2+2] cycloaddition products previously reported by other members of the
Wagner research group. Product assignments depended heavily on comparison of

NMR chemical shifts and coupling constants.

32

Table 2: Selected chemical shifts and coupling constants of some 4-acetyl-11-
oxabicyclo[6.3.0]undeca—l 3.5—triene (COT) derivatives

 

    

Chemical Shiftsa(cou lin constants)b Ref. Chemical Shiftsa (cou lin constants)b Ref.
5.92(12.5,6.8) 2.35(l3,8,8.2)

18 2.503.432 195 129 35 32
3.06 \/ 3.1 . ( 0 0 9 )

5.950 l.3,7.9,4.0) . 13(12,9,6,5

 

     
  
 

   

/
6.26(11.3,2.1.2.l)

0 4.280 2,9,5)

4.16.4.24
42029.5)

 

 

      

   
 
   
   

  
    
   

 

 

o
7- ‘3) 54“" CDCla 7.12011) 54101.1) C0301)
6.02013,7.9,7.9) 1930.5)
225 53/133017 82 6/ EH3 82
_ '2.19 CH3
1 .6 CH3
6.89 3.0 .
( ) 536010.22) CDC13 7.1069. 1.2) 530.9) CD3OD
2.06(16,5.5,2) S.88(qdd,l.5,9.5,6.7)
l.67(16.9) 33 2.45(14.9.4) 20904.7,4) 83
231 \ 3.03
[3.50.8.5)
\3.7(s,7,7)
5.360) C696 6.88 (s) CDCl3
o 0
2.2303433) 84 34
. 304034.19)
7.13(6.2 7.13(5.7)
K ' 4.02
I \4.13 I
5.75(13.0,6.2) ‘ 543402.057)

60603.38) 5.340.319) CDC13 612025.17) 5.17(7.7) CDCl3

 

82

5.13(13.2,6.1) \ ‘
601032.94) 5330.435) CDCI:

m ppm

b: Hz

 

 

 

 

 

 

33

Table 3: Selected chemical shifts and coupling constants of some 4-acetyl-ll-
oxatricyclo[6.3.0.01'4]undeca-2,5-diene (ACB) derivatives

 

 

          

 

    

 

 
 

 

 

 

 

  
       

Chemical Shiftsa (coupling constants)b Ref. Chemical Shiftsa (coupling constants)b Ref.
. , . 5.7500230)
583(d11 1) 84 o / 82
V 5.8500.2.4.5,2.2)
627(28)‘ ' /
637(28)’ 0.6 1
C6D5 W? ““239 CD3OD
/\
3.64(2.7,8,8) 351(m)
5.43(q.1 .5) 82 527(quint.l .4)) 82
o
643(29)‘ cur—1.7805) 631(29)‘ Y cur—1750.4)
I, 2 08(7 4) l! I 2.220 4 14)
6500.9)" '03, 6.4109)" .- €33
CH3 m 9 CH3
ch‘ CD300 H3C"‘ CD3OD
570.829) 82 5.7400131) 82
yo II 6.01(9.8.6.8.2.6) 5 1001 6 6 2 3)
621(30)‘ / 629(23)‘ ) . , . , .
I 113905.963) 7 / 2.26(17,7,2)
6339”) : 515059.292.» 6420.8)" \2.14(17.8.3.2)
W“; CH3 \10 9? H
.CH CD or) é, 2.51(12.8,8,6,2)
3 3 H3C' CD3OD
1.4915
m[151305) 33 \( l 0 [5.620680 83
5.9705) 0 3 Ha
\ \? 5.34(qdd,l.5,4.2.4.0)
' I , 2.08(11.l)
5.83(dq.0.6.15) 0"" 5 H\ 1.7(m)
1° 9" 1.7(m) C696
‘ 1.80:1) €st 3.65(8.4.8.3) 3570.87)
3-62(8.7.6) 3.72(9,8,6.5)

 

 

 

 

 

asppm

bzllz

34

Table 4: Selected chemical shifts and coupling constants of some 4-acetyl-11-
oxatricyclo[6.3.O.03'6]undeca-1,4-diene (LCB) derivatives

 

Chemical Shiftsa (coupling constants)b Ref.

l.85-2(14)

18

    

604080;), f
' 3320.609) \

4.98(6.6) €st

 

 

3540.4) 4 3.79(2.5,8.5.8.5)
4.970.427) C6D5
, , 22403.9)
2 1203 5) 25

 

82

 

3.42(6.6,1.7)
4.72(6.6.2.5) CD301)
2.1104) 1.8204)
0 / CH3

 

20

  
   

6.36(2.8,0.9) / O 4-07

3-49(6.6.0.9) 4.76(6.6) CD3OD

0.5911116
1.43(13,5,l.6) (165) 83

2.46 H

 

NC /

312034.409) 1
4.89(6.3,2.4) €st

 

 

 

 

a' PPm
szz

 

35

Table 5: Selected chemical shifts and coupling constants of some 4-acetyl-1 l-
oxa-tricyclo[6.3.O.01'6]undeca-2,4-diene (CHD) derivatives

 

 

  
  
 

 

 

 

 

Chemical Shiftsa (coupling constants)b Ref.
5340.8)
0 17
16968216) 2.4705. 1.8)
., 3.68011)
5530.836) 4 o "
5.43(9.6) C606
82
5300.1) C0300
6.26(5.4)
85
ocu3 ' CDC];

 

 

 

 

36

Table 2 presents selected chemical shifts and coupling constants of some
4-acetyl-1l-oxabicyclo[6.3.0]undeca-1,3,5-triene (COT) derivatives. It shows
that cis vinylic protons couple to each other with coupling constant about 11.0—
13.5 Hz. Also H2 couples to the bridgehead proton, Hg with a coupling constant
of 2.0~2.5 Hz.

Table 3 presents selected chemical shifts and coupling constants of some
4-acetyl-11-oxatricyclo[6.3.0.01'4]undeca-2,5-diene (ACB) derivatives. It shows
that vinylic cyclobutene protons couple to each other with coupling constants of
2.7~3.0 Hz. On the other hand, vinylic cyclohexene protons couple to each other
with about a 10 Hz coupling constant. Also, H5 couples allylically to only one of
the protons at C7 with a coupling constant about 1.4-3.1 Hz.

Table 4 presents selected chemical shifts and coupling constants of some
4-acetyl-11-oxatricyclo[6.3.O.O3'6]undeca-1,4-diene (LCB) derivatives. Again, it
shows that vinylic cyclobutene protons couple to each other with about a 2.8 Hz
coupling constant. It also shows that H2 couples allylically to Hg with about 2.5
Hz and vicinally to H3 with about 6.5 Hz coupling constants.

37

Cfll'lil'

Among the features that have made 1H NMR one of the most useful tools
in organic chemistry, the ability to apply vicinal proton-proton coupling
constants to structural and stereochemical analysis. Karplus defined a
mathematical relationship between 3111-091; and the H-C-C-H dihedral angle <1).
These calculations are approximate and do not take into account such factors as
electronegative substituents, H-C-C bond angles, or bond lengths. The Karplus86
rule is usually expressed by the following equations:

111.0010: 8.5 eos2 <0 - 0.3 06 < <0 < 906
109w: 9.5 eos2 <0 - 0.3 906 < <0 < 1806

‘3

Geometry optimization can be done using several computational methods
and levels. In this work, photoproduct structures were optimized at the semi-
empirical level (AMI). From the dihedral angles, vicinal coupling constants were
calculated by the Karplus equations. The best geometry and dihedral angles of
various photoproducts and their coupling c0nstar1ts are described in the Results

chapter.

RESULTS

In this work, several ring substituted alkenoxyacetophenones were
prepared to study their regioselectivity of their photocycloaddition reaction. The
effect of changing the tether anchor atom was also studied by replacing the
oxygen with nitrogen and sulfur. Some alkynoxyacetophenones and
trifluoromethyl derivatives were also studied. The structures and corresponding

thesis notations are listed below.

38

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X Y R1 R2 Name Thesis Notation

CH3 H H H 4—(3-Buten-l-oxy)-3-methyl— m-Me-pBA
acetophenone

t—Bu H H H 4w(3—Buten-l-oxy)-3-t-butyl- m-tBu-pBA
acetophenone

i-Pr CH3 H H 4-(3-Buten-l-oxy)-3-isopropyl-5- m-Me-iPr-pBA
methylacetophenone

i-Pr CH3 H CH3 4—(2-Methyl-3-buten-1-oxy)-3- m-Me-iPr-Mez-pBA
isopropyl-S-methylacetophenone

CONH2 H H H 4wAcetyl-l-(3-buten-1-oxy) m-Amide-pBA
benzamide

COOMe H H H Methyl-5-acetyl-2-(3-buten-l-oxy) m-Est-pBA
benzoate

CN H H H 4—(3-Buten-l-oxy)-3-cyano- m-CN-pBA
acetophenone

CF3 H H H 4-(3-Buten-l-oxy)-3- m-CFs-pBA
trifluoromethylacetophenone

0CH3 H H H 4—(3-Buten-1-oxy)-3-methoxy- m-OMe-pBA
acetophenone

0CH3 H CH3 H 4-(3-Methyl-3-buten-1-oxy)-3- m-OMe-Me3-pBA
methoxyacetophenone

SCH3 H H H 4~(3-Buten-l-oxy)-3- m-SMe-pBA

 

 

 

 

 

(methylmercapto)acetophenone

 

 

4O

 

 

 

 

 

 

 

 

 

 

Com ound Name Thesis Notation
2-(3—Buten-l-oxy)-3-methyl- m-Me-oBA
M
acetophenone
o
3-(3—Buten-l-oxy)-4-methoxy- p-OMe-mBA
0M acetophenone
OCT-I3
WM 4»(3-Buten-1-mercapto)— p-Thio-AP
acetophenone
4-(3-Buten-l-amino)acetophenone p-NH-AP
WW
N-Acetyl-4—(3-buten-1-amino)- p-N A c-AP
WM acetophenone
Ac
2-(3-Butyn-l-oxy)acetophenone o-Ac-TB-H
0
$0M“
4—(3-Pentyn-l-oxy)acetophenone p-Ac-TB-Me
mama
3
. 2-(Buten-1-oxy) a,a,or-trifluoro- o-BTFAc
CF: acetophenone
0M
CF 2-(Propen-1-oxy) a‘,or,0t-trifluoro- o-PTFAc
3

 

acetophenone

 

 

 

41

WW

m-Amide-pBA was prepared by the direct coupling of 5-acetyl-2-
hydroxybenzamide with 4-bromo-1-butene in dry DMF. Dehydration of the
product using trifluoroacetic anhydride/pyridine mixture gave m-CN-pBA in
72% yield (Scheme 41).

 

 

 

 

 

 

 

   

OH 0
Trifluor acetic
N H2 M, B; anhydride >
K2C03IDMF Pyridine!
droxane
O
m-Amide-pBA m-CN-pBA

 

 

Scheme 41

m-Me-pBA, m-tBu-pBA, m-OMe-pBA and m-SMe-pBA were prepared
by Fries rearrangement of their corresponding acetates in nitrobenzene followed
by coupling with the alkenyl halide in DMF. For m-Est-pBA, 5-acetylsalicylic
acid was esterified before coupling with the alkenyl halide (Scheme 42).

42

 

 

 

 

 

 

  
 

 

 

 

 

 

OH OH R
X X
l-CH3COCl/Pyridine W31“
2-A1C13/Nitrobenzene K2C03/ DMF
O
X=CH3, t-Bu, OCH3, X‘CH
- 39 t.Bu!
SCH3, COOH CH3OH/ 0013’ SCH3
sto,
OH
COOMe
K2CO3/ DIWF
v E?
R
O
Scheme 42

m-Me-iPr-pBA and m-Me-iPr-Mez-pBA were prepared by diazotizing

and hydrolyzing 2-isopropyl-6-methylaniline. The resulting phenol was acylated

using acetyl chloride and pyridine, followed by Fries rearrangement (anhydrous

aluminum chloride, room temperature) to the corresponding acetophenone.

Etherification gave the final products (Scheme 43).

 

43

 

 

 

 

 

 

 

 

 

 

 

OAC
NHz
1)NaN02/H3O*CH3COC1
0 2)sto4/A Pyridine
OH
A1C13 WOTS
, _p
Nitrobenzene or MEI
K2CO3/ DMF
0
Scheme 43

m-Me-oBA was prepared by treating o-methylphenyl acetate with
anhydrous aluminum chloride and heating at 160°C. The resulting compound, 2-
hydroxy-3-methylacetophenone was etherified with 4-bromo-1-butene (Scheme

44).

CH3
AlCl3 \/\/ Br
160°C K2C03/ DMF

Scheme 44

 

 

 

 

 

 

 

 

 

m-CF3-pBA was prepared by diazotizing and hydrolyzing 4-bromo-
a,a,a-trifluoro-o-toluidine. The resulting phenol was coupled to 4-bromo-1-

butene in DMF to give 5-bromo-2-(3-buten-1-oxy)-a,a,or-trifluorotoluene which

44

was reacted with magnesium and quenched with acetyl chloride to give the final

product (Scheme 45).

 

 

01231:, OH
02CF3 ©CF3 CF3
HBF4 0110002)2 O
NaNo2 3’
Br

 

’

 

6Q; “Mg/"ii

K2C03/ DMF 2)AcCll-78°C

 

CF3

 

 

 

 

Scheme 45

p-OMe-mBA was prepared by acylating guaiacol by a mixture of acetic
anhydride and sulfuric acid. The resulting compound, 3-acetoxy-4-methoxy-
acetophenone, was hydrolyzed with sodium hydroxide to give 3-hydroxy-4-
methoxyacetophenone which was etherified with 4-bromo-1-butene to give the

final product (Scheme 46).

 

 

 

 

OCH OCH3
3
OH 1)ACZO/HZSO4> 0H \A/B’
b
”Nam“ K2C03/ DMF
3)H,o+
o

 

 

 

 

Scheme 46

 

45

p-Thio-AP was prepared by reacting 4-fluoroacetophenone with excess
sodium sulfide in DMF. The resulting product, 4-mercaptoactophenone was

reacted with 4-bromo-1-butene to give the final product (Scheme 47).

 

 

 

 

 

 

 

 

0 O _
> )\_.< >._:/
F SH
Scheme 47

p-NH-AP was prepared by coupling 4-aminoacetophenone with 4—bromo-
l-butene in DMF. The resulting amine, p-NH-AP, was acylated with acetic
anhydride to give p-NAc-AP (Scheme 48)

 

 

 

\ Br
W
N32CO3/Nal
DMF

 

 

 

 

 

 

Scheme 48

o-Ac-TB-H was prepared by coupling o-hydroxyacetophenone with 3-
butynyl-l-tosylate in DMF (Scheme 49).

46

 

m + W0“ KZCO3/DMF
OH

 

 

 

 

 

Scheme 49

p-Ac-TB-Me was prepared by coupling p-hydroxyacetophenone with 3-
pentynyl-l-tosylate (Scheme 50).

 

 

 

/ K2CO3/DMF
m OH + W OTS »

 

 

 

 

 

Scheme 50

o-BTFAc was prepared by reacting phenol with trifluoroaceu'c anhydride
to give phenyl trifluoroacetate. This was reacted with anhydrous aluminum
chloride at 100°C to give 2—hydroxy-a,a,or-trifluoroacetophenone which was
coupled with 3-buten-l-triflate to give the final product. Alternatively, 2-
hydroxy-a,or,or-trifluoroacetophenone could be coupled with allyl bromide to
give o-PTFAc (Scheme 51).

47

 

 

OH

AlC13/A

H0 y

 

0H
(CF,C0)2o
> 0

 

 

 

 

 

 

 

Scheme 51

48

21 I l ll'l' 111 I11 l' [121 I l I

Ketone solutions in deuterated methanol or benzene were irradiated in an
NMR tube, with medium pressure mercury are filtered through Pyrex so as to cut
off any wavelength below 290 nm. In some cases filtered wave lengths of 313,
365 or > 334 nm were used for irradiation. 1H NMR spectroscopy was used to
follow the reaction course. If the NMR spectra were taken immediately after
irradiation, 4-acetyl-1l-oxauicyclo[6.3.0.O3'6]undeca—l,4-diene (Linear Cyclo-
Butene, LCB) and/or 4-acetyl-11-oxat1icyclo[6.3.O.01'4]undeca-2,5-diene
(Angular CycloButene, ACB) derivatives were generally observed as the final
photoproducts . Large scale irradiations were performed using ~0.3 gm of ketone
in argon-bubbled methanol or benzene. In some cases, unstable photoproducts
were identified using their partial 1H NMR because of the broadening of the
NMR signals that may be attributed to the formation of some polymeric
byproducts.

Irradiation of p-alkenoxy-m-substituted acetophenone may lead to two
primary cycloaddition products. In one of them, the double bond adds to the
benzene ring towards (syn, s) the substituent to give 4-acetyl-11-oxa-
tricyclo[6.3.O.Ol'6]undeca-2,4-diene derivatives (CycloHeaniene, CHDS), while
for the other isomer, the double bond adds away (anti, 8) from the substituent to
give the cyclohexadiene derivatives (CHDa). Due to thermal rearrangement, 4-
acetyl-l1-oxabicyclo[6.3.0]undeca-1,3,5-triene derivatives (CycloOctaTreiene,
COT; or COTa) are formed. Further photochemical reactions lead to ACB and/or
LCB (Scheme 52). This means that one or more of eight different isomers are
expected to be formed after irradiation. These isomers were identified from each
other by 1H NMR spectroscopy. Taking advantage of the fact that vinylic

coupling constants depend on ring size37v88 and that chemical shifts depend on

49

the environment around the protons88 allowed us to identify each of the formed
isomeric products by their unique 1H NMR spectrum. In some cases homonuclear

decoupling and 1H NMR peak simulation were used to help in

 

 

 

 

 

Scheme 52

determining the coupling constants. Nuclear Overhauser effect (nOe) experiments
were used to determine the stereochemistry of the products when possible. Semi-
empin'cal quantum mechanical calculations (AMl) were used to calculate the best
geometry for some of the isomers allowing an estimate of the dihedral angle
between protons. This helped to predict coupling constants and compare them to
the experimental ones.

If the double bond adds to the benzene ring syn to the meta substituent,
the primary photoproduct C111)s will have three vinylic protons. The 1H NMR

spectrum is expected to show H5 as a singlet at ~6.5-7 .0 ppm due to conjugation

50

with theacetyl group. H2 and H3 are expected to appear at 5.5 and 6.4 ppm,
respectively, with a coupling constant about 10.0 Hz. On the other hand, if the
double bond adds anti to the substituent, the primary photoproduct CHDa is
expected to have only two olefinic protons. H5 is expected to be a doublet (J ~5.5
Hz) at about 6.5-7.0 ppm while H3's chemical shift and coupling constant would
be dependent upon the substituent at C2.

Thermal ring opening of CHD results in the formation of COT. COTS has
three olefinic protons. H2 is expected to appear at 5.0-5.5 ppm due to its enol
ether character. It also expected to couple allylically to Hg with a I value about
2.5 Hz and couple vicinally to H3 with coupling constant about ~7.0-9.0 Hz. H3
is expected to be a doublet at 6.5-7.0 ppm. H5‘s coupling constant and chemical
shift will vary depending on the substituent at C5. COTa also has three olefinic
protons. H3 is expected to be a singlet at 6.6-7.0 ppm. H5 and H5 are expected to
appear at about 6.3 and 5.9 ppm, respectively, and couple to each other with a I
value about 11.5-13.5 Hz. They also couple to H75 and H75.

COT reacts photochemically to give either ACB or LCB. ACBs has three
olefinic protons. H2 and H3 are expected to appear at about 5.9-6.50 ppm and
couple to each other with J ~2.9 Hz. H5's chemical shift depends on the C5
substituent. It is expected to couple allylically to only one of the protons at C7
(c.f. table 3). ACBa also has three olefinic protons. H5 and H5 are expected to
appear at 5.6-6.0 ppm and to couple to each other with a I value about 10.0 Hz.
H5 is also expected to couple to one of the protons at C7 while H5 couples to
both protons at C7.

LCBs has only two olefinic protons. H5 is expected to be a singlet at
about 6.5-7.0 ppm while H2 is expected to appear at 5.0-5.5 ppm because of its
enol ether character. It is expected to couple allylically to Hg with a I value about
2.5 Hz. It is also expected to couple to H3. If the molecule has H3 syn to the

51

cyclobutene ring then 123 is expected to be about 5.5-6.6 Hz while if H3 is anti to
the cyclobutene ring then 123 is expected to be about 2.3 Hz (cf. table 8).
Alternatively, LCBa has only one vinyl proton (H5). It is expected to be a
doublet at about 6.5-7.0 ppm and couple to H5 with J5 ,5 about 1.0 Hz.

 

 

J hv Pyrex

 

 

o , \S/
O Methanol-d4, "' [1210/16 3
or C6D6
O
NH2 10 \
m-Amide-pBA m-Amide-ACB, Not Famed

 

 

 

Scheme 53

A CD3OD solution of m-Amide-pBA in an NMR tube was taped to an
immersion well and irradiated for one hour using Pyrex filtered light (70 2 290 nm).
Immediately after irradiation, the solution was colorless. A yellow color started to
develop after a few minutes. 1H NMR analysis showed the formation of two
products; 4-acetyl-6-amido—1 1-oxabicyclo[6.3 .0] undeca-l ,3,5-trienc (m-Amide-
COTS) and 4-acetyl-6-amido-l1-oxatricyclo[6.3.0.01'4]undeca-2,5-diene (m-
Amide-ACBS) in a ratio of 1 : 1. 1H NMR-showed that the ratio became 1.3 : 1
twenty five minutes after the irradiation, and 1.8 : 1 after thirty five minutes. m-
Amide-ACBs was totally converted to m-Amide-COTS when the sample was
left overnight at room temperature in the dark. Preparatory scale photolysis (1.0

gm of the ketone in 500 ml dry methanol) was carried out to isolate the

40

0.1.

N.)

AC
dcx

An
bor

001‘

10“]

age

deu't

0310:
ACE
WI.

52

photoproduct. The mixture was purified by column chromatography (silica gel,
40% ethyl acetate/hexanes) to give 0.3 gm of 4-acetyl-6-amido-11-
oxabicyclo[6.3.0]undeca-1,3,5-triene (m-Amide-COTS).

To obtain a pure sample of m-Amide-ACBS, m-Amide-pBA in CD3OD in
NMR tube, degassed, and irradiated for 5 hours. 1H NMR at -70°C (to slow
down rearrangement of Amide-ACBS to Amide-COTS) showed that m-Amide-
ACB; has three olefinic protons; a doublet (J = 2.78 Hz) at 6.31 ppm (H3), a
doublet of doublets (J = 2.78, 0.6 Hz) at 6.48 ppm (H2) and a doublet (J = 2.88
Hz) at 6.58 ppm (H5). This pattern can only be achieved if the double bond of m-
Amide-pBA adds to the benzene ring towards the amide group. If the double
bond adds away from the substituent, the cyclobutene(s) formed would have
only one olefinic proton and the cyclohexene ring would have two olefinic
protons coupled to each other with a I value about 10 Hz.

The cyclooctatriene m-Amide-COTS also has three olefinic protons; a
doublet (J = 8.51 Hz) at 7.3 ppm (H3), a singlet at 7.16 ppm (H5) and a doublet of
doublets (J = 8.51, 2.01 Hz) at 5.49 ppm (H2). H3 and H5 appear at relatively high
field due to their conjugation with electron-withdrawing groups while H2 is at
lower field because of its enol-ether character. This supports the observation that
the double bond adds towards the amide group, since this spectrum does not
agree with that expected for the cyclooctatriene resulting from addition of the
double bond away from the amide group

Irradiation of m-Amide-pBA was also performed in benzene-d5 (Scheme
54). 1H NMR showed the formation of m-Amide-ACBS as the only product. The
other regioisomer was not detected by NMR. Also noticed was that m-Amide-
ACB; did not isomerize to m-Amide-COTS during the NMR experiment as when
methanol was employed as solvent. 1H NMR of m-Amide-ACBS showed also the

53

3.22.32: s .eooeeaié Co 5.58% «22 m. H. 9...»...—

 

 

zam «

m

m

w

m m m m

hbberpP.bb+p.~_Fbp.bb.p._..P._br.___..b—_..p-g..p...PbCpF..P.prp-hppprpb

 

m.m

 

 

3 v a

9m v6 ad ad cg mg

 

 

    

€862.52:

 

 

 

 

 

54

presence of three olefinic protons. Chemical shifts in benzene were; 5.6 ppm (H3),
5.97 ppm (H2) and 6.23 ppm (H5).

 

  

 

 

 

 

 

 

HZN
NHz CD3OD, RT
4 7’
hv, Pyrex
O
m-Amide-ACB, m-Amide-COT,
Scheme 54

When m-Amide-ACBS in CD3OD was left overnight at room temperature
the sample color turned yellow. 1H NMR showed the complete disappearance of
m-Amide-ACBs peaks and the formation of m-Amide-COTS. Irradiation of the
resulting solution using Pyrex-filtered light led to quantitative formation of m-
Amide-ACES.

55

 

 

 

 

 

m-CN-pBA m-CN-COT, m-CN-LCBuw

 

 

Scheme 55

In an NMR tube, a solution of m-CN-pBA in benzene-d5 was irradiated
with Pyrex filtered light 0. 2 290 nm). After 60 minutes irradiation, 1H NMR
analysis showed that the starting ketone had been totally consumed. New sets of
peaks were formed corresponding to two products: 4-acetyl-6-cyano-11-
oxatricyclo[6.3.O.O3'6]undeca-1,4-diene (m-CN-LCBs,ami) and 4-acetyl-6-
cyano-l 1-oxatricyclo[6.3.0.01'4]undeca-2,5-diene (m-CN-ACBS) in a ratio of 3.5 :
1.0, respectively. When the sample was left at room temperature in the dark for
one week, 1H NMR showed the formation of new peaks which are due to the
formation of 4-acetyl-6-cyano-l1-oxabicyclo[6.3.0]undeca-1,3,5-triene (m-CN-
COTS)

Another sample of m-CN-pBA was irradiated at 313 nm. At the early stage
of irradiation (17 minutes, 2% conversion), m-CN-COTS was the only product
detected by 1H NMR spectroscopy. After 1 h, 45 min, 1H NMR showed a mixture

56

of three products; m-CN-COTS, m-CN-ACBS and m-CN-LCBs,anti in a ratio of
1.2 : 2.0 : 23.0. After about 4 hours irradiation, m-CN-COTS disappeared totally.

Preparative scale photolysis (0.3 gm of m-CN-pBA in 250 ml of dry
benzene) was carried out in order to isolate the photoproduct. After solvent
evaporation, the mixture was separated by column chromatography to give 0.02
gm of m-CN-pBA, 0.03 gm of m-CN-LCBsmfi and 0.085 gm of m-CN-COTS.

1H NMR and 13C NMR spectra of the isolated m-CN-COTs ( in benzene-
d5) agree with the proposed structure and show that the double bond in m-CN-
pBA adds to the benzene ring towards the substituent (cyano group). The
cyclooctatriene which would arise from the addition of the double bond away
from the substituent could not be detected.

The structure of m-CN-LCBs,ami was determined by 1H NMR analysis
(CDCl3). The two olefinic protons appear as a singlet at 5 6.63 ppm (H5) and a dd
at 5.0 ppm (H2) (J = 6.4, 2.45 Hz). The two bridgehead protons appear at 2.35
ppm (H3) (multiplet) and 3.9 ppm (H3) (d, J = 6.6 Hz). The relatively large 2.45 Hz
allylic coupling between H2 and H3 is due to a dihedral angle of 85° between H3-
C3-C1-C2 (AMI calculation) indicating that the Cg-Hg bond is parallel to the 71:
orbital of C1-C2 bond.90 To check whether H3 is syn or anti to H3, the dihedral
angle H2-C2-C3-H3 was calculated for both isomers using AMI semi-imperical
calculation. The result showed an angle of 30° for the anti isomer and 60° for the
syn isomer. Coupling constants were calculated using the Karplus equation as 6.0
Hz for the anti and 1.8 Hz for the syn. Experimental results showed that J2,3 = 6.5
Hz (cf. table 8). This result suggested that the product has the anti configuration.
An nOe experiment supported this result. Irradiation of the bridgehead proton at
C3 (2.35 ppm) induced enhancements of H95 (2.96%), H5 (2.3%), H105 (1.5%) and
H75 (0.32%). Similarly irradiation of H5 (6.53 ppm) led to the enhancement of H3
(3.02%) and H75 (1.37%).

57

6-5.8226 5 aimuézoé Co 8.58% «22 E a 8:3...

 

zaa «

.p..._

m _m v m m m m

...._...__....L...._ .rb.bp+.._...._.PLbrF..—Lp.-_.P-.—....—.._b_.p.-_

 

 

 

 

d4 5

 

 

ran a... mé v... 9v we ob

00...p.»h..h._.Lrbb_b.L_..p._...._»..-_....h_.b._FL__—bphr_...

1 557 - 92..

 

 

 

 

 

 

 

 

58

The other cyclobutene m-CN-ACBS was neither isolated nor produced in
pure form, but it was identified by comparing its 1H NMR spectrum (olefinic
region) with that of m-Amide-ACBS. The partial spectrum of m-CN-ACBS in
benzene-d5 is: 5 5.37 (d, J = 2.8 Hz, 1H) 5.80 (dd, J = 2.8, 0.5 Hz, 1 H) and 6.34
(broad d, J = 2.8 Hz, 1 H). For m-Amide-ACBS it is: (benzene-d5) 5 5.6 (d, J = 2.8
Hz, 1H) 5.97 (dd, J = 2.8, 0.6 Hz, 1H) and 6.23 (broad d, J = 2.8 Hz, 1H). These

data suggest that the two compounds have similar structures.

 

 

 

 

 

 

5.7 : 1.0
m-OMe-pBA m-OMe-CHD, m-OMe-ACB, m-OMe-ACB,
Scheme 56

In an NMR tube, a solution of m-OMe-pBA in benzene-d5 was irradiated
using Pyrex-filtered light (A Z 290 nm). The reaction was monitored by 1H NMR.
After 45 minutes, 1H NMR showed the formation of new peaks that correspond
to three products: 4-acetyl-2-methoxy-11-oxa-tricyclo[6.3.O.01'6]undeca-2,4-
diene (m-OMe-CHDa), 4-acetyl-2-methoxy-l 1-oxatricyclo[6.3.0.01'4]undeca-2,5-
diene (m-OMe-ACBa) and 4-acetyl-6-methoxy-11-oxatricyclo[6.3.0.01’4]-

59

undeca-2,5-diene (m-OMe-ACBS) in a ratio of 1.5 : 4.3 : 1.0 respectively . After
3.5 hours (~100% conversion ), only m-OMe-ACBa and m-OMe-ACBS were
present in a ratio of 5 .7 : 1.0 respectively.

Generally, product identification depended on 1H NMR spectra, especially
in the olefinic region. Cycloadduct m-OMe-CHDa (chloroform-d) has two
olefinic protons: a doublet (J = 0.83 Hz) at 5.75 ppm (H3) and a doublet of
doublets (J = 5.76, 0.83 Hz) at 6.44 ppm (H5). Cycloadduct m-OMe—ACBa was
identified from its partial spectrum in benzene-d5. It shows three olefinic protons:
a singlet at 4.65 ppm (H3), a doublet of doublet of doublets (J = 9.95, 6.8, 1.83
Hz) at 5.75 ppm (H5) and a doublet of doublets (J = 9.9, 2.98 Hz) at 6.15 ppm
(H5). m-OMe-ACBS has three olefinic protons; a doublet at 4.65 ppm (H5), a
doublet (J = 2.85 Hz) at 5.96 ppm (H3) and a doublet of doublets (J = 2.85, 0.53
Hz) at 6.05 ppm (H2).

Irradiation was repeated at 313 nm. After 80 minutes, 1H NMR showed the
formation of m-OMe-CHDa as the only product. Irradiation was continued for 12
hours. 1H NMR showed the formation of peaks corresponding to m-OMe-ACBa,
m-OMe-ACBS, m-OMe-CHDa (5 : 1 : 1) beside singlets at 4.62, 4.94, 5.44, a
multiplet at 5.5 and a multiplet at 6.08 ppm. The solution was left at room
temperature for 20 hours and then heated at 100°C for 90 minutes. 1H NMR
showed the m-OMe-CHDa concentration had increased at the expense of m-
OMe-ACBa and the three singlets at 4.62, 4.94 and 5.44 ppm. A new compound
was also observed and was identified as 4-acetyl-2-methoxy-11-
oxatricyclo[6.3.0.03'6]undeca-1,4-diene (m-OMe-LCBmami). The identification
was based on comparing the 1H NMR spectrum of m-OMe-LCBa with those of
4-acetyl-2-t-butyl-l l-oxatricyclo[6.3.0.03'6]undeca-1,4-diene (m-tBu-LCBa,anti)

and 4-acetyl-2-mercaptomethyl-1 1-oxatricyclo[6.3.0.03'6]undeca-1 ,4-diene

358226 5 55629:. .8 5.58% «22 m. a 9...»...—

 

6O

 

2%. m m v m m n

LP..—.-bp_L..rT_.hLL—b.7._p.p._...._.h-_—-..._....__..._...._-...

17.411.53.11 l 13.1de fl 4... -

 

 

 

 

O.
n

 

 

 

 

 

 

 

 

61

.23: B§Ekoim m5»: cute—.85.. 5 $3620....

Co 5:23.... B 85...... $3626.... 2... £3629... co 23...... e Co 5.58% «22 m. a. 8:3...

 

2% a

m

m v m m m m

.lpbb_b._rh...._...._b..__-r.._h_.._..p._Frbp—brpr_...LhLP.hpp.._—...._b.k.-_

 

 

1"!

 

a )3 .. .1 r

 

2%. me oh m.m vb m.m m.m ob mm

lrlt irrllr l) b 1.111 ”11166“.
ijfi {It 14 1 ‘11 414
/

.n

 

 

 

.1— » hm
a6<52¢3fl 50¢...qu (mares—Or:—

o
.. Co: 5.6
+ 5%. 02¢
635 .. n a. o
o o H

    

 

 

 

 

 

61

.Ew: c23E-5..§ as»: omécficon 5 $3-929:—

.0 8.3.3... B 85...... .mu<.~2o.... 2... £3.33... 3 23...... a .o 5.58% «22 m. a. 9...»...

 

2% u

m m

m m m m

p..._..-.-...-_.~P._..LpPTP..~....p..p.—....Fu.?._tr.bL...PL...—-.-._L.h._

 

 

Jll

3

 

 

 

 

 

 

 

 

j 1:3 1 .1 4

m.m «in m.m m.m ob Wm

.thE.r:.—:.._::_C:_.:L:.Et._::b:.p_.p:—#::.P:Ppp:_::_.

 

94 u hm

   

.nU<.oEO.E 50?..298 <n._.u2G.E

 

62

(mSMe-LCBa,anti). The high similarity between their spectra suggested that m-
OMe'LCBmanti has the same stereochemistry as m-tBu-LCBa,ami and m-SMe-
LCBafinfi (the bridgehead proton, H3, is syn to the cyclobutene ring and anti to

H3).(cf. Table 7).

 

 

 

O
Benzene-d6
[ls 100°C/9O '
M e0 . mm.
m-OMe-ACB. m-OMe-LCBmu

 

 

 

Scheme 57

In an NMR tube the ketone was dissolved in benzene-d5 and irradiated
using uranium-filtered light (7t 2 334 nm). After 43 hours of irradiation (> 80%
conversion), 1H NMR showed the presence of m-OMe-ACBa and m-OMe-
ACB; in a ratio of 2.8 : 1.0. The solution was left at room temperature in the dark
for 5 days. 1H NMR showed the formation of three products; m-OMe-CHDa and

 

 

 

m-OMe-ACB, m-OMe-COT,

 

 

 

Scheme 58

63

938258. :52 .a 03.53 05 wetsu— cS. 03-2.8.8: 5 53.020...—
.o 8.3.5... E 85...... Rout—2o... 2... Sassoé .o 23...... a .o 5.58% «22 m. .m 2...»...

 

 

2% « m

tb-[h—bb-nhnnb-Pb-bp—y-an—pnbh—

41......

 

 

 

J

 

 

v m

m n

.. PL _. .L p—‘P. .. .. .. ._ p. p. —.x.. FL .. .. —. f

 

m

g

 

m.m 2am m.m ed

 

 

 

:ljlllwl

m.m v6 ad ad

 

,br.h_...._-p..—.b.p-PL.._.bp-bpb.._...._..b._..p.—..b.—....b...~—F

{lltrgl’e Ill I

 

 

$9.29....

oonmu
M... Ewen—c 3% >5 020

 

 

 

64

m-OMe-COTs in a ratio of 2.5 : 1.0 and an unidentified product. m-OMe-COTs
was identified from its partial 1H NMR spectrum (olefinic protons region): 5 5.54
(dd, J = 8.5, 2.4 Hz, 1H) 5.86 (broad singlet, 1H) and 6.78 (dd, J = 8.5, 0.90 Hz).
The 1H NMR partial spectrum for m-CN-COTS in benzene-d6 is as follows: 5 5.28
ppm ( dd, J = 8.23, 1.75 Hz, 1H) 6.69 (d, J = 8.23 Hz, 1H) and 7.2 ( broad singlet,
1H). The only difference between the spectra is the chemical shift of H5 which is
due to the difference between the electronic effect of the cyano and methoxy
groups.

A sample of m-OMe-pBA in benzene-da was placed in ice-water bath and
irradiated using Pyrex—filtered light. After 1 hour, 1H NMR showed the presence
of starting material (45%), m-OMe-CHDa (2.1%), m-OMe-ACBa (7.1%) and m-
OMe-ACBS (1.7%). After 4 hours the percentages became 2.3%, 2.0%, 18.5%
and 4.4%.

The previous experiment was repeated at 55°C. After 40 minutes, 1H
NMR showed the presence of starting material (69.4%), m-OMe-CHDa (2.9%),
m—OMe-ACB; (16.1%)and m-OMe-ACBs (4.4%). After 4 hours the percentages
became 0.0%, 0.0%, 44% and 4.6%.

O :0 O
OMe OMe
hv, 1:313nm ’. + [.6 + 7
O C5D5 o
O
2.8 ' : 1.0 : 6.0

 

 

OMe

m-OMe-CHD. m-OMe-pBA m-OMe-ACB.

 

 

 

Scheme 59

65

23...... 3 5.329... .c 83...»... .3
83...... 3333...... 3 c.8829... 3... .a:u...2o.... .c 23...... a .c 33.8... 322 m. 3 9...»...

 

 

e m m \.
.

.pPLb>pP.p-bppprL-p_rbpb-PFPPL.ppppbppp

 

 

 

 

 

 

 

 

 

 

 

 

 

 

66

In an NMR tube a solution of m-OMe-CHDa in C6D6 was irradiated at
313 nm. After 40 minutes ( 12% conversion), 1H NMR showed the formation of
m-OMe-pBA and m-OMe-ACBa in a ratio of 2.8 :10 and an unidentified
product. This ratio remained the same at up to 72% conversion.

Preparative scale photolysis (1.0 gm of the ketone in 500 ml dry benzene)
was canied out. After solvent was evaporated, 1H NMR of the residue (CDC13)
showed the presence of three compounds; m-OMe-pBA, m-OMe-CHDa and 4-
acetyl-2—methoxy-11-oxabicyclo[6.3.0]undeca-1,3,5-triene (m-OMe-COTa) in a
ratio of 1.0 : 5 .5 : 3.5. When the sample was left overnight, 1H NMR showed that
m-OMe-COTa totally disappeared while the concentration of m-OMe-CHDa
increased. The mixture was purified by column chromatography (silica gel, 20%
ethyl acetate/hexanes) to give 0.11 gm of starting material and 0.37 gm of 4-
acetyl-2-methoxy-11-oxa-t1icyclo[6.3.0.01'6]undeca-2,4-diene (m-OMe-CHDa).
m-OMe-COTa was identified from its partial NMR spectrum. It has three olefinic
protons: doublet of triplets (J = 13.13, 5.96 Hz) at 5.94 ppm (H6), a doublet of
triplets (J = 13.19, 2.19 Hz) at 6.28 ppm (H5) and a broad singlet at 6.98 ppm (H3).

 

 

l 0
Me hv, Pyrex
Benzene-d6) _ ‘

 

m-Me-AP m-Me-ACB,

 

 

 

Scheme 60

67

A solution of m-Me-pBA in benzene-d5 was degassed and irradiated using
Pyrex-filtered light. After 2 hours irradiation, 1H NMR showed that 4-acetyl-6-
methyl-l1-oxatricyclo-6.3.0.01'4]undeca-2,10—diene (m-Me-ACBS) was the only
product 1H NMR spectrum of this compound showed three olefinic protons; a
broad singlet at 5.5 ppm (H5), a doublet (J = 2.88 Hz) at 5.91 ppm (H3) and a
doublet of doublets (J = 2.8, 0.5 Hz) at 6.07 ppm (H2).

0
hv, Pyrex
[- Benzene- ‘do’
0

m-Me-ACB, di-rt-ml di-n-mz

 

 

 

 

 

Scheme 61

When the solution was further irradiated, new peaks started to appear [ 8
5.35 (dd, J = 5.6, 2.5 Hz); 5.13 (dd, J = 5.6, 0.8 Hz) and 3.05 (dd, J = 2.5, 0.8 Hz)].
Structure assignment depended upon this partial spectrum. The 5.5 Hz coupling
constant is characteristic of cyclopentene olefinic protons.”88 This suggested
that a cyclopentene ring is present, also from comparing the partial 1H NMR
spectrum of this compound (C6D5) with that of compounds 1 (CDC13) [ 5 5 .5 (d, J
= 5.6 Hz, 1H) 5.68 (dd, J = 5.6, 2.2 Hz, 1H)] and 2 (CDC13) [8 2.55 (d, J = 2.3 Hz,
1H) 5.41 (dd, 1: 5.3.2.3 Hz, 1H) 5.69 (dd, I: 5.3, 2.3 Hz, 1H)],91 its structure was
proposed to be either tetracyclic compound di-rt-ml which may be due to the di-
n-methane photoreaction of m- Me-A CBS or its vinyl cyclopropane

rearrangement product, di-rt—m2.

68

.5»: 3.85-5.5. use. {-8859 5
5:33... .3... 8.68.. EoEowEaesoga a: E... .5352-..— uo 235:. a we 8.58% 4:22 I. K. 953%

 

 

1% u m m v m m m m

_.p.p_._.pp.._r_._.._...L_.L-pt...—C.L...._P-bb_rk._—+..Ph..bp—.p£_.-.._

 

it

s. outfit: s t - a: s

 

 

tam m.m 7m 9m 06 ed

pprppbh..pp—phhprb.h._r..p—pp.._.rbbbp.Pp-L..L—..r..

 

 

 

«9...... .35.... £052.... cued—2....

 

 

 

 

 

 

.2»: 8.0.5-5.».— mfig {655.2 5
5.2.68: .2... 8..er EoEowESBQena m: E... fives—2a: we 23...... a .o 5.58% M22 1. ”b 9...»...—

 

68

 

zna « m m v m m m m

.pbprL....b+..P_.L.._...L_....—..P._-..?P..bp_p..h.PP.F—LL.LL....—.PPL_.L_._

 

 

it

.t JJJs._+itds-4

 

 

 

 

 

 

 

 

2.... m.m .2... 9m 9m o...
.pr..._.er..rr._...._....P.LLF.....h..p._.._L_.Lr..
3...... 3...... .552...— 5.32....
o
o o 4.235.. &
yafiVlflt 4.3.2..
o o no IV

 

 

 

69

 

   

 

 

 

Scheme 62

In order to prevent the occurrence of the secondary photoreaction,
irradiation of m-Me-pBA was performed again using uranium filter which permits
only light of wavelengths longer than 334 nm at which the carbonyl group of m-
Me-ACBS does not absorb. The NMR tube was taped to the immersion well and
hence the solution temperature was slightly higher than room temperature. The
reaction was slower due to lower light intensity. After 105 hours of irradiation,
only two compounds were observed by 1H NMR spectroscopy; m-Me-ACBS
which arises from the addition of the double bond towards the benzene ring, and
its regioisomer 4-acetyl-2-methyl-l 1-oxatrr'cyclo[6.3.0.01'4 ]undeca-2,5-diene (m-
Me-ACBa). The product ratio was ~ 8 : 1 and chemical yields was 60% and 7.5%
with respect to m-Me-pBA consumed. When the NMR tube was placed about
one inch away from the immersion well and irradiation was repeated under the
same conditions, m-Me-ACBa was not observed by NMR. The structure of m-
Me-ACB; was determined using its partial 1H NMR spectrum. It has three
olefinic protons; a doublet of doublets of doublets (J = 9.8, 6.2, 3.5 Hz) at 5.57
ppm (H6), a quartet (J = 1.6 Hz) at 5.64 ppm (H2) and a doublet of doublets of
doublets (J = 10.0, 2.5, 1.3 Hz) at 5.92 ppm (H5).

70

m-Me-ACBS and m-Me-ACBa were stable in C6D5 solution at room
temperature for at least 14 days. When a crystal of p-toluenesulfonic acid was
added to the solution, a yellow color developed within seconds. 1H NMR
analysis showed the disappearance of the peaks corresponding to the cyclo-

 

 

 

 

 

 

 

 

 

 

O
[.6 PTSA
+
. Benzene-d6 O
O
m-Me—ACB, m-Me-COT,
Scheme 63
0
[Is PTSA
>-
. Benzene-d5 O
O
m-Me-ACB. m-Me-COT.
Scheme 64

butenes along with the appearance of new peaks corresponding to 4-acetyl-6-
methyl-11-oxabicyclo[6.3.0]undeca-1,3,5-triene (m-Me-COTS) and 4-acetyl-2-
methyl-1l-oxabicyclo[6.3.0]undeca-1,3,5-triene (m-Me-COTa). 1H NMR showed
that m-Me-COTs has three olefinic protons; a doublet of doublets (J = 8.2, 1.9
Hz) at 5.58 ppm (H2), a broad singlet at 6.54 ppm (H5) and a doublet (J = 8.2 Hz)

crosses a. ....8...2.... .e 5.58% «22 z. a. 9...»...

 

Ian. H m m v m m m

_.p.._...._.b.._..p._...p—bbp._prhb_bp.._._p._.....L..._........._...._....b.

£227. a... s... d . _ m

 

 

 

9m 1%. m.m ob m.m To ed

up . z. .7 ..

 

 

 

71

.532...

 

 

 

 

 

 

 

 

72

at 6.84 ppm (H3). m-Me-COTa also has three olefinic protons, a doublet of
triplets (J = 12.6, 4.39 Hz) at 5.65 ppm (H5), a doublet of triplets (J = 12.6, 2.32
Hz) at 6.58 ppm (H5) and a singlet at 6.83 ppm.
m-Me-pBA was irradiated in benzene-d6 at 55°C using Pyrex-filtered light
(7L 2 290 um). After 40 minutes, 1H NMR showed the presence of starting material
(65%), m-MeACBs (7.3%) and 4-acetyl-2-methyl-11-oxatricyclo[6.3.0.03'6]-
undeca-1,4 diene (m-Me-LCBa,anti) (14.2%). After 4 hours the percentages
became 27.5%, 10.0% and 13.6% respectively. The 1H NMR spectrum of m-Me-
LCBafimi showed the presence of only one olefinic proton, which appeared as a
doublet at 6.04 ppm (J = 1.3 Hz, H5) coupled to a ddt at 2.66 ppm (bridgehead
proton, H6). The methyl group appeared as a doublet at 2.27 ppm. The relatively
large chemical shift of the methyl group is due to its being allylic. It couples to Hg
with a homoallylic coupling constant of 2.27 Hz. Comparing the 1H NMR spectra
of m-Me-LCBmami with those of m-SMe-LCBafimti and m-tBu-LCBa,ami
showed great similarities between chemical shifts and coupling constants (cf.
table 7). This suggested that they have the same stereochemistry specifically that
m-Me-LCBamfi has H3 syn to the cyclobutene ring.

<=

0 0
Me
0 IN, A > 334 nm ’ _‘
Benzene-d6ISS°C
. .
O

m-Me-pBA m-Me-ACB,

 

 

 

 

 

 

Scheme 65

73

.5: men 2. {6:85.— 833 E 53.92.:—
.o .5523... .3 35.2.... zoning—.02.... E... .no<.oE.E .o 235:. m we 8.58% 522 I. ”a 9.5»...—

 

 

xaa « m m w m

r...._p.»p__..F_...._....—...»Fb...bLtP.._....F.-.._pbrb—..P.pr..—......_p...

. ___ .a

 

 

 

     
 
      

5m ed. m.m eh «.m

 

 

3833.30:
a. an“ d .2— 02

     
   

.N ‘
.n

 

 

 

 

 

 

74

m-Me-pBA was also irradiated at 365 nm in C6D5, The solution became
warm during the irradiation because of the lamp. 1H NMR showed that two
products were formed; m-Me-ACBs and m-Me-LCBa,anti in a ratio of 1 : 2.
When this experiment was repeated, 1H NMR showed the formation of three
products; m-Me-ACBS, m-Me-ACBa and m-Me-LCBafimti in a ratio of 2.1 : 3.3
:1.

Irradiation was also performed at low temperature. In an NMR tube, a
solution of m-Me-pBA in benzene-d5 was placed in an ice-water bath and
irradiated using Pyrex-filtered light. After 1 hour, 1H NMR showed the presence
of starting material (84.8%) and m-Me-ACBS (5.4%). After 4 hours the
percentages became 55.2% and 13.1%, whereas after 9 hours it became 35.5%
and 17.1%, respectively.

Large scale irradiation of 1.0 gm of m-Me-pBA in 500 ml of dry benzene
using Pyrex filtered light led to the formation of only 0.1 gm of m-Me-COTS after

isolation using column chromatography.

 

hv, 365 run
>
O Benzene-d6

 

O

 

m—Me-COT, m-MeeACB, m-Me-LCB,

 

 

 

Scheme 66

75

Irradiation of isolated m-Me-COTS at 365 nm in C6D5 for 4 hours at room
temperature led to the formation of m-Me-ACBS as the major product in addition
to a minor product. The partial NMR spectrum of the minor product showed a
broad doublet at 3.05 ppm (J = 6.32 Hz), a singlet at 6.14 ppm and a doublet of
doublets at 5.3 ppm (J = 6.35, 2.5 Hz). This suggested that this compound was 4-
acetyl-6-methyl-l1-oxatn'cyclo[6.3.0.03'6]undeca-1,4 diene (m-Me-LCBs,anti).

The ratio of the two compounds was 3.6 : 1.0

 

 

=3 0
0 Benzene-d
Q 0 6 r [I
hv, Pyrex
RT 0
m_tBu_pB A m-‘Bu-ACB,

 

 

 

Scheme 67

In an NMR tube, a solution of m-tBu-pBA in benzene-d6 was degassed
and irradiated using Pyrex-filtered light. After 40 minutes irradiation (~7%
conversion) new sets of olefinic peaks were detected by 1H NMR: 5.88 ppm, ((1, J
= 2.85 Hz), 6.10 ppm (dd, J = 2.75, 0.55 Hz) and 5.68 ppm ((1, J = 2.35 Hz) .
Product yield was found to be 70% (with respect to reacted starting material).
Starting material totally disappeared after 20 hours irradiation . The product yield
dropped from 70% to 10%. Based on the partial 1H NMR spectrum the

76

photoproduct was proposed to be 4-acetyl-6-t-butyl-1l-oxatricyclo[6.3.0.01'4]-
undeca-2,5-diene (m-tBu-ACBS)

m-tBu-pBA was irradiated in ice-water cooled benzene-d6 using Pyrex-
filtered light. After 1 hour, 1H NMR showed the presence of starting material
(94.6%) and m-tBu-ACBS (4.9%). After 4 hours the percentages became 66.0%
and 14.6% where as after 9 hours became 30% and 19.1% respectively.
Placement of the NMR tube in boiling water for 40 minutes, resulted in no change
to m-tBu-ACBS by 1H NMR.

 

 

 

m-‘Bu-pBA m-‘Bu-LCBuw m-‘rru-ACB,

 

 

 

Scheme 68

The previous experiment was repeated at 55°C. After 40 minutes, 1H
NMR showed the presence of starting material (62.4%), m-tBu-ACBS (2.2%) and

4-acetyl-2-t-butyl-1 1-oxatricyclo[6.3.0.03'6]undeca-1,4-diene (m-tBu-LCBa,ami)
(20.1%). After 4 hours the percentages became 18.9%, 3.4%, and 27.9%
respectively.

77

success... 5 _........o............ .c 5.58... m2... 2. u... 8.9....

 

 

Ea. m m v m m m

_..___....P__F._...._...._.._._._.__|p_.._._..—.L.|_Lr£.._._.r—L..._...._

.1.ng #

a

 

ms. :3 8m mm... 8...
Egg

 

..._.=..u.........=.

 

 

 

.= e...

 

 

 

 

 

78

Large scale irradiation was performed using 0.50 gm of m-tBu-pBA in 150
ml dry benzene. After 12 hours irradiation using Pyrex-filtered light, it was
noticed that the solution had warmed from the uv lamp (~400C). 1H NMR
showed the formation of (m-tBu-LCBamlti). The photoproduct was isolated by
prep TLC and identified by 1H and l3c-NMR analysis. 1H NMR (benzene-d5)
showed the presence of only one olefinic proton at 5.97 ppm ((1, J = 1.3 Hz) while
13C NMR showed the presence of two double bonds. Homonuclear decoupling
experiments supported the proposed structure.

The stereochemistry of m-tBu-LCBa,ami was established by nOe
experiments which showed that H3 is syn to the cis-cyclobutene ring. Irradiation
of H5 led to the enhancement of H3 (8.6%) , H5 (7.6%) and Hm (3.64%), while Hg
was not affected. On the other hand, when H5 was irradiated, an enhancement of

H5(4.46%) and H3 (2.86%) was observed.

 

Benzene-d6/PTSA

 

 

‘ or CDC13/(HC1)

 

m-‘rru-chrr_,,,,,I

 

 

 

Scheme 69

When m-tBu-LCBa,anti was treated with catalytic amount of para-

toluenesulfonic acid in benzene-d6, 1H NMR showed the formation of 1:1 mixture

 

79

e5.8.8.8.. 5. <2... 5... .........o......... .e .8585
B .8558 .........u............ o... .........u......... .o 25...... e .c 5.58... .52 m. a. 8.5....

 

 

2.... a m m w m m m m

Pbpr._..p._p.brhr.p.—....—|_FbP...PL..p._...._....bpr.__l..L._....—...._£kr_.

. t 37....-.

 

 

ENG...“ vmfi 86. 8d.
FEE—ELEV

 

 

 

..........u............ 5.3.6.55}

  
  

 

 

 

<38 t .M.
4-0.85.8 be...

 

 

 

 

 

80

of m-tBu-LCBa,anfi and 4~aeetyl-2-t-butyl-l1-oxatricyclo[6.3.0.03'6]undeca-13,4
diene (m-tBu-LCB'a,anti). The same mixture was formed when m-tBu-LCBa-
anti was dissolved in chloroform—d which may contain some acidic impurities.
After prep TLC isolation of m-tBu-LCB'mmti, its structure was assigned using
1H and 13C NMR. 1H NMR showed the presence of an olefinic proton at 5.94
ppm (J = 1.33 Hz) which is almost identical to that of m-tBu-LCBa,anti. This
suggested that the cyclobutene ring remained intact. However the chemical shifts
of all the methylene protons moved to a lower field compared to those of m-tBu-
LCBamnti (1.9—2.7 ppm instead of 0.85-1.74 ppm). This finding agrees with the
proposed structure of m-Wu-LCB'manti which has the cyclobutene ring
junction as in m-tBu-LCBa-anti. Moving the double bond between C1 and C3
caused H7 and H9 to be allylic which accounts for the change in chemical shifts.

A sample of m-tBu-LCB'a,anti in benzene-d6 was treated with para-
toluenesulfonic acid. 1H NMR analysis showed the formation of the same 1:1
mixture of m-tBu-LCBa,ami and m-tBu-LCB'a,ami. It is noteworthy that m-
tBu-LCBMmfi did not lose its stereochemistry.

 

t, tr» ta

 

 

m-‘Bu-Lcn'manti m-‘Bu-LCB'W
Scheme 70

 

81

m-tBu-LCB'Mmfi has two possible stereochemical configurations; one of
which has the t-butyl group syn to the cyclobutene ring (m-tBu-LCB'a,syn)
while the other has the t-butyl group anti to the cyclobutene ring (m-tBtr-
LCB'a,anti). AMI semiemperical calculations showed that the anti isomer is 4
kcal/mo] more stable than the syn isomer. Also, the lowest energy geometry was
calculated for both isomers and showed that the dihedral angle between H2 and
H3 is 52° for the syn and 92° for the anti. Experimentally H2 does not couple
with H3 which suggests that the formed product has the anti geometry. 1H NMR
nOe experiments agreed with the proposed stereochemistry. Irradiation of the
bridgehead proton, H6, induced enhancements of H3 (2.3%). Irradiation of the
olefinic proton, C5, led to the enhancement of Hz (2.8%). These results, again,
suggested that the t-butyl group is anti to the cis-fused cyclobutene ring.

Large scale irradiation of m-tBu-pBA (0.3 gm in 150 ml dry methanol) was
performed at low temperature. 1H NMR analysis showed the formation of m-tBu-
ACBs. No m-tBu-LCBmami was detected. The photoproduct was isolated by
prep TLC (10% ethylacetate/hexane) as 4-acetyl-6-t-butyl-11- oxabicyclo[6.3.0]-
undeca-1,3,5-t1iene (m—tBu-COTS).

82

 

 

 

Bhotochcmimormahreizuaa
— ‘\ O I, ”’
o ] CD3OD l5 '5‘
O > ,’ s‘ 7
Q hv > 334 nm

11
r
m-Me-‘Pr-pBA m-Me-‘Pr-ACB, m-Me-‘Pr-ACBll

Not formed

 

 

 

Scheme 71

In an NMR tube, a solution of m-Me-iPr-pBA in methanol-d4 was
irradiated using uranium-glass-filtered light. After 200 hours of irradiation, 1H
NMR analysis showed that starting material disappeared with the formation of 4-
acetyl-6-isopropyl-2-methyl-11-oxatricyclo[6.3.0.01'4]undeca-2,5-diene (m-Me-
iPr-ACBS) as the major product. The other regioisomer 4-acetyl-2-isopropyl-6-
methyl-l1~oxatricyclo[6.3.0.01’4]undeca-2,5-diene (m-Me-iPr-ACBa) was not
detected by 1H NMR.

The structural differentiation between the two regioisomers was based on
the coupling constants of the olefinic protons. For m-Me-iPr-ACBS, H3 is
expected to appear as a quartet with an allylic coupling constant 1~2 Hz and H5 a
doublet of doublets with one allylic coupling constant of 2~2.5 Hz (compare to
m-tBu-ACBS) and another allylic coupling constant <2.0 Hz. On the other hand,
for m-Me-iPr-ACBa, H3 is expected to appear as a doublet with an allylic

coupling constant < 2.0 Hz and H5 should appear as a doublet of quartets or a
broad singlet (compare to m-Me-ACBS). 1H NMR showed the presence of two

83

olefinic protons; 5.42 ppm, (dd, J = 2.0, 1.1 Hz), 5.9 ppm, (q, J = 1.57 Hz). These
data agree with m-Me-iPr-ACBS as the product.

 

 

 

hv / CD3OD
‘ $
0 CD3OD (HWRT

m-Me—‘Pr-COT, m-Me-‘Pr-ACB,

 

 

 

 

Scheme 72

m-Me-iPr-ACBS solution in methanol-d4 was left in the dark for 3 days at
room temperature. The solution became yellow and 1H NMR showed the
formation of new peaks corresponding to 4~acetyl-6-isopropyl-2-methyl-ll-
oxabicyclo[6.3.0]undeca-1,3,5-triene (m-Me-iPr-COTS). Large scale irradiation
of m-Me-iPr-pBA was performed using 0.4 gm of the material dissolved in 150 ml
dry methanol. Irradiation was performed at < 0°C and by using Pyrex-filtered
light. Reaction was complete after 2 hours irradiation, after which the
cyclooctatriene (m-Me-iPr-COTS) was isolated. 1H NMR showed the two
olefinic protons of m-Me-iPr-COTS; a broad singlet at 6.06 ppm (H5) and a broad
singlet at 7.04 ppm (H3) 0

A solution of 6.6 mg of m-Me-iPr-COTS was dissolved in 0.75 ml of
methanol-d4 and irradiated for 40 minutes using Pyrex-filtered light. 1H NMR
showed the formation of m-Me-iPr-ACBS as the only product. This product was

.52. 8.2.58... 2.... e...o....u..e..
s .59....825 .o 8.8.2.... E 85...... .8... 82.... .o 5.58... 522 m. ”a. 9...»...

 

84

 

zaa _ m m w m m N m

»~.h._pth_LPFFr..._...._.-.._.._._..L..r...__.bp—_..._-P..pp...—bb......p_.

n

 

 

cw
vb 2.... m.m m.m 5m m.m mg.“

P»—.F..—p...—..prhrrp._lpbpb..b.bP.-pr..p.b#..k-prPF.

t ‘1 tl’

 

£3.33...- .5212...

 

o.
O O
no.8 o

. Aug .2.

 

 

 

 

 

 

85

found to be stable to heat, as it remained unchanged when heated at 1000C for
one hour or left at room temperature in the dark for four days. This result

contradict a previous result which showed that another sample of m-Me-iPr-
ACB; isomerized to m-Me-iPr-COTS when treated similarly. The only difference

in the conditions under which these samples of m-Me—iPr-ACBS was subjected

was the use of different ampoule of methanol-d4.

 

 

 

 

 

 

 

o 3””
O O Methanol-d4 > Other isomer
)2. 344nm
m-Me-‘Pr-Mez-pBA m-Me-‘Pr-Mez-ACB,
9 : 1
Scheme 73

In an NMR tube a solution of m-Me-iPr-Mez-pBA was irradiated at A 2
334 nm. 1H NMR showed the formation of 4-acetyl-6-isopropyl-2-methyl-11-
oxatricyclo[6.3.0.01'4]undeca-2,lO-diene (m-Me-iPr-Mez-ACBS) as the major
product and another unidentified product in a ratio of 9 : 1 respectively.

Large scale irradiation (0.08 gm of m-Me—iPr-Mez-pBA in 150 ml of dry
methanol) was carried out for 2 hours using pyrex-filtered light at low

temperature (ice-salt bath). After removing the solvent, 1H NMR showed the
formation of m-Me-iPr-Mez-ACBS. The photoproduct was isolated as 4-acetyl-

86

6-isopropyl-2,9-dimethyl-1 1-oxabicyclo[6.3.0]undeca-1 ,3 ,5-triene (m-Me-iPr-
MBZ-COTs).

 

Methanol-d4
hv2290, 30 min

 

   

m-Me-‘Pr-Mez-COT, m-Me'Pr-Mea-ACB.

 

 

 

Scheme 74

In an NMR tube a solution of m-Me-iPr-Mez-COTS (3.1 mg in 0.75 ml
methanol-d4) was purged with argon and irradiated at A 2 290 nm. After 30
minutes, 1H NMR showed the formation of m-Me-iPr-Mez-ACBS

The two products were identified by 1H NMR. m-Me-iPr-Mez-ACBS
(methanol-d4) has two olefinic protons; a doublet of doublets (J = 2.8, 0.9 Hz) at
5.42 ppm (H5) and a quartet (J = 1.54 Hz) at 5.87 ppm (H3). From the coupling
constants it was suggested that this cyclobutene is a result of the double bond
addition to the benzene ring towards the isopropyl group (compared to m-Me-
iPr-ACBS). The stereochemistry of m-Me-iPr-Me2-ACBs was determined using
a 1H NMR nOe experiment at 25°C (methanol-d4, 500 MHz). Irradiation of the
methyl group at C9 (1.0 ppm) induced enhancement of H3 (3.03%) and H105
(2.4%) while irradiation of C3 (1.87 ppm) caused enhancement of the methyl
group at 1.0 ppm (4.33%) and H103 (1.16%). This indicates that the methyl group
at C9 is syn to the bridgehead proton H3. No enhancement was observed for the

methyl group at C2. This is due to the large distance between the two groups. The

87

distance between the centroids of the three hydrogen atoms of the two methyl
groups was calculated to be 4.37 A (Scheme 75). The distance between any two
hydrogen atoms was not considered since the rotational motion of the methyl
groups will be very fast compared to the relaxation rate of the single proton and

the net effect at the single proton must be averaged over this motion.92'93

 

 

 

 

 

Scheme 75

m-Me-iPr-Mez-COTS (methanol-d4) has two olefinic protons: a broad
singlet at 6.06 ppm (H5) and a singlet at 7.05 ppm (H3). Homonuclear decoupling
NMR experiment showed that H5 couples to H7“, H7p and the isopropyl methine.
The stereochemistry of m-Me-iPr-MeLCOTs was determined using a 1N MR
nOe experiment at 25°C (methanol-d4, 500 MHz). Irradiation of the bridgehead
proton H3 lead to the enhancement of the methyl group at C9 (2.61%), H3
(1.06%), H9 (1.02%) and H105 (1.02%). Irradiation of H9 caused the enhancement
of as (1.17%), H100: (4.05%), Hm (2.04%) and the methyl group attached to C9
(3 .02%). Irradiation of the methyl group attached to C9 lead to the enhancement
of H3 ( 2.9%), H103 ( 1.9%), H9 (2.7%) and H75 (1.27%). This indicates that the
methyl group at C9 is syn to the bridgehead proton, H3.

88

 

 

 

 

 

 

V0 H rigs ’3"

Benzene-d6 = .--9\/1\’/,

O a [a 8 § m6 )1 s ,
hv2290nm ”b ’3’ 2“ no

0
CH3 I” O \\

m-Me-oB A m-Me-o-LCBmu m-Me—o—LCB‘
Not Formed
Scheme 76

Irradiation of m-Me-oBA in benzene-d6 in NMR tube through pyrex-
filtered light provided 6-acetyl-2-methyl-11~oxatricyclo[6.3.0.03'6]undeca-1,4-
diene (m-Me-o-LCBs,anti) as the only product. This cyclobutene is a result of
the double bond addition to the benzene ring towards the acetyl group. The
other regioisomer; 2-acetyl-6-methyl-11-oxatricyclo[6.3.0.03'6]undeca-l,4-diene
(m-Me-o-LCBa) was not detected by 1H NMR. When a catalytic amount of p-
toluenesulfonic acid was added to a m-Me-o-LCBs,anti solution in benzene-d5,
yellow color was developed immediately. 1H NMR showed the formation of 6—
acetyl-Z-methyl-l 1-oxabicyclo[6.3.0]undeca—1,3,5-triene (m-Me-o-COTS). Again,
the other regioisomer, 2-acetyl-6-methyl-11-oxabicyclo[6.3.0]undeca-1,3,5-triene
(m-Me-o-COTa), was not detected by NMR.

89

 

Benzene-d6
H +

 

Benzene-d V0 H
v=365 nm ‘ “'9
5 [HQ ”1)

0
CH3

 

m-Me-o-LCB,

 

 

 

Scheme 77

Structural differentiation between the regioisomers was based on 1H NMR
coupling constants and chemical shifts of selected protons. For m-Me-o-
LCBsMfi (benzene-d5), there are two olefinic protons: a doublet (J = 2.88 Hz)
at 5.81 ppm (H5) and a doublet of doublets (J = 2.88, 0.89 Hz) at 5.93 ppm (H4).
The 2.88 Hz coupling constant is typical for cyclobutene vinylic protons The
methyl group at C2 of m-Me—o-LCBs,ami appears as a doublet (J = 2.21 Hz) at
1.81 ppm due to the allylic character. The 2.21 Hz coupling constant is due to the
homoallylic coupling with Hg. On the other hand, m-Me-o-LCBa would have the
methyl group on C5 and it would be a singlet at about 1.0 ppm.

The stereochemistry of m-Me-o-LCBs,anfi was determined using a 1H
NMR nOe experiment at 15°C (benzene-d5, 500 MHz). Irradiation of H4 (H5 was
partially irradiated) led to the enhancement of H3 (5.8%) and H3 (1.75%).
Irradiation of H5 (H4 was partially irradiated) induced enhancement of H3 (2.4%),
H3 (4.1%) and the acetyl group (2.5%). Irradiation of H3 led to the enhancement
of H4 (8.0%), CH3 (6.5%), acetyl group (6.1%) and H3 (1.0%). Irradiation of H3
induced enhancement of H4 (2.0%), H5 (3.71%), H103 (1.94%). These results
indicates that the bridgehead proton H8 is syn to the cyclobutene ring.

90

The other product, m-Me—o-COTS has three olefinic protons (chloroform-
d): a doublet of doublets (J = 12.37, 6.8 Hz) at 5.9 ppm (H4), a doublet (J = 12.36
Hz) at 6.04 ppm (H3) and a doublet (J = 6.80 Hz) at 7.0 ppm (H5). H5 has a
chemical shift of 7.0 ppm as a result of being conjugated with the acetyl group.
On the other hand, the other regioisomer m-Me—o-COTa would have a methyl
group on C6, thus, H5 would be a broad singlet (doublet of doublet of quartet
with allylic coupling constants) with chemical shift about 6.0 ppm (compare to m-
Me-COTS)

Large scale irradiation of m-Me-oBA (0.3 gm in 150 ml dry benzene) was
carried using Pyrex-filtered light. Solvent was removed and photoproduct was
isolated (preparatory TLC) as m-Me—o—COTs. Irradiation of a sample of the
product in benzene-d6 (I. = 365) led to its complete conversion to m-Me-o-
LCBs,anti-

 

 

 

 

;? 0 o
hv (pyrex [- 8M6
Benzene MeS .
O
7.1 : 1 : l
m-SMe-pBA m-SMe-ACB. m-SMe-LCBmu m-SMe-ACB,

 

 

Scheme 78

A solution of m-SMe-pBA in benzene-d5 was irradiated with Pyrex-
filtered light. After one hour of irradiation at room temperature, 1H NMR showed

91

the formation of three products: 4-acetyl-2-methylmercapto-1 1-
oxatricyclo[6.3.0.01'4]undeca-2,5-diene (m-SMe-A CB3), 4-acetyl-6-
methylmercapto-l1-oxatricyclo[6.3.0.01'4]undeca-2,5-diene (m-SMe—ACBS) and
4-acetyl-2-mercaptomethyl-1 1-oxatricyclo[6.3.0.03'6]undeca-1,4-diene (m-SMe—
LCBa) in aratio of7.5: 1 :1.

 

 

 

 

 

 

 

 

O MeS
SMe --
[.6 811108 gel
0 O
O
m-SMe-ACB, m-SMe-COT.
Scheme 79
O
Benzene
[Is 24 0?: + \(ng
MeS . hours
0 MeS
2 l
m-SMe-ACB. m-SMe-CHD. m-SMe-COT,I
Scheme 80

Large scale irradiation (0.3 gm in 150 ml dry benzene ) was carried out for
6 hours using Pyrex—filtered light. 1H NMR showed the formation of the previous

 

92

three products (note that excessive irradiation led to the disappearance of m-

SMe—ACBa). When the reaction mixture was left in the refrigerator for 24 hours,
1H NMR showed the disappearance of m-SMe-ACBa and the formation of 4-
acetyl-Z-mercaptomethyl-l l-oxa-tricyclo[6.3.0.01’6]undeca-2,4-diene (m-SMe-
CHDa) and 4-acetyl-2-mercaptomethyl-l1-oxabicyclo[6.3.0]undeca-l,3,5-triene
(m-SMe-COTa). Preparative TLC led to the isolation of m-SMe-LCBa, a m-SMe-
C H D a/m- S Me- C 0 T a mixture, and 4-acetyl-6-mercaptomethyl-11-
oxabicyclo[6.3.0]undeca-l3.5-triene (m-SMe-COTS).

All Photoproducts were identified by 1H NMR spectroscopy. m-SMe-
ACBa has three olefinic protons: a singlet at 5 .7 ppm (H3), a ddd at 5.75 ppm (H5)
and a ddd at 5.99 ppm (H5). H5 and H5 are coupled to each other with a I value
of 9.28 Hz . m-SMe-ACBs has three olefinic protons: a broad doublet (J = 2.35
Hz) at 5.36 ppm (H5), a doublet (J = 2.8 Hz) at 5.86 ppm (H3) and a doublet of
doublet (J = 2.8, 0.55 Hz) at 6.0 ppm (H2). The 2.8 Hz coupling constant is
characteristic of cyclobutene olefinic protons.

m-SMe-LCBMmfi has only one olefinic proton that appears as a doublet
(J = 1.35 Hz) at 6.08 ppm (benzene-d5) and at 6.80 ppm (H5) (chloroform-d). H5
couples to H5 with a I value of 1.35 Hz since the dihedral angle between the two
protons is ~70° (AMI calculation). The stereochemistry of m-SMe-LCBa,anti
was determined using nOe experiment (benzene-d5, 15°C). Irradiation of the
bridgehead proton H3 (3.71 ppm, H105 was partially irradiated) induced
enhancements of H5 (6.92%) and the thiomethoxy group (2.0%). Similarly
irradiation of H5 (2.62 ppm, thiomethoxy group was partially irradiated) led to the
enhancement of H3 (8.9%), H75 (0.83%) and H75 (2.34%). Irradiation of H5 led to
the enhancement of H5 (2.9%), H75 (0.60%), acetyl group (2.41%) and H3 (0.8
%). This indicates that the cyclobutene ring is syn to the bridgehead proton H3.

93

m-SMe-COTS has three olefinic protons (chloroform-d); a doublet of
doublets at 5.50 ppm (J = 9.05, 2.43 Hz) (H2), a broad singlet at 6.06 ppm (H5)
and a doublet of doublets at 6.96 ppm (J = 9.05, 0.88 Hz) (H3). The 9.05 Hz
coupling constant is due to the vicinal coupling between H2 and H3. H3 also
couples to the bridgehead proton Hg with an allylic coupling constant of 2.43 Hz.

It should be noted that m-SMe-Clma and m-SMe-COTa were isolated as
a 2:1 mixture (1H NMR integration). m-SMe-COTa has three olefinic protons
(benzene-d5): a ddd at 5.5 ppm,(J = 13.25, 4.53, 4.53 Hz) (H5), a ddd at 6.50 ppm
(J = 13.25, 2.21, 2.21 Hz) (H5) and a singlet at 7.07 ppm (H3). The 13.25 Hz
coupling constant between H5 and H5 is typical for cis cyclooctene protons.90 m-
SMe—CHDa has two olefinic protons (benzene-d5): a doublet of doublets at 5.98
ppm (J = 5.75, 0.70 H2) (H5) and a doublet at 6.53 ppm (J = 0.70 H2) (H3). The
5.75 Hz coupling constant of H5 is due to the vicinal coupling to the bridgehead
proton H5. The 0.70 Hz coupling constant is due to W-coupling between H3 and

H5.

 

O

”‘08

Mes O

1; 2

 

 

m-SMe-LCB. m-SMe-ACB, m-SMe-pBA
Benzene-d6, RT

 

313 nm, 2 hours ’ 23% 69% 3%

O
Benzene-d6, ~10°C
0 MeS J 365 nm,2hours

 

 

> 18% 82% 0%

 

 

 

Scheme 81

94

m-SMe-CHDa/m-SMe-COTa mixture was irradiated at two different wave
lengths. A solution of the mixture in benzene-d5 was irradiated at room
temperature using 313 nm light for two hours (65% conversion). 1H NMR
showed the formation of m-SMe—LCBamfi, m-SMe-ACBa and m-SMe—pBA in
a ratio of 28 : 69 : 3. When irradiation was performed using 365 nm light for 2
hours at 10°C, 1H NMR showed the disappearance of starting material and the
formation of m-SMe-LCBmfi and m-SMe-ACBa in a ratio of 18 : 82

 

O

Benzene-d6
[- ‘ 65°C/30 m' >
MeS . m'

 

 

m-SMe-ACB. m-SMe—LCBm“

 

 

 

Scheme 82

In order to study the thermal chemistry of m-SMe-ACBa, a sample of the
compound had to prepared by irradiating the m-SMe-CHDa/m-SMe-COTa
mixture (3 mg in .75 ml benzene-d5 in an NMR tube) using 365 nm light for 2
hours. 1H NMR showed the formation of m-SMe-ACBa and m-SMe-Lcnmnfi
in a ratio of 4 : l. The temperature of the NMR probe was then raised to 65°C for
30 minutes. 1H NMR showed the complete. transformation of m-SMe-ACBa to
m-SMe-LCBganfi.

95

 

9.53.85 5 .SUdSmé .o 838% E22 2. a. 9...»...

 

2am _ m m v m m m m

—__.._Fpr_.bb.—-.~._.F»._b+rp__p..—....bep._~.Ph_L.p._.~Pb_P~bpp..-.—b.p...

41(\.l. -llilt..ll\ 1'11: .
n
o
o

m.mzaa v.m o.m m.m o.c m.m v.m m.m m.m c.m

41.24 ,7?

 

 

 

 

 

 

 

 

   

.._.ou.o2m....

 

 

 

 

 

 

96

s........2..o.. o. .heodzmé
2... Snooze... .o 22...... 5.5.5.... .o afioo... «.22 m. .3 9...»...

 

 

l... m .9 m »
—-pP»—»-__—m

h m

—pr_-—P-pp

114331313 Lime

b-kbLFp—

 

 

2.... m.» c.» m.» w.» mm

 

 

 

 

        

 
 

n N

.pooozmé .ezuozmé

 

 

 

 

 

 

96

...2.55.... ... goods»...
2... 5:922»... .o 23...... ................o... .558... «22 m. a. 9...»...

 

 

 

 

 

 

 

 

 

5.... m m w m m n m
PLm_hp——b—»_—»-_.— .- ——-p-——.—-—r_p-—.
Joli-r4? A — -
Eng m.m c o m. vb mm mm 0S
—
1: mirg‘ 1 ‘41
o n
.. . .
.n
. »
Ravage. 4.5.8.»...
mo:

 

 

 

 

o
“M...
.o

 

 

 

 

...... S» .. .2825. ... ....ou...2»....

...... 55222:. ... 22...... .. ... 8.2.3.... .. 822.... .2322»... ... 2.5.2.... ..22 ... n». 9...»...

 

97

 

an: m
_

Lir— - b p p B

41.23..

 

 

 

 

m v

— b p p p _ — p p h h — — h b p b b p p P — p .

LO
LO
[x

 

{an mh.m mm.m mo.m mo.m

—b_b-—»pp_—-b_h—th~—-._-_bbbp—up-P—-.-—.

 

 

 

 

 

 

 

 

CE

TE

98

 

 

 

 

 

O
SMe Benzene-d6 .
[I , > No reactron
. ~100°Cl60 min.
m-SMe-ACB,
Scheme 83

On the other hand, m-SMe-ACBS was found to be thermally more stable
than its regio isomer, m-SMe-ACBa. A solution of m-SMe-ACBs (and other

isomers) in benzene-d5 was placed in boiling water bath for 60 minutes. 1H NMR
showed that m-SMe—ACBS remained unchanged.

 

 

 

m-OMe-Me3-pBA m-OMe-Me3-ACB,

 

 

 

Scheme 84

Irradiation of m-OMe-Me3-pBA (0.29 gm in 150 ml of dry benzene) was
carried out using a Pyrex-filtered light (2.2 290 nm) under argon atmosphere. The

reaction progress was monitored by 1H NMR. After 15 hours irradiation, solvent

99

was removed under vacuum. 1H NMR analysis showed the formation of 4-acetyl-
6-methoxy-8-methyl-1 1-oxatricyclo[6.3 .0.01'4]undeca-2,5-diene (m-OMe—Me3-
ACBs) as the only product. Preparative TLC purification led to the isolation of
the photoproduct as 4-acetyl-6-methoxy-8-methyl-11-oxabicyclo[6.3.0]undeca-
1,3,5-triene (m-OMe-Me3-COTS)

The two products were identified by 1H NMR. m-OMe-Me3-ACBS has
three olefinic protons (benzene-d5): a doublet (J = 2.0 Hz) at 4.46 ppm (H5), a
doublet (J = 2.93 Hz) at 6.0 ppm (H2) and a doublet (J = 2.93 Hz) at 6.02 ppm
(H3). The fact that H5 appears at 4.46 (higher field than the other protons) is due
to its enol ether character. The 2.93 Hz coupling constant between H2 and H3 is
typical for cyclobutene olefinic protons. m-OMe-Me3-COT5 also has three
olefinic protons (CDCl3): a doublet (J = 6.2 Hz) at 5.24 ppm (H2), a broad singlet
at 5.36 ppm (H5) and a doublet (J = 6.2 Hz) at 6.98 ppm (H3).

 

 

 

MeO
Srlrca gel
>
Benzene- O
hv2290 nm 0
m-OMe-Me3-ACB, m-OMe-Mes-COT.

 

 

 

Scheme 85

A solution of m-OMe-Me3-COTS in benzene-d5 was purged with argon
and irradiated with Pyrex-filtered light. After one hour of irradiation at rOOm
temperature, 1H NMR showed the formation of m-OMe-Me3-ACBS at the
expense of m-OMe-Me3-COTS.

100

c.9385... ... .hOU»oZ-uEO.—: .... 22...... a ... 8.58..» «22 m. .... 9...»...—

 

 

 

 

 

 

o 1%.. m m v m m m m
r.h.;.9r_.b+.bprLl—_h..._...._..P._...PPF..._..F.r.L.P_....—[Ppbpr.—......TPL.
‘ ‘IIJ 'i 2:1-a 1‘ 1‘ 1 3".
N 1g
n
o.m o6 md 96 ad ad

 

 

2......

 

 

 

1‘

£11.

 

 

€822.29...

  

 

 

 

100

ouéconcon E Haven—2-026.:— uo 235:. a .6 8.58% «22 I. 6— «...—«E

 

 

o 2%

_

m

m

V

m

m

m m

—..L._+.PP—-b~.__p..Fpr.—p..._hpk._.bbb_p..._..b._...-__.pr_p...—....__..._...b-.

JAJ

 

 

 

!

 

Tm

 

o.m

‘

 

1.1—114':

 

 

....cu.32.~20.a

 

 

 

 

 

 

101

The stereochemistry of m-OMe-Me3-ACBS was determined using nOe
experiment (benzene-d6, 15°C). hradiation of the methyl group at 0.70 ppm led
to the enhancement of the doublet at 6.0 ppm (3.82%) and the doublet at 6.02
ppm (0.90%). This indicates that the cyclobutene ring is syn to the methyl group
at the bridgehead carbon (C3).

 

 

 

 

O
O I w COOMe
O Benzene-d6

hv, 12. 290 nm H

COOMe ‘

O\/

1 l

m-Est-pBA m-Est-ACB, m-Est-LCB,

 

 

 

Scheme 86

Irradiation of m-Est-pBA in benzene-d5 was performed using Pyrex
filtered light. 1H NMR spectroscopy showed the formation of 4-acetyl-6-
methoxycarbonyl-l l-oxatricyclo[6.3 .O.O3'6]undeca-l ,4-diene (m-Est-LCBs,anti)
and 4-acetyl-6-methoxycarbonyl-ll-oxatn'cyclo[6.3.O.Ol'4]undeca-2,5-diene (m-
Est-ACBS) in a ratio of 1 : 1. These products were identified from their partial 1H
NMR spectra. m-Est-ACBS has three vinylic protons (benzene-d5): a doublet of
doublets (J = 2.65, 0.60 Hz) at 7.24 ppm (H5), a doublet of doublets (J = 2.8, 0.54
Hz) at 5.98 ppm (H2) and a doublet (J = 2.8 Hz) at 5.59 ppm (H3). H2 and H3

102

couple to each other with a J value of 2.8 Hz. H5 couples allylically to H7a and
H75 with a I value of 0.62 and 2.65 Hz. The 7.24 ppm chemical shift is due to
conjugation with the ester group. (compared to m-Amide-ACBS)

The other photoproduct, m-Est-LCBs,ami, has two vinylic protons
(benzene-d5): a singlet at 6.22 ppm (H5) and a doublet of doublets (J = 6.7, 2.4
Hz) at 5.38 ppm (H2). The 6.7 Hz coupling constant between H2 and H3 suggests
that H3 is anti to H3. AMI calculation showed that the dihedral angle H3-C3-C2-
H2 is 67.720 for the syn isomer and 33.340 for the anti isomer. Coupling
constants were calculated, using the Karplus equation, as 5.63 Hz for the anti and
0.92 Hz for the syn isomer. The stereochemisu'y was also confirmed by comparing

H2-H3 coupling constant with those of several syn and anti isomers (of. table 8).

 

 

 

 

 

MeOOC
COOMe .... mom
[.6 Benzene-ds
m-Est-ACB, m-Est-LCme m-Est-COT,
Scheme 87

Treatment of m-Est-LCBsfinti/m-Est-ACBS mixture with catalytic amount
of p-toluenesulfonic acid led to the formation of 4-acetyl-6-methoxycarbonyl-11-
oxabicyclo[6.3.0]undeca-l3.5-triene (m-Est-COTS). Product was identified by its
partial 1H NMR spectrum (which was found to be similar to that of m-CN-COTS).

103

It has three vinylic protons (benzene-d6): a singlet at 8.1 ppm (H5), a doublet (J =
8.8 Hz) at 6.87 ppm (H3), and a doublet of doublets (J = 8.8, 2.0 Hz) at 5.46 ppm

(Hz)-

 

 

 

— o
0 o] Methanol-d4 7’ [I CF3
hv, 12290 nm
0

c1=3

m-CF3-pBA m-CF3-ACB,

 

 

 

Scheme 88

A methanol-d5 solution of m-CF3-pBA in an NMR tube was irradiated
using Pyrex-filtered light (A 2 290 n.m.). After 80 minutes of irradiation, 1H NMR

showed the formation of 4-acetyl-6-trifluromethyl-l l-oxatricyclo[6.3.0.01'4]-
undeca-2,5-diene (m-CF3-ACBS). This product was identified from its partial 1H
NMR spectrum. It has three olefinic protons: a doublet (J = 2.96 Hz) at 6.49 ppm
(Hz), a multiplet at 6.46 ppm (H5) and a doublet (J = 2.96 Hz) at 6.33 ppm (H3).
The 2.96 Hz coupling constant is due to coupling between H2 and H3.

104

 

 

— O
o CF3
Benzene-d6
+
) ()0 hv,}.2290nm ’ [.6
O

CF3 Warm

 

2 3 1

m-CF3-pBA m-CF3-ACB, m-CFs-LCan

 

 

 

Scheme 89

Irradiation of m-CF3-pBA was also done in benzene-d5 using Pyrex-
filtered light (A 2 290 nm). After 145 minutes, 1H NMR showed the formation of
m-CF3-ACBS and 4-acetyl-2-trifluoromethyl-ll-oxatricyclo[6.3.0.03'6]undeca-
1,4-diene (m-CF3-LCBa,anti) in a ratio of 2 : 1. It was identified by comparing its
1H NMR spectrum with those of m-SMe-Lcnmmi and m-tBu-Lcrimnfi (cf.
table 7). The high similarity between their coupling constants suggested that they
have the same stereochemistry (H3 is anti to H3).

The previous experiment was repeated at low temperature. The NMR tube
was placed in ice-water bath during irradiation. 1H NMR showed the formation

of m-CF3-ACBS with only traces amount of m-CF3-LCBa,anti.

105

 

 

 

O

O _

I Benzene-d6 ’ Gradual disappearance
O hv 2290 nm 0f starting material
OCH3

p-OMe-mBA

 

 

 

Scheme 90

Irradiation of OMe-m-AP (1.2 mg in 0.75 ml benzene-d6 in an NMR tube)
was performed using Pyrex filtered light (A 2 290 nm). 1H NMR analysis showed
the gradual disappearance of the starting material with the appearance of very
broad signals between 0.3 and 3.5 ppm. Starting material was consumed in about

4 hours.

 

 

S n /
Benzene-d6 O 0
’ ... +
hv 2290 nm

 

 

p-Thio-AP

 

 

 

Scheme 91

106

p-Thio-AP was irradiated in benzene-d6 in an NMR tube for 30 minutes
using Pyrex-filtered light (7. 2 290 nm). 1H NMR showed the formation of three
products: 3-(4-acetylphenyl)- tetrahydrothiophene, 4-acetylstyrene and 4-acetyl-
a—methylstyrene.

Irradiation of p-Thio-AP (0.62 gm in 200 ml of dry benzene, 9t. 2 290 nm)
was carried for three hours under argon atmosphere. After preparative TLC
separation, 1H NMR analysis showed the isolated products to be 4-acetylstyrene;
4-acetyl-a-methylstyrene and 3-(4-acetylphenyl)tetrahydrothiophene. 4-
Acetylstyrene and 4—acetyl-a-methylstyrene were not separated from each other.
1H NMR was taken for the mixture while mass spectra and hi-resolution mass
spectra were aided by GC. isolation.

Mass spectrum showed that 4-acetylstyrene has molecular ion peak of
146. High resolution mass spectra suggested the molecular formula is C10H100.
1H NMR spectra (CDC13) showed the presence of three olefinic protons: a
doublet of doublets (J = 10.82, 0.66 Hz) at 5.38 ppm, a doublet of doublets (J =
17.45, 0.66 Hz) at 5.88 ppm and a doublet of doublets (J = 17.45,10.82 Hz) at
6.74 ppm. This part of the spectrum suggested the presence of a monosubstituted
ethylene part in the molecule. Also, a doublet (J = 8.17 Hz, 2H) at 7.47 ppm and a
doublet (J = 8.17 Hz, 2H) at 7.91 ppm suggested that the molecule has para-
disubstituted benzene unit. A singlet (3H) at 2.58 ppm along with the 7.91 ppm
chemical shift of two of the aromatic protons suggested that the acetyl group is
still intact.

4-Acetyl-a-methylstyrene was found to have molecular a formula of
C11H120 (High resolution Mass Spectrum). 1H NMR spectrum showed the
presence of two olefinic protons: a sixtet (J = 1.33 Hz) at 5.19 ppm and a doublet
of quartets (J = 1.33, 0.66 Hz) at 5.46 ppm. These two protons couple to the 0:-
methyl group at 2.16 ppm (dd, J = 1.33, 0.66 Hz).

107

Mass spectroscopy showed that 3-(4-acetylphenyl)-tetrahydro thiophene
has the same molecular ion peak as the starting ketone, p-Thio-AP. 1H NMR
spectroscopy showed signals corresponding to para-disubstituted benzene with
the acetyl group as the substituent. The rest of the spectrum shows the presence
of seven aliphatic protons. Homonuclear decoupling experiment showed that H3
couples to Hza, H25, mat and H43. The experiment also showed that H50: and H55
couple only to H401 and H43. All coupling constant were found to agree with the
proposed structure.

 

 

 

O -
Q ; Methanol d4 > No Reaction
.H hv, A2 290nm

p-NH-AP

 

 

 

Scheme 92

Irradiation of p-NH-AP (1.2 mg in 0.75 ml methanol-d4 in an NMR tube)
was performed using Pyrex filtered light. 1H NMR Showed no reaction even after

50 hours of irradiation.

108

 

 

O
0 j Methanol-d4 > [.6
\ hv, A2 290nm
Ac AC'
p-NAc-AP p-NAc—ACB

 

 

 

Scheme 93

p-NAc-AP (1.3 mg in 0.75 ml of methanol-d4) was irradiated using Pyrex
filtered light. 1H NMR Showed the formation of N—acetyl-4-acetyl-1 1-
azatlicyclo[6.3.0.01'4]undeca-2,5-diene (p-NAc-ACB) in low chemical yield. It
was identified from its partial 1H NMR spectrum. It has four olefinic protons: a
multiplet at 5.52 ppm, a multiplet at 5 .86 ppm, a doublet (J = 2.84 Hz) at 6.1 ppm
(H3) and a doublet (J = 2.84 Hz) at 6.37 ppm (H2).

 

 

 

O ]
M -

0 ethanol d4 b No Reaction
hv, X2290 nm

 

 

 

Scheme 94

109

p-Ac-TB-Me Was irradiated (1.1 mg in 0.75 ml methanol-d4 in NMR tube)
using Pyrex filtered light. 1H NMR showed no reaction even after 20 hours
irradiation.

 

H-—_.—_j
Q Benzene-d5 ’ ?

O hv 2290 nm
0

o-AC-TB-H

 

 

 

Scheme 95

o-Ac-TB-H was irradiated (1.1 mg in 0.75 ml benzene-d6 in NMR tube)
using Pyrex-filtered light. 1H NMR showed the disappearance of peaks

corresponding to starting material with the appearance of new peaks in both the
aliphatic and aromatic regions. Products formed may be a result of a hydrogen

abstraction.

110

 

 

 

O
CF3
0 0‘ 1

I Benzene-d6 9
> 10

F3C 0 hv, 7.2 290 nm 11
O
o-TFA-AP o—TFA-COT,

 

 

 

Scheme 96

A solution of o-TFA-AP (1.5 mg in 0.75 ml of benzene-d6 in an NMR
tube) was irradiated using pyrex-filtered light (7t 2 290 nm). After 15 minutes of
irradiation (~70% conversion), 1H NMR showed the formation of 6—a,0t,0t-
trifluoroacetyl—l1-oxabicyclo[6.3.0]undeca-1,3,5-triene (o-TFA-COTS). Large
scale irradiation (1.0 gm in 500 ml dry benzene) also gave o-TFA-COTS after
preparatory TLC purification.

1H NMR spectroscopy (chloroform-d) showed that o-TFA-COTS has four
olefinic protons: a doublet of doublets (J = 9.5, 1.95 Hz) at 5.46 ppm (H2), a
doublet of doublets (J = 13.25, 6.8 Hz) at 5.83 ppm (H4), a doublet of doublets (J
= 13.25, 9.50 Hz) at 6.64 ppm (H3) and a doublet (J = 6.8 Hz) at 7.29 ppm (H5).
This spectrum is very similar to that of the acetyl analog, 6-acetyl—1 l-
oxabicyclo[6.3.0]undeca-l,3,5-triene in chloroform-d.86 1H NMR showed the
presence of four olefinic protons: a doublet of doublets (J = 8.8, 1.9 Hz) at 5.34
ppm (H2), a doublet of doublets (J = 13.0, 6.2 Hz) at 5.75 ppm (H4), a doublet of
doublets (J = 13.0, 8.80 Hz) at 6.06 ppm (H3) and a doublet (J = 6.2 Hz) at 7.13

will (H5).

111

 

   

o-PTFAc

 

 

 

Scheme 97

In an NMR tube, a solution of o-PTF Ac in benzene-d5 was irradiated
using Pyrex filtered light ( A 2 290 nm). After 35 minutes, 1H NMR showed the
complete disappearance of starting material with the formation of two new
compounds: Z- and E-3-hydroxy-3-trifluoromethyl-2—vinyl-2,3-dihydro-
benzofuran (Z-BTHF1 and E-BTHF1) in a ratio of 9 : 1 (by NMR integration of
the two doublets of triplets at 5.23 and 5.28 ppm and by GC analysis).
Preparatory scale irradiation led to the isolation of Z-BTHF1 in pure form.

 

 

 

 

 

 

Scheme 98

112

cute—Bacon E
2.9:... cc 8:2an 2. Basso ...—End o5 ...—End 2.. 2:22 a .o 5.58% «22 E s. 9...»...—

 

 

zaa m m w m m s

. p c p _ Ptblb - _ p p p P._ . . . . P._lh . . b p . . b _ .tb » . _ . . . . _ . . . p _ L b . b _ p p . p h . . . b —

 

l

J... - It 1 ..-.lat -

 

 

o6. zaq «.m m.m m.m Tm m.m m.m 5m m.m m.m ob «.m

...._L».___..._...-.b.._...._....—.-.p_.phb_..b.—.~..—.-.._..Ph_.._.b...b__..b—.pbhhh...bhp..—_.~.P.-.__...p....bP

NwN

 

 

 

Qp

 

22.2..
\/\ O

\ 58mg .2.

Q Adam o

 

E

 

 

 

 

6522.8 .8 36:8. .3 332—8 madam—Exq‘eutucficon 5 35:...
2o 832E .3 Basso ...—End. 23 ...—:53 2o 2255 a ea 5.58% .522 z. ”a. 8:»...—

 

113

 

ran a m m w m m m m

_V-_.—.h_._~_5Lpbp...L-V—T.P.PpcpP—...pPFp.-—r.p._....—.-~—...._p..._.rrr_

1" lJ‘II 4 qll 7'!

9m m.m «in m.m oh o.m

 

_pp-p_......t.—b.ppgppp._p»-P~.p._p»prb.+p_...b.7._.—..-._...._ P

«J

9N

 

n. I
\
~ cat

5 ...:

 

 

E—Etfl NhEfltN «SP—Lie
3: nu: c
2: t‘ o . m
.o A E.— RNNK 2-
. a nw.._..._z.....s..a o

 

 

.mu

 

 

 

 

114

Z-BTHF1 was found to have 1H NMR spectrum similar to that of 3-
phenyl-2-vinyl-2,3-dihydro-3-benzofuranol (Ph-BTHF) obtained by photolysis
of o-allyloxy benzophenone in benzene-d5.94 Partial spectrum of Z-BTHFl
shows a doublet of triplets (J = 6.58 and 1.24 Hz) at 4.99 ppm (H2), doublet of
triplets (J = 10.7 and 1.34 Hz) at 5.02 ppm (H14). doublet of triplets (J = 17.28 and
1.44 Hz) at 5 .23 ppm (H13), doublet of doublets of doublets (J = 17.27, 10.69 and
6.58 Hz) at 5.59 ppm (H12) and doublet of triplets (J = 8.23 and 0.72 Hz) at 6.71
ppm (H7) whereas Ph-BTHF has doublet of doublets of doublets (J = 6.3, 1.2 and
1.4 Hz) at 4.85 ppm (H2), doublet of doublets of doublets (J = 10.7, 1.9 and 1.2
Hz) at 5.13 ppm (H14), doublet of doublets of doublets (J = 17.3, 2.0 and 1.4 Hz)
at 5.25 ppm (H13), doublet of doublets of doublets (J = 17.2, 10.8 and 6.3 Hz) at
6.02 ppm (H12) and doublet of triplets (J = 7.41 and 1.0 Hz) at 6.72 ppm (H7).

Previous work by Wagner and coworkers95 showed that ortho-alkoxy-
acetophenones react photochemically to give products with structures similar to
that of BTHFz as the major product and BTHF1 as the minor product. Although
Z-BTHF] structure is in agreement with the 1H NMR data, BTHFz is also
expected to show a similar spectrum.

 

 

Burr, BTHF,

 

 

 

Scheme 99

115

Differentiation between the two compounds was based on 13C NMR
spectrum. The chemical shifts were calculated for two model compounds: 0-
methoxy benzylalcohol and o-xylene-or,a'-diol. Calculation was based on
assuming a chemical shift of 128.5 ppm for unsubstituted benzene, then adding or
subtracting a constant that correspond to the type of substituent and its position
in the benzene ring.96 The observed chemical shift was found to match those of
oemethoxy benzyl alcohol (cf. Table 6). This suggested that Z-BTHFl is the
product formed.

Table 6: 13C NMR chemical shifts (ppm) for Z-BTHF1 and BTHFz

 

[Z'BTHFI
Calculated C

    

 

   
 

     

Calculated Observed

 

 

 

 

 

 

 

 

 

 

 

4 128.1 3 125.7 125.02
5 119.4 4 125.7 121.72
6 128.1 5 125.7 125.02
7 112.7 6 125.7 110.94
8 158.5 7 139.4 160.08
9 126.4 8 139.4 123.38

 

 

116

 

CF3

0 Benzene-dGIPy-ds
hv, A2 290 nm
0M

 

 

o-PTFAc 1.2 ; 1

 

 

 

Scheme 100

In order to increase the yield of the minor product, irradiation was
performed in presence of pyridine. Thus, two drops of pyridine-d5 was added to a
solution of o-PTFAc in benzene-d6 and irradiated using Pyrex filtered light. 1H
NMR showed the formation of Z-BTHF] and E-BTHF1 with a ratio of 1.2 : 1
(1H NMR integration). It was noticed that pyridine acted as a shift reagent since
almost all of signals were shifted from their positions in the absence of pyridine. In
order to resolve the spectra of the two isomers, solvent was removed under
vacuum and the NMR was taken again in benzene-d5, also the 1H NMR spectra
of isolated Z-BTHF] was taken in the same mixture of benzene-ddpyridine-ds

 

H2 F F

JP H
H§ o‘ 4.: H

.° .OH H s,
H H

Z-BTHFI

 

 

 

 

Scheme 101

117

The two isomers were found to have almost the same chemical shifts and
coupling constants for most of their protons. The major difference was in the
coupling constants for H2 and H12. For Z-BTHF], H2 is doublet of triplets with a
J value of 6.58 and 1.24 Hz; H12 is doublet of doublets of doublets (J = 17.27,
10.69 and 6.58 Hz). For E-BTHF]; H2 is a doublet of sixtets (J = 7.26 and 1.26
Hz) whereas H12 is doublet of doublets of doublets of sixtets (J = 17.2, 10.34,
7.35 and 2.38 Hz). In case of E-BTHF1 H2 has an extra coupling which is
attributed to the long range W-coupling with the fluorine atoms. The anti
configuration between H2 and the CF3 group allowed the W-configuration to
occur. This configuration cannot occur for the Z-isomer. The extra coupling for
H12 is due to through-space interaction between H12 and the CF3 group (Scheme
101). Again the E-configuration allowed H12 to be close to the CF3 group. This
type of coupling is reported in other systems (Scheme 102).97

 

' 0.0

v v
0.5 Hz 8.3 Hz

 

 

 

Scheme 102

118

 

 

 

 

 

Scheme 103

BTHF] was found to be relatively stable to weak acids since it did not
dehydrate on silica gel column. Also a sample of the compound in chloroform-d
was treated with two drops of trifluoroacetic acid. 1H NMR analysis showed no
reaction. When two drops of trifluoromethane sulfonic acid were added, 1H NMR
showed the disappearance of BTHF1 with the formation of its dehydration

product ; 3-trifluoromethyl-2-vinyl—benzofuran.

119

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

      

 

 

 

 

 

 
 

 

 

 

 

 

  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

a .33 ... PS 3 33.: a 3.: ... 8L 2
:33 $31 33 3 .3 33 33333 83 :333 F3 c.3333 flip
3 .3 3.: E a 33 33333.: E 3. 33.: E1333 3.: ELF
3o 33 S 33 o: 333
a .33 .3EMM: a E 3333.: .313 33333.: Ella
33 .8: 33.3.: 33 33.: 83 3o: 33 .8:
3:33.: Pr 33:33:16: 3 3 33.: E 32:33.: 3: .E3: 8.: F
a 33.: a Na: 8 3.: a 83 a 33 3
333333: 8: 3.833: 3.1:. mm. .33. _ 3.3 33.33.: Vt. 333%: of P
_.c.c.__.Pm_lE 133:3: 3% 33:33: E 33:. 3: 33 3333.: EL
5233 E .3 33 32 33 33 ...: .3
. v. 33 .333 E 33.83 33 . . . a3 3 3 3331Elel
m: 83 is: . 33.: 83 m
. S33 3
I-

 

 

 

£00 .353

emu .3: .35 "x

 

 

 

 

120

Table 8: 12,3 Coupling Constants for Some LCBs

lEomEound IJ;2(Hz) lRef. lComEound [122011) lRef. I
a 5,7 2.24

i134 55 W— 85
I, ’3
fizfip iiii‘p

 

 

 

 

 

 

 

 

 

 

B n

5.53 85 a 7—23 _85
B I! g B H

g 5.86 28 0—H “—2.24 W

a 4.V— 34 67‘ T—
“ffiiho Em

NC a a
I! n
0 a E 6 5 T1118 0 a 6 7 Thls

“vc ' work use ‘> ' work
a B

 

 

 

 

 

 

 

 

121

E . ISI 1'

a-Conformational Analysis

Photoproduct structures were optimized at the semi-empirical level (AM).
From the dihedral angles, vicinal coupling constants were calculated by the
Karplus equation. The best geometry and dihedral angles of various

photoproducts and their coupling constants are shown in the following pages.

Table 9: Coupling Constants of m-Amide-COTS

 

15
v)

Figure 19: Best Geometry of m-Amide-COTS

 

 

 

 

 

 

 

 

 

 

Atoms dihedral angle 0 J(calc) J (exp)
H23-C2-C3-H19 -50.235 3.18 §.51
1120,0708-sz -169.681 0.9? 7.9
Hn-Cng-sz ~54.586 2.55 0.0
sz-Cs-Cg-Hu 1037770 0.25.4 m
sz-Cg-Cg-st -16.651 7.5 11.6
Ww-Hz. 17797 7.41 57——
H24-C9-C10-H27 -108.183 0.63 2‘5—
H25-C9-C10-H26 138.050 4.95 102—'—
Hfi-Cg-Clo-Hy 15370 "773 8.15

 

 

 

 

 

 

 

 

123

 

Figure 20: Best Geometry of m-CN-COTS

Table 10: Coupling Constants of m-CN-COTs

 

 

Table 11: Coupling Constants of m-Me-COTS

Figure 21: Best Geometry of m-Me-COTS

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Atoms dihedral angle 4) J (calc) J (exp)
H17-C3-C3-H21 -51.513 2.99 8.2
ng-Cs-Cg-Hzo -1 69.696 9.0 9.5 8
H19-C5-C6-Hzo -54.584 fir—“T54
T{_20-C6-C9-H22 1042-03 0.27 6.6
fitters-(39-1123 -162‘09 734 9.0—‘—
sz-Cg-Clo-Hu 16.197 7T4 6.6
H22-C9-C1o-H25 -1 (m (T73 IF—‘
H23-C9-C10-H24 156—TM 4.7 77—_—‘
133-€91,30st 10793—5 7'89 8.64

 

 

 

 

 

 

 

 

125

 

Figure 22: Best Geometry of m-Amide-ACBS

Table 12: Coupling Constants of m-Amide-ACBS

 

 

 

 

 

 

 

 

 

 

 

Atoms dihedral angle (1) J(calc) J (exp)
H19-C7-C3-H21 -164.816 8.55 5.7
H20-C7-C3-H21 47.918 Trio——
H21-C3-C9-H22 4.2713 7.8 ll.9__—
W-Hzg; TM 634 6r—
Wmnu 134.300 4.34 9.9
sz-Cg-Clo-st 9.669 7.95 8.8
H23-C9-C10—H7A 14.61: 7.66 6r—
H23-C9-C1o-H25 410316 0.81 7.54

 

 

 

 

 

 

126

 

Figure 23: Best Geometry of m-Me-ACBS

Table 13: Coupling Constants of m-Me-ACBs

 

 

 

 

 

 

 

 

 

 

 

Atoms dihecFaI angle 9 J (alc) J (exp)
H19-C3-C9-H21 108.751 0.7 6.7
Hzo-Cg-Clo-sz 137.668 59? 6fi—_—1
Wm—Hfi 7:798 8_.-04 8—8_—- ‘
Hzl-Cg-Clo-sz 17.794 T87 6. 8
H21-C9-C10-H23 411.976 1.03—— 7.88

 

 

 

 

 

 

127

 

Figure 24: Best Geometry of m-OMe-CHDa

Table 14: Coupling Constants of m-OMe-CHDa

 

128

 

Figure 25: Best Geometry of m—CN-LCBs,anti

Table 15: Coupling Constants of m-CN-LCBs,anti

 

 

 

 

 

 

 

 

 

 

 

 

 

Atoms dihedral angle 0 J (calc) J (exp)
ng-Cz-C3-H17 30.753 5.98 6.5 ,
H21-C9-C10-H19 -132.951 4.11 11.7
sz-Cg-Clo-ng 47.908 778 5.67——
H21-C9-C10-H20 m 8.05 8 ET—
H22-C9-C10-H20 117.3% 1.08 0.8
H23-C3-C9-H21 139.746 5.73 11.11
W412; 19.176 7.28 7.9
H24-C7-Cg-H23 469W sfi 11.9
H25-C7-C3-H23 -51.559 f 98 5 .T—

 

 

 

 

 

 

128

 

'3

Figure 25 : Best Geometry of m-CN-LCBs,anti

Table 15: Coupling Constants of m-CN-LCBs,anti

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Atoms dihedral angle 0 J(calc) J (exp)
H13-C2-C3-H17 30.753 5.98 6.5
1121394310.ng 437.951 4.11 11.7——
sz-Cg-Clo-ng - 13.908 .778 5 67—— ‘
H21-C9-C10—H20 7337 8.05 8 .6?—
H22-C9-C10-H20 117.385 1.08 0.8
Wg-Hzl 139.746 513 11.11
Wg-Hfl 19.fi6 7.28 7.9
H24-C7-C3-H23 - 16974—7 8 . 817 1 1 .9
H25-C7-C3-H23 -51 .559 2.98 5 .T—

 

 

 

 

 

 

129

V 4 ‘ ’1
. Cl ‘-
i 9

[o

\o

39‘

1

Figure 26: Best Geometry of m-CN-LCBsgyn (Not Formed)

Table 16: Coupling Constants of m-CN-LCBs,syn

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Atoms dihedral angle (1: J(calc) J (exp)
H17-C3-C2-H13 68.360 0.85 6.5
ng-Clo-Cg-H21 -1 15.139 1.4 0. 8
H19-C10-C9-H22 4.9fi 8.1 W—9
fizo-Clo-Cg—Hzl W ’7—9 11.7___
W933 130—273 3—.7——_fl_7—_
WEE-H23 -18.653 7.3 11.11
H22-C9-C3-H23 -1 39.085 5.1
23-C3-C7-H24 563-20 24 .

H23-C3-G—H25 177.553 9.1 l 1.9———

 

 

 

 

 

 

130

 

 

 

 

 

 

 

 

 

1280 .13,
“’- u, v
3
14'}
I “ :9
1 0|
1 .3- s
Figure 27: Best Geometry of m-Me-LCBsmfi
Table 17: Coupling Constants of m-Me-LCBsfinti
Atoms dihedral angle 4’ J(calc) J(exp)
H15-C3-C2-H17 32_.285 5.8 6.35
ng-Clo-Cg-Hzo 47.859 7.4 8. 7
ng-Clo-Cg-Hzl -13_'§8.1 4 4R 5._55 ‘
H19-C10-C9-H20 1(T—7 .475 6.5 0.8
‘ Hw-Elo-Eg-Hzl -12.797 7.78 8.8

 

 

 

 

 

 

131

in F
q. in
5‘ a 0i '1
. {a 3 £19
’ 5‘ ’1 a I:
. Ir @-
1 .16:
‘2) 1'

Figure 28: Best Geometry of m-Me-LCBs,syn (Not Formed)

Table 18: Coupling Constants of m-Me-LCBs,syn

 

 

 

 

 

 

 

Atoms dihedral angle 4) J(calc) ] (exp)

H17- 2-C3-H16 69.205 0.77 6.35
Hzo-Cg-Clo-ng 6.706 8.1 8-7——
Hzl-Cg-Clo-ng -1 14.676 IIT—_ W—
Hzo-Cg-Clo-ng 181—.3—56 3733—— '5—55—
Wlo-ng 11I17 WT—

 

 

 

 

 

 

132

 

Figure 29: Best Geometry of m-SMe-LCBafiyn (Not Formed)

Table 19: Coupling Constants of m-SMe-LCBa,syn

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Atoms dihedral angle 11) J(calc) J(exp)
H17-C3- 6'Hl9 1.096 8.2 4.1
H32-C9-C10-H24 -115.251 1.44 1.0
H31-C9-C10-H24 4E6 E4 8.5-'—
H32-C9-C10-H23 9.933 7E5 5.6
meg 130.634 3.73 11.8——
sz-Cg-Cg-H32 -18 .802 7-37— -7. 8
‘Wg-Hgl 439.356 m 116?“—
W332; 56.313 2.32 5.16 '
Hgo-C-I-Cg-sz W6 9.1 11.76-—
filo—Cyter] -§9. 849 6 .09 1.6
H19-C6-C7-H20 448.101 6.55 5.97——
‘ 13- 5- -H19 69%? 0.77% 1.35—— ‘

 

 

 

 

 

 

 

133

2'9
1: 23
L
y.
3‘9
g 1
l '3 {'2
8.».
a
. ['
1- 23 91

Figure 30: Best Geometry of m-SMe-LCBamti

Table 20: Coupling Constants of m-SMe-LCBafinti

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Atoms dihedral angle 6 J(calc) J (exp)
H17-C3-C5-H25 -0J._'_726_- 8 .2 4 . 3
—_—H20-C9-C10-H13 428.874 3.46 11.8—
Wm-ng 8'8? 8.0 5.62
fio-cg-Clo-ng 37731 8.16 85—"—
H21-C9-C10-H19 116f96 1.5? 1.6—‘—
22-C3-C9-Hzo 13'9‘741 EZT 11.63—
H22-C3-C9-H21 1 9.828 W m—
erg-le 469.7728 8T5 11.71——
Wm .51695 2.937 5.16
25-C6-C7-H23 45.659 4.1 6:11——
H25-C6-C7-H24 578367 0.35 l .6
W413 69.721?) of 1T

 

 

Figure 31: Best Geometry of m-Me-o-LCBs,anti

Table 21: Coupling Constants of m-Me-o-LCB

 

 

 

 

 

 

 

 

 

 

 

 

Atoms dihedral angle 6 J(calc) J(exp)
H16-C3-C4-H25 67.638 0.91} 0.88 ,
H19-C9-C10-H17 -129.758 3.59 11.65
mam ©7527 WW—
Wlo-ng -5629 8.12 8.4
Hzo-Cg-Clo-ng 114.6% 1.35 1.6
H21-C3-C9-H19 140.900 5.42 113?—
H21-C3-C9-H20 W624 T2 7.6
H22-C7-C3-H21 469.485 8.88 11.87—
Wg-Hzl 52792 2. 3T“—

 

 

 

 

 

 

 

135

b-Rotational Barriers

Semi-empirical calculations were carried to provide an idea of the
rotational barriers around the C--O bond of the excited triplet states of the
substituted alkenoxyacetophenones. Thus, various meta substituted para-
ethoxyacetophenones were used as model compounds. The calculations were
done using the semi-empirical level (AMI) and by using unrestricted Hartree-
Fock (UHF) treatment.

136

 

 

 

 

 

5-acetyl-2-ethoxy benzamide

Table 22: Calculated rotational barrier around C—OEt bond for S-acetyl-Z-ethoxy
benzamide excited triplet state.

A 6 I AG(kcal/mol) I
0.0 0.0

90 4.0
180 6.0

 

 

 

 

 

 

 

137

 

 

 

 

 

3—cyano—4-ethoxyacetophenone

Table 23: Calculated rotational banier around C—OEt bond for 3-cyano-4-ethoxy-
acetophenone excited triplet state.

I 6 I AG(kcal/mol) I

0.0 0.0
90 ' 4.0
180 4.0

 

 

 

 

 

 

138

 

 

 

 

 

- 4—ethoxy 3-methylacetophenone

Table 24: Calculated rotational barrier around C—OEt bond for 4-ethoxy 3-methyl-
acetophenone excited triplet state.

I e I AG(kcal/mol) I

0.0 0.0
90 3.8
180 6.0

 

 

 

 

 

 

 

139

 

 

 

 

 

3-t—butyl-4—ethoxyacetophenone

Table 25: Calculated rotational barrier around C—OBt bond for 3-t-buty1-4-ethoxy-
acetophenone excited triplet state.

I e IAG(kcal/mol) I

0.0 0.0
90 3.7
180 7.6

 

 

 

 

 

 

 

140

 

 

 

 

4—ethoxy-3-methoxyacetophenone

Table 26: Calculated rotational barrier around C—OEt bond for 4-ethoxy-3-methoxy-
acetophenone excited triplet state.

I 6 I AG(kcal/mol) I

0.0 0.0
90 3.0
180 0.55

 

 

 

 

 

 

 

141

 

6:0.0

 

 

 

4—ethoxy-3-mercaptomethylacetophenone

Table 27 : Calculated rotational barrier around C-OEt bond for 4—ethoxy-3-
mercaptomethylacetophenone excited triplet state.

0 AG(kcal/mol) I

0.0 0.0
90 2.15
180 0.75

 

 

 

 

 

 

 

142

 

 

 

 

4-ethoxy-3-isopropyl-5-methylacetophenone

Table 28: Calculated rotational barrier around C—OEt bond for 4-ethoxy-3-isopropyl-5-
methylacetophenone excited triplet state.

I 9 I AG(kcal/mol) I
0.0 4.3

 

 

 

 

75 0.0
90 1.1
110 0.4

 

 

 

 

180 7.0

 

143

c-Heats of Formation

The heat of formation of some photoproducts and proposed intermediates
were calculated using the semi-emperical level (AMI). Results are presented in
table.29.

144

Table 29: Calculated Heat of Formations For Some Compounds.

 

 

 

 

 

 

Compound AHa Compound AHa Compound Alia
0 o
47.1 m -239 . 48.2
E Me [$1
Me 0 H
o
YOS -405 45.9 I a 49.0
0 I e
0 Me ® / ’
H
w" o
YEG‘> -244 m -20.8 -210
0 Me
0
o

 

 

0
Me 0
Ac
0 124 131 ° 215
eS Q/A @Me
Mes o H
(:8
m 46.2 -46.9 ”:3 -52.6
0 0
e0

 

0
Me
0
Me
Me
1“"
.5
M I
m”) 46.8 0% 45,2 0% -16.2
0 M SMe
Ac
0
01:39
Q9
Ac

0 o
-46.9 -49.1 -54.6
MeO It», MeO % OMe
H

 

 

 

 

 

 

 

 

145

 

 

 

Table 29 (cont'd)
MeO
-69.00 -3459 YO» -7270
o o
0 OMe 0 SMe 0
o
M o 0
-34.66 -34.86 -72.14
. o
MeS 0 MeO O
O MeO
-25.35 -67.80

 

 

 

 

 

 

 

a: kcal/mo]

 

DISCUSSION

B . ! I.“

The intramolecular [2+2] photocycloaddition of double bonds to meta
substituted para-alkenoxyacetophenones showed variable regioselectivity.
Generally, electron-withdrawing groups direct the double bonds to add towards
them while strong electron-donating groups reverse the selectivity and direct the
double bonds away (Scheme 104). The specificity induced by the electron-
withdrawing groups is not surprising, as it was observed that o-butenoxy-

13 30 and benzonitriles98 show complete

acetophenones, acetonaphthones,
selectivity. Surprisingly, alkyl groups which are moderately electron-donating
also produce high selectivity towards their direction (Scheme 104). This indicates

that there is a second major factor that determines regioselectivity.

 

O X I O X
4—4— ht) Q-IL —>-—>
RTO RT
X0 0

— X=CN, CONH2, COOMe,
X— OCH3, SCH3 CF3, CH3, t-Bll

 

 

 

Scheme 104

In order to understand the reason for this regioselectivity, each step of the

reaction mechanism must be analyzed. Both electronic and steric effects must also

146

147
be considered. Possible mechanisms for the subsequent thermal rearrangements

will be discussed.
Overall Mechanism

The general picture of the overall reaction mechanism is shown in (Scheme

105).

 

X

Y \> Y \> O Y?»
O \
00 h‘) ‘fi-@ 0
x X

Triplet Exciplex

Y
<— W
C6.
0
X
Biradical

Scheme 105

 

 

 

 

Triplet-State and Exciplex Formation

The first step of the reaction is proposed to be exciplex formation between
the electron-donor double bond and the electron-rich benzene ring. The
approach of the double bond is affected by the charge distribution at the
benzene ring. Donor ring substituents (OMe and SMe) donate electrons to the
ring and cause the ring side close to the substituent to be electron richer relative

to the other side, on the other hand electron-withdrawing substituents (CN,

148

-CONH2, -COOMe and -CF3) have the opposite effect and cause their side of the
benzene ring to be more electron deficient than the other side (Scheme 106). The
overall results are consistent with the donor double bond avoiding electron-rich
sites on the benzene ring and being attracted to electron-deficient sites. This
picture is analogous to the one originally suggested to explain regioselectivity in
the photocycloaddition of enones to double bonds.56 However, recent studies
ruled out the importance of exciplexes in enone cycloadditions.99 On the other

hand, triplet decay kinetic studies support the postulated donor—acceptor

O, fl who

“‘0’ n \f‘ 0""
0

Scheme 106

 

 

 

 

behavior in our system.23 However, the change in rate constants is much smaller
than the variation in regioselectivity. Moreover, a methyl group promotes mostly
syn addition, even though it slows down the reaction. This means that there is
another factor that causes this selectivity.

One of these possible factors is steric interactions during exciplex
formation. The exciplex has the double bond and the benzene ring placed in

parallel planes and separated by 2.5~3.0 A. In the case of p-butenoxy-

149

acetophenone, this will result in the formation of two possible exciplexes. Excpl
has cyclohexane boat-like structure and is expected to have a higher energy than
Excp2 which has a chair-like structure (Scheme 107). These two structures are
similar to the transition states of the hexenyl radical cyclization proposed by
Beckwithloo and Houk.1°1

 

H o “1'
EH =f‘6.
\ / 9

 

 

 

O O
Excpl Excpz
Boat-like Chair-like

Scheme 107

When a substituent is placed ortho to the tether, four different exciplexes
could be formed. However, only the chair-like exciplexes, Excp3 and Excp4 will
be considered because of their lower energy (Scheme 108). Excp4 which leads to
anti photocycloaddition, suffers from serious nonbonded interactions between H1
and the substituent ortho to the tether whereas Excp3 which leads to the syn
addition has much less non bonded interactions. These interactions will always
favor the addition syn to the ring substituent. In case of electron-withdrawing

ring substituents, both electronic and steric effects favor the double bond

150

 

 

Excp3 Excp4

 

 

 

Scheme 108

addition syn to the substituent. Experimental results showed the specificity of the
reaction in such cases. With strong electron donating ring substituents (OMe,
SMe), the electronic effect favors double bond addition anti to the ring
substituent whereas the steric effect favors addition syn to the substituent.
Experimental results showed that the syn / anti product ratio was about 1 : 6
(OMe) and 1 : 8 (SMe). This shows that electronic the effect overcomes the steric
effect in these cases because of the strong electron-donating effect and relatively
small size of the methoxy and thiomethoxy groups.

Alkyl ring substituents act as weak electron-donating groups, as observed
by kinetics, but have a strong steric effect because of their relatively large size. At
room or lower temperatures, t—butyl or methyl groups ortho to the tether caused
the double bond to add towards them. These results show that large substituents
force the double bond to add syn to them. To confirm this observation, a
competitive experiment in which methyl and isopropyl groups were placed ortho
to the tether showed that the double bond adds syn to the isopropyl group.

151

 

 

 

0“5 - G I513“ 0,0 ‘— a
)2.“

Scheme 109

 

 

 

Steric interactions can also suppress the anti addition of m-OMe-pBA. A
methyl group on the internal double bond position completely reverses the
regioselectivity and promotes only syn addition product. This may be a result of
the non-bonded interactions between the ring methoxy group and the methyl
group on the double bond, which are created during the exciplex formation

(Scheme 109).

 

hv
MeO 366 nm
MeO 2C

 

R R: H, i-Pr

   

 

 

 

Scheme 110

152

This result is similar to those observed by Schultz and coworkers. They
found that the intramolecular photocycloaddition of cross-conjugated
cyclohexenone to double bonds is regoiselective depending on the substituents
on the dienone double bonds. A methoxy group on the C3 position of the
dienone forced the olefin to add to the unsubstituted double bond. When a chiral
center (isopropyl group) was placed on the butenyl side chain (Cz'), steric
interactions between the carbomethoxy and isopropyl groups was found to
direct [2+2] photocycloaddition to preferentially one of the two dienone double
bonds (Scheme 110).102

.Q .8 £324

153-2,6 Exc Z-2,6 Exc Z-1,3 Exc

 

hv

hv

a. ....Me

 

 

 

 

153

Selectivity is thought to be strongly influenced by steric interactions
during exciplex formation in meta photocycloaddition reaction. E-6-phenylhex-
2-ene was found to undergo meta photocycloaddition across the donor directing
group (IE-2,6 Exc). The Z-isomer does not exhibit the same regioselectivity due to
steric destabilization during the exciplex formation. Interestingly, meta-
cycloaddition is still observed but through the double bond addition to the arene
carbons 1 and 3 (Z-l,3 Exc) (Scheme 111)

Since 1t,1t* triplets have radical and cationic character on the benzene
ring,12 the oxygen of p-alkenoxyacetophenones stabilizes the excited triplet and
are partially conjugated with the benzene ring.12 AMI calculations for the triplet
excited state of various meta— substituted p-ethoxyacetophenones showed that in
the conformation with the lowest energy, the O—C bond of the side chain lies in
the plane of the benzene ring and anti to the meta-substituent (Anti-Triplet).
One indication of the participation of the oxygen is the existence of a barrier to

rotation around the O—C bond. For most meta substituents.

 

\l

Calculated energy, kcal/mo] a~

 

 

P
o

 

0.0° . 360°
Dihedral angle, 0

Figure 32: Dihedral drive for rotation around C—OEt bond for S-acetyl-Z-ethoxy
benzamide excited triplet state.

154

 

:F
{‘2

Calculated energy, keel/mo]

 

O

.0

 

 

0'00 Dihedral angle, 0 3600

Figure 33: Dihedral drive for rotation around C—OEt bond for 3-cyano-4-ethoxy-
acetophenone excited triplet state.

 

9‘
o

Calculated energy. kcal/mol

 

 

.0
o

 

0.0° 360°
Dihedral angle, 0

Figure 34: Dihedral drive for rotation around C—OEt bond for 4-ethoxy 3-methyl-
acetophenone excited triplet state.

155

 

10.45

Calculated energy, kcal/mo]

 

 

P
o

 

0.0° 360"
Dihedral angle, 0

Figure 35: Dihedral drive for rotation around C—OEt bond for 3-t-butyl-4—ethoxy-
acetophenone excited triplet state.

 

9’
:3

Calculated energy, kcal/moi

 

.°
C

 

 

0.0° 360"
Dihedral angle, 0

Figure 36: Dihedral drive for rotation around C—OEt bond for 4—ethoxy-3-methoxy-
acetophenone excited triplet state.

156

 

N
U)

kcal/moi 1"

Calculated energy,

 

 

S"
o

 

0.0° 360°
Dihedral angle. 0

Figure 37 : Dihedral drive for rotation around C—OEt bond for 4-ethoxy-3-
mercaptomethylacetophenone excited triplet state.

       

 

 

 

     

 

 

 

 

 

 

7.03 r g 2.78
'5 i 3 e
8 = = 8
I l
*1 i i a.
:8 l I is
8 : ' g
g 1 B
- s
| 8
8 : 8
I
0.0 i 0.0
00° 45° 135° 360° 45° 135°
Dihedral angle, 9 Dihedral angle, 0

Figure 38: Dihedral drive for rotation around C—OEt bond for 4-ethoxy-3-isopropyl—5-
methylacetophenone excited triplet state.

157

The barrier was calculated to be about 4 kcal/mol. The high energy
conformation of the triplet is reached when the O—C bond is orthogonal to the
plane of the benzene ring (Orthogonal-Triplet). Continuing rotation leads to a
higher energy conformation (Syn-Triplet) at which the O—C bond is in the
plane of the ring and syn to the meta-substituent. This conformation is about 4~8
kcal/mol higher than the Anti-Triplet for all substituents except methoxy and
thiomethoxy, for which are only 0.55 and 0.75 kcal/mol higher in energy (Scheme
112)

 

AAG=4~8kcallmol

‘--

 

AAG=~4 kcal/mo] Q 51 @

HO):—E

o
\9: -
M (Q) 0 '\/\\

 

 

 

O H." - X Syn-Triplet
Orthogonal-Triplet
X
Anti-Triplet
Scheme 112

This means that in most cases, the Anti-Triplet is the major contributor to
the triplet ketones. This should affect the pathway by which the side chain and
the double bond reach on top of the benzene ring to form the exciplex. However,
this may not be a key contributor to the observed regioselectivity. AMI

calculation showed that for 3-isopropyl-4-methoxy-5-methylacetophenone,,

158

the Orthogonal-Triplet is about 3.2 and 6.0 kcal/mol lower in energy than
Anti-Triplet and Syn-Triplet respectively (Scheme 113). In such a case the
double bond is free to add either way. Experimental results shows that the double
bond adds exclusively towards the isopropyl group.

 

AAG=6.0kcal/mol

 

H11

Syn-Triplet

 

Orthogonal-Triplet

 

 

 

Scheme 113

Radical Addition

Syn and anti exciplexes can either collapse to form syn and anti biradicals,
undergo reversible dissociation to the triplet state or undergo irreversible
radiationless decay to the ground state (Scheme 114). The efficient cis-trans
isomerization of the double bond observed by Wagner and Nahm demands high
efficiency for biradical formation.17 This means that radiationless decay may not

be a significant factor in regioselectivity.

159

 

 

 

 

 

 

Scheme 114

Following exciplex formation, the radical center para to the acetyl group
will add to the internal double bond position forming a 1,4 biradical. Theoretical
treatment of the hexenyl radical transition state predicted that the C—C bond
being formed has a bond distance of about 2.27 A and the angle between the
double bond plane and the incipient bond of about 108°.101 Applying these
results to our system suggested that the transition state for the radical addition
reaction is similar in structure to the exciplex with some minor differences; the
distance between the ring carbon and the internal double bond carbon becomes
about 2.27 A and the external double bond carbon moves away from the plane of

the benzene ring to reach the 1080 proposed angle of addition (Scheme 115).

160

These two differences together will push C1 of the side chain more towards the
ring and intensify the steric interactions between H1 of the side chain and the ring

substituent ortho to the tether.

 

 

 

 

 

 

Ac

 

 

 

Scheme 115

Closure of Biradicals

Once the biradicals are formed, they can either cyclize to the initial photo-
adduct or cleave back to the ground state of reactant. It is possible that kps at
kpa, but in order for the differential biradical partitioning to be totally responsible
for the observed regioselectivity kps>>kpa must hold, since there can be little
difference between the rate of the syn and anti biradical decays to the ground
state of the starting material. The two biradicals must have essentially the same
stability relative to starting material since in both cases the pentadienyl radical
moiety is conjugated to X in each mode of addition independent of the geometry
of the five-atom ring. Moreover, the syn and anti biradicals do not have similar
steric interactions as those observed during exciplex formation and radical

addition because the benzene ring carbon baring the tether becomes sp3 and the

161

tether oxygen atom as well as C1 of the tether move away from the plane of the

benzene ring leading to almost no interactions with the ring substituents.

 

 

 

 

 

 

 

 

 

 

 

Scheme 116

Another factor that may contribute to regioselectivity is the equilibrium
between the primary photoproduct, CHD, and its thermal rearrangement product,
COT. Our results showed that irradiation of m-OMe-CHDa led to the formation
of the corresponding starting ketone as the major product. Also, irradiation of an
equilibrium mixture of m-SMe-CHDa and m-SMe-COTa led to the formation of

the corresponding starting ketone as a minor product.

162

 

0
Cl ...
O
MeX O O MeX
X=S 66% X=S 33%
X=0 >95% X=O <5%

 

 

 

Scheme 117

It is also known from these and other studies that substituents alter the
cyclohexadiene-cyclooctatriene equilibrium.l9'2°'28 A methoxy group at C2

causes the equilibrium to shift towards m-OMe-CHDa. The thermal
rearrangement product, m-OMe-COTa, was not detected by 1H NMR in a sample
of m-OMe-CHDa, but a small amount could be detected by UV. However, after
large scale irradiation of m-OMe-pBA, 1H NMR showed the presence of m-OMe-
COT; as a result of a fast acid catalyzed opening of m-OMe—ACBa. After 24
hours, NMR showed the disappearance of peaks corresponding to m-OMe-
COT; with increasing the intensity of the OMe-CHDa peaks. This finding
supports the supposition of a slow equilibrium between the two isomers. A

thiomethoxy group at C2 was also found to shift the equilibrium towards m-SMe—
CHDa as 66% of the product.

163

 

O X X R
o
0 o

(5% >95%

R: H, x: CH3, OMe, SMe, t-Bu, CN, CONH2
R: CH3, x= OMe

 

 

 

Scheme 118

All substituents at C6 were found to shift the equilibrium towards the
cyclooctatriene component. For all the products studied that have a substituent
at C6, no cyclohexadiene was detected by N MR during irradiation of the starting
ketone. NMR of the isolated COT's showed no peaks corresponding to any
CHD. This indicates that in these cases the equilibrium favors the cyclooctatriene
which may be due to either the relief of steric interactions that exist in the
cyclohexadiene isomer or because of increased conjugation of substituents with
the double bonds in the cyclooctatriene.

Could these variations in equilibrium affect the regioselectivity? In the
case of m-OMe-pBA, it was shown that the equilibrium favors m-OMe-CHDa,
which was detected at the early stages of the reaction, Also the fact that
cyclohexadienes revert photochemically to starting ketone with high efficiency
gives an indication that this process will lower the efficiency of the anti
cyclization. However, for the other regioisomer, the equilibrium favors the
cyclooctatriene. m-OMe-CHDS was not detected at any point during irradiation
which indicates that it has very low concentration in the reaction medium, thus

has a little chance to revert photochemically to the starting ketone. If this process

164

were responsible for controlling the regioselectivity, it would be expected that
the syn isomer to be the major product. However experimental results showed a 6

: 1 ratio of anti to syn cycloaddition products at all reaction stages.

I IEEfiIClll'I'B'lI"I

Temperature was found to have great effect on the regioselectivity of the
cycloaddition. Upon irradiation at room temperature, m-Me-pBA gave m-Me-

ACB; as the only product, favoring the addition syn to the ring substituent.

However when the irradiation was performed above room temperature,

regioselectivity was reversed and m-Me-ACBS and m-Me-LCBa,anti were

obtained in a ratio of 1 :2

O R
hv
?/ A>RT
O

 

 

 

 

 

R=‘Bu, CH3, CF3 ACB, LCBmu
not formed at room
or lower temperatures
Scheme 119

Similar results were obtained for m-tBu-pBA, since m-tBu-ACBS was

formed at room temperature, whereas at higher temperature a mixture of m-tBu-
ACB; and m-tBu-LCBa,anti was obtained in a ratio of 1 : 10, favoring the

addition anti to the t-butyl group.

165

It should be noted that the observed ratios do not reflect the true change
in selectivity. Irradiation of both m-Me-pBA and m-tBu-pBA at either 0°C or
55°C was monitored by NMR with an internal standard. Material balance
decreased with more irradiation, which means that either one or all the products
decompose by irradiation. Heating a sample of m-tBu-ACBS at 95°C for 40
minutes did not change it concentration, as shown by NMR. For m-tBu-pBA at
55°C m-tBu-LCBa,ami accounted for 20% of the products at about 38%
conversion, whereas m-tBu-ACBs accounted for 2.2%. This leaves about 16%
unaccounted for. Similarly, m-Me-pBA at 35% conversion gave 7.3% of m-Me-
ACB; and 14% of m-Me-LCBafinfi which leaves 14% unaccounted for.

The trifluoromethyl group has a similar effect. At room temperature m-CF3-
ACB; was obtained favoring the addition syn to the substituent whereas at
higher temperature m-CF3-LCBa,ami was obtained as a minor product besides
m-CFg-ACBS in a ratio of 1 : 2.

The above results show that increasing the temperature leads to the
appearance of the other regioisomer. It may be formed at low temperature in a
concentration too low to be detected by NMR. The rate of formation of the anti
isomer is more susceptible to temperature change because of its higher activation

energy.

Wm

Thermal ring opening of cis-cyclobutene to all cis-cyclooctatriene was
proposed to proceed via a stepwise mechanism. A concerted thermal ring opening
would produce cis-trans-cis-cyclooctatriene, which was never observed. It is clear
from both these and previous studies that rates for thermal opening of

cyclobutene to cycloocatatriene vary significantly with str'ucture.19'20'28 With

166

carbon anchors the rates are much slower than with oxygen anchors. Moreover,
electron-withdrawing substituents at C6 of the cyclobutenes were found to

facilitate the ring opening. Also, the reaction was found to be fast in

O {6}? +OH
X X ‘

tlfi —“"~ E" -* MC
0 O O

OH OH
X X +
-» ._. ._., o
/ 0
+0 0

 

 

 

 

 

 

 

Scheme 120

methanol and slow in benzene. Catalytic amount of p-toluenesulfonic acid added
to the cyclobutene solution in benzene greatly enhanced the reaction and caused
the ring to open in seconds. Based on these observations, it is suggested that the
reaction is acid catalyzed. A proton from the medium will protonate the acetyl
group forming a carbocation, followed by heterolytic cleavage of the C1—C4
bond . In the transition state, the developing negative charge on C4 will be
stabilized by the carbocation as well as by any electron withdrawing substituent
at C6. The developing carbocation at C1 will be stabilized by the a-oxygen atom.

167

 

 

 

 

O O
I W
-—>
CH3OH
MeO
0
Scheme 121

Chapman and Pasto103

reported a similar isomerization. They found that 5-
methoxybicyclo[3.2.0]heptane-2-one opens rapidly in acid solution to give

cycloheptane-l ,4-dione (Scheme 121).

B . lSI l l"| [£019 1' I'

Results from this and previous studies showed that substituted 4-(3-buten-
1-oxy)acetophenones cyclize photochemically and yield the corresponding
angular cyclobutenes, ACB, as the final productsl7'18'l9’20'28. m-Est-pBA and m-
CN-pBA are exceptions, since they give a mixture of the corresponding angular

(ACB) and linear (LCB) cyclobutenes.

168

 

 

 

 

O
O
X X
“-0 4‘ >
_ e 0
o I O
)0 O hv hv LCB
x o 0 Only if x: CN, COOMe
.. 0 m6
0
0
COT
Scheme 122

AMl calculations on the excited singlet state of various 6-substituted-4-
acetyl-11-oxabicyclo[6.3.0]undeca-1,3,5-trienes were carried out. Results showed
that for X: CH3, t-Bu and CONH2, C1 and C3 are positively charged whereas C2,
C4, C5 and C6 are negatively charged with C4 carrying most of the charge. This
suggests that cyclooctatriene ring closure to cyclobutene is likely to occur
between C1 and C4. On the other hand, when X: CN and COOMe, charge
distribution showed that ring closure is likely to occur between C1 and C4 to give
ACB and between C3 and C6 to give LCB. Although the calculations agrees
with experimental results, there may be other factors such as steric effects that

also contribute to the observed selectivity

 

 

 

 

Table 30 : Charge Distribution for the Excited Singlet State of Some COT's

I l X=CH3 I X=t-Bu |X=CONH2| X=COOMe| X=CN| X=OMe I X=SMe I

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

C1 +0.35 +0.36 +0.33 +0.34 +0.34 +0.29 +0.33
fl -0. 14 -0.14 -0.1 -0.13 -O. l 3 +0.05 -0.23
C3 +0.29 +0.29 +0.01 +0.3 +0.3 +0.3 +0.34
C4 -0.67 067 -O.42 ~0.54 -0.54 -0.68 -0.68
CS -0.1 l -0.12 -0.06 -0.06 -0.07 -0.1 l --0.11
C5 -0. l7 -0. 16 -0.27 -0.35 -0.27 -0.22 -0.22
C12 +0.2 +0.2 +0.2 +0.22 +0.22 +0.2 +0.2
011 -0. 12 -0.12 -0.08 -0.11 -0.1 -0. 14 -0.14
013 -0.44 -0.44 -0.4 -0.37 -0.37 -0.43 -0.43

 

 

Irradiation of m-Me-pBA, m-tBu-pBA, and m-CF3-pBA in warm benzene
led to the formation of the corresponding linear cyclobutene. The reaction
presumably involves the formation of the angular cyclobutene as the final
photoproduct, which rearranges thermally to the linear cyclobutene. Similar
rearrangement was observed in the case of m-SMe-ACBa and m-OMe-ACBa.
They were found to rearrange thermally to m-SMe-LCBafimti and m-OMe-
LCBa,anti.

170

 

AC

hv / A A
Ac
Benzenex 3 Benzene
O" , Ac

0v?

 

 

x= Me, t-Bu, CF3, SMe, OMe

 

 

 

Scheme 123

Results from this and previous studies showed that substituted
cyclooctatrienes cyclize photochemically stereoselectivelly to the angular
cyclobutene with the bridgehead substituent syn to the cyclobutene ring. The
disrotatory ring closure occurs only in one direction. The reason for this

stereospecificity is not well understood at this moment.

 

 

Ac 0

 

 

 

 

Scheme 124

171

Derivatives of 4-acetyl-ll-oxatricyclo[6.3.0.01'4]undeca-2,5-diene, ACB,
were found to be unstable in acidic media and rearrange to their corresponding
cyclooctatrienes. In the absence of acids, the syn addition products ACBs were
found to be relatively stable. However, warming the anti addition product
derivatives ACBa led to the formation of 4-acetyl-l1-oxatricyclo[6.3.0.03'6]-

undeca-l ,4-diene derivatives, LCBmfi (Scheme 125).

 

 

Ac “‘ H H x"
H\ =- 3”
£33 I”
I:~:’
“ I"; ~“s O
X o’ .5 59’ H i
. ,’ x ‘\
ACB, Notformed
Us; Noreaction
Benzene
ACBs

 

 

 

Scheme 125

Alehashem87 found that similar systems rearrange after heating in toluene
and give the corresponding linear cyclobutene derivatives but with the
cyclobutene ring syn to the five membered ring. They suggested that the reaction
occurred via an antara-antara Cope rearrangement, a process which is thermally

allowed and explains the product stereochemistry (Scheme 126).

172

 

H R'

  
  
  

 

 

 

R' b 5
... 100°C
0» ;{ toluene R C X
'fi fi/ 3
2.5 hrs
R3C O H
R=F, H
X=C, 0
Scheme 126

Applying the Cope rearrangement mechanism to the thermal
transformations observed in this work leads to products having the cyclobutene
ring syn to the five-membered ring. The actual stereochemistry of the products is
anti, i.e. the cyclobutene ring is anti to the five-membered ring (Scheme 127). This

indicates that the rearrangement occurs by a different mechanism.

 

 

Not observed

 

 

 

Scheme 127

An alternative mechanism involves the formation of the corresponding cis-
trans-cis-cyclooctatriene which then closes to the final product. This mechanism
is similar to the one used by Baldwin for a similar transformation.81 In our system,
the angular cyclobutene AC B can open thermally in a symmetry allowed
conrotatory process (route a) to give cis,trans,cis-cyclooctatriene at which the

C3—C4 bond is orthogonal to the C7—C3 bond (Orthogonal-c,t,c-COT). Route

173

b is impossible because of the very high strain of the resulting product. By
rotation around C2—C3 and C4—Cs bonds (route c), Orthogonal-c,t,c-COT can
interconvert to another cyclooctatriene in which the C3—C4 bond is parallel to
the C7—C3 bond (Parallel-qtfi-COT) (Scheme 128). AM] calculations showed
that Orthogonal-c,t,c-COT is about 2-3 kcal/mo] more stable than Parallel-que-
COT, which means that Parallel-c,t,c-COT contributes less than 4% to an
equilibrium mixture of the two isomers. On the other hand, the activation energy
of this transformation is very high because it requires the molecule to be flat with
H3 pointing inside the ring. This will dramatically increase strain energy and steric

interactions during the transformation.

 

   

ACB Orthogonal-c,t,c-COT

 

 

Parallel-c,t,c-COT

 

 

 

Scheme 128

174

The initially formed Orthogonal-c,t,c-COT can either close to the linear
cyclobutene, LCBa,ami (route a), close to the linear cyclobutene, LCBa,syn
(route b), revert to ACB, or interconvert to parallel-c,t,c-COT (Scheme 129).
AM] calculations showed that Orthogonal-c,t,c-COT and LCBganti have very

similar geometries and only a slight conrotatory rotation around C3—C4 and
C5—C5 bonds of COT (route a) is required to form LCBa,ami through a

symmetry allowed process. This implies that this step is fast with a relatively small

activation energy.

 

 

 

 

 

Parallel-c,t,c-COT LCB.m (not formed)

 

 

 

Scheme 129

175

On the other hand, AMI calculations showed that Orthogonal-c,t,c-COT

and LCBa,syn have different geometries and a > 270° conrotatory rotation

around C3—C4 and C5—C6 bonds of COT (route b) is required to form

LCBafiyn. The least motion principle2 suggests that route a predominates over
route b. Moreover, route a is suggested to be much faster than interconversion to

parallel-c,t,c-COT. This means that Orthogonal-c,t,c-COT can either form
LCBmti or revert to ACB. AMI calculations showed that LCB's are 4-7

kcal/mo] more stable than their corresponding ACB's, which means that

LCBafimi will predominate over the formation of other products if the whole

system is in equilibrium.

176

Attempts to isomerize tBu--LCBa,anti to the corresponding

cyclooctatriene using catalytic amount of para toluenesulfonic acid led to the

formation of an equilibrium mixture of tBu-LCBMmfi and tBu-LCB'Mmti.

 

 

 

 

 

Scheme 130

The isomerization proceeded via protonation of C2 to form an a-alkoxy
tertiary carbocation at C1. Deprotonation of H3 led to the formation of tBu-
LCB'a,anti whereas deprotonation of H2 led to reversion to starting material.
Similarly, treatment of tBu-LCB'manti with acid led to the formation of the same
equilibrium mixture of the two cyclobutenes. Once more, the same carbocation is
formed giving the same product ratio. The stereospecifity observed in both

rearrangements may be attributed to facial selectivity during the protonation step.

177

W

Irradiation of m-Me-pBA at 3. 2 290 led to the formation of m-Me-ACBS
at the early stages of the reaction. Prolonged irradiation led to the formation of a
new product which is proposed to be either di-n-ml or di-n-mz. When
irradiation was performed at I. 2 334, where m-Me-ACBS is not expected to

absorb, no dim-methane product was observed.

vinylcyclopropane
[- rearrangement ’

m-Me—ACB di-n-ml

 

 

 

 

 

 

Scheme 131

The mechanism of the reaction involves bonding between C3 and C5 of m-
Me-ACBS to form a cyclopropane ring and two radical centers at C2 and C5.
Homolytic cleavage of the C3—C4 bond lead to the formation of a double bond
between C2 and C3 and a 1,3 biradical at C4 and C5 which gives di-n—ml upon
closure. The specificity in cleaving C3—C4 bond instead of C4—Cs is driven by
the relief of the four membered ring strain. di-rt-ml can undergo vinyl-
cyclopropane rearrangement leading to the formation of di-tt—mz. The two

compounds are indistinguishable by NMR.

178

O 0 o O
o +§~§j+
o O

m-Me-ACB, di-n-ml

 

     

 

 

 

Scheme 132

/
q
Benzene ’ + +
hv 2290 nm
0 O O

p-Thio-AP

 

 

 

 

 

 

Scheme 133

The photochemistry of p-Thio-AP was investigated in order to check the
possibility of incorporating a sulfur atom in the polycyclic product systems.
Previous work showed that 4-thiomethoxyacetophenone has a lowest 1t,1t*
triplet with energy of 64 kcal/mol.12 So it was assumed that p-Thio-AP will react
similarly to its oxygen analog. Irradiation of the compound gave no cycloaddition
product. Instead, 4-acetylstyrene, 4-acetyl-a-methylstyrene and 3-(4-acetyl-
phenyl) tetrahydrothiophene were obtained.

179

The reaction mechanism is proposed to be similar to that of the oxygen
analog up to 1,4 biradical formation. The 1,4 biradical in the case of the oxygen
analog either couples to give the primary cycloaddition product or cleaves
efficiently to the starting ketone. In case of the biradical driven from p-thio-Ap,
C—S bond cleavage apparently is much faster than both the radical cyclization
and the C—C bond cleavage. The 1,5 sulfur biradical can either cyclize to give 3-
(4-acetyl-phenyl) tetrahydrothiophene or disproportionate to give the
corresponding thioaldehyde (Scheme 134).

 

q

Benzene
hv 2290 nm

p-Thio-AP

 

H3C

 

 

 

 

Scheme 134

180

The thioaldehyde is assumed to be excited either by direct irradiation or by
triplet energy transfer from the arylcarbonyl moiety. Following the excitation 7-
hydrogen abstraction will occur to give a 1,4 biradical which will undergo B-
cleavage and yield 4-acetylstyrene and an olefin. On the other hand, the excited

thion may also undergo a-cleavage followed by disproportionation to give 4-

acetyl-a-methylstyrene and thiofomaldehyde (Scheme 135)

 

H3

ESQ
o
m
3’
.5“
0'}
o
m
if.“
n:
o

SVH

H3 H3C H o

(Jr-cleavage dispropor-
—> . .
tronatron

 

W
O
O

 

 

 

 

H3C

H H
+

 

Scheme 135

 

181

 

 

0 o
>\ . 0 41’“ a.
'o
X

p-Ac-TB-Me Biradical

 

 

 

Scheme 136

Irradiation of o-Ac-TB-H gave no cycloaddition products, instead, it led to
the formation of other products presumably arising from hydrogen abstraction
reaction. On the other hand, p-Ac-TB-Me was photostable even after irradiation
for 48 hours at A 2 290 nm. The lack of reactivity is presumably due to a fast
efficient cleavage of the formed vinylic 1,4 biradical which may be due to the
high strain during the closure of the biradical.

 

 

 

o
O Q j Methanol-d4 _‘
\ hv,}t_>.290nm
Ac Ac-
p-NAc-AP p-NAc-ACB

 

 

 

Scheme 137

182

p-NH-AP was found to be photostable. It gave no products after
irradiation for 48 hours. However, its N-acetyl derivative, p-NAc-AP, underwent
photocycloaddition and gave p-NAc-ACB as a product. The lack of reactivity of
p-NH-AP presumably is due to charge transfer quenching of the triplet state by
the nitrogen. Introducing an N-acetyl group led to the involvement of the
nitrogen lone pair in bonding with the acetyl group, hence, it became unavailable

for quenching the reaction.

El l' Ellll I'll II

The photochemistry of o-allyloxy trifluoroacetophenone was studied in
order to see whether enhanced reactivity of the triplet might allow cycloaddition
with a shorter tether. Instead, no cycloaddition was observed and 5-hydrogen
abstraction occurred to provide Z- and E—3-hydroxy-3-trifluoromethyl-2-vinyl-
2,3-dihydro-benzofuran (Z-BTHF] and E-BTHF1) with a ratio of 9 : 1

 

 

CF Ho CF

3 3H

+ H
g
o H H
o
o-PTFAc z-BTHFl E-BTHF,
9 r

 

 

 

Scheme 138

183

This finding is very interesting since it shows that 1,5 biradicals derived
from o-alkoxy trifluoroacetophenones behave like their benzophenone analogs.
On the other hand, biradicals derived from similar acetophenones behave

differently.104

 

R
O} 0 $HH gz)’ @ O R'QH
[ j Ph 1“! @ ‘fi fast [jls'OH 6‘?!)

 

 

 

Scheme 139

Wagner explained the difference of behavior in terms of the rotational
barrier around the aryl group and benzylic radical center.104 This rotation is the
key step to reach the required conformation for five-membered ring formation
(Scheme 139). In case of acetophenones, this rotation will twist the benzylic
radical center out of conjugation. This restricted rotation allows the formation of
the spirocyclic compound which is the key step for other product formation. In
the benzophenone—derived biradicals, rotation required for the five-membered
ring formation is faster because the second phenyl ring can twist and thus

maintain full benzylic conjugation (Scheme 140)

184

 

 

 

 

R R H R H
J #6 R
o o 0 0H 0 0 CH3 0 ,OH
0
CH3 CH CH3
©/l hvi Q 3 slow won I
all?“
0 0H
Scheme 140

In case of the trifluoroacetyl derivative, the similar behavior to the
benzophenone derivative suggests that rotation around the benzyl bond is facile
in the intermediate biradical. This can be explained by the hypothesis that
fluorine hyperconjugation may enhance the charge separated resonance form of
the hydroxy radical center and minimize the benzylic conjugation that impedes

benzylic bond rotation (Scheme 141).

 

10H ton OH OH
M5263 stronger .ACF weaker CFs

Scheme 141

 

 

 

EXPERIMENTAL

W

All 1H NMR and 13c NMR spectra were obtained using a 300 MHz
Varian Gemini, a 300 MHz Varian VXR-3OO or a 500 MHz Varian VXR-SOO
instrument. All the IR spectra were recorded on a Nicolet 2R/42 Fourier
Transform IR spectrometer. UV spectra were recorded on a Shimadzu UV-160
spectrometer. Mass spectra were recorded on a Finigan 4000 GC/MS, Hewlett
Packard 5890 GC/MS trio-1 and a Joel JMS—HXIOO Mass spectrometer. Gas
chromatographic analysis were performed on Varian 1400 or 3400 machines with
flame ionization detector. Data were recorded on either a Hewlett-Packard
HP3392A, I-IP3393A or HP 3395A integrators. Three types of columns were used
for GC; Megabore DB1, Megabore DB210 and Megabore D8225. For column
chromatography, Mallinckrodt silica gel 60 (230 - 300 mesh) was used. For
preparative TLC, Analtech Uniplate silica gel plates of 20 X 20 cm, 1000 micron
were used. Melting points were recorded using Thomas Hoover Capillary Melting

Point Apparatus.
E 'fi |° [Ch . I

Benzene:105 3.5 L of reagent grade benzene was stirred with 0.5 L of
concentrated sulfuric acid for 24 hours. The benzene layer was separated and
extracted with 200 ml portions of concentrated sulfuric acid several times until
the sulfuric acid layer does not turn yellow. After separating the benzene, it was
washed with distilled water then with saturated sodium carbonate solution and

dried over anhydrous magnesium sulfate. It was then filtered into a 5 L round

185

186

bottomed flask, about 100 gm of phosphorous pentoxide was added and refluxed
overnight. Then benzene was distilled through a meter column packed with
stainless steel helices. The first and final 10% portions were discarded. (b.p.:78°C)

Methanol:106 100 ml of reagent grade absolute methanol, 5.0 gm of
magnesium tumings and 0.5 gm of iodine were placed in 2 L round bottomed
flask and refluxed until all magnesium reacted. Then 900 ml of methanol was
added and the mixture was refluxed for 30 minutes and distilled through a half
meter fractionating column ( b.p.: 65°C). The first and last 10% portions were
discarded.

I I'I'E I

0.01 -0.03 M solution of ketones in deuterated methanol or benzene was
placed in an NMR tube. The tube was stoppered with a rubber septum, then the
solution was purged with argon using a long needle. Then the top of the tube
was wrapped with Teflon tape to prevent the diffusion of air. Irradiations were
performed with medium pressure mercury are filtered through pyrex so as to cut
any wave length below 290 nm. In some cases wave lengths of 313, 365 or > 334
nm were used for irradiation. 1H NMR spectroscopy was used to follow the
reaction course. Generally 4-acetyl-1I-oxatricyclo[6.3.0.03'6]undeca-1,4-diene
(Linear Cyclo Butene, LCB) and/or 4-acetyl-1I-oxatricyclo[6.3.0.01'4]undeca-
2.5-diene (Angular Cyclo Butene, ACB) derivatives were the final photoproducts
if the NMR were taken immediately after irradiation.

Large scale irradiations were performed using ~0.3 gm of ketone in argon
bubbled methanol or benzene. Solutions were placed in container surrounding

the immersion well. Hanovia 450 W medium pressure lamp with a Pyrex filter tube

187

was used as a light source. Products were usually isolated by column

chromatography or preparative TLC using hexanes/ethyl acetate as eluent.

188

 

 

 

 

 

 

 

Br 1 9 5 °C
0 K2C03
on + % Br
DMF
o
83)!
4-Bromo-I-butene:

Caution: Hexamethylphosphoric triamide is highly toxic cancer suspect agent.
The experiment was done in the fume hood and all the waste was placed in
labeled containers and disposed of by qualified personnel.

The title compound was prepared according to the general procedure of
Kraus and Landgrebe for bromo-alkenes.107 Hexamethylphosphoric uiamide (150
ml) was added dropwise to stirred 1,4-dibromo butane (180.0 g, 100 ml, 0.83 mol)
at 195°C. The product was distilled off from the reaction mixture as soon as it is
formed and was collected into a dry ice-cooled rb flask. After the rate of product
formation decreased, reaction temperature was raised to 220°C for 5 minutes. The
product was redistilled at atmospheric pressure (found 94-950C, lit 99-1000C) to
give 58.5 g, (52%).

189

1H NMR (coon) (300 MHz): 5 2.6 (tq, J = 1.19, 6.9 Hz, 2H), 3.39 (t, J = 7.05
Hz, 2H), 5.11 (ddt, J = 10.43, 1.64, 1.16 Hz, 1H), 5.12 (dq, J = 17.0, 1.59 Hz, 1H),
5.78 (ddt, J = 10.31, 16.98, 6.66 Hz, 1H)

m-Amide-pBA:

4-Bromo—I-butene (2.25g, 0.017 mol) was added to a mixture of 5-acetyl
salycilamide (Aldrich) (3.0 g, 0.017 mol) and anhydrous potassium carbonate (3.0
g, 0.022 mol) in 30 ml of dry DMF. The mixture was stirred at 50°C for 5 days
under argon atmosphere, water was added and the product was extracted with
ethyl acetate. The organic layer was washed four times with 10% sodium
hydroxide solution and dried over anhydrous magnesium sulfate. The solvent
was evaporated using the rotary evaporator to afford 3.4 g of yellowish solid
which was crystallized from benzene to give 2.8 g of white crystals (mp: 112-
113°C), (72%).

1H NMR (CDCI3) (300 MHz): 5 2.59 (s, 3H), 2.65 (tq, J = 1.32, 6.3 Hz, 2H), 4.26
(t, J = 6.2 Hz, 2H), 5.17 (ddt, J = 9.92, 1.34, 1.38 Hz, 1H), 5.22 (dq, J = 17.21, 1.55
Hz, 1H), 5.88 (ddt, J = 17.1, 10.26, 6.72 Hz, 1H), 6.18 (broad, s, 1H), 7.02 (d, J =
8.8 Hz, 1H), 7.71 (broad, s, 1H), 8.10 (dd, J = 2.41, 8.73 Hz, 1H), 8.76 (d, J = 2.47
Hz, 1H)

13C NMR (CDCl3) (75 MHz): 8 26.37, 33.39, 68.34, 112.30, 118.18, 120.44,
130.50, 133.11, 133.74, 133.8, 160.45, 166.16, 196.4

IR (CI-ICI3): 3511, 3391, 3005, 1667, 1580, 1497, 1426, 1364, 1260, 1156 cm“1

190

MS (m/e): 233 (M+), 203, 188, 179, 162, 147, 129, 119, 107, 91, 79, 63, 55 (base),
43

Hi-Res MS: C13H15NO3, Calculated: 233.1052, Found 233.1056

 

 

o I Trifluoroacetic
Q o anhydride
Pyridine]
o dioxane

The amide group of m-Amide-pBA was dehydrated according to the

 

 

 

 

 

 

procedure of Campagna and coworkerslos, trifluroaceticanhydride (2ml, 0.014
mol) in 5 ml anhydrous dioxane was added to ice cooled suspension of 4-acetyl-
1-(3-buten-1-oxy) benzamide in anhydrous dioxane (15 ml) and anhydrous
pyridine (2.1 ml, 0.026 mol). The solution temperature was kept below 5°C
during the addition, then it was kept at room temperature overnight, water was
added and the product was extracted with ether. The organic layer was washed
with 10% HCl (2 X), water (I X) then with 10% sodium hydroxide solution (1 X)
and dried over anhydrous magnesium sulfate. Solvent was removed using rotary
evaporator and the product was purified using silica gel column (20% ethyl
acetate/hexanes), then crystallized from benzene/hexane to provide 2.0 g of

white crystals (mp: 53-54°C), (72%).

191

1H NMR (CDC13) (300 MHz): 8 2.54 (s, 3H), 2.62 (ddq, J = 1.31, 1.26, 6.73 Hz.
2H), 4.17 (t, J = 6.75 Hz, 2H), 5.13 (ddt, 1:10.23, 1.65,1.16 Hz, 1H), 5.19 (dq, J:
17.18, 1.56 Hz, 1H), 5.88 (ddt, J = 17.13, 10.27, 6.8 Hz, 1H), 7.00 (d, J = 8.76 Hz,
1H), 8.11 (dd, I: 8.61, 226 Hz, 1H), 8.14 (dd, J: 2.23, 0.58 Hz, 1H)

13C NMR (CDCI3) (75 MHz): 5 26.25, 33.07, 68.81, 102.34, 111.90, 115.36,
118.14, 130.13, 133.01, 134.58, 134.64, 16359, 194.80

IR (c1103): 3019,2240, 1684, 1500, 1360,1280,1139, 1124 cut-1

MS (m/e): 215 (M+), 214, 200, 187, 172, 146, 118, 101, 90, 77, 63, 55 (base), 43

Iii-Res MS: C13H13NO2, Calculated: 215.0946, Found 215.0945

 

01C
ca:

03 OH
CH; CH;
CH3COCI AlCl, 0
. —> _>
P)’ '1de Nitrobenzene
O

M/ 8:
190031 DMF

 

 

 

 

 

 

 

 

 

192

2-Methyl-phenylacetate:

Acetyl chloride (38 ml, 0.56 mol) was added dropwise to ice cooled
solution of o-cresol (50 ml, 0.49 mol) and pyridine (55 ml, 0.68 mol) in 100 ml of
dry benzene. The solution was stirred during the addition while temperature was
mentained below 20°C. The solution was left stirring at room temperature
overnight, water was added and the organic layer was isolated. The aqueous
layer was extracted twice with ether. The combined organic layers were washed
with 10% Her (2X), water, then with 10% sodium hydroxide solution. After
drying over anhydrous magnesium sulfate, the solvent was removed by the rotary
evaporator . Vacuum distillation (90°C/asp) gave 61 g (84.7%) of pure product.

1H NMR (CDCI3) (300 MHz): 5 2.17 (s, 3H), 2.3 (s, 3H), 6.98 (dd, J = 7.97, 1.65
Hz, 111), 7.1-7.3 (m, 3H)

4-Hydroxy-3-methylacetophenone:

Anhydrous aluminum chloride (10.0 g, 0.075 mol) was stirred in dry
nitrobenzene at 70°C under argon atmosphere until all the solid dissolved. The
solution was cooled to about 10°C and o-methyl-phenyl acetate (10.0 g, 0.067
mol) was added dropwise in such a rate that the temperature did not exceed
20°C. The mixture was left stirring at room temperature overnight. 10% HCI was
added, and the mixture was stirred for 10 minutes. The mixture was cooled and
extracted with ether. The product was extracted with 10% sodium hydroxide
solution several times (until the aqueous layer was colorless). The combined
aqueous layers were acidified with 10% HCl to give the free phenolic product
which was extracted into ethylacetate. The organic layer was washed with water
then with sodium bicarbonate solution, and dried over magnesium sulfate. The

solvent was removed using a rotary evaporator to give a yellowish solid which

193

was recrystallized from benzene then vacuum distilled (kugelrohr) to give 5.2 g
(52%) of pure product.

1H NMR (CDCI3) (300 MHz): 5 2.28 (s, 3H), 2.54 (s, 3H), 6.1 (broad, s, 1H), 6.83
(d, J = 8.24 Hz, 1H), 7.74 (dd, J = 8.24, 2.19 Hz, 1H), 7.77 (broad, m, 1H)

m-Me-pBA:

4-Bromo-l-butene (4 g, 0.03 mol) was added to a mixture of 4-hydroxy-3-
methylacetophenone (3.0 g, 0.02 mol) and anhydrous potassium carbonate (4.0 g,
0.029 mol) in 30 ml of dry DMF. The mixture was stirred at room temperature for
one week under an argon atmosphere, water was added, and the product was
extracted with diethyl’ ether. The organic layer was washed with 10% sodium
hydroxide solution 4 times and dried over anhydrous magnesium sulfate. The
solvent was evaporated using the rotary evaporator to afford 1.8 g of a yellowish
oil which was purified by vacuum distillation using a kugelrohr to give 1.3 g
(32%) of pure product.

1H NMR (CDCI3) (300 MHz): 5 2.22 (s, 3H), 2.52 (s, 3H), 2.56 (tq, J = 1.29, 6.6
Hz, 2H), 4.06 (t, J: 6.58 Hz, 2H), 5.01 (ddt, J = 10.2, 1.8, 1.13 Hz, 1H), 5.16 (dq, J
= 17.12, 1.6 Hz, 1H), 5.81 (ddt, J= 17.12, 10.29, 6.78 Hz, 1H), 6.8 (d, J: 8.24 Hz,
1H), 7.75 (d, J = 2.23 Hz, 1H), 7.78 (dd, J = 8.24, 2.23 Hz, 1H)

13C NMR (CDCI3) (75 MHz): 5 16.02, 26.08, 33.40, 67.14, 109.74, 117.05,
126.67, 128.25, 129.55, 130.67, 134.04, 160.87. 196.83

IR (each): 3009, 2928, 1671, 1601, 1503. 1360, 1265,1144, 1132, 1030 end-1

194

MS (m/e): 204 (M+), 189, 176, 161, 150. 135. 121, 107, 91 . 77, 55 (base), 43

Hi-Res MS: C13H1502, Calculated: 204.1150, Found 204.1138

 

 

 

 

 

- - - h JBIL-HBAIL
OB ' on 03
Bu" m9 311‘
CH3COCI AlCl,
’ >
Pyridine Nitrobenzene
0
MB:
>
choy DMF

 

 

 

 

 

Lt-Butylephenylacetate:

Acetyl chloride (27 ml, 0.40 mol) was added dropwise to ice cooled
solution of o-t-butyl phenol (50 ml, 0.34 mol) and pyridine (40.0 ml, 0.50 mol) in
100 ml of dry benzene. The reaction was carried on following the procedure of 2-
methyl-phenylacetate. Vacuum distillation (110°C/asp) gave 61 g (95%) of pure
product.

1H NMR (ouch) (300 MHz): 5 1.36 (s, 9H), 2.33 (s, 3H), 6.98 (dd, J = 1.74, 7.63
Hz, 1H), 7.15 (dt, J = 1.73, 7.49 Hz, 1H), 7.21 (dt, J = 1.9, 7.49 Hz, 1H), 7.38 (dd, J
= 7.66, 1.95 Hz, 1H)

195

3-t-Butyl-4-hydroxyphenol:

Anhydrous aluminum chloride (2.2 g, 0.017 mol) was stirred in 10 ml dry
nitrobenzene at 70°C under argon atmosphere until all the solid dissolved. The
solution was cooled to about 10°C and o-t-butyl-phenylacetate (2.6 g, 0.014
mol) was added dropwise in such a rate that the temperature did not exceed
20°C. The mixture was left stirring at room temperature overnight. It was worked
up in the same manner as 4-hydroxy-3-methylacetophenone. The resulting solid
was recrystallized from benzene/hexanes to give 1.0 g (38%) of white crystals,
mp: 167-170°C.

1H NMR (CDCI3) (300 MHz): 5 1.42 (s, 9H), 2.54 (s, 3H), 5.4 (s, broad, 1H), 6.72
(d, J = 8.27 Hz, 1H), 7.71 (dd, J = 8.27, 2.2 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H)

m-tBu-pBA:

4-Bromo-1-butene (3 .0 g, 0.022 mol) was added to a mixture of 3-t-butyl-
4-hydroxyacetophenone (1.90 g, 0.01 mol) and anhydrous potassium carbonate
(2.5 g, 0.018 mol) in 30 ml of dry DMF. The mixture was stirred at room
temperature for 4 days under an argon atmosphere, water was added and the
product was extracted with diethyl ether. The organic layer was washed with
10% sodium hydroxide solution 4 times and dried over anhydrous magnesium
sulfate. The solvent was evaporated using the rotary evaporator to afford a
yellowish oil which was purified by vacuum distillation using kugelrohr to give
0.6 g (24.7%) of pure product.

1H thR (CDCI3) (300 MHz): 5 1.41 (s, 9H), 2.56 (s, 3H), 2.64 (tq, J = 1.2, 6.59
Hz, 2H), 4.13 (t, J: 6.49 Hz, 2H), 5.15 (ddt, J = 10.2, 1.74, 1.19 Hz, 1H), 5.22 (dq, J

196

= 17.15, 1.16 Hz, 1H), 5.95 (ddt, J= 17.09, 10.29, 6.72 Hz, 1H), 6.88 (d, J: 8.61
Hz, 1H), 7.82 (dd, J = 2.35, 8.55 Hz, 1H), 7.96 (d, J = 2.23 Hz, 1H)

131: NMR (coon) (75 MHz): 5 26.28, 29.59, 33.74, 34.97, 67.48, 110.96,
117.45, 127.13, 128.62, 129.59. 134.41,138.05, 161.7,197.22

IR (ouch): 3005, 2961. 2873, 1672, 1595, 1468,1360, 1269, 1242, 1163, 1090,
1026 end-1

MS (m/e): 246 (M+), 231, 189,177, 161,149, 133, 115, 91, 77, 55 (base), 43

Hi-Res MS: C15l-I2202, Calculated: 246.1620, Found 246.1615

 

 

 

 

 

 

 

m: 03
1)NaN02/H3O*;‘\‘ CH3COCI
Q 2)sto4/A Pyridine
OB
“C's Q Ma”
’ >-
Nitrobenzene K2C03/ DMF
O

 

 

 

 

 

2-Isopropyl-6-methyl phenol:
2-Isopropyl-6-methyl aniline (Aldrich) (9.33 g, 0.063 mol ) was dissolved

in a mixture of 11 ml of concentrated sulfuric acid and 50 ml of water. The

197

solution was cooled to -5°C and diazotized by adding ice cooled solution of
sodium nitrite (4.44g, 0.064 mol) in 10 ml of water in such a rate that temperature
did not exceed 0°C (about 30 min.). The solution was left for 10 minutes at -5°C,
then added to a solution of 50 ml of concentrated sulfuric acid and 50 ml water.
Nitrogen gas started to evolve immediately and the solution was warmed to 50°C
and left for 30 minutes. The reaction mixture was steam distilled. The distillate was
extracted with diethyl ether. The organic layer was dried over magnesium sulfate
and solvent was removed to give 5.5 g of product which was vacuum distilled

(kugelrohr) or (109-111°C/asp) to give 5.36 g (60%) of the product.

1H NMR (CDCI3) (300 MHz): 5 1.24 (d, J = 6.87 Hz. 6H), 2.24 (s, 3H), 3.18
(septet, J = 6.87 Hz, 1H), 4.63 (s, broad, 1H), 6.82 (t, J = 7.63 Hz, 1H), 6.96 (d of
quintet, J = 7.43, 0.86 Hz, 1H), 7.05 (dt, J = 7.69, 0.82 Hz, 1H),.

2-Isopropyl-6-methyl-phenylacetate:

Acetyl chloride (3 .4 ml, 0.05 mol) was added dropwise to ice cooled
solution of 2-isopropyl-6-methyl phenol ( 5.0 g, 0.033 mol) and pyridine (5 .4 ml,
0.067 mol) in 50 ml of dry benzene. The reaction was carried on as in o-acetoxy

toluene. Vacuum distillation (123°C/asp) gave 5.83 g of pure product.

1H NMR (CDCl3): 5 1.19 (d, J = 7.07 Hz, 6H), 2.13 (s, 3H), 2.33 (s, 3H), 2.95
(septet, J = 7.07 Hz, 1H), 7.05 (ddd, J = 7.07, 1.76, 0.66 Hz, 1H), 7.11 (dd, J =
7.74, 7.07 Hz, 1H), 7.14 (dd, J = 7.73, 1.98 Hz, 1H),.

4-Hydroxy-S-Isopropyl-S-methylacetophenone:
Anhydrous aluminum chloride (2.0 g, 0.015 mol) was stirred in 10 ml dry

nitrobenzene at 70°C under argon atmosphere until all the solid dissolved. The

198

solution was cooled to about 10°C and 2-isopropyl-6-methyl acetoxy benzene
(2. g, 0.01 mol) was added dropwise at such a rate that the temperature did not
exceed 20°C. Then it was left stirring at room temperature for 6 days. The mixture
was worked up as with 4-hydroxy-3-methylacetophenone. The resulting solid
was recrystallized from benzene/hexanes to give 1.50 g (75%) of white crystals,
mp: 111- 112°C.

1H NMR (CDC13) (300 MHz): 5 1.37 (d, J = 6.85 Hz, 6H), 2.28 (s, 3H), 2.53 (s,
3H), 3.18 (septet, J = 6.85 Hz, 1H), 5.2 (broad, s, 1H), 7.61 (dd, J = 2.21, 0.88 Hz,
1H), 7.71 (d, J = 2.21 Hz, 1H)

m-Me-iPr-pBA:

4-Bromo-1-butene (2.0 g, 0.015 mol) was added to a mixture of 2-
isopropyl-6-methyl acetoxy benzene..(l.4 g, 0.0073 mol) and anhydrous
potassium carbonate (2.0g, 0.014 mol) in 30 ml of dry DMF. The mixture was
stirred at room temperature for 10 days under argon atmosphere. Then it was
worked up following the procedure of 4-(3-buten-1-oxy)-3-methylacetophenone
to give a yellowish oil which was purified by vacuum distillation using a

kugelrohr to give 0.9 g (50%) of the product.

1H NMR (CDClg) (300 MHz): 5 1.22 (d, J = 6.93 Hz, 6H), 2.31 (s, 3H), 2.54 (s,
3H), 2.57 (tq, J = 1.34, 6.69 Hz, 2H), 3.31 (septet, J = 6.89 Hz, 1H), 3.81 (t, J =
6.68 Hz, 2 H), 5.12 (ddt, I: 10.23, 1.8, 1.19 Hz, 1H), 5.18 (dq, I: 17.16, 1.7 Hz,
1H), 5.94 (ddt, J = 17.12, 10.29, 6.78 Hz, 1H), 7.61 (dd, J = 2.26, 0.76 Hz, 1H), 7.71
(d, 22 Hz, 1H)

M

H

5‘.

 

P)’

to]

We

ad.

MI

1186

199

13C NMR (CDCI3) (75 MHz): 5 16.74, 23.74, 26.50, 34.72, 72.59, 117.22,
124.83, 129.24, 131.21, 133.21, 134.41, 142.14, 159.04, 197.69

IR (CHC13): 3020, 2969, 2932. 2875. 1677, 1361, 1308, 1281, 1185 cm'1

MS (m/e): 246 (M4), 231, 191, 177, 161, 147, 129, 112, 91, 77, 70, 55 (base), 43

Iii-Res MS: C15H2202, Calculated: 246.1620, Found 246.1606

 

 

 

- -U’.l - -. ~.- -01 - -° so on - -!l‘! ._ ‘ 00 ‘t'!’ 1!.'U"'l-BL
Meg-113A);
OB
\ or:
>
K2CO,IDMF
O

 

 

 

 

 

2-Methyl-3-butenyl-I-tosylate:

2-Methyl-3-butene-l-ol (Aldrich) (1.0 g, 0.0116 mol) was dissolved in
pyridine (2 ml, 0.025 mol). The solution was cooled in ice bath and p-
toluenesulfonyl chloride (2.4 g, 0.0126 mol) was added in portions. After addition
was complete, the mixture was left at room temperature overnight. Water was
added and the solution was extracted with ether. The ether layer was washed
with dilute sulfuric acid then with 10% sodium hydroxide solution, dried over
magnesium sulfate and evaporated to give 2.1 g (92%) of the product which was
used in the next step without further purification.

an

CV

US

200

1H NMR (c0013) (300 MHz): 5 0.98 (d, J = 6.83 Hz, 3H), 2.43 (s, 3H), 2.49 (t of
septet, J = 1.16, 6.72 Hz, 1H), 3.82 (dd, J = 9.43, 6.87 Hz, 1H), 3.9 (dd, J = 9.40,
6.38 Hz, 1H), 5.01 (dt, J: 10.59, 1.31 Hz, 1H), 5.02 (dt, 1: 17.0, 1.38 Hz, 1H), 5.61
(ddd, J = 17.24, 10.69, 7.02 Hz, 1H), 7.32 (d, J = 8.20 Hz, 2H), 7.77 (d, J = 8.44
Hz, 2H)

m-Me-iPr-Mez-pBA:

2-Methyl-3-butenyl-1-tosylate (1.0 g, 0.0042 mol) was added to a mixture
of 4-hydroxy-3-isopropyl-5-methylacetophenone (0.8 g, 0.0042 mol) and
anhydrous potassium carbonate (1.00 g, 0.0072 mol) in 10 ml of dry DMF. The
mixture was stirred at room temperature for one week under an argon atmosphere,
water was added and the product was extracted with diethyl ether. The organic
layer was washed with 10% sodium hydroxide solution 4 times and dried over
anhydrous magnesium sulfate. The solvent was evaporated using the rotary
evaporator to afford yellowish oil which was purified by vacuum distillation

using a kugelrohr to give 0.58 g (46%) of the product.

1H NMR (CDCI3) (300 MHz): 5 1.19 (d, J = 6.81 Hz, 3H), 1.22 (d, J = 6.9 Hz, 6H),
2.33 (s, 3H), 2.54 (s, 3H), 2.7 (broad septet, J = 6.65 Hz, 1H), 3.3 (septet, J = 6.87
Hz, 1H), 3.6 (dd, J = 8.76, 6.56 Hz, 1H), 3.66 (dd, J = 8.76, 6.29 Hz, 1H), 5.09 (dt, J
= 10.32, 1.36 Hz, 1H), 5.15 (dt, J= 17.31, 1.52 Hz, 1H), 5.91 (ddd, J: 17.38, 10.38,
6.96 Hz, 1H), 7.60 (dd, J = 225, 0.71 Hz, 1H), 7.71 (d, J = 2.38 Hz, 111)

13C NMR (CDC13) (75 MHz): 5 16.40, 16.64. 23.60. 26.34. 26.39, 38.44. 77.43.
114.71, 124.72, 129.19, 131.10, 133.15, 140.28, 142.02, 158.93, 197.41

11

 

201

IR (CHCI3): 3009. 2967. 2930. 2872, 1676, 1597,1462, 1420, 1358, 1306, 1279,
1186, 1007, 920 cm‘1

MS (m/e): 260 (M+), 192, 177 (base), 161, 149, 129, 105, 91, 77, 69, 55, 43, 41

Hi-Res MS: C17H2402, Calculated: 260.1776, Found 260.1793

 

 

03

01C
0
CH! CH;
0 ’ >
160 C may DMF

2-Hydroxy-3-methylacetophenone:

 

 

 

 

 

 

 

2-Methyl-phenyl acetate (30.0 g, 0.20 mol) and anhydrous aluminum
chloride (30.0 g, 0.23 mol) were stirred together at 150°C under an argon
atmosphere for 2 hours after which the reaction mixture became a black solid.
After cooling, dilute HCl was added and the mixture was boiled until the solid
dissolved. The resulting solution was steam distilled. The distillate was extracted
with ether. The organic layer was dried over magnesium sulfate and the solvent
was removed using a rotary evaporator. The crude was vacuum distilled

(116°C/asp) to give 6.0 g (20%) of product.

1H NMR (CDCI3) (300 MHz): 5 2.24 (s, 3H), 2.61 (s, 3H), 6.79 (t, J = 7.68, Hz,
1H), 7.35 (d, J = 7.2 Hz, 1H), 7.6 (dd, 1: 7.96, 1.09 Hz, 1H), 12 55 (s, 1H)

M

3-11
no]
The
am
The
(1116
rota
colu

V 3C1

(s, 3
17.2.
111),

13c

127.

202

m-Me-oBA:

4-Bromo-1-butene (8.0 g, 0.06 mol) was added to a mixture of 2-hydroxy-
3-methylacetophenone (5.0 g, 0.033 mol), potassium t-butoxide (3.74 g, 0.033
mol) and anhydrous potassium carbonate (5.0 g, 0.036 mol) in 50 ml of dry DMF.
The mixture was stirred at room temperature for 8 days under an argon
atmosphere, water was added and the product was extracted with diethyl ether.
The organic layer was washed with 10% sodium hydroxide solution 4 times and
dried over anhydrous magnesium sulfate. The solvent was evaporated using the
rotary evaporator. The crude product was filtered through a short silica gel
column (prep TLC type, hexane). Solvent was evaporated and product was
vacuum distilled (kugelrohr) to give 1.5 g (22%) of product.

1H NMR (ouch) (300 MHz): 5 2.29 (s, 3H), 2.52 (tq, J = 1.33, 6.8 Hz, 2H), 2.60
(s, 3H), 3.81 (t, J = 6.75 Hz, 2H), 5.09 (ddt, J = 10.2, 1.8, 1.19 Hz, 1H), 5.15 (dq,
17.24, 1 1.62 Hz, 1H), 5.88 (ddt, I: 10.28, 17.15, 6.81 Hz, 1H), 7.04 (t, J = 7.58 Hz
1H), 7.29 (ddd, J = 7.45, 1.04, 0.67 Hz, 1H), 7.37 (ddd, J = 7.66, 0.65, 1.7 Hz, 1H)

13C NMR (CDCI3) (75 MHz): 5 16.13, 30.54, 34.58, 74.12, 117.28, 123.84,
127.18, 132.17, 133.94, 134.22, 134.66, 156.17, 201.50

IR (CHCI3): 3009, 2920, 1684, 1588, 1464, 1431, 1379. 1358, 1281, 1260, 990

cm'1

MS (m/e): 204 (M+), 189, 176, 163, 150, 136 (base), 129, 121, 105, 91, 77, 55, 43

Iii-Res MS: C13H15O2, Calculated: 204.1150, Found 204.1141

 

Ac
cor
C01

wa

30

7.9

5-1

5111

nit)

203

 

 

 

 

 

OH on 08
coon coon
AczO c°°n AlCl,
-———> 3»
HZS O4 Nitrobenzene
O
on
COOK.
Methanol M Br
H2804 K2C03l DMF

 

 

 

 

 

Acetyl salicylic acid (aspirin):1°9

Salicylic acid (30.0 g,0.22 mol), acetic anhydride (42 ml, 0.44 mol) and
concentrated sulfuric acid (15 drops) were stirred at 60°C for 30 minutes. After
cooling water was added, the formed precipitate was filtered, washed with cold
water and recrystallized from a mixture of 90 ml ethanol and 225 ml water to give
30.6 g (78.8%) of aspirin, mp: 137-139°C.

1H NMR (CDCI3) (300 MHz): 5 2.33 (s, 3H), 7.12 (dd, J = 1.09, 8.02 Hz, 1H),
7.34 (dt, J= 1.13, 7.75 Hz, 1H), 7.61 (dt, J = 1.67, 7.84 Hz, 1H), 8.1 (dd, J = 1.85,
7.94 Hz, 1H)

S-Acetyl-Z-hydroxy-benzoic acid
The title compound was prepared according to the procedure of
Shah.“°Anhydrous aluminum chloride (52.0 g, 0.39 mol) was stirred in dry

nitrobenzene at 70°C under an argon atmosphere until all the solid dissolved.

204

The solution was cooled to about 10°C and aspirin (15.0 g, 0.083 mol) was added
in portions a rate that the temperature did not exceed 20°C. The mixture was left
stirring at room temperature for 3 hours, 10% HCl was added, stirred for 20
minutes. Nitrobenzene was removed by steam distillation, the product was
collected by suction filtration and recrystallized from ethanol/water (40:60) to
give 7.7 g (51%) of white needles of the product (mp: 216-217°C)

1H NMR (CDCI3) (300 MHz): 5 1.63 (broad. s, 1H), 2.57 (s, 3H), 7.05 (d, J = 8.85
Hz, 1H), 8.13 (dd, J = 2.29, 8.91 Hz, 1H), 8.52 (d, J = 2.6 Hz, 111), 11.02 (s, 1H)

Methyl-(5-acetyl-2-hydroxy) benzoate:

5-Acetyl-2-hydroxy benzoic acid (7.0 g, 0.039 mol), methanol (80 ml) and
concentrated sulfuric acid (1.0 ml) were boiled for six hours. Solvent was
removed and the residue was dissolved in ethylacetate, washed with sodium
bicarbonate solution, and dried over magnesium sulfate. After removing the ethyl
acetate a yellow solid was left which was purified by passage through a short
column of basic alumina using ethyl acetate/hexanes as eluent to finally give 4.5
g of product which was further purified by vacuum distillation (kugelrohr) to give
4.3 g ( 61 %) of white solid, mp: 62-64°C

1H NMR (CDCI3) (300 MHz): 5 2.56 (s, 3H), 3.98 (s ,3H), 7.02 (d, J = 8.79 Hz,
1H), 8.07 (dd, J = 2.23, 8.79 Hz, 1H), 8.49 (d, J: 2.41 Hz, 1H), 11.22 (s, 1H)

m-Est-pBA

4-Bromo-1-butene (2.7 g, 0.02 mol) was added to a mixture of methyl-(5-
acetyl—2-hydroxy) benzoate (3.10 g, 0.016 mol) and anhydrous potassium
carbonate (2.80 g, 0.02 mol) in 30 ml of dry DMF. The mixture was stirred at room

205

temperature for 4 days. The reaction mixture was then worked up following the
procedure of 4-(3-buten-1-oxy)acetophenone to give an oil which was purified

by vacuum distillation using a kugelrohr to give 0.2 g (5%) of the product.

1H NMR (CDCI3) (300 MHz): 5 2.57 (s, 3H), 2.61 (qt, J = 6.81,1.17 Hz, 2H), 3.9
(s, 3H), 4.15 (t, J: 6.62 Hz, 2H), 5.13 (dq, J = 10.19, 1.13 Hz, 1H), 5.19 (dq, J=
17.22, 1.62 Hz, 1H), 5.93 (ddt, J: 10.29, 17.18, 6.77 Hz, 1H), 7.00 (d, I: 8.85 Hz,
1H), 8.08 (dd, J = 2.35, 8.79 Hz, 1H), 8.38 (d, J = 2.28 Hz, 1H),.

13c NMR (cnc13) (75 MHz): 5 26.17, 33.26, 51.96, 68.28, 112.47, 117.35
119.99,129.34,132.50, 133.44, 133.68, 161.71, 165.88, 195.87

IR (ouch): 3012, 2953, 1727, 1680, 1605, 1501,1439, 1362. 1271,1154, 1100,
1078 cm-1

MS (m/e): 248 (M"’), 217, 207, 194, 179, 162, 147, 119, 91, 79, 63, 55 (base), 45

Hi-Res MS: C14H15O4, Calculated: 248.1049, Found 248.1053

206

0 . . . . . . ...
3- '1- -l. -- 10011.13 .Hl 1H 11- -1-,

 

 

NZBF4 0H
CF13 CF3 CF13
HBF4 ClléNozh, 0
5 5
Br

 

 

MB? magma"

...» 1»on ..

choy 1) 2)AcCll-78 C
CF,

 

 

 

 

 

4-Bromo-2-(a,a,a—trifluoromethyl) benzene-diazonium tetrafluoroborate.
4-Bromo-a,a,a-trifluoro-o-toluidine was diazotized using a general
procedureln. Fluoroboric acid (48%, 30 ml) was added to 4-bromo-0t,a,or-
uifluoro-o-toluidine (2.4 g,0.01 mol) in 40 ml of water. The resulting solution was
cooled to 5°C and a solution of sodium nitrite (0.71 g, 0.01 mol) in water (2.5 ml)
was added dropwise. the solution was cooled to 0°C. The formed solid was
collected by filtration, washed with ice-cold 10% fluoroboric acid, ice-cold 2-

propanol, and ether to give about 3.0 g of wet product.

4-Bromo-0t,a,a-trifluoro-o-cresol:

The diazonium salt was hydrolyzed according to the general procedure of
Cohen and coworkersuzCopper nitrate (900 g, 4.8 mol) was dissolved in water
(600 ml) and the diazonium salt (~3.0 g) was added The solution was stirred until
all the salt dissolved. Cuprous oxide (0.60 g) was added and stirring was

continued for 3 hours (until solution showed negative azodye test). The solution

207

was extracted by ethyl acetate. The organic layer was washed with saturated
sodium chloride solution, dried over magnesium sulfate, and evaporated to give
~2.0 g of crude product which was vacuum distilled (kugelrohr) to give 1.73g
(72%) of the product, mp 83-84°C

1H NMR (CDC13) (300 MHz): 5 5.5 (q, J = 2.05 Hz, 1H), 6.84 (d, J = 8.28 Hz,
1H), 7.5 (dd, I: 1.95, 8.76 Hz, 1H), 7.6 (d, 1: 2.41 Hz, 110

S-Bromo-Z-(S-buten-l-oxy)-a,or,a-trifluorotoluene:

4-Bromo-l-butene (4 g, 0.03 mol) was added to a mixture of 4-bromo-
a,a,a-trifluoro—o-cresol( 1.5 g, 0.006 mol) and anhydrous potassium carbonate
(1.5 g, 0.011 mol) in 30 ml of dry DMF. The mixture was stirred at room
temperature for 10 days under argon atmosphere, water was added and the
product was extracted with diethyl ether. The organic layer was washed with
saturated potassium carbonate solution three times and dried over anhydrous
magnesium sulfate. The solvent was evaporated using the rotary evaporator to
afford 1.65 g of product which was purified by column chromatography (silica
gel 5% ethylacetate/hexanes). It was further purified by vacuum distillation using
kugelrohr to give 1.6 g (87%) of pure product.

1H NMR (CDCI3) (300 MHz): 5 2.55 (tq, J = 1.32, 6.68 Hz, 2H), 4.04 (t, J = 6.53
Hz, 2H), 5.10 (ddt, 1:10.19, 1.8, 1.16 Hz, 1H), 5.15 (dq, J: 1718, 1.56 Hz, 1H),
5.88 (ddt, J = 10.29, 17.12, 6.77 Hz, 1H), 6.84 (d, J = 6.79 Hz, 1H), 7.55 (dd, J =
8.82, 2.47 Hz, 1H), 7.65 (d, J = 2.48 Hz, 1H)

208

m-CF3-pBA

The title compound was prepared from the reaction of Gignard reagent
with acetyl chloride according to the general literature procedure in the
literature.113 Magnesium (0.25 g, 0.01 mol), and dry THF (5 ml) were placed in a
250 ml 3—necked rb. flask equipped with dropping funnel. 5~bromo-2-(3-buten-1-
oxy)-a,a,0t-t1ifluorotoluene (1.5 g, 0.005 mol) in dry THF (50 ml) was placed in
the dropping funnel and added to the magnesium dropwise. The reaction was
initiated by adding few drops of 1,2-dibromoethane, then by heating. After
addition was complete, the solution was boiled for 2 hours.

In another dry 250 ml 3-necked flask equipped with a dropping funnel
and a thermometer, freshly distilled acetyl chloride (1.0 ml, 0.015 mol), and dry
THF (15ml) were placed and cooled to -78°C. The Grignard reagent was
transferred to the dropping funnel using a canula, and was added dropwise to the
acetyl chloride with vigorous stirring while the temperature kept at —78°C. After
addition was complete the mixture was mentained at room temperature overnight.
The reaction was quenched with water and the product was extracted with ethyl
acetate which was then dried over magnesium sulfate, filtered, and evaporated to
give the crude product. The product was purified using a dry silica gel column
(5% ethyl acetate/ hexanes) to give 0.2 g (mp: 46-49°C), (15.4%) of product.

1H NMR (CDCI3) (300 MHz): 5 2.59 (s, 3H), 2.62 (tq, J = 1.25, 6.66 Hz, 2H), 4.18
(t, I: 6.56 Hz, 2H), 5.14 (ddt, J = 10.22, 1.68, 1.16 Hz, 1H), 5.20 (dq, J = 17.18,
1.55 Hz, 1H), 5.92 (ddt, J = 17.12, 10.25, 6.81 Hz, 1H), 7.04 (d, J: 8.79 Hz, 1H),
8.12 (dd, J: 2.04, 8.73 Hz, 1H), 8.2 (d, J: 1.92 Hz,1H)

13g
111‘)
195

 

MS

Hi-l

 

209

13C NMR (CDC13) (75 MHz): 5 2618, 33.20, 68.42, 112.19, 117.2, 118.86 (q. 31.6
Hz), 123.06 (q, 271.1 Hz), 127.86 (q. 5.2 Hz),129.30, 133.42, 133.80, 160.30,
195.59

MS (m/e): 258 (M"'), 230, 215, 204, 189, 169, 160, 144, 127, 113, 55 (base), 43

Hi-Res MS: C13H13F3O2, Calculated: 258.0868, Found 258.0860

 

 

 

 

4- - - - - - - M
OH
OCH OCH OCH3

CH COCI 3 AlCl3
Pyridine Nitrobenzene

Mm.

’
choy DMF

 

 

 

 

 

o-Acetoxyanisol (guaiacol acetate):

The title compound was prepared according to the procedure of
Mottern.“4Acetyl chloride (19.0 ml, 0.28 mol) was added dropwise to an ice
cooled solution of guaiacol (27.5 ml, 0.25 mol), and pyridine (27.0 ml, 0.34 mol) in
60 ml of dry benzene. The solution was stirred during the addition and the

temperature was kept below 20°C. The solution was stirred at room temperature

210

overnight before water was added and the organic layer was isolated. The
aqueous layer was extraCted twice with ether The combined organic layers were
washed with 10% BC] twice, water, then with 10% sodium hydroxide solution.
After drying over anhydrous magnesium sulfate, the solvent was removed by the
rotary evaporator . Vacuum distillation (129-131/ asp) gave 38.0 g (92%) of pure
product.

1H NMR (CDC13) (300 MHz): 5 2.3 (s, 3H), 3.82 (s, 3H), 6.9-6.97 (m, 2H), 7.02
(dd, J = 7.72, 1.66 Hz, 1H), 7.19 (ddd, J = 1.65, 8.25, 7.50 Hz, 1H)

4-Hydroxy-3-methoxyacetophenone (apocynin):

Anhydrous aluminum chloride (33.0 g, 0.25 mol) was stirred in dry
nitrobenzene (75 ml) at 70°C under an argon atmosphere until all the solid
dissolved. The solution was cooled to about 10°C and o—acetoxy anisol (20.0 g,
0.12 mol) was added dropwise in such a rate that the temperature did not exceed
20°C. The mixture was mentained at 80°C for 45 minutes and then stirred at
room temperature overnight. 10% BC] was then added, and the mixture was
stirred for 10 minutes. The mixture was cooled and extracted with ether. The
product was extracted with 10% sodium hydroxide solution several times (until
the aqueous layer was colorless). The combined aqueous layers were acidified
with 10% HCl to give the free phenolic product which was extracted with
ethylacetate. The organic layer was washed with water then with sodium
bicarbonate solution, and dried over magnesium sulfate. The solvent was removed
using a rotary evaporator to give a yellowish solid which was vacuum distilled

(170°C/asp) to give 8.7 g (43.5%) of the product.

211

1H NMR (CDCI3) (300 MHz): 5 2.56 (s, 3H), 3.95 (s, 3H), 6.12 (broad, s, 1 H),
6.95 (d, J = 8.62 Hz, 1H), 7.53 (dd, J = 1.99, 8.84 Hz, 1H), 7.53 (d, J = 1.76 Hz, 1H)

m-OMe-pBA:

4-BromO-l—butene (6.0 g, 0.04 mol) was added to a mixture of 4-hydroxy-
3-methoxyacetophenone (5 .0 g, 0.03 mol) and anhydrous potassium carbonate
(6.0 g, 0.044 mol) in 30 ml of dry DMF. The mixture was stirred at room
temperature for one week under an argon atmosphere, water was added and the
product was extracted with diethyl ether. The organic layer was washed with
10% sodium hydroxide solution four times and dried over anhydrous magnesium
sulfate. The solvent was evaporated using the rotary evaporator to afford

yellowish solid which was purified by vacuum distillation using a kugelrohr to

give 4.2g (64%) of white crystals, mp: 56-57°C.

1H NMR (CDCI3) (300 MHz): 5 2.57 (s, 3H), 2.64 (tq, I: 1.32, 6.96 Hz, 2H),
3.93 (s, 3H), 4.14 (t, J = 7.02 Hz, 2H), 5.14 (ddt, I: 10.19. 1.68, 1.25 Hz, 1H),
5.2(dq, J= 17.15, 1.58 Hz, 1H), 5.92 (ddt, J = 17.15, 10.28, 6.77 Hz, 1H), 6.8 (d, J
= 8.18 Hz, 1H), 7.53 (d, J = 1.92 Hz, 1H), 7.56 (dd, J = 8.18, 2.08 Hz, 1H),

13C NMR (CDCl3)(75 MHz): 5 26.06, 33.34, 55.93, 68.11, 110.18, 111.73,
117.17, 123.21. 130.26. 133.84. 148.11. 153.57. 196.61

[R (CHCI3): 3008, 2940, 1675, 1590. 1514, 1470, 1421, 1361, 1277, 1184, 1157,
1030 cm'1

MS (m/e): 220 (M+), 192, 166, 151, 123, 108, 91, 79, 65, 55 (base), 43

212

Hi-Res MS: C13H1503, Calculated: 220.1099, Found 220.1104

-U'_l -- ‘1--I.‘ --ll'.10.1.'.Hl'101' 11".U'U'l:6 '

 

 

OH

 

O
b 0
may DMF

O OCH,

 

 

 

 

4-Bromo-2-methyl-1-butene (1.70 g, 0.011 mol) was added to a mixture of
4-hydroxy-3-methoxyacetophenone (1.65 g, 0.01 mol) and anhydrous potassium
carbonate (1.60 g, 0.012 mol) in 30 ml of dry DMF. The mixture was stirred at
room temperature for 48 hours under an argon atmosphere, water was added and
the product was extracted with diethyl ether. The organic layer was washed with
10% sodium hydroxide solution four times and dried over anhydrous magnesium
sulfate. The solvent was evaporated using the rotary evaporator to afford
yellowish oil which was purified by vacuum distillation using kugelrohr to give
1.33 g (57%) the product.

1H NMR(CDCI3) (300 MHz): 5 1.8 (t, J = 0.89 Hz, 3H), 2.54 (s, 3H), 2.57 (t,
broad, J = 7.42 Hz, 2H), 3.90 (s, 3H), 4.20 (t, J = 7.24 Hz, 2H), 4.79 (m, 1H), 4.82
(m, 1H), 6.87 (d, J = 8.24 Hz, 1H), 7.5 (d, J = 2.02 Hz, 1H), 7.54 (dd, J = 2.04, 8.27
Hz, III)

13C NMR (CDCI3) (75 MHz): 5 22.90, 26.18, 36.86, 56.04, 67.58, 110.52, 111.16,
112.34, 123.18, 130.4,141.63, 149.24.152.68, 196.77

213

IR (CHCI3): 3011, 1673. 1588, 1510, 1466, 1418, 1271, 1181, 1150, 1032 cm'1

MS (m/e): 234 (M+), 166, 151 (base), 135,123, 91, 77, 69, 55, 43, 41

Iii-Res MS: C14H1303, Calculated: 234.1256, Found 234.1257

 

 

 

 

 

1" --1 lm =_1.t'-.~.'Hf|l' ll‘W
OH 0A5 OH I
SCH, SCH, SCH
CH,COC1 AlCl,
> >
Pyridine Nitrobenzene
0
MRI.
,
K,CO,/ DMF

 

 

 

 

 

 

2-(Methylmercapto)phenylacetate:

Acetyl chloride (2.80 ml, 0.04 'mol) was added dropwise to an ice cooled
solution of 2-(methylmercapto) phenol (4.81 g, 0.34 mol) and pyridine (3.60 ml,
0.045 mol) in 40 ml of dry benzene. The solution was stirred during the addition

and temperature was kept below 20°C. The solution was then stirred at room

temperature overnight, water was added and the organic layer was isolated. The

aqueous layer was extracted twice with ether. The combined organic layers were

washed with 10% HCl twice, water, then with 10% sodium hydroxide solution.

After drying over anhydrous magnesium sulfate, the solvent was removed by the

214

a rotary evaporator . Vacuum distillation (kugelrohr) afforded 5.0 g (92%) of the
product.

1H NMR(CDC13) (300 MHz): 5 2.33 (s, 3H), 2.42 (s, 3H), 7.03 (dd, J = 7.42, 1.86
Hz, 1H) 7.14-7.29 (m, 3H),.

4-Hydroxy-3-(methylmercapto)acetophenone:

Anhydrous aluminum chloride (0.90 g, 0.0067. mol) was stirred in dry
nitrobenzene at 70°C under argon atmosphere until all the solid dissolved. The
solution was cooled to about 10°C and 2-(methylmercapto) phenyl acetate (1.0 g,
0.0055 mol) was added dropwise in such a rate that the temperature did not
exceed 20°C. The mixture was kept at room temperature for four days, 10% HCl
was then added, stirred for 10 minutes. The mixture was cooled and extracted
with ether. The product was extracted with 10% sodium hydroxide solution
several times (until the aqueous layer was colorless). The combined aqueous
layers were acidified with 10% HCl to give the free phenolic product which was
extracted with ether. The organic layer was washed with water then with sodium
bicarbonate solution, and dried over magnesium sulfate. The solvent was removed
using a rotary evaporator to give a brownish solid which was purified by a flash
silica gel column (20% ethyl acetate/hexanes) to give 0.15 g (15%) of pale brown
solid, mp: 115-116°C.

1H NMR (CDCI3) (300 MHz): 5 2.35 (s, 3H), 2.53 (s, 3H), 7.02 (d, J = 8.61 Hz,
1H), 7.04 (s, broad, 1H), 7.86 (dd, J = 2.2, 8.61 Hz, 1H), 8.14 (d, J = 2.21 Hz, 1H)

215

m-SMe-pBA:

4-Bromo-1-butene (0.1g, 0.75 mmol) was added to a mixture of 4-hydroxy-
3-(methylmercapto)acetophenone (0.1 g, 0.55 mmol) and anhydrous potassium
carbonate (0.18 g, 1.3 mmol) in 5 ml of dry DMF. The mixture was stirred at room
temperature for three days under an argon atmosphere, water was added and the
product was extracted with diethyl ether. The organic layer was washed with
10% sodium hydroxide solution four times and dried over anhydrous magnesium
sulfate. The solvent was evaporated using the rotary evaporator to afford
yellowish solid which was purified by vacuum distillation using kugelrohr to give
0.1 g (79%) the product, mp: 35-37°C.

1H NMR (CDCI3) (300 MHz): 5 2.45 (s, broad, 3H), 2.54 (s, 3H), 2.61 (tq, J =
1.31, 6.75 Hz, 2H), 4.13 (t, J = 6.68 Hz, 2H), 5.12 (ddt, J=10.19, 1.8,1.13 Hz.1H),
5.19 (dq, J=17.18, Hz, 1H), 5.93 (ddt, J =17.09, 10.22, 6.81 Hz, 1H), 6.81 (d, 1:

8.52 Hz. 1H), 7.72 (dd, J = 2.13, 8.45 Hz, 1H), 7.72 (d, J = 2.01 Hz, 1H)

13C NMR (CDCI3) (75 MHz): 5 14.38, 26.27, 33.39, 68.14, 109.73, 117.55,
125.47, 127.28, 128.46, 130.58. 133.86. 159.13. 196.58.

IR (CHCI3): 3005, 2925, 1673, 1584, 1487, 1356, 1256, 1071 cm”1

MS (m/e): 236 (M"’), 221, 195, 182, 167 (base), 149, 139, 121, 111, 95, 77, 69, 55,
43

I-Ii-Res MS: C13H15O2S, Calculated: 236.0871 , Found 236.0862

216

 

 

OCH,

OCH,
p
O 2)NaOI-I/A K2 C O 3, DMF
3)H30+
O

3-Hydroxy-4-methoxyacetophenone:

 

 

 

 

 

 

 

The title compound was prepared according the published procedure.115
Concentrated sulfuric acid (25 ml) was added carefully to a well stirred mixture of
guaiacol (25.0 g, 0.20 mol) and acetic anhydride (175.0 ml). The mixture was
cooled during the addition (water bath) so that the temperature did not exceed
80°C. It was then stirred at room temperature for 24 hours before 1.5 liter of
water was added, and the reaction stirred for 30 minutes. The mixture was
extracted with ether and washed with water. After evaporation of the ether, the
oily dark brown residue was boiled with 10% sodium hydroxide (some ethanol
was added) for 2 hours, then the reaction was cooled, acidified and extracted
with ether. The ether layer was washed with water, and sodium bicarbonate
solution, then dried over anhydrous magnesium sulfate, and evaporated to give
11.0 g of a sticky brown oil. This oil was stirred with chloroform, filtered and
evaporated to give 8.0 g of a solid which was filtered, through short column of
silica gel using methylene chloride as eluent. Vacuum distillation (kugelrohr)
followed by crystallization from benzene gave 4.0 g (12%) of pure product.(mp:
89-91°C)

217

1H NMR (CDCI3) (300 MHz): 5 2.51 (s, 3H), 3.93 (s, 3H), 5.75 (broad, s, 1H), 6.86
(d, I: 9.04 Hz. 1H), 7.51 (d, J=1.86 Hz, 1H), 7.52 (dd, J: 2.17, 9.1 Hz, 1H)

p-OMe-mBA:

4-Bromo-1-butene (5.0 g, 0.037 mol) was added to a mixture of 3-
hydroxy-4-methoxyacetophenone (3.4 g, 0.02 mol), anhydrous potassium
carbonate (3.5 g, 0.025 mol), and potassium-t-butoxide (2.3 g, 0.02 mol) in 30 ml
of dry DMF. The mixture was stirred at room temperature for one week under
argon atmosphere, water was added and the product was extracted with diethyl
ether. The organic layer was washed with 10% sodium hydroxide solution four
times and dried over anhydrous magnesium sulfate. The solvent was evaporated
using the rotary evaporator to afford a solid which was purified by vacuum
distillation using kugelrohr to give 2.1 g (47%) of pure 3-(3-buten-1-oxy)-4-
methoxyacetophenone (mp: 48-49°C)

1H NMR (CDCI3) (300 MHz): 5 2.55 (s, 3H), 2.61 (tq, J = 1.22, 6.93 Hz, 2H), 3.92
(s, 3H), 4.11 (t, I: 6.93 Hz, 2H), 5.11-(ddt, J=10.19,1.6 , 1.15 Hz, 1H), 5.18 (dq,
17.24, 1.65 Hz, 1H), 5.91 (ddt, J = 10.22, 17.06, 6.81 Hz, 1H), 6.88 (d, J = 8.31 Hz,
1H), 7.52 (d, J = 2.02 Hz, 1H), 7.57 (dd, J = 2.07, 8.27 Hz, 1H)

l3C NMR(CDC13) (75 MHz): 5 26.1, 33.3, 55.9, 68.0, 110.4, 111.1, 117.4, 123.1,
130.3. 133.6, 149.1, 152.6. 196.6

IR (CHC13): 3009, 1673, 1588, 1512, 1427, 1358. 1269, 1181, 1148, 1024 cm“1

MS (m/e): 220 (M+), 205, 192, 177, 166, 151, 137, 123, 109,91, 79, 65, 55 (base),
43

218

Hi-Res MS: C13H15O3, Calculated: 220.1099, Found 220.1096

 

 

 

>
80°C/24 h K2003! DMF
SH

 

 

 

 

 

 

4-Mercaptoacteophenone:

Hydrated sodium sulfide (Na2S-9H2O), (90.0 G, 0.375 mol) was dried by
heating at 100°C under vacuum (rotary evaporator) until no water distilled, then
under high vacuum for 2 hours. 4-Fluoroacetophenone (5.2 g, 0.038 mol), and
DMF were added and the mixture was heated overnight at 80°C, before being
cooled, and quenched by the addition of ice and water. The resulting solution
was acidified with HCl( CAUTION: a considerable amount of H2S gas was
evolved with foaming). The acid was added dropwise with vigorous stirring. The
product was extracted with ether. The ether layer was washed with sodium
bicarbonate solution. Extraction with 10% sodium hydroxide and acidification
with 10% HCl gave the product which was extracted with ether, washed with
sodium bicarbonate, and dried over anhydrous magnesium sulfate. Solvent was

evaporated to give 2.1 g (37%) of the product, mp: 27-29°C (lit. 27-28.5°C),116

1H NMR (CDCI3) (300 MHz): 5 2.58 (s, 3H), 3.65 (s, 1H), 7.3 (d, J = 8.75 Hz, 2H),
7.8 (d, J = 8.75 Hz, 2H)

219

4-(3-Buten-l-mercapto)acetophenone:

4-Bromo-l-butene (3.4 g, 0.025 mol) was added to a mixture of 4-
mercaptoactophenone (3.75g, 0.025 mol), sodium hydroxide (1.00 g, 0.025 mol)
in aqueous ethanol. The mixture was boiled for 2 hours, before being cooled
Water was added and mixture extracted with ether. The organic layer was
washed with 10% sodium hydroxide solution twice and dried over anhydrous
magnesium sulfate. The solvent was evaporated using the rotary evaporator to
afford an oil which was purified by column chromatography (20% ethyl
acetate/hexanes) then recrystallized from cold acetone to give 3 g of white
crystals (mp: 30-31°C).

1H NMR (CDCI3) (300 MHz): 5 2.44 (broad, dt, J = 6.93, 6.93 Hz, 2H), 2.56 (s,
3H), 3.05 (t, J = 7.48 Hz, 2H), 5.08 (dq, I: 10.17, 1.58 Hz, 1H), 5.12 (dq, J = 17.03,
1.58 Hz, 1H), 5.86 (ddt, J = 10.31, 17.03, 6.6 Hz, 1H), 7.3 (d, J = 8.76 Hz, 2H), 7.85

(d, J = 8.76 Hz, 2H)

13C NMR (CDCI3) (75 MHz): 5 26.28, 31.16, 32.73, 116.55, 126.32, 128.62,
133.75, 135.71, 144.22, 196.96

IR (CHCI3): 3021, 1677, 1590, 1362. 1265, 1102 em-l

MS (m/e): 206 (M+), 191, 165, 137, 129, 123, 108, 91, 77, 69, 55, 43 (base)

Hi-Res MS: C12H14OS, Calculated: 206.0766, Found 206.0764

220

 

 

NB
Na,Co,/Nar

 

 

 

 

 

 

4-Bromo-1-butene (1.0g, 0.0074 mol) was added to a mixture of 4-amino-
acetophenone (3.0 g, 0.022 mol), anhydrous sodium carbonate (1.0 g, 0.01 mol),
and sodium iodide (0.11 g, 0.0007 mol) in 40 ml of dry DMF. The mixture was
stirred at 80°C for 48 hours under an argon atmosphere, water was then added
and the product was extracted with diethyl ether. The organic layer was washed
with water four times and dried over anhydrous magnesium sulfate. The solvent
was evaporated using the rotary evaporator to afford a solid which was purified
by flash column (silica gel, 25% ethylacetate/hexanes) to give 0.9 g of the
product which was recrystallized from hexanes-ethyl acetate to give 0.81 g
(58%) of colorless crystals, mp: 54-55°C.

1H NMR (CDCI3) (300 MHz): 5 2.39 (tq, J = 1.31, 6.74 Hz, 2H), 2.48 (s, 3H), 3.24
(t, J = 6.77 Hz, 2H), 4.37 (broad, s, 1H), 5.1-5.18 (m, 2H), 5.8 (ddt, J = 10.25, 17.09,

6.81 Hz, 1H), 6.56 (d, J = 8.85 Hz, 2H), 7.81 (d, J = 8.95 Hz, 2H)

13C NMR (CDC13) (75 MHz): 5 25.99, 33.33, 42.08, 111.40, 117.54, 126.62,
130.78, 135.1, 152.08. 196.31.

IR (CHC13): 33428, 3007, 1661, 1601, 1574, 1528, 1482, 1360, 1279, 1181 cm'1

221

MS (m/e): 189 (M‘l’), 174, 148 (base), 132, 119, 105, 91, 77, 65, 51, 43

Hi-Res MS: C12H15NO, Calculated: 189.1154, Found 189.1161

 

 

 

 

 

 

 

 

4-(3-Buten-1-amino)acetophenone (4.0 g, 0.022 mol) was added to a
mixture of acetic anhydride (2.2 ml, 0.022 mol) and acetic acid (2.0 ml, 0.034 mol).
The mixture was heated over a steam bath for 1 hour, water (10.0 ml) was added
and stirred for 20 minutes After cooling, ether was added and the mixture was
washed with 10% sodium hydroxide solution. The ether was dried (magnesium
sulfate) and evaporated to give an oil which was vacuum distilled (138-

139°C/0.3 mm) to give 3.62 g (74%) of the product.

1H NMR (CDCI3) (300 MHz): 5 1.86 (broad, s, 3H), 2.24 (broad, t, J = 7.17 Hz,
2H), 2.61 (s, 3H), 3.79 Giroad, t, J = 7.39 Hz, 2H), 4.99-5.07 (m, 2H), 5.71 (ddt, J =
10.41, 16.94, 6.69 Hz, 1H), 7.27 (d, J = 8.63 Hz, 2H), 8.00 (d, J = 8.51 Hz, 211)

13C NMR (CDCI3) (75 MHz): 5 22.82, 26.63, 32.24, 48.24, 116.94, 128.28,
129.95, 134.93, 136.21, 147.10, 169.70. 196.86.

222

IR (CHCI3): 3007, 2936. 1688, 1657, 1651. 1601,1509, 1395, 1360, 1265, 1177,
1144, 959, 922 cm-1

MS (m/e): 231 (M+), 190, 148 (base), 132, 120, 106, 91, 77, 55, 43

Iii-Res MS: C14H17NO2, Calculated: 231.1259, Found 231.1257

 

 

’

so,Cl
/ \r—OOH

Pyridine K2C03IDMF

 

 

 

 

CH,

 

3—Pentynyl-l-tosylate:

3-Pentyne-1-ol (10 g, 0.12 mol) was dissolved in pyridine (16 ml, 0.2 mol).
The solution was cooled in an ice bath and p-toluenesulfonyl chloride (27.2 g,
0.14 mol) was added in portions. After addition was complete, the mixture was
stirred at room temperature overnight. Water was added and the solution was
extracted with ether. The ether layer was washed with 10% HCl then with 10%
sodium hydroxide solution, dried over magnesium sulfate and evaporated to give
28 g of the crude product which contained some p-toluenesulfonyl chloride.
Attempts at purification by vacuum distillation led to decomposition of the

product. The compound was therefor used without further purification.

223

4-(3-Pentyn-1-oxy)acetophenone:

3-Pentynyl-l-tosylate (5.4 g, 0.023 mol) was added to a mixture of 4-
hydroxyacetophenone (4.0 g, 0.03 mol) and sodium hydroxide (1.18 g, 0.03 mol)
in 30 ml of dry DMF. The mixture was stirred at room temperature for one week
under an argon atmosphere, water was then added and the product was extracted
with diethyl ether. The organic layer was washed with 10% sodium hydroxide
solution four times and dried over anhydrous magnesium sulfate. The solvent was
evaporated using the rotary evaporator to afford 3.5 g of yellowish solid which
was purified by vacuum distillation using kugelrohr to give 3.1 g (67.7%) of pure
4-(3-pentyn-1-oxy)acetophenone (mp: 64-65°C).

1H NMR (CDCI3) (300 MHz): 5 1.79 (t, J = 2.56 Hz, 3H), 2.54 (s, 3H), 2.64 (tq, J
= 2.59, 7.09 Hz, 2H), 4.09 (t, J = 7.15 Hz, 2H), 6.93 (d, J = 8.91 Hz, 2H), 7.92 (d, J

= 8.94 Hz, 2H)

13C NMR (CDCI3) (75 MHz): 5 3.33, 19.51, 26.16, 66.55, 74.46, 77.45, 114.04,
130.29. 130.40. 162.30, 196.54

IR (CHCI3): 3011, 2926, 1674, 1601, 1578, 1510, 1360, 1256, 1173, 1034 cm”1

MS (m/e): 202 (M+), 187,159, 145, 121, 91, 77, 67 (base), 43, 41

Hi-Res MS: C13H14O2, Calculated: 202.0994, Found 202.0993

 

 

 

 

 

 

 

 

 

3-Butynyl-1-tosylate:

3-Butyne-1-ol (5.0 g, 0.07 mol) was dissolved in pyridine (36 ml, 0.45 mol).
The solution was cooled in ice bath and p-toluenesulfonyl chloride (15.5 g, 0.08
mol) was added in portions. After the addition was complete, the mixture was
stirred at room temperature overnight. Water was added and the solution was
extracted with ether. The ether layer was washed with dilute sulfuric acid then
with 10% sodium hydroxide solution, dried over magnesium sulfate and
evaporated to give 16 g of the product which was used in the next step without
further purification.

1H NMR (CDC13) (300 MHz): 5 1.95 (t, J = 2.72 Hz, 1H), 2.43 (s, 3H), 2.53 (dt, J
= 2.71, 7.11 Hz, 2H), 4.08 (t, J = 7.11 Hz, 2H), 7.33 (d, J = 8.52 Hz, 2H), 7.79 (d, J
= 8.24 Hz, 2H)

2-(3-Butyn-l-oxy)acetophenone:

3-Butynyl-1-tosylate(1.65 g, 0.0074 mol) was added to a mixture of 2-
hydroxyacetophenone (1.0 g, 0.0074 mol) and sodium hydride (0.22 g, 0.0092
mol) in 10 ml of dry DMF. The mixture was stirred at room temperature for one
week under an argon atmosphere, water was then added and the product was

extracted with diethyl ether. The organic layer was washed with 10% sodium

225

hydroxide solution four times and dried over anhydrous magnesium sulfate. The
solvent was evaporated using the rotary evaporator to afford 0.215 g of white
solid which was recrystallized from benzene-hexanes to give 0.19 g (14%) of the
product, mp: 53-54°C. ‘

1H NMR (CDCI3) (300 MHz): 5 2.03 (t, J = 2.71 Hz, 1H), 2.65 (s, 3H), 2.74 (dt, J
= 2.72, 6.56 Hz, 2H), 4.18 (t, J = 6.58 Hz, 2H), 6.91 (d, J = 7.97 Hz, 1H), 7.00 (dt, J
= 1.01, 7.57 Hz, 1H), 7.43 (ddd, J = 1.89, 7.39, 8.52 Hz, 1H), 7.74 (dd, J = 1.92,

7.69 Hz. 1H)

13C NMR(CDC13) (75 MHz): 5 19.57. 32.19. 66.41. 70.21, 80.28, 112.19, 120.97.
128.4, 130.53, 133.61.157.7, 199.77

IR (CHCI3): 3310, 3011, 2118, 1673, 1599,1487.1453, 1360. 1296, 1246, 1163,
1129, 1045. 1032 cm-1

MS (m/e): 188 04*), 173, 149, 145, 131, 121 (base), 115, 105, 91, 77, 65, 53, 43

Hi-Res MS: C12H12O2, Calculated: 188.0837, Found 188.0837

226

 

O

' F C o
OH oJL CF, 3

Q (CF,CO),O * @ MCI 31A 0 OH
—-———>
Mason“, 0 j

} O
O

 

 

   

 

 

   
 

 

F,C

 

 

 

Phenyltrifluoroacetate:

The title compound was prepared according to the procedure of Weggand
and Popsch.‘”Trifluoroaceticanhydride (77 ml, 0.5 mol) and phenol (47 g, 0.5
mol) were stirred together. The reaction mixture became hot and started boiling
for about 10 minutes, it was then heated at 100°C for 1 hour. The mixture was
distilled twice through a fractionation column. The product was collected as the
fraction boiling at 144-145°C (literature 149°C-150°C)

2-Hydroxy a,a,a-trifluoroacetophenone:

Following the procedure published by Matsumoto and coworkers.118
Phenyl trifluoro acetate (10.0 g, 0.053 mol) was added dropwise to a suspension
of anhydrous aluminum chloride (8.1 g, 0.061 mol) in carbon disulfide (11 ml). The
mixture was stirred at room temperature for one hour, then heated under gentle
refluxing for an additional hour. The solvent was distilled off and the reaction

temperature was raised gradually to 115°C for 15 minutes then lowered to 90°C

227

where it was kept for 90 minutes. After cooling the reaction mixture was treated
with diluted HCl and steam distilled. The distillate was extracted with ether,
washed with water and dried over magnesium sulfate. The organics were filtered
and evaporated to give the crude product which was vacuum distilled (118-

120/asp) to give 3.8 g (38%) of the product.

1H NMR (CDCI3) (300 MHz): 5 6.69 (ddd, J = 1.13, 7.2, 8.3 Hz, 1H), 7.07 (dd, J
= 1.1, 8.61 Hz, 1H), 7.61 (ddd, J=1.63, 7.21, 8.8 Hz, 1H), 7.81 (d of quintets, 1:
8.39, 2.11 Hz, 1H), 11.05 (s, 1H)

3-Buten-1-tr'iflate:

The title compound was prepared by applying the same method used for
preparing 3-butyn-1-triflate.119 Trifluoromethanesulfonic anhydride (15g, 0.054
mol) and methylene chloride (30 ml) were placed in a 3-neck rb. flask. The
solution was stirred under an argon atmosphere, and cooled to 40°C. Finely
powdered anhydrous sodium carbonate (3.0 g, 0.028 mol) was added. Then 3-
buten-l-ol (3.0 g, 0.042 mol) was added dropwise over a period of 20 minutes
while temperature was mentained at -40 to -50°C. Stirring was continued at
-30°C for 2 hours, and at 0°C for one hour. The reaction was quenched by the
dropwise addition of 10 ml of water. The organic layer was separated and dried
over anhydrous magnesium sulfate. After filtration the solvent was removed using

rotary evaporator (at room temperature). The product was vacuum distilled

(45°C/ asp) to give 5.2 g (61%) of the product.

1H NMR(CDC13) (300 MHz): 5 2.56 (ddq, J = 1.4, 1.12, 6.61, 6.61 Hz, 2H), 4.54
(t, J = 6.56 Hz, 2H), 5.16~5.28 (m, 2H), 5.74 (ddt, J = 17.31, 10.05, 6.7 Hz, 1H)

228

2—(Buten- I-oxy) a,or,a-trifluoroacetophenone:

The title compound was prepared using a general method published by
Beard and coworkers.120 3-Buten-I-triflate (5.2 g, 0.025 mol) was added to a
mixture of 2-hydroxy-or,Ot,a-trifluoroacetophenone (4.85 g, 0.025 mol) and
anhydrous potassium carbonate (17.0 g, 0.128 mol) in 50 ml of dry methylene
chloride. The mixture was stirred at room temperature for 24 hours under an
argon atmosphere, water was added and the product was extracted three times
with ether. The organic layer was washed with a diluted potassium carbonate
solution and dried over anhydrous magnesium sulfate. The solvent was
evaporated using the rotary evaporator to afford 4.6 g of oil which was purified
by vacuum distillation (128-130/ 0.3 mm) to give 3.2 g (52%) of the pure product.

1H NMR (CDCI3) (300 MHz): 5 2.57 (tq, J = 1.31, 6.74 Hz, 2H), 4.09 (t, J = 6.68
Hz, 2H), 5.1 (ddt, J = 10.23, 1.77, 1.16 Hz, 1H), 5.16 (dq, J = 17.18, 1.6 Hz, 1H),
5.88 (ddt, J = 10.28, 17.15, 6.78 Hz, 1H), 6.98 (d, J = 8.51 Hz, 1H), 7.04 (dt, J =
0.91, 7.57 Hz, 1H), 7.55 (ddd, I: 1.77, 7.41, 8.45 Hz, 1H), 7.63 (dd, J = 1.71, 7.73
Hz, 1H)

13C NMR (CDCI3) (75 MHz): 5 33.15, 68.24, 112.56, 116.17 (q, J = 289 Hz),
117.42, 120.66, 122.04, 131.38, 133.76, 135.71, 158.95, 183.49 (q. J = 37 Hz)

IR (CI-103): 3085, 2942, 1711, 1601, 1489, 1453, 1283, 1252, 1167, 940 cm"1

MS (m/e): 244 (M+), 203, 188, 175, 153, 121, 95, 92, 65, 55 (base), 39

Hi-Res MS: C12H11F302, Calculated: 244.0711, Found 244.0708

229

 

 

 

OH DMF
/\/ 31'
O + / K,Co,

 

 

 

 

 

Allyl bromide (7.1 ml, 0.083 mol) was added to a mixture of 2-hydroxy-
a,a,a-trifluoroacetophenone (5.0 g, 0.0263 mol) and anhydrous potassium
carbonate (3.65 g, 0.0.264 mol) in 50 ml of dry DMF. The mixture was stirred at
65°C for 72 hours under an argon atmosphere. After cooling water was added
and the product was extracted with ether. The organic layer was washed with
dilute potassium carbonate solution and dried over anhydrous magnesium sulfate.
The solvent was evaporated using the rotary evaporator to afford 4.16 g of oil
which was purified by vacuum distillation (Kugelrohr) to give 3.36 g (55.2%) of
the pure product.

1H NMR (CDCI3) (300 MHz): 5 4.63 (dt, J = 5.25, 1.52 Hz, 2 H), 5.30 (dq, J =
10.59, 1.38 Hz, 1 H), 5.43 (dq, J = 17.28, 1.55 Hz, 1 H), 6.03 (ddt, I: 17.81, 10.56,
5.25 Hz, 1H), 6.99 (d, J = 8.43 Hz, 1 H), 7.03 (dt, J = 0.88, 7.51 Hz, 1 H), 7.54 (ddd,
J: 1.8, 7.41, 8.48 Hz, 1 H), 7.65 (dd, 1: 7.97, 1.37 Hz, 1 H)

13C NMR (CDCI3) (75 MHz): 5 69.61, 113.13, 116.15 (q. I: 291 Hz), 118.14,
120.76, 121.95, 131.25, 131.95. 135.64,158.70, 184.26 (q, J= 36.64 Hz)

IR (CHC13): 3025. 1716. 1606. 1490. 1282. 1185. 1169. 997, 943 ml

230

MS (m/e): 231 (lvfl-I‘l', base), 230 (M+), 219, 203, 179, 136, 121, 107, 75, 50

Hi-Res MS: C11H9F3O2 (observed as MH+: C11H10F302). Calculated: 231.0633
Found 231.0634

231

II I'fi I' [Ell I I

In an NMR tube, 3.1 mg of m-OMe-pBA was dissolved in 0.75 ml of
benzene-d5 and purged with argon for 5 minutes. It was irradiated using Pyrex
filtered-light 0. 2 290 nm). After 45 minutes (30% conversion), 1H NMR analysis
showed the formation of new peaks that corresponds to three products; 4-acetyl-
2-methoxy-11-oxa-tricyclo[6.3.0.01’6]undeca-2,4-diene (m-OMe-CHDa), 4-
acetyl-2-methoxy-l 1-oxatricyclo[6.3 .0.01'4]undeca-2,5-diene (m-OMe-ACBa)
and 4-acetyl-6-methoxy-II-oxatricyclo[6.3.0.01'4]undeca-2,5-diene (m-OMe-
ACBs) in a ratio of 1.5 : 4.3 : 1.0 respectively (NMR integration of doublet at
6.08 ppm , doublet of doublets at 6.15 ppm and doublet at 5.96 ppm). After 3.5
hours (100% conversion ), only m-OMe-ACBa and m-OMe-ACBS were present
with a ratio of 5.7 : 1.0 respectively (NMR integration of dd at 6.15 ppm and d at
5 .96 ppm). They were identified from their partial NMR spectra.

 

 

m-OMe-ACB,

 

 

 

232

WWW - - ' - M -
Acne);
1H NMR (C5D5) (300 MHz) (Partial spectrum): 5 2.3 (s, 3H, COCH3), 3.03 (s, 3H,

OCH3), 4.65 (s, 1H, H3). 5.75 ( ddd, J = 1.83, 6.8, 9.95 Hz, 1 H, H5), 6.15 (dd, J =
2.98, 9.9 Hz, 1H, H5)

 

OMe

O
109

m-OMe-ACB,

 

 

 

1H NMR (C505) (300 MHz) (Partial spectrum): 5 2.18 (s, 3H, COCH3), 3.2 (s, 3H,
OCH3), 4.65 (d, overlapped with a peak of the other isomer, H5). 5.96 (d, J = 2.85
Hz, 1H, H3), 6.05 (dd, J = 2.85, 0.53 Hz, 1H, H2),

3.3 mg of the ketone in 0.75 ml of benzene-d6 was irradiated in an NMR
tube at 313 nm. After 80 minutes, 1H NMR showed the formation of m-OMe-
CHDa as the only product. Irradiation was continued for 12 hours. 1H NMR
showed the formation of peaks corresponding to m-OMe-ACBa, m-OMe-ACBS,
m-OMe-CI-IDa (5 : 1 : 1) beside singlets at 4.62, 4.94, 5.44, a multiplet at 5.5 and a

multiplet at 6.08 ppm. The solution was left at room temperature for 20 hours then

233

heated at 100°C for 90 minutes. 1H NMR showed that the m-OMe-CHDa
concentration had increased at the expense of m-OMe-ACBa, and the three
singlets at 4.62, 4.94 and 5.44 ppm. A new compound was also observed and
identified as 4-acetyl-2-methoxy-11-oxatricyclo[6.3.0.03'6]undeca-l,4-diene (m-
OMe-LCBafinfi).

 

 

m-OMe-LCBmu

 

 

 

 

1H NMR (C505) (300 MHz): 5 0.72 (ddd, J = 13.00, 11.63, 6.1 Hz, 1H, H7), 1.15
(dddd, J =11.51, 11.51, 11.05, 8.63 Hz, 1H, H9), 1.45 (m, 1H, H9), 1.60 (ddd, J =
13.00, 4.95, 1.65 Hz, 1H, H7), 1.85 (m, 1H, H3), 1.95 (s, 3H, CH3CO) 2.67 (dddd, J =
5.98, 4.43, 1.47, 1.47 Hz, 1H, H5), 3.48 (ddd, J = 11.75, 8.46, 5.5 Hz, 1H, H10), 3.61
(dd, J = 4.4, 1.25 Hz, 1H, H3), 3.79 (ddd, J = 8.49, 8.49, 1.1 Hz, 1H, H10), 3.95 (s,
3H, OCH,), 6.14 (d, J = 1.37 Hz, 1H, H5)

In an NMR tube 1.7 mg of the ketone was dissolved in 0.75 ml benzene-
d5, degassed and irradiated using uranium-filtered light (A 2 334 nm). After 43

hours of irradiation (> 80% conversion), 1H NMR showed the presence of m-

234

OMe-ACBa and m-OMe-ACBS in a ratio of 2.8 : 1.0 (NMR integration of
doublet of doublets at 6.15 and doublet at 5.96 ppm). The solution was left at

room temperature in the dark for 5 days. 1H NMR showed the formation of three
products; m-OMe-CHDa and m-OMe-COTs in a ratio of 2.5 : 1.0 (NMR

integration of doublet at 6.08 and doublet of doublets at 6.78 ppm) and an
unidentified product. m-OMe-COTS was identified from its partial NMR

spectrum.

 

 

O

m-OMe-COTs

 

 

 

‘-; ‘1-111'.tt.‘- -t.=.t .01 I l'ifi' . .'!I'l' 11".U' 0

1H NMR (C5D5) (300 MHz) (Partial spectrum): 5 5.54 (dd, J = 8.5, 2.4 Hz, 1H,
H2). 5.86 ( broad singlet, 1H, H5), 6.78 (dd, J: 8.5, .90 Hz, 1H, H3)

1.0 g of the ketone in 500 ml dry benzene was irradiated using Pyrex-
filtered light (A. 2 290 nm) for 12 hours. Solvent was rotary evaporated. 1H NMR
of the residue (CDCl3), showed the presence of three compounds; m-OMe-pBA,
m-OMe-CI-IDa and 4-acetyl-2-methoxy-1I-oxabicyclo[6.3.0]undeca-l,3,5-triene
(m-OMe-COTa) in a ratio of 1.0 : 3.8 : 2.3 (NMR integration of doublet at 6.86,
singlet at 5.74 and doublet of triplets at 6.28 ppm). When the sample was left

235

overnight, 1H NMR showed that m-OMe-COTa had totally disappeared while
the concentration of m-OMe-CHDa increased. m-OMe-COTa was identified
from its partial NMR spectrum.

The mixture was purified by column chromatography (silica gel, 20% ethyl .
acetate/hexanes) to give 0.11 g of starting material and 0.37 g of 4-Acetyl-2-
methoxy-l l-oxa—tricyclo[6.3.0.01’6]undeca-2,4-diene (m-OMe-CHDa).

 

 

 

 

 

1H NMR (CDCI3) (500 MHz): 5 1.75 (dddd, 19,9 = 12.6, J9,1o = 6.12, 19,10 = 3.7,
13,9 = 2.65 Hz, 1 H, H9), 1.91 (ddd, J7,7 = 12.1, 175 = 105.17,; = 3.8 Hz, 1 H, H7),
2.05 (dt, J7,7 = 121,175,175 = 8.6 Hz, 1 H, H7), 2.13 (dddd, 19,9 = 12.6, J9,10 =
9.0.159 = 8719,10 = 7.8 Hz, 1 H, H9), 2.30 (s, 3 H, COCH3), 3.25 (broad t, J =
8.84 Hz, 1 H, H3), 3.30 (dddd, J57 = 10.5, J57 = 8.6.155 = 5.85, J55 = 1.8 Hz, 1 H,
H5), 3.66 (s, 3 H, OCH3), 4.20 (dt, 19,15 = 6.1.1510, 110,10 = 9.0 Hz, 1 H, H10), 4.24
(ddd, J10,1o = 9.0, J9,1() = 7.8, 19,10 = 3.7 Hz, 1 H, H10), 5.75 ((1, J35: 0.83 Hz, 1 H,
H3), 6.44 (dd, 135: 083,155 = 5.76 Hz, 1 H, H5),

236

13C NMR (CDCI3) (75 MHz): 5 25.22, 28.96, 33.71, 40.79, 48.49, 55.4, 69.24,
81.41, 92.34, 131.77, 134.52, 155.78. 196.95 (C=O)

13C NMR (C5D5) (75 MHz): 5 24.95, 28.91, 34.25, 41.36, 48.50, 54.62, 69.66,
92.58, 131.14, 134.98, 157.12, 195.69

UV-Visible (Benzene): 2cm = 315 nm, e = 3515

MS (m/e): 220(M+), 205, 189, 177, 166, 151, 115, 91, 77, 55 (base)

 

 

 

 

 

. O
‘-1 ---11'11. -1.'-._1 11 1.__11"-.- - '1' 11--0u'

£01121:

1H NMR (CDC13) (300 MHz) (Partial spectrum): 5 2.37 (s, 3H, COCH3). 3.56 ( s,
3H, OMe) 5.94 (dt, J = 13.13, 5.94 Hz, 1H, H5), 6.28 (dt, J = 13.19, 2.19 Hz, 1H,
H5). 6.98 (br s, 1H, H3),.

237

I l' I' [ -QM:CIID'

In an NMR tube a solution of 2.8 mg of m-OMe-CHDa in 0.8 ml C5D5 was
purged with argon for 5 minutes then irradiated at 313 nm. After 40 minutes (12%
conversion), NMR showed the formation of m-OMe-pBA, m-OMe-ACBa and
another product that has a singlet at 4.9 ppm in a ratio of 2.8 : 1.0 : 6.0 (NMR
integration of doublet at 6,48, singlet at 4.65 and singlet at 4.9 ppm, assuming it
corresponds to one proton of the unknown product) . This ratio remained the

same up to 72% conversion.

W

In an NMR tube, a solution of 4.1 mg of m-OMe-pBA and 1.9 mg of
methylbenzoate in 0.75 ml of benzene-d5 was purged with argon, placed in ice-
water bath and irradiated using Pyrex-filtered light. After 1 hour, 1H NMR
showed the presence of starting material (45%), m-OMe-CHDa (2.1%), m-OMe-
ACB; (7.1%)and m-OMe-ACBS (1.7%). After 4 hours the percentages became
2.3%, 2.0%, 18.5%, and 4.4%. Ratios were determined using 1H NMR integration
with methyl benzoate as an internal standard. The following peaks were chosen
for the integration; doublet of doublets at 8.1 ppm for methyl benzoate, singlet at
3.32 ppm for m-OMe-pBA, doublet at 5.75 and doublet of doublets at 6.44 for
m-OMe-CHDa, doublet of doublets at 6.15 for m-OMe-ACBa and doublet at
5.96 and doublet of doublets at 6.05 ppm for m-OMe-ACBS.

The previous experiment was repeated at 55°C. After 40 minutes, 1H
NMR showed the presence of starting material (69.4%), m-OMe-CHDa (2.9%),
m-OMe-ACBa (16.1%), and m-OMe-ACBS (4.4%). After 4 hours the
percentages became 0.0%, 0.0%, 44%, and 4.6%.

238

0.29 g of m-OMe-Me3-pBA in 150 ml of dry benzene was irradiated using
Pyrex-filtered light (2. 2 290 n.m). The reaction progress was monitored by 1H
NMR spectroscopy. After 15 hours irradiation, solvent was removed under
vacuum. 1H NMR analysis showed the formation of 4-acetyl-6-methoxy-8-
methyl-11-oxatricyclo[6.3.0.01'4 ]undeca-2,5-diene (m-OMe-Meg-ACBS) as the
only product. Preparative TLC purification led to the isolation of 0.15 g of the
photoproduct as 4-acetyl-6-methoxy-8-methyl-11-oxabicyclo[6.3.0]undeca-I,3,5-
triene (m-OMe-Me3-COT5).

 

OMe

 

 

 

m-OMe-Me3-ACB,

 

1H NMR (C505) (500 MHz) (partial spectrum): 5 0.70 (s, 3H, CH3), 2.13 (s, 3H,
CH3CO) 3.2 (s, 3H, OCH,), 3.50 (ddd, J: 9.49, 8.17, 7.06 Hz, 1H, H10), 3.59 (ddd,
J = 9.72, 8.17, 2.65 Hz, 1H, H10), 4.64 (d, J = 2.0 Hz, 1H, H5), 6.00 (d, J = 2.93 Hz,
1H, H3), 6.02 (d, J: 2.93 Hz, 1H, H2)

239

nOe NMR Experiment:

(C5D5, 500 MHz, 15°C), Irradiation of the singlet at 0.70 ppm led to the
enhancement of the doublet at 5 6.00 (3.82 %) and the doublet at 5 6.02 (0.90%).

O'M‘H H I 3.82%
\

CH3 ('33—2
0’ ’c. (yo—CK cgcfiH

H‘ C\\ \scu.... HC’H

/C ‘9‘ H

In an NMR tube, 3.5 mg of m-OMe-Me3-COT5 0.75 ml of benzene-d5 and
purged with argon for 5 minutes. It was irradiated using Pyrex filtered-light (2t 2
290 nm). After 60 minutes of irradiation, 1H NMR analysis showed the formation
of m-OMe-Me3-ACB5 with the disappearance of m-OMe-Me3-COTS.

 

 

m-OMe-Meg-COT,

 

 

 

 

IA

I . O
;' --lH' H.’ --ll‘l - M.” It I l" - - 'l‘ H-

W

‘ o

1H NMR (CDCI3) (300 MHz): 5 1.16 (s, 3H, CH3), 1.72 (broad, dd, J = 12.15, 5.22
Hz, 1H, H9), 2.14 (d, J = 14.1 Hz, 1H, H7), 2.35 (s, 3H, CH3CO) 2.43 (ddd, J = 11.8,
11.8, 9.34 Hz, 1H, H9), 2.52 (d, J = 14.1 Hz, 1H, H7), 3.65 (s, 3H, OCH3), 4.17 (m,
2H, H10), 5.24 (d, J = 6.16 Hz, 1H, Hz), 5.36 (s, 1H, H5), 6.98 (d, J = 6.25 Hz, 1H,
H3)

In an NMR tube, 1.3 mg of m-SMe-pBA was dissolved in 0.75 ml of
benzene-d5 and purged with argon for 5 minutes. It was irradiated using Pyrex
filtered light 0. 2 290 nm ). After 65 minutes of irradiation, 1H NMR analysis
showed the formation of new peaks that correspond to three products; 4-acetyl—
2-methylmercapto—1l-oxatricyclo[6.3.O.01'4]undeca-2,5-diene (m-SMe-ACBa), 4-
acetyl-6-methylmercapto-1 1-oxatricyclo-6.3 .0.01'4]undeca-2,5-diene (m-SMe-
ACBs) and 4-acetyl-2-mercaptomethyl-11-oxatricyclo[6.3.O.O3'6]undeca-1,4-
diene (m-SMe-LCBa,ami) in a ratio of 7.5 : 1.2 : 1 (NMR integration of the
multiplet at 5.7-5.8 ppm, doublet at 5.86 and doublet at 6.08 ppm).

The NMR tube was placed in a boiling water bath for one hour. 1H NMR
analysis showed that peaks corresponding to m-SMe-ACBa disappeared while
increasing the concentration of m-SMe-LCBa,ami. Peaks corresponding to m-
SMe-ACB; remained unchanged.

For preparatory scale irradiation, 0.3 g of the ketone in 150 ml dry benzene
was irradiated using Pyrex-filtered light (A 2 290 nm ) for 12 hours under argon
atmosphere. 1H NMR of a sample of the reaction mixture (CDCl3), showed the

 

241

presence of a small amount of the starting ketone and m-SMe-ACBa as the major
product in addition to m-SMe-ACBS and m-SMe-LCBamfi as minor products.
Continuing irradiation for three more hours led to the disappearance of m-SMe-
ACB; without changing the ratio between m-SMe-ACBS and m-SMe-
LCBaJmti.

The previous experiment was repeated but irradiation was performed for
only 6 hours. A two ml sample was taken from the reaction mixture and the
solvent was removed under vacuum. 1H NMR of the residue (CDCl3), again
showed the formation of m-SMe-ACBa as the major product. When the solution
was heated for 25 minutes at 95°C, 1H NMR showed the disappearance of the
signals corresponding to m-SMe-ACBa with the appearance of new peaks
corresponding to m-SMe-LCBa,anti. Signal integration indicated that this
transformation was quantitative.

The remaining of the reaction mixture was placed in the refrigerator for 24
hours. 1H NMR showed the disappearance of peaks corresponding to m-SMe—
ACBa and the formation of new peaks corresponding to two new compounds; 4-
acetyl-Z-mercaptomethyl-l 1-oxa-tricyclo[6.3.0.01'6]undeca-2,4-diene (m-SMe-
CHDa) and 4-acetyl-2-mercaptomethyl-11-oxabicyclo[6.3.0]undeca-l,3,5-triene
(m-SMe-COTg). Prep TLC (hexanes/ ethylacetate) led to the isolation of m-SMe-
LCBa’anti, 4-acetyl-6-mercaptomethyl-ll- oxabicyclo[6.3.0]undeca-13.5-triene
(m-SMe-COTS), and a mixture of m-SMe-CHDa and m-SMe-COTa. 1H NMR
(C5D5), of the m-SMe-CHDa lm-SMe-COTa mixture showed that they have a
ratio of 2 z 1 (NMR integration of doublet of doublets at 5 .96 and doublet of
triplets at 5.6 ppm). This ratio remained the same after 24 hours.

 

 

m-SMe-LCBmu

 

 

 

1H NMR (Cng) (500 MHz): 5 0.73 (ddd, J = 12.93, 11.76, 5.97 Hz, 1H, H7), 1.09
(dddd, J = 11.82, 11.82, 11.03, 8.53 Hz, 1H, H9), 1.42 (dddd, J = 11.87, 7.82, 5.63.
1.0 Hz, 1H, H9), 1.6 (ddd, J = 12.93, 5.16, 1.6 Hz, 1H, H7), 1.93 (m, 1H, H3), 1.97 (s,
3H, COCH3), 2.42 (s, 3H, SCH3), 2.62 ( dddd, J = 5.9, 4.4, 1.5, 1.4 Hz, 1H, H5), 3.44
(ddd, J = 11.82, 8.6, 5.62 Hz, 1H, H10), 3.71 (dd, J = 4.3, 1.0 Hz, 1H, H3), 3.75 (ddd,
J = 8.6, 8.5, 1.0 Hz, 1H, H10), 6.08 (d, J = 1.35 Hz, 1H, H5)

1H NMR (CDCI3) (500 MHz): 5 1.25 (ddd, J = 13.03, 11.71, 5.96 Hz, 1H, H7),
1.75 (dddd, J = 11.93, 11.93, 11.27, 8.62 Hz, 1H, H9), 2.24 (s, 3H, SMe) 2.24 (m,
2H), 2.32 (s,3H, CH3CO) 2.43 (m, 1H), 3.18 (dddd, J = 5.96, 4.41, 1.44, 1.44 Hz, 1H,
H5), 3.75 (dd, 4.42, 1.1 Hz, 1H, H3), 4.03 (ddd, J = 11.93, 8.61, 5.74 Hz, 1H, H10),
4.32 (dd, J = 8.6, 8.6 Hz, 1H, H10), 6.8 (d, J = 1.35 Hz, 1H, H5),.

Homonuclear Decoupling NMR Experiment (CDCl3),

Irradiation of the doublet at 6.8 ppm caused the signal at 3.18 ppm (dddd)
to appear as doublet of doublets of doublets (J = 5.96, 4.41, 1.44 Hz).

243

The stereochemisz of the tricyclo compound was determined using 1H
NMR nOe experiment at 15°C (C6D6, 500 MHz). Irradiation of the bridgehead
proton at C3 (3.71 ppm, H105 was partially irradiated) induced enhancements of
H6 (6.92%) and the thiomethoxy group (2.0%) Similme irradiation of H5 (2.62
ppm, thiomethoxy group was partially irradiated) led to the enhancement of H3
(8.9%), H75 (0.83%) and H70, (2.34%). Irradiation of H5 led to the enhancement of
H5 (2.9%), H73 (0.60%), acetyl group (2.41%) and H3 (0.8 %).

100% 9% 3.9%
“'0'“\ 11 lam/2 1233% arc—(Ski SW¢=21%
H
4&3 {Til/Egg: far/c?
«K " ..trK Ci”
’e6\7/K9§‘H 11% 4.17%
.f H H fi,’\ fiH ‘11
6.92% H 10; 100% f \2.34%
0.33%
O
\\
pup—C SM.
1 \ H \ °
Ilia“: \1”
H
=$HI \ \/
°\/\ if

244

 

MeS

 

 

 

 

"é 'm-l-ll' :- ‘Jl'J -_- I41! 'I |-l'-i'-_-_ -l,'l‘ ll-

SMe-£1119;

1H NMR (CDCI3) (500 MHz): 8 1.98 (ddt, J = 12.37, 8.39, 11.71 Hz, 1H, H9), 2.18
(m, 1H, H9), 2.29 (dd, J = 13.7, 7.95 Hz, 1H, H7), 2.33 ( s, 3H, SMe) 2.36 (s, 3H,
CH3CO) 2.37 (dd, J = 13.92, 2.21 Hz, 1H, H7), 2.95 (m 1H, H3), 4.1 (ddd, J = 11.3,
8.61, 5.3 Hz 1H, H10), 4.25 ( td, J: 8.5, 1.11 Hz, 1H, H10), 5.5 (dd, J = 9.05, 2.43
Hz, 1H, Hz), 6.06 ( s, 1H, H5), 6.96 ( dd, J = 9.05, 0.88 Hz, 1H, H3)

 

 

m-SMe-CHD.

 

 

 

245

WWW
W

1H NMR (C6D6) (500 MHz): 5 1.15 (ddt, J = 12.37, 5.52, 1.55, Hz, 1H, H9), 1.40(
ddd, J = 12.25, 10.5, 4.86 Hz, 1H, H7), 1.69 (ddd, J = 12.25, 9.28, 7.07 Hz, 1H, H7),
1.80 (m, 1H, H9), 1.84 (s, 3H, SMe) 1.92 (s, 3H, CH3CO )2.84 (dddd, J = 10.50.
7.06, 5.75, 1.54 Hz, 1H, H5), 3.12 (m 1H, Hg), 3.83 ( ddd, J = 10.6, 9.15, 5.52 Hz, 1H,
H10), 4.08 (ddd, J = 9.15, 7.73, 1.77 Hz, 1H, H10). 5.98 (dd, J = 5.75, 0.70 Hz, 1H,
H5), 6.53 (d, J = 0.70 Hz, 1H, H3)

Homonuclear Decoupling NMR Experiment:

Irradiation of the signal at 4.08 ppm (ddd) caused the signal at 1.15 (dddd)
to appear as a doublet of doublets of doublets and changed the shape of the
multiplet at 1.80 ppm. Irradiation of doublet of doublets of doublets at 3.83 ppm
caused the signal at 1.15 (dddd) to appear as a doublet of doublets of doublets
and changed the shape of the multiplet at 1.80 ppm. Irradiation of the multiplet at
3.12 ppm caused the signal at 1.15 (dddd) to appear as a doublet of doublets of
doublets and the doublet of doublets of doublets at 1.4 to appear as a doublet of
doublets and the doublet of doublets of doublets at 1.69 to appear as a doublet of
doublets. IrradiatiOn of the signal at 2.84 ppm (dddd) caused the doublet of
doublets of doublets at 1.40 to appear as a doublet of doublets and the doublet of
doublets of doublets at 1.69 to be doublet of doublets and the doublet of
doublets at 5 .98 to appear as a doublet. Irradiation of the doublet of doublets at
5.98 caused the doublet of doublets of doublets of doublets at 2.84 to appear as
a doublet of doublets of doublets and the doublet at 6.53 to appear as a singlet.

 

 

 

 

 

‘-i ‘§.--,l' .11 '11' 1 - a '.":-| -11 1,135-2- . .-!. ‘1‘ 11_--,.U‘

C—QTall

1H NMR (C5D5) (500 MHz): 5 0.84 (ddt, J = 12.25, 6.19, 2.55 Hz, 1H, H9), 1.32
(dddd, J = 12.25, 10.16, 8.62, 7.74 Hz, 1H, H9), 1.73-1.82 (m, 2H, H7), 1.97 (s, 3H,
SMe) 2.08 (s, 3H, CH3CO) 2.71 (m, 1H, H3), 3.64 ( ddd, I: 8.84, 8.84, 1.84 Hz, 1H,
H10), 3.71 (ddd, J = 10.16, 8.84, 6.18 Hz, 1H, H10). 5.60 (ddd, 13.25. 4.53, 4.53 Hz,
1H, H6), 6.50 (ddd, J = 1325, 2.21, 2.21 Hz, 1H, H5), 7.07 (s, 1H, H3)

A 3 mg mixture of m-SMe—CHDa lm-SMe-COTa in an NMR tube was
dissolved in 0.75 ml of benzene-d5, purged with argon for 5 minutes and
irradiated at room temperature at 313 nm. After 2 hours (65% conversion), 1H
NMR analysis showed the formation of m-SMe-ACBa (69%), m-SMe-LCBmfi
(28%) and m-SMe-pBA (3%) as shown by integrating; doublet of doublets of
doublets at 5 .99, doublet at 6.08 and doublet at 6.8 ppm.

A 3 mg mixture of m-SMe-CHDa lm-SMe-COTa in an NMR tube was
dissolved in 0.75 ml of benzene-d5, purged with argon for 5 minutes and

irradiated at 365 run while placed in ice-water bath. After 2 hours irradiation

247

(~100% conversion), 1H NMR analysis showed the formation of m-SMe—ACBa
and m-SMe-LCBumfi in a ratio of 4.5 : 1. No m—SMe-pBA was detected.

Variable temperature NMR of the previous solution at 65°C for 30
minutes, showed that the starting material had totally converted to m-SMe-
LCBamfi.

 

 

m-SMe-ACB.

 

 

 

Mal;

1H NMR (C6D5) (500 MHz): 5 1.36 (dddd, J = 11.49, 7.07, 5.97, 1.77 Hz, 1H, H9),
1.65 (m, 1H, H9), 1.66 (s, 3H, SMe) 1.77 ( ddd, J = 12.37, 3.3, 5.96 Hz, 1H, H3), 1.85
(ddd, J = 12.37, 2.5, 2.5 Hz, 1H, H7), 1.9 (m , 1H, H7), 2.22 (s, 3H, CH3CO) 3.69
(ddd, J = 9.28, 8.4, 7.07 Hz, 1H, H10), 4.08 (ddd, J = 9.28, 8.4, 1.98 Hz, 1H, H10),
5.7 (s, 1H, H3), 5.75 (ddd, J = 9.72, 6.63, 1.77 Hz, 1H, H5), 5.99 (ddd, 9.72, 2.5,
0.60 Hz, 1H, H5)

248

In an NMR tube, 1.9 mg of the ketone was dissolved in 0.75 ml of
benzene-d5 and purged with argon for 5 minutes. It was irradiated using Pyrex
filtered light (A 2 290 nm ). The starting ketone totally disappeared after 60
minutes. 1H NMR analysis showed the formation of new peaks that corresponds
to two products; 4-acetyl-6-cyano-l1-oxatricyclo[6.3.O.03'6]undeca-1,4-diene (m-
CN-LCBs,anfi) and 4-acetyl-6—cyano-l 1-oxatricyclo[6.3.0.01'4]undeca-2,5-diene
(m-CN-ACBS) in a ratio of 3.5 : 1.0 respectively (NMR integration of singlet at
5.54 and doublet of doublets at 5.8 ppm). When the solution was left at room
temperature for 24 hours, 1H NMR showed the formation of new signals which
were attributed to 4-acetyl-6-cyano-11- oxabicyclo[6.3.0]undeca-l,3,5-triene (m-
CN-COTS).

4.7 mg of the ketone in 1.0 ml of benzene-d6 was irradiated in an NMR
tube at 313 am. After 17 minutes (2% conversion) NMR analysis showed the
formation of m-CN-COTS. After 1h, 45 minutes NMR showed the formation of m-
CN-COTs, m-CN-ACBS, and m-CN-LCBsMfi in a ratio of 1 : 1.66 : 20.3 (NMR
integration of doublet at 6.68, doublet at 5.38 and singlet at 5.55 ppm). After 3 h
the ratio became 1: 2 : 23. After 4h, 30 minutes the ratio became O: l : 12.

 

 

m-CN-ACB,

 

 

 

1H NMR (C60,) (300 MHz) ( partial spectrum): 5 1.92 (s, 3H, COCHg),. 3.26 (m,
1H. H16). 3.43 ( dt, J = 2.75, 8.58 Hz, 1H. H10), 537 (d, J = 2.8 Hz, 1H, H3). 5.80
(dd, J = 2.8, 0.5 Hz, 1H, Hz), 6.34 (br d, J: 2.8 Hz, 1H, H5)

A 0.3 g sample of the m-CN-pBA in 250 ml dry benzene was irradiated
using Pyrex filtered light (2» 2 290 nm ) for 24 hours. The mixture was purified by
column chromatography (silica gel, 20% ethyl acetate/hexanes) to give 0.02 g of
starting material, 0.03 g 4-acetyl-6-cyano-ll-oxatricyclo[6.3.0.03'6]undeca-1,4-
diene (m-CN-LCBs,anti) and 0.085 g 4-acetyl-6-cyano-11- oxabicyclo[6.3.0]-
undeca-1,3,5-triene (CN-COTS).

A 4.1 mg sample of m-CN-COTs. in 0.75 ml benzene-dé in an NMR tube
was irradiated for 25 minutes using Pyrex-filtered light. 1H NMR analysis showed
the formation of 4-acetyl-6-cyano-l l-oxatricyclo[6.3.0.03'6]undeca-1,4-diene (m-
CN-LCBs,anfi) and 4-acetyl-6-cyano-1l-oxatricyclo[6.3.0.01'4]undeca-2,5-diene
(m-CN-ACBS) in a ratio of 1.0 : 3.5 respectively (NMR integration of singlet at
5.55 and doublet at 5.38 ppm).

250

 

 

 

 

 

. .
‘i~.'\-I Eli-1.211.111 |._l"-r.’"'..9"l' \- 0

1H NMR (Cng) (500 MHz): 5 1.0 (dddd, J = 12.0, 9.26, 8.59, 7.61 Hz, 1H, H9),
1.13 (dddd, J = 12.0, 7.3, 6.49, 4.32 Hz, 1H, H9), 1.82 (ddd, J = 15.0, 8.74, 1.14 Hz,
1H, H7), 1.84 (s, 3H, COCH3) 1.95 (dd, J = 15.0, 2.98, 1H, H7), 2.28 (m, 1H, H3),
3.35 (ddd, J = 8.7, 8.59, 6.49 Hz, 1H, H10), 3.46 (ddd, J = 8.7, 7.61, 4.2 Hz, 1H,
H10), 5.28 (dd, J = 8.23, 1.75 Hz, 1H, H2), 6.69 (d, 8.23 Hz, 1H, H3), 7.2 (broad, s,
1H, H5),

Homonuclear Decoupling NMR Experiment:

Irradiation of the multiplet at 2.28 ppm (dpwr = 20) caused the doublet of
doublets at 5.28 to be a doublet (J = 8.23 Hz). Irradiation at 3.4 ppm (dpwr = 25),
caused the signal at 1.0 ppm (dddd) to appear as a doublet of doublets (J = 12.0,
9.26 Hz) and the signal at 1.1 ppm (dddd) to appear as a doublet of doublets (J =
12.0, 7.3 Hz). Irradiation of the broad singlet at 7.2 ppm (dpwr = 15), caused the
doublet of doublets of doublets at 1.82 to appear as a doublet of doublets (J =
15.0, 8.74 Hz)

251

13C NMR (C6D6) (125 MHz): 5 26.01, 30.96, 32.06, 40.99, 69.20, 96.36, 115.30,
120.66, 130.34, 140.03, 140.73, 172.15, 195.8

UV-Visible (Benzene): km = 356 nm, e = 7110
MS (m/e): 215 (M+), 200, 172, 154, 144, 130, 117, 103, 89, 77, 55, 43 (base)

 

 

 

 

 

1H NMR (Cng) (500 MHz): 5 0.87 (dddd, J = 12.0, 11.7, 11.11, 8.63 Hz, 1H, H9),
0.99 (dd, J = 13.0, 11.9 Hz, 1H, H7), 1.23 (ddddd, J = 12.0, 7.9, 5.9, 0.90, 0.80 Hz,
1H, H9), 1.55 (m, 1H, H3), 1.61 (s, 3H, COCH3), 1.7 (broad dd, J = 13.0, 5.2 Hz, 1H,
H7), 3.29 (ddd, J = 11.7, 8.6, 5.9 Hz, 1H, H10), 3.59 (d, J = 6.5 Hz, 1H, H3), 3.62
(ddd, J = 8.63, 8.6, 0.8 Hz, 1H, H10), 4.99 (dd, J = 6.5, 2.5 Hz, 1H, H2), 5.54 (s, 1H,
H5)

Homonuclear Decoupling NMR Experiment:

Irradiation of the doublet of doublets of doublets (ddd) at 3.29 ppm (dpwr
= 25), caused the signal at 1.23 ppm (ddddd) to appear as a doublet of doublets
of doublets of doublets (dddd, J = 12.0, 7.9, 0.90, 0.80 Hz). Irradiation at 3.6 ppm

 

252

(dpwr = 20) caused the doublet of doublets of doublets of doublets (dddd) at
0.87 to appear as a doublet of doublets of doublets (ddd, J = 12.0, 11.7, 11.11 Hz),
and the doublet of doublets (dd) at 4.99 ppm to be a doublet (d, J = 2.5 Hz)

1H NMR (CDC13) (500 MHz): 5 1.6 (dd, J = 11.80, 13.00 Hz, 1H, H7), 1.73 (dddd,
J = 11.81, 11.63, 10.95, 8.40 Hz, 1H, H9), 2.21 (s, 3 H, COCH3), 2.23 (m, 1H, H9),
2.35 (m, 1H, H3), 2.57 (dd, J = 13.00, 5.01 Hz, 1H, H7), 3.90 (d, J = 6.6 Hz, 1H, H3),
3.93 ( ddd, J = 11.81, 8.60, 5.52 Hz, 1H, H10), 4.22 ( dd, 8.60, 8.40 Hz 1H, H10), 5.0
(dd, J = 6.4, 2.45 Hz, 1H, H2), 6.63 (s, 1H, H5)

The stereochemistry of the tricyclo compound was determined by 1H
NMR nOe experiment at -10°C (CDC13, 500 MHz). Irradiation of the bridgehead
proton, H3 (2.35ppm) induced enhancements of H93 (2.96%), H10 (2.3%), H105
(1.5%), and H75 (0.32%). Similarly irradiation of H5 (6.53 ppm) led to the
enhancement of H3 (3.02%) and H75 (1.37%). These results suggested that H3

and the cyclobutene ring are syn to each other.

\ \
9°) 1' .....‘\ H r
r‘r/\f/O\c:m—15% fits/6% \’H
2.3%—>H’c\ m°\ / 5H =>H’c\' /rk°\ /%H
/°\a/ %‘H‘M 2“”? if"
N///00.32%—>H H H //c1.37%J 1” H
_ , _ , .

In an NMR tube, 1.0 mg of the ketone was dissolved in 0.75 ml of CD3OD
and purged with argon for 5 minutes. It was irradiated using Pyrex filtered light (A

2 290 nm ). After 15 minutes (~ 50% conversion), the solution was colorless.

253

Yellow color started to develop a few minutes after stopping the irradiation.
NMR analysis showed the formation of new peaks that corresponds to two
products; 4-acetyl-6-amido-11-oxabicyclo[6.3.0]undeca-1,3,5-triene (m-Arnide-
COTS) and 4-acetyl-6-amido—11-oxatricyclo[6.3.0.01'4]undeca-2,5-diene (m-
Amide-ACBS) in a ratio of 1 : 1 (NMR integration of doublet of doublets at 5.5
and doublet at 6.3 ppm). The solution was left overnight in the dark at room
temperature, NMR showed that peaks corresponding to m-Amide-ACBS had
totally disappeared and the concentration of m-Amide-COTs was doubled. The
solution was irradiated for one more hour (~100% conversion), NMR was taken
immediately after irradiation to show that rn-Amide-ACBs was the major
component with trace of m-Amide-COTS. After 25 minutes, the m-Amide-COTS
: m-Amide-ACBS ratio was 1.3 : 1.0 and 1.8 : 1.0 after 35 minutes (NMR
integration of doublet at 7.3 and doublet at 6.3 ppm). When the solution was left
overnight in the dark rn-Amide-ACBS was totally converted to m-Amide-COTs.
Irradiation of the m-Amide-COTS for one hour converted it back to m-Amide-
ACBs.

Irradiation of m-Arnide-pBA was repeated in benzene-d5. After 80
minutes of irradiation, 1H NMR analysis showed the formation of m-Amide-
ACBS as the only product. The other regioisomer could not be detected by NMR.

To get a pure sample of m-Amide-ACBS for NMR analysis, 2.0 mg of the
ketone dissolved in 0.75 ml of CD3OD in an NMR tube degassed and irradiated
for 5 hours. The NMR tube was placed in a dry ice-acetone bath immediately
after irradiation. The tube was placed in a precooled NMR probe (-70°C) to slow

down rearrangement of the m-Arnide-ACBS to m-Amide-COTS.

 

 

m-Amide-ACB,

 

 

 

1H NMR (CD3OD) (500 MHz, -70°C) 5 1.77 (ddt, J = 9.9, 9.0 , 11.93 Hz, 1H, H9),
1.89 (ddt, J = 12.0, 2.57, 6.9 Hz, 1H, H9), 2.21 (s, 3H, CH3CO) 2.24 (ddd, J = 17.0,
5.7, 3.0 Hz, 1H, H7), 2.45 (m, 1H, H3), 2.71 (dd, J = 17.0, 3.0 Hz, 1H, H7), 3.71 (ddd,
J = 8.7, 8.2, 2.54 Hz, 1H, H10), 3.78 (ddd, J = 9.9, 8.2, 6.9 Hz, 1H, H10), 6.31 (d, J =
2.78 Hz, 1H, H3), 6.48 (dd, J = 2.78, 0.6 Hz, 1H, H2), 6.58 (broad, d, J = 2.88 Hz,
1H, H5)

Homonuclear Decoupling NMR Experiment:

Irradiation of proton at 6.48 ppm (dpwr = 10), caused the doublet at 6.31
to appear as a singlet. Irradiation of the doublet at 6.58 ppm caused the signal at
2.24 ppm (ddd) to appear as a doublet of doublets (dd, J = 17.0, 5.7 Hz) and the
doublet of doublets (dd) at 6.48 to be a doublet (d, J = 2.78 Hz). Irradiation at 3.8
ppm (dpwr = 25), caused the doublet of doublets of triplets (ddt) at 1.77 to be a
triplet (t, J = 11.93 Hz) and the doublet of doublets of triplets (ddt) at 1.89 to be
doublet of doublets (dd, J = 12.0, 6.9 Hz)

 

255

1H NMR (C6D6) (300 MHZ): 5 2.1 (s, 3H, CH3CO) 2.81 (ddd, J: 17.1, 2.8 Hz,
1H), 3.38 (ddd, J: 9.56, 8.15, 6.69 Hz, 1H, H10), 3.53 (dt, J = 2.69, 9.04 Hz, 1H.
H10), 5.6 (d, J = 2.8 Hz, 1H, H3), 5.97 (dd, J = 2.8, 0.6 Hz, 1H, Hz), 6.23 (d, J = 2.8
Hz. 1H. Ha) I

13c NMR (CD3OD) (125 MHz, -70°C): 5 24.15, 28.02, 30.12, 40.76. 67.97.
68.08, 92.37, 132.51, 132.89, 139.35, 140.99, 173.31, 212.84

A 1.0 g sample of the ketone in 500 ml dry methanol was irradiated using
Pyrex filter (3. 2 290 nm) for 24 hours. The mixture was purified by column
chromatography (silica gel, 40% ethyl acetate/hexanes) to give 0.3 g of 4-acetyl-
6-amido-l 1-oxabicyclo[6.3.0]undeca-1,3,5-triene (m-Amide-COTS).

 

 

 

 

 

I C ‘ O C .
_.‘. gr-l 2-11.." -'._:-1_ -01 '.-l_t‘-a-=_-. -l_'1‘ ll'é 11-"- 0

1H NMR (013301)) (300 MHz): 8 1.89 (ddt, J = 8.0, 10.40, 11.58, 1H, H9), 2.25 (m,
1H, H9), 2.37 (s, 3H, CH3CO) 2.44 (dd, J = 13.8, 7.9 Hz, 1H, H7), 2.89 (dd, J = 13.8,
2.8 Hz, 1H, H7), 3.05 (m, 1H, H3), 4.16 (ddd, J = 10.1, 8.3, 5.7 Hz, 1H, H10), 4.25
(ddd, J = 8.3, 8.3, 2.5 Hz, 1H, H10), 5.49 (dd, J = 8.5 , 2.0 Hz, 1H, H2), 7.16 (s, 1H,
H5), 7.30 (d, J: 8.5 Hz, 1H, H3)

256

13c NMR (c0300) (125 MHz, -40°C): 5 26.49, 29.23, 33.1, 44.31. 70.71. 97.05,
131.58, 132.36, 138.70, 142.05, 173.5, 175.38, 201.54

UV-Visible (Methanol): Kmax = 353 nm, e = 4707

In an NMR tube 1.3 mg of m-Me-pBA was dissolved in 0.75 ml of
benzene-d5 and purged with argon for 5 minutes. It was irradiated using Pyrex-
filtered light (3. 2 290 nm). The reaction course was monitored by 1H NMR. After
2 hours of irradiation (70% conversion), 4-acetyl-6-methyl-11-
oxatricyclo[6.3.0.01'4]undeca-2,5-diene (m-Me-ACBS) was the only product
detected by 1H NMR (12% yield, measured by using the solvent peak as an
internal standard). After 5 hours another product was detected, and was
characterized as a dim-methane product of m-Me-ACBS in a ratio of 1.0 : 2.17
(NMR integration of doublet of doublets at 5.13 and doublet at 5.9 ppm). This
ratio became 1.0 : 1.0 after four more hours of irradiation, and their formation yield

with respect to consumed starting material was 20% (combined).

 

 

 

 

 

1H NMR (CgHg) (500 MHz): 5 1.33 (ddt, J = 11.8, 2.9, 6.7 Hz, 1H, H9), 1.57
(broad singlet, 3H, CH3), 1.68-1.75 (m, 2H), 1.85- 1.91 (m, 2H), 2.13 (s, 3H,
COCH3), 3.52 (ddd, J = 9.27, 8.02, 6.99 Hz, 1H, H10), 3.67 (ddd, J = 8.8, 8.28,
2.88 Hz, 1H, H10), 5.5 (broad singlet, 1H, H5), 5.91 (d, J = 2.88 Hz, 1H, H3), 6.07
(dd, J = 2.8, 0.50 Hz, 1H, H2),

In an NMR tube, 2.4 mg of m-Me-pBA in 0.75 ml benzene-d5 was
degassed and irradiated using uranium glass filtered light (A 2 334 nm). The tube
was taped to the immersion well (this caused the solution temperature to be
slightly higher than room temperature). The reaction was followed by 1H NMR.
After 105 hours of irradiation (85% conversion), 1H NMR showed the formation
of m-Me-ACBS and 4-acetyl—2-methyl-11-oxatricyclo[6.3.0.01'4]undeca-2,5-
diene (m-Me—ACBa) in a ratio of 6.3 : 1.0 and with a chemical yield of 72% and
11.5% respectively (with respect to consumed m-Me-pBA). Irradiation was
continued until m-Me-pBA disappeared. The ratio became 8.0 : 1.0 and the
chemical yield was 60% and 7.5%. The experiment was repeated with placing the

258

NMR tube about one inch away from the immersion well. NMR showed the
formation of only m-Me-ACBS.

The solution was left at room temperature in the dark for two weeks. 1H
NMR showed that both (m-Me-ACBS) and (m-Me—ACBa) remained unchanged.
A catalytic amount of p-toluenesulfonic acid was added to the solution and
shaken. Yellow color was developed in a few seconds. 1H NMR showed that m-
Me-ACBs and m-Me-ACBa had disappeared with the formation of 4-acetyl-6-
methyl-l1-oxabicyclo[6.3.0]undeca-l,3,5-trienc (Me-COTt) and 4-acetyl-2-
methyl-1 1-oxabicyclo[6.3.0]undeca-1,3,5-triene (Me-COTa).

 

 

 

 

 

1H NMR (C5H6) (300 MHz) (partial spectrum): 5 1.48 (d, J = 1.60 Hz, 3H, CH3),
5.57 (ddd, J = 9.8, 6.2, 3.5 Hz, 1H, H6), 5.64 (q, J = 1.6 Hz, 1H, H3), 5.92 (ddd, J =
10.0, 2.5, 1.3 Hz, 1H, H5)

259

 

 

 

 

 

'6-‘\"H'l ’ ..‘7' .11 1 1'31.“ '!'l'll'\l' .

1H NMR (C5H5) (300 MHz) (partial spectrum): 5 5.65 (dt, J = 12.6, 4.39 Hz, 1H,
H6). 6.58 (dt, J = 12.6, 232 Hz, 1H, H5), 6.83 ( s, 1H, H3),

In an NMR tube 2.4 mg of m-Me-pBA dissolved in 0.75 ml benzene-d5
was degassed and irradiated for 7 hours at 55°C using uranium filtered light (A 2
334 nm). 1H NMR analysis showed the formation of 4-acetyl-2-methyl-11-
oxauicyclo [6.3.0.03'6]undeca-1,4 diene (m-Me-Lcrimnfi) and rn-Me-ACBt in
a ratio of 4.0 : 1.0 (NMR integration of doublet at 6.04 and doublet at 5 .92 ppm).
Irradiation was continued for 48 more hours (90% conversion). The ratio became
1.0 : 1.7 while chemical yields were 3.6% and 6.2% respectively (with respect to
m-Me-pBA consumed).

Similarly, 3.4 mg of m-Me-pBA in 0.75 ml benzene-d5 was irradiated at
365 nm (during irradiation the solution became warm from the lamp). After 24
hours irradiation (~ 33% conversion), 1H NMR showed the formation of m-Me-
LCBamfi and m-Me-ACBS in a ratio of 2.0 : 1.0 (NMR integration of doublet at
6.08 and s at 5.91 ppm) and chemical yields of 67% and 33% with respect to m-
Me-pBA consumed. After 100 hours irradiation, the ratio became 1 : 1.2 while

chemical yield went down to 11% and 9%.

260

The previous experiment was repeated. 1H NMR showed the formation of
three products; rn-Me-ACBS, m-Me-ACBa, and m-Me-LCBMmfi with a ratio of
2.1 : 3.3 : 1 (NMR integration of doublet at 6.08, doublet at 5 .95, and doublet at
6.08 ppm). At the end of irradiation the ratio became 3.5 : 5.5 : 1.

 

 

m-Me-LCBunu

 

 

 

1H NMR (Col-16) (300 MHz): 5 0.86 (ddd, J = 12.80, 11.60, 6.0 Hz, 1H, H7), 1.21
(dddd, J = 11.57, 11.57, 11.41, 8.39 Hz, 1H, H9), 1.55 (dddd, I: 11.56, 7.41, 5.43.
0.95 Hz, 1H, H9), 1.78 (ddd, J = 12.9, 5.2, 2.0 Hz, 1H, H7), 1.92 (m, 1H, H3), 2.27 ( d,
J = 2.27 Hz, 3H, CH3), 2.66 ( ddt, J = 5.97, 4.2, 1.4 Hz, 1H, H5), 3.38 (dd, J = 4.10,
0.75 Hz, 1H, H3), 3.52 (m, 1H, H10), 3.81 (dt, J =.55, 8.24 Hz 1H, H10), 6.03 (d, J =
1.3 Hz, 1H, H5)

Homonuclear Decoupling NMR Experiment:
Irradiation of proton at 6.03 ppm caused doublet of doublets of triplets (ddt) at
2.66 to appear as a doublet of doublets of doublets (ddd, J = 5.97, 4.2, 1.4 Hz )

261

A 1.0 g sample of m-Me-pBA in 500 ml dry benzene was irradiated using
Pyrex filtered light (3. 2 290 nm) for 24 hours. The mixture was purified by
column chromatography (silica gel, 10% ethyl acetate/hexanes) to give 0.1 g of 4-
acetyl-6-methyl-11- oxabicyclo[6.3.0]undeca—1,3,5-t1iene (m-Me-COTS).

 

 

 

 

 

‘r‘.-'i 111'-1- -1."~..1 -11 ' .-1I'-r-=...!d'1' ll'U' .

1H NMR (C5116) (300 MHz): 5 1.11 (dddd, J = 11.6, 9.0, 8.7, 7.9 Hz, 1H, H9), 1.28
(ddt, J = 11.5, 4.10, 6.6 Hz, 1H, H9), 1.6 (d, J = 1.46 Hz, 3H, CH3), 1.78 ( dd, J =
14.07, 2.54 Hz, 1H, H7), 1.99 (ddd, J = 14.05, 9.58, 0.90 Hz, 1H, H7), 2.08 (s, 3H, .
COCH3), 2.41 (m, 1H, H3), 3.51 (dt, J = 6.32, 8.64 Hz, 1H, H10), 3.64 (ddd, J = 8.6,
7.7, 4.0 Hz, 1H, H10), 5.58 (dd, J = 8.20, 1.90 Hz, 1H, H2), 6.54 ( broad singlet, 1H,
H5), 6.84 (d, J = 8.20 Hz, 1H, H3),.

In an NMR tube 2.0 mg of m-Me-COTS was dissolved in benzene-d5,

degassed and irradiated at 365 nm for four hours. 1H NMR showed the formation
of m-Me-ACBS and m-Me-LCBmfi in a ratio of 3.6 : 1.0

 

 

m-Me-LCB,

 

 

 

 

- - - - - ' hmdecazlAdisnLtm-Me-LCBs,antilt

1H NMR (C6115) (300 MHz) (partial spectrum): 5 0.99 (s, 3H, CH3 ) 1.86 (s, 3H,
COCH3), 3.05 (broad d, J = 6.32 Hz, 1H, H3), 3.49 ( ddd, J = 11.8, 8.67, 5.55 Hz,
1H, H10), 3.8 (dt, J = 0.80, 8.80 Hz, 1H, H10), 5.32 ( dd, J = 6.35, 2.5 Hz, 1H, H2),
6.14 ( s, 1H, H5),

W

In an NMR tube, a solution of 3.8 mg of m-Me-pBA and 2.2 mg of
methylbenzoate in 0.75 ml of benzene-dg was purged with argon, placed in ice-
water bath and irradiated using Pyrex-filtered light. After 1 hour, 1H NMR
showed the presence of starting material (84.8%) and rn-Me-ACBS (5.4%). After
four hours the percentages became 55.2% and 13.1% where as after 9 hours they
became 35.5% and 17.1% respectively. Ratios were determined using 1H NMR
integration and methyl benzoate as the internal standard. The following peaks
were chosen for the integration; doublet of doublets at 8.1 ppm for methyl
benzoate, the multiplet at 5 .01-5.16 ppm for m-Me-pBA and doublet at 5.91 ppm
for m-Me-ACBS.

263

The previous experiment was repeated at 55°C. After 40 minutes, 1H
NMR showed the presence of starting material (65%), m-MeACBs (7.3%) and m-
Me-LCBganti (14.2%). After 4 hours the percentages became 27.5%, 10.0% and
13.6% respectively. Doublet at 6.03 ppm was chosen for NMR integration for m-
Me-LCBa,anti.

In an NMR tube, 1.3 mg of m-tBu-pBA was dissolved in 0.75 ml of
benzene-d5 and purged with argon for 5 minutes. It was irradiated using Pyrex-
filtered light (A 2 290 nm) at room temperature. The reaction course was
monitored by 1H NMR. After 40 minutes of irradiation , 4-acetyl-6-t-butyl-11-
oxatricyclo[6.3.0.01'4]undeca-2,5-diene (m-tBu-ACBS) was the only product

detected by 1H NMR. After 20 hours irradiation, starting material totally
disappeared and rn-tBu-ACBS was the only product detected by 1H NMR

analysis.

 

 

m-‘Bu-ACB,

 

 

 

264

WWW

1H NMR (C5115) (500 MHz) (partial spectrum): 5 0.95 (s, 9 H,t-Bu) 2.15 (s, 3H,
CH3CO) 3.56 (ddd, J = 9.28, 8.17, 7.07 Hz, 1H, H10), 3.68 (ddd, 1: 8.83, 7.95,
2.87 Hz, 1H, Hro). 5.68( broad d, J = 2.35 Hz, H5), 5.88 (d, J = 2.85 Hz, H3), 6.10
(dd, J = 2.75, 0.55 Hz, H2),

A 0.5 g sample of m-tBu-pBA in 150 ml of dry benzene was irradiated
using Pyrex filtered light (3. 2 290 nm). The solution became warm during
irradiation. After 12 hours, solvent was evaporated and 1H NMR showed the
formation of a new product. Preparative TLC purification (5 % ethyl acetate-
hexanes) led to the isolation of 0.05 g of unreacted starting material and 0.15 g of

the new product which was identified as 4-acetyl-2-t-butyl-1l-oxatricyclo
[6.3.0.03'6]undeca-1,4-diene (rn-tBu-Lcriunfi).

 

 

 

 

 

265

1H NMR (cant) (500 MHz): 5 0.85 (ddd, J = 12.4, 11.93, 6.19 Hz, 1H, H7), 1.18
(tdd, J: 11.7, 11.05, 8.62 Hz, 1H, H9), 1.53 (dddd, I: 11.71, 7.74, 5.53, 1.1 Hz, 1H,
H9), 1.67 (s, 9 H, t-Bu) 1.74 ( ddd, J = 12.50, 4.86, 1.55 Hz, 1H, H7), 1.81 (s, 3H,
CH3CO ) 2.02 (tdd, broad, J = 11.5, 7.3, 4.1 Hz, 1H, Hg), 2.67 (ddt, J = 5.96, 4.3,
1.55 Hz, 1H, H5), 3.47 ( ddd, J = 11.71, 8.62, 5.74 Hz, 1H, H10). 3.77 (td, J= 8.17,
1.11 Hz, 1H, H16). 3.82 (dd, J: 4.2, 0.88 Hz, 1H, H3), 5.97 (d, J: 1.3 Hz, 1H, H5)

Homonuclear Decoupling NMR Experiment (C5D5, 300 MHz):

Irradiation of proton at 2.67 ppm caused doublet at 5.97 ppm to appear as
a singlet, doublet of doublets at 3.88 ppm to appear as a doublet (J = 0.88 Hz),
doublet of doublets of doublets (ddd) at 0.85 to appear as a doublet of doublets
(J = 12.3, 12.3 Hz) and doublet of doublets of doublets (ddd) at 1.74 to be
doublet of doublets (dd, J = 12.5, 4.8 Hz )

13c NMR (c606) (75 MHz): 5 25.16, 29.90, 31.45, 31.83, 34.04, 34.47, 40.69,
41.74, 68.40, 111.21, l44.77,l48.57. 154.02, 192.63

MS (m/e): 246(M+), 231, 203, 189, 177, 163, 147, 119, 105, 91, 77, 55 , 43(base)

The stereochemistry of m-tBu-LCBafimfi was determined using 1H NMR
nOe experiment at 25°C (benzene-d5, 500 MHz). Irradiation of the bridgehead
proton, H6 (2.67 ppm) induced enhancements of H5 (7.6%), H3 (8.6%) and
H7a(3.64%). Similarly, irradiation of H5 lead to the enhancement of H6 (4.46%),
Hg (2.86%) and CH3CO (6.45%). These results suggested that Hg and the

cyclobutene ring are syn to each other.

266

   

A sample of m-tBu-LCBafinfi in benzene-d6 was treated with a catalytic
amount of p-toluenesulfonic acid. 1H NMR showed the formation of a new
compound in equilibrium with m-tBu-LCBa,anfi in a ratio of 1 : 1.16 (NMR
integration of doublet at 5.97 and doublet at 5.94 ppm). When m-tBu-LCBafinfi
was dissolved in CDCl3 (which has acidic impurities) the same mixture was
observed by 1H NMR. This mixture was separated by preparative TLC (5%
ethylacetate/ hexanes) and the new product was identified as 4-acetyl-2-t-butyl-
ll-oxatricyclo [6.3.0.03'6]undeca-lg,4 diene (m-tBu-LCB'mti).

m-tBu-LCB'a,anti in benzene-d6 was treated with a crystal of p-
toluenesulfonic acid. 1H NMR showed the formation of the same 1 : 1 mixture of
m-tBu-LCBmfi and m-tBu-LCB'mfi.

 

 

t-Bll-LCB ' I’ll!“

 

 

 

267

l-! H -l Il-ll- |' 11530023] I _] 44. C 43.12
1 93' I')

1H NMR (C5D5) (500 MHz): 5 1.03 (s, 9 H, t-Bu) 1.72 (s, 3 H, CH3CO) 1.87
(broad d, J = 16.57 Hz, 1H, H7), 2.25 (m, 3H), 2.69 (dd, J = 7.6, 4.2'Hz, 1H, H5),
2.88 (broad s, 1H, H2), 3.31 (d, J = 4.2 Hz, 1H, H3), 3.94 (ddd, J = 10.39, 9.05, 9.05
Hz, 1H, H10), 4.03 (ddd, J = 10.16, 8.84, 7.2 Hz, 1H, H10), 5.94 (d, J = 1.33 Hz, 1H,
H5).

Homonuclear Decoupling NMR Experiment (C5D5) (500 MHz).

Irradiation of protons at 2.24 ppm caused doublet of doublets of doublets
(ddd) at 4.03 ppm to appear as a doublet (J = 9.05 Hz), doublet of doublets (ddd)
at 3.94 ppm to appear as a doublet (J = 9.05 Hz), doublet of doublets (dd) at 2.69
ppm to appear as a doublet (J = 4.0 Hz) and doublet at 1.87 to appear as a singlet.
Irradiation of proton at 3.31 ppm caused doublet of doublets (dd) at 2.69 ppm to
be a doublet (J = 7.7 Hz).

13c NMR (C60,) (75 MHz): 5 24.86, 23.47, 33.93, 36.65, 39 11.42.51, 44.87,
68.00, 101.84, 145.11, 148.21,153.1, 192.4

MS (m/e): 246 (M+), 231, 189, 175, 147, 120, 91, 84, 57 , 43 (base)

The stereochemistry of m-tBu-LCB'mti was determined using 1H NMR
nOe experiment at 35°C (benzene-d5, 500 MHz). Irradiation of H5 (2.69 ppm)
induced enhancements of H5 (5.4%) and H3 (2.3%). Irradiation of H5 lead to the
enhancement of H5 (1.3%), H2 (2.8%), and the methyl group (2.8%).

268

 

 

Similarly, irradiation of H3 caused enhancement of H5 (4.2%), H2 (4.8%),
and the t-butyl group (6.1%), while irradiation of H2 lead to the enhancement of
H3 (0.9%) and the t-butyl group (3.2%).

4.2%
,1, 11 ’2 ,1

        

 

H3C\

\ 1’} ll -
H 'Bu' ‘— 6.1% H Ruhr—3.2%
0 O 0.9% U

A 0.3 g sample of rn-tBu-pBA in 150 m1 of dry methanol was placed in a
container surrounding the emmersion well and purged with argon during
irradiation. The reaction container was surrounded with ice-water bath to prevent
heating of the reaction mixture, then it was irradiated using Pyrex-filtered light (A.

2 290 nm). After 6 hours, solvent was removed under vacuum. 1H NMR analysis
showed the formation of m-tBu-ACBS. N o m-tBu-LCBafimi was detected. The

269

photoproduct was isolated using preparative TLC (10% ethylacetate/hexane) as
4—acetyl-6-t-butyl-1 l-oxabicyclo[6.3.0]undeca—1,3,5-triene (m-tBu-COTS).

 

 

O

m-‘Bu-COT,

 

 

 

1H NMR (C5115) (500 MHz): 5 1.08 (s, 9H, t-Bu) 1.13 (dddd, J = 11.71,
11.71,10.83, 8.18 Hz, 1H, H9), 1.37 (m, 1H, H9), 2.05 (s, 3H, CH3CO) 2.2 (broad, d, J
= 13.48 Hz, 1H, H7), 2.27 (ddd, J = 13.38, 8.62, 0.85 Hz, 1H, H7), 2.47 (m, 1H, H3),
3.43 (ddd, J = 10.6, 8.52, 5.52 Hz, 1H, H10), 3.58 (ddd, J = 8.4, 8.4, 1.77 Hz, 1H,
H10), 5.55 (dd, J = 9.28, 2.3 Hz, 1H, H2), 6.75 (s, broad, 1H, H5), 6.82 (d, J = 9.28
Hz, 1H, H3)

Homonuclear Decoupling NMR Experiment (C5D5, 500 MHz):
Irradiation of the broad singlet at 6.75 ppm caused the broad doublet at
2.20 ppm to appear as a sharp doublet of doublets (dd, J = 13.48, 1.74 Hz).

270

W

In an NMR tube, a solution of 4.7 mg of m-tBu-pBA and 2.6 mg of
methylbenzoate in 0.75 ml of benzene-d5 was purged with argon, placed in ice-
water bath, and irradiated using Pyrex-filtered light After 1 hour, 1H NMR
showed the presence of starting material (94.6%) and m-tBu-ACBS (4.9%). After
4 hours the percentages became 66.0% and 14.6% where as after 9 hours they
became 30% and 19.1% respectively. The NMR tube was placed in boiling water
for 40 minutes. 1H NMR showed that m-tBu-ACBS remained unchanged. Ratios
were determined using 1H NMR integration and methyl benzoate as internal
standard. The following peaks were chosen for the integration; doublet of
doublets (dd) at 8.1 ppm for methyl benzoate, the multiplet at 5.15-5.2 ppm for m-
tBu-pBA and doublet at 5.88 ppm for m-tBu-ACBS.

The previous experiment was repeated at 55°C. After 40 minutes, 1H
NMR showed the presence of starting material (62.4%), m-tBu-ACBS (2.2%), and
m-tBu-LCBa,anti (20.1%). After 4 hours the percentages became 18.9%, 3.4%
and 27.9% respectively. The doublet at 5.97 ppm was chosen for NMR
integration for m-tBu-LCBmti.

Elll' (41.1%“,

In an NMR tube, 1.8 mg of m-Me-iPr-pBA was dissolved in 0.75 ml of
methanol-d4 and purged with argon gas for 5 minutes. It was irradiated at room
temperature using uranium glass-filtered light (A 2 334 nm). The reaction was
followed by 1H NMR. The starting material had totally disappeared after about
200 hours of irradiation. 1H NMR Showed the formation of 4-acetyl-6-isopropyl-
2-methyl-11-oxatricyclo[6.3.0.01'4]undeca-2,5-diene (m-Me-iPr-ACBS) as the

271

major product (65% with respect to all products formed). The olefinic proton
region showed only signals corresponding to m—Me-iPr-ACBs and trace amount
of its corresponding cyclooctatriene; 4-acetyl-6-isopropyl-2-methyl-11-
oxabicyclo[6.3.0]undeca-1,3,5-triene (m—Me—iPr-COTS). The solution was left at
room temperature in the dark for 3 days. 1H NMR analysis showed the formation
of 1 : 1 mixture of the two compounds.

A 0.15 g sample of m-Me-iPr-pBA was dissolved in 150 ml dry methanol.
The solution was placed in a container surrounding the emmersion well and
purged with argon during irradiation. The reaction container was surrounded
with an ice-salt bath to prevent heating of the reaction mixture, then it was
irradiated using Pyrex-filtered light (A 2 290 nm). After 2.5 hours, solvent was
removed using rotary evaporator. 1H NMR analysis of the crude product showed
the formation of m-Me-iPr-ACBS. Attempts to isolate a pure sample of this
product were not successful (preparative TLC, hexane/ethylacetate), the isolated
product (0.027 g) had some impurities which could not be separated from the
product.

A 0.4 g sample of m-Me-iPr-pBA was irradiated the same way as the
previous experiment. After the solvent was removed, 1H NMR showed the
formation of m-Me-iPr-ACBS. The crude product was dissolved in ethylacetate
and a crystal of p-toluenesulfonic acid was added to the mixture. The color
turned yellow immediately. Preparatory TLC (5 % ethylacetate/hexane) gave 0.61
g (15%) of the product. 1H NMR showed that the product was m-Me-iPr-Cors.

272

 

 

 

 

 

‘-; CIOIO. it ”11'; - -1,:_1 It I (1'14:- -9'1'11-

1H NMR (CD30D) (300 MHz): 5 1.07 (d, J = 6.08 Hz, 3H, CH3 of ipr), 1.08 (d, J
= 6.8 Hz, 3H, CH3 of ipr), 1.75 (broad s, 3H, 2-Me), 1.82 (dddd, J = 12.3, 6.2, 2.8,
2.8 Hz, 1H, H9), 2.15 (dddd, J = 12.3, 10.0, 8.6, 7.5 Hz, 1H, H9), 2.30 ( broad sept, J
= 6.8 Hz, 1H, ipr methine), 2.34 (m. 2H, H7), 2.35 (s, 3 H, CH3CO), 3.09 (m, 1H, Hg),
4.24 (ddd, J = 8.64, 8.64, 2.88 Hz, 1H, H10), 4.39 ( ddd, J = 9.87, 8.64, 6.17 Hz, 1H,
H10), 6.06 (broad s, 1H, H5), 7.04 (broad s, 1H, H3)

A 6.6 mg sample of m-Me-iPr-COTs was dissolved in 0.75 ml of
methanol-d4 and purged with argon gas for 5 minutes. The solution was
irradiated using Pyrex-filtered light (A 2 290 nm). After 40 minutes, 1H NMR
showed the formation of m-Me-iPr-ACBs as the only product. The solution was
placed in boiling water bath for one hour. 1H NMR showed that the compound
remained unchanged even after standing at room temperature for four days (note

that the methanol-d4 used in this experiment was different from the one used

before).

 

 

m-Me—‘Pr-ACB,

 

 

 

‘O' ' -.. ||r.| .-JJ‘ ‘NQZ . .. 'l l n C .

(rush/19m

1H NMR (013301)) (300 MHz): 5 1.02 (d, J = 6.8 Hz, 3H, CH3 of ipr), 1.04 (d, J =
6.8 Hz, 3H, CH3 of ipr), 1.72 (d, J = 1.59 Hz, 3H, 2-Me), 1.89 (m, 2H, H9), 2.10 (s,
3H, CH3CO ), 2.11 (ddd, J = 16.4, 5.6, 2.0 Hz, 1H, H7), 2.19 ( dd, J = 16.5, 4.3 Hz,
1H, H7), 2.27 (broad sept, J = 6.8 Hz, 1H, ipr methine), 2.35 (m. 1H, H3), 3.79 (dd, J
= 8.4, 4.0 Hz, 1H, H10), 3.80 (dd, J = 8.4, 6.7 Hz, 1H, Hro). 5.42 (dd, J = 2.0, 1.1 Hz,
1H, H5), 5.9 (d, J = 1.57 Hz, 1H, H3)

1H NMR ((361),) (300 MHz) ( partial spectrum): 5 0.945 (d, J = 6.36 Hz, 3H, CH3
of ipr) 0.949 (d, J = 6.86 Hz, 3H, CH3 of ipr), 1.53 (d, J = 1.53 Hz, 3H, 2-Me) 2.14
(s, 3H, CH3CO), 2.53 (m, 1H, H3), 3.57 (ddd, I: 8.67, 8.67, 7.21 Hz, 1H, H10), 3.71
(ddd, J: 8.6, 8.6, 3.3 Hz, 1H, H10), 5.64 ( broad s, 1H, H5), 5.68 (q, J = 1.51 Hz, 1H,
H3)

274

MM

In an NMR tube, 1.5 mg of m-Me-iPr-Mez-pBA was dissolved in 0.75 ml
of methanol-d4 and purged with argon gas for 5 minutes. It was irradiated at
room temperature using Pyrex-filtered light (A 2 334 nm). 1H NMR Showed the
formation of 4-acetyl-6-isopropyl-2-methyl-11-oxatricyclo[6.3.O.01'4]undeca-2,5-
diene (m-Me-iPr-Mez-ACBS) as the major product and another isomer in a ratio
of 9 : 1 (NMR integration of doublet at 1.74 and doublet at 1.64 ppm).

A 0.08 g sample of m-Me-iPr-Mez-pBA was dissolved in 150 ml of dry
methanol. The solution was placed in a container surrounding the emmersion well
and purged with argon during irradiation. The reaction container was surrounded
with an ice-salt bath to prevent heating of the reaction mixture, then it was
irradiated using Pyrex-filtered light (3. 2 290 nm). After 2.0 hours, solvent was
removed using rotary evaporator. 1H NMR analysis of the crude product showed
the formation of m-Me-iPr-Mez-ACBS. The oil was dissolved in 1 ml of ethyl
acetate and treated with a catalytic amount of p-toluenesulfonic acid. The color
turned yellow immediately. The product was isolated using preparatory TLC (5%
ethylacetate/hexane). 1H NMR showed the isolated product to be m-Me-iPr-
Mez-COTS (0.10 g, 12%).

 

 

m-Me-‘Pr-MefCOT,

 

 

 

 

"' "UIUOII O .‘UI'Q'I. - .,".|. .81 | .l'tiu _-|."'

1H NMR (CD30D) (300 MHz): 5 0.99 (d, J = 6.87 Hz, 3H, 9-Me), 1.15 (d, J =
6.86 Hz, 6H, isopropyl), 1.76 (broad singlet, 3H, 2—Me), 2.12 (m, 1H, H9), 2.23 (ddd,
J = 16.8, 10.11, 1.22 Hz, 1H, H7), 2.27 (broad septet, J = 6.6 Hz, 1H, ipr methine),
2.35 (s, 3H, CH3CO), 2.41 (ddd, J = 16.3, 3.69, 1.34 Hz, 1H, H7), 2.66 (m, 1H, H3),
3.78 (dd, J = 8.75 Hz, 1H, H10), 4.46 (dd, J = 8.75, 6.0 Hz, 1H, H10), 6.06 (broad, s,
1H, H5), 7.05 (s, 1H, H3)

Homonuclear Decoupling NMR Experiment:

Irradiation of methyl group at 0.99 ppm simplified the pattern of the
multiplet at 2.12 ppm. Irradiation of the olefinic proton at 6.06 ppm caused the
doublet of doublets of doublets (ddd) at 2.41 ppm to appear as a doublet of
doublets (dd, J = 16.3, 3.84 Hz) and the doublet of doublets of doublets (ddd)at
2.23 ppm to appear as a doublet of doublets (dd, J = 16.3, 10 Hz) and the broad
septet at 2.27 to appear sharp. Irradiation of the methyl group at 1.76 ppm
simplified the multiplet at 2.66 ppm to appear as a doublet of doublet of doublets
(ddd, J = 10.2, 4.15, 3.55 Hz)

The stereochemistry of rn-Me-iPr-Mez.COTs was determined using 1H
NMR nOe experiment at 25°C (methanol-d4, 500 MHz). Irradiation of the
bridgehead proton H3 lead to the enhancement of the methyl group at C9
(2.61%), H3 (1.06%), H9 (1.02%) and H103 (1.02%). Irradiation of H9 caused the
enhancement of H3 (1.17%), H105 (4.05%), H75 (2.04%) and the methyl group
attached to C9 (3.02%). Irradiation of the methyl group attached to C9 lead to the
enhancement of H3 ( 2.9%), H103 (1 .9%), H9 (2.7%) and H73 (1 .27%).

276

1.05%\\H
all, | EH; CIH3 L 533
O’KC/C3\C\\ 261% KIC/ C\\ 302%
H~C %a‘ /C 1 H'~c . H /
C ,\ a \ \ 3\ H
\>C\ c/C8\'9 C51 \/C\ 7c/C‘K '9 C1111)
4. r H 1,, .5
Prl H H 3‘ Pr' 5‘ f 3% so”,
CH, 11 CH3
1 C\ /
°=C\C/ C
I 29% \\ 19%
H‘C H /C$O
‘ 8 CH3\c’H
[KC/\‘I ’[110
Pr' 4 ’“H :=

3.1 mg of m-Me-iPr-Mez-COTS was dissolved in 0.75 ml of methanol-d4

and purged with argon gas for 5 minutes. The solution was irradiated using
Pyrex-filtered light (it 2 290 nm). After 30 minutes, 1H NMR showed the
formation of m-Me-iPr-Mez-ACBS as the only product.

 

277

 

 

m-Me-‘Pr-Mez-COT,

 

 

 

Winn-5mm

1H NMR (CD3OD) (500 MHz): 5 1.0 (d, J = 6.41 Hz, 3H, C9-Me), 1.01 (d, J =
6.85 Hz, 3H, isopropyl CH3), 1.03 (d, J = 6.85 Hz, 3H, isopropyl CH3), 1.74 (d, J =
1.57, 3H Hz, C2-Me), 1.87 (ddd, J = 10.99, 5.44, 2.43 Hz, 1H, H3), 2.04 (ddd, J =
16.79, 5.52, 2.87 Hz, 1H, H7), 2.11 ( s,3 H, CH3CO) 2.13 (m, 1H, H9), 2.18 (dd, J =
16.79, 2.43 Hz, 1H, H7), 2.27 (broad septet, J = 6.85 Hz, 1H, isopropyl methine),
3.31 (dd, J = 9.94, 7.95 Hz, 1H, H10); 3.86 (dd, J = 7.95, 7.95 Hz, 1H, H10), 5.42
(dd, J = 2.8, 0.90 Hz, 1H, H5), 5.87 (q, I = 1.54 Hz, 1H, H3)

Homonuclear Decoupling NMR Experiment:

Irradiation of proton at 2.27 ppm caused the doublet of doublets (dd) at
5.42 ppm to appear as a doublet, doublet at 1.01 ppm to appear as a singlet and
doublet at 1.03 ppm to appear as a singlet. Irradiation of olefinic proton at 5.42
ppm caused the doublet of doublets of doublets (ddd) at 2.04 ppm to appear as a
doublet of doublets (dd). Irradiation of methyl groups at ~ 1.02 ppm caused the
septet at 2.27 ppm to appear as a broad singlet .

278

The stereochemistry of Me-iPr-MLACBt was determined using lNMR
nOe experiments at 25°C (methanol-d4, 500 MHz). Irradiation of the methyl
group at C9 (1.0 ppm) induced enhancement of H3 (3.03%) and H103 (2.4%)
while irradiation of Hg (1.87 ppm) caused enhancement of the methyl group at 1.0
ppm (4.33%) and H103 (1.16%).

H CH3
c=ci 1.16%

(Si-(3 ’ ‘ .. 3.03% 1 CH3 Q/i

 

 

C '00" n H //G' ""l’ ‘u--
H‘c\ actr..'.1..\chH3 301...... 1:20
\C\ / :‘c\\c /H ‘9 4.133%
CH3 / 3 H CH3 / \§\ H
/ H H /C\ H H
CH3 CH3 H

In an NMR tube, 1.0 mg of rn-Me-oBA was dissolved in 0.75 ml benzene-
d5 and purged with argon gas for 5 minutes. The solution was irradiated using
Pyrex-filtered light (A 2 290 am). After 100 minutes irradiation (75% conversion),
1H NMR showed the formation of new peaks corresponding to 6-acety1-2-
methyl-ll-oxatricyclo [6.3.0.03'6]undeca-l,4-diene (m-Me-o-LCBs,anti) as the
only product (90% yield with respect to reacted starting material). When a
catalytic amount of p-toluenesulfonic acid was added, yellow color developed

immediately. 1H NMR showed that peaks corresponding to m-Me-o-LCBs,anti

279

had totally disappeared with the formation of new peaks corresponding to 6-
acetyl-2-methyl-l 1-oxabicyclo[6.3.0]undeca—1,3,5-triene (m-Me-o-COTS).

A 0.3 g sample of m-Me-oBA in 150 ml dry benzene was irradiated using
Pyrex-filtered light (A 2 290 nm) for 5 hours. After removing the solvent under
vacuum, 1H NMR analysis showed the formation of m-Me-o-LCBs,anti. After
preparative TLC (10% ethylacetate/hexanes), 0.073 g of m-Me-o-COTs was

isolated.

 

 

 

 

 

0-.‘.--,‘§u‘1--.0..1 .. o ..-.. -'..-.- ...U-. o

1H NMR (061),) (300 MHz): 8 1.20 (dddd, J = 12.91, 6.6, 3.3, 3.3 Hz, 1H, H9),
1.59 (dddd, J = 12.55, 9.34, 8.25, 7.42 Hz, 1H, H9), 1.87 (s, broad, 3H, Cz-Me), 1.92
(s, 3H, CH3CO), 2.58 (broad, dd, J = 17.3. 3.84 Hz, 1H, H7), 2.68 (broad, dd, J =
17.3, 10.17 Hz, 1H, H7), 2.94 (m, 1H, H3), 3.64 (ddd, J = 8.52, 8.52, 3.52 Hz, 1H,
H10). 3.81 (ddd, J = 8.79, 8.79, 6.32 Hz, 1H, H10), 5.48 (dd, J = 12.36, 6.59 Hz, 1H,
H4), 5.94 (d, J = 12.36 Hz, 1H, H3), 6.61 (broad, d, I: 6.59 Hz, 1H, H5)

1H NMR (CDCI3) (300 MHz): 8 1.71 (broad, s, 3H, Cz-Me), 1.86 (dddd, J = 12.22,
6.17, 2.96, 2.96 Hz, 1H, H9), 2.22 (dddd, J = 12.22, 9.70, 8.50, 7.47 Hz, 1H, H9),
2.33 (s, 3H, CH3CO), 2.67(broad, d, J = 6.81 Hz, 2H, H7), 3.2 (m, 1H, H3), 4.22
(ddd, J = 8.56, 8.56, 3.05 Hz, 1H, H10), 4.38 (ddd, J = 9.70, 8.67, 6.29 Hz, 1H, H10),

280

5.90 (dd, J = 12.37, 6.8 Hz, 1H, H4), 6.04 (d, J = 12.36 Hz, 1H, H3), 7.0 (broad, d, J
= 6.80 Hz, 1H, H5),.

In an NMR tube, 3.1 mg of m-Me-o—COTS in 0.75 ml of benzene-d5 was
irradiated at A. = 365 nm for 40 minutes. 1H NMR analysis showed the complete
disappearance of m-Me-o-COTs peaks with the appearance of peaks

corresponding to m-Me-o—LCBs,ami.

 

 

m-Me-o-LCme

 

 

 

1H NMR (C6D5) (500 MHz): 51.23 (dddd, J= 11.71, 11.71, 11.27, 8.39 Hz, 1H,
H9), 1.43 (dd, J = 12.95, 11.93 Hz, 1H, H7), 1.50 (dddd, J = 11.71, 7.73, 5.52, 0.89
Hz, 1H, H9), 1.79 (dd, J = 12.95, 7.96 Hz, 1H, H7), 1.81 (d, J = 2.21 Hz, 3H, Cz-Me),
1.85 (s, 3H, CH3CO), 2.1 (m, 1H, H3), 3.17 (broad, s, 1H, H3), 3.52 (ddd, J = 11.93,
8.4, 5.52 Hz, 1H, H10), 3.82 (ddd, J = 8.4, 8.4, 0.88 Hz, 1H, H10), 5.81 (d, J = 2.88
Hz, 1H, H5), 5.93 (dd, J = 2.88, 0.89 Hz, 1H, H4)

281
nOe Experiment;

The stereochemistry of m—Me-o-LCBs,anfi was determined using 1H NMR
nOe experiments at 15°C (benzene-d5, 500 MHz). Irradiation of H4 (H5 was
partially irradiated) led to the enhancement of H3 (5 .8%) and H3 (1.75%).
Irradiation of H5 (H4 was partially irradiated) induced enhancement of H3 (2.4%),
H3 (4.1%) and the acetyl group (2.5%). Irradiation of H3 led to the enhancement
of H4 (8.0%), CH3 (6.5%), acetyl group (6.1%) and H3 (1.0%). Irradiation of H3
induced enhancement of H4 (2.0%), H5 (3.71%), H105 (1 .94%).

 

1 % 58% 3% 24% CH:
"\ , I
:f-(g: 2::Ic8/11 1.1 Kc/rci\ ’H
8.4% 100% 3 I1 1 h.
1.c\75% r[\9>BHH “/C 6 413:“ 8 9f H
\g‘u H .7 %‘H
o H ‘9‘11 H ch o ,‘f‘H H
25%
80% 20%

fl 0H.<—65% {\H CH:

H g 1.211%
ri/2\ /fi\ H JFi/2\ 1/11\ ’11
c: 3 1"? 10 %H 3'71'K1i9/1F’M
\ 6 10% GK9/ 1/ ”(a 7/

In an NMR tube, 1.8 mg of m-CF3-pBA was dissolved in 0.75 ml of
methanol-d4 and purged with argon for 5 minutes. It was irradiated using Pyrex
filtered light (7t 2 290 nm). After 80 minutes of irradiation, 1H NMR analysis

282

showed the formation of 4-acetyl-6-trifluoromethyl-ll-oxatficyclo[6.3.0.01'4]-
undeca-2,5-diene (m-CF3-ACBS).

The irradiation was also carried out in benzene, in an NMR tube, 1.8 mg of
m-CF3-pBA was dissolved in 0.75 ml of benzene-d5 and purged with argon for 5
minutes. It was irradiated using Pyrex filtered light (A 2 290 nm). After 145
minutes of irradiation, 1H NMR analysis showed the formation of 4-acetyl-6-
trifluoromethyl-ll-oxatricyclo[6.3.O.01'4]undeca-2,5-diene (m-CF3-ACBS) and 4-
acetyl-Z-trifluoromethyl-ll-oxatricyclo [6.3.0.03'6]undeca-l,4-diene (m-CF3-
LCBa,anti) in a ratio of ~ 2 : 1 (NMR integration of doublets at 5.9 and 5.46
ppm)

In an NMR tube, 4.0 mg of m-CF3-pBA in 0.9 ml of benzene-d6 was
purged with argon, placed in ice-water bath, and irradiated for two hours using
Pyrex-filtered light. 1’H NMR showed the formation of m-CF3-ACBS with traces
of m-CF3-LCBmfi.

 

 

m-CF3-ACB.

 

 

 

W

1H NMR (C60,) (300 MHz) (partial spectrum): 5 6.48 (m, 1H, H5). 5.89 (d, J = 2.8
Hz, 1H, H3). 5.46 (d, J = 2.8 Hz, 1H, H2), 2.01 (s, 3H, (311300)

283

1H NMR (CD3OD) (300 MHz) (partial spectrum): 5 2.2 (s, 3H, CH3CO) 6.49 (d, J
= 2.96 Hz, 1H, H3). 6.46 (m, 1H, H5), 6.33 (d, J = 2.96 Hz, 1H, H2)

 

 

m-CIQ-LCBW“

 

 

 

1H NMR (C6D5) (300 MHz): 8 0.55 (ddd, J = 12.81, 11.88, 6.02 Hz, 1H, H7), 0.88
(tdd, J = 11.88, 11.27, 8.66 Hz, 1H, H9), 1.23 (m, 1H, H9), 1.44 (ddd, J = 12.78, 5.21,
1.55 Hz, 1H, H7), 1.80 (m, 1H, H3), 1.88 (s, 3H, CH3CO) 2.53 (ddt, J = 6.06, 4.39,
1.43 Hz, 1H, H6), 3.28 (ddd, J = 11.71, 8.75, 5.82 Hz, 1H, H10), 3.65 (td, J = 8.8, 1.0
Hz, 1H, H10). 3.77 (d, J = 4.39 Hz, 1H, H3), 5.91 (d, J = 1.37 Hz, 1H, H5),.

In an NMR tube, 1.4 mg of m-Est-pBA was dissolved in 0.75 ml of
benzene-d5 and purged with argon for 5 minutes. It was irradiated using Pyrex
filtered-light 0. 2 290 nm). After 45 minutes, 1H NMR showed the formation of 4-
acetyl-6-methoxycarbonyl-l l-oxatricyclo[6.3.O.O3'6]undeca-1,4-diene (m-Est-
LCBs,ami) and 4-acetyl-6-methoxycarbonyl—11-oxatn'cyclo[6.3.O.Ol'4]undeca-
2.5-diene (m-Est-ACBS) with a ratio of 1 : 1 (NMR integration of s at 6.22 and

284

doublet at 5.6 ppm). When catalytic amount of p-toluenesulfonic acid was added,
the solution color turned yellow and 1H NMR showed the formation of 4-acetyl-
6—methoxycarbonyl-l 1-oxabicyclo[6.3.0]undeca-13.5-triene (m-Est-COTS) with
the disappearance of m-Est-LCBs,anti and m-Est-ACBS.

 

 

m'ESt'LCBmu

 

 

 

1H NMR (c606) (300 MHz) (partial spectrum): 5 6.22 (dd, J = 6.7, 2.4 Hz, 1H,
H2), 5.38 (s, 1H, H5)

 

 

m-Est-ACB,

 

 

 

285

W5);

1H NMR (cans) (300 MHz) (partial spectrum): 5 5.59 (d, J: 2.8 Hz, 1H, H3),
5.98 (dd, J = 2.8, 0.54 Hz, 1H, Hz). 7.24 (dd, J = 2.65, 0.60 Hz, 1H, H5)

 

 

 

 

 

. C
‘i' -H.'.H.' .'-__"1"".'-._' .11 I 1"'J."'..!l'l' H- -

£29151;

1H NMR (cans) (300 MHz) (partial spectrum): 5 5.46 (dd, J = 8.8, 2.0 Hz, 1H,
H2), 6.87 (d, J = 8.8 Hz, 1H, H3). 8.1 (s, 1H, H5)

In an NMR tube, 1.2 mg of OMe-m-AP was dissolved in 0.75 ml of
benzene-d5 and purged with argon gas for 5 minutes. The solution was irradiated
with Pyrex-filtered light 0. 2 290 nm) 1H NMR analysis showed the gradual
disappearance of the starting material with the appearance of very broad signals
between 0.3 and 3.5 ppm. Starting material was consumed in about 4 hours.

286
In an NMR tube, 1.1 mg of o-Ac-TB-H was dissolved in 0.75 ml of
benzene-d5 and purged with argon gas for 5 minutes. The solution was irradiated
using Pyrex-filtered light (A 2 290 nm). 1H NMR showed the disappearance of
peaks corresponding to starting material with the appearance of new peaks in
both the aromatic and aliphatic regions. No peaks corresponding to olefinic

protons were observed.

Walkman-Me;
In an NMR tube, 1.1 mg of p-Ac-TB-Me was dissolved in 0.75 ml of
methanol-d4 and purged with argon gas for 5 minutes. The solution was

irradiated using Pyrex-filtered light (A. 2 290 nm). 1H NMR showed that no

reaction even after 20 hours of irradiation.

In an NMR tube, 1.2 mg of p-NH-AP was dissolved in 0.75 ml of
methanol-d4 and purged with argon gas for 5 minutes. The solution was

irradiated using Pyrex-filtered light (7t 2 290 nm). 1H NMR Showed that no

reaction even after 50 hours of irradiation.

In an NMR tube 1.3 mg of p-NAc-AP was dissolved in 0.75 ml of
methanol-d4 and purged with argon gas for 5 minutes. The solution was
irradiated for 30 minutes using Pyrex-filtered light (7. 2 290 nm). 1H NMR
showed the formation of N-acetyl-(4-acetyl-11-azatricyclo[6.3.O.Ol'4]undeca-2,5-
diene) (p-NAc-AP-ACB) in low chemical yield.

287

 

 

 

 

 

p-NAc-ACB

1H NMR (CD3OD) (300 MHz) (Partial spectrum): 5 1.95 (s, 3H, CH3CON-), 2.3 (s,
3H, CH3CO), 5.52 (m ,1H, H5). 5.86 (m, 1H, Hé), 6.1 (d, J = 2.84 Hz, 1H, H3). 6.37 (d,
J = 2.84 Hz, 1H, H2)

2] | I . I II . 12‘

In an NMR tube 1.3 mg of p-Thio-AP was dissolved in 0.75 ml of
benzene-d5 and purged with argon gas for 5 minutes. The solution was irradiated
for 30 minutes using Pyrex-filtered light (71. 2 290 nm). 1H NMR Showed the
formation of 3-(4-acetylphenyl)tetrahydrothiophene, 4-acetylstyrene and 4-
acetyl-Ot-methylstyrene.

A 0.62 g sample of p-Thio-AP in 200 ml of dry benzene was irradiated
using Pyrex-filtered light (A. 2 290 nm) for 3 hours. After removing the solvent
under vacuum, 1H NMR analysis showed the formation of three products with
the disappearance of starting material. Products were separated using preparative
TLC (10% ethylacetate/hexanes). 1H NMR analysis showed that these products
are; 4-acetylstyrene, 4-acetyl-0t-methylstyrene and 3-(4-acetylphenyl)tetrahydro—
thiophene. 4-Acetylstyrene and 4-acetyl-0t-methylstyrene were not separated

288

from each other. 1H NMR was taken of the mixture while mass spectra and hi-

resolution mass spectra were done by the aid of GC separation.

 

 

 

 

W

1H NMR (CDCI3) (500 MHz): 5 2.579 (s, 3H, CH3CO), 5.38 (dd, J = 10.82, 0.66
Hz, 1H), 5.88 (dd, J = 17.45, 0.66 Hz, 1H), 6.74 (dd, J = 17.45. 10.82 Hz, 1H), 7.47
(d, J = 8.17 Hz, 2H), 7.91 (d, J: 8.17 Hz, 2H)

MS (m/e): 146 (M+), 131 (base), 103, 77, 51, 43

[Ii-Res MS: CloHloO, Calculated: 146.0732, Found 146.0736

 

 

 

 

289
1H NMR (CDC13) (500 MHz): 5 2.16 (dd, J = 1.33, 0.66 Hz, 3H, CH3), 2.583 (s,
3H, CH3CO) 5.19 (dq, J = 1.33, 1.33 Hz, 1H), 5.46 (dq, J = 1.33, 0.66 Hz, 1H), 7.54
(d, I: 8.17 H, 2H), 7.91 (d, J: 8.17 Hz, 2H)

MS (m/e): 160 (M+),145 (base), 115, 91, 63, 51, 43

Iii-Res MS: C11H120, Calculated: 160.0888, Found 160.0889

0 4 .
3
O 1s

 

 

 

 

 

1H NMR (CD30D) (500 MHz): 5 2.07 (dddd, J = 12.37, 10.09, 9.28, 7.29 Hz, 1H,
H4), 2.41 (dddd, J = 12.37, 5.95, 5.62, 3.76 Hz, 1H, H4), 2.58 (s, 3H, CH3CO), 2.90
(dd, J = 10.38, 9.28 Hz, 1H, H2), 2.95 (ddd, J = 10.39, 6.9, 3.75 Hz, 1H, H5), 2.96
(ddd, J = 10.39, 9.4, 5.95 Hz, 1H, H5), 3.15 (dd, J = 10.38, 9.28 Hz, 1H, H2), 3.42
(dddd, J = 10.09, 9.28, 6.85, 5.62 Hz, 1H, H3), 7.45 (d, J = 8.15 Hz, 2H), 7.95 (d, J
= 8.15 Hz, 2H)

MS (m/e): 206 (M+), 191, 163, 145, 115, 103, 91, 77. 60, 43

290

In an NMR tube 1.5 mg of o-TFA-AP was dissolved in 0.75 ml of
benzene-d5 and purged with argon for 5 minutes. It was irradiated using Pyrex-
filtered light 0. 2 290 nm). After 15 minutes of irradiation (40% conversion), In
NMR.showed the formation of 6-a,a,a-trifluoroacetyl-11- oxabicyclo[6.3.0]-
undeca-1,3,5-triene (o-TFA-COTS).

A 1.0 g sample of o-TFA-AP in 500 ml dry benzene was irradiated using
Pyrex-filtered light (A. 2 290 nm) for 4 hours. Solvent was removed under
vacuum. The mixture was purified by column chromatography (silica gel, 10%
ethyl acetate/hexanes) to give 0.38 g of o-TFA-COTS.

 

 

o-TFA-COT

 

 

 

1H NMR (CDCI3) (300 MHz): 5 1.91 (dddd, J = 11.71, 10.92, 10.92, 8.09 Hz, 1H,
H9), 2.3 (dd, J = 13.52, 7.96 Hz, 1H, H7), 2.34 (m, 1H, H9), 2.7 (m, 1H, Hg), 3.12 (d, J
= 13.52, 1.53 Hz, 1H, H7), 4.10 (ddd, 1: 10.44, 8.79, 5.55 Hz, 1H, H10), 4.20 (ddd,
J = 8.52, 8.52, 2.19 Hz, 1H, H10), 5.46 (dd, J = 9.5, 1.98 Hz, 1H, H2), 5.83 (dd, J =

291

13.25, 6.80 Hz, 1H, H4), 6.64 (dd, J = 13.25, 9.50 Hz, 1H, H3): 7.29 (d, J = 6.80 Hz,
1H, H5)

1H NMR (C5115) (300 MHz): 5 1.12 (dq, J = 7.97, 11.26 Hz, 1H, H9), 1.5 (m, 1H,
H9), 1.98 (dd, J = 13.11, 8.51 Hz, 1H, H7), 2.1 (broad q, J = 8.97 Hz, 1H, H3), 2.83
(d, J = 13.11 Hz, 1H, H7), 3.35(ddd, J = 10.71, 8.79, 5.77 Hz, 1H, H10), 3.46 (dt, J =
2.2, 8.79 Hz, 1H, H10), 5.38 (dd, J = 13.31, 7.00 Hz, 1H, H4), 5.45 (dd, J = 9.45,
2.12 Hz, 1H, H2), 6.88 (dd, J = 13.31, 9.45 Hz, 1H, H3), 7.18 (broad d, J: 7.00 Hz,
1H, H5)

13C NMR (C5D5) (75 MHz): 5 29.04, 32.42, 43.26, 68.62. 97.13, 117.71 (q, J =
291 Hz), 117.99, 134.18, 134.44, 143.99 (q, I = 3.68 Hz), 172.07, 180.00 (q)

WW
1. In benzene

In an NMR tube, 2.7 mg of o-PTFAc was dissolved in 0.75 ml of benzene-
d5, purged with argon for 5 minutes and irradiated with Pyrex-filtered light (A. 2
290 nm). After 35 minutes, 1H NMR showed the complete disappearance of the
starting material and the appearance of signals corresponding to two new
products in a ratio of 9:1 (GC and NMR integration of the two doublet of triplets
at 5 .23 and 5.28 ppm). The major isomer was identified as 3-hydroxy-3-
trifluoromethyl-2-vinyl-2,3-dihydro-benzofuran from its 1H NMR spectrum.
Preparatory scale photolysis was carried out to isolate the product. o-PTFAc (0.5
g) was dissolved in dry benzene (500 ml) and irradiated using Pyrex-filtered light.
The reaction progress was monitored by TLC. After 6 hours irradiation, solvent

was evaporated, and the product was purified using dry column flash

292

chromatography (5% ethylacetate/hexanes) to give 3-hydroxy-3-tlifluoromethyl-
2-vinyl-2,3-dihydro-benzofuran (0.274 g, 55%)

 

 

 

 

 

1 1.‘ - ”1.1111131 .-, '1 -.-1_ 131.111.0111-!

1H NMR (c6136) (500 MHz): 5 1.7 (s, 1H, OH, disappears by adding D20), 4.99
(dt, J = 6.58, 1.24 Hz, 1H, H2), 5.02 (dt, J = 10.7, 1.34 Hz, 1H, H14), 5.23 (dt, J =
17.28, 1.44 Hz, 1H, H13), 5.69 (ddd, J = 17.27, 10.69, 6.58 Hz, 1H, H12), 6.64 (dt, J
= 1.05, 7.4 Hz, 1H, H5), 6.71 (dt, J = 8.23, 0.72 Hz, 1H, H7), 6.94 (ddd, J = 8.23,
7.41, 1.2 Hz, 1H,116), 7.25 (broad d, I: 7.25 Hz, 1H, H4)

1H NMR (CDCI3) (300 MHz): 5 2.45 (broad singlet) 5.18 (dt, J = 6.42, 1.17 Hz,
1H, Hz), 5.5 (dt, J =310.59, 1.23 Hz, 1H, H14), 5.64 (dt, J = 17.31, 1.34 Hz, 1H, H13),
6.01 (ddd, J = 17.19, 10.71, 6.6 Hz, 1H. H12), 6.92 (broad d, J = 8.16 Hz, H7), 6.99
(dt, J= 0.84, 7.55 Hz, 1H, H5), 7.35 (ddd, I: 8.25, 7.5, 1.41 Hz, 1H, H5), 7.47
(broad d, J = 7.68 Hz, 1H, H4),

13c NMR (CDC13)(125 MHz): 5 81.2 (q, J: 30.5 Hz, C3). 85.82 (C2). 110.94,
121.55, 121.72, 123.38, 124.57 (q.J= 282.25, CF3), 125.02, 129.95, 132.36,
160.08

293

2. In benzene-pyridine
In an NMR tube, 3.1 mg of o-PTFAc and two drops of pyridine-d5 were

dissolved in 0.75 ml of benzene-d5, purged with argon for 5 minutes and
irradiated with Pyrex-filtered light (A 2 290 nm). After 150 minutes, 1H NMR
showed the formation of Z- and E-3-hydroxy-3-trifluoromethyl-2-vinyl-2,3-
dihydro—benzofuran in a ratio of 1.2 : 1 (9 : l in the absence of pyridine). The two
isomers were identified from their 1H NMR as a mixture and by comparison to the
spectrum of the isolated Z-isomer in benzene-d5 up on the addition of two drops
of pyridine-d5. Determination of the stereochemistry of the products was based
on the fact that the E-isomer has H2 anti to the CF3 group. This allowed a
through bonding W-type coupling of 1.28 Hz between the fluorine atoms and H2.
Also, H12 is closer to the fluorine atoms in the E-isomer than in the Z-isomer which
allowed a through space coupling of 2.47 Hz between the fluorine atoms and

H12. These couplings were not observed in the spectrum of the Z-isomer
-- tI.‘--Ii.1lll'1--lt. - "lf'1'l't'lil

1H NMR (C5D¢+2 drops pyridine-d5) (300 MHz): 5 5.2 (dt, J = 10.72, 1.38 Hz,
1H, H14), 5.3 (dt, J= 6.53, 1.18 Hz, 1H, H2), 5.43 (dt, 1:17.18, 1.45 Hz, 1H, H13),
6.33 (ddd, J = 17.16, 10.5, 6.66 Hz, 1H, H12), 6.65 (dt, J = 1.0, 7.48 Hz, 1H, H5),
6.77 (broad d, J = 8.24 Hz, 1H, H7), 6.96 (ddd, J = 8.3, 7.39, 1.4 Hz, 1H, H6), 7.52
(broad d, J = 7.57 Hz, 1H, H4)

 

294

 

 

 

 

 

1H NMR (cause drops pyridine-d5) (300 MHz): 5 5.15 (dt, J = 10.44, 1.35 Hz,
1H, H14), 5.33 (d of sextet, J = 7.14, 1.28 Hz, 1H, H2), 5.48 (dt, J = 17.3, 1.38 Hz,
1H, H13), 6.22 (dddq, J = 17.58, 10.44, 7.14, 2.47 Hz, 1H, H12), 6.59 (dt, J = 0.83,
7.42 Hz, 1H, H5), 6.81 (broad d, J = 8.24, 1H, H7), 6.98 (dt, J = 1.37, 8.24 Hz, 1H,
116), 7.56 (broad d, J = 7.69 Hz, 1H, H4)

In order to compare the spectra of the two isomers in absence of pyridine,

solvent was removed under vacuum and sample was dissolved in benzene-d5.

1H NMR (cans) (300 MHz): 5 1.8 (singlet, 1H, disappears by adding D20), 4.76
(d of sextet, J = 7.26, 1.26 Hz, 1H, H2), 5.06 (dt, J = 10.4, 1.13 Hz, 1H, H14), 5.33
(dt, J = 17.07, 1.38 Hz, 1H, H13), 5.96 (dddq, J = 17.2, 10.34, 7.35, 2.38 Hz, 1H,
H12), 6.65 (dt, J = 1.0, 7.5 Hz, 1H, H5), 6.72 (broad d, J = 8.2 Hz, 1H, H7), 6.95
(ddd, J: 8.1, 7.5, 1.44 Hz, 1H, H5), 7.19 (broad d, J: 7.9 Hz, 1H, H4)

In order to further establish the structure of E -3-hydroxy-3-
trifluoromethyl-2-vinyl-2,3-dihydro-benzofuran, it was dehydrated using an acid.

A solution of the compound in chloroform-d was treated with two drops of

295

trifluoroacetic acid. 1H NMR analysis showed no change in the spectrum. Then
two drops of trifluoromethane sulfonic acid were added, this time 1H NMR
analysis showed the total disappearance of starting material with the formation of
the dehydration product; 3-tlifluoromethyl-2-vinyl-benzofuran.

 

 

 

 

 

1H NMR (CDCI3) (300 MHz): 5 5.62 (dd, J = 11.26, 1.1 Hz, 1H. H9). 6.2 (dd, J =

17.35, 1.18 Hz, 1H, H10). 6.87 ( ddq, I: 17.34, 11.3, 1.13 Hz, 1H, H3), 7.28 (dt, 1:
1.2, 7.48 Hz, 1H), 7.36 (dt, J = 1.4, 7.37 Hz, 1H), 7.48 (dd, J = 8.08, 1.03 Hz, 1H),
7.64 (broad d, J = 7.76 Hz, 1H),

296

C II' ”1.5

The ground state geometry of some of the photoproducts was optimized
using the Cache implementation of MOPAC.121 Output structure was altered by
varying some dihedral angles and then redoing the calculation in order to
distinguish between local minima and the global minimum for each compound.
The following parameters were used: Optimized geometry, singlet , and AMI122

For some cyclooctatrienes, geometries were optimized for their ground
states then for their excited singlet states. Charge distribution on various atoms

was obtained from the Cache output archive file. The following parameters were

used: Optimized geometry, excited singlet and AMI

L
o
o
tb=0\
Et
8

Rotational barriers around Ar—OEt bond of some meta-substituted para-
ethoxyacetophenones were calculated for their triplet states. The ground state
geometry of each compound was first optimized. An optimized search was done
by computing energies for various dihedral angles of rotation around the
benzene-oxygen bond. A dihedral angle, 41 = 0 was assumed for the ethoxy
group in the plane of the benzene ring and syn to the smaller ortho group. <I> was
varied by 15 degrees from 0° to 360°. For 4-ethoxy-3-isopropyl-5-
methylacetophenone, search was also done with varying (I) every 5 degrees
between 45° and 135°. The following parameters were used: Optimized search,

reaction coordinate, triplet using UHF, AM] and noanci key word.

(1)
(2)

(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)

(13)

(14)
(15)

(16)
(17)
(18)
(19)
(20)
(21)

(22)

(23)
(24)

(25)

REFERENCES

Gilbert, A.; Baggott, J. Essentials of Molecular Photochemistry; 1991.
Lowry, T. H.; Richardson, K. S. Mechanisms and Theory in Organic
Chemistry; Harper and Row: New York, 1987, pp 661 and 1029
Nitzan, A.; Jortner, J.; Rentzepis, P. M. Chem. Phys. Lett. 1971, 8, 445
Hochstrasser, R. M.; Lutz, H.; Scott, G. W. ibid. 1974, 24, 162

Padwa, A. Tetrahedron Lett., 1964, 3465

Walling, C.; Gibian, M. J.; J. Amer. Chem. Soc.,1965, 87, 3361

Wagner, P. J. Acc. Chem. Res., 1971, 4, 168

Petruska, J. J. Chem Phys, 1961, 34, 1120

Lamola, A. A., ibid., 1967, 47, 4810

Hochstrasser, R. M.; Marzzaco, C. ibid., 1968, 49, 971

Wagner, P. J.; Thomas. M. J.; Harris, E. J. Amer. Chem. Soc., 1976, 98, 7275
Wagner, P. J.; Kemppainen, A. E.; Schott, H. N. J. Amer. Chem. Soc. 1973,
95, 5604.

Yang, N. C.; McClure, S. L.; Murov, S. L.; Houser, J. J.; Duesenbery, R.
ibid., 1967, 89, 5466

Wagner, P. J.; Siebert, E. J. J. Amer. Chem. Soc. 1981, 103, 7329.

Wender, P.; Siggel, L.; Nuss, J. in “Organic Photochemistry”, Padwa, A.,
Ed.; Dekker: New York, 1989; Vol. 10, pp 357

Cornelisse, J. Chem. Rev. 1993, 93, 615

Wagner, P. J.; Nahm, K. J. Amer. Chem. Soc. 1987, 109, 4404.

Wagner, P. J.; Nahm, K. J. Amer Chem. Soc. 1987, 109, 6528.

Smart, R. P.; Wagner, P. J. Tetrahedron lett. 1995, 36, 5131.

Wagner, P. J.; Cheng, K.-L. Tetrahedron Lett. 1993, 34, 907.

a. Mattay, J. Tetrahedron 1985, 41, 2405.

b. Bryce-Smith, D.; Foulger, B.; Forrester, J.; Gilbert, A.; Orger, B. H.; Tyrrel,
H. M. J. Chem. Soc. Perkin Trans. 1 1980, 55.

Dadson, M.; Gilbert, A.; Heath, P. J. Chem. Soc. Perkin Trans. 1 1980,
1314.

Wagner, P. J.; Sakamoto, M. J. Amer. Chem. Soc. 1989, 111, 8723.
Paquette, L. A.; Cottrell, C. M.; Snow, R. A. J. Amer. Chem. Soc. 1977, 99,
3723.

Wagner, P. J.; May, M. J. Chem. Phys. Lett. 1976, 39, 350.

297

(26)

(27)
(28)
(29)
(30)
(31)

(32)
(33)
(34)
(35)

(36)
(37)

(38)

(39)
(40)

(41)

(42)
(43)

(44)
(45)

(46)
(47)

(48)
(49)

298

Hirota, N.; Wong, T. C.; Harrigan, E. T.; Nishimoto, K. Mal. Phys. 1975, 29,
903.

Cheng, K.-L.; Wagner, P. J. J. Amer. Chem. Soc. 1994, 116, 7945.
Wagner, P. J .; Alehashem, H. Tetrahedron Lett. 1993, 34, 911.

Wagner, P. J .; McMahon, K. J. Amer. Chem Soc. 1994, 116, 10827.
Wagner, P., J; Sakamoto, M. J. Amer. Chem. Soc. 1989, 111, 9254.
Al-Qaradawi, S.; Cosstick, K; Gilbert, A. J. Chem. Soc. Perkin Trans. 1
1992, 1145.

Angus, H. J. F.; Bryce-Smith, D. Proc. Chem Soc. 1959, 326.

Wilzbach, K. E.; Kaplan, L. J. Amer. Chem. Soc. 1966, 88, 2066.
Bryce-Smith, D.; Gilbert, A.; Orger, B. H. J. Chem Soc. Chem Commun.
1966, 512.

Felree, W., Jr", Grutzner, J. B.; Morrison, H. J. Amer. Chem. Soc. 1971, 95,
5502.

Sket, B.; Zupancic, N.; Zupan, M. Tetrahedron 1986, 42, 753.

Aoyama, H.; Arata, Y.; Omote, Y. J. Chem. Soc. Chem Commun. 1990,
736.

Neijenesch, H.; Ruiter, R.; Ridderikhoff, B.; Ende, J .; Laarhoven, L.; Putten,
L.; Cornelisse, J. J. Photochem. Photobiol. A: Chem. 1991, 60, 325.
Blakemore, D.; Gilbert, A. J. Chem Soc. Perkin Trans. 1 1992, 2265.
Mani, J .; Schuttel, S.; Zhang, C.; Bigler, P.; Muller, C.; Keese, R. Helv. Chim.
Acta 1989, 72, 487.

Atkinson, J. G.; Ayer, D. B.; Buchi, G.; Robb, E. W. J. Amer. Chem Soc.
1963, 85, 2257.

Gilbert, A.; Taylor, G.; Samsudin, M. J. Chem Soc. Perkin I 1980, 869.
a. Al-Jalal, N.; Gilbert, A.; Heath, P. Tetrahedron 1988, 44, 1449.

b. Gilbert, A.; Heath, P. Tetrahedron Lett. 1987, 28,5909.

O'Conner, D. V.; Ware, W. R. J. Amer. Chem Soc. 1976, 98, 4706.

Dopp, D.; Kruger, C.; Merariam, H. R.; Tsay, Y.-H. Angew. Chem, Int. Ed
Engl., 1985, 24, 1048

a. Tinnemans, A.; Neckers, D. J. Amer. Chem Soc. 1977, 99, 6459.

b. Wender, P.; Fisher, K. Tetrahedron Lett. 1986, 1857.

Lippke, W.; Ferree, W.; Morrison, H. J. Amer. Chem. Soc. 1974, 96, 2134.
Pirrung, M. J. Org. Chem. 1987, 52, 1635.

Bryce-Smith, D.; Gilbert, A.; Orger, B. H.; Tyrrell, H. M. Chem Commun.
1974, 334.

(50)
(51)
(52)
(53)

(54)
(55)
(56)

(57)

(58)
(59)
(60)

(61)
(62)
(63)
(64)

(65)

(66)

(67)
(68)
(69)
(70)
(71)
(72)

(73)
(74)
(75)

299

Monison, H.; Ferree, J., W. 1]. Chem. Soc. Chem Commun. 1969, 268.
Leismann, H.; Mattay, J. Tetrahedron Lett. 1978, 4265.

Houk, K. N. Pure Appl. Chem 1982, 54, 1633.

Van der Hart, J. A.; Mulder, J. J. C.; Cornelisse, J. J. Mol. Struct.
(Theochem) 1987, 151, 1.

Eaton, P. E. J. Amer. Chem Soc. 1962, 84, 2454.

Schuster, D.; Lem, G.; Kaplinidis, K Chem Rev. 1993, 93, 3.

Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Amer. Chem Soc.
1964, 86, 5570.

Andrew, D.; Hasting, D.; Oldroyd, D.; Rudolph, A.; Weedon, A.; Wong, D.;
Zhang, B. Pure Appl. Chem 1992, 64, 1327.

Hasting, D.; Weedon, A. J. Amer. Chem Soc. 1991, 113, 8525.

Maradyn, D.; Weedon, A. Tetrahedron Lett. 1994, 35, 8107.

Schaffner, K; Demuth, M. in “Rearrangements in Ground and Excited
States”, de Mayo, P., Ed.; Academic press: New York, 1980; Vol. 3, pp 281
Zimmerman, H. B.; Schuster, D. I. J. Amer. Chem Soc. 1962, 84, 4527.
Zimmerman, H.; Schuster, D. J. Amer. Chem Soc. 1961, 83, 4486.
Schultz, A. G.; Taveras, A. G. Tetrahedron Lett. 1988, 29, 6881.

Schultz, A. G.; Plummer, M.; Taveras, A. G.; Kulling, R. K J. Amer Chem
Soc. 1988, 110, 5547.

Cope, A. C.; Haven, J., A. C.; Ramp, F. L.; Trumbull, E. R. J. Amer. Chem
Soc. 1952, 74, 4867.

Huisgen, R.; Boche, G.; Dahem, A.; Hechetl, W. Tetrahedron Lett. 1968,
5215.

Cotton, F. A.; Deganello, G. J. Amer. Chem Soc. 1973, 95, 396.

Oda, M.; Kanao, Y. Bull. Chem. Soc. Japan 1979, 52, 3765.

Lyttle, M. H.; Streitwieser, A.; Miller, M. J. Org. Chem 1989, 54, 2331.
Vogel, E. Angew. Chem. Int. Ed. 1963, 2, 1.

Fujiwara, T.; Ohsaka, T.; Inoue, T.; Takeda, T. Tet. Lett. 1988, 29, 6283.
Chapman, O. L.; Borden, G. W.; King, R. W.; Winkler, B. J. Amer Chem
Soc- 1964, 86, 2660.

Zimer, J.; Winstein, 8. Proc. Chem Soc. 1964, 235.

Roth, W. R.; Peltzer, B.Angew. Chem. Int. Ed. 1964, 3, 441.

a. Bender, C. O.; Bengston, D. L.; Dolman, D.; O'Shea, S. F. Can. J. Chem.
1986, 64,237.

b-Bender, C. O.; Dolman, D.; Murphy, G. K. Can. J. Chem 1988, 66, 1656.

(76)

(77)
(78)
(79)
(80)
(81)
(32)
(83)
(84)
(85)
(36)
(37)

(88)

(89)
(90)

(91)
(92)
(93)

(94)
(95)
(96)
(97)
(98)

(99)

(100)

300

c-Bender, C. O.; Clyne, D. S.; Dolman, D. Can. J. Chem. 1991, 69, 70.
Bender, C. O.; Bengston, D. L.; Dolman, D.; Herle, C. E. L.; O'Shea, S. F.
Can. J. Chem. 1982, 60, 1942.

Miyashi, T.; Nitta, M.; Mukai, T. Terahedron Lett. 1967, 3433.

Kimura, M.; Mukai, T. Tetrahedron Lett. 1970, 4207 .

Baldwin, J. B.; Kaplan, M. S. J. Amer. Chem Soc. 1971, 93, 3969.
Baldwin, J. B.; Kaplan, M. S. J. Amer. Chem Soc. 1972, 94, 4696.
Baldwin, J. E.; Kaplan, M. S. J. Amer. Chem Soc. 1972, 94, 668.

Cheng, K.-L., Ph.D. Dissertation, Michigan State University, 1994

Smart, R., Ph.D. Dissertation, Michigan State University, 1994

Nahm, K, Ph.D. Dissertation, Michigan State University, 1987

Alehashem, H., Ph.D. Dissertation, Michigan State University, 1992
Karplus, M. J. Chem Phys. 1959, 30, 11.

Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectroscopic Identification
of Organic Compounds; John Wiley: New York, 1981, pp 235

Jackman, L. M.; Stemhell, S. Applications of Nuclear Magnetic
Resonance Spectroscopy in Organic Chemistry; 2nd ed; Pergamon Press:
New York, 1969, p. 303

Reference 87, page 229

Lambert, J. B.; Shtn'vell, H. F.; V., L.; Cooks, R. G.; Stout, G. H. Organic
Structural Analysis; Macmillan: New York, 1976. pp 72

Wender, P. A.; Dreyer, G. B. Tetrahedron 1981, 37, 4445.

Bell, R. A.; Saunders, J. K. Can. J. Chem 1970, 48, 1114.

Neuhaus, D.; Williamson, M. P. The Nuclear Overhauser Effect in
Structural and Conformational Analysis; VCH: New York, 1989, pp
173

Laidig, G., M.S. Dissertation, Michigan State University, 1990

Wagner, P. J.; Jang, J-S., J. J. Amer. Chem Soc. 1993, 115, 7914.
Reference 87, page 265

Reference 90, page 77

Cosstick, K. B.; Drew, M. G. B.; Gilbert, A. J. Chem Soc. Chem Commun.
1987, 1867.

Schuster, D. 1.; Heibel, G. B.; Brown, P. B.; Turro, N. J.; Kumar, C. V. J. Amer
Chem. Soc. 1988, 110, 8261.

Beckwith, A. L. J.; Easton, C. J .; Lawrence, T.; Serelis, A. K. Aust. J. Chem.
1983, 36, 545.

(101)
(102)

(103)
(104)

(105)

(106)

(107)
(108)
(109)
(110)
(111)

(112)
(113)
(114)
(115)
(116)
(117)
(118)

(119)
(120)
(121)

(122)

301

Spellmeyer, D., C,; Houk, K. N. J. Org. Chem 1987, 52, 959.

a. Schultz, A. G.; Geiss, W. J. Org. Chem. 1989, 54, 3158.

b. Schultz, A. G. Pure Appl. Chem 1988, 60, 981.

Chapman, O. L.; Pasto, D. J. J. Amer Chem Soc. 1960, 82, 3642.
Wagner, P. J.; Meador, M. A.; Park, B.-S. J. Amer. Chem Soc. 1990, 112,
5199.

Gordon, A., J; Ford, R. A. The Chemist's Companion; Wiely: New York,
N.Y., 1972.

Furniss, B. S.; Hannaford, A. J .; Rogers, V.; Smith, P. W.; Tatchell, A. R.
Vogel 's Textbook of Practical Organic Chemistry; 4th ed.; Longman:
London, 1978, p 268

Kraus, G. A.; Landgrebe, K. Synthesis 1984, 885.

Campagna, F.; Carotti, A.; Casini, G. Tetrahedron Lett. 1977, 1813.
Reference 106, page 831

Shah, D. N.; Shah, N. M. J. Ind. Chem. Soc. 1949, 26, 235.

Homing, D. B.; Ross, D. A.; Muchowski, J. M. Can. J. Chem 1973, 51,
2347.

Cohen, T.; Dietz, A. G. J.; Miser, J. R J. Org. Chem. 1977, 42, 2053.
Sato, F.; Inoue, M.; Oguro, K; Sato, M. Tetrahedron Lett. 1979, 4303.
Mottem, H. J. Amer. Chem. Soc. 1934, 56, 2107.

Schneider, W.; Kraft, E. Ber., 1922, 55B, 1892.

Hertz, A. H.; Tarbell, D. S. J. Amer. Chem Soc. 1953, 75, 4657.
Weggand, F.; Popsch, A. Chem. Ber. 1959, 92, 2095.

Matsumoto, S.; Kobayashi, H.; Ueno, K. Bull. Chem. Soc. Jpn. 1969, 42,
960.

Hanack, M.; Dehesch, T.; K, H.; Nierth, A. Organic Synthesis 54, 84.
Beard, C. D.; Baum. K; Grakauskas, V. J. Org. Chem 1973, 38, 3673.
Stewart, J. J. P. MOPAC version 94.0; Cache Scientific, 1.; Beaverton, OR
97006.

Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Amer Chem
Soc. 1985, 107, 3902.

llHHllllllll’

5
2
8
9
8
6
1
3
0
3
9

ill?HIHHHllililllllllllllll

1
312

EIHIHIHIH;