Reaction of cyclohexanone benzylimines with ethylidenemalonate diesters. Diphenyl 2-ethylidenemalonate: A highly electrophilic synthetic equivalent of crotonic esters

Article abstract of DOI:10.1021/jo005657h

The diastereoselective Michael alkylation of α-substituted and α,α′-disubstituted cyclohexanone benzylimines with ethylidenemalonate diesters was carried out for mechanistic and synthetic purposes. In the first case, an reverse regioselectivity occurred m comparison with what is generally observed since the Michael adducts resulted from alkylation of the non substituted enamine tautomer. With α,α′-disubstituted imines, in all cases, the stereochemistry of the major diastereomer the one anticipated from a mechanism including a chairlike complex approach with a preferred was exo position for the β-methyl group of the ethylidenemalonic acid diesters. Furthermore, diphenyl 2-ethylidenemalonate 4 was found to be a highly electrophilic synthetic equivalent of crotonic esters.

Full text of DOI:10.1021/jo005657h

256
J . Org. Chem. 2001, 66, 256-261
Rea ction of Cycloh exa n on e Ben zylim in es w ith
Eth ylid en em a lon a te Diester s. Dip h en yl 2-Eth ylid en em a lon a te: A
High ly Electr op h ilic Syn th etic Equ iva len t of Cr oton ic Ester s
Ivan J abin,* Gilbert Revial,† Nicolas Monnier-Benoit, and Pierre Netchita¨ılo
URCOM, Universite´ du Havre, Faculte´ des Sciences et Techniques, 25 rue Philippe Lebon, BP 540, 76058
Le Havre Cedex, France, and Laboratoire de Chimie Organique, CNRS (ESA 7084), ESPCI,
10 rue Vauquelin, 75231 Paris Cedex 05, France
ivan.jabin@univ-lehavre.fr
Received September 22, 2000
The diastereoselective Michael alkylation of R-substituted and R,R′-disubstituted cyclohexanone
benzylimines with ethylidenemalonate diesters was carried out for mechanistic and synthetic
purposes. In the first case, an inverse regioselectivity occurred in comparison with what is generally
observed since the Michael adducts resulted from alkylation of the non substituted enamine
tautomer. With R,R′-disubstituted imines, in all cases, the stereochemistry of the major diastereomer
was the one anticipated from a mechanism including a chairlike complex approach with a preferred
exo position for the â-methyl group of the ethylidenemalonic acid diesters. Furthermore, diphenyl
2-ethylidenemalonate 4 was found to be a highly electrophilic synthetic equivalent of crotonic esters.
Sch em e 1
In tr od u ction
Since the first report concerning the general method
of deracemizing Michael alkylation using chiral imines
of 2-substituted cyclanones,1 studies have been under-
taken in order to find a valid transition-state model for
this important reaction and consequently to rationalize
the high stereoselectivity observed. First, a theoretical
ab initio SCF-CI MO calculation study of the addition
of vinylamine to propenal has shown that the reactive
complex has a compact structure (syn approach) with
attractive secondary interactions between the C-atom of
the carbonyl group and the N-atom, largely outweighing
the steric interactions. Within the syn approaches, the
energy of the chairlike complex is about 4 kcal/mol lower
than the boatlike one. The reaction proceeds with con-
comitant formation of the C-C bond and H-transfer
(Scheme 1).2
Sch em e 2
dride).3 As expected, the observed diastereoselectivity was
high in each case (de from 89% to 99%). The major adduct
had the stereochemistry predicted by a mechanism
involving a chair complex approach of the reactants as
shown in Scheme 2 (the example given being with methyl
methacrylate, the olefin being arbitrarily shown above
the enamine).
Furthermore, a study with chiral imines and methyl-
substituted acrylic esters has shown that the expected
major diastereomer (resulting from the chairlike geom-
etry of the complex) was also produced with a high
enantioselectivity4 and that the favored diastereofacial
selectivity was in accordance with a heuristic rule
elaborated previously.2a The utility of this highly stereo-
selective reaction with substituted olefins has since been
illustrated by synthetic applications in the terpene field.5
Nevertheless, the examples mentioned above, i.e., with
substituted electrophilic olefins, have also shown that
Later, the proposed chair geometry of the reactive
complex was experimentally confirmed by reacting the
imine obtained from 2-methylcyclohexanone and benzyl-
amine with R or â-substituted electrophilic olefins (meth-
yl methacrylate, methyl crotonate and maleic anhy-
† CNRS (ESA 7084).
(1) Pfau, M.; Revial, G.; Guingant, A.; d’Angelo, J . J . Am. Chem.
Soc. 1985, 107, 273-274. Pfau, M.; Revial, G. (KIREX), 1985, PCT
WO 85 04873. Reviews: Revial, G.; Pfau, M. Org. Synth. 1991, 70,
35-46. Oare, D. A.; Heathcock, C. H. Topics Stereochem. 1991, 20,
87-170 (see pp 114-115). d’Angelo, J .; Desmae¨le, D.; Dumas, F.;
Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459-505. d’Angelo,
J .; Cave´, C.; Desmae¨le, D.; Dumas, F. Trends Org. Chem. 1993, 4, 555-
616. Guingant, A. Advances in Asymmetric Synthesis; J AI Press Inc.:
Greenwich, 1997; Vol. 2, pp 159-174. Developments and applica-
tions: J abin, I.; Revial, G.; Melloul, K.; Pfau, M. Tetrahedron: Asym-
metry 1997, 8, 1101-1109 and references included. J abin, I.; Revial,
G.; Pfau, M.; Decroix B.; Netchita¨ılo, P. Org. Lett. 1999, 1, 1901-1904.
Lim, S.; J abin I.; Revial, G. Tetrahedron Lett. 1999, 40, 4177-4180.
Revial, G.; Lim, S.; Viossat, B.; Lemoine, P.; Tomas, A.; Duprat A. F.;
Pfau, M. J . Org. Chem. 2000, 65, 4593-4600.
(3) Pfau, M.; Tomas, A.; Lim, S.; Revial, G. J . Org. Chem. 1995, 60,
0, 1143-1147.
(4) J abin, I.; Revial, G.; Tomas, A.; Lemoine, P.; Pfau, M. Tetrahe-
dron: Asymmetry 1995, 6, 1795-1812.
(2) (a) Sevin, A.; Tortajada, J .; Pfau, M. J . Org. Chem. 1986, 51,
2671-2675. (b) Sevin, A.; Masure, D.; Giessner-Prettre, C.; Pfau, M.
Helv. Chim. Acta 1990, 73, 552-573. See also: (c) Lucero, M. J .; Houk,
K. N. J . Am. Chem. Soc. 1997, 119, 826-827.
(5) Revial, G.; J abin, I.; Pfau, M. Tetrahedron: Asymmetry, submit-
ted. Revial, G.; J abin, I.; Redolfi, M.; Pfau, M. J . Chem. Soc., Perkin 1,
submitted.
10.1021/jo005657h CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/09/2000

Reactions of Cyclohexanone Benzylimines
J . Org. Chem., Vol. 66, No. 1, 2001 257
Sch em e 3
Sch em e 4
Sch em e 5a
regioisomers, resulting from an R-alkylation at the less
substituted position of the imine, are formed in signifi-
cant proportions. Likewise, a drastic loss of reactivity was
observed with R or â-substituted electrophilic olefins in
comparison with non substituted ones, thus limiting their
synthetic usefulness.
The present study was undertaken for mechanistic and
synthetic purposes. First, it was interesting to see if good
diastereoselectivity would also be observed when imines
are reacted with diesters of ethylidenemalonic acid.
Indeed, in such a case the crucial attractive secondary
interaction between the C-atom of the carbonyl group and
the N-atom of the enamine can take place with either
carbonyl of the two ester groups. Thus, two reactive
complexes with a chairlike geometry are possible (I and
II), each of them leading to a different diastereomer (syn
or anti respectively). In other words, our aim was to
determine the tendency of the R2 group to adopt an exo
(complex I) or endo (complex II) position in the reactive
complex (Scheme 3). Moreover, a high reactivity was
expected for diesters of ethylidenemalonic acid and if
such olefins could lead to diastereoselective Michael
reactions, they would constitute interesting synthetic
equivalents of crotonic esters.
a
Key: (i) NaOH, MeOH, 70 °C; (ii) 110 °C, toluene.
Ta ble 1. Mich a el Rea ction w ith Cr u d e Im in e 7
(Sch em e 5)
diastereo-
% overall
yield
regio-
selectivityb
8:9
selectivity
for 8
reaction
conditions
entry olefin
from 7a
cis/transb
1c
2
3
1
2
4
120 °C, 10 d
110 °C, 7 d
110 °C, 15 h
89
59
55
74:26
70:30
19:81
98:2
97:3
84:16
a
For the mixture of diastereomers cis and trans of 8 and 9 after
b
flash chromatography. Relative % by GC-MS analysis of crude
mixtures of regioisomeric lactams 8 and 9. c Reference 3.
Recently an example of a stereoselective Michael
reaction of a secondary enaminone with a â-substituted
electrophilic olefin (mixture of Z and E isomers) contain-
ing two different electronwithdrawing groups (an ester
and a keto groups) has been described.6 The present work
will contribute to the rationalization of the remarkable
stereoselectivity observed in this case.
lonate 4 was finally obtained (48% yield) under acidic
conditions at high temperature according to a literature
procedure dealing with closely related compounds.9 It is
important to note for synthetic purposes that 4, despite
its high electrophilicity, is a stable solid which can
withstand flash chromatographic purification on silica gel
(Scheme 4).
In a first set of experiments, imine 7 was reacted with
phenyl crotonate 2 and with diphenyl ethylidenemalonate
4 leading respectively to regioisomeric bicyclic lactams
8 and 9 or 10 and 11 (Scheme 5 and Table 1).10 Through
decarboxylation, crude lactam esters 10 and 11 were
readily converted to the corresponding lactams 8 and 9.
To have a reliable measurement of the regioselectivity,
GC-MS analyses were carried out on the crude mixtures
of lactams 8 and 9. Isolation of these mixtures by flash
chromatography allowed the determination of the overall
yield from imine 7.
Resu lts a n d Discu ssion
Preliminary results have shown that phenyl esters of
crotonic or methacrylic acid are much more electrophilic
than methyl ones.4 Thus, we decided to compare the
reactivity and the stereoselectivity of the Michael reac-
tion with methyl and phenyl crotonic esters 1 and 2 and
their corresponding ethylidenemalonic acid diesters 3 and
4. The synthesis of diphenyl ethylidenemalonate 4 was
achieved in a two-step procedure from malonic acid 5.
Diphenyl malonate 6 was obtained in 98% yield according
to a literature procedure.7 A first attempt to prepare 4
from diphenyl malonate 6 according to the classic Kno-
evenagel procedure8 failed. Diphenyl 2-ethylidenema-
(9) Liu, H.-W.; Auchus, R.; Walsh, C. T. J . Am. Chem. Soc. 1984,
106, 5335-5348.
(10) Imine 7 was also reacted with olefin 3 affording Michael adducts
which were converted to regioisomeric lactams 8 and 9. However, GC-
MS analysis of the reaction mixture has shown that other regioisomers
have also been formed in this case, thus complicating the interpretation
of the results. These regioisomers are certainly due to the different
position that can adopt the double bond in structure 9.
(6) Abdallah-El Ayoubi, S.; Toupet, L.; Texier-Boullet, F.; Hamelin,
J . Synthesis 1999, 1112-1116.
(7) Auger, B. C. R. Hebd. Seances Acad. Sci. 1903, 556.
(8) Kretchmer, R. A.; Laitar, R. A. J . Org. Chem. 1978, 43, 4596-
4598.

258 J . Org. Chem., Vol. 66, No. 1, 2001
J abin et al.
Sch em e 6a
Ta ble 2: Mich a el Rea ction betw een Cr u d e Im in e 13 a n d
Olefin s 1, 2, 3, or 4 (Sch em e 6)
% overall diastereo-
reaction
conditions
%
yield of 14 selectivity
entry olefin
conversiona from 12b
cis/transc
1
2
3
4
5
6
7
8
9
1
2
2
3
3
3
4
4
4
110 °C, 11 d
rt, 9 d
110 °C, 11 d
rt, 9 d
70 °C, 3 d
110 °C, 15 h
rt, 9 d
70 °C, 12 h
110 °C, 2 h 30
<1
<1
>99
ca. 12
>99
>99
ca. 90
53
48
94:6
87:13
85:15
>99
>99
61
73:27
75:25
a
b
By GC-MS determination. For the mixture of diastereomers
cis and trans of 14 after flash chromatography. c For the reactions
with complete conversion of imine 13, by GC-MS analysis of crude
lactam 14.
a
Key: (i) benzylamine, Et2O, TiCl4; (ii) NaOH, MeOH, 70 °C;
(iii) 110 °C, toluene.
As mentioned above, these results show that substi-
tuted olefins lead to an important proportion of regio-
isomeric adducts (i.e., lactams 9 and 11 in the present
instance). For the first time, an adduct resulting from
the alkylation of the less substituted secondary enamine
tautomer is even the major compound of the reaction
(Table 1, entry 3). The regioselectivity of the Michael
reaction of R-substituted imines with electrophilic olefins
could not be clearly rationalized yet.11 In our case, (Table
1), we can suggest that steric interaction with the methyl
group of the enamine is responsible for the tendency of
bulky electrophilic olefins to react with the less substi-
tuted enamine form.
As it has been mentioned above, olefins with a phenyl
ester electronwithdrawing group are much more reactive
than their methyl ester counterpart (Table 2, entries 1
vs 3 and entries 5 vs 8). Moreover, as expected, the
presence of a second ester function greatly enhances the
electrophilicity of the olefin (Table 2, entries 1 vs 6 and
entries 3 vs 9). Addition of these two structural factors
as in diphenyl 2-ethylidenemalonate 4, gives a highly
reactive synthetic equivalent of methyl crotonate 1 (Table
2, entries 1 vs 9).
The structure determination of the major diastereomer
of 14 was made by H NMR analysis of the inseparable
1
The structure determination of the major diastereomer
1
of 8 was made by H NMR analysis of the inseparable
cis/trans diastereomeric mixture obtained after flash
chromatography. One can note that the cis/trans diaste-
reoselectivities measured on 1H NMR spectra of the
purified mixture of diastereomers 14 are quasi-identical
with those obtained by GC-MS analysis of the crude
compound.14 In the three instances (Table 2, entries 3,
5, and 8), 1H NMR spectra of the major diastereomer
were similar and again in accordance with a cis relation-
ship of the two vicinal methyl groups (the coupling
constants of 7.8 and 10.2 Hz for the two H-atoms in the
R-position of the carbonyl group are characteristic of an
axial position for the vicinal tertiary H-atom). The
relative configuration between the vicinal methyl groups
was also confirmed by NOEDIFF experiment.
cis/trans diastereomeric mixture obtained after flash
chromatography. The 1H NMR spectrum of the major
diastereomer was in accordance with a cis relationship
of the two vicinal methyl groups. Indeed, the two H-atoms
in the R-position of the carbonyl group display two
coupling constants (besides their geminal coupling of 18.4
Hz) of 5.9 and 12.5 Hz, which are characteristic of an
axial position for the vicinal tertiary H-atom. In the two
examples, the stereoselectivity of the Michael reaction
strongly favors the formation of the cis diastereomer.
Thus, the stereochemistry of the major diastereomer is
the one anticipated from a mechanism including a
chairlike complex approach with an exo position for the
methyl group of the electrophilic olefin.
To avoid the formation of regioisomeric adducts result-
ing from alkylation at the less substituted R-position, the
symmetrical R,R′-disubstituted imine 13 was used in all
other experiments. Thus, imine 13 was reacted with
electrophilic olefins 1, 2, 3, and 4 (Table 2) giving either
no reaction (with 1)12 or cyclized adducts 14, 15, and 16,
respectively. As before, the crude lactam esters 15 and
16 were readily converted into lactam 14.13 The stereo-
selectivity of the Michael reaction with electrophilic
olefins 2, 3, and 4 was determined by GC-MS analysis
of crude lactam 14. In each case, purification of the crude
lactam 14 by flash chromatography gave a mixture of
inseparable diastereomers, allowing determination of the
overall yield from 2,6-dimethyl-cyclohexanone 12 (Scheme
6).
If one considers the results displayed in Table 2, the
following deductions can be made:
(1) With trans olefin 2 bearing only one electronwith-
drawing group, the usual high diastereoselectivity is
observed (entry 3, cf. Table 1, entry 2), resulting from a
chairlike approach of the reactants, implying an exo
position for the methyl group. The small occurrence of
an adduct having the opposite stereochemistry results
from the presence of cis olefin 2 and/or from a boat
approach of the reactants.
(2) When two identical electron-withdrawing groups
are present (olefins 3 and 4), one can a priori expect that
both possible chairlike complexes (Scheme 3) have close
energies, i.e., that only a small diastereoselectivity would
occur. In fact, one still observes a significant diastereo-
selectivity (lower than that observed with olefin 2) in
(11) Comments on regioselectivity have been previously discussed.4
(12) Traces of diastereomeric adducts 14 were detected by GC-MS
analysis of the reaction mixture after 11 days at 110 °C.
(13) In other experiments, lactams 15 and 16 have been isolated
and characterized.
(14) Since GC-MS determinations were done on crude mixtures of
diastereomers and since GC-MS measurements are usually more
precise than NMR ones, GC-MS values are used for the discussion.

Reactions of Cyclohexanone Benzylimines
J . Org. Chem., Vol. 66, No. 1, 2001 259
at 90 °C for 2 min, then 10 °C/min up to 290 °C. All reactions
were performed under an inert atmosphere. All extractions
were usually followed by water and saturated NaCl aqueous
solution washings, MgSO4 drying, filtration, and evaporation.
Syn th esis of Dip h en yl 2-Eth ylid en em a lon a te (4). To a
mixture of malonic acid 5 (11.0 g, 106 mmol) and phenol (19.95
g, 212 mmol) was slowly added at 0 °C POCl3 (11.5 mL, 123
mmol). The mixture was heated at 115 °C until strong release
of HCl ceased (about 1.5 h). The upper layer was poured into
150 mL of water and three extractions with ether followed by
the usual workup gave diphenyl malonate 6 (26.6 g, 98%) as
a pale brown solid which was pure enough to be used without
further purification in the next step. An analytical sample of
6 was obtained by recrystallization from a mixture of ether/
pentane: mp 51 °C (ether/pentane) (lit.15 mp 50 °C (EtOH/
H2O)); EIMS m/z (rel int) 256 (M+, 2), 95 (12), 94 (base), 77
favor of an approach with the methyl group in the exo
position (entries 6 and 9, cf Table 1, entry 3). This result
can be rationalized, assuming that when the methyl
group is in the endo position, some steric interaction with
the enamine should occur (Scheme 3, II, R2 ) Me). Of
course, the observed diastereoselectivity also depends
somewhat on the contribution of a boat approach.
(3) The lower diastereoselectivity observed with olefin
4 compared to olefin 3 (entries 9 and 6) can in turn be
rationalized if one now admits that some steric interac-
tion should occur between the exo-methyl group of the
electrophilic olefin and the bulky phenyl group of the
ester function not included in the chair.
(4) Slight elevation of the reaction temperature does
not affect significatively the stereoselectivity of the
Michael reaction (Table 2, entries 5 vs 6 and 8 vs 9).
If we consider the previously reported example men-
tioned above in the Introduction,6 the observed stereo-
selectivity is in accordance with our results since the only
stereoisomer which is obtained should result from a
chairlike complex approach of the reactants with an exo
position for the â-substituent (i.e., the phenyl group). It
is worthy to note that in this case, the attractive
secondary interaction between the nitrogen atom of the
enaminone takes place preferentially with the carbon
atom of the carbonyl group of the ketone rather than that
of the ester group.
1
(18), 65 (13); IR (Nujol) 1746, 1731 cm-1; H NMR (CDCl3) δ
3.95 (s, 2H), 7.10-7.50 (m, 10H); 13C NMR (CDCl3) δ 41.81,
121.5 (4C), 126.5 (2C), 129.7 (4C), 150.5 (2C), 164.9 (2C).
A mixture of diphenyl malonate 6 (5.05 g, 19.7 mmol),
acetaldehyde (2.33 mL, 41.3 mmol), and acetic anhydride (2.96
mL, 31.6 mmol) was heated at 110 °C in a bomb for 16 h. After
distillation under reduced pressure of the acetic anhydride, a
flash chromatography (10% EtOAc/hexanes) of the residue
gave diphenyl 2-ethylidenemalonate 4 (2.69 g, 48%) as a
colorless oil which crystallized on standing. An analytical
sample of 4 was obtained as a white solid by recrystallization
from a mixture of ether/pentane: mp 52 °C (ether/pentane);
EIMS m/z (rel int) 282 (M+, 5), 190 (10), 189 (85), 121 (78), 95
(base), 94 (38), 93 (11), 77 (51), 65 (29), 53 (17), 51 (15); IR
(Nujol) 1746, 1730, 1714 cm-1; 1H NMR (CDCl3) δ 2.18 (d, J )
7.5 Hz, 3H), 7.10-7.50 (m, 11H); 13C NMR (CDCl3) δ 16.19,
121.6 (4C), 126.3 (2C), 128.6, 129.7 (4C), 149.1, 150.6 (2C),
162.4, 163.6. Anal. Calcd for C17H14O4: C, 72.33; H, 5.00.
Found: C, 72.36; H, 5.03.
Con clu sion
Reaction of imine 7 with diphenyl 2-ethylidenema-
lonate 4 has shown that Michael alkylation of the less
substituted enamine tautomer largely prevails. A study
on the regioselectivity of this reaction is in progress in
our Laboratory in an attempt to rationalize this result.
Additions of imine 13 with diesters of ethylidenema-
lonic acid (i.e., olefins 3 and 4) have shown that the
geometry of the major diastereomeric Michael adduct (cis)
is the one which arises from a mechanism involving a
chairlike complex. In all examples, an exo approach of
the â-substituent (methyl group) of the electrophilic olefin
is observed. With 3 and 4, the observed diastereoselec-
tivities are good to moderate (87:13 and 75:25, respec-
tively) but their reactivity is much higher than those
observed with crotonic esters. The example of diphenyl
2-ethylidenemalonate 4 is remarkable since it can lead
to Michael adducts, using moderate temperatures and
short times. Thus 4 constitutes a highly reactive syn-
thetic equivalent of crotonic esters in cases where the
problem of regioselectivity does not occur, i.e., when
imines are identically substituted in the R and R′ posi-
tions (e.g., imine 13) or when secondary enamino esters
or ketones (e.g., ref 6) are used. Its use in reactions other
than Michael additions is under investigation in our
laboratory.
Syn th esis of 1-Ben zyl-4,4a-dim eth yl-3,4,4a,5,6,7-h exah y-
d r oqu in olin -2(1H)-on e (8) a n d 1-Ben zyl-4,8-d im eth yl-
3,4,5,6,7,8-h exa h yd r oqu in olin -2(1H)-on e (9). Rea ction of
im in e (7) w ith p h en yl cr oton a te (2). A mixture of imine 73
(0.37 g, 1.84 mmol) and phenyl crotonate 24 (0.41 g, 2.53 mmol)
in the presence of a trace of hydroquinone was heated at 110
°C for 7 d. A GC-MS analysis showed the presence of four
isomers with the following retention times in min: 12.090
(regioisomer 9, 11%), 12.377 (diastereomer of 9, 19%), 12.654
(diastereomer trans of 8, 2%), 12.889 (diastereomer cis of 8,
68%).16 The reaction mixture was diluted in 20 mL of ether,
washed with an aqueous solution of NaOH (10%) then with
an aqueous solution of HCl (10%). After extraction with ether
and the usual workup, the residue was purified by flash
chromatography (15% then 25% and 30% EtOAc/hexanes)
affording a mixture of lactams 8 and 9 (0.29 g, 59%) as a
colorless oil. During the chromatography, a fraction gave an
analytical sample of a mixture 90:10 of diastereomers cis and
trans of 8. 8 (diastereomer cis): EIMS m/z (rel int) 270 (13),
269 (M+, 65), 268 (12), 226 (31), 200 (22), 199 (30), 198 (13),
91 (base), 65 (21); IR (film) 1667, 1644 cm-1; 1H NMR (CDCl3)
δ 0.90 (d, J ) 6.6 Hz, 3H), 0.94 (s, 3H), 1.15-2.18 (m, 7H),
2.32 (dd, J 1 ) 18.4 Hz, J 2 ) 12.5 Hz, 1H), 2.62 (dd, J 1 ) 18.4
Hz, J 2 ) 5.9 Hz, 1H), 4.57 (d, J ) 16.0 Hz, 1H), 4.98 (dd, J 1
)
5.1 Hz, J 2 ) 3.1 Hz, 1H), 5.22 (d, J ) 16.6 Hz, 1H), 7.15-7.40
(m, 5H); 13C NMR (CDCl3) δ 14.33, 16.19, 17.96, 24.87, 35.55,
35.94, 36.44, 37.75, 47.87, 106.6, 126.5 (2C), 126.8, 128.5 (2C),
138.0, 143.6, 168.8. 8 (diastereomer trans): EIMS m/z (rel int)
270 (12), 269 (M+, 71), 268 (12), 226 (45), 200 (22), 199 (36),
198 (13), 91 (base), 65 (18). 9 (minor diastereomer): EIMS m/z
(rel int) 269 (M+, 45), 255 (11), 254 (52), 178 (17), 92 (12), 91
(base), 65 (14). 9 (major diastereomer): EIMS m/z (rel int) 269
(M+, 23), 254 (30), 178 (11), 91 (base), 65 (12).
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded,
respectively, at 200 and 50 MHz. Thin-layer chromatographies
(TLC) were performed with aluminum plates (0.20 mm)
precoated with fluorescent silica gel, using EtOAc/hexanes as
eluent. Reaction components were then visualized under UV
light and dipped in a Dragendorff solution. Silica gel (230-
400 mesh) was used for flash chromatography separations. Gas
chromatography-mass spectrometry (GC-MS) was performed
with a GC apparatus equipped with a 25 m capillary column,
(15) J unek, H.; Ziegler, E.; Herzog, U.; Kroboth, H. Synthesis 1976,
332-334.
(16) Diastereomers of 9 as well as diastereomers of 8 have an
identical mass spectrum pattern with slightly different relative
intensities. On the other hand, these spectra are different from those
of their respective regioisomers. For further precisions, see ref 4.

260 J . Org. Chem., Vol. 66, No. 1, 2001
J abin et al.
Rea ction of Im in e (7) w ith Dip h en yl 2-Eth ylid en em a -
lon a te (4). A mixture of imine 7 (0.37 g, 1.84 mmol) and
diphenyl 2-ethylidenemalonate 4 (0.68 g, 2.41 mmol) in the
presence of a trace of hydroquinone was heated at 110 °C for
15 h. A GC-MS analysis showed the absence of imine 7 and
peaks corresponding to decomposition products of compounds
10 and 11. A 20 mL portion of methanol and 10 mL of an
aqueous solution of NaOH (2.5 M) were added, and the
reaction mixture was heated at 70 °C for 15 h. After removal
of the methanol under reduced pressure, the residue was
acidified with an aqueous solution of HCl (10%). Extraction
with CH2Cl2 followed by the usual workup afforded a residue
which was diluted in 15 mL of toluene and heated at 110 °C
for 15 h. A GC-MS analysis showed the presence of four
isomers with the following retention times in min: 12.082 (9,
21%), 12.371 (diastereomer of 9, 60%), 12.653 (diastereomer
trans of 8, 3%), 12.874 (diastereomer cis of 8, 16%). After
removal of the toluene under reduced pressure, the residue
was diluted in 20 mL of ether and washed with an aqueous
solution of NaOH (10%). After extraction with ether and the
usual workup, the residue was purified by flash chromatog-
raphy (15% then 25% EtOAc/hexanes) affording a mixture of
lactams 8 and 9 (0.27 g, 55%) as a colorless oil. A fraction of
this chromatography gave an analytical sample of a mixture
ca. 85:15 of respectively diastereomers cis and trans of 9. The
four mass spectra (diastereomers cis and trans of 8 and 9) were
identical with those of the compounds obtained from the
reaction of imine 7 with phenyl crotonate 2. 9 (mixture ca.
85:15 of diastereomers cis and trans): IR (film) 1664 cm-1; 1H
NMR (CDCl3) (major diastereomer) δ 1.00 (d, J ) 7.0 Hz, 3H),
1.02 (d, J ) 6.4 Hz, 3H), 1.28-1.75 (m, 4H), 1.80-2.70 (m,
6H), 4.19 (d, J ) 16.0 Hz, 1H), 5.57 (d, J ) 16.0 Hz, 1H), 7.10-
7.35 (m, 5H); 13C NMR (CDCl3) (major diastereomer) δ 17.34,
18.37, 20.54, 25.68, 28.04, 29.63, 30.54, 40.65, 43.34, 120.8,
126.3 (2C), 126.8, 128.5 (2C), 135.6, 138.6, 171.6.
Syn t h esis of 1-Ben zyl-4,4a ,8-t r im et h yl-3,4,4a ,5,6,7-
h exah ydr oqu in olin -2(1H)-on e (14). P r epar ation of N-Ben -
zyl-N-(2,6-d im eth ylcycloh exylid en e)a m in e (13).1717 2,6-
Dimethylcyclohexanone 12 (10.8 mL, 79.0 mmol) and benzyl-
amine (26.0 mL, 238 mmol) were dissolved in 50 mL of
anhydrous ether. To the stirred reaction mixture was slowly
added TiCl4 (4.40 mL, 39.5 mmol) in solution in 30 mL of
anhydrous pentane at 0 °C. The reaction mixture was then
stirred vigorously at room temperature for 16 h. The resulting
precipitate was removed by filtration and washed with toluene
and the solvent evaporated under reduced pressure yielding
17.2 g of crude imine 13, which was used without further
purification in the next step: EIMS m/z (rel int) 215 (M+, 21),
92 (19), 91 (base), 65 (13), 55 (11); IR (film) 1651 cm-1; 1H NMR
(CDCl3) δ 1.08 (d, J ) 7.0 Hz, 3H), 1.12 (d, J ) 6.4 Hz, 3H),
0.94 (s, 3H), 1.17-2.10 (m, 6H), 2.51 (m, 1H), 3.15 (m, 1H),
4.63 (s, 2H), 7.18-7.33 (m, 5H); 13C NMR (CDCl3) δ 14.72,
17.38, 17.46, 20.71, 31.41, 33.36, 36.97, 52.97, 126.3, 127.4
(2C), 128.3 (2C), 141.4, 179.5.
melting point. Mixture of diastereomeric lactams 14 (cis and
trans), IR (Nujol) 1644 cm-1. Diastereomer cis of 14: EIMS
m/z (rel int) 283 (M+, 30), 240 (10), 192 (47), 91 (base), 69 (19),
1
65 (21), 55 (10); H NMR (CDCl3) δ 0.28 (s, 3H), 0.77 (d, J )
7.0 Hz, 3H), 1.10-2.15 (m, 7H), 1.72 (s, 3H), 2.01 (dd, J 1
)
18.4 Hz, J 2 ) 10.2 Hz, 1H), 2.57 (dd, J 1 ) 18.0 Hz, J 2 ) 7.8
Hz, 1H), 4.23 (d, J ) 14.1 Hz, 1H), 5.32 (d, J ) 14.1 Hz, 1H),
7.15-7.35 (m, 5H); 13C NMR (CDCl3) δ 15.42, 15.89, 19.17,
21.21, 33.44, 37.53, 38.00, 38.16, 38.67, 50.48, 120.6, 127.4,
128.1 (2C), 129.5 (2C), 137.9, 139.5, 171.3. Diastereomer trans
of 14: EIMS m/z (rel int) 283 (M+, 44), 240 (14), 213 (13), 192
(47), 91 (base), 69 (18), 65 (17). Anal. Calcd for C19H25NO: C,
80.52; H, 8.89; N, 4.94. Found: C, 80.42; H, 9.18; N, 5.08.
Rea ction of Im in e (13) w ith Dim eth yl 2-Eth ylid en -
em a lon a te (3). A mixture of crude imine 13 (1.20 g) and
dimethyl 2-ethylidenemalonate 3 (1.06 g, 6.71 mmol) in the
presence of a trace of hydroquinone was heated at 70 °C for 3
d. A GC-MS analysis showed the absence of imine 13 and
peaks corresponding to lactam 15 and its decomposition
products. A 20 mL portion of an aqueous solution of HCl (10%)
was added, and extraction with CH2Cl2 followed by the usual
workup afforded a residue which was purified by flash chro-
matography (15% then 20% EtOAc/hexanes) giving a mixture
(ca. 90:10, determined by 1H NMR) of two diastereomers of
lactam 15 (0.94 g, 50% overall yield from 12) as a pale yellow
solid. An analytical sample of the major diastereomer of 15
was obtained by recrystallization from EtOAc/hexanes (10:90)
as a white solid: mp 93 °C (EtOAc/hexanes); EIMS m/z (rel
int) 341 (M+, 29), 250 (37), 95 (12), 92 (10), 91 (base), 69 (16),
1
65 (11); IR (Nujol) 1740, 1640 cm-1; H NMR (CDCl3) δ 0.34
(s, 3H), 0.85 (d, J ) 6.7 Hz, 3H), 1.20-1.45 (m, 2H), 1.55-
1.80 (m, 2H), 1.71 (s, 3H), 1.95-2.20 (m, 3H), 3.06 (d, J ) 9.4
Hz, 1H), 3.73 (s, 3H), 4.33 (d, J ) 14.1 Hz, 1H), 5.18 (d, J )
14.5 Hz, 1H), 7.15-7.35 (m, 5H); 13C NMR (CDCl3) δ 14.51,
16.85, 19.01, 20.99, 33.21, 37.33, 38.55, 42.59, 51.33, 52.58,
55.97, 122.4, 127.5, 128.1 (2C), 129.2 (2C), 137.3, 138.3, 167.0,
171.4. Anal. Calcd for C21H27NO3: C, 73.87; H, 7.97; N, 4.10.
Found: C, 73.86; H, 8.18; N, 4.18.
The same reaction procedure was repeated on a different
scale, i.e., with 0.27 g of crude imine 13 and 0.22 g (1.40 mmol)
of dimethyl 2-ethylidenemalonate 3, affording crude lactam
15 which was dissolved in 15 mL of methanol and 7.5 mL of
an aqueous solution of NaOH (2.5 M) and heated at 70 °C for
15 h. After removal of the methanol under reduced pressure,
the residue was acidified with an aqueous solution of HCl
(10%). Extraction with CH2Cl2 followed by the usual workup
afforded a residue which was diluted in 6 mL of toluene and
heated at 110 °C for 2 h. A GC-MS analysis showed the
presence of two diastereomers with the following retention
times in min: 12.546 (diastereomer trans of 14, 13%), 12.702
(diastereomer cis of 14, 87%). After removal of the toluene
under reduced pressure, the residue was directly purified by
flash chromatography (25% EtOAc/hexanes) affording a mix-
ture of diastereomeric (cis and trans) lactams 14 (0.17 g, 48%
overall yield from 12) as a colorless oil. All analytical data for
the diastereomers cis and trans of 14 were identical with those
obtained from reaction of imine 13 with phenyl crotonate 2.
Rea ction of Im in e (13) w ith Dip h en yl 2-Eth ylid en -
em a lon a te (4). A mixture of imine 13 (0.12 g) and diphenyl
2-ethylidenemalonate 4 (0.19 g, 0.67 mmol) in the presence of
a trace of hydroquinone was heated at 55 °C for 24 h. A GC-
MS analysis showed the absence of imine 13 and peaks
corresponding to decomposition products of lactam 16. The
reaction mixture was directly purified by flash chromatography
(20% EtOAc/hexanes) giving a mixture (ca. 70:30, determined
Rea ction of Im in e (13) w ith P h en yl Cr oton a te (2). A
mixture of crude imine 13 (1.01 g) and phenyl crotonate 2 (0.84
g, 5.19 mmol) in the presence of a trace of hydroquinone was
at 110 °C for 11 d. A GC-MS analysis showed the absence of
imine 13 and the presence of two isomers with the following
retention times in min: 12.495 (diastereomer trans of 14, 6%),
12.649 (diastereomer cis of 14, 94%). The reaction mixture was
diluted in 40 mL of ether, washed with an aqueous solution
of NaOH (10%) then with an aqueous solution of HCl (10%).
After extraction with ether and the usual workup, the residue
was purified by flash chromatography (15% then 25% and 30%
EtOAc/hexanes) affording a mixture of diastereomeric lactams
14 (cis and trans)18 (0.71 g, 53% overall yield from 12) as a
colorless oil which crystallized on standing. Attempts to
recrystallize the major isomer of lactam 14 failed because of
its high solubility even in cold pentane and its apparently low
1
by H NMR) of two diastereomeric lactams of 16 (0.14 g, 62%
overall yield from 12) as a colorless oil: IR (film) 1767, 1659,
1592 cm-1; major diastereomer of 16: 1H NMR (CDCl3) δ 0.40
(s, 3H), 0.75-2.10 (m, 6H), 0.96 (d, J ) 7.0 Hz, 3H), 1.68 (s,
3H), 2.16 (dd, J 1 ) 9.1 Hz, J 2 ) 7.0 Hz, 1H), 3.28 (d, J ) 9.4
Hz, 1H), 4.40 (d, J ) 14.1 Hz, 1H), 5.13 (d, J ) 14.9 Hz, 1H),
7.00-7.45 (m, 10H); 13C NMR (CDCl3) δ complex mixture of
isomers.
(17) Imine 13 was prepared according to a known procedure: White,
W. A.; Weingarten, H. J . Org. Chem. 1967, 32, 213-214.
(18) Diastereomers cis and trans of 14 possess the same Rf on TLC
(eluent, 10% EtOAc/hexanes).
This reaction was repeated on a different scale, i.e. with 0.31
g of crude imine 13 and 0.49 g (1.74 mmol) of diphenyl

Reactions of Cyclohexanone Benzylimines
J . Org. Chem., Vol. 66, No. 1, 2001 261
2-ethylidenemalonate 4 at 70 °C for 12 h, affording crude
lactam 16. The latter was dissolved in 20 mL of methanol and
11.5 mL of an aqueous solution of NaOH (2.5 M) and heated
at 70 °C for 15 h. After removal of the methanol under reduced
pressure, the residue was acidified with an aqueous solution
of HCl (10%). Extraction with ether followed by the usual
workup afforded a residue which was diluted in 10 mL of
toluene and heated at 110 °C for 1 h. A GC-MS analysis
showed the presence of two diastereomers with the following
retention times in min: 12.553 (diastereomer trans of 14, 27%),
12.710 (diastereomer cis of 14, 73%). After removal of the
toluene under reduced pressure, the residue was diluted in
ether and washed with an aqueous solution of NaOH (10%).
After extraction with ether and the usual workup, the residue
was purified by flash chromatography (15% EtOAc/hexanes)
affording a mixture of diastereomeric (cis and trans) lactams
of 14 (0.25 g, 61% overall yield from 12) as a colorless oil. All
the analytical data for the diastereomers cis and trans of 14
were identical with those obtained from reaction of imine 13
with phenyl crotonate 2.
Ack n ow led gm en t. We thank Dr. Michel Pfau for
his support for this work.
Su p p or tin g In for m a tion Ava ila ble: The 1H and 13C
NMR spectra of compounds 4, 6, 8 (mixture ca. 90:10 of
diastereomers), 9 (mixture ca. 85:15 of diastereomers), crude
13, 14 (mixture ca. 95:5 of diastereomers), 15 and the 1H
spectrum of 16 (mixture ca. 70:30 of diastereomers) as well as
the NOEDIFF spectra of compound 14. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O005657H