THE KMEHCALLY CONTROLLED
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R583 fiLEERT LEE
1 373

LIBRARY 3
I Michigan State

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This is to certify that the

thesis entitled
THE KINETICALLY CONTROLLED ENOLIZATION 0F
Q)B -UNSATURATED KETONES AND ITS SYNTHETIC UTILITY

presented by

ROSS ALBERT LEE

has been accepted towards fulfillment
of the requirements for

F1 '0‘ degree in 6%“?

mm

Major professor

Date é/Jol/PJ

0-7639

  
  
  

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ABSTRACT

THE KINETICALLY CONTROLLED ENOLIZATION OF
a.B-UNSATURATED KETONES AND ITS SYNTHETIC UTILITY

BY

Ross Albert Lee

The enolization of a,B-unsaturated ketones under condi-
tions of kinetic control was shown to involve preferential
a'-proton abstraction regardless of the degree of alkyl
substitution at the al-and y-sites. A general method for
the irreversible formation of a'-dienolate bases was devel-
oped using the strong base lithium isopropylcyclohexylamide
in tetrahydrofuran solution.

Selective methylation of the a'-dienolate bases derived
from pulegone (l) and 5,5-dimethylcyclohex-2-enone (2)

gave the a'-methyl derivatives 2 and g, respectively, in

a gt a

2, 2», 2,

good yield.

2H

Ross Albert Lee
Bicyclo[2,2,2]octanones 2 and g were synthesized stereo-
selectively, in high yield (90%), by the reaction of methyl
acrylate with the cross—conjugated dienolate bases derived

from cyclohex-Z—enone (Z) and iSOphorone (§) reSpectively.

O O

O I
L; H H «0

z i», 23, 6

N

A sequential Michael mechanism is favored over a Diels-Alder
cycloaddition in rationalizing this useful reaction.
Anomalous results were obtained when trityllithium was
used instead of the amide base. These reactions gave either
coupling products (e.g. 2) or products derived from a-alkyla—
tion of the fully conjugated dienolate anion formed by y-

proton abstraction (e.g. 12). These unexpected results

0
¢3c \0
§
2. 12.

were explained by an electron transfer mechanism (equation 1).

Ross Albert Lee

r 7
o , OM
II I . I

(1) RCHZCH:CH-C-R' > ‘RCHZCH-C=C-R

 

 

H-abstraction

 

+ ¢3CM : + <I>3C- .
L J
(M = Li or Na) coupling
OM
RCHch-CH=C':-R'
c¢3

1
OM

RCH=CH-C=é-R'

+ ¢3CH

THE KINETICALLY CONTROLLED ENOLIZATION OF

a,B-UNSATURATED KETONES AND ITS SYNTHETIC UTILITY

BY

Ross Albert Lee

A THESIS

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

DOCTOR OF PHILOSOPHY

Department of Chemistry

1973

To Cheryl

XL. .33.... i...

ii

ACKNOWLEDGMENT S

The author is deeply grateful to Professor William
Reusch for his expert guidance, enthusiasm, and encourage-
ment during the course of this work. For his unfailing
willingness to listen to "new“ ideas and answer questions
and for the independence he afforded to eXplore many dif-
ferent projects (and with each his continued interest) the
author is sincerely thankful.

Special thanks are extended to my parents, for their
understanding and moral support over the years and for making
this opportunity possible. Thanks are also extended to
Cheryl McAndrews, above all for her love and moral support,
but also for conducting most of the experimental work in
the pulegone studies.

Appreciation is given to my colleagues, both past and-
present, for intriguing ”chalk talks", for generating a
cheerful surroundings, and for their much valued friendship.

Finally, the author would like to thank Dr. A. S.

Kende (University of Rochester) for helping to make this
opportunity possible and the National Science Foundation,
National Institutes of Health and the Department of Chem—

istry, Michigan State University, for financial support.

iii

TABLE OF CONTENTS

INTRODUCTION . . . . . . . . . . . . . . . . . . .
RESUDTS AND DISCUSSION . . . . . . . . . . . . . .
EXPERIMENTAL . . . . . . . . . . . . . . . . . . .

General . . . . . . . . . . . . . . . . . . .

Methylation of Pulegone Q) Using Lithium Iso-
propylcyclohexylamide LiICA) as the Base .

Methylpulegones (2). . . . . . . . . . .

b) Minor . . . . .

Ea) Major . . . . .

Methylisopulegones (12)

a Major . . . . . . . . . . . . .
b Minor . . . . . . . . . . . . .

Attempted Epimerization of the Methylated
Pulegone Mixture . . . . . . . . . . . . .

Base Catalyzed Deuterium Exchange of Pulegone
5,5-Dimethylcyclohex—2-enone (12) . . . . . .
5,5,6dTrimethylcyclohex-2-enone (1Q) . . . .

Methylation of Pulegone (Q) Using Triphenyl-
methyllithium as the Base . . . . . . . . .

3dTriphenylmethy1-2,5,5-trimethylcyclo-
hexanone (22) . . . . . . . . . . . . . . .

3-Triphenylmethy1-5,5-dimethy1cyclo-
hexanonte) ...............

3-(1,1,1 -Tripheny1methyl)Abutanoic Acid (49)

3-Triphenylmethyl-2-methylcyclohexanone (42)

iv

~

Page

10
47

47

48
49

49
49

49
49
49
50
5O
51
52

53

54

55
56

57

TABLE OF CONTENTS (Cont.)

Page
Methylation of 3<Methylcyclohex-2-enone (42)

Using Triphenylmethyllithium as the Base . 58
2,3-Dimethylcyclohex-2-enone (44) . . . . . . 60
Electron Spin Resonance Study of Reaction 32 61
Low Temperature NMR Studies . . . . . . . . . 61
Lithium in Ammonia Reduction of 5,5-Dimethyl-

cyclohex-Z-enone (l2) . . . . . . . . . . . 62

5-endo-Carbomethoxybicyclo[2,2,2]octan-Z-one (53)63

8-Carbomethoxy-4,6,6-trimethylbicyclo-
[2,2,2]0Ctan-2-One o o o o o o o o O 0 o o 64

5-endo-Carbomethoxybicyclo[2,2,2]oct—2-ene (51) 65

Bicyclo 2,2,2]oct-2-ene—5-endo-carboxylic
Acid 5g) . . . . . . . . . . . . . . . . . 67

6+Hydroxybicyclo[2,2,2]octan—2-carboxylic'

Acid y-Lactone (52) . . . . . . . . . . . . 68
Syn-5-Hydroxybicyclo[2,2,2]octan-2-carboxylic
ACid (g) C C I O O O O O O I O O O O O O O 69
5-Hydroxybic clo[2,2,2]octan-Z-carboxylic Acid
6"LaCt0ne ”GE’) 0 a o o o o o o o o o o o o 70
Sodium Borohydride Reduction of Keto-ester Ea 70
REFERENCES . . . . . . . . . . . . . . . . . . . 73
APPENDIX 0 O O O O O O O O O O O O O O O O O O O O 77

LIST OF TABLES
TABLE Page

I. Mass spectral data for base catalyzed
deuterium exchange . . . . . . . . . . . . . 12

vi

LIST OF FIGURES

FIGURE Page

1. ESR traces of trityllithium solution (A)
before addition of enone, -78° (B) immedi-
ately after addition, -780 (C) increased
amplitude, 0° (D) increased amplitude, 25° 33

2. (A) 60Hz nmr spectrum of trityllithium in
tetrahydrofuran immediately after addition
of enone 1§'(B) same solution and temperature
just prior to addition of 15 . . . . . . . . 35

3. Infrared spectrum of methylpulegone (2,
major isomer) . . . . . . . . . . . . . . . . 77

4. Infrared spectrum of 5,5,6—trimethylcyclo-
hex-2 -en0ne (ll-(Q) o o o o o o o o o o o o o o 78

5. Infrared spectrum of 3-tri henylmethyl-2,5,5-
trimethylcyclohexanone (32' ... . . . . . . . 79

6. Infrared spectrum of 3-triphenylmethyl-
5,5-dimethylcyclohexanone (31). . . . . . . . 80

7. Infrared spectrum of 3-(1,1,1-triphenylmethyl)-
butanoic acid (42) . . . . . . . . . . . . . 81

8. Infrared spectrum of 3-triphenylmethyl-2-methyl-
cyclohexanone (42) . . . . . . . . . . . . . 82

9. Infrared Spectrum of the dihydrodimer (52) . 83

10. Infrared spectrum of 5-endo-carbomethoxybicyclo-
[2,2,2]octan-2-one (52) . . . . . . . . . . .

11. Infrared spectrum of 8-carbomethoxy-4,6,6-tri-
methylbicyclo[2,2,2]octan-2-one (53) . . . . 85

12. Infrared spectrum of 5-endo-carbomethoxybi-
cyclo[2,2,2]oct-5-ene (21) . . . . . . . . . 86

13. Infrared Spectrum of syn-S-hydroxybicyclo-
[2,2,2]octan-Z-carboxylic acid (fig) . . . . . 87

vii

INTRODUCTION

The powerful synthetic utility of carbon-carbon bond
formation by alkylation of enolate anions is well estab-
lished.1'2 In the case of a,B-unsaturated ketones, having
the general structure 1, two types of proton abstraction
giving rise to enolate anions g, or 3' are clearly pos-

sible:

  
 

7-H abstraction

o'-H abstraction

 

There is abundant evidence indicating that the fully con-
jugated enolate anion 2’ resulting from y-proton abstrac-
tion, undergoes alkylation at the a-carbon atom.“2 The
majority of these alkylation reactions are reported to give
mono and dialkylated fi,y-unsaturated ketones as well as the

conjugated monoalkylation products (e.g. equations 1 and 2).

 

 

 

3 1)NaOAmt, ¢H
(1) 3e
2) CH3I
4 l)KOBut,HOBut
(2)
2) CH3I
o

 

CH3

Reports of products derived from the cross-conjugated
enolate anion 3’ obtained by selective abstraction of an
a'tproton, are exceedingly rare. Indeed, Conia reported in
19632 that "the only known case of a'-a1kylation of an 0:6-
unsaturated ketone that can undergo tautomerism“ was his
own Observation5 of a'-allylation of 2-allylcyclohex-2-enone.
Two reports of a'-alkylated products derived from enolates
formed by the action of sodium amide on a,B-unsaturated
ketones are questionable. In 1924 Haller and Ramart6 de-
scribed an a'-methy1ation of pulegone, using sodium amide
in ether as the base, and noted that the alleged a'—methyl

derivative was levorotatory. This contrasts with our

3
observation (discussed later) that the major isomer of the
a'-methylation of pulegone is dextrorotatory. A patent
issued to Schering Corporation7 describes the 2a-methylation
of testosterone, using sodium amide in a liquid ammonia—
tetrahydrofuran solvent mixture followed by reaction with
methyl iodide (no yields were reported in the abstract)

(equation 3). This however, contrasts with the work of

   

l

1)NaNH liq. NH ,THEE“
2/ 3:

 

(3)

2) CH3I

Newman 35 31,8 in which the same base (sodium amide in
liquid ammonia, no tetrahydrofinan cosolvent) was instru-
mental in effecting cyclObisalkylation of 3-methylcyclohex-
2-enone gig enolates derived from y-proton abstraction
(equation 4). The homogeneity of the reaction medium may

well be a significant factor here.

CH3 CH2 CH3

(4) 1)NaNH2/lig. NH3 3 +
2) Br(CH3)nBr

(CH2)

4

Reports of sequential Michael additions in which an
a,5-unsaturated ketone acts both as an enolate acceptor and
an enolate donor generated by abstraction of an a'-proton
further illustrate the powerful synthetic potential of these
intermediate enolate anions. In 1920 Ruzicka9 proposed
structures 2' and 6' for the ketonic dimers formed from
base treatment of 3—methy1cyclohex-2-enone. Similar struc-
tures were also proposed for the dimers obtained from iso-

phorone, and 3,5-dimethylcyclohex-2-enone.

O 0Na 0 ONa

C I.
o§ gi: / I)”
5 Q, 0

~

 

219.

These structures were, however, later refuted by Bflchi st 21,}0
and the dimeric product obtained from the reaction of 3-
methylcyclohex-Z-enone was shown to have structure 1, de-

rived by an initial y-proton abstraction.

7
On the other hand, Jones and Koch11 reported that base

catalyzed dimerization of acetylcyclohexene proceeded via
a'-proton abstraction, when a suspension of sodium amide

in ether was used as the base (equation 6).

:5)
{

gONa
a \\———>
o)

@3503

More recently catalysis of a “thermal" double Michael addi-

Etzo

 

tion by base“:13 has been explained by the same type of
a'-proton abstraction followed by sequential Michael addi-
tions of the a'-enolate anion. Bellamy14 has invoked a
similar mechanism to account for the tricyclic dimer Obtained

by base treatment of 4,4-dimethylcyclopent-2-enone (equation 7).

KOBut

 

M = K,Na

 

The formation and isolation of stable enol derivatives
of a,B-unsaturated ketones has been widely studied.15113017018
In many cases these derivatives have been formed in §i£u_
and trapped by subsequent Diels-Alder cycloaddition reac-
tions. As expected, steric hindrance reduces the effective-

ness of this approach (cf. equations 8 and 9).

 

 

 

 

7

Nevertheless, these reactions offer a potentially useful
means of preparing substituted bicyclo[2,2,2]octane systems.

In the case of unsymmetrically substituted saturated
ketones, factors influencing the formation of the two pos-
sible enolate bases have been carefully studied.20 Selec-
tivity of enolate alkylations has traditionally been
achieved by the use of activating or blocking groups at the
less substituted, a—position. Alternatively, it has been
found that under equilibrating conditions, in which some
proton donor (e.g. protic solvent or unionized ketone) is
present, an abundance of the more highly substituted enolate
anion is observed. Under kinetically controlled conditions,
in which the ketone is added slowly to an excess of strong
base in an aprotic solvent, the less substituted enolate

anion predominates (equation 10).1.3°

0 Old OIJ

25°
(10) + ¢3CLi % a + ‘
glyme

 

 

 

Reaction Conditions Composition
Ketone added to excess base (kinetic control) 28% 72%
Excess ketone added to base (equilibrium) 99% 6%

From these results it seems reasonable to assume that under

equilibrating conditions, enolization of a,B-unsaturated

8

ketones (e.g. 2) leads predominantly to a fully conjugated

resonance stabilized anion (e.g. 2).

 

1. ,2.

However, surprisingly little work seems to have been

directed at elucidating the nature of those enolate anions
derived from a,6-unsaturated ketones under non-equilibrating
or rate controlled reaction conditions. In 1964, Ringold
and Malhotra observed21 that the base catalyzed deuterium
exchange of testosterone with sodium deuteroxide in di-
glyme led to the specific incorporation of one atom of

deuterium at C-2 (equation 11):

NaOD/Dgo
diglyme

 

 

a similar result was noted in the weak acid catalyzed enoli-
zation of testosterone with deuterioacetic acid. These
results were interpreted as an indication that kinetically

controlled enolization of o,6-unsaturated ketones of this

9
kind involves preferential a'-proton abstraction. Further
support for this view derived from the fact that potassium
Efbutoxide induced methylation of 23—deuterioandrost-4-ene-
3,17-dione gave both 4,4-dimethylandrost-5—ene-3,17-dione
and recovered starting material free of deuterium (equation

12). No investigation, however, was made of the applicability

D 2 1) H
KOBut,ButOH

(12) a>

2) CH3I

   

 

of this interpretation to other substrates or of the effect
of substituents at the a'-carbon atom in the determination
of the kinetically controlled enolate. Furthermore, no
attempt was made to generate irreversibly the kinetically
controlled enolate by the slow addition of enone to an excess
of strong base in an aprotic solvent. If this should prove
to be a general method for selectively generating the cross-
conjugated dienolate bases of a,B-unsaturated ketones, then
these should be valuable synthetic intermediates which

might undergo selective alkylation or Michael addition re-
actions. Indeed, the latter might offer a versatile alterna-
tive to DielseAlder cycloaddition. An investigation of

these possibilities is reported in this dissertation.

RESULTS AND DISCUSSION

The methylation of pulegone (2) under thermodynamic-
ally controlled conditions is known to give a mixture of
methylisopulegones (12) arising from abstraction of a y-

proton (equation 13)3. It was found that the slow addition

1)NaOAmt, on

 

 

of pulegone to an excess of lithium isoprOpylcyclohexyl-
amide in tetrahydrofuran at 0° (kinetically controlled
conditions) followed by methylation with methyl iodide at
room temperature gave, as the major product, a mixture of
methylpulegones arising from predominate abstraction of an

o'-proton (equation 14). Product g'proved to be an

 

€337
1)Lir{ , THF, 00
(14) ‘ c6311 + g 4%
2) CHSI, 1.12.0.1}.
o o +-12'23%
g g 56%

10

11
equilibrium mixture of epimers since the relative amounts
were unchanged after refluxing the product mixture in
methanolic potassium hydroxide.

Using the terpene pulegone, it was shown by mass
spectrometric analysis of the products obtained from base
catalyzed deuterium exchange that the rate of proton abstrac-
tion at the a'-carbon atom is greater than at either of the
two y-carbon atoms. The major fragment ions Observed in
the mass spectra of the various pulegone samples used in
this study are shown in Table 1.

After only fifteen minutes of treatment with a heavy
water solution of sodium deuteroxide, a sample of pulegone
proved to have the composition 5.5% d1, 54% d2, 28% d3, 8%
d4 and 3% d5. The loss of only fifteen mass units (no M-16,
.m-17, or M-18 fragment ions) in forming fragment ions 22,
22, and 12, together with the shift of the base peak from
m/e 81 to m/e 82 (identical to the shift Observed for d7,d8-
pulegone (prepared by exhaustive exchange) but not for C-9 d3-
pulegone (prepared according to the procedure of Coleman93))
indicates that the a'-methylene group has experienced rapid
and complete proton exchange while the y-methyl groups are
largely unaffected. These results are in agreement with
those Obtained by Malhotra and Ringold21 for testosterone.

In order to determine whether the kinetically favored
conjugate base formed from a,B-unsaturated ketones usually

involves preferential aI-proton abstraction, other substrates

12

 

 

 

 

 

AHsMos Ammvmm .onwos Ausomo Anewao .Amvvsw Amovso «H
“waves Anovwo.xuvvsm .
+
Aoofivsw mooflvno Aoofiwmm Aoofivnm Aco2vum goon onus
Aenvusfl Avfivmus.fiwuvwsfl .Aomvnfln, . AHNVNHH.AnvaHH vavmofi ma
Awnvmofi Amnvusfl.xnavfian h
. . .. .m:
Asuvoafl Amvmwa.xauvmvfi AofivfiVA anvovn.xouvmns . nuvsna +.
nomvhmfi Anavfiefl ANHVovH.Aofivmnfi
. AmemH.AoHvsmH AnMsnfi .Avymna .
Auvvmnfl.xomvmnfi vavomfi.flmvvmnfi Amfivmnfl.xmflvnmu Amnvnnfi.xmvvvnu Awnvunfi
Afimvmnfi.xovumfi Aryans Anvmma

 

 

Ahuawcouufl Hmuv AmuwmcquH Honv
one O\E
«nocuwoanmnnpmuu ocomoasmlno.sc

Amuamcoucw Huuv
o\E
has a .o«n\oomz

Amuwmcoucfl Houv

0\E

nae nH.oun\nomz

AmOAnGOUCH Houv
0\E :OH ucoemuum
onomoasm

 

.omcn£UXo Edauousov nowhaauoo Oman now cusp Houuuomn and:

.H OHAMH

WV

 

 

13
of varying structural characteristics were also investi-
gated. 5,5-Dimethylcyclohex-2—enone (22) was chosen since
the degree of steric hindrance at the o'- and y-positions
should be similar and both types of proton abstraction would'
lead to homoannular dienolates. Methylation of this com-
pound under the same conditions described for pulegone gave

the a'-methyl derivative ig'in high yield (equation 15).

C3H7
1)LiN: ,THF, 00
(15) C6H11

2) CH3I, r.t.

'I‘
O

12. 13. 83%

In a separate study on the methylation of steroids,conducted
by Patel in this laboratory, the following results were ob-
tained with 3-cholest-4-enone (22) and 2-methyl-3-cholest-4-

enones (lg'and 12) (equation 16).

 

 

 

 

H
3 7
1min? ,
C6331
(16) THF' .f-ab.
2)CH3I, r.t.
o - 0
11. 1§,85% £2.
18 or 19 . Same ’uu.
w - —'C—'aon Rions

22' >95%

14
The a'-methylation of 19-nortestosterone has recently
been described by the Roussel group23 in France. The addi-
tion of potassium Efbutoxide to a solution of the enone in
tetrahydrofuran containing methyl iodide and hexamethylphos-
phorus triamide presumably allows trapping of the o'-

enolate before equilibration can occur (equation 17).

WHO

‘17) KOBut,THF,HMPA

)
O O

 

"good yield"

In a study of sequential Michael additions (discussed later)
the a'-dienolate anions of both cyclohexenone and isophorone
were generated in high yield (> 90%) under similar conditions.
The degree of alkyl substitution and steric hindrance
to approach at the a'-carbon atom are clearly different in
these substrates. In pulegone and isophorone, for example,
the a'-carbon atom is secondary and at least one y-carbcn atom is
primary. In both Zo- and 25-methylcholest-4-en-3-one the
a'-carbon atom is tertiary while the y-carbon atom is second-
ary. In isophorone, steric hindrance to approach is greater
at the a'-carbon atom (neOpentyl) than at the C-3 methyl y-
position. While both homoannular andlmxeroannular dienolate
anions are possible in the case of cholest-4-ene-3-one and

isophorone, only homoannular dienolate anions are possible

15
for 5,5-dimethylcyclohex-2-enone and cyclohex-Z—enone. Thus,
while in the case of saturated ketones,alkyl substitution at
the site of proton abstraction is a major factor in deter-
mining which of two different enolate anions will be formed
most rapidly, it appears that a'-proton abstraction is
favored in the generation of dienolate anions from a,B-un-
saturated ketones under non—equilibrating conditions, regard-
less of the degree of alkyl substitution at the different
sites.

It has been assumed in this argument that the products
of alkylation reflect the composition of the initially
formed enolate anion mixture. If this were not the case,
then equilibration of enolate anions would be taking place
either prior to or during alkylation. Four arguments indi-
cate that this is not happening. First, the slow addition
of ketone to an excess of strong base in an aprotic medium
under oxygen and moisture-free conditions makes equilibra-
tion prior to alkylation highly unlikely. The effectiveness
of this procedure has been well established in the case of
saturated ketones}:20 Second, if equilibration were taking
place during alkylation then the rate of proton exchange
would have to exceed the rate of alkylation. However, Stork24
and House“):28 have shown that lithium enolates are particu-
larly slow to equilibrate yig_proton exchange with unionized
ketone. Indeed, House20 reported that even when as much
as 20 mole percent excess of ketone is present lithium enol-

ates take 30 minutes or more to come to equilibrium. Third,

‘nrf

 

 

16

the use of a large excess of a reactive alkylating agent
increases the rate of the alkylation reaction making equi-
libration during alkylation even more unlikely. Again,
House25 has found that cases in which the thermodynamically
more stable enolate is 1.7-2.3 times more reactive toward
alkyl halides than the less stable, rate favored enolate
anion, give, under similar conditions, the product derived
from the latter (> 75 %). Finally, the fact that these
results are in agreement with those of the deuterium ex-
change experiments21 and that no a'-alkylated products had
been observed under conditions in which equilibration is
allowed suggests that the initial assumption is valid.

In the case of unsymmetrically substituted ketones,
the increased rate of proton abstraction at the less sub-
stituted carbon atom has been attributed to inductive ef-
fects,26 steric effect527o33a39 and stereoelectronic con-
trol?0 An argument based on inductive effects must neces-
sarily assume a transition state resembling ketone. Such
a transition state would be characterized by a low degree
of carbon-carbon double bond formation but sufficient Ca-H
bond breaking to produce a significant negative charge on
the o-carbon atom. Alkyl substituents generally destabilize
carbanions. Studies by Swain and Rosenberg31 suggest that
the stronger the base the shorter the Ca-H bond is stretched
and the closer the transition state resembles ketone. Never-
theless, some carbon-carbon double bond character must be

present in the transition state for proton abstraction, since

17
stereoelectonic factors requiring that the breaking C-H bond
be perpendicular to the carbonyl group are well established,

eSpecially in the case of bicyclic ketones (e.g. 22).32

 

While stereoelectronic factors alone have been used to
account for the results obtained with unsymmetrical acyclic
ketones3° they do not explain the results obtained in cases
such as 2—methylcyclohexanone or 2-methylcyclopentanone.
Steric factors may, in fact, be the largest single contri-
buting factor influencing the rate of base catalyzed enoliza-

tion, as the results of Antony and Maloney28 (equation 18)

O 0L1 OLi

(18) ¢3CLi (xs)
glyme

 

18% 82%

and Champagne ggwgl.33 (equation 19) suggest.

18

0 OAC OAC

{3f—0Ac,conc H2804

u” (kinetic control) .nn nu

 

62% 38%

These factors, alone or in combination, will not explain

the increased rate of o'eproton abstraction over y-proton
abstraction in the a,B-unsaturated ketone substrates studied
here.

Ringold and Malhotra21 attributed the preferential a'-
proton abstraction they Observed in the testosterone series
to a ketone-like transition state, in which the inductive
effect of the carbonyl group increased the acidity at C-2
relative to C-6. They also suggested that stereoelectronic
control, favoring abstraction of those protons whose C-H
bonds are perpendicular to the carbonyl group (C-ZS or C-SB).
would afford greater resonance stabilization to the proton
adjacent to the carbonyl group (C-ZS). The increased
acidity of A5-3-ketones (e.g. 22) relative to A4-3-ketones

(e.g. 22) was cited as corrOborating evidence. While the

C8H17 C8H17

19

inductive effect of the carbonyl group may be a significant
factor, the argument for enhanced resonance stabilization
at the a'-position is not convincing. Perhaps the most re—
asonable assumption that can be made concerning the nature
of the transition state for a'- or y-proton abstraction is
that their resemblence to the product dienolate anions is
not sufficient for this to be a dominant factor. Further—
more, it may be that some factor other than an inductive
effect or steric hindrance is favoring a'—proton abstraction.

Two rationalizations for the regiospecific a'-effect
noted above will be considered here, one concerning a cyclic
transition state and the other derived from the principle of
least motion. The essence of the first proposal is that a
six-membered cyclic transition state similar to that shown

in equation 20 would necessarily favor a'-proton abstraction.

OLi .
/R
-——-e> +'HN\R.

Such a transition state has been prOposed1 to account for

 

THF,O°

   

 

 

the formation of the less stable cis-enolate 2§'in the kine-
tically controlled enolization of 22'(equation 21). However,

we would expect the stability of such a metal-oxygen

 

 

 

 

 

C5H11
>r_fi\ C5H11
.Q H >
L1 _ ~' i
,c3H7 _. 3.4
o LiN\ 2’5" 84%
II C H
(21)9_-C4H9CH2CCH3 -6 11
glyme, O0
2.2, _ .1
> C4H9 C4H9
0 H 9
Li—N OLi H
~ R! ‘R
26 9%

coordinated transition state to be sensitive to cation and
solvent variations. Since specific a'-proton abstraction
has been observed with lithium (LiNRz), sodium (NaOD), and
potassium (KOBut)21 bases in solvents such as tetrahydro-
furan, deuterium oxide/diglyme, 21 deuterium oxide/dioxane,
Efibutanol,31 and tetrahydrofuran containing tetramethyl-
ethylene diamine (in studies performed by Patel), this pro-
posal loses some of its appeal. Certainly, the specific
solvating properties of tetramethylethylene diamine for Li9
should be evident if a six-membered cyclic transition state
were involved in the proton transfer, however, the results
were identical to those Obtained with tetrahydrofuran alone.

The second proposal is based upon the principle of least

motion.34c3° This principle was originally enunciated by

21
Rice and Teller34 and was shown to have semi-quantitative
and qualitative application to problems in organic chemistry
by Hine.35 According to this principle "those elementary
reactions will be favored that involve the least change in
atomic position and electronic configuration."34 Hine
applied this principle to explain the kinetically favored
a-protonation of mesomeric carbanions such as 21 (equation
22) (and by microscopic reversibility the increased rate of
proton abstraction of A5-34ketones) and the increased rate
of proton abstraction of phenylacetylene (pKa = 21) over

nitroethane (pKa = 10) (equations 23 and 24).

 

 

 

+ HOH
ONa
(24) \CH2N02 a CH=Né + HOH
kr = 1 \ e

22
In the last two cases little change in molecular motion was
anticipated for reaction 23, while several changes in bond
distances and bond angles was anticipated for reaction 24.
Essentially identical reasoning leads to the prediction
that for a,B-unsaturated ketones a'—proton abstraction will

be favored energetically over y-proton abstraction (equations

25 and 26).
OLi

o'-H abstraction
\

I

 

 

O OLi

y-H abstraction

 

(26)

V/

In equation 25 bond reorganization must occur at C6-C1 and
the carbonyl group while in equation 26 bond reorganization
must involve C4-C3, C3-C2, C2-C1 and the carbonyl group.
Thus, assuming the transition state characterized previous-
ly, the activation energy for a'-proton abstraction should
be less than for y-proton abstraction. A recent report of
preferential y-proton abstraction over e-proton abstraction

in the kinetically controlled enolization of an a,B,y,é-
cyclohexadienone by Hart g£_§l,3° could be explained by the

same principle (equation 27). A steric hindrance effect

23

o OLi
l
..... . . "" CH I
(27) L1N[(CH3) 81] 3
THF, 03 i

 

might also be important in this case. Investigations into
other systems, where for example, a'—proton and y-proton
abstraction may compete with e-proton abstraction (e.g. 22),

could further corroborate this principle and perhaps be

 

29

synthetically useful. An apparent contradiction to the ap—
plication of this principle is found in the report of Barton
.gt.al.37 that the kinetically controlled enolization of 22'
yielded the A1'3'5 trienolate anion 2l'(equation 28). The
isomeric A9.11 enolate anion was found to be thermodynamic-
ally favored over 22; However, a concurrent report by

Tanabe and Crowe38 indicates that products from'both enolate

24

 

BzOC1 /J:::::t:f::r/
B20

:22, w >809:

3w

bases (e.g. 22 and 24) were formed when an enolate anion
mixture derived from reaction of 22'with the same base in
tetrahydrofuran was quenched with carbon dioxide and subse-

quently treated with diazomethane (equation 29).

1)Na[(CH3)3SiJ2 cps
THF. 200
(29) 30. s) +
- 2) H30
3 CH2N2. Et20 0
£40% OzMe

:22, 10%

 

The formation of 22'was explained as arising from the carbon-

ation of enolate anion 22, The formation of 2§'(or other

NaO

25

possible cyclo-enolates) must require greater bond reorgani—
zation in the transition state than the formation of 2;;
Thus, the principle of least motion may be consistent with
the observations cited in this case.

The strong base trityllithium (pKa of ¢3CH = 33) has
been widely used to effect the irreversible formation of
the conjugate bases of ketones and esters, a particularly
good example being the previously noted unsymmetrically
substituted ketones. Anomalous results were Obtained, how-
ever, with a,B—unsaturated ketone substrates. When pulegone
was added slowly to an excess of trityllithium in cold (0°)
tetrahydrofuran solution and the resulting dienolate anion
mixture was quenched by reaction with methyl iodide, the
major product proved to be the stereoisomers of the methyl-

isopulegones (equation 30). The predominance of aimethyla—

1) ¢3CLi(XS),THF, 0°

2
o ) CH3: . .

 

2m

g 20% Lg 61%

tion under conditions that favored rate-controlled formation
of the cross-conjugated dienolate ion was unexpected and in-
consistent with the results obtained using the 2°-amide base.

As argued earlier equilibration of the conjugate bases prior

26
to alkylation seemed highly unlikely. Furthermore, if equi—
libration were occurring during the alkylation step, this
would require a significant enhancement of the rate of
proton transfer and/or a decrease in the rate of alkylation
for the trityllithium reaction compared with the 2°-amide
reaction. The possibility that the 2°-amine necessarily
present in the latter alkylation reactions was causing such
rate changes was eliminated by the observation that addition
of one equivalent of iSOpropylcyclohexyl amine to the tri-
tyllithium reaction prior to the alkylation step failed to
alter the course of the methylation. In a parallel study
by Patel, the trityllithium promoted methylation of cholest-
4-ene-3-one, again yielded products derived from the more

stable y-dienolate anion (equation 31). However, when the

1) ¢3CLi(XS),THF,0°
2) CH,I(XS)

 

(31)

 

reaction was applied to 5,5-dimethylcyclohex-2-enone (12),

quite a different transformation was noted (equation 32).

27

OLi

  

¢3CLi(XS),THF.O°
->

 

¢3c

 

mac

22.

Conjugate addition reactions of trityllithium or tri-
tylsodium to unsaturated carbonyl systems are rare, as are
other conjugate additions of alkyllithiums not catalyzed by
copper. Michael and Saffer39 reported the conjugate addition
of tritylsodium to cinnamate esters and benzalacetopheonone
but not to methyl crotonate (y-proton abstraction was re-
ported in this case). However, McPhee and Lindstrom,‘° ob-
served conjugate additions of tritylsodium to methyl acrylate
and ethyl crotonate, irrespective of the mode of addition.
This striking disagreement has remained unresolved until now.
In the course of this study the reaction of trityllithium
with ethyl crotonate (22) was Observed to proceed in the

manner reported by McPhee and Lindstrom (equation 33).

¢,cni
(33) cascn=cncogcana fififij-tggu—e’¢3CCH(CHs)C32C°2C235
22. =22.
39 KOH
.ee -§35§——e> ¢accn(cna)cnacogn

'22. 65¢

28
A similar conjugate addition of tritylsodium to 4,4-di-

methylcyclopent-Z-enone (equation 34) was reported by

 

\V

1) ¢3CNa, Etzo, 0° .
2) H20

Bellamy.14 This unexpected result was rationalized by a

 

6
on
O

steric hindrance effect of the 4,4-dimethyl group. The
dipole-dipole interaction of the enone and trityllithium
was suggested as the governing factor in orienting the
trityl anion on the C-3 side of the ggmrdimethyl group in
the ground state description of reactants. In order for
proton abstraction to occur at the acidic protons at C-5,
migration of the trityl anion past the gem-dimethyl group
is required; this energy barrier was deemed sufficient to
make a Michael addition of the trityl anion to the enone
predominate. This argument, however, is theoretically un-
sound, and a more plausible mechanism that accounts for both
the formation of the y-dienolate conjugate base and the in-
frequently Observed conjugate‘addition products from the
reactions of a,5-unsaturated ketones with trityl bases is

shown in equation 35. An initial electron transfer generates

 

 

 

OM
- Cou - _ ,
T [fig-oncnacn-cné R
3 ?M 2a
(35) RCH,CH=CH-c-R' —> RCH,&H-CH=c-R -
+ «vacu ‘ + ¢3c sttL—wractmnncaxH-cx R
(M = Li or Na) .1 + ¢3CH

29
a ketyl intermediate which immediately reacts with the

accompanying triphenylmethyl radical. The resulting enol-
ate anions, when alkylated or protonated, then lead to the
observed products. Whether coupling products or products
derived from y-hydrogen abstraction are obtained appears
to be a consequence of the degree of alkyl substitution

at the B-carbon atom. Thus pulegone (2) and cholest-4-

en—3-one (12), in which the intermediate radical anion

I C8H17
O ¢§[::::f::EE;::t::E>
0
§. 11.

would be tertiary at the B-carbon atom, give products de—
rived from y-hydrogen abstraction while with ethyl crotonate

(22) and 5,5-dimethylcyclohex-2-enone (22), in which the

O
H i
> : H 3
H C02C2H5 '

38 15

W m

corresponding intermediate would be secondary at the

30
B-carbon atom, coupling products are observed. In support
of this argument, only coupling products were obtained when
the reaction was applied to cyclohex-Z-enone (22), while
3-methylcyclohex—2-enone (22) gave products derived from
y-hydrogen abstraction (no coupling products were observed

in this case) (equations 36 and 37). The results obtained

 

 

 

o o
(36) 1) ¢3CLi(XS),THF,O° >
2) CH3I
$3
2.1.. 2.2. 60%
0 'o
d't'

(37) same COD 1. 10118 9 +

$51 22. 23% 2E. 20%

in the case of cyclohex-2-enone clearly rule out the steric
hindrance effect suggested by Bellamy.1‘ In summary, it
appears that coupling is the preferred reaction but when
steric hindrance is sufficient, and an abstractable y-hydro-
gen atom is present, dienolate anion formation becomes the
predominant reaction.

In the course of determining the structure of 22, a
product of reaction 37, a novel “single pot" synthesis from

2-methylcyclohexane-1,3-dione (22) was developed. (Equation 38.)

31

O O NaO 0L1 G o
1 NaH,Et O
(38) - ) ,2» H30 3
2) CH3L1

:12 2:2, 60%

 

 

While reactions of carboxylic acid salts with methyllithium
to give methylketones are well known,‘2 apparently no vinyl-
gous analogs have been reported. An equivalent transforma-
tion involving mono-enol ethers of 1,3—cyclohexanediones has
been reported;43 however, the above scheme is particularly
attractive for its directness and ease of work-up. The use
of metal enolates as protective groups appears to be a general
and versatile synthetic procedure.44

Electron transfer reactions involving the trityl anion
and unsaturated electron acceptors are well documented.
Schlenk, in 1928, reported45 the formation of a pinacol from

the reaction of tritylsodium with benzophenone (equation 39).

P 7

¢ ¢ ¢ ¢

39 ¢ \ ' ¢ - H___>30 ¢\ /

( ) + 3CNa ——> f-ONa 4’ 3C Air -(.2 ?\¢
¢

¢ OH OH

 

 

L- .1

+ ¢3C-O-O-C¢3

In 1964, Russell 25.22343 conducted an electron spin reso-
nance study of radical anions produced by electron transfer

from tritylsodium (produced reversibly from triphenylmethane

32
and sodium ethoxide) to nitrobenzene, m-dinitrobenzene and
azObenzene.

In an effort to support the mechanism proposed in
equation 35 further, direct evidence for the intermediate
ketyl was sought. When 5,5-dimethylcyclohex-2-enone (22)
was added to an argon blanketed tetrahydrofuran solution of
trityllithium, held at -78° in the resonance cavity of an
E-4 Varian ESR Spectrometer, the characteristic signal
pattern of the triphenylmethyl radical appeared. This per-
sisted up to 0°, but vanished at 25°. No other resonance
signals were observed (Figure 1). The absence of any

resonance signal from the ketyl 47 was, however, not unex-

pected. Russell and Stevenson47'have noted that when

H

47

NV

enolizable a'- or y-protons are present in a,B-unsaturated
ketones, the resulting ketyls are so short-lived that detec-

tion by electron spin resonance spectroscopy is unsuccessful.

Another, relatively recent, instrumental method for
the detection of paramagnetic intermediates is derived from
the principle of chemically induced dynamic nuclear polari-

zation (CIDNP)€°0‘9 According to this principle, enhanced

33

(D ) :‘éfli-fk‘éircr t»;3*-'v3“f'-“ix..’x‘49WWW“)W"W’IWWW

 

 

! : ‘i ’ u ) I
‘. .e In F) (M (gs) ( l.
x. M) )I)'§Il“|w”fl:””'3) If“)! 1) a)!" (MIN

3

 

_.
.‘I-
-—-c
‘ "’
....- .—
m —
fil-
“ii—'-
——mwz-;-c s'...?. .‘ .
“37"”.-. "
- ...-..-...
o—m— " " '_'
“—- —
.—.
.1.
«

 

 

 

Figure 1. ESR traces of trityllithium solution, (A) before

addition of enone, -78°, (B) immediately after

addition, -78°, (C) increased amplitude, 0°,
(D) increased amplitude, 25°.

34

absorption and/or emission of r.f. radiation may be observed
in the nmr spectrum of a reaction mixture, as a result of
overpopulation of certain nuclear energy levels in compounds
derived from radical intermediates produced during the re-

action. When a solution of the enone lé'in tetrahydrofuran

12.

was added to a cold (-90°) solution of trityllithium in an
nmr tube, the low temperature nmr spectrum showed no en-
hanced absorption or emission in the region of the C-3 pro-

ton or trityl group of 22; However, in one experiment strong

 

emissiOn from the solvent (THF) was Observed immediately
following the addition of enone 22.to a cold trityllithium
solution. A puzzling weak emissiOn was also noted prior
to the enone addition (Fig. 2). Analogous experiments were

conducted with cholest-4-ene-3-one, a substrate which does

35

 

 

 

 

(B) )

 

 

(A)
w.

 

 

 

(A) 60Hz Nmr spectrum of trityllithium in tetra-
hydrofuran immediately after addition of enone
15, (3) same solution and temperature just prior

33 addition of lg.

Figure 2.

36

not yield coupling products with trityllithium. In this
case, no enhanced absorption or emission was observed in
the region of the methine proton in triphenylmethane.
Attempts to trap ketyl intermediates have been un-
successful. Reductions of a,fi-unsaturated ketones with
solutions of lithium in liquid ammonia are generally be-
lieved to proceed gig ketyl intermediates.1 It was found
that lithium in ammonia reduction of enone 22 gave a sub-

stantial amount of the dihydrodimer 22 (equation 40).

1)Li/NH3,THF,-§3°
2 )NH‘C]. ; '780

 

   

Similar reductive dimerizations have been reported by House
.2E.E£-:5° and it has been suggested"1 that such dimeriza-
tions proceed gig reaction of an intermediate ketyl with
unreduced enone.‘ However, when the reaction of'12.with
trityllithium was carried out in the presence of'a large
excess of the enone no dimer (22) was obtained.

An attempt to use excess triphenylmethane as a hydrogen-
atom trap to reduce the ketyl (equation 41) also failed.
The coupling reaction (32) was unchanged and no 3,3-dimethyl-

cyclohexanone could be detected among the products.

37

OLi OLi

 

     

(32) ¢3CLi, THF

 

A possible explanation of these results is that the
proposed ketyl intermediate and the trityl radical react
with each other very rapidly, either by coupling or 7-
hydrogen abstraction. The presence of lithium cation in a
solvent such as tetrahydrofuran may well be a significant
factor in determining this rate, inasmuch as House g£'§$,5°
have observed that added Li6 significantly shortens the
lifetime of ketyls prepared by electrolysis of a,B-unsat-
urated ketones by promoting coupling and hydrogen abstrac-
tion reactions. A small amount of ketyl may, however,
escape the solvent cage and would be rapidly destroyed,
either by reaction with solvent or another paramagnetic
species. The remaining triphenylmethyl radical may then
give rise to the Observed esr spectrum.

With a method for the selective generation of o'-

dienolate anions from a,B-unsaturated ketones in hand, the

38
intriguing possibility of sequential Michael reactions of
these intermediates with unsaturated carbonyl compounds
was explored. The addition of methyl acrylate to the cross-
conjugated dienolate bases derived from cyclohex-Z-enone
and iSOphorone led to the bicyclo-[2,2,2]octan-2-ones E2,

and 22, respectively, in high yield (equation 42). The'

 

 

 

22": R 2 Ho 90%: £0 R = CH3: 98%

reactions were Observed to be highly stereoselective, giving
rise in each case to a single diastereomer as evidenced by
sharp melting points [22.(2,4 DNP) 139-140°, 22' 53-54°

17 54-55.5°)] chromatographic homogeneity'(glpc, tlc),

(lit.
and sharp carbomethoxy singlets in the nmr spectra (22, 6
3.69; 22, 6 3.70). The nmr spectrum of 22 proved identical

to that reported for this compound by H. Nozaki SE 22,17

39
These workers prepared 22 by the reaction of methyl acrylate

with the cross—conjugated dienamine of isophorone (equation

 

   

43).
o
VOZMe ,A,7hr COzMe
<43) 1) >
K 2) H20,MeOH
0Q
:22. 2:: 29% 2?. 23%

The configuration of the carbomethoxy function at C-5
in 22 was demonstrated by two distinct chemical approaches.
In the first, keto-ester 22'was converted to the ens-ester

21 by the general method of Lewis and Pearce53 (equation 44).

 

 

Product gz'proved to be identical (glpc, ir, nmr) with the
major isomer formed in the Diels-Alder cycloaddition of

methyl acrylate with 1,3—cyclohexadiene (equation 45).

40

(45)

 

9.6 : 0.4

The major product of reaction 45 was reported54 to be the

endo-isomer, and this was further established by conversion
of the ene-ester gz'to the known endo-ene-acid 22, mp 54-550

(lit.55 56-57°), and subsequent lactonization (equation 46).

A 5% aq. NaOH

‘. COzMe

H

(46)

 

 

g1 58 59

The melting point of the stereoisomeric g§gfene~acid is
46-47°. While this approach established the bicyclo[2,2,2]-
octane skeleton in 22, and showed the stereochemistry of

the C-5 carboxyl function, it did not permit exclusion of
the isomeric structure 22, In the second approach, keto-

ester 22'was saponified to the keto-carboxylate 22, which

41

° (
‘. COzMe

H
60

m

was then reduced by catalytic hydrogenation to give, in 80%
yield, a mixture containing 89% syn-hydroxy-acid g2'and 11%

of the anti-isomer 631(equation 47). A similar stereoselec-

O
(47) l 5% aq. NaO
‘. 02Me
H

52

m

 

 

 

tive reduction of sodium cyclohexan-l-one-4-carboxylate has
been reported by Plattner g£.g$,°° In contrast, sodium
borOhydride reduction of 22 gave a 50:50 mixture of the
hydroxy-esters and a small amount of a compound tentatively
identified as the diol 22, The absence of epimerization at

C-5 during saponification was demonstrated by methylation

42

OH

!. OH

O O

5% aq. NaOH

V

(48) l

‘.H COzMe

61
Et20

02H

  

65

Lactonization of the gyn-hydroxy-acid Q2'was accomplished
in refluxing toluene containing pgggftOIuenesulfonic acid
(equation 49). Attempts to effect this conversion with

acetic anhydride or dicyclohexylcarbodiimide and pyridine

were unsuccessful. The absence of skeletal rearrangement

43

H OH
pTSA,¢CH3,A,30 min.

 

A

COzH 5% aq. NaOH

 

62 66

in the lactonization was shown by saponification of lactone
‘gg to the starting hydroxy-acid 22; A lactone alleged to
be fig was prepared by Storm and KOshland57 by reaction of

ene-acid Qg'with 75% sulfuric acid (24 hr). The properties

4

I.

£2.“

characterizing the lactone prepared here by reaction 49 (ir
1750 cm-1, mp 204.5-205.5°) are clearly different, however,
from those (ir 1735 cm-1, mp 229-230°) reported by these
workers and while a compound absorbing at this frequency
(1735 cm-1) in the ir was noted in the reaction (46) giving
Qg,it was not identical to fig'by glpc analysis. .This

discrepancy strongly suggests that the structural assignment

44

 

in the earlier work is incorrect. Very recently, Moriarty
and Adams58 also contested the assignments made by Storm
and Koshland, and showed that acid induced lactonization of
§§ does not yield 22, but gives instead the bicyclo[3,2,1]-

octyl é-lactone §Z)(equation 50).

(50) 66

 

or C-2 epimer

The mechanism of the cyclization involving cross-con-
jugated dienolate bases and Michael acceptors has not been
rigorously defined. A Diels-Alder cycloaddition is clearly
possible; however, in view of the very high yields observed
under exceptionally mild conditions with substrates of vary-
ing steric hindrance, a path involving sequential Michael

additions seems more favorable.

45
The observed stereochemistry could be rationalized in
such a mechanism by a metal-oxygen coordinated transition

state, such as that shown in equation 51. A similar effect

1)LiNRz.THF,-23°
(51) I. s
2) 0R
fir

 

 

 

 

 

 

has been invoked1 to explain the observed stereochemistry in

certain other Michael reactions (equations 52 and 53).

 

 

 

 

C0 Me
Y ’ “- “1
? t , NaOH JEt . OMe
(52) Et-(E-COzne O—> r
Cl Solvent,20-60 8 0
M60 ‘ -. 'E 9
Na
.. l ..J
Solvent Etm
¢cn3

M802C
(DH + HMPA

 

46

   

 

 

e \
O 9 trans-
O H fer
(53) ‘9 co Me 3’
NaOME,MeOH 2 aldol
conden-
sation MeOZC

The large product dependency on solvent observed in reaction
52 suggests that an investigation of different solvent sys-
tems in the reaction of cross-conjugated dienolate bases

with Michael acceptors may well prove worthwhile in further

elucidating the mechanism.

EXPERIMENTAL

General

Infrared spectra were recorded on a Perkin-Elmer 237B
grating spectrophotometer. Nuclear magnetic resonance (nmr)
spectra were Obtained with a Varian T-60 high resolution
spectrometer; low temperature nmr Spectra were recorded on
a Varian A56/60 high resolution spectrometer; tetramethyl-
silane was used as an internal standard in all cases. Elec-
tron spin resonance spectra were obtained with a Varian E-4
spectrometer. Ultraviolet spectra were recorded on a Unicam
SP—800 spectrophotometer. Mass spectra were obtained with
an Hitachi RMU-G mass spectrometer.

Melting points were taken on either the Hoover-Thomas
apparatus (capillary tubes) or on a hot-stage microscOpe
and are uncorrected. Optical rotations were determined with
a Perkin-Elmer Model 141 polarimeter.

Gas-liquid phase chromatographic analyses (glpc) were
conducted with either a Varian 1200 flame ionization gas
chromatograph or an Aerograph A-90P3 thermal conductivity
instrument.

Micro-analyses were performed by either Spang Micro-
analytical Labs, Ann Arbor, Michigan or Chemalytics, Inc.,

Tempe, Arizona.
47

48

In reactions involving moisture.and oxygen sensitive

reagents the reaction flask was flame-dried under argon.

Methylation of Pulegone (8) Using Lithium Isgpropylcyclo-
f
hexylamide (LiICA) as the,Base

 

To a solution of 55.6 mg of durene (internal standard)
in 12 ml dry (distilled from a benzophenOne ketyl solution)
tetrahydrofuran (THF) was added 0.23 ml (1.45 mmoles) of
isopropylcyclohexyl amine (ICA). The stirred solution was
cooled (0°) while 0.6 ml of 2.2M (1.32 mmoles) g-butyllithium
in hexane was added under an argon atmosphere. After the
reaction was stirred at 0° for 25 minutes, 188 mg (1.23 m-
moles) of pulegone was slowly added and the resulting solu-
tion of the conjugate base was held at 0° for one hour.
Rapid addition of 0.8 ml (12.8 mmoles) of methyl iodide
completed the reaction, and the resulting mixture was allowed
to warm to room temperature while it was stirred. After it
had stood overnight, the reaction was worked-up by the addi-
tion of water and ether, the aqueous phase was extracted
several times. The combined ether extracts were washed
twice with five percent hydrochloric acid and once each with
dilute sodium bicarbonate and saturated sodium sulfate solu-
tions. Gas chromatographic analysis (20% 88-30, 163°) of
the dried (M9304) concentrated (reduced pressure) extracts
showed 56% methylpulegones (2), (45% major, 11% minor) and
23% methyliBOpulegones (‘12.), '(17% major, 6% minor). Analy-
tical samples (preparative glpc) gave the following spectral

data:

49
Methylpulegones (9;;

(a) £212; ir (liquid film) 1675 cm-1, 1620 cm-1;

nmr (001,) 61.87 (s, 3H, vinyl ggs), 1.75 (s, 3H, vinyl 953),
1.05 (d, 6H, J 7H2, c-2 Hcggs. c-3 HCQHS),‘3.0-1.2 (m, 6H):
nmr (benzene) 62.20 (s, 3H, vinyl 938): 1.48 (s, 3H, vinyl
£53), 1.16 (d, 3H, J 6H2, c-2 Hcggs), 0.82 (d, 33, J 6H2,

c-3 Hcggs),.2.6-1.0 (m, 6H); mass spectrum (70 ev) m/e (rel
intensity) 166(100), 167(17), 95(92): calcd for C11H130:

P + 1(167)= 0.122P(166). A sample of 56. 2 mg of the pure
major isomer of methylpulegone Obtained by auto-annular vacu-
um Spinning band distillation (Nester/Faust Auto Annular
Teflon Spinning Band Distillation Column) had bp 125-128°

(14-18 mm), [61D = (+)57.30 (0.562 g/100 ml chloroform).

(b) Minor Mass spectrum (70 ev) m/e (rel intensity)
166(66), 167(8), 95(100); p + 1(167)= 0.121P(166). Calcd.
for C11H180:‘ p + 1(167) = 0.125P(166).

.Methylisopulegones (122_;

(a) Major ir (liquid film) 1703 om'1, 1643 cm—1,

nmr (CC14) 64.87 (d, 2H, J 7H2, vinyl protons), 1.68 (s,
3H, vinyl CH ), 1.10(s, 3H, c-6 c-CH ), 0.96 (d, an, 3 5H2:

c-3 HCCH ), 2. 75-1. 0 (m, 7H): mass spectrum (70 ev) m/e
(rel intensity) 166(14),

(b) Minor ir (liquid film) 1705 cm‘1, 1640 cm-1:

nmr (CC14) 64.85 (d, 2H, J 10.032, vinyl protons), 1.68 (s,

50
3H, vinyl 953), 1.05 (d, 3H, J 6Hz, c-3 Hcggs), 1.01 (s, 3H,
C-6 CCHa), 2.6-1.2 (m, 7H): mass spectrum (70 ev) m/e (rel

intensity) 166(24), 123(100).
Attempted Epimerization of the Methylated Pulegone Mixture

The crude mixture of methylpulegones (2) and methyliso-
pulegones (22) was dissolved in methanol and a small amount
of solid pOtassium hydroxide added. The solution was re-
fluxed for one hour, cooled to 25° and stirred at this
temperature for one hour. The methanol was removed under
reduced pressure, the residue neutralized with 6N HCl and
the aqueous solution extracted twice with ether. The com-
bined ether extracts were washed once each with water and
saturated sodium sulfate solution and dried over M9804.

Gas chromatographic analysis (15% SE-30, 125°) of the con-
centrated solution (reduced pressure) showed identical

ratios of products as found in the original mixture.
Base Catalyged Deuterium Exchange of Pulegone (2)

To 10 ml of deuterium oxide under dry nitrogen at 0°
was added 100 mg of sodium peroxide and 1.0 g of pulegone.
Dioxane (20 ml) was added to the stirred solution to achieve
homogeneity, and the mixture was held at 0° for 15 minutes.
A small aliquot was removed and the recovered pulegone, col-
lected by preparative glpc (15% 88-30, 125°), was subjected

to mass spectroscopic analysis (see Table I). The remaining

51

solution was warmed to 25° and stirred for one day, following
which a second sample of pulegone was obtained in the same
manner (see Table I). The remaining solution was extracted
with pentane and the combined extracts evaporated under
reduced pressure. Deuterium oxide, sodium peroxide and di-
oxane were then added to the residue, and the resulting
mixture was stirred at room temperature for one week. A
third sample of pulegone collected at this time proved to

be mainly a mixture of d7- and da-pulegone (see Table I).
5,5-Dimethylcyclohex-2-enone (22)

This compound was prepared by the general method of
Gannon and House."3 3-Methoxy-5,5-dimethylcyclohex-2-enone
(15.4 g, 100.0 mmoles) in 16 ml of ether was added slowly
(1 hr) to a solution of 2.0 g (52.5 mmoles) lithium alum-
inum hydride (LAH) in 60 ml of anhydrous ether. The mix-
ture was refluxed-for 30 min and cooled to 0°. water (5 ml)
‘was added cautiously to the stirred mixture, and after 10
minutes at 25°, the resulting mixture was poured into 200 ml
of cold, ten percent sulfuric acid. The combined organic
extracts from these ether extractions of the aqueous mix-
ture were washed once each with water and saturated sodium
bicarbonate solution and then dried over M9504. The ether
was removed from the extract solution by distillation through
a 20 cm vigreaux column. Distillation of the residue through

the same column afforded 10.05 g (84%) 22’ bp 48.0-48.5°
(3.0 mm) [lit.°° 77-78° (18 mm)]: ir (liquid film) 1675 om";

52
nmr (cc14) 66.80 (dt, 1H, .13.2 10Hz, J3'4'a'e 4Hz, H3), 5.90
(dt, 1H, J2'3 10.0Hz, J2’4a’e 2H2, H2), 2.16 (bs, 4H, H2a,e,

H4a,e), 1.03 (s, 6H, C(CH3)2).
5,5L6-Trimethylcyclohex-2-enone(Lag)

To a solution of 1.6 mmoles LiICA. prepared from 0.281
ml (248 mg, 1.76 mmoles) ICA and 0.729 ml of 2.2M g-butyl-
lithium in hexane in tne same manner described for pulegone
(2), in THF at 0° under a nitrogen atmosphere and containing
48.7 mg durene (internal standard), was added, over a period
of 10 min, 187 mg (1.51 mmoles) enone 22; The reaction mix-
ture was stirred under nitrogen at 0° fOr 1 hr, 15 min, and
then quenched by rapid addition of excess methyl iodide.
The mixture was allowed to warm to 25° and was then stirred
at this temperature overnight. Water and ether were added,
the aqueous solution was extracted three times, and the com-
bined extracts were washed twice with 1N hydrochloric acid,
and once each with water, dilute sodium bicarbonate and
saturated sodium sulfate solutions. Glpc analysis (20% SE-
30, 145°) of the dry (MgS04), concentrated (reduced pressure)
solution showed a mixture of 2§,(83%), 22'(10%) and an im-
purity (5%) present in the starting material (22). An
analytical sample of 5,5,6-trimethylcyclohex-2éénone (22)
obtained by preparative glpc exhibited the following prOper-
ties: Amax(EtOH) 227 nm (58850) [lit.°1 xmax 227.5 nm (e
5950)]; ir (liquid film) 1680 cm“; nmr (cc1,) 66.72 (do,

In, 33,, 10.0Hz, 33,,a'e 4H2, 33), 5,95 kdt, lg, 33’3'10.0Hz,

53

J2 43,9 2H2, H2), 2.22 (m, 3H, H4a,e, H6), 1.07, 0.88 (6H,
C-5 C(CH3)2), 1.00 (d, 3H, J 6.5Hz, C-6 Hcggs); mass spec-
trum (70 ev) m/e (rol intensity) 138(24), 139(3.0), 68(100);
p + 1(13a) = 0.129(138); calcd for c,H1,0: p'+ 1(139) = '
0.0999(138). ‘ ‘

Methylation of Pulegone (8) Using Triphenylmethyllithium
as the Base '

 

(a) To 2.02 g (8.3 mmoles) of triphenylmethane in dry
THF at 0° under nitrOgen, was added 3.2 ml of 2.39M g-
butyllithium in hexane to the stirred mixture. The result-
ing red solution was warmed to room temperature and stirred
for one hour, before being cooled to 0° again. A solution
of durene (internal standard) in dry THF was added followed
by the dropwise addition of pulegone (2) (1 ml, 6.12 mmoles)
over a 10 min period. After the orange reaction mixture was

stirred at 0° for 1 hr, methyl iodide (0.572 ml, 9.2 mmoles)
was added and the mixture was refluxed overnight. The resi-
due remaining after the solvent (THF) was removed under re-
duced pressure, was added to ice water and extracted with
ether. The combined extracts were washed once each with

aqueous ammonium chloride and water and dried over M9804.

Gas chromatographic analysis of the concentrated ether solu-
tion showed 20% methylpulegones (2) (14% major, 6% minor)
and 61% methylisopulegones (22) (48% major, 13% minor).

(b) The same procedure as in (a) was followed with

the exception that 1.25 equivalents of tetramethylethylene-

54

diamine (TMEDA) was added to the THF solution of triphenyl-
methane. Glpc analysis showed a mixture containing 2.(5%)

and 22'(68%) (52% major, 16% minor).

(c) The same procedures as in (a) was followed except
that 1.25 equivalents of ICA was added immediately pre-
ceding the addition of methyl iodide. Glpc analysis of the
final mixture showed 2'(14%) and 22'(68%) (54% major, 14%

minor).
3-Triphenylmethyl-2L5,5-trimethylcyclohexanone (2g)

Enone 2§'(1.2 g, 10.0 mmoles) was added slowly to a
stirred cold'(0°) solution of 12.31 mmoles of triphenyl-
methyllithium in dry THF [prepared from 5.15 ml of 2.39M
n-butyllithium and 3.27 g (13.4 mmoles) triphenylmethane
as described in the previous section] maintained under an
argon atmosphere, and containing 304 mg durene as an internal
standard. After the mixture was stirred for one hour at 0°;
methyl iodide (1.4 ml, 22.4 mmoles) was added and the solu-
tion kept at reflux overnight. Water and ether were added
to the cooled mixture, and the aqueous solution was ex-
tracted and the combined extracts washed once each with
water and saturated sodium sulfate solution. After removal
of the solvents from the dried extracts under reduced pres-
sure, the residue was mixed with ether to afford 949 mg of
a white solid, mp 191-197°. Recrystallization from ethyl

acetate and sublimation gave colorless crystals of 22,

0 I

55

mp 204.5-207°; ir 1700 cm-1; nmr (CC14) 67.34 (m, 15H, -C¢3),
3.67 (bt, 1H, 33,,a, 33'4a 1132, H3), 1.92 (m, 4H, Hza, H2e,
H6a,e). 1.18 (s, 3H, c-5 233): 0.92 (s, 3H, C-5 ggs), 0.92
(m, 1H, H4a), 0.67 (d, 3H, J 6H2, c-2 Q§3)7 the mass spec-
trum did not show a parent ion, highest m/e (70 ev) was
243 (¢3C +).

5:13;. Calcd. for C33H300: c, 87.91; H, 7.91.

Found: C, 87.91; H, 7.75.

Glpc analysis (5% 83-30, 200°) of the remainder of the
949 mg of white solid showed 65.4% ’32, 24.8% a, and 10% of
an unidentified impurity. Glpc analysis of the filtrate
residue containing the internal standard showed 2.26 g 22’

and 235 mg 21'. The total yield of 26 was 75%.
3-Triphenylmethyl-5,5-dimethylcyclohexanone (21)

Freshly distilled enone lé'was added to a stirred solu-
tion of 0.66 mmoles of triphenylmethyllithium in THF (pre-
pared in the usual manner) at 0° under argon. After the
mixture was stirred for 5 min at this temperature, water
and ether were added and the aqueous solution extracted.

The combined extracts were washed twice with water, once
with saturated sodium sulfate solution and dried (MgSO‘).
After removal of the solvent under reduced pressure, ether
was added to afford 61 mg of 21, mp 225—230°. The filtrate
residue was subjected to preparative thick layer chroma-

tography (silica gel, methylene chloride) and gave 45 mg

56

additional 21’ mp 223-229° (total 106 mg, 77%). An analy-
tical sample obtained by recrystallization from ethyl
acetate had mp 230.5-232°; ir 1704 cm-1; nmr (100 mHz, CDC13)
67.34 (bs, 15H, —933), 3.78 (tt, 1H, J,,,a, 33'2a 12.5Hz,
J3'4e,.J3’2e 2.5Hz, H3), 2.57 (dd, 1H, J29,2a 12.5Hz,
Jze,3 2.5Hz, H2e), 2.07 and 1.88 (ABq, 2H, J 13.5Hz, H6a,e),
1.84 (dd, 1H, J4e’4a 12.5Hz, J4e'3 2.5Hz, H4e), 1.56(t, 1H,
Jza,ze, Jza'3 12.5Hz, H2a), 1.17 (s, 3H, c-5 ggs), 0.94 (s,
3H, C-5 EH3), 0.95 (t, 1H, J4a,e0 J4a,3 12.5Hz, H4a); mass
spectrum (70 e7) showed no parent ion; 60% of the total ion
current consisted of m/e 243 (¢3C +).

Aggl, Calcd. for C27H230: C, 88.00; H, 7.66.

Found: C, 88.02; H, 7.87.
3-(1,1,ldrriphenylmethyl)-butanoic Acid (42)

Ethyl crotonate (22) (319 mg, 2.8 mmoles) was added
slowly to a stirred sOlutiOn of 3.92 mmoles of triphenyl-
methyllithium (prepared in the usual way) in 12 ml of dry
THF at -23° (Dry Ice, CCl4) under argon. After the mix-
ture was stirred at this temperature for 25 min it was ex-
tracted with ether and the combined extracts washed and
dried. Glpc analysis (5% SE-30, 220°) of the concentrated
solution showed one major peak at longer retention time than
triphenylmethane and no ethyl crotonate. The viscous resi-
due (1.4 g) Obtained after removal of solvent was saponi-

fied with refluxing 10% ethanolic potassium hydroxide.

57

After removal of the solvent under reduced pressure, the
residue was washed three times with ether and then acidi-
fied with 6N hydrochloric acid. Extraction with methylene
chloride and chloroform, however, afforded only 10 mg of
the acid 22, The previously obtained ether extracts were
combined, methylene chloride and 6N hydrochloric acid were
added and the acidic aqueous solution was extracted with
methylene chloride. The combined extracts were washed twice
with water, once with saturated sodium sulfate solution,
dried (M9804) and concentrated to leave 1.0 g of residue
which yielded 389 mg of crude, solid acid gg'after mixing
with ether. An analytical sample was obtained by recrys-
tallization of a small amount of this from aqueous methanol
and had mp 219-2200 (lit.4° 213.5-215.5°); ir 3000 cm-1,
1700 cm'1; nmr (cools) 57.34 (m, 153, -933), 4.02 (m, 1H,
H3), 2.84 (bd, 1H, Jag,a 1532; H2 gauche to H3), 1.55 (dd,
1H, 62a,g 1532, J,a,3 11Hz, H2 anti to H3), 0.95 (d, 3H,
J 6Hz, C-3 Egg). .

A portion (117 mg) of the ethereal filtrate residue
(542 mg) was subjected to preparative thick layer chroma-
tography (silica gel, methylene chloride) and yielded 35 mg
of acid 22, The total yield of 22,is 575 mg (65%).

3-Triphenylmethyl-2-methylcyclohexanone_ggg)

To a cooled (0°) stirred solution of 2.37 mmoles tri-
phenylmethyllithium, containing 82 mg of durene (internal

standard) was added, under an argon atmosphere 185 mg (1.93

58
mmoles) of cyclohex-Z-enone in dry THF. The mixture was
stirred at 0° for 1 hr followed by the addition of 1 ml
(2.28 g, 16.0 mmoles) of methyl iodide. After the mixture
was warmed to 25° and stirred for 2 hrs, it was diluted
with water and ether. The aqueous solution was extracted
three times, and the combined extracts were washed twice
with water, once with saturated sodium sulfate solution and
finally dried over MgSO4. Glpc analysis (20% SE-30, 140°)
showe no volatile products. Preparative thick layer chroma-
tography (silica gel, methylene chloride) of 174 mg of the
residue (1.1 g) remaining after removal of the solvent
afforded 63 mg (60%) of ketone 22; An analytical sample
obtained by recrystallization from ethyl acetate and aqueous
ethanol had mp 162-164°; ir (KBr) 1765 cm"; nmr (c0013)
57.34 (m, 15H, - 923), 3.67 (m, 1H, H3), 2.75-1.90 (m, 3H,
C-2 methine and C-6 methylene protons), 1.80-1.20 (m, 4H,
C-4, C-5 methylene protons), 1.16 (d, 3H, J 7Hz, C-2 Efls)°
Aggi, Calcd. for CgaHgooz C, 88.09; H, 7.39.
Found: C, 87.94; H, 7.33.

Methylation of 3-Methylcyclohex-2-enone (22}_UsingTriphenyl-
methyllithium as the Base '

To a cooled (0°) solution of 2.0 mmoles triphenylmethyl-
‘1ithium in dry THF under argon was added slowly 172 mg

(1.56 mmoles) of freshly distilled 3-methylcyclohexenone
(22). After 20 min at 0°, methyl iodide was added (1 ml,

16.0 mmoles) and the mixture was allowed to warm to 25° and

59

was stirred at this temperature for 4 hr. Water and ether
were added and the aqueous solution was extracted in the
usual manner. Glpc analysis (4% QF-l, 150°; 5% SE-30, 70°)
of the concentrated solution showed at least 8 components:
recovered 3-methylcyclohex-2-enone (22) (9%), 2,3-dimethyl-
cyclohex—Z-enone (22) (23%), 2,2,3-trimethylcyclohex-3-
enone (22;) and 2,2-dimethy1-3-methylenecyclohexanone (222;)
(20% of a 50:50 mixture by nmr and glc analysis. Insepar-
able on 4% QF-l and only partially resolved on fl SE-30)
and four minor unidentified compounds of approximately equal
abundance (total 11%). Temperature programmed glpc analysis
(up to 250°) showed the absence of any material at longer
retention times than triphenylmethane. A sample of the
mixture of double bond isomers géi'and gggi'obtained by
preparative glpc was examined by: ir (liquid film) 1715 cm-1,
1630 cm-1, 885 cm"1 (ecng); nmr (cel,) (a) 2,2,3-trimethyl-
cyclohex-3-enone 65.5(1H, m, C-4 vinyl proton), 2.4 (m, 43,
C-5, C-6 methylene protons), 1.7 (bs, 3H, C-3 SE3): 1.23
[s, 3H, c-2 C(CH3),], 1.13 [s, 3H, c-2 C(CHa):l: (b) 2,2-
dimethyl-3-methylenecyclohexanone 64.8 (bs, 2H, C-3 =CH3),
2.4 (m, 4H, C-4, C-6 methylene protons), 1.7 (m, 2H, C-5
methylene protons), 1.23 [s, 3H, C-2 C(CH3)3], 1.13 [s, 3H,
c-2 C(Cfis)a]7 mass spectrum (70 ev) m/e (rel intensity) 138
(37), 139(4.0), 96(93), 81(100), 67(82): p + 1(139) =
0.12P (138). Calcd. for C9H1‘0: P + 1(139) = 0.10P(138).

A sample of 2,3-dimethylcyclohex-2-enone (22) Obtained

by preparative glpc had identical glpc retention time

60

(4% QF-l, 5% SE-BO) and identical ir and nmr Spectra as a
sample prepared independently from 2-methylcyclohexane-1,3-

dione.
2,3-Dimethylcyclohex—2-enonegggi)

To a stirred solution of 2-methylcyclohexane-1,3-dione
in 100 ml of anhydrous ether maintained at room temperature
under argon, was added 44 mmoles of sodium hydride (from
2.0 g of 52.8% oil diSpersion after washing with pentane).
After it had stirred at 25° for 2 hr, the heterogeneous
mixture was refluxed for one hour, cooled to 25° and treated
with 25 ml of 2.3M methyllithium in ether (57.5 mmoles).
Evolution of gas suggests that enolate salt formation with
sodium hydride may not have been complete. The reaction
mixture was stirred at room temperature overnight then
quenched with saturated ammonium sulfate solution and ex-
tracted with ether. The combined ether extracts were washed
three times with-dilute sodium carbonate solution and once
each with water and saturated sodium sulfate solution and
finally dried over MgS04. Removal of the solvent under
reduced pressure left 2.3 g of crude 2,3-dimethylcyclohex-
2-enone 23,(60%). Distillation through a short-path still
afforded 1.7 g colorless 22, bp 95° (15 mm) [lit.°° 90-96°
(14 mm)]; ir 1665 em“, 1630 em’1; nmr (ccl,) (essentially
identical to undistilled material) 62.3 (m, 4H, C-4, C-6
methylene protons), 2.0 (m, 2H, C-5 methylene protons), 1.88

(s, 3H, C-3 vinyl 233): 1.67 (s, 38, C-2 vinyl SE3)-

61

Electron Spin Resonance Study of Reaction 32

A 3mm o.d. esr tube was modified by removing a one
inch piece from the top and sealing an equivalent length
of 7 mm o.d. tubing in its place. A rubber septum was af-
fixed to the tube and an argon atmosphere maintained over
the contents gig inlet and outlet syringe needles. The
tube was cooled to -78 1 3° in the cavity of a Varian E-4
spectrometer by means of a Varian Variable Temperature Con-
troller containing a Dry Ice-acetone slurry in the Dewar
flask. A solution of triphenylmethyllithium (0.2 ml of 1M
¢scLi in THF prepared in the usual way) was introduced and
scan A, Fig. 1 recorded. Enone 22'(1 drOp) was then added
and scan B, Fig. 1 recorded. Scans C and D were Obtained

by successively warming this solution to 0° and 25°.
Low-Temperature NMR Studies

A trityllithium solution (0.4 ml of 0.25M 03CLi in THF)
was introduced along with a small amount of TMS into a con-
ventional nmr tube previously dried, flushed with argon
(15-20 min) and equipped with a rubber septum. The contents
were then cooled to a specified temperature (13°) in the
probe of a Varian A56/60 spectrometer by means of a Varian
Variable Temperature Controller containing liquid nitrogen
in the Dewar flask. A THF solution of the enone (60-70 mg/ml)
was cooled to -78° in a previously dried and argon flushed

container equipped with a rubber septum. After the nmr

62
spectrum of the initial triphenylmethyllithium solution was
scanned, the cold solution of the enone was added (~o0.2 ml)
and the spectrum immediately scanned (3-5 sec), starting at
the region of interest with a sweep rate of 100 sec. Re-
peated scans of the solution were made at several tempera-

tures between -90° and 20°.

Lithium in Ammonia Reduction of 5,5-Dimethylcyclohex-2-

enone (22)

Liquid ammonia (50 ml) was distilled into a 100 ml
three-necked flask equipped with a magnetic stirrer and a
Dry Ice condenser. Lithium (0.4 cm ribbon, 3.4 mmoles)
was added and the resulting dark blue solution was stirred
at reflux (~33°) for 5 min. A solution of enone 22'(212 mg,
1.7 mmoles) in 3 ml of dry THF was then added over a period
of 5 min. After it was stirred at -33° for 2 hr the mixture
was cooled to -78° and solid ammonium chloride was added.
The Dry Ice condenser was replaced with a water condenser
and the ammonia was allowed to evaporate overnight. ‘Water
and ether were added to the residue; the aqueous solution
was extracted; and the combined extracts were washed twice
with water, once with saturated sodium sulfate and dried
over.MgS04. Removal of the solvents under reduced pressure
left 250 mg of an oil from which 33 mg of dimer gg'crystal-
lized, mp 141-145°. Recrystallization from a pentane and
methylene chloride solution afforded an analytical sample

that had mp 148-149°; ir 1700 om“; nmr (cc1,) 52.05 (s, 4H,

63
H2a,e H2'a,e), 2.44 t 1.17 (m, 103, H4a,e, H4'a,e, H5, 35',
H6a,e, H6'a,e), 1.08 (s, 6H, C-3, 3' -g§3), 0.87 (s, 6H,
c-3, 3'-g§3); mass spectrum (70 ev) m/e (rel. intensity)
250(8), 125(100).
523;, Calcd. for C16H2303: C, 76.75; H, 10.47.
Found: C, 76.67; H, 10.52.

The mother liquor was subjected to glpc analysis (4%
QF-l, 110°) and proved to be a mixture of 3,3-dimethylcyclo-
hexanol (22) (17%) containing an impurity present (5%) in
the starting enone 22, 3,3-dimethylcyclohexan-l-one ($2)
(53%) and dimer ’59, (12%). '

An analytical sample (preparative glpc) of 3,3-dimethy1-
cyclohexan—l-one (22) was characterized by ir (liquid film)
1713 em‘1 and nmr (cc1,) 52.06 (s, 23, H2a,e), 2.4-1.4 (m,

6H, C-4,5,6 methylene protons), 1.0 (s, 6H, C-3 gem-dimethyl).
Qnggg:Carbomethoxybicyclo[2,2,2]octan-2-one (52)

To a stirred solution of 21 ml of ICA (18.6 g, 0.132
moles) in dry THF at -23° (Dry Ice and CC14), under argon,
‘was added 55 ml of 2.2M.grbutyllithium in hexane (0.121
moles); and the resulting mixture was stirred for 20 min.
Cyclohex-Z-enone (109) was added to this solution over a 15
min period and the solution was stirred at -23° for 50 min.
Methyl acrylate (11.3 g, 0.132 mmoles) was then added over
a 15 min period, and the resulting solution was stirred at
-23° for 2 hr. Water and ether were added to the reaction

mixture and the aqueous solution was extracted. The

64

combined extracts were washed four times with 1N hydro-
chloric acid and once each with water and saturated sodium
sulfate and then dried over MgS04. Removal of the solvent
under reduced pressure gave 17.8 g (90%) of keto-ester 22,
which proved to be homogeneous by glpc (4% QF-l, 180°) and
tlc (silica gel, 1:1 ether/hexane). A short path distilla-
tion afforded 10.4 g of clear colorless 22, bp 100—104°

1, 1735 cm-1; nmr

(0.65-0.75 mm); ir (liquid film) 1725 cm“
(CC14) (essentially identical to undistilled material) 6
3.69 (s, 3H, -C02gg3), 2.8-1.8 (m, 11H, methine and methylene
protons); mass spectrum (70 ev) m/e (rel intensity) 182(30),
96(100). I '

A 2,4-dinitr0phenylhydrazone derivative of 22! mp 139-
1400, was prepared.-

Found: C. 53.03: H, 5.01; N, 15.43.

8-Carbomethoxy-4,6,6-trimethylbicycloL2,2,2]octan-2-one

To a stirred solution of LiICA (1.6 mmoles)[prepared
as described in the previous section from 246 mg (1.74 mmoles)
of ICA and 0.85 ml of 1.9m g-butyllithium (1.6 mmoles)] in
dry tetrahydrofuran at -23° under argon was added 210 mg
(1.5 mmoles) isophorone in 5 ml of dry THF over a period of
10 min. The mixture was stirred at -23° for 50 min, then
methyl acrylate (150 mg, 1.7 mmoles) was added in 4 m1 of

dry THF over a period of 10 min and the resulting solution

65

was stirred at —23°, under argon for 3.5 hr. Water and
ether were added to the reaction mixture and the aqueous
solution was extracted. The combined extracts were washed
three times with 1N hydrochloric acid and once each with
water and saturated sodium sulfate solution and then dried
over M9804. Removal of the solvent under reduced pressure
afforded 330 mg of the keto-ester 22'(98%) as a pale yellow
oil, which was homogeneous by glpc (4% QF-l, 150°) and tlc
(silica gel, 1:1 ether hexane) and exhibited the following
properties: ir (liquid film) 1725 cm-1, 1735 cm-1; nmr
(cc1,) 53.70 (s, 3H, -c03CH3), 2.87-1.46 (m, 6H, c-l, c-3,
C-7, C-8 methylene and methine protons), 1.30 (bs, 2H, C-5
methylene), 1.10 (s, 3H, C-6 methyl gagg_to carbonyl), 0.94
(s, 6H, C-6 methyl g§9_to carbonyl and C-4 methyl); mass
spectrum (70 ev) m/e (rel intensity) 224(6)P, 123(100).

A small sample which was collected by glpc crystallized
on cooling (Dry Ice) and had mp 53-54° (lit.17 54.5-55.5°).
Using one of these crystals as a ‘seed", the remaining

material was crystallized from hexane, mp 53.5-54.5°.

5-enerCarbomethobeicyclo[2,2,2]oct-2-ene (57)

 

 

(a) From 5-ggggfcarbomethoxybicyclo[2,2,2]octan-2-one
(22):- Toja solution of pyrrolidine (190 mg, 2.7 mmoles)
in 10 ml of dry benzene was added keto-ester 22'(416 mg,
2.2 mmoles) and the solution was then refluxed under nitro-
gen overnight with a Dean-Stark water trap containing molec-

ular sieves (4A). Glpc analysis (5% SE-30, 180°) of the

66

benzene solution showed greater than 90% conversion to the
enamine 22, The benzene and pyrrolidine were removed under
reduced pressure and an ir that was taken of the crude
enamine showed xmax at 1620 cm-1. Without further charac-
terization the crude enamine was dissolved in 10 m1 of dry
THF and 2.5 ml of 1.29M diborane in THF (3.2 mmoles) was
added and the solution was stirred under argon at room
temperature for 3 hr. Glacial acetic acid (1.5 ml) was
added and the mixture then refluxed for 1 hr. Tlc analysis
(silica gel, 1:1 ether/hexane) showed no keto-ester and no
components at higher Rf values. The THF was removed under
reduced pressure, diglyme (10 ml) and glacial acetic acid
(1 ml) were added and the mixture was refluxed for 45 min.
After cooling to 25°, it was stirred overnight at this
temperature, then the reaction mixture was diluted with
water and the aqueous solution was extracted with ether.
The combined extracts were washed four times with water and
once with saturated sodium bicarbonate solution and dried
over MgS04. Removal of the solvent under reduced pressure
left a residue (5 ml) containing diglyme and acetic acid.
Pentane and water were added; the aqueous solution was ex-
tracted with pentane and the combined extracts were washed
four times with water (until neutral), once with saturated
sodium sulfate solution and finally dried over M9804. Re-
moval of the pentane under reduced pressure left a residue
(1.5 ml), glpc analysis (5% SE-30, 120°) of which showed

diglyme and 5-endo-carbomethoxybicyclo[2,2,2]oct-2-ene(§1)

67

(> 90%). Column chromatographic separation (30 g silica

gel, eluting with 1:4 ether/hexane) gave 60 mg of sweet-
smelling g1, which had ir (liquid film) 1735 cm'1; nmr (ccl,)
56.21 (m, 23, n2, H3), 3.60 (s, 3H, -co,gg3), 2.91 (m, in,
H5), 2.57 (m, 23, H1, H4), 1.76-1.1 (m, 6H, C-6,7,8 methylene

protons).

(b) From Diels-Alder reaction of 1,3-cyclohexadiene
and methyl acrylate: 1,3-Cyclohexadiene (900 mg, 11.25
mmoles) was added to 4 ml of methyl acrylate and the result-
ing mixture was refluxed for 36 hr. Excess methyl acrylate
was then distilled off and the viscous residue was extracted
with ether. The combined extracts were dried over MgS04
followed by the removal of ether under reduced pressure to
give 752 mg sweet smelling oil (40%). Glpc analysis (4%
QF-l, 155°) of this showed two peaks in the ratio of 0.4:9.6.
The major peak was increased in amplitude upon addition of
gl'prepared as in (a). The ir spectrum of the oil was
identical to that reported for 22, The nmr spectrum was
essentially identical with the exception of a new carbometh-
oxy peak at 63.63 which was approximately 5% of the peak at
63.60 (from £1).

J ##1.

Bicyclo[2,2,2]oct-2-ene-5-endnrcarboxylic Acid (22)

To 43 mg (0.259 mmoles) of ens-ester gz'(prepared in
the manner described for (a) above) was added 3 ml of five

percent aqueous sodium hydroxide and the solution stirred

68
for 4 hr at room temperature (until homogeneous). After
acidification with 6N hydrochloric acid, the solution was
saturated with ammonium sulfate and extracted four times
with chloroform. After washing the combined extracts with
water and saturated sodium sulfate solution and drying over
magnesium sulfate the solvent was removed under reduced
pressure to give 31 mg (82%) solid, mp 44-48°. Recrystal-
lization (3X) from pentane at -78° afforded ene-acid 22“

mp 54-55° (lit.55 56-57°).
Sefiydroxybicyclo[2,2,2]octan-Z-carboxylic Acid y-Lactone (52)

The procedure of Wagner gt; 31.52 was followed. To 23
mg (0.151 mmoles) of the ene-acid gg'was added 2 ml of 30%
aqueous sulfuric acid and the mixture was refluxed at 110°
for 1 hr.. The cooled mixture was then poured into ice
water and extracted four times with chloroform. The com-
bined chloroform extracts were washed with 10% aqueous sodium
bicarbonate solution and dried over magnesium sulfate. Re-
moval of the solvent under reduced pressure left 18 mg of
lactone £2,contaminated with a minor (-20%) impurity (glpc
analysis, 4% QF-l, 100°). Recrystallization from hexane
gave 22, mp 208-2100 (11:.62 207-2080); ir (cac1,) 1765 cm"1
and a small absorption at 1735 cm"1 (impurity): mass spec-

trum (706V) m/e (rel intensity) 152(3), 108(18), 66(100).

69

Syn-S-Hydroxybicyclo[2,2121octan-2-carboxylic Acid (22)

The ketoéester 52 (875 mg, 4.8 mmoles) was added to a
solution of 5% aqueous sodium hydroxide and stirred at room
temperature for 20 min (until homogeneous). Platinum
oxide (170 mg, 82%) was then added and the solution was
hydrogenated at room temperature and atmospheric pressure
for 2 days (theoretical uptake of hydrogen). After filtering
off the catalyst through a celite mat, the solution was
acidified with 2N hydrochloric acid, saturated with ammonium
sulfate and extracted four times with chloroform. After
the combined extracts were washed with saturated sodium
sulfate solution they were dried with M9804 and the solvent
was removed under reduced pressure to give 650 mg of white
solid. Glpc analysis (4% QF-l, 155°) of the methyl esters
of this material (prepared by treatment with methanolic
diazomethane) showed 89% of gygfmethyl-S-hydrobeicyclo-
[2,2,2]octan—2-carboxylate and 11% of ggEifmethyl-S-hydroxy-
bicyclo[2,2,2]octan-Z-carboxylate. An analytical
sample of gygyS-hydroxybicyclo[2,2,2]octan-2-carboxylic acid
was Obtained by recrystallization of the white solid from
ethyl acetate and had mp 143-144°: ir (KBr) 3350 cm-1,
1700 cm-1; nmr (CDC13) 67.27 (concentration dependent)

(bs, ZH, -OH), 3.87 (m, 1H, HS), 2.85 to 1.33 (m, 11H, C-1,
2,3,4,6,7,8 methine and methylene protons); mass spectrum
(70 ev) m/e (rel intensity) 170(5), 152(85), 80(100).
' £121. calcd. for c,n,,o,: 'c, 63.51; H, 8.29.

Found : C, 63.63; H, 8.22.

70

5-HydroxybicycloL2,2,219ctan-2-carboxylic Acid 6-Lactone(§§)

To a solution of 10 ml of toluene containing a small
amount of pgrgftoluenesulfonic acid was added 100 mg (0.59
mmoles) of hydroxy-acid Qz'and the resulting mixture was
refluxed 30 min with a Dean-Stark water trap containing
molecular sieves (4A). Ether was added to the cooled solu-
tion and the organic mixture was washed with cold (3°) five
percent sodium bicarbonate and saturated sodium sulfate
solutions and dried over MgSO4. Removal of the solvents
under reduced pressure left 91 mg of a solid residue. Pre-
parative thick layer chromatography of this afforded 35 mg
of the lactone 22'(40%). Crystallization from petroleum
ether and hexane gave colorless crystals, mp 204.5-205.5°;
ir (CHcla) 1750 cm-1; nmr(cc1,) 64.79 (m, 1H, 36), 2.80 (m,
1H, H2), 2.18 (m, 23, H1, H4), 1.75 (m, 8H, C-3,6,7,8 meth-
ylene protons); mass spectrum (70 ev) m/e (rel intensity)
152(10), 66(100), 80(86).

' Saponification with 5% aqueous sodium hydroxide gave
hydroxy-acid Q2, mp 139-1400; mass spectrum (70 ev) identi-

cal to Qg'prepared above.
Sodium Borohydride Reduction of Keto-ester 5%

To a stirred solution of 4.5 g (24.8 mmoles) of keto-
ester QQ'in 50 m1 of methanol at 0°, was added 2.2 g (58
mmoles) sodium borohydride and the mixture held at 0° for

2.5 hr. After the removal of methanol under reduced

71
pressure, water and ether were added and the aqueous solu-
tion was extracted twice with ether. The combined ether
extracts were washed once each with 1N hydrochloric acid,
water, and saturated sodium sulfate solution and finally
dried over M9304. Removal of the solvent under reduced
pressure left 3.75 g (82%) of colorless oil. Glpc analysis
of this material (4%‘QF-1, 150°) showed two peaks of ap-
proximately equal area, with the same retention times as
those of the hydroxy-ester mixture previously prepared by
treatment of hydroxy-acids gg'and gz'with methanolic diazo-
methane. Tlc analysis (silica gel, ether) showed two com-
ponents at Rf 0.8 and Rf 0.3. Preparative thick layer
chromatography of 164 mg of the crude oil gave 80 mg of a
mixture of the epimeric alcohols (Rf 0.8) in «'50:50 ratio
as determined by nmr and glpc and which exhibited the fol-
owing characteristics: ir (liquid film) 1730 cm-1, 3360
cm-1; nmr (cc1,) 63.8 (m, 13, géon), 3.70, 3.64 (s, 3H,
-C03Q§3), 2.9-1.0 (m, 12H, methine and methylene protons,
-OH): mass spectrum (70 ev) m/e (rel intensity) 184(3),
166(11), 80(100). ' '

. From the lower Rf fraction (Rf 0.3) was Obtained 14 mg
of oil having the following characteristics: ir 3350 cm-1,
(very strong), essentially transparent in the 1730 cm"1
carbonyl region; nmr (cnclg) 64.1-3.3 (bm, 3H, géOH, -CH,OH),

2.2 (concentration dependent) (bs, 2H, -OH), 2.0-1.3 (bm,

72
11H, methine and methylene protons); mass Spectrum (70 ev)
mle (rel intensity) 156(3), 138(33), 79(100). These data

are most consistent with structure 64;

REFERENCES

REFERENCES

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74

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75

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76

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Org, Chem., 88, 4060 (1968).

 

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Aust. J. Chem., 88, 2531 (1970).

 

APPENDIX

8.0

6.0

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MICRONS

 

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1400

1600

 

........

 

 

 

 

 

1800

 

 

  

.0 4
E moz<E2mz<E

1000

1200

2000

major

~

).

Infrared spectrum of methylpulegone (9,
isomer

Figure 3.

78

..IJ.
8

 

 

 

 

 

i
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I
1
1
1
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1 1
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2000 1500
o M'CRONS 10.0 11012.0 _

 

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1800

,5,6-trimethylcyclohex-2-

w

Infrared spectrum of 5

enone (16).

Figure 4.

79

M'CRONS 5.0 6.0 — 8.0

TRANSMITTANCE (7Z1)

 

3500 3000 2500 2000 1500
5.0 6.0 7.0 . 8.0 M'CRONS 10.0 11.0120 16.0

 

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Figure 5. Infrared spectrum of 3-tri hepylmethy1-2,5,5-
tr imethylcyclohexanone (36$ .

w

80

 

 

 

 

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