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WE’STS

 

 

This is to certify that the

dissertation entitled
SYNTHETIC UTILITY 0F

ALPHA-LITHIO SULFOXIDES

presented by

John B. Dickenson

has been accepted towards fulfillment
of the requirements for

Pk 9‘ degreein (/Q‘emckaYY

 

 

mom

 

Major professor

Date (’ 2g f. g 3

 

MS U is an Affirmative Action/Equal Opportunity Institution 0-12771

 

 

MSU

LIBRARIES
m

 

 

RETURNING MATERIALS:
Place in book drop to
remove this checkout from
your record. FINES wiII
be charged if book is
returned after the date
stamped below.

 

 

 

 

 

SYNTHETIC UTILITY OF

ALPHA-LITHIO SULFOXIDES

BY

John B. Dickenson

A DISSERTATION

Submitted to

Michigan State University

in partial fulfillment of the requirements

for the degree of

DOCTOR OF PHILOSOPHY

Department of Chemistry

1982

G (3(35‘13

ABSTRACT

SYNTHETIC UTILITY OF

ALPHA-LITHIO SULFOXIDES

BY

John B. Dickenson

Interest in organosulfur chemistry has grown explosively in
the past decade. Researchers have shown that many synthetic
transformations once difficult to achieve can now readily be
accomplished by means of organosulfur reagents or sulfur-

containing intermediates.

We have been interested in studying some synthetic applica-
tions of sulfoxides; in particular, our research has
centered on reactions made possible by the ability of the

sulfoxide group to stabilize adjacent carbanions.

Two syntheses of general interest have evolved from this
research. The first allows the transformation of cyclic
ketones into exocyclic allylic alcohols. Phenylsulfinyl-
methyllithium, formed by metallation of phenylmethyl

sulfoxide, is condensed with a ketone, and the resulting

B-hydroxysulfoxide is dehydrated to afford an allylic
sulfoxide. Treatment of this allylic sulfoxide with a
thiophilic reagent yields an allylic alcohol by intercepting

a {2,3} sigmatropic rearrangement.

The second synthetic method developed here permits elabora-
tion of a cyclohexanone to a tetralin system. This reaction
sequence also makes use of the phenylsulfinylmethyllithium
reagent, and it is interesting to note that the methyl group
of phenylmethylsulfoxide eventually becomes one of the
aromatic ring carbons. The cyclic aliphatic ketone is first
converted to a masked B-ketoaldehyde, in this study the a-
methoxymethylene derivative. Condensation of phenylsulf-
inylmethyllithium with this enol ether, followed by acid
hydrolysis, yields a B-(phenylsulfinylmethyl) unsaturated
aldehyde. Deprotonation of this aldehyde, followed by a
Michael addition to ethyl acrylate, aldol condensation and a
pyrolytic elimination, gives the desired tetralinic ester.
Overall yields are good in a simple model system, but
apparently the reaction scheme is sensitive to steric

factors, since yields drop greatly in hindered systems.

DEDICATION

To my parents, Joseph and Pauline;

and to my wife Andrea

ii

ACKNOWLEDGEMENTS

I wish to thank Professor William Reusch for his guidance
throughout my stay at Michigan State. Appreciation is also
extended to the MSU Department of Chemistry and the MHESLA

for financial support.

Special thanks to Marge Dunn, who prepared the final
manuscript on the word processor, and to my wife Andrea, who
typed the initial draft and provided much love and
understanding. And many thanks to my parents, whose gift of

a chemistry set led to all this.

iii

TABLE OF CONTENTS

INTRODUCTION................ ...... ................... 1
RESULTS AND DISCUSSION
PART A.......................................... 18
PART B.......................................... 37
EXPERIMENTAL......................................... 55
APPENDIX ................ . ...... . ................. .... 79

REFERENCESOOOO0.0I.OOOOOOOOOOOOOOOOOOOOOOOO0.0.0.0...131

iv

LI ST OF TABLES

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

l.
2.

4.

5.

6.

7.

8.

9.

10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.

LIST OF FIGURES

Pmr study of isomer ratios ........ ........

Estrone and Calamenin..... ........ ........

Numbering of tetralin aromatic

ring.......

Structures of 68 and 69 ...................
~ ~

IR spectrum of 23.. ................ . ......

IR spectrum of

IR spectrum of

IR spectrum of

IR spectrum of

IR
IR
IR
IR
IR
IR
IR
IR
IR
IR

1 IR
IR
IR

IR

spectrum of
spectrum of

spectrum of

spectrum of

spectrum of

spectrum of

spectrum of

spectrum of

spectrum of

spectrum of

spectrum of

spectrum of

spectrum of

spectrum of

~
290000000000coo-00000.0...
S

and 8~600000000000000000

26
37
42
43
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
. Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

24. PMR spectrum of 29 ......................... 98

25.
26.
27.
28.
29.
3o.
31.
32.
33.
34.
35.
36.
37.
38.
39.
4o.
41.
42.
43.
44.

45.

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

PMR

spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum

spectrum

of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of
of

29 ........................ 98
31. ....................... 99
N
34 ........................ 99
M
.3 ........................ 100
29 ........................ 100
gg ........................ 101
22 and 49 ................. 101
4~O O O OOOOOOOOOOOOOOOOOOOO 102
l ....................... .102
52 ........................ 103
59 ........................ 103
69a ....................... 104
6 b0. .0. O .......... O ..... .104
6~OCOO O O. O 0000000000 O ...... 105
61 ........................ 105
63 ........................ 106
6 C I O O O O O O OOOOOOOOOOOOOO O .106
~
68. O .0. O O 0.. O O ....... O O. O .107
~
73. .0. O O O O O. O .0. O. ...... O .107
~
La......... 0 0.... ........ 108
7 b...... O ..... O I. 0.. O O. .0108
‘v

vii

Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.

PMR
PMR
13

PMR
PMR

250

PMR

Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass
Mass

M358

‘Mass

M388

Mass

M388

. .109

spectrum of 25c ............... ......
spectrum of fig ...................... ..109
NMR spectrum of £9 .................... 110
spectrum of 83 ........................ 111
spectrum of g; ........................ 111
MIR PMR spectrum of g} ................ 112
NMR spectrum of £3... ............... ..113
spectrum of 25 and 96..... ........... .114
spectrum of 22 ....................... 115
spectrum of 29 (CI) .................. 115
spectrum of 29 ...................... .116
spectrum of 99 (CI)..... ........... ..116
spectrum of 23. ...... .... ........... .117
spectrum of 25... .................... 117
spectrum of 25 (CI) ................. .118
spectrum of £6 ..................... ..118
spectrum of 33.......................ll9
spectrum of 22..... ...... ............ll9
spectrum of 29..... ............. .....120
spectrum of 43... .................. ..120
spectrum of 51... ........... . ..... ...121
spectrum of 53.. ........ .............121
spectrum of

53.......................122

2

viii

Figure
Figure
'Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure
Figure

Figure

69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.

Mass

Mass

Mass

M388

Mass

Mass

Mass

Mass

Mass

Mass

Mass

Mass

M388

Mass

spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum
spectrum

spectrum

of
of
of
of
of
of
of
of
of
of
of
of
of
of

69c ................. ....122
61 ..................... .123
63... .................. .123
E} (CI) ................. 124
63. .................... .124
63 ............. .........125
68 .................... ..125
~

13. .................. ...126
73b.. ................... 126
7 c.. ................. ..127
I»

8 . ..... . ..... .. ....... .128
N

83... ...... . ........... .129
~

8 .. .................. ..130
N

86 ...................... 130
N

ix

INTRODUCTION

Achieving carbon-carbon bond formation is a vital part of
any total synthesis; it is in this way that complex mole-
cules are assembled from simple building blocks. Almost all
common carbon-carbon bond formation reactions involve
reaction of a carbanion with an electrophilic species,1
although electrocyclic reactions are a noteworthy
exception. Thus it is the ability to form a specific
carbanion and cause it to react with a suitable electrophile
that allows the synthetic organic chemist to perform a

myriad of reactions -- a Grignard addition, an aldol conden-

sation, alkylation of an enolate, and so on.

In a few cases, such as Grignard reagents and organolith-
iums, no extra stabilization is afforded to the carbanion.
In a majority of carbanions, however, the negative charge on
carbon is alleviated to some degree by inductive or
resonance delocalization of charge. The benefit is twofold:
the reagent is more stable, and the product of the reaction

may then contain additional desired functionality.

Among the class of carbanions stabilized only by an a-

heteroatom, those containing silicon, sulfur, and phosphorus

are generally the most stable and synthetically useful.
Oxygen and nitrogen provide limited stabilization due to
their lesser polarizability.2 Equation 1 provides a vivid
example of the superior effect of sulfur in the metallation

of 2-ethoxy-l-pentylthioethylene 1.3

 

t-BuLi s
S ——>
M W THF -700 R/ / “a";
Csz ’
Li

2. R=C5H1T

1.5

Eqn 1

S, IVCHO
/ / C2“;

R OH

10

Sulfur-containing carbanions are especially valuable in
synthesis, due to the flexibility provided by the many
oxidation states available to sulfur. Three major classes
of organosulfur compounds are capable of stabilizing an
adjacent negative charge. These are sulfides, sulfones, and

sulfoxides. Each will be discussed in turn.

Sulfides

Sulfides represent the lowest oxidation state of organo-
sulfur compounds, and may be synthesized easily by displace-
ment of halide by the conjugate base of a thiol or thio-

phenol.4

Eqn2 Rs“+ R’x ——-> RSR’+ x"

Compared to sulfoxides and sulfones, a sulfide provides the
least stabilization to an adjacent carbanion. The pKa of
thioanisole in DMSO (dimethyl sulfoxide) solution is 49.5
Nevertheless, even simple dialkyl or arylalkyl sulfides can
be metallated with very strong bases. Thus thioanisole can
be lithiated by n-butyllithium-diazabicyclooctane (n-BuLi-
DABCO),6 and even methylthiomethyllithium has been formed
‘yig_reaction of dimethyl sulfide with n-butyllithium-

tetramethylethylenediamine (n-BuLi-TMEDA).7

Once formed, these powerful nucleophiles can react with a
variety of substrates. For example, phenylthiomethyllithium
adds to ketones in good yields. The adducts can be elimi-
nated to methylene compounds,8 thus providing an alternative
to the Wittig reaction for ketones which are highly hindered

or prone to enolization.

«pficmu HO 3
II o s"
c ‘6
R/ \\R,
R R’
Eqni3

n c14

LAH

3° amine

 

Phenylthiomethyllithium has also been used in a one-carbon

homologation of primary alkyl halides, as reported by

 

Corey.9 This homologation proceeds in high yield and in
only two steps. Fhenylthiomethyllithium is alkylated by the
primary halide, and the resulting sulfide is then heated
with excess methyl iodide in dimethyl formamide (DMF). The
overall yield for the transformation of l-iododecane to

l-iodoundecane is 76 per cent.

 

 

SCH Li
RCHZI 14—» RCHZCHZS¢
4 5
"_ _ ~ CH3I
R -C9H19 DMF
Eqn 4 *
r.
<—_ _ Rcuzcnzs’rzp
6
CH3 ~

RCHZCHzl + ¢SCH3
7 8

~ ~

Perhaps the most renowned application of sulfide-stabilized
carbanion chemistry is Corey and Seebach's 1,3-dithiane
synthesis.10 Here, 1,3-dithiane 2 serves as an 'acyl anion
equivalent” because of its reactivity toward electrophiles
and because alkylated 1,3-dithianes can be transformed into
aldehydes or ketones. Typically, 1,3-dithiane is lithiated
by n-butyllithium in tetrahydrofuran at -20°; the anion is
then alkylated by alkyl halide, and the resulting 2-a1ky1-
1,3-dithiane can be hydrolyzed to an aldehyde, or alkylated
once again. A 2,2-dialkyl-l,3-dithiane yields a ketone upon
hydrolysis.

SCHEME I

 

CS n-BuLi
> ?
£5 THF

RCHO <— *—

 

 

I ‘
R R

CZXL‘

RX

 

I. n—BuLi
2. R'X

 

Yields of alkylated 1,3-dithianes are high with primary and
secondary halides; hydrolysis, however, is not trivial.
Many different hydrolysis reagents and conditions have been

used, but none were found to be general.
Sulfones

The higher oxidation states of sulfur are often synthesized
from the corresponding sulfide. Thus displacement of halide
by thiophenoxide, followed by treatment with two equivalents

of an oxidant, yields a sulfone.11

O
.. 2(0) ll
sqns ms + RX——-—->ArSR ————->ArfiR

Alternatively, sulfones may be prepared directly by alkyla- '

tion of sodium aryl sulfinates.12

0
II
a... s Arso;Na+ + RX ..._———> Ar'SIR

Sulfones are more acidic than sulfides and sulfoxides. Most
sulfones have pRa's in the range of 23-27.13 Due to their

”soft“ nature, sulfone anions often add to unsaturated

carbonyl compounds in a 1,4 fashion. For example, Schatz
has reported a convergent synthesis of methyl chrysanthemate
12 which is so straightforward that he recommends it for
inclusion in an undergraduate laboratory course.14 The key
step in this synthesis is a conjugate addition of a sulfone-

derived anion followed by an intramolecular displacement of

 

 

 

 

 

arylsulfinate.
SCHEME II
° + rfl+0
\_ _ O
/—/Kocu3 >— g
1.9 11.
O I
ll
_ ocn,
base
our ’ Ars , K
\\\
> + Arso,
___r ._.. _.
90% ”(30,013

Sulfoxides

Sulfoxides are intermediate in acidity between sulfides and
sulfones, having pKa's in the neighborhood of 35.13 The
simplest sulfoxide, DMSO, has found extensive use as an
industrial solvent,15 and lately has received much publicity
concerning its medicinal properties.16 The sodium salt of
DMSO, known as 'dimsyl sodium”, is often used as a strong
base.17 Until recently, few sulfoxides more complex than
DMSO were studied. A review of the current literature,
however, reveals a dramatic increase of interest in sulf-
oxide chemistry. Pioneering researchers such as Evans and

Trost have demonstrated the synthetic utility of sulfoxides.

It was perhaps the difficulty of synthesis and instability
of sulfoxides which deterred earlier chemists from studying
them. It is known that the sulfoxide oxidation state is
unstable with respectto sulfides and sulfones. For
example, thiophenol and benzenesulfinic acid are stable
compounds, but attempts to synthesize benzenesulfenic acid

led only to disproportionation products.18

ll
5w 7 4(¢sou) ———> ¢ss¢ + W” + 2:420

10

Fortunately, recent developments have greatly facilitated

sulfoxide synthesis. Some of the effective methods include:

1. Oxidation of a sulfide. In the past, this has been the
most common method, but has suffered from over-oxidation to
sulfones. However, aqueous sodium metaperiodate oxidizes
sulfides to sulfoxides in near-quantitative yield, with no
sulfone contaminants.19 A somewhat less satisfactory
alternative oxidant is meta-chloroperbenzoic acid at very

low temperatures.20

2. Reaction of a Grignard reagent with an aryl sulfinate
ester. Because this reaction proceeds with 100% inversion

of the sulfur configuration, it is useful in the synthesis

of chiral sulfoxides.21

3. Friedel-Crafts acylation of suitable aromatic substrates

with an aryl sulfinyl haiide.22

 

4. Sulfenylation of an allylic alcohol. Reaction of
allylic alcohols with benzenesulfenyl chloride has been used
as a synthesis of allylic sulfoxides.23 This last method of
sulfoxide synthesis exemplifies a unique aspect of sulfoxide
chemistry, the {2,3} sigmatropic rearrangement of allylic
sulfoxides. The first evidence for this rearrangement was

noted by Mislow.24 Observing that chiral sulfoxides with a

11

B-Y double bond slowly racemized, he postulated that such
sulfoxides were in equilibrium with an achiral sulfenate

ester (Eqn 8).

This hypothesis was later proved by Evans, who showed that
allylic sulfoxides were converted to allylic alcohols by
reagents which cleaved the sulfur-oxygen bond of the
intermediate sulfenate ester.25 Such reagents are known as
'thiophiles' and include trimethyl phosphite, thiophenoxide,

and secondary amines.

Owing to the lesser stability of sulfenate esters vis-aevis

 

allylic sulfoxides, the equilibria do not favor formation of
sulfenate esters, and such compounds are not normally
present in detectable concentrations.26 Thus sulfenylation
of allylic alkoxides proceeds.gig a transient sulfenate

ester, the end product being a sulfoxide.

12

 

'0
H 05R
5 -———> N
Eqn 8 R/*W ‘i / achiral
“RI! //
ii
5
R/3*\\//§§
“s”
__ 05C]
¢s/\/

The technique of enolate sulfenylation is useful in the

synthesis of enones from ketones. The intermediate

B-ketosulfide is oxidized to the sulfoxide; thermolysis then

yields an a,B unsaturated ketone.

13

SCHEME III

 

1. LDA
2. ¢ss¢

 

   

The hydrolysis problem alluded to earlier in the 1,3-
dithiane synthesis has been alleviated completely by
Schlessinger gtugl;.with a mixed sulfoxide-sulfide reagent
{7.28 This system has been shown to alkylate in the same
manner as 1,3-dithiane, and hydrolysis proceeds with
excellent yields in the presence of a catalytic amount of

perchloric acid.

14

SCHEME IV

C2H5\ c2H5
S» \\‘s
/ dial kylate R
(”72 -_7 e~—)>

5:0 “I s=o

/

Csz
" HCIO4

O

A + c,H.ssc,H,
I

Furthermore, in contrast with the exclusive 1,2 additions
exhibited by 1,3-dithianes, this mixed sulfide-sulfoxide
adds 1,4 to unsaturated carbonyls, thus providing an
efficient synthesis of l,4-dicarbonyl compounds, which are
difficult to produce by classical methods. It is interest-
ing to note that the dimethyl analog of I? alkylates with
difficulty and will not dialkylate at all.

15

The synthetic utility of allylic sulfoxides has received
much attention, and forms a major part of this thesis.

Evans used an allylic sulfoxide in his elegant synthesis of
nuciferal (Scheme V).29 Alkylation of sulfide IS with
bromide 19 gave sulfide 29. Oxidation to the sulfoxide
followed by 2,3 sigmatropic rearrangement afforded allylic
alcohol 21. Nuciferal 2% was then obtained by a manganese
dioxide oxidation. It can be seen that allylic sulfoxides

serve as a véallylic alcohol anion equivalent.

SCHEME V

 

I. RC03H
2. EtZNH

80-85%

2.9

 

16

Finally, Hauser has reported a method by which a toluate
ester can be elaborated to an o-naphthol.3O Repetition of
this reaction sequence would, in principle, lead to linear
aromatic systems of any length; for example, compound 23.
Part of this thesis describes an aromatic annulation scheme
which complements Hauser's nicely, allowing saturated ring

Systems to be converted to tetralins bearing a variety of

substituents.

 

17

Scheme VI

Br

9
I
s

 

 

305:";
23 2‘}
.. l w
¢
© ? [ 1
0
co,c,H, O‘C‘H‘
26
“' 2.5
fl
¢s==O
3
_, ©©
.l COfiH, 02C":
__ OH
27
(repeat
M @©©
1, the".

 

18

RESULTS AND DISCUSSION

A. Conversion of Cyclic Ketones to Exocyclic Allylic

Alcohols

We have developed a reaction sequence whereby a cyclic

ketone may be elaborated to an allylic alcohol, as indicated

in Scheme VII.

 

 

 

Scheme VII
0
II . F“: 5&0
¢SCH2LI "
I
..4153
i .
II
5c»
HO thiophlle
“__

Overall yields are good. It should be noted that the

transformation is not equivalent to a-methylenation followed

19

by reduction: rather, the carbonyl carbon becomes part of
the methylene group. Thus this method also involves a 1,2
transposition of oxygen functionality, which may prove

useful in certain cases.

The first step is the condensation of the ketone with an
u-metallated sulfoxide. To this end, phenyl methyl
sulfoxide was prepared in high yield by oxidation of
thioanisole with aqueous sodium metaperiodate.31 The
sulfoxide was treated with lithium diisopropylamide (LDA) in
THF solution to afford the lithium salt, which was then

reacted with a variety of ketones.

The yields in this addition were highly dependent upon the
structure of the ketone substrate. Addition to
cyclohexanone and cyclopentanone went smoothly; 6-meth-
oxytetralone 32 also gave good yields of the adduct. When
the reaction was attempted with sterically hindered ketones,
however, the results were less satisfactory. Camphor 33
failed to react at all; apparently enolization took place.
The bicyclic ketone 13 gave only moderate yields of

adduct. This is not surprising, as the small, reactive
reagent vinyl magnesium bromide is reported to add to 13 in
only fifty per cent yield.32 The best conversions to 33
were achieved when the reaction was carried out at -78° and
then quenched. When the reaction mixture was refluxed in an

attempt to force further reaction, only starting material

20

was isolated. Finally, we observe that the lithium salt of

35 reverts to ketone 19 and sulfoxide under reflux (Eqn 11).

Recently another experimenter has reported a similar method,
developed independently from ours. The author also cites an

example of elimination of B-hydroxysulfoxide anions derived

from hindered ketones.33

SCHEME VIII

 

 

21

Eqn 10

 

 

 

_ o . _
> . + ¢SCH2Li
A 3 a
o

13

~

 

22

Once formed, the highly polar B—hydroxysulfoxides were iso-
lated and recrystallized. It was observed that the methy-
lene group gave rise to an AB system in the proton NMR be-
cause the protons are diastereotopic and thus exhibit
mutual spin-spin splitting. Another interesting phenomenon
occurs in the mass spectra; in most cases, these (Lhydroxy-
sulfoxides show a prominent M+1 peak instead of a parent
ion. This may be rationalized as the result of an ion-mole—
cule reaction whereby the basic sulfoxide oxygen is proto-
nated. When the mass spectra are obtained yi§_chemical
ionization (reagent gas: methane), the same M+1 peak is
observed, indicating the correct mass for the compound. The
corresponding B—hydroxysulfides do not exhibit this proton

transfer phenomenon.

Dehydration of the B—hydroxysulfoxide products presented
some challenges. For instance, the initial compound studi-
ed, l-phenylsulfinyl-l-cyclohexanol 29, was resistant to a
large number of conventional dehydration reagents; in fact,
2? was recovered unchanged after prolonged reflux with p-
toluenesulfonic acid in toluene solution. Other reagents

either failed to induce a reaction, or gave tars.

In contrast to the unreactivity of 2?, B-hydroxysulfide 38
(prepared from cyclohexanone and phenylthiomethyl lithium)
dehydrates readily, as one might expect a normal tertiary

alcohol to do. Refluxing 38 in benzene with p-toluenesul-

23

fonic acid gave a mixture of the two isomeric alkenes 3g and

40.
m

It is not obvious why the presence of the sulfoxide oxygen
so greatly attenuates the reactivity at the tertiary alcohol
site. I propose that intramolecular hydrogen bonding might
hinder the approach of reagents to the hydroxyl group. Some
support for this theory was obtained from a study of acety-
lation reactions of 29 and 38; Thus 38 reacted with acetic
anhydride in pyridine at room temperature to give acetate 41
in good yield. Sulfoxide 29, on the other hand, required
long periods of reflux with acetic anhydride/pyridine in the
presence of dimethylaminopyridine (DMAP) to achieve even
partial conversion to its acetate derivative 42. DMAP is an
acylation catalyst which has been reported to increase

acetylation reaction rates by factors of 1,000 or more.34

24

 

 

 

Eqn12
H
5" ""5“ .n.
3 «tom, + N
A
23
Son 13
OH
-'I'
¢H +
45 A
as 39 4o
Eqn 14
OH OH
Aczo/pv CCH’
DMAP
$=O (slew)
(6 ¢S=O
2.9 42
£0» 15
I?
OH ecu,

 

Ac20/93!
¢ (rapid) $ ¢

25

Dehydration of 23 to 39 was finally effected in high yield
by boron trifluoride etherate in refluxing toluene. It
proved important to quench the reaction after forty minutes

to one hour, as prolonged reflux led to extensive decomposi-

tion.

Uh=C)

E n 85
q H s¢ BF3' (02H5I2O

II
0 «tons , A

In contrast, the product 33 derived from phenylmethylsulf—
oxide and 6-methoxytetralone was dehydrated quantitatively
by p-toluenesulfonic acid in refluxing benzene. The faci-
lity of this reaction is no doubt due to the increased sta-

bilization afforded the tertiary-carbocation by the elec-

tron-rich aromatic ring.

 

 

26

When the dehydration reaction was allowed to proceed at
reflux for twenty minutes or longer, only the arr-unsaturat-
ed product 44 was observed. However, by quenching the reac-
tion mixture with sodium bicarbonate after only five
minutes, a mixture of unsaturated sulfoxides 43 and 44 was
obtained. The ratio of the B,‘7isomer 44 to a,8 isomer 43

was approximately 2/1 by pmr analysis (Figure 1).

After 5 Minutes After 30 Minutes

 

 

 

 

 

Figure 1. Comparison of vinyl region of pmrs showing

effect of reaction time on isomer ratio.

Thus it seems that isomer 43 is the kinetically favored
dehydration product, but is converted to the thermodynamic-

ally more stable 4: under the reaction conditions.

27

Eqn 18

 

P'TSA
’,/Sv)
+ ..
c..,o O
44 ‘Q§
1 ~ J

 

Although it may seem surprising that the less-conjugated
isomer is thermodynamically more stable, there is ample
evidence for this in the literature. O'Connor and Lyness
measured the equilibrium concentrations of<:,8- and BfY'
unsaturated sulfides, sulfoxides, and sulfones.35 Their

data are summarized in Table 1.

28

TABLE 1
Type of Sulfur Moiety Equilibrium Product Distribution
% 01,5 % 3,7
\~ ,!
¢s R 66 34
M
¢fi R s 95
O I
II /\\""'/\ <1 >99
(08 R
ll
0

Of course, other variables such as differences in double
bond substitution and the presence of rings (endocyclic or
exocyclic) may perturb these ratios, but our work is in
qualitative agreement with the findings of O'Connor and
Lyness. Hence, sulfoxides tend to be almost entirely
B,y-unsaturated, whereas sulfides exhibit only a slight

preference for the a,p form.

29

In the case of alcohol 35 no conditions were found to accom-
plish dehydration. This is not entirely unexpected, inas-
much as the structurally similar benzthiazole adduct 45 had
previously been shown not to dehydrate under a variety of

conditions.36

   

1.5 (R=.::>_) 4.9

Over 85% of 35 could be recovered after five days of reflux
with p-toluenesulfonic acid in benzene. A subsequent
attempt to form the tosylate ester of 35 gave an interesting
result. Reaction of 35 with tosyl chloride and DMAP in
refluxing pyridine gave a complex reaction mixture, the
major component of which was identified as 47. This diene
is most likely formed_yia the desired allylic sulfoxide 13»
Since 42 would be in equilibrium with an allylic sulfenate
ester, a sulfenate elimination could take place. Recently a

synthesis of dienes from allylic sulfoxides has been report-

ed:37 and in one instance an intermediate allylic sulfoxide

30

was not observed, but apparently eliminated directly to the

diene, much as we have observed here.

 

 

 

   

 

 

TsCl
E" 20 DMAP
PY
g
‘
9.7 — _

 

 

In light of the difficulties encountered in this dehydration
step, a Wittig-like reagent might offer an effective alter-
native route to unsaturated sulfoxides, particularly for
certain small-scale reactions. Phenyl sulfinylmethylphos-
phonate 43 has been shown to be effective in converting
aldehydes and ketones to a,B-unsaturated sulfoxides,38 which
39

could then be isomerized to the more stable B,yisomers.

This reagent is readily available by oxidation of sulfide

31

50,40 which is formed via a Michaelis-Arbuzov reaction of

phenylchloromethylsulfide and triethyl phosphite.41

Although the use of such ylides avoids problems associated
with the dehydration of intermediate fi-hydroxysulfoxides,
the reagent derived from 4% does not react with sterically
hindered ketones. Thus no reaction was observed with ketone

13.
m

Eqn 21

Eqn 22

32

¢SCHzC' + (C3H.O)3P -——-'> ¢SCH13(OCZHI)2

/[o]

 

o O

49 ¢gCHgg(032Hs)2
O

R/iL/R, «4326?: u(oc,H,), /§¢
—> R R,
111..
R \ ’
O

33

Once formed, the allylic sulfoxides were treated with tri-

methyl phosphite to generate allylic alcohols.42 It was

important to distill the trimethyl phosphite from sodium

metal to remove dimethyl phosphonate, which tended to result

in by-product formation and lower yields of the desired

allylic alcohols.

Eqn 24

Sun 25

 

» ¢ 05¢
---———u»
< .
3.19
/ (MeO) 3P

 

g .
0*
II
5¢
S¢
@.
cup 9 cup
1.3

OH
cH,o

51

~

Allylic alcohol 51 proved to be unstable. Upon Kugelrohr

distillation, crude 51 was completely isomerized to B-tetra-

lone 52.

’1»

N

34

Son 26

O

 

 

93 52

This unexpected result suggests an alternative to Stork's
classic synthesis of a-monoalkyl-B-tetralones. Because
fl-tetralones are notoriously prone to dialkylation, Stork

chose to proceed from all-tetralone (Scheme IX).43

SCHEME IX

I. “H

-H20

0 e R'co,H R
e
sI=,-o(c,H,,)2

R
0‘

 

 

    
 

35

Retone 53 is a clear, mobile liquid, but on exposure to air
it was rapidly transformed into a viscous, blood-red
material. As a consequence of this reaction, the methyl
doublet in the pmr of 52 became a singlet and shifted down-
field slightly. The crude reaction product yielded a crys-
talline semicarbazone derivative (5}), and the mass spectrum
of this derivative showed a parent ion 32 mass units higher
than expected for the semicarbazone of 52. This confirmed
our suspicions that 53 had reacted with molecular oxygen to

give a hydroperoxide of structure 54.

Eqn127
OOH
O
O
o °= ..
-——-——.. CHJJ
001,0 ‘ ~
.3 i4
OOH

NNHCNH,
O. 3
CH4:

gs

36

There is certainly precedent for this type of auto-oxida-
tion, including the important industrial preparations of
cumene hydroperoxide and t-butylhydroperoxide. Since the a-
proton in 52 is at once tertiary and benzylic gng.activated
by the carbonyl group, it should be easily attacked by

oxygen. A group of Polish researchers have reported a

similar auto-oxidation of an¢x-alkyl-8-tetralone (Eqn 28).44

 

 

37

B. Aromatic Annulation of Cyclic Ketones

Many naturally occurring compounds contain an aromatic ring
fused to one or more saturated rings, examples being estrone

5] and calamenin 58.

Figure 2. Estrone and Calamenin

In almost all cases, synthesis of such compounds begins with
an aromatic precursor and the other rings are then added by
well-established annulation methods.45 In many instances,
however, it would be convenient to begin with the saturated
rings and then attach the aromatic ring. This is especially
true in cases where either the aromatic ring is not highly
functionalized with respect to the remainder of the
molecule, or when a synthon for the non-aromatic portion of

the molecule is readily available.

38

With this in mind, we set out to develop a synthetic

sequence capable of converting a cyclic ketone to a

tetralin.

Eqn 29

 

‘* G

Our aromatic annulation route is outlined in Scheme x. 2-
hydroxymethylenecyclohexanone 53, prepared from
cyclohexanone and ethyl formate according to the procedure
of Ainsworth46, was converted to an enol ether derivative.
Several different protecting groups were evaluated for this

purpose.

39

SCHEME X

R
O _
a»
| a 69!) -S -BU
l

R 69¢ -OCH3

 

 

 

 

 

.59 ii
0
ll
i + F S¢ '
J ! H20 0”
H0
61
.. I- R J
air
1 ) LDA
2) /\c02c|..|3
* fi¢ ¢s==0
O
02H
64 COZCHg

2) H+ ,H 20
C02" co,cH
9.5

40

The first derivative to be considered was the isopropyl enol
ether. It is reported that a-hydroxymethylene ketones can
be converted to isoprOpyl ethers by O-alkylation with 2-
bromopropane in dimethylformamide solution.47 However,
reaction of 2-hydroxymethylene cyclohexanone under these
conditions afforded only a 15% yield of isopropyl ether 69a,
after distillation, along with a large residue of tarry

material.

Reaction of 69a with phenylsulfinylmethyllithium followed by
hydrolysis afforded 6} in moderate yield. On exposure to
air, this aldehyde was found to be slowly oxidized to the
corresponding carboxylic acid 64. Once contaminated with
acid, the aldehyde could be purified by dissolution in
tetrahydrofuran and filtration, leaving the insoluble acid
behind. Pure aldehyde was stored under nitrogen or argon to

prevent oxidation.

Although the conversion of 69a to unsaturated aldehyde-
sulfoxide 6} proceeded in poor overall yield, sufficient 6}
was obtained to test the pr0posed aromatic annulation
sequence. Optimization of the synthesis of 61 was thus

deferred.

Based on reports of Lansbury that 7-arylsulfonyl groups

directed alkylation of a,fl unsaturated ketones to the

41

1-site 48

, it was believed that the phenylsulfinyl group in
21 might promote Michael addition a to the sulfoxide

function.

When a THF solution of 6} was treated at low temperature
with one equivalent of LDA, a bright yellow solution of the
derived anion resulted. Reaction of this anion with methyl
acrylate led to 63, presumably through Michael addition
followed by a Knoevenagel condensation-dehydration
reaction. Compound 63 then underwent a mild pyrolytic
elimination (THF, reflux) to yield tetralinic ester 63.
Saponification of 6} yielded the known tetralin carboxylic
acid 65.

In this synthesis, the sulfoxide moiety serves several
purposes; first, the methyl group of phenyl methyl sulfoxide
ultimately becomes one of the aromatic ring carbons;
secondly, the arylsulfinyl group serves to direct the
Michael addition to the carbon atom 7 to the aldehyde; and
lastly, the facile elimination of the sulfoxide from the

cyclohexadiene brings about aromatization.

Many variations of this scheme are possible, which in
principle could be used to introduce a variety of

substituents on the aromatic ring.

42

Figure 3. Numbering of tetralin aromatic ring.

One can envision the introduction of an R1 group in two
distinct ways; first, one could begin with a substituted
sulfoxide. Utilizing phenylethylsulfoxide, for example,
would yield aldehyde éf. The Michael reaction would then

lead to a product bearing a methyl substituent on the new

ring (67).

Eqn 30
_ ..
x —* ..
CHO (:02CH3
H
66 67

An alternative involves alkylation of the unsubstituted
sulfoxide E}. It was expected that alkylation of the anion
from El would take place 1 to the aldehyde, in analogy to

the Michael addition. However, the anion of 61 failed to

43

react with methyl iodide at -78°. When the reaction mixture
was warmed to 0°, self-condensation of the aldehyde took
place, resulting in polymeric material. An attempt to form

the anion at 0° also produced a polymer.

R2 substituents may be introduced by a suitable choice of
Michael acceptor. A drawback here is that the yields are
lower, due to steric factors. We have been able to
synthesize 29 by using methyl crotonate; but a similar
attempt to synthesize the biphenyl Q? by using ethyl
cinnamate failed.

Figure 4. Structures of 68 and 69.

O.

~ ~

  

In a similar fashion, varying the Michael acceptor would
afford products with different R3 substituents. Here,
obviously, the choices are limited to vinyl compounds
bearing strong electron-withdrawing groups. Ester, ketone,
cyano, and nitro are all possibilities; nitroethene would be
a particularly interesting candidate for further study as

reduction followed by diazotization could lead to a large

number of ”Sandmeyer' products.

44

Finally, the carbonyl moiety in 2} could be modified. For
example, an ester function would lead to phenols in the
manner demonstrated by Hauser.3o Furthermore, reaction of
g} with methyllithium might yield 19, which could then be
oxidized to Z}.

This keto sulfoxide would then yield R4-substituted
tetralins. Such a route proved infeasible, however, when it
was discovered that g} was rapidly converted to its enolate

on addition of methyllithium.

SCHEME XI

OCH 0C};

I [o]

CI=KQ’

45

This behavior corresponds to that of other active methylene
compounds bearing two electron-withdrawing groups, such as

acetoacetic ester.

It was hoped that this aromatic annulation procedure might
provide a stereoselective synthesis of calamenin g? from 1-

carvone 72. The proposed synthesis is shown in Scheme XII.

46

SCHEME XII

 

0° ""38
a"\\

23' '12 N'OCzfls

c,u,ocuo

   

'76 (R- n-sus- ) 7i! 3- ae eno-
A' ;fllh-n-t$-
jglhlmo-
H“. mo

 

” NM
8) “00,6!“
3 A

 

«o Liam.
3) P8,,

‘)LUUHk

 

z: >"'

47

The first step in this synthesis requires hydrogenation

of l-carvone. During initial attempts at hydrogenation over
a palladium on carbon catalyst in ethanol solution, it was
observed that only a small percentage of the stoichiometric
amount of hydrogen was consumed before all reaction

ceased. Isolation of the product showed that most of the
carvone Z} was converted to carvacrol Z? by way of a double

bond migration and subsequent aromatization of the resulting

 

 

cyclohexadienone.
Egn 31
. O' OH
_.. —»
2K _ -
7.3 2.9

Fortunately, hydrogenation could be performed readily with a
platinum catalyst, and the completely saturated compound Z}

Was isolated in high yields.

Treatment of 23 with ethyl formate in the presence of sodium
ethoxide provided the formyl derivative ZS. Reaction of
this crude enol with 2-bromopropane in DMF afforded enol
ether Z§a in 59% yield. This yield was encouraging, since
cyclohexanone itself had given a rather poor yield of the
corresponding enol ether, §9a, together with substantial
amounts of a tarry residue. Since a-hydroxymethylene

ketones are known to polymerize readily ‘6, and should be

48

protected immediately as their enol ethers, the long
reaction times necessary for the reaction with secondary
alkyl halide may have contributed to the decomposition
observed. The increased alkyl substitution on Z} apparently

provides enough steric hindrance to retard polymerization.

During exposure to base in the enol ether synthesis, the
methyl group in Z} is presumably epimerized so that it and
the isoprOpyl group can assume a trans-diequatorial
configuration. A 1H nmr study of Z} using europium shift
reagents was inconclusive, however, and we were unable to
assign an unequivocal configuration to the methyl group in
Z§a. In any event, our synthesis of calamenin suffered a
major setback when enol ether Zéa proved to be completely

inert toward our nucleophilic sulfoxide base.

Because addition to the carbonyl carbon of Zéa was vital to
the proposed synthesis of calamenin, many experiments under
varying reaction conditions were conducted. One of the
first strategies to be tried involved varying the nature of
the enol ether group. Since Ireland had reported enhanced
reactivity of n-butylthiomethylene ketones, compared to the
corresponding alkyloxymethylene ketones, we decided to
evaluate the n-butylthio protecting group.49 In the model
system, treatment of hydroxymethylene compound é? with n-
butylthiol/p-TSA in refluxing benzene gave the desired

thioenol ether 60b without complications. This compound

49

reacted readily with methyllithium to yield §9, and with

phenylsulfinylmethyllithium to give §}° These products were

characterized by spectral analysis, and in addition a sample

of 80 was hydrolyzed to the known aldehyde 82. 50

 

Eqn 32 O
dirwhll Eh,
O
\ I OH
' ‘u
s/AV/\ sgfiv”\
MeLi 00') Q1
HgCl2
S'M 32 o / CH3CN CHO
80’ 82

~ ~

A disadvantage of the n-butylthio protecting group was soon
discovered; whereas the alkoxy enol ethers were readily
hydrolyzed with dilute aqueous mineral acid at room
temperature, the thioenol ethers required days of reflux
with mercury (II) chloride in aqueous acetonitrile.51 Under
these rigorous conditions the yield of aldehyde é} was

greatly reduced.

50

An interesting phenomenon was observed during vacuum
distillation of §}' Crude g}, a dark brown oil, on
Kugelrohr distillation afforded a straw-colored distillate
which solidified upon standing. Analysis showed this
material to be diene 29' Indeed, the 25° ”32 PIOtOD nmr
spectrum of g} is remarkable in that every unique set of

protons appears as a well-defined and distinct signal.

Eqn 33 (I?
¢’
H _, ff
\ §
‘1 gm
s¢/”\\/’\\
gp 83

Reaction of hydroxymethylene carvomenthone 15 with n-
butylthiol/p—TSA proceeded more slowly than with the model
system. It was observed that equimolar amounts of thiol and
enol produced some polymeric material along with the
expected ng, whereas excess n-butylthiol gave a mixture of

75b and thioacetal 25°

Eqn 34

   

51

The best yield of Zéb, after distillation, was about 65%.
This n-butyl thiomethylene derivative of tetrahydrocarvone
also proved to be disappointingly unreactive in the
subsequent step of the proposed synthesis. After trying the
phenylsulfinylmethyllithium reaction under many different
conditions, it was observed that prolonged reaction of Z§b
at room temperature with an excess of
phenylsulfinylmethyllithium gave a mixture containing a
small amount of adduct 29 along with a large amount of
unreacted Zéb. Extensive purification and recrystallization
afforded a 2% yield of 29. Many attempts to force this
reaction to completion were fruitless. In light of this
poor reactivity and the difficulty in hydrolyzing thioenol

ethers, this approach was abandoned.

Speculating that it may have been steric effects rather than
electronic effects which were causing the low reactivity of
ng, we searched for a smaller blocking group. To this end
a preparation for a-methoxymethylene ketones was devised. The
O-methyl derivative §9c had been previously prepared by
Belanger, but in low yields of about 34$.52 This method
required the use of toxic dimethyl sulfate, and in our hands
afforded only a 15% yield of §9c after two tedious
distillations. However, the discovery that qgc reacted
instantly with phenylsulfinylmethyllithium, and that
hydrolysis of the adduct gave a 77% overall yield of g},

stimulated a search for a better synthesis of figc.

52

Eventually we discovered that by dissolving §9 in anhydrous
methanol and adding a catalytic amount of p-toluenesulfonic
acid, a near quantitative yield of figc could be

obtained.53 Moreover, the only impurity was a small amount
of starting material, easily removed by washing with dilute
aqueous caustic. The high yields of pure product make this

the method of choice for synthesis of methoxy enol ethers.

Returning to the calamenin system, we prepared a-methoxy
methylenecarvomenthone Z§c in high yield. This product was
a mixture of the two possible geometric isomers, as
indicated by two signals in the vinyl region of the pmr
spectrum and two almost overlapping signals for the methoxy
group. Attempts to condense Zéc with phenyl-
sulfinylmethyllithium were all unsuccessful. When
dimsylsodium was substituted for phenylsulfinylmethyl-
lithium, enolization of 23c resulted. In an experiment to
determine whether the ketone group in 22c was reactive
toward ggy_nucleophiles, it was treated with 1.1 equivalents
of methyllithium. Under these conditions, lie was
completely consumed but the product was not the expected

adduct.

The In nmr spectrum of the product showed a complex vinyl
region, and GC/Ms indicated that two compounds of identical
mass, sixteen atomic mass units less than that of Tie, were

present. Furthermore, the infrared spectrum showed a

53

prominent carbonyl band. Based on this evidence, we have
assigned structures §§ and 86 to the product mixture. Thus
it seems that this reaction represents a novel 1,4 addition

of an alkyl lithium, followed by a p-elimination of

methoxide.
in» 35
. ° 0'
+
75c '
N \ 93 86

    

LA -

In the literature there are many examples of 1,4 addition of

 

 

Grignard reagents to systems such as alkoxymethylene
ketones, but to our knowledge this represents the first
example of conjugate addition of an alkyllithium reagent to
an unsaturated carbonyl compound. It is likely that severe
steric hindrance at the carbonyl function forces the

addition to take place at the less-hindered fl'carbon.

Later it was discovered that under forcing conditions
(HMPA-TMEDA-reflux) Z§c reacted with phenylsulfinyl-

methyllithium to yield a mixture of products. Spectral

S4

analysis indicated that these products had undergone a
complete loss of the methoxy group. It appears that the
major product here was also the result of a conjugate

addition.

We have shown that a simple ketone can easily be elaborated
to a fused bicyclic tetralin system. In order for this
technique to be generally useful, however, the problems we
observed in sterically hindered systems will have to be

dealt with.

55

EXPERIMENTAL

E22511.

Reactions were conducted in standard laboratory glassware.
Most non-aqueous reactions were carried out under a dry
argon atmosphere. Magnetic stirrers and teflon-coated
magnetic stir bars were used for agitation. Most reactions
were worked up by extraction into ether and drying of the

organic layer over anhydrous sodium sulfate.

The progress of most reactions was followed by thin-layer
chromatography or gas chromatography. Thin layer plates
were silica with fluorescent indicator, and were visualized
either by UV light or by spraying with dilute sulfuric acid
followed by charring. A Varian 1200 gas chromatograph
equipped with either a 4% QF-l or 10% SE-30 column was used

for GO analysis.

Melting points were determined on a Hoover-Thomas apparatus
and are uncorrected. Infrared spectra were taken on a
Perkin-Elmer 237B grating spectrOphotometer and were
measured relative to a polystyrene standard. Proton

magnetic resonance spectra were recorded on either a varian

56

T—60 or a Bruker 250 spectrometer. Carbon-13 spectra were
obtained on a Varian CFT-20 spectrometer. All nuclear
magnetic resonance samples were dissolved in
deuterochloroform containing tetramethylsilane as an

internal standard.

Mass spectra were obtained on a Finnegan 4000 gas

chromatograph/mass spectrometer.

Micro-combustion analyses were performed by Spang

Microanalytical Labs, Ann Arbor, Michigan.

57

Preparation of l-[(phenylsulfinyl)methyl]-l-cyclohexanol 22.

 

To a cold (~7a°) solution of lithium diisopropylamide (LDA)
in THF (30 mL), prepared from 1.01 g of diisopropylamine

and 4.35 mLof 2.3 M n-BuLi, was added a solution of 1.4 g
(10 mmol) phenyl methyl sulfoxide in a small amount of dry

THF.

This solution was stirred for fifteen minutes, 1 mL (10
mmol) of cyclohexanone was added, and the resulting mixture
was warmed to room temperature and stirred for two hours.
The reaction mixture was quenched with 5 mL water, then
extracted with three lS-mL portions CH1C13. The combined
extracts were dried over anhydrous sodium sulfate, and after
removal of the solvent yielded a cream-colored oil which
solidified upon standing. Recrystallization from 1:1
CHZClZ/ether afforded 1.60 g (67%) of white needles; mp
94.5-97.0°; IR (CHC13) 3425 (br), 1450, 1190 cm-l; PMR
(coc13) 57.3-7.7 (m, 53), 3.77 (s, 1H), 2.98 (d, J-l4 Hz,
1H), 2.70 (d, J=l4 Hz, 1H), 1.3-2.1 (m, 10H); MS (70 eV) m/e
239 (3), 126 (24), 113 (29), 95 (100), 78 (24), 77 (20), 67
(20), 55 (25), 43 (32), 41 (29); MS (CI, CH4) m/e 239.

58

Preparation of 1-[(phenylsulfinyl)methyl]-l-cyclohexene 39.

A solution of l-(phenylsulfinylmethyl)-l-cyclohexanol 22
(1.27 g) in 50 mL dry toluene was treated with 6.35 mL BF3
EtaO and refluxed for one hour. The reaction mixture was
then cooled to 0° and quenched with 50 mL 10% aqueous sodium
hydroxide. The layers were separated and the aqueous layer
was discarded. The organic layer was washed twice with
water, once with brine, and then dried over anhydrous sodium
sulfate. Removal of the solvent gave 1.14 g (973) of an
oil. A small non-polar impurity was removed gig_column
chromatography (silica, 1:1 ether/hexanes) to yield a solid
product, melting point 50-520. The product could be
crystallized from ether-pentane: melting point 50.5-52.5°;
m (CC14 ) 1450, 1085, 1060 curl; PMR (coma) 7.5 Sun, 53),
5.4 (br s, 1H), 3.49 (d, J-13 Hz, 1H), 3.21 (d, J-l3 Hz,
1H), 1.9 (m, 4H), 1.4 (m, 4H); MS (70 eV) m/e 221 (0.8), 126
(17), 95 (100), 77 (24), 67 (33), 55 (20), 41 (26); MS (CI,
CH4) m/e 221. Analysis: Calc. for C H SO : C, 70.86%;

13 18 2
H, 7.32%. Found: C, 71.32%; H, 7.37%.

59

Preparation of 2-methylidene-ljgyclohexanol 31.

 

To a solution of l-(phenylsulfinylmethyl)-cyclohexene (920
mg) in 20 mL dry THF was added 0.5 g (MeO)3 P (freshly
distilled from sodium metal) and 2 mL dry MeOH. The
resulting mixture was then stirred for four days at room
temperature. Removal of solvents yielded 440 mg of crude 2-
methylidene cyclohexanol 31. Column chromatography
(pentane/ether on silica) afforded 395 mg of pure 31 (yield
84%): pan (coc13) 54.77 (m, 13), 4.53 (m, 1H), 3.8-4.2 (m,
23), 1.2-2.4 (m, an).54

Condensation of 6-methoxy-l-tetralone with phenylsulfinyl-

methyllithium (Preparation of:€-hydroxysulfoxide 24.)

A solution of 10 mmol LDA in THF was prepared from 1.01 g
(1.40 mL) of diisOprOpylamine and 6.25 mL of 1.6 M_n-BuLi at
0°. Phenyl methyl sulfoxide (1.4 g, 10 mmol) was added as a
solution in 5 mL of THF and the reaction mixture stirred
thirty minutes at 0°. A solution of 6-methoxytetralone
(1.762 g, 10 mmol) in 5 mL THF was then added, the ice bath
removed, and the reaction stirred four hours at room
temperature. The reaction was quenched with saturated

ammonium chloride and extracted with diethyl ether. Drying

over anhydrous sodium sulfate and removing the ether

60

yielded 3.18 g (100%) of adduct 24: IR (neat) 3350 (br),
2920, 1675, 1605, 1500, 1250 om’f; pun (CDC13) S7.2-7.6 (m,
6H), 6.4-6.8 (m, 2H), 3.63 (s, 3H), 1.8-3.2 (m); as m/e 299
(3), 192 (13), 191 (100), 174 (21), 173 (81), 172 (35), 158
(34).

Condensation of diene 13 with phenylsulfinylmethyllithium

(Preparation of Q-Mdroxysulfoxide 33.)

To a cold (0°) solution of LDA prepared from 10 mmol of
diisopropylamine and 10 mmol of 2.6 M n-butyllithium in
30 mL dry THF, was added a solution of 1.4 g (10 mmol)

phenylmethylsulfoxide in 5 mL THF.

This solution was stirred 15 minutes, cooled to -78°, and
then a solution of 1.8 g (10 mmol) of 13 in 10 mL THF was
added and the resulting solution stirred at -78° for a

period of thirty minutes.

The reaction mixture was neutralized with saturated ammonium
chloride and the organic layer was separated. The aqueous
layer was extracted with two 10 mL portions of ether. The
combined extracts were dried over anhydrous sodium sulfate;
removal of the solvents gave 2.68 g of a tan solid, which
was shown to be approximately a 1:1 mixture of 13 and 35.

Compound 35 was conveniently isolated by stirring the
4 ~

61

mixture overnight in a small amount of diethyl ether; 13
dissolved, leaving sparingly soluble 35 behind as a solid:
Yield 1.42 g, 42%, mp 154-156°; IR (CDC13) 3425 (br):
2950, 2250, 1740 cm']; pun (c0c13) 7.5 (s, 5H), 4.42 (s,
1H), 3.03 (d, J=13 Hz)lH) , 2.64 (d, J=13 Hz)1H), 1.4-2.4
(m), 1.32 (s, 3H), 0.83 (s, 3H); MS m/e 321 (4), 305 (22),
303 (41), 195 (37), 193 (45), 177 (28), 162 (21), 137 (30),
135 (40), 126 (100), 125 (48), 124 (23), 123 (47), 122 (37),
121 (23); us (c1, CH4) m/e 321.

Preparation of l-(phenylsulfinylmethyl)-1-Cyclopentanol 39.

To a cold (0°) solution of 2.2 mmoles of
phenylsulfinylmethyllithium (prepared in the usual fashion)
was added 168 mg (2 mmol) of cyclopentanone. The resulting

solution was stirred overnight at ambient temperatures.

After standard work-up, the crude product was recrystallized
from ether/CH2C12. The first crop of crystals weighed 160
mg and had a melting point of 102-106°. Upon concentration
of the mother liquors a second crop of 35 mg was obtained
for a 63% yield: PMR (CDC13) 97.42 (s, 58), 3.82 (s, 18)
3.14 (d, J-13 HleH), 2.76 (d, J-13 Hz)lH), 1.4-2.2 (m, 8H);
MS m/e 225 (7), 126 (40), 99 (64), 81 (100).

62

Preparation of l-(phenylthiomethyl)-1-cyclohexanol 38.

To a solution of 5.8 g TMEDA and 20.7 mL of 2.42.M_n-BuLi in
hexane at 0° was added 5.8 g of thioanisole. After this
mixture had stirred for four hours, 10 mL dry THF was added
to dissolve the solid which had formed, and the resulting
solution was cooled to -78°. A solution of 5 mL
cyclohexanone in 20 mL dry THF was added dropwise, and this
mixture was warmed to room temperature and stirred for two
hours. After quenching with saturated ammonium chloride
solution, the reaction mixture was extracted with diethyl
ether, washed with dilute aqueous hydrochloric acid,
saturated aqueous NaHCO3, and then dried over anhydrous
sodium sulfate. Kugelrohr distillation yielded 4.65 g of
1-(pheny1thiomethyl)—l-cyclohexanol (45%), as well as
substantial amounts of unreacted thioanisole and
cyclohexanone: IR (neat) 3425 cm"1 (br); PMR (CDC13) 56.9- t
7.3 (m, 5H), 3.00 (s, 3H), 2.2 (s, 18), 1.3-1.7 (m, 10H); MS
(70 eV) m/e 222 (17), 124 (100), 123 (35), 109 (41), 99
(29), 81 (35), 77 (22), 55 (24), 41 (30).

63

Preparation of l-(phenylthiomethyl)-l-gyclohexene 29 and

,(phenylthiomethylidene)-cyclohexane 49.

To a solution of 1.37 g of 1-(pheny1thiomethyl)-1-
cyclohexanol 38 in 50 mL of dry benzene was added 50 mg of
p-toluenesulfonic acid monohydrate (p-TSA) and this mixture
was then refluxed through a Dean-Stark trap for 48 hours.
The solution was cooled, then washed with saturated sodium
bicarbonate, water, and dried over anhydrous sodium
sulfate. Removal of the solvent gave 1.01 g (80%) of a
mixture of the two possible dehydration products.
Integration of the pmr spectrum showed the ratio of
endocyclic isomer 32 to exocyclic isomer 49 to be 2:1: IR
(neat) 2935, 1590, 1485, 1445 om‘l; PMR(CDC13) 57.2 (10, SH),
5.83 (s, l/3H), 5.47 (br s, 2/3H), 3.4 (s, 2H of endocyclic
isomer), 1.4-2.4 (m);

MS (70 eV) Endocyclic isomer 33 m/e 204(60), 110(33),
95(100), 79(37), 67(36);

Exocyclic isomer 49 m/e 204(100), 110(18), 95(57), 91(19),
79(25), 67(22).

Preparation of Allylic Sulfoxide 14.

A solution of 3.18 g (10 mmol) of alcohol 33 in 50 mL dry

benzene was treated with 50 mg p-TSA and refluxed for

64

twenty minutes. The solution was then cooled and the
benzene removed. The residue was dissolved in diethyl ether
and washed with three portions saturated NaHCO3, once with
brine, and then dried over anhydrous sodium sulfate.

Removal of the ether gave 2.792 g (94%) alkene 44, all

P'Y: IR (neat) 1675, 1600, 1500, 1250 cm'l; PMR (c0c13)
£6.5-7.4 (m, 8H), 5.50 (t, ass Hz, 1H), 3.70 (s, 3H), 1.9-
3.1 (m, 4H); MS m/e 298 (l), 173 (100), 172 (95), 158 (37).

Preparation of l-methylidene-l,2,3,4-tetrahydro-6-methoxy

 

naphthalen-Z-ol 51.
~

 

To a solution of 63 mg of allylic sulfoxide 43 in 5 mL THF
and 0.5 mL methanol was added 0.2 mL of trimethyl
phosphite. The reaction was monitored by thin-layer
chromatography, and was found to be essentially complete
within 2 to 4 hours, although longer reaction times had no

adverse effect on the observed yields.

The solvents were removed under reduced pressure and the
residual oil was subjected to column chromatography
(ether/silica gel). Yield of crystalline allylic alcohol 2}
was 33 mg (82%), mp 81-82°.

65

IR (KBr) 3350 (br), 1600, 1500, 1320, 1265, 1225, 1075,
1045, 1025 cm‘l; PMR (c0c13)56.4-7.5 (m, 38), 5.33 (br s,
1H), 5.07 (br s, 18), 4.2-4.5 (m, 1H), 3.70 (s, 38), 2.6-3.1
(m, 28), 1.7-2.1 (m, 28); us m/e 190 (100), 175 (28), 173
(25), 172 (42), 163 (38), 159 (20), 147 (35), 131 (26), 129
(58), 128 (36), 115 (60), 103 (52), 102 (26), 91 (46), 77
(48), 63 (37), 51 (28).

Analysis:Calculated: 75.76% C, 7.42% H.
Found: 75.73% C, 7.49% H.

Preparation of 6-methoxy-01-methyl-jg-tetralone 53.
1

Upon Kugelrohr distillation of 2.79 g of crude 21, 1.30 g of
a clear mobile liquid was collected. Analysis of the
distillate showed it to be tetralone 5}, the result of a
thermally induced double bond migration. Pp: 2000 (0.1 mm
89); IR (neat) 1710, 1495 om‘l; PMR (00013) S6.6-7.6 (m,
3H), 3.72 (s, 3H), 2.3-3.6 (m, 5H), 1.42 (d, J c 8 Hz, 38);
MS m/e 190 (52), 147 (100), 91 (35).

Auto-oxidation of 52.
~
Compound 23 was found to react rapidly with atmospheric

oxygen to yield a viscous, blood-red oil. PMR analysis of
the crude oil showed that the methyl doublet at $1.42 in 52

66

had been replaced by a singlet at $2.40. On that basis, it
was believed that the product 53 was a hydroperoxide. This
was confirmed when it was found that upon treatment with
semicarbazide 53 yielded a semicarbazone 54 which showed a
parent ion in the mass spectrograph 32 units higher than

that expected for 22 semicarbazone.

Preparation of 2-hydroxymethylenecyclohexanone 52.
2-Hydroxymethylenecyclohexanone 59 was prepared from
cyclohexanone and ethyl formate according to the Organic
Synthesis procedure using the sodium metal method.46 The
crude product was not distilled, and was used directly in
the preparation of isopropoxymethylenecyclohexanone 60a,
methoxymethylenecyclohexanone 63b, and 2-(n-butylthio-

methylene)cyclohexanone 60c.
~

Preparation of 2-isOpropoxymethylenegyclohexanone 629.

A solution of 10 g 2-hydroxymethylenecyclohexanone 22, 10 g
2-bromopropane, and 20 g anhydrous potassium carbonate in 30
mL dry dimethylformamide (DMF) was heated overnight on a
steam bath. The reaction mixture was filtered and the
filter cake was washed with several portions of ether. The

combined filtrates were washed sequentially with water, cold

67

dilute caustic, and brine. After the solution was dried
over sodium sulfate, the solvents were removed under
reduced pressure, affording a crude yield of 10.43 9.
Fractional vacuum distillation gave 2.0 g of product,

bp 80—850 at 0.25 mm Hg. There was a small forerun and
a large amount of gummy polymeric material remained in
the pot. The distillate was analyzed by pmr: PMR(CDC13)
6'8.33 (s, 1/3H), 7.2-7.4 (t, 2/3H), 3.9-4.6 (m, 1H),

2.0-2.6 (m, 4H), 1.4-1.9 (m, 4H), 1.1-1.3 (d, J=6Hz, 6H).

Preparation of 2-(n-butylthiomethylene)-cyclohexanone 629.

 

A solution of 109 g of crude 2-hydroxymethylenecyclohex-

anone 52 in 500 mL benzene was refluxed through a Dean—

Stark trap to remove any water preSent. The solution was
cooled to ambient temperature, and 92.5 mL of n-butane-

thiol and 150 mg of p-TSA were addded. The reaction mixture
was then refluxed through the Dean-Stark trap for an
additional two hours. The benzene and excess n-butanethiol
were removed at reduced pressure. The crude product was
dissolved in ether, washed with dilute caustic, water, and
brine. After drying and removal of solvent, the crude product
was distilled under vacuum. The cut boiling at 152-1540

at 13 mm Hg weighed 71 g (41%) and was shOwn to be pure 6213:
IR (neat) 2930, 2860, 1675, 1550, 1310, 1150, 815 om’l;
PMR (CDC13) 87.38 (t, J=2Hz, 1H), 2.80 (t, J=7Hz, 281,
2.1—2.4 (m, 4H), 1.2-1.8 (m,8H), 0.8-1.0 (m, 3H): MS (70 ev)
m/e 198 (27), 141 (100).

68

 

Preparation of 2-methoxymethylenecyclohexanone 60c.

Crude 2-hydroxymethylenecyclohexanone from 49 g of
cyclohexanone was dissolved in 500me of absolute methanol
containing 25 mg of p—TSA. Equilibrium.was established

within fifteen minutes; the ratio of 629 to 53 was deter—

mined to be approximately 5:1 by gas chromatographic

analysis. One gram of anhydrous Na2C03 was added to neutralize
neutralize the sulfonic acid catalyst, and the mixture was

then filtered. After the methanol was removed by distillation
at reduced pressure, the resulting oil was dissolved in

ether and filtered again. The ether solution was washed

with small portions of 5% NaOH solution until gas chro-
matographic analysis showed that 53 was absent. The ether
(Solution was then washed with brine and dried over sodium
sulfate. Following removal of the ether, bulb-to-bulb
distillation of the residual oil gave 26 g of 623 (37%

from cyclohexanone): IR (neat) 1720, 1675, 1595, cm’l;
PMR (c0013)87.13 (t, J=2Hz, 18), 3.80 (s, 3H), 2.2-2.6

(m, 4H), 1.8-2.0 (m, 4H).

69

Preparation of 61.
N

A solution of 1.01 g (10 mmol) diisoprOpylamine in 10 mL dry
THF was cooled to 0°. To this solution was added 10 mmol of
n-BuLi (6.25 mL of a 1.6‘M_solution in hexane), and this
mixture was stirred fifteen minutes at 0°. Phenyl methyl
sulfoxide (1.4 g, 10 mmol) in 10 mL THF was added yig_a
syringe, and the resulting yellow solution was stirred
thirty minutes at 0°. The ice bath was then replaced with a
dry ice-ether bath and 1.4 g (10 mmol) of 2-methoxymethylene
cyclohexanone, 62b, dissolved in 10 mL THF was added in one
portion. This solution was stirred at -80° for five minutes
and then allowed to warm to room temperature and stirred

twenty-four hours.

The reaction was quenched with saturated ammonium chloride
solution and the organic layer separated. The THF was
removed under reduced pressure and the residue taken up in
ether. This ether solution was washed sequentially with 6 N
HCl, water, saturated NaHCO3, and brine. At this point the
product may crystallize as it is sparingly soluble in dry
ether. The combined aqueous layers were extracted with
three 25-mL portions of methylene chloride, and the combined
ether and methylene chloride extracts were dried over
anhydrous sodium sulfate. Removal of the solvents and

recrystallization from either CH2C12/ether or THF/ether

7o
afforded 1.92 g (77%) of product: mp 118.5—119.5°;
IR (KBr) 1660, 1620, 1440, 1160, 1085, 1030 om'l;
PMR (cn813)Ԥ9.48 (s, 18), 7.37 (s, 58), 3.87 (s, 28),'
2.0-2.4 (m, 4H), 1.4-1.8 (m, 4H); MS m/e 248 (1), 126
(23), 123 (100), 95 (35). Analysis: Calc. for C14H16802:
c, 67.71%; 8, 6.50%. Found: c, 66.87%; H, 6.46%.

A portion of 6} was reacted with 2,4—dinitrophenylhydrazine
in acidic aqueous ethanol and afforded an orange-red 2,4-D
derivative: mp 185°. Analysis: Calc. for C20H20N4SOS:

C, 56.06%; H, 4.71%. Found: C, 55.92%, H, 4.57%.

Isolation of chlohexadiene Intermediate 62.

 

To a solution of 100 mg (0.11 mmol) of 61 in 5 mL dry THF at
-78° was added a solution of 0.4 mmol LDA in hexane. This
solution was stirred thirty minutes, during which time the
bright yellow color of the anion became evident. Methyl
acrylate (63’pl, 0.6 mmol) was then added, and the reaction
mixture was stirred fifteen minutes at -78°, followed by
twenty-four hours at ambient temperature. After quenching
with saturated ammonium chloride solution, the organic layer
was separated and the aqueous layer was extracted twice with

10 mL portions of diethyl ether. The combined organic

71
layers were then washed sequentially with 1% hydrochloric
acid, water, and brine. The solution was dried over
sodium sulfate, and the solvents were removed under
reduced pressure taking care that the bath temperature
did not exceed 30°. Compound 62 was a light yellow
unstable solid: mp l33-134°; IR (KBr) 1730, 1425 cm-1;
PMR (cuc13) 37.47 (m, 58), 7.17 (s, 1H), 3.62 (s, 38),
3.2-4.2 (m, 3H), 1.4-2.8 (m, 8H); MS m/e 250 (l) ( 1328202
decomposition product), 218 (2) ( £282 decomposition
product), 191 (25), 190 (33), 149 (27), 131 (100),

126 (45), 107 (47); MS (CI, CH4) m/e 317 (M+1).

Preparation of 6-carbomethoxy-1,2,3,4-tetrahydronaphthalene
63.
N

The cyclohexadiene 63 (prepared from 100 mg 61) was
dissolved in dry THF and refluxed for two hours. The
reaction was conveniently followed by TLC. At the end of
the reaction period, the solvent was removed and the
products (diphenyl disulfide, S-phenyl phenylthiolsulfonate,
and 63) were separated by column chromatography
(CH2C12/silica). Yield of 63 was 65 mg (86% overall from
61)! IR (neat) 1720, 1430, 1270 cm'lz PMR (CDC13) S7.4-7.8
(m, 2H), 7.0 (d, 1H), 3.87 (s, 3H), 2.7-3.0 m, 4H), 1.7-2.0
(m, 4H); MS m/e 190 (28), 159 (40), 131 (93), 87 (30), 85
(100). '

72

Saponification of ester 63 to known tetralincarboxylic acid

~

65.
N

To a solution of 30 mg of ester 63 in 5 mL 95% ethanol was
added 0.5 mL of 40% sodium hydroxide solution. The
resulting solution was refluxed for two hours, and then
cooled to room temperature. Acidification with 6 M
hydrochloric acid yielded a fluffy white precipitate, which
was collected by filtration and washed with water. The
product correlated with the known 5,6,7,8-
tetrahydronaphthalene-2-carboxylic acid, and had mp 152-1530
(literature mp 154°):5S 8596176 (37), 131 (100), 91 (18).

Preparation of Methyl-substituted Tetralinic Ester 6g.

Ester 66 was prepared by substituting methyl crotonate for
methyl acrylate in the preparation of 62. Thus 61 (0.5
mmol) was treated with LDA (0.5 mmol) at -78° in THF.
Methyl crotonate (0.75 mmol) was added and the mixture

stirred 24 hours at room temperature.

In contrast to 62, no solid material was obtained but rather
a mixture of the expected cyclohexadiene and a considerable

amount of polymeric material. Thermolysis (refluxing THF, 4

hours) followed by column chromatography (C82C12/311104 961)
afforded 24 mg of 68 as an oil (24% yield from 61): PMR

73

(c0c13) 37.8 (s, 18), 7.2 (s, 18), 3.87 (s, 3H), 2.8-3.0 (m,
48), 2.6 (br s, 38), 1.8-2.0 (m, 48); us m/e 204 (38), 186
(23), 172 (45), 145 (100); Analysis:Ca1cu1ated: 76.44% C,
7.40% 8; Found: 76.61% c, 7.41% 8.

Preparation of 2-methyl-5-(l-methylethyl)-cyclohexanone 73.

M

Method A. One-step method. A Parr bottle was charged

 

with 30 g of l-carvone, 100 mg of platinum (IV) oxide

(Adam's catalyst), and sufficient absolute ethanol to

bring the total volume to 250 mL. The bottle was alternately
evacuated and purged with hydrogen gas to remove air,

and then agitated under 3—4 atmosperes of hydrogen for

two hours at ambient temperature. The platinum catalyst

was very finely divided and removal by filtration was
difficult. Yield of carvomenthone 23 containing traces

of olefinic contaminants was 27.1 g, 88%.

Method B. Pre-reduced catalyst method. The Parr bottle

 

was charged with 100 mg Adam's catalyst and 100 mL of
absolute ethanol. Air was removed as in Method A and then
the catalyst was agitated for a few minutes under 4
atmospheres of hydrogen. The flask was vented, 30 g of
l-carvone was added, and diluted to 250 mL with additional
absolute ethanol. After two hours of reduction at 3-4

atmospheres pressure, the product was isolated by filtration

74
and removal of solvent. In this case, filtration was
easier and the product contained no residual olefin. Yield
of Z} was 29.3 g, 95%? IR(neat) 1720 cm-1; PMR 51.3-2.6

(m, 9H), 1.0-1.3(m,9H); MS m/e 154(27), 112(13), 111(100),
110(11), 97(16), 95(23), 83(24), 69(26), 55(98),41(60).

Preparation of “thdroxymethylenecarvomenthone 14.

Carvomenthone (19.5 g) and ethyl formate (28.8 g) were
dissolved in 500 mL of dry ether. Sodium metal (9 g) and

1 mL of absolute ethanol were added and the reaction mixture
was stirred for 24 hours. Work-up?6 followed by bulb-to-
bulb distillation, gave 15.2 g of'drhydroxymethylene-

carvomenthone 14, 66% yield.
Preparation of isopropyl enol ether 75a.

A solution of 14.92 g enol 74 and 10.09 g 2-bromopropane
in 150 mL dry DMF was treated with 20.7 g anhydrous
potassium carbonate and heated at 1000 overnight. The
reaction mixture was filtered and the filter cake washed
with ether. The combined organic layers were washed
several times with dilute caustic to remove unreacted
starting material. Drying of the organic layer followed
by removal of the solvents yielded 13.10 g (73%) of crude

enol ether 75a. Kugelrohr distillation afforded 11.41 g
N

75
of pure material: PMR(CDC13)67.0-7.2 (m,1H), 3.8-4.3 (m,lH),

0.7-2.9 (m,22H).

Preparation oftK-(n-butylthiomethylene)-carvomenthone :32.

A solution of 21.47 g of enol ZS, 12.74 g n-butyl thiol,

and 30 mg of p-TSA in 400 mL dry benzene was refluxed through
a Dean-Stark trap until no more water came over (about 48
hours). The benzene solution was washed sequentially with
saturated aqueous sodium bicarbonate, water, brine, and

dried over sodium sulfate. Removal of solvent yielded

25.33 g of thioenol ether 12b, 85%: IR(neat) 2955, 2930,
2870, 1680, 1550, 1470 om'l; PMR 7.20 (br s, 1/28),

6.93 (s, l/2H), 0.8-3.0 (m, 23H); MS m/e 254 (25), 212 (12),

211 (100), 209 (17), 197 (16).

 

Preparation of(x-methoxymethy1enecarvomenthone 13c.

A solution of 15.2 g of A-hydroxymethylenecarvomenthone 13
in 500 mL of dry methanol was treated with 50 mg of p-TSA.
Gas chromatographic analysis showed that equilibrium was
reached in thirty minutes. Approximately 1 g of anhydrous
sodium carbonate was added to neutralize the catalyst. The
reaction mixture was filtered, and the solvent stripped off
at reduced pressure. The resulting semi-solid was dissolved
in dry ether, and filtered again. The ether solution was

washed with dilute caustic until gas chromatographic

76
analysis showed no traces of residual enol 14. Drying and
removal of solvent afforded 12.4 g of 73c, 76% yield, as a
mixture of two geometric isomers: IR (neat) 1680, 1605,
1245 cm'l; PMR-(CDC13) 87.00 and 6.90 (2s,.18), 3.75 and
3.72 (25, 3H), 1.3-2.6 (m, 7H), 1.10 (d, J=6 Hz, 3H),
0.7-1.0 (m, 6H); MS m/e 196 (7), 154 (10), 153 (100),

125 (30), 93 (17).

Preparation of l-methyl-Z-(n-butylthiomethylidene)-cyclo-

 

 

hexan-l-ol 80.
~

A solution of 3.68 g of 62b in 50 mL of THF was cooled

to -78°. To this solution was added 14.6 mL of 1.4 E;
methyllithium solution in ether. The reaction mixture was
stirred for 10 minutes at -78°, and then warmed to room
temperature. Analysis of an aliquat of the reaction mixture

showed complete conversion of 60b to 8 Yield of 80

0.
N N
after work-up was 3.87 g, 97%: IR (neat) 3500 (br),

2950, 2890, 1675, 1550 om'l; PMR 55.92 (s, 18), 1.4-3.0

13

(m, 158), 1.35 (s, 38), 0.8-1.1 (m, 38); c NMR $143.51,

116.29, 73.23, 42.38, 33.64, 32.40, 28.10, 27.25, 26.76,

23.44, 21.81, 13.67; MS m/e 196 (M+-H 0, 90), 140 (14),

2
139 (33), 125 (13), 111 (13), 108 (34), 107 (100), 106 (37),

105 (57), 97 (14), 95 (20), 93 (32), 91 (68).

77
Preparation of sulfoxide diene 83 and intermediateL3-hydroxy-
N
\

sulfoxide 81.
N

 

A solution of 7.92 g thioenol ether 62c in THF was added

to a cold (-78°) solution of phenylsulfinylmethyl lithium
in THF. The reaction mixture was allowed to stir for 5
minutes at -78°, and then slowly warmed to room temperature.
The reaction was quenched with water and extracted into

ether. Crude yield of é-hydroxysulfoxide [8‘1 was 97%.

A portion of the crude adduct was subjected to bulb-to-bulb
distillation. A forerun of excess phenyl methyl sulfoxide
was observed, followed by more volatile material as the
temperature reached 1800 at 0.1 mm Hg. The bulk of the
material failed to distill under these conditions. Upon
cooling, the residue solidified. Recrystallization from
ether afforded 63 as white needles. Overall yield from
thioenol ether 62; was 51%: mp 74-760; PMR (250 MHz)
37.52 (m, 58), 6.09 (s, 1H), 5.31 (br s, 1H), 3.90(d,
J=13 Hz, 1H), 3.42 (d, J=13 Hz, 1H), 2.75 (t, J=8 Hz, 2H),
2.30 (t, J=6 Hz, 28), 2.0 (m, 28), 1.5-1.6 (m, 68),

13c NMR 5144.03, 132.25, 131.84,

0.95 (t, J=6 Hz, 3H);
131.15, 128.75, 126.52, 124.50, 122.25, 63.62, 34.03,

32.55, 27.35, 25.92, 21.73, 21.57, 13.68; MS m/e 320 (3),
196 (11), 195 (92), 139 (27), 138 (39), 137 (100), 110 (17);

106 (10), 105 (76), 97 (31).

78
Reaction of methyllithium witth-methoxymethylene-

carvomenthone 739 (Preparation of E- and Z- isomers of

 

ethylidenecarvomenthone 66 and 66).

To a solution of 196 mg of 75c in 10 mL dry THF at -780
~

was added 1.1 mmol of 1.6 M methyllithium in ether. After
15 minutes, the reaction was quenched with saturated aqueous
ammonium chloride and worked up. Spectral analysis
idicated that the product was predominantly a mixture
of isomers 85 and 86. A small amount of alcohol was

N ~
formed, owing to the excess methyllithium used: IR (neat)

3450 (br, wk), 2950, 1700, 1630 cm"1 , PMR 86.0-6.6 (complex

multiplet); GC/MS Isomer I: m/e 180 (4), 152 (43), 138 (31),
137 (91), 109 (94), 96 (100); Isomer II: m/e 180 (18),
152 (24), 138 (40), 137 (100), 109 (81), 96 (98).

APPENDIX

100

8 8

TRANSMITTANCEOS)
8

N
0

go

TRANSMITTANCEDS)

3500

1800

1600

Figure 5.

79

2500

1400 1200

IR spectrum of 29.

800

 

-1

81

)00

w w
1532.12.28.23“:

 

m

2500

.m.

  
 

36325252345

IR spectrum of 35.

Figure 7.

82

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

100

 

33 82.5.3233

 

  

153258.522»

I200

I400

‘800

 

~

IR spectrum of 35.

Figure 8.

83

100

0
8

w w

5502:2525»

 

100

80

(I 4444444

.........

m

15323252345

 

o
2

1600 I400 1200 "MD

-1800

...m

~

IR spectrum of 38.

Figure 9.

84

8 8 8

mansmnancrm)

3

 

2500 ZXD 1500 of

So
‘4
3

ramsmnnncem)

 

1800 1600 1400 1200 1000 800 ear

Figure 10. IR spectrum of 69 and 69.

85

'00

w . w
sexuz<t§mz<fi

 

o
2

1500 cm

2500

am

 

13:02:21,135»

I200

1400

1800

Figure 11.

IR spectrum of 45.

86

100

w

w w
3332:2325»

 

o
2

1500 cm

2500

3500

om

 

samuzfitzmzte

1400

1800

IR spectrum of 51.

Figure 12.

87

I00

w
1532142225»

 

m

2500

3500

...m

I500

  

13:35:28.5:

I000

I400

1800

 

IR spectrum of 52.

Figure 13.

I00

.
.
. . . . . ,

w w

3:325:55:

 

m.

I500

2“!)

.m

IOO'

V .
. _
.
_
1

w w
.fivmuzipimzfip

..._

 

m

1600 I400 EH!) I000

1800

..m

~

IR spectrum of 60b.

Figure 15.

89

I00

w w
.ssuuztrzmzie

 

m

I500

2“!)

om

I00

m

xesuu

m. m

2(. ..iaZ(~:

 

69c.

IR spectrum of

Figure 14.

90

I00

8 S 8

mmsmmANcrm)

N
O

 

2500 2000 I500 cm-

go
‘5
E

’TRANSMITTANCE(%)

 

I800 I600 I400 _I 200 I000 800 cm.

Figure 16. IR spectrum of 61.

91

m

w w
3362.42.28.25»

m

 

100

. . 1
.
. _

   

m...m

1532322823.:

I600 I400 I200 I000

I800

Figure 17.

62.

IR spectrum of

~

92

I00

w w
18.323.22.622»

 

m

NED

2i!)

..m

I00

w w
8:625:55:

 

m

IOU)

I600 I400

I800

. ., A. _
. ,. , .1
.00
, ,. .m ...U . .,.1.. o . . .. ..
.. . .
, . . . . .1 . a.
. ... . _ . .. _ ,
... .1 . .. . _.. . .... . . e,
. . . .
_ .. .p .. i, .. n. 1.. . . ..
1 . _ . . . . .

I200

IR spectrum of 6}.

Figure 18.

93

I00

NE _

w m

1532.42.24.25»

 

0
2

2500

om

 

Seemuzztingp

800

I200

I400

I800

73.

IR spectrum of

Figure 19.

94

I00

0
8

 

w w
3:325:55:

 

I00

0 ,
8
3&3

w m
z<t.zmz<E

0
2

000000

44444

 

I400 RKX) I000 800

I600

I800

om

73b.

IR spectrum of

Figure 20.

95

 

TRANSMITTANCEOG)

 

1800 1600 1400 1200 1000 800 ci'

Figure 21. IR spectrum of 73c.

96

100

  

0
8

w w
Aéwuzfittmzih

    

0
2

1500

om

 

  
 

Aimuztttmzzb

~

IR spectrum of 80.

Figure 22.

97

 

 

 

 

 

 

 

 

1500

-1

2500

3500

 

 

w w w m
as wuz<Ezmz<fi

  

Aiwuzfihimzth

1600 1400 1200 1000 800

1800

 

gs.

f8_.f>and

IR spectrum 0

Figure 23.

98

 

Figure 24. PMR spectrum of £3.

 

Figure 25. PMR spectrum of 23'

99

 

Figure 26. PMR spectrum of a}.

up“?

 

Figure 27. PMR spectrum of 33'

100

 

 

Figure 29. PMR spectrum of 16’.

101

 

Figure 30. PMR spectrum of 23.

 

Figure 31. PMR spectrum of 22 and 19.

o

'1
-|
‘-
n

u
c

 

PMR spectrum of 44.

igure 32.

 

m?

PMR spectrum of 51.

"'1"

no...

Figure 33.

 

PMR spectrum of 52.

Figure 34.

 

PMR spectrum of 59.

Figure 35.

104

 

Figure 36. PMR spectrum of Ega.

 

Figure 37. PMR spectrum of gap.

105

 

Figure 38. PMR spectrum of 92c.

 

Figure 39. PMR spectrum of g}.

106

 

Figure 40. PMR spectrum of £3.

1 CED)... _,

 

Figure 41. PMR spectrum of 6 .

~

107

 

N

PMR spectrum of 68.

Figure 42.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A A A
an '9‘

I.

 

 

 

 

f 73.
~

PMR spectrum 0

Figure 43.

108

 

Figure 44. PMR spectrum of 75a.

CPL

 

Figure 45. PMR spectrum of 13b.

109

 

Figure 46. PMR spectrum of ch.

C6...

 

Figure 47. PMR spectrum of §g.

110

my
.om «0 esuuowmm «:2 o

m._..

.mv masses

 

111

 

Figure 49. PMR spectrum of E2

 

Figure 50. PMR spectrum of E}.

112

 

066

\\\€

 

rt

2
. m m0 Esuuommm mZm NEE omN

.Hm mnsmwh

 

o .53

t .1“ “EN

 

3..“

 

r-é

 

 

 

 

91

113

.Mm mo Efinuoomm mzz 0

ma

.Nm wnsmfim

 

114

 

Figure 53. PMR spectrum of 85 and 86 .
~ ~

115

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

IUJ~ ’ 5
F
O »
n
110 15¢
L
”'6‘
43
1 _ 1 3 b
3 78 xx
4 a
m
m
, ‘40 \- ,' .7 '3 .25 2&1 T
I ' V ' I ' I W
we a nu 19 .w £5
Figure 54. Mass spectrum of 29.
a ,.
- 0...- r
J h
‘ r
0
. fl .
HO ,s¢ »
23
. (CI)
”.0- . . Z" i-
1 m b
J ‘ ' p
. l 279
j” .F? m F .
V . ' - - ‘ 1 v 1 ' 1 V I '1 v 1‘ ' 1 c A' v *—
"E It"? 150 2&0 250 339

Figure 55. Mass spectrum of 23 (CI).

116

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

'am- 5 .
‘ r
‘ L
¢ h
E? S
1:
4 L
n
25.0“ 7? I-
”? .
um
W »
an
a
‘ . .~ 149 to; 294 13’
I ‘ I ' 1 ‘ 1 1 T ' I T ' j ' I ‘ I ' I ' I
IVE 501:: ISO IL 250
Figure 56. Mass spectrum of 29.
'“s.q ” r
‘ k
’2?
(CI)
1 ,,
”0" r-
p
1 L
zu
J
1
u: ‘5
W1 an :3 w as

Figure 57. Mass spectrum of 29 (CI).

“.0-

500‘
C

 

 

 

 

 

Figure 58.

 

 

Figure 59.

91

9?

1%

121

115

147

.129 141

117

 

150

 

 

11

1!

11

 

2%

 

Mass spectrum of 23.

 

 

 

 

 

Mass spectrum of 23.

282
p
p.
b
p
b
p
1 _
1 .
M. I“ I“
'— 50“ I.
b
D
b
b
-
}
1 t
l .
VTIVYVV' VVVVVV vAfijvvvv':VWV—'

1...-

 

 

as.“

 

 

HIE

118

 

 

 

 

 

 

 

 

 

 

 

 

 

0 (Cl) .
1_ 1n
3 ‘ ‘_ ’9‘ ‘ 1 ‘9 I ‘3. ‘ 0 1" . ’
a a so 1 m m m m 220
3:21...“ -
p
b
as
p
I ,
‘I
lfl‘ N P
‘ as
,“ .
1 P
Q! 331
“I"r'""‘U""""'Ifi“"“‘U"';"'I""l"“
an so an «a
Figure 60. Mass spectrum of a; (CI).
u r
L
‘5
HO ¢
r
15 .
43 n L
‘a
' .4
m .
I b
5' m
h. . a at, 99 J,; 4 1. In
a a :9

Figure 61. Mass spectrum of a9.

1U.0 -

$.0-

 

Hr‘E

 

41

 

41

 

 

51

l

69

81

 

80

119

 

 

 

 

 

 

um _
b
b
L.
1%
w L
m H 9
m i 5
J 1 L1 2.:
| . rtfi. -‘.,- “'T-qvwf‘rfi-
um no 1w pa 1&' an 2m

Figure 62. .Mass spectrum of 29°

 

H

 

9 r
+
s¢ 2'4
79
110
. r-
H. ; '
.. a g'; - g ‘ m i
”I . Nil 103 I: 1‘ 1‘ 53 75 '-
.1" m 1' 1‘0 1” -"- 220

 

 

 

 

 

Figure 63. Mass spectrum of 22.

120

 

 

 

 

 

 

 

 

 

 

umo- an
i
I /s¢
as
am~
- n
w
‘ 4‘ 9‘ no
435‘
‘ a ’3 1 ‘_ H? r:
y . a . '1” . .1“ ‘g n:
we no a so m m use m
Figure 64. Mass spectrum of 39.
«mo- 1
1 I
§ !
r l
. ‘ l
}
_a..‘1 I w
is i
i
‘ I
!
' 1 :
15 '
g ., g
In 77 m '
31 ‘5 '3 ‘ z i
, " 1'I' ‘IfiU'I'VjTiU'I‘V'I‘
we a n- :9 as

Figure 65. Mass spectrum of 15.

 

 

 

 

 

 

33 51
43
1 ' 'Wr
40

 

Figure 66.

m
n
a 1‘
4 .ii"?
1
Figure 67.

69

 

 

121

 

 

 

Mass spectrum of g}.

.‘ s

 

115

 

 

 

 

141

 

1417

 

H~ J
I” .H! “.111

Mass spectrum of 52..
~

11

"'1

140

1417

 

 

 

 

 

 

 

 

 

1s
m
us
1m
1 I.
1",, ,rffitfij
we 1m
2»

 

 

1U.0-

 

H4

1... 1

.0.‘

 

 

 

Figure 68.

'nvx

nu
Figure 69.

97

‘..

122

 

 

Mass

1.;

Mass

1?“

160 1% 205

 

 

 

 

 

 

150 208

spectrum of g3.
nu

 

1.

1, . 11 . n
m m m
spectrum of 69b.

 

 

123

310.0- _. ‘fi’ ~ .

 

 

 

 

 

 

 

 

 

 

 

1 b
4 b
. s“: r
‘IJ- .
S
1 ‘7 b
4 a F
41
1 ‘ r
1 ~ III
, . 1 3| 7 I ' .11“ 2 O
u ‘ 13 an
Figure 70 . Mass spectrum of 6;.
10.0- m . P
vfio b
‘ OD '
COfiN.
q - b
3.0 78 *-
fi
107 1:5
1 ‘4 .
91
s: f
4 a I I r
97 13 M
_< I! _. II 1.1 1,1 ”vIHI11I‘ . I
u a m a

Figure 71. Mass spectrum of 63.

 

 

8.0-1

 

124

 

m
. 1
‘ A"
91;!1 91:1 29 5.
a m m m no no 240
.860
€05“:
n
as an an an on «0

Figure 72. Mass spectrum of 63 (CI).

‘T

llllfllil‘amfifla

 

 

7? 1 '

:a II 13 M. an In
Figure 73. Mass spectrum of 63.

 

"Y

 

 

 

125
~11u- 1:11 _

 

 

 

 

au- _
1x '
. r
‘ 91 148 r
15
77 1 L
in a a u 1 - 1a 140 1a 1a

Figure 74. Mass spectrum of fig.

 

 

 

 

 

 

 

 

1.0.0- “5
73 f
4
I 0.611.
1 s1 .
a..- l-
1
1 1 .
n
4 as “‘9 1
VJ.IIJI 9.‘ 9.7 .1
T' ‘I*W' - * 'l'1 ‘I 1*! I‘ITT' ‘IjU'I'V'l'I'I'I
we at 15 1s ' zL- -zn

Figure 75. Mass spectrum of 65.

 

 

 

 

 

126

 

 

 

 

 

 

 

 

 

umoI ‘5 1‘ .
d
a
. n ’A\ ,
saw .
‘ P
‘ 1M .
69 m 5
‘25 137
111 .1 1 1.] l. .11 1119531141111 1111 I” v"
..,- -,--..T...., ..TT. .1.........T11..,.-..,....,. .,,-...,....,. ti 2%“
we a so a we 1% no 1% we
Figure 76. Mass spectrum of 73.
umo- .5, 2n
'0.“
an
!.
u
‘ 1s .
5 9 11 ' .
77 85 1.:
' 1 1? 1a . ll
1‘:- . l I

 

 

 

 

Figure 77. Mass spectrum of 23p.

127

1125

 

 

 

 

 

 

11 If
Wilgfi'lrv‘ T1 ‘ffiTiI'
210

19

Figure 78. Mass spectrum of 75c.
H

128

’p’beI“

.bbb”

00¢

p””h>b”t*0’pFP’D

\l\
. m mo Esuuommm mmmz

Ova

F

 

 

 

 

 

or

[\(Q

A

 

 

.mn musmwm

.ma

 

 

—4

 

 

 

ipbh

 

 

 

 

 

 

..__ _

«b

 

 

 

 

 

 

 

 

IO.“

 

129

 

 

 

 

 

 

11!?

1...

'1

I 195

185
M
50.01
S?
79
91
85 1 4c
1 1. r1 25,7

IVE 1 '- 13. . '1 250

Figure 80. Mass spectrum of 83.

 

130

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

  

 

1”...
F
15
up
,
,
1 L
33- -
1m
67 F
m
41 123
< l 55 l b
m5 1%
“NJ. vvvvv IL 111.th ”II III. Llnszu mil 1
, , ,.fi.v.”,u.fir..l ........ VsnTn.,.n, -W.H-V.HT.
ma « a m 1% 1m 1m 1m 1w
Figure 81. Mass spectrum of 8;.
1'..‘ x 1”?
F
d
P
1%
'1 L
A
”.0‘ v-
p
’7’
1 ‘ ’
a ,, H
13
, 11 1h“ 1"” 111‘? I 1
1.n¢,n..v.filgn..n..r-rq.. ,n-.,.1q..n,-n
w: n so so 1 120 m 160 109

Figure 82. Mass spectrum of 89.

10a.

10b.

11.
12.
13.

131

REFERENCES

 

Strietwieser, A., and Heathcock, C. H., "Intro-
duction to Organic Chemistry," Macmillan,
1976, pp 1215-1220.

Stowell, J. C., "Carbanions in Organic Synthesis,"
John Wiley and Sons, 1979, p 83.

Vlattas, I.,Vecchia, L., and Lee, A., J. Amer.
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March, J., ”Advanced Organic Chemistry," McGraw—
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Bordwell, F. 6., Pure Appl. Chem. 49,
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Corey, E. J., and Seebach, D., J. Org. Chem. 31,
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Peterson, 0. J., J. Org. Chem. 32, 1717 (1967).

 

Coates, R. M., and Sowerby, R. L., J. Amer.
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Watanabe, Y., Shiono, M., and Mukaiyama, T.,
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Corey, E., and Jautelat, M., Tetrahedron
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Corey, 3:, and Seebach, D., J. Org. Chem. 40,
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Grobel B-T and Seebach D. 812thesis
357 (1677).' ' ' '

See reference 4, p 887.

Otto, L., Berichte 18, 154 (1885).

 

House, H., ”Modern Synthetic Reactions,“
2nd edition, W. A. Benjamin, 1972, p 494.

14.
15.

16.

17a.

17b.

18a.
18b.

19.

20.

21.
22.

23.

24.

25.

26.

27a.

27b.

28a.

132

Schatz, P., J. Chem. EduC. 55, 468 (1978).

 

Technical gulletin on DMSO, Crown Zeller-
bach Corporation.

Tsarhis, 8., "DMSO - The True Story of a
Remarkable Pain-killing Drug," wm. Morrow
and Co. (1981).

Corey, E., J. Amer. Chem. Soc. 84, 866 (1962).

 

Corey, E., J. Amer. Chem. Soc. 87, 1345 (1965).

 

Fromm, E., Berichte 41, 3397 (1908).

 

Fromm, E., and Erfurt, F., Berichte 42,
3816 (1909).

 

Johnson, C., and Leonard, N., J. Org. Chem. 27,
282 (1962).

 

Trost, B., Salzmann, T., J. Amer. Chem. Soc. 98,
4887 (1976).

Anderson, R., Tetrahedron Lett., 93 (1962).

 

Fujisawa, T., Kakutani, M., Kobayashi, N.,
Bull. Chem. Soc. Jap. 46(11), 3615 (1973).

 

Evans, D., Andrews, 6., and Sims, C., J. Amer.
Chem. Soc. 93, 4956 (1971).

 

Mislow, K., et a1., J. Amer. Chem. Soc. 90,
4869 (1968).

 

Evans, D., Andrews, 6., Wells, D., and
Fujimoto, T., Tetrahedron Lett. 16, 1389 (1973).

 

Evans, D., Andrews, 6., Fujimoto, T., and
Wells, D., Tetrahedron Lett. 16, 1385 (1973).

 

Chenera, 8., unpublished results from
this laboratory.

Trost, 8., Salzmann, F., J. Amer. Chem.
Soc. 95, 6840 (1973).

 

Richmann, J., Herrman, J., Schlessinger, R.,
Tetrahedron Lett. 35, 3267 (1973).

 

28b.

29.

30.
31.
32.
33.

34.

35.

36.

37.

38.

39.

40.

41.
42.

43.

44.

45.

46.
47.

133

Herrmann, J., Richmann, J., Schlessinger, R.,
and Wepplo, F., Tetrahedron Lett. 47, 4707 (1973).

 

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