On the Stereochemistry of Diaryl-Substituted Cyclohexanones Formed by Michael Reactions. Trans to Cis Isomerization of Their Ketals under Basic Conditions

Article abstract of DOI:10.1021/jo9801059

The stereochemistry of C-1-substituted 2,6-diphenylcyclohexan-4-ones 1-3 prepared by Michael reactions has been investigated. While preparations of these compounds have been reported over the past 70 years, in many instances the correct stereochemistry at

Full text of DOI:10.1021/jo9801059

J . Org. Chem. 1998, 63, 4359-4365
4359
On th e Ster eoch em istr y of Dia r yl-Su bstitu ted Cycloh exa n on es
F or m ed by Mich a el Rea ction s. Tr a n s to Cis Isom er iza tion of
Th eir Keta ls u n d er Ba sic Con d ition s
Alex T. Rowland,* Sandra A. Filla, Marilyn L. Coutlangus, Mark D. Winemiller,
Mark J . Chamberlin, Gary Czulada, and Steven D. J ohnson
Department of Chemistry, Gettysburg College, Gettysburg, Pennsylvania 17325
Michal Sabat
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901
Received J anuary 21, 1998
The stereochemistry of C-1-substituted 2,6-diphenylcyclohexan-4-ones 1-3 prepared by Michael
reactions has been investigated. While preparations of these compounds have been reported over
the past 70 years, in many instances the correct stereochemistry at C-2 (6) and, in some instances
at C-1, was uncertain. We show here that in one case in which two identical substituents (CN) are
present at C-1, it is possible to isomerize the initially formed trans isomer 1d to the cis isomer 3f.
When a cyano group and a dissimilar substituent are present at C-1, the initially formed trans
isomer may be isomerized to the cis compound. The stereochemistry is vertified by NMR
spectroscopy and by X-ray analysis. Reaction of the ethylene ketals (4 and 5) of these ketones
with KOH in DMSO at elevated temperatures gives rise to cis products, and deuterium-labeling
studies demonstrated the acidity of the benzylic hydrogen at C-2 (6). Isomerization was evident
since the trans ketal 4a and the cis ketal 4b gave the same amide 6a . 1H and 13C NMR spectra
provided conclusive evidence for the cis f trans rearrangement.
The Michael reaction of 1,5-diaryl-1,4-pentadien-3-ones
with active methylene compounds has long been em-
ployed to prepare highly substituted cyclohexanones. The
products of these reactions are of interest in terms of
their stereochemistry and as starting materials for the
synthesis of compounds with possible biological activity.1
The assignment of stereochemistry in some of these
Michael products has been uncertain or, in some cases,
incorrect.
When R1 ) R2 in the methylene compound and Ar )
Ph, the product may exist as a trans (dl) or cis (meso)
isomer. When R1 * R2, a trans isomer (dl) or two meso
compounds (cis) are possible. The uncertainty regarding
the stereochemistry in a Michael product is exemplified
by the case R1 ) R2 ) CO2Me (1a ). We recently resolved
(1b), only the trans isomer is formed;3 the same result is
found when R1 ) R2 ) CO2 Et (1c).4 When R1 ) R2 )
CN (1d ), the initially formed Michael product has been
alternately reported as unspecified5 and as cis.6 X-ray
analysis of 1d shows unambiguously that this is the trans
isomer. When R1 * R2, the initially formed isomer (trans)
may often be converted into one of the cis isomers 2. For
example, the trans Michael products 2a , 2b, 2c, and 2d
have been reported to be converted by base (or acid) into
the cis isomers 3a ,7,8 3b,9 3c,5 and 3d .8,10
The literature suggests that when R1 ) R2 the ther-
modynamically stable isomer is the trans (dl), whereas
when R1 * R2, one of the two possible meso isomers is
this question by X-ray crystallography, which showed
that 1a is the trans isomer.2 When R1 ) R2 ) CO2-t-Bu
(1) (a) Rele, D. N.; Baskaran, S.; Korde, S. S.; Vora, J . D.; Trivedi,
G. K. Indian J . Chem., Sect. B 1996, 35B, 431. (b) Reddy, D. B.;
Padmavathi, V.; Reddy, M. M. Indian J . Chem., Sect. B 1992, 31B,
407. (c) Reddy, D. B.; Padmavathi, V.; Reddy, P. V. R. Indian J . Chem.,
Sect. B 1992, 31B, 774.
(2) Rowland, A. T.; Winemiller, M. D.; Sabat, M. Tetrahedron Lett.
1997, 38, 1287.
(3) Coutlangus, M. L.; Filla, S. A.; Rowland, A. T. J . Chem. Educ.
1989, 66, 520.
(4) Kohler, E. P.; Dewey, C. S. J . Am. Chem. Soc. 1924, 46, 1267.
(5) Kingsbury, C. A.; J ordan, M. E. J . Chem. Soc., Perkin Trans. 2
1977, 364.
(6) Otto, H.-H.; Triepel, J .; Schmelz, H.; Meyer-Schaar, J . Arch.
Pharm. (Weinheim, Ger.) 1976, 309, 786.
S0022-3263(98)00105-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/02/1998

4360 J . Org. Chem., Vol. 63, No. 13, 1998
Rowland et al.
the most stable compound. We find that reaction of
dibenzalacetone with tert-butyl cyanoacetate gives the
trans compound 2e, which is isomerized to the cis
compound 3e by treatment with NaOH in EtOH. X-ray
crystallography shows that the ester group occupies the
equatorial position on the chair, providing conclusive
evidence for the position of substituents at C-1. Kings-
bury5 used C-H coupling constants to conclude that the
cyano group in the cyano ester 3b is axial, not equatorial
as was reported earlier.11 It thus appears that the cyano
group occupies an axial position in the cis isomers 3.
As indicated previously, only the trans isomers of
compounds 1 are known. Since the cis compounds 3
demand an axial orientation of the linear cyano group,
the bulky substituent at C-1 apparently cannot be
accommodated in the axial position. The cis dicyano
ketone 3f, however, does not suffer from the same
restrictions. We have found that the trans isomer 1d is
readily converted to 3f by treatment with Triton B in
EtOH at room temperature. Mention is made of 3f in a
footnote in an earlier publication8 with no supporting
data. The trans phenyl ketone 2c was not isomerized to
the cis compound 3c by treatment with Triton B; 3c was
obtained by hydrolysis of the cis ketal 5f (vide infra).
Each of the cis isomers 3a -f exhibits a deceptively
simple AMX pattern (d of d, t, d of d) for the cyclohexane
ring protons,3,5,7 whereas the trans isomers 1a -d and
2a -e show complicated patterns for the related protons
(see also the Experimental Section). Since a meso isomer
posseses a σ through C-1/C-4, 13C NMR analysis easily
differentiates this compound from its trans precursor.
We investigated the reactions with base of the ethylene
ketals of several Michael ketones in order to determine
if the trans f cis conversion would occur without the
complication of a retrograde reaction that takes place
with the free ketone.12 The base system was a hetero-
geneous mixture of concd aqueous KOH in DMSO at
temperatures ranging from room temperature to 150 °C.
When the cis cyano ketal 5a was reacted at ∼150 °C
for 4 h, the amide 6a was isolated in 80% yield. The
reaction involved saponification of the ester, decarboxy-
lation, and partial hydrolysis of the nitrile. The 13C NMR
and other spectral data substantiate the structure and
stereochemistry of 6a ; X-ray analysis verifies the amide
group in an equatorial position. Hydrolysis of the ketal
group in 6a gave the keto amide 3g. Under the reaction
conditions used for 5a , the trans cyano ketal 4a gave the
same amide 6a , indicating an inversion of configuration
at C-2 (C-6) at some point in the sequence. When the
ketal 4a was treated with KOD/D2O in DMSO-d6 at ∼150
°C, the amide 6b was obtained in which the C-1, C-2,
and C-6 hydrogens were replaced by deuterium as shown
in the 13C NMR spectrum by the disappearance of the
C-1 signal (54.5) and very weak peaks due to C-2 and
C-6 (44.2). The 1H NMR spectrum also indicated the
absence of the corresponding hydrogen signals. To verify
the lack of acidity of the C-3 and C-5 methylene hydro-
gens under the basic conditions of the reaction, the
3,3,5,5-tetradeuterio derivative (7) of the cis ketal 3b was
prepared, converted to its ethylene ketal (7b), and treated
with KOH/H2O in DMSO at 150 °C. The spectral data
of the resulting amide (7c) indicated complete retention
of the C-3 and C-5 deuterium atoms.
The reaction of the trans ketal 4a with base was
conducted at lower temperatures in order to see if the
isomerization would occur under milder conditions. At
steam bath temperature for 18 min, 4a underwent
saponification and loss of CO2 to give the known7 trans
nitrile 4b with retention of configuration. At rt, the trans
cyano ester 4a underwent saponification in 1 h to give
the trans cyano acid 4c. The cis cyano ester 5a required
a higher temperature (∼90 °C) for saponification to the
cis cyano acid 5c, apparently due to steric hindrance of
the equatorial ester group imposed by the flanking
aromatic rings.
The results of the saponification reactions indicate that
the base abstracts a benzylic proton from C-2 (C-6) at
elevated temperatures from the mono cyano intermediate
to generate a carbanion that may be reprotonated to give
the more stable cis isomers.
The cis f trans isomerization was tested with other
ketals. The ketal (4d ) of the trans dicyano ketone 1d
was treated at 150 °C for 5 h to give the amide 6a
obtained previously. In like fashion, both the trans cyano
amido ketal (4e) and the isomeric cis compound 5e gave
the ketal amide 6a upon reaction with base at 150 °C.
In each of these cases, the saponification of the preexist-
ing amide group leads to the same cyano intermediate
formed from 4a , 5a , and 4d under the basic conditions.
A somewhat different result was obtained when the
trans phenyl ketal (4f) of the ketone 2c was saponified
at 150 °C. The product mixture was separated cleanly
by chromatography to give 1,2,3-triphenylbenzene (8a )
and the cis phenyl ketal (5f). The ketal 5f was identified
by its spectra and by hydrolysis to the known5,13 ketone
3c. The aromatic product 8a was identical to that
(7) Rowland, A. T.; Gill, B. C. J . Org. Chem. 1988, 53, 434.
(8) Ahmed, M. G.; Ahmed, S. A.; Rasul, G.; Bakar, M. H. J .
Bangladesh Chem. Soc. 1988, 1, 45.
(9) Kohler, E. P.; Helmkamp, R. W. J . Am. Chem. Soc. 1924, 46,
1018.
(10) Otto, H.-H. Monatsh. Chem. 1978, 109, 681.
(11) Otto, H.-H. Arch. Pharm. (Weinheim, Ger.) 1972, 305, 913.
(12) Rowland, A. T.; Hohneker, J . A.; McDaniel, K. F.; Moore, D. S.
J . Org. Chem. 1982, 47, 301.
(13) Helmkamp, R. W.; Tanghe, L. J .; Plati, J . T. J . Am. Chem. Soc.
1940, 62, 3215.

Stereochemistry of Diaryl-Substituted Cyclohexanones
J . Org. Chem., Vol. 63, No. 13, 1998 4361
produced by an Ullmann reaction;14 the spectra of 8a
were identical to those of the commercially available
material (Aldrich 27,677-4). The production of ketal 5f
further illustrates the acidity of the C-2(6) benzylic
hydrogens in type 4 compounds. No amide was detected
in this case, presumably due to hindrance by the C-1
phenyl group to saponification of the nitrile. When the
reaction of 4f was conducted with KOD/D2O in DMSO-
d6, the 4,5,6-trideuterated derivative (8b) of 8a was
obtained accompanied by the dideuterated cis phenyl
ketal 9. When the cis phenyl ketal 5f was heated with
base in DMSO at 150 °C, only starting material was
recovered. It thus appears that the trans compound 4f
but not the isomeric 5f has C-2 (6) hydrogens acidic
enough to initiate the aromatization reaction. This
observation is being investigated further.
change (cis f trans) was anticipated. Reaction of the
diester 13 with KOH/H2O in DMSO at 120 °C for 20 min
(or 150 °C for 7 h) gave the trans ketal monoacid 14 as
predicted. When the reaction was conducted in DMSO-
1
d6, 13C and H NMR analysis showed that only the C-1
hydrogen in 14 had been replaced by deuterium as was
anticipated by reaction of the intermediate carbanion of
the initially formed monoester with hydrogen (or deute-
rium). Protonation at C-1 followed by saponification of
the remaining ester then generates the salt of 14 with
no benzylic hydrogen abstraction.
The 4-deoxy relative (11) of the ketone 3b was studied.
Clemmensen reduction of 3b gave a mixture of the
unsaturated cyano ester (10) and <10% of the saturated
ester 11. Catalytic hydrogenation of 10 gave pure 11
that, after heating with KOH/H2O in DMSO at 146 °C
and chromatography of the crude product, gave the cis
amide 12a . When the saponification was conducted in
DMSO-d6 with KOD/D2O at 150 °C, the amide 12b was
obtained. The 13C NMR spectrum of 12b indicated the
absence of the C-1 signal (δ 55.1) and the dimunition of
the C-2(6) signal at δ 47.0, again reflecting the lesser
acidity of the benzylic hydrogens in cis isomers. Reaction
of ester 11 with base in DMSO at ∼100 °C gave the cyano
acid 12c, illustrating the stability of the carboxylate
anion in the cis cyano compounds relative to the trans
isomers (cf. 4a f 4b).
The results of this investigation illustrate the advan-
tage that may be taken of the acidity of benzylic hydro-
gens in the trans isomers to facilitate isomerization to
cis isomers. Work is in progress on relatives of 4f to
determine if the production of substituted benzenes of
type 8 from the appropriate ketals may be a general and
efficient synthesis.
Exp er im en ta l Section
Gen er a l Meth od s. Basic procedures have been noted
elsewhere.7,12 1H NMR and 13C NMR spectra were recorded
at 80.13 and 20.15 MHz, respectively, in the indicated solvents.
Signals in 13C NMR spectra were assigned from BB and DEPT
techniques. Coupling constants (J ) are given in Hz. Some IR
spectra were obtained on disposable polyethylene cards (PEC).16
The general procedure for reactions of ketals with base in
DMSO was as follows: To a magnetically stirred mixture of
the compound in DMSO heated to ca. 100 °C was added the
KOH/H2O solution. The temperature of the bath was then
raised to (2 °C of the indicated value for the specified time.
The cooled reaction mixture was diluted with H2O, and the
precipitate was collected, washed with H2O, and recrystallized.
The procedure for the preparation of the ethylene ketals has
been given elsewhere.7 The principal author has deposited
atomic coordinates for compounds 1d , 3e, 3f, and 6a with the
Cambridge Crystallographic Data Centre. The coordinates can
be obtained on request from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK. “Drops” in the following procedures were measured from
14.5-cm Pasteur pipets.
The behavior of the ketal diester 13 toward the basic
medium was examined. It had been shown previously12
that 13 undergoes decarbalkoxylation to give a mo-
noester.15 Unlike the other examples discussed above,
the product of saponification-decarboxylation before
acidification should be the monoanion of the ketal acid
14. The formation of the anion should inhibit the
abstraction of a benzylic hydrogen from C-2(6) to give a
doubly charged intermediate; therefore, no configuration
ter t-Bu tyl 1-Cya n o-2(e),6(a )-d ip h en yl-4-oxocycloh ex-
a n e-1-ca r boxyla te (2e). To a magnetically stirred suspen-
sion of 10.002 g (42.69 mmol) of dibenzalacetone in 150 mL of
MeOH was added 7.00 mL (48 mmol) of tert-butyl cyanoacetate
and 25 drops of a 25% NaOMe-MeOH solution. A heavy
precipitate formed within 2 min as the dibenzalacetone dis-
solved. After 10 min, the mixture was cooled, collected by
filtration, and washed with cold MeOH. The solid was warmed
(14) Ozasa, S.; Fujioka, Y.; Kikutake, J .; Ibuki, E. Chem. Pharm.
Bull. 1983, 31, 1572.
(15) The decarbalkoxylation of 13 was erroneously believed12 to
involve a rearrangement of cis to trans with respect to the phenyl
groups. We now know that the diester 13 is the trans isomer.2
(16) Wigman, L. S.; Hart, E. E.; Gombatz, C. J . Chem. Educ. 1996,
73, 677.

4362 J . Org. Chem., Vol. 63, No. 13, 1998
Rowland et al.
in 40 mL of acetone to dissolve unreacted dibenzalacetone,
cooled to 0 °C, and collected to give 11.094 g (69%) of 2e: mp
184-185 °C dec; IR (CHCl3) 2245, 1725 cm-1; 1H NMR (CDCl3)
δ 1.03 (s, 9 H), 2.61-3.35 (m, 4 H), 3.88-4.10 (m, 2 H), 7.29-
7.32 (m, 10 H); 13C NMR (CDCl3) δ 27.3, 41.8, 42.7, 43.0, 47.2,
56.1, 84.6, 119.0, 128.4, 128.7, 129.0, 136.9, 137.6, 165.3, 201.4.
Anal. Calcd for C24H25NO3: C, 76.77; H, 6.71; N, 3.73.
Found: C, 76.55; H, 6.57; N, 3.65.
through cotton to remove some gelatinous material, and
concentrated to give 1.198 g of 2(e),6(e)-d ip h en yl-4,4-(eth -
ylen ed ioxy)cycloh exa n e-1(e)-ca r boxa m id e (6a ) as white
plates: mp 234-237 °C; IR (PEC) 3480, 3360, 1670, 1605 cm-1
;
1H NMR (DMSO-d6) δ 1.77-1.90 (m, 4 H), 2.58-3.31 (m, 3
H), 3.90 (t, J = 2.4, 4 H), 6.08 (br s, 1 H), 6.59 (br s, 1 H), 7.23
(s, 10 H); 13C NMR (DMSO-d6) δ 41.9, 44.2, 54.5, 63.6, 63.9,
107.4, 126.0, 127.6, 127.9, 143.4, 173.6. Anal. Calcd for
ter t-Bu t yl 1(a )-Cya n o-2(e),6(e)-d ip h en yl-4-oxocyclo-
h exa n e-1(e)-ca r boxyla te (3e). To a magnetically stirred
suspension of 1.112 g (2.962 mmol) of the trans tert-butyl ester
2e in 225 mL of 95% EtOH at room temperature was added
15 drops of freshly prepared 10% NaOH (aq) solution. An
additional five drops of the base were added after 25 min, and
the mixture was stirred for a further 75 min. The colorless
solution was diluted with 225 mL of water and the product
gradually coagulated upon cooling. The powder was collected,
washed with water, and taken up in CHCl3. The dried solution
was concentrated and diluted with MeOH to give 795 mg of
3e: mp 221-223 °C dec; IR (CHCl3) 2245, 1730 cm-1; 1H NMR
(CDCl3) δ 0.93 (s, 9 H), 2.70 (d of d, J ) 14.4, 3.2, 2 H), 3.26 (t,
J ) 14.4, 2 H), 3.68 (d of d, J ) 14.4, 3.2, 2 H), 7.36 (m, 10 H);
13C NMR (CDCl3) δ 27.2, 44.0, 49.5, 59.1, 84.3, 116.6, 128.4,
128.6, 128.7, 136.6, 165.2, 203.7. Anal. Calcd for C24H25NO3:
C, 76.77; H, 6.71; N, 3.73. Found: C, 76.27, 76.48; H, 6.73,
6.85; N, 3.70. An additional 158 mg of 3e was obtained by
concentrating the mother liquor: mp 221-223 °C dec; total
yield, 86%.
C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.96; H,
6.88; N, 4.20.
Concentration of the mother liquor gave two additional crops
of 6a : 377 mg (mp 234.5-237 °C) and 224 mg (mp 233-236.5
°C): total yield, 80%.
2(e ),6(e )-D ip h e n y l-4-o x o c y c lo h e x a n e -1(e )-c a r b o x -
a m id e (3g). A mixture of 1.039 g (3.08 mmol) of the cis amide
6a , 4 mL of H2O, and 14 drops of concd HCl in 25 mL of
acetone was heated under reflux for 1 h. The warm mixture
was diluted with 21 mL of H2O and cooled, and the precipitate
was collected and washed with 1:1 acetone-H2O to give 781
mg (86%) of 3g as glistening colorless plates: mp 308-313 °C
dec, with slight softening at ∼304 °C; IR (PEC) 3455, 3130,
1
1693, 1665 cm-1; H NMR (DMSO-d6) δ 2.25-2.40 (m, 2 H),
2.76-3.20 (m, 5 H), 6.27 (br s, 1 H), 6.84 (br s, 1 H), 7.31 (br
s, 10 H); 13C NMR (DMSO-d6) δ 46.3, 47.8, 54.0, 126.3, 127.4,
128.0, 142.3, 172.7, 207.4. Anal. Calcd for C19H19NO2: C,
77.79; H, 6.53; N, 4.78. Found: C, 77.79; H, 6.50; N, 4.93.
Rea ction of th e Tr a n s Meth yl Ester 4a w ith Ba se. A
mixture of 2.485 g (6.58 mmol) of 4a ,7 26 mL of DMSO, and
2.6 g (39 mmol) of KOH in 2 mL of H2O was heated at 148 °C
for 4 h. Recrystallization of the crude product from acetone
gave 1.178 g of the amide 6a , mp 234.5-237 °C. Concentration
of the mother liquor gave two additional crops of 6a : 401 mg
(mp 230-236 °C) and 146 mg (mp 233-237 °C); total yield,
78%. Spectra of this product were identical in all respects to
the amide obtained from the cis methyl ester 5a .
Isom er iza tion of 1d to 2(e),6(e)-Dip h en yl-4-oxocyclo-
h exa n e-1,1-d ica r bon itr ile (3f). To a magnetically stirred
solution of 1.548 g (5.15 mmol) of the trans dicyano ketone
1d 7 in 460 mL of 100% EtOH at room temperature was added
12 drops of Triton B. After 1.1 h, 24 drops of glacial HOAc
were added to the pinkish colored solution. The mixture was
allowed to evaporate to dryness overnight, and the residue was
chromatographed on 25 g of neutral alumina. Elution with
60 mL of acetone gave a colorless fraction, which was concen-
trated to ∼8 mL and diluted with petroleum ether to give 1.322
g (85%) of 3f, mp 210-211 °C. Recrystallization from acetone-
ethyl ether gave the following data: mp 211.5-212.5 °C; IR
Rea ction of th e Tr a n s Meth yl Ester 4a in DMSO-d 6.
A mixture of 1.018 g (2.697 mmol) of 4a , 10 g of DMSO-d6,
and 1.5 mL of a 40% KOD/D2O solution was heated at 150 °C
for 4.2 h. The slightly cooled mixture was diluted with 30 mL
of D2O, and the resulting precipitate was isolated in the usual
manner. Recrystallization from acetone gave 399 mg of
1(a ),2(a ),6(a )-Tr id eu t er io-2(e),6(e)-d ip h en yl-4,4-(et h yl-
en ed ioxy)cycloh exa n e-1(e)-ca r boxa m id e (6b): mp 234.5-
1
(CHCl3) 1715 cm-1; H NMR (CDCl3) δ 2.77 (d, br legs, J )
14.4, ∼2, 2 H), 3.26 (t, J ) 14.4, 2 H), 3.62 (d of d, J ) 14.4,
13
2.4, 2 H), 7.44 (s, 10 H); C NMR (CDCl3) δ 43.0,47.9, 50.2,
1
112.4, 113.5, 128.3, 129.3, 129.7, 135.2, 202.6. Anal. Calcd
for C20H16N2O: C, 79.98; H, 5.37; N, 9.33. Found: C, 79.76,
79.50; H, 5.60, 5.49; N, 9.47.
238 °C; H NMR (DMSO-d6) δ 1.82 (m, 4 H), 3.89 (t, J ) 3.2,
4 H), 6.07 (br s, 0.5 H), 6.57 (br s, 0.5 H), 7.23 (s, 10 H); 13C
NMR (DMSO-d6) δ 41.9, 63.7, 64.0, 107.6, 126.1, 127.7, 128.0,
143.5, 173.6. Two more crops of 6b were isolated from the
mother liquor: 176 mg (mp 232.5-235.5 °C) and 81 mg (mp
233.5-235.5 °C); total yield, 71%.
Attem p ted Isom er iza tion of th e Tr a n s Tr ip h en yl Ke-
ton e 2c. To a magnetically stirred solution of 1.009 g (2.87
mmol) of 2c13 in 300 mL of 100% EtOH at ∼55 °C was added
12 drops of Triton B. After 13 h, the solution was acidified
with 24 drops of glacial HOAc, and the solvent was evaporated
with air and low heat. The residue was recrystallized from
acetone-MeOH to give 720 mg of starting material (2c): mp
Met h yl
1(a )-Cya n o-2(e),6(e)-d ip h en yl-3,3,5,5-t et r a -
d eu ter io-4-oxocycloh exa n e-1(e)-ca r boxyla te (7a ). To a
magnetically stirred solution of 4.750 g (14.25 mmol) of the
cis methyl ester 3b9 in 70 mL of MeOD was added 7 drops of
a 25% NaOMe-MeOH solution. After 30 min at room tem-
perature, the solution was distributed between ether and
water. The layers were separated, and the aqueous phase was
extracted twice with ether. The combined ether extracts were
washed three times with water, dried, concentrated, and
diluted with petroleum ether to yield 4.536 g (94%) of 7a : mp
1
190-191.5 °C; H NMR identical to the starting material.
Meth yl 1(a )-Cya n o-2(e)6(e)-d ip h en yl-4,4-(eth ylen ed i-
oxy)cycloh exa n e-1(e)-ca r boxyla te (5a ). A mixture of 19.7
g (59.1 mmol) of the cis oxo ester 3b,9 15 mL (270 mmol) of
ethylene glycol, and 0.82 g of TSA in 300 mL of benzene was
boiled for 4 h. The dried solution was concentrated to 50 mL
and then diluted with 80 mL of ethyl ether. The ketal 5a (16.8
g) gradually separated as large chunks of colorless crystals:
1
147-148 °C; H NMR (CDCl3) δ 3.22 (s, 3 H), 3.73 (s, 2 H),
7.33 (s, 10 H); 13C NMR (CDCl3) δ 49.1, 52.8, 59.4, 115.8, 127.8,
128.6, 128.7, 136.4, 166.9, 204.4.
1
mp 156-158 °C; IR (CHCl3) 2245, 1740, 1250 cm-1; H NMR
(CDCl3) δ 1.99 (br d of d, J ) 13.6, 3.2, 2 H), 2.53 (t, J ) 13.6,
2 H), 3.25 (s, 3 H), 3.72 (d of d, J ) 13.6, 3.2, 2 H), 3.99 (s, 4
H), 7.32 (s, 10 H); 13C NMR (CDCl3) δ 37.4, 47.5, 52.6, 60.0,
64.7, 107.2, 116.1, 128.1, 128.2, 128.5, 137.9, 167.8. Anal.
Calcd for C23H23NO4: C, 73.19; H, 6.14; N, 3.71. Found: C,
73.56, 73.38; H, 6.38, 6.22; N, 3.65.
Concentration of the mother liquor and additon of petroleum
ether gave an additional 4.2 g of 5a : mp 156-157 °C; total
yield, 94%.
Met h yl 1(a )-Cya n o-3,3,5,5-t et r a d eu t er io-2(e),6(e)-d i-
p h en yl-4,4-(et h ylen ed ioxy)cycloh exa n e-1(e)-ca r b oxy-
la te (7b). A mixture of 2.00 mL (36 mmol) of ethylene glycol,
197 mg of TSA, 16 mL of D2O, and 80 mL of benzene was boiled
until (2 h) 16 mL of an aqueous phase was collected in the
sidearm.7 To the benzene phase was added 2.001 g (5.93
mmol) of the tetradeuterio ketone 7a and 20 mL additional
benzene. The mixture was boiled for 3 h and then worked up
in the usual manner.7 Crystallization from ethyl ether gave
2.091 g (92%) of 7b: mp 156.5-158 °C; 1H NMR (DMSO-d6) δ
3.35 (s, 3 H), 3.64 (s, 2H), 3.96 (s, 4 H), 7.30 (s, 10 H); 13C
NMR (DMSO-d6) δ 46.6, 52.6, 60.0, 64.3, 106.2, 115.7, 127.7,
128.1, 128.5, 137.8, 167.3.
Rea ction of th e Cis Meth yl Ester 5a w ith Ba se.
A
mixture of 2.520 g (6.68 mmol) of 5a , 26 mL of DMSO, and
2.6 g (39 mmol) of KOH in 2 mL of H2O was heated at 148 °C
for 4 h. The product was dissolved in hot acetone, filtered

Stereochemistry of Diaryl-Substituted Cyclohexanones
J . Org. Chem., Vol. 63, No. 13, 1998 4363
Rea ction of th e Tetr a d eu ter io Keta l 7b w ith Ba se. A
mixture of 397 mg (1.04 mmol) of 7b, 5 mL of DMSO, and 0.30
g (4.6 mmol) of KOH in 0.5 mL of H2O was heated at 149 °C
for 4 h. Recrystallization of the crude product from CH2Cl2-
petroleum ether gave 239 mg (67%) of 2(e),6(e)-d ip h en yl-
3,3,5,5-t et r a d eu t er io-4,4-(et h ylen ed ioxy)cycloh exa n e-
1(e)-ca r boxa m id e (7c): mp 231.5-234 °C; 1H NMR (DMSO-
d6) δ 2.72-3.20 (m, 3 H), 3.90 (t, J ) 2.4, 4 H), 6.08 (s, 1 H),
6.59 (s, 1 H), 7.23 (m, 10 H); 13C NMR (DMSO-d6) δ 44.2, 54.6,
63.7, 64.0, 107.5, 126.1, 127.7, 128.0, 143.5, 173.7.
2(e),6(a )-Dip h en yl-4,4-(eth ylen ed ioxy)cycloh exa n e-1-
ca r bon itr ile (4b). A mixture of 1.011 g (2.68 mmol) of the
trans cyano ketal 4a , 10 mL of DMSO, and 0.91 g (14 mmol)
of KOH in 1 mL of H2O was magnetically stirred on a steam
bath for 18 min. Dilution with water and filtration gave a
white solid that was recrystallized from acetone-MeOH to give
546 mg of 4b: mp 147.5-149.5 °C (lit.7 mp 146-148 °C). The
1H NMR spectrum was identical to that reported for 4b.7 An
additional 83 mg of 4b, mp 146-147 °C, was recovered from
the mother liquor. Total yield, 73%.
237 °C) and 146 mg (mp 235-237 °C); total yield, 59%.
Spectra of this product were identical to those of the amide
6a obtained from the cis methyl ester 5a .
1(a )-Cya n o-2(e ),6(e )-d ip h e n yl-4,4-(e t h yle n e d ioxy)-
cycloh exa n e-1(e)-ca r boxa m id e (5e). A mixture of 3.012 g
(9.46 mmol) of the cis cyano amide 3d ,10 4.0 mL (72 mmol) of
ethylene glycol, and 0.20 g of TSA in 70 mL of benzene was
boiled for 5.2 h. The neutralized reaction mixture was allowed
to evaporate from the aqueous wash. The resulting solid was
collected, washed well with water, and recrystallized twice
from acetone-MeOH to give 1.900 g (55%) of 5e: mp 256-
258 °C; IR (PEC) 3460, 3370, 3260, 3210, 2220, 1695, 1600,
1
1155; H NMR (DMSO-d6) δ 1.91 (d of d, br, J ) 13.6, ∼3, 2
H), 2.34 (t, J ) 13.6, 2 H), 3.66 (br d of d, J = 13, 3, 2 H), 3.96
(s, 4 H), 7.03-7.31 (m, 12 H); 13C NMR (DMSO-d6) δ 37.7, 45.9,
59.7, 64.0, 106.4, 117.5, 127.5, 128.1, 138.5, 166.6. Anal. Calcd
for C22H22N2O3: C, 72.91; H, 6.12; N, 7.73. Found: C, 72.90;
H, 5.94; N, 7.60.
1-Cya n o-2(e),6(a )-d ip h en yl-4,4-(et h ylen ed ioxy)cyclo-
h exa n e-1-ca r boxa m id e (4e). A mixture of 4.532 g (14.2
mmol) of the trans cyano amide 2d ,10 6 mL (110 mmol) of
ethylene glycol, and 0.30 g of TSA in 110 mL of benzene was
boiled for 5.7 h. The neutralized reaction mixture was allowed
to evaporate from the aqueous wash. The suspended solid was
collected, washed with water, and recrystallized from acetone-
MeOH. The crude product (4.16 g, mp 204-213 °C) was boiled
in acetone, filtered to remove some insoluble material, con-
centrated, and diluted with MeOH. The ketal 4e (2.452 g,
48%) separated upon cooling: mp 214-216 °C; IR (PEC) 3450,
1-Cya n o-2(e),6(a )-d ip h en yl-4,4-(et h ylen ed ioxy)cyclo-
h exa n e-1-ca r boxylic Acid (4c). A mixture of 1.113 g (2.95
mmol) of the trans methyl ester 4a in 10 mL of DMSO and
0.75 g (11 mmol) of KOH in 1 mL of H2O was stirrred
magnetically at room temperature for 65 min. The mixture
was diluted with 30 mL of water and extracted twice with
ether. To the basic aqueous phase was added 3 mL of 6 M
HCl and ether. The mixture was shaken and separated, and
the aqueous layer was extracted again with ether. The
combined organic phases were dried, filtered, and evaporated.
The resulting oil was crystallized from CH2Cl2-petroleum
ether to give 959 mg (89%) of the acid 4c: mp 194.5-196 °C
3320, 2230, 1695, 1600, 1110 cm-1 1H NMR (DMSO-d6) δ
;
1.72-2.10 (m, 2 H), 2.33-3.00 (m, 2 H), 3.39-4.08 (m, 6 H),
6.64 (s, 1 H), 7.18-7.30 (m, 11 H); 13C NMR (DMSO-d6) δ 35.4,
36.2, 41.6, 46.2, 56.4, 63.7, 63.8, 108.9, 120.3, 127.5, 128.3,
128.7, 138.3, 139.4, 167.0. Anal. Calcd for C22H22N2O3: C,
72.91; H, 6.12; N, 7.73. Found: C, 72.87; H, 5.93; N, 7.62.
Rea ction of th e Tr a n s Cya n o Am id e 4e w ith Ba se. A
mixture of 1.038 g (2.86 mmol) of 4e, 10 mL of DMSO, and
0.97 g (15 mmol) of KOH in 1 mL of H2O was heated at 150
°C for 4.5 h. The crude product was recrystallized from
acetone to give 413 mg of the amide 6a , mp 236-238 °C. Two
additional crops were obtained by concentration of the mother
liquor: 187 mg (mp 235-237 °C) and 128 mg (mp 233-235
°C); total yield, 75%. Spectra were identical to those of the
amide 6a produced from the cis methyl ester 5a .
1
dec; IR (PEC) 3300-2600, 1740 cm-1; H NMR (DMSO-d6) δ
1.89-2.07 (m, 2 H), 2.33-2.90 (m, 2 H), 3.47-4.02 (m, 6 H),
7.29-7.32 (m, 11 H); 13C NMR (DMSO-d6) δ 35.0, 35.9, 42.4,
45.7, 57.3, 63.7, 108.7, 119.2, 127.6, 128.0, 128.2, 128.3, 128.4,
137.9, 138.9, 168.3. Anal. Calcd for C22H21NO4: C, 72.71; H,
5.83; N, 3.86. Found: C, 72.57; H, 5.65; N, 3.71.
1(a )-Cya n o-2(e ),6(e )-d ip h e n yl-4,4-(e t h yle n e d ioxy)-
cycloh exa n e-1(e)-ca r boxylic Acid (5c). To a magnetically
stirred solution of 15.045 g (39.86 mmol) of the cis methyl ester
5a in 134 mL of DMSO at 93 °C was added a solution of 9.95
g (150 mmol) of KOH in 13.3 mL of H2O. The mixture was
stirred at 88 °C for 50 min and then poured into water and
filtered to remove a small amount of solid. The cooled filtrate
was acidified with 40 mL of 6 M HCl, and the resulting solid
was collected, washed with water, and recrystallized from
acetone to give 12.891 g (89%) of 5c: mp 235-239 °C dec; IR
Rea ction of th e Cis Cya n o Am id e 5e w ith Ba se.
A
mixture of 1.002 g (2.76 mmol) of 5e, 10 mL of DMSO, and
0.91 g (14 mmol) of KOH in 1 mL of H2O was heated at 150
°C for 5 h. The crude solid was recrystallized from acetone to
give 399 mg of the amide 6a , mp 236-238 °C. Two additional
crops were obtained by concentration of the mother liquor: 298
mg (mp 235.5-238 °C) and 46 mg (mp 230-233.5 °C); total
yield, 80%. Spectra of this product were identical to those of
6a obtained from the cis methyl ester 5a .
1,2(e),6(a )-Tr ip h en yl-4,4-(eth ylen ed ioxy)cycloh exa n e-
1-ca r bon itr ile (4f). A mixture of 15.00 g (42.7 mmol) of the
trans triphenyl ketone 2c,13 24 mL (430 mmol) of ethylene
glycol, and 1.22 g of TSA in 380 mL of benzene was boiled for
17 h. The oil obtained by evaporation of the benzene was
crystallized twice from acetone-MeOH to give 13.12 g of 4f:
mp 136-137 °C; IR (CHCl3) 2245, 1120 cm-1; 1H NMR (DMSO-
d6) δ 2.07-2.29 (m, 2 H), 2.50-2.89(m, 2 H), 3.69-4.05 (m, 6
H), 6.99 (s, 5 H), 7.08-7.10 (s, 10 H); 13C NMR (CDCl3) δ 36.4,
38.7, 43.7, 50.0, 54.9, 64.2, 64.4, 109.2, 122.3, 126.8, 127.2,
127.5, 127.7, 127.8, 128.0, 128.5, 129.1, 135.5, 138.6, 139.5.
Anal. Calcd for C27H25NO2: C, 82.00; H, 6.37; N, 3.54.
Found: C, 81.83; H, 6.66; N, 3.52.
1715 cm-1 1H NMR (DMSO-d6) δ 1.94 (d of d, br legs, J )
;
12.8, 2.9, 2 H), 2.34 (t, J ) 12.8, 2 H), 3.60 (d of d, J ) 12.8,
3.2, 2 H), 3.95 (s, 4 H), 7.32 (s, 10 H); 13C NMR (DMSO-d6)
37.2, 46.5, 59.7, 64.2, 106.4, 116.6, 127.9, 128.1, 128.4, 138.2,
168.1. Anal. Calcd for C22H21NO4: C, 72.71; H, 5.83; N, 3.86.
Found: C, 72.69; H, 5.66; N, 3.82.
2(e),6(a )-Diph en yl-4,4-(eth ylen edioxy)cycloh exa n e-1,1-
d ica r bon itr ile (4d ). A mixture of 1.011 g (3.37 mmol) of the
dicyano ketone 1d , 1.0 mL (18 mmol) of ethylene glycol, and
47 mg of TSA in 20 mL of benzene was boiled for 3 h. The
residue obtained by evaporation of the dried solution was
crystallized from acetone-MeOH to give 828 mg of 4d as white
1
needles: mp 146-147.5 °C; IR (CHCl3) 2245, 1135 cm-1; H
NMR (CDCl3) δ 2.11-2.68 (m, 4 H), 3.65-3.83 (d of d, 2 H),
3.93 (m, 4 H), 7.32-7.56 (m, 10 H); 13C NMR (CDCl3) δ 36.0,
45.8, 64.5, 107.4, 114.6, 128.8, 128.9, 136.9. Anal. Calcd for
C
22H20N2O2: C, 76.72; H, 5.85; N, 8.14. Found: C, 76.94; H,
5.90; N, 7.93.
Concentration of the mother liquor, followed by the addition
of MeOH, gave an additional 188 mg of 4d : mp 145-146 °C;
total yield, 87%.
The residues obtained from the mother liquors were recrys-
tallized from acetone-MeOH to give 1.88 g of 4f: mp 135-
137 °C; total yield, 89%.
Rea ction of th e Tr a n s Dicya n o Keta l 4d w ith Ba se. A
mixture of 1.039 g (3.02 mmol) of 4d , 10 mL DMSO, and 0.95
g (14 mmol) of KOH in 1 mL of H2O was heated at 150 °C for
5 h. Recrystallization of the crude product gave 182 mg of
the amide 6a as plates with mp 237-238 °C. Concentration
of the mother liquor gave two more crops: 276 mg (mp 234-
Rea ction of th e Tr a n s Tr ip h en yl Cya n o Keta l 4f w ith
Ba se. A mixture of 3.118 g (7.88 mmol) of 4f, 30 mL of DMSO,
and 2.98 g (45 mmol) of KOH in 3 mL of H2O was heated at
150 °C for 9.5 h. The crude product was chromatographed on
55 g of neutral alumina. Elution with cyclohexane gave 1.119
g of an oil, which crystallized from CH2Cl2-MeOH to give

4364 J . Org. Chem., Vol. 63, No. 13, 1998
Rowland et al.
1.038 g of 1,2,3-tr ip h en ylben zen e (8a ): mp 160-161 °C
(lit.14 mp 158.4 °C); MS (EI/eV) m/z 306.1; 1H NMR (CDCl3) δ
6.89 (m, 5 H), 6.98 (m, 10 H), 7.41 (s, 3 H); 13C NMR (CDCl3)
δ 125.8, 126.1, 127.1, 127.2, 127.5, 129.5, 129.9, 131.6, 139.2,
139.6, 142.0. The IR, 1H NMR, and 13C NMR spectra were
identical to those of commercially available 8a . The mother
liquor deposited an additional 33 mg of 8a : mp 158-159.5
°C: total yield, 44%.
the following data: mp 153.5-155 °C; IR (CHCl3) 2245, 1740,
1655 cm-1; 1H NMR (CDCl3) δ 2.03-3.24 (m, >2 H), 3.25 (s, 3
H), 3.55 (d of d, J = 12, 4, 1 H), 4.36 (m, 1 H), 5.78 (d of d, J
= 10.4, 1.6, 1 H), 6.0 (m, 1 H), 7.30 (m, 10 H); 13C NMR (CDCl3)
δ 29.9, 47.5, 49.8, 52.6, 57.7, 116.2, 127.1, 127.9, 128.2, 128.3,
128.5, 128.6, 128.8, 138.3, 138.4, 168.2. Anal. Calcd for
C
21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found: C, 79.43; H,
6.15; N, 4.35. The 13C NMR spectrum displayed trace absorp-
tions corresponding to the saturated cyano ester 11. These
are not listed above.
Elution of the column with 50% CH2Cl2-cyclohexane gave
1.366 g of a solid that was recrystallized from CH2Cl2-MeOH
to give 856 mg of 1(e),2(e),6(e)-tr ip h en yl-4,4-(eth ylen e-
d ioxy)cycloh exa n e-1(a )-ca r bon itr ile (5f): mp 143-144 °C;
Meth yl 1(a )-Cya n o-2(e),6(e)-d ip h en ylcycloh exa n e-1(e)-
ca r boxyla te (11). A solution of 0.82 g (2.6 mmol) of the
unsaturated ester 10 in 60 mL of ethyl acetate was hydroge-
nated in the presence of Pd-C at room temperature for 30
min. After purging, the mixture was filtered and evaporated
to dryness. The residue was recrystallized from MeOH to give
0.69 g (83%) of 11 as white plates, mp 141-143 °C. Recrys-
tallization from acetone-MeOH gave the following data: mp
1
IR (CHCl3) 2245, 1140 cm-1; H NMR (CDCl3) δ 2.09 (d of d,
br legs, J ) 12.8, ∼3, 2 H), 2.73 (t, J ) 12.8, 2 H), 3.71 (d of d,
J ) 12.8, 3.2, 2 H), 4.02 (s, 4 H), 7.05 (s, 15 H); 13C NMR
(CDCl3) δ 39.3, 50.3, 57.1, 64.7, 107.6, 119.2, 127.1, 127.4,
127.6, 128.1, 128.7, 136.3, 138.7. Anal. Calcd for C27H25NO2:
C, 82.00; H, 6.37; N, 3.54. Found: C, 81.72; H, 6.39; N, 3.46.
An additional 272 mg of 5f was obtained from the mother
liquor: mp 147-148 °C; total yield, 36%. Recrystallization
from CH2Cl2-MeOH gave mp 152.5-153.5 °C.
1
145-146.5 °C; IR (CHCl3) 2240, 1735 cm-1; H NMR (CDCl3)
δ 1.6-2.55 (m, 6 H), 3.20 (s, 3 H), 3.34 (d of d, J ) 12.8 and
3.2, 2 H), 7.30 (m, 10 H); 13C NMR (CDCl3) δ 25.8, 28.4, 50.6,
52.3, 60.4, 116.8, 127.9, 128.2, 128.4, 139.4, 168.1. Anal. Calcd
for C21H21NO2: C, 78.97; H, 6.63; N, 4.39. Found: C, 78.85;
H, 6.52; N, 4.30.
Treatment of this ketal (5f) with KOH-H2O in DMSO at
1
147 °C for 6 h gave only starting material (mp and H NMR).
Hyd r olysis of th e Tr ip h en yl Cis Keta l 5f. A solution of
359 mg (0.908 mmol) of 5f in 8 mL of acetone containing 1
mL of H2O and 10 drops of 6 M HCl was heated under reflux
for 10 h. (An additional six drops of the acid were added after
7.5 h.) The solution was diluted with water, and the precipi-
tate was collected, washed with water, dried, and recrystallized
from CH2Cl2-cyclohexane to give 118 mg of 1(e),2(e),6(e)-
tr ip h en yl-4-oxocycloh exa n e-1(a )-ca r bon itr ile (3c): mp
Rea ction of th e Cis Meth yl Ester 11 w ith Ba se.
A
mixture of 815 mg (2.55 mmol) of 11, 8 mL of DMSO, and 0.85
g (13 mmol) of KOH in 1 mL of H2O was heated at 146 °C for
5.5 h. The crude product (657 mg) was chromatographed on
15 g of neutral alumina. Elution with 50% CH2Cl2-cyclohex-
ane through 100% CH2Cl2 gave 602 mg of homogeneous
fractions (1H NMR) that were combined and crystallized from
CH2Cl2-cyclohexane to give 367 mg of 2(e),6(e)-d ip h en yl-
cycloh exa n e-1(e)-ca r boxa m id e (12a ) as plates: mp 235-
213.5-215 °C (lit.13 mp 213 °C); IR (CHCl3) 2235, 1720 cm-1
;
1H NMR (CDCl3) δ 2.80 (d with br legs, J ) 12.8, 2 H), 3.49 (t,
J ) 12.8, 2 H), ∼3.75 overlaps 3.49 signal (m, 2 H), 7.09 (“s”,
15 H). These NMR data are in agreement with those reported
for 3c.5
236 °C; IR (PEC) 3520, 3400, 1680, 1585 cm-1 1H NMR
;
(CDCl3) δ 1.66-2.03 (m, 6 H), 2.39 (t, J ) 10.4, 1 H), 2.85-
3.15 (m, 2 H), 4.47 (br s, 2 H), 7.23 (s, 10 H); 13C NMR (DMSO-
d6) δ 26.3, 34.4, 47.0, 55.1, 125.9, 127.7, 127.9, 144.9, 174.0.
Two additional crops of 3c were obtained by concentration
of the mother liquor: 56 mg (mp 212.5-215 °C) and 39 mg
(209.5-213 °C); total yield, 67%.
Anal. Calcd for
C19H21NO: C, 81.68; H, 7.58; N, 5.01.
Found: C, 81.44, 81.36; H, 7.19, 7.26; N, 4.84, 4.87.
Two additional crops of 12a were obtained from the mother
liquor: 128 mg (mp 235-236 °C) and 51 mg (mp 231-234 °C);
total yield, 77%.
Rea ction of th e Tr a n s Tr ip h en yl Cya n o Keta l 4f w ith
DMSO-d 6. A mixture of 1.503 g (3.80 mmol) of 4f, 15 g of
DMSO-d6, and 2 mL of a 40% KOD-D2O solution was heated
at 150 °C for 8.5 h. The red-brown colored mixture was diluted
with 30 mL of D2O, cooled overnight, and filtered. The dried
solid was chromatographed on 21.5 g of neutral alumina.
Elution with cyclohexane gave 550 mg of a solid that was
recrystallized from CH2Cl2-95% EtOH to yield 486 mg (41%)
of 4,5,6-tr ideu ter io-1,2,3-tr iph en ylben zen e (8b): mp 159.5-
160 °C; 1H NMR (CDCl3) δ 6.87-6.90 (m, 5 H), 7.08 (s, 10 H);
13C NMR (CDCl3) δ 125.8, 126.2, 127.2, 127.5, 129.9, 131.7,
139.2 (weak), 139.6, 142.0.
Elution with 50% CH2Cl2-cyclohexane gave 365 mg of a
foam that crystallized from CH2Cl2-MeOH to give 259 mg
(17%) of 2(a ),6(a )-d id eu ter io-1(e),2(e),6(e)-tr ip h en yl-4,4-
(et h ylen ed ioxy)cycloh exa n e-1(a )-ca r b on it r ile (9): mp
154.5-155 °C; 1H NMR (CDCl3) δ 2.08 (d, J ) 12.8, 2 H), 2.72
(d, J ) 12.8, 2 H), 4.00 (s, 4 H), 7.05 (s, 15 H); 13C NMR (CDCl3)
δ 39.2, 49.9 (v weak t), 57.0, 64.7, 107.8, 119.3, 127.2, 127.5,
127.7, 128.2, 128.7, 136.4, 138.9.
Clem m en sen Red u ction of th e Keton e 3b. A mixture
of ZnHg [prepared17 from 11.00 g (40.5 mmol) of HgCl2 and
50.0 g (0.76 mol) of Zn dust], 15.01 g (45.0 mmol) of the cis
cyano ketone 3b, and 50 mL of concd HCl in 250 mL of 95%
EtOH was heated under reflux for 5 h. (After 1.8 h, an
additional 40 mL of the acid was added.) The warm mixture
was filtered, the ZnHg rinsed with 95% EtOH, and the
colorless solution was concentrated to 350 mL. Upon standing
overnight at room temperature, 11.73 g (82%) of m eth yl 1(a )-
cya n o-2(e ),6(e )-d ip h e n yl-3-cycloh e xe n e -1(e )-ca r b oxy-
la te (10) precipitated as needles with mp 151.5-153 °C, soften
at 150 °C. Recrystallization of a sample from 95% EtOH gave
Rea ction of th e Cis Meth yl Ester 11 in DMSO-d 6.
A
mixture of 710 mg (2.22 mmol) of 11, 7 mL of DMSO-d6, and
1 mL of a 40% KOD-D2O solution was heated at 152 °C for
5.5 h. The warm solution was diluted with 30 mL of D2O, and
the precipitate was collected and washed with water. The
dried solid was chromatographed on 15 g of neutral alumina.
Elution with 60% CH2Cl2-cyclohexane and 100% acetonitrile
gave 511 mg of a solid that was recrystallized from CH2Cl2-
cyclohexane to yield 404 mg of 2(e),6(e)-d ip h en yl-1(a ),
2(a ),6(a )-t r id e u t e r io c y c lo h e x a n e -1(e )-c a r b o x a m id e
(12b): mp 235.5-236.5 °C; 1H NMR (CDCl3) δ 1.59-2.03 (m,
6 H), ∼3.0 (trace of signal), 4.45 (br s, 2H), 7.23 (s, 10 H); 13
C
NMR (DMSO-d6) δ 26.3, 34.3, 47.0 (weak), 125.9, 127.7, 128.0,
144.9, 174.1. An additional 59 mg of 12b was recovered from
the mother liquor: 59 mg (mp 232-235.5 °C); total yield, 74%.
1(a )-Cya n o-2(e),6(e)-cycloh exa n e-1(e)-ca r boxylic Acid
(12c). A mixture of 819 mg (2.56 mmol) of the cis ester 11, 8
mL of DMSO, and 0.82 g (12 mmol) of KOH in 1 mL of H2O
was heated at 102 °C for 1.3 h. The warm mixture was diluted
with 35 mL of water and then acidified with 5 mL of 6 M HCl.
The resulting precipitate was collected, washed with water,
and recrystallized from acetone-cyclohexane to give 420 mg
of 12c, mp 251-260 °C dec. The mother liquor deposited an
additional 187 mg of 12c, mp 245-250 °C dec, total yield, 78%.
Recrystallization from 100% EtOH gave the following data:
1
mp 250-253 °C dec; IR (PEC) 1710 cm-1; H NMR (DMSO-
d6) δ 1.78-2.21 (m, 6 H), 3.29-3.39 (m, 2 H), 7.31 (s, 10 H);
13C NMR (DMSO-d6) δ 25.2, 28.6, 49.2, 60.0, 117.5, 127.6,
128.2, 128.3, 140.0, 168.3. Anal. Calcd for C20H19NO2: C,
78.66; H, 6.27; N, 4.59. Found: C, 78.66; H, 6.21; N, 4.73.
Rea ction of Dim eth yl 2(e),6(a )-Dip h en yl-4,4-(eth yl-
en ed ioxy)cycloh exa n e-1,1-d ica r boxyla te (13) w ith Ba se.
A mixture of 1.102 g (2.69 mmol) of 13,12 10 mL of DMSO,
(17) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; J ohn
Wiley: New York, 1967; pp 1287-1288.

Stereochemistry of Diaryl-Substituted Cyclohexanones
J . Org. Chem., Vol. 63, No. 13, 1998 4365
and 0.75 g (11 mmol) of KOH in 1 mL of water was heated at
120 °C for 20 min. The mixture was diluted with water, cooled
to 0 °C, poured into a separatory funnel with 3 mL of 6 M
HCl and ice, and extracted three times with ether. The
combined ether phases were washed three times with water,
dried, and evaporated to give 876 mg of white solid. Recrys-
tallization from ethyl ether-petroleum ether gave 819 mg
(90%) of 2(e),6(a )-d ip h en yl-4,4-(eth ylen ed ioxy)cycloh ex-
a n e-1-ca r b oxylic a cid (14a ): mp 164.5-166 °C (lit.12 mp
a cid (14b): mp 165-166 °C; 13C NMR (CDCl3) δ 36.1, 39.1,
39.8, 40.0, 64.0, 64.2, 109.3, 126.5, 126.7, 127.3, 128.1, 128.3,
128.5, 141.5, 143.9, 178.3.
Ack n ow led gm en t. Thanks to Molly E. Hoke and
Caroline Ladd of the University of Maryland for obtain-
ing the GCMS data for compound 8a . Gratitude is
extended to Craig Fryhle and J . J . Grzybowski for aid
in recording NMR spectra. The support of this work in
its early stages by Research Corp. and the National
Science Foundation is gratefully acknowledged.
1
165.5-166.5 °C); H NMR identical to that reported.12
Rea ction of th e Tr a n s Dim eth yl Ester 13 w ith DMSO-
d 6. A mixture of 1.019 g (2.48 mmol) of 13, 10 g of DMSO-d6,
and 1.0 mL of a 40% NaOD-D2O solution was heated at
118 °C for 1 h and then cooled, diluted with 15 mL of D2O,
and poured into a mixture of ether, 26 mL of 1 M HCl, and
ice. The mixture was shaken, the layers were separated, and
the aqueous phase was extracted again with ether. The
organic extracts were washed twice with water, dried, and
concentrated. Recrystallization of the residue from ether-
petroleum ether gave 757 mg (90%) of 1-d eu ter io-2(e),6(a )-
d ip h en yl-4,4-(et h ylen ed ioxy)cycloh exa n e-1-ca r b oxylic
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagrams
for compounds 1d , 3e, 3f, and 6a (42 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O9801059