Imidazole-mediated cascade [2 + 2 + 2] annulation reactions: A highly diastereoselective synthetic protocol for the construction of multiply substituted cyclohexanes

Article abstract of DOI:10.1002/ejoc.200800853

A novel imidazole-mediated [2 + 2 + 2] annulation process that enables the diastereoselective synthesis of multiply substituted cyclohexanes 3 in a one-pot, three-component manner from two units of (arylmethylidene) malononitriles 1 and one unit of nitroalkenes 2 is described. These cyclohexane derivatives were obtained in moderate to good yields under mild conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800853

FULL PAPER
DOI: 10.1002/ejoc.200800853
Imidazole-Mediated Cascade [2 + 2 + 2] Annulation Reactions: A Highly
Diastereoselective Synthetic Protocol for the Construction of Multiply
Substituted Cyclohexanes
Xu-Guang Liu[a] and Min Shi*[a,b]
Keywords: Imidazole / (Arylmethylidene)malononitriles / Nitroalkenes / Multiply substituted cyclohexanes / One-pot three-
component reactions
A novel imidazole-mediated [2 + 2 + 2] annulation process
that enables the diastereoselective synthesis of multiply sub-
stituted cyclohexanes 3 in a one-pot, three-component man-
ner from two units of (arylmethylidene)malononitriles 1 and
one unit of nitroalkenes 2 is described. These cyclohexane
derivatives were obtained in moderate to good yields under
mild conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
form cyclopentenes from allenoates and alkenes under
phosphane catalysis conditions has been applied in the syn-
thesis of several natural products.[9] Very recently, Kwon re-
ported phosphane-catalyzed [4 + 2] annulations for the syn-
thesis of tetrahydropyridines and cyclohexenes.[10] Although
many catalytic systems for a variety of important transfor-
mations have been developed, catalytic cascade chemistry
has not yet achieved its full potential. The development of
novel reactions, useful reagents, and efficient catalysts to
enable the formation of carbon–carbon bonds, particularly
in the construction of ring systems, is highly desirable.
The construction of highly functionalized cyclohexane
frameworks plays an important role in many natural prod-
uct syntheses,[11] providing a highly attractive research field
in the form of the development of mild, efficient, and mod-
ular methods for the synthesis of these densely substituted
systems. (Arylmethylidene)malononitriles[12] and nitro-
alkenes[13] have proven to be extremely useful reagents in
organic synthesis. Their reactivities and synthetic diversity
provide an important platform for the development of novel
cascade strategies. Here we wish to disclose a facile syn-
thetic protocol for multiply substituted cyclohexane com-
pounds through the use of imidazole-mediated[14] [2 + 2 +
2] annulations with two units of (arylmethylidene)malono-
nitriles 1 and one unit of a nitroalkene 2 under mild condi-
tions. This new chemistry can provide a straightforward,
diastereoselective, and potentially powerful method for the
modular construction of highly substituted cyclohexanes.
Introduction
The development of efficient methods to allow rapid
transformation of readily accessible starting materials into
complex cyclic molecules is an ongoing challenge in prepar-
ative chemistry.[1] Advances in these methodologies have
mainly focused on metal-catalyzed procedures, with palla-
dium, rhodium, ruthenium, nickel, and gold being the most
prevalent.[2] A recent new direction in this field is the devel-
opment of cascade or tandem reactions based on organo-
catalysis.[3] This approach also allows the rapid construc-
tion of structurally complex molecules from simple starting
materials in only one operation, thereby minimizing cost,
waste, and manual effort.
In particular, chiral secondary amines have been used
successfully in cascade reactions as a result of their two
modes of activating carbonyl compounds (enamine and
iminium activation).[4] A great number of examples have
been reported, including
a secondary-amine-catalyzed
triple-cascade/Diels–Alder sequence,[5] tandem Michael/
Morita–Baylis–Hillman reactions,[6] tandem Michael/aldol
reactions,[7] and tandem Michael/Henry reactions.[8]
In addition to the above enamine and iminium activation
modes, nucleophilic phosphane catalysis has emerged re-
cently as an efficient means of generation of carbo- and
heterocycles. In particular, Lu’s [3 + 2] cycloaddition to
[a] School of Chemistry and Molecular Engineering, East China
University of Science and Technology,
130 Meilong Road, Shanghai 200237, China
Fax: +86-21-64166128
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Results and Discussion
Fax: +86-21-64166128
We initially examined the reaction between benzylidene-
malononitrile (1a) and nitroalkene 2a (ratio of 1a/2a = 1:1)
in the presence of several amine and phosphane promoters
E-mail: Mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
6168
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Highly Diastereoselective Synthesis of Multiply Substituted Cyclohexanes
(50 mol-%) in tetrahydrofuran (THF) at room temperature contains two units of the benzylidenemalononitrile (1a)
(20 °C), and the results of these experiments are summa- component and one unit of the nitroalkene component 2a,
rized in Table 1. As can be seen, in the presence of PPh3 it was found that the yield of 3a could be slightly improved
and PPh2OMe as the promoters, no reactions had occurred to 66% when the reaction was carried out with 2 equiv. of
after 24 h (Table 1, Entries 1 and 3), whereas use of other 1a and 1 equiv. of 2a under otherwise identical conditions
nucleophilic phosphanes as the promoters afforded complex (Table 1, Entry 17).
product mixtures (Table 1, Entries 2 and 4–5). Moreover,
Encouraged by the above results, we examined the reac-
use of tertiary amines – such as 1,4-diazabicyclo[2.2.2]- tion in further detail under a variety of sets of conditions in
octane (DABCO), 4-(dimethylamino)pyridine (DMAP), an attempt to improve the yield of 3a. A survey of solvents
Et3N, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), piper- revealed that THF was the best solvent for this reaction
idine, and pyrrolidine – as the promoters resulted in com- (Table 2, Entries 1–8). Interestingly, in all these solvents, 3a
plex product mixtures (Table 1, Entries 6–9, 11, and 12). was produced as a single diastereoisomer. In addition, it
With pyridine as the promoter, no reaction occurred was observed that prolonging the reaction time did not give
(Table 1, Entry 10). To our delight, however, the reaction any improvement in the yield of 3a in THF (Table 1, En-
proceeded smoothly to give the annulation product 3a in try 9). Moreover, it was also found that increasing the em-
35% yield in 24 h when N-methylimidazole was used as the ployed amounts of imidazole to 100 mol-% did not improve
promoter (Table 1, Entry 15), although traces of 3a were the yield of 3a, whereas decreasing the employed amounts
also formed in the presence of 1,2,4-triazole and pyrazole of imidazole to 20 mol-% resulted in the formation of 3a in
(Table 1, Entries 13 and 14). The yield of 3a was improved lower yield under otherwise identical conditions (Table 2,
to 60% when imidazole was used as the promoter instead Entries 10 and 11). When the reaction was conducted at a
of N-methylimidazole (Table 1, Entry 16). It should be higher temperature (45 °C), no improvement in the yield of
noted that 3a was formed diastereospecifically, as no other 3a was observed, 3a being obtained in 21% yield in THF
diastereoisomers could be detected in the 1H NMR spectro- (Table 2, Entry 12). Further optimization of the reaction
scopic data for the crude reaction mixtures (see the Sup- conditions revealed that when the reaction was carried out
porting Information). Because the structure of product 3a with 1a (3.0 equiv.) and 2a (1.0 equiv.) in the presence of
imidazole (50 mol-%) in THF at room temperature over
24 h, 3a was obtained in 58% yield (Table 2, Entry 13).
Table 1. Survey of several amine and phosphane promoters for the
Therefore, the best conditions found to carry out the reac-
[2 + 2 + 2] annulation of benzylidenemalononitrile (1a) and nitroal-
kene 2a.[a]
Table 2. Solvent effects and other conditions in the imidazole-medi-
ated [2 + 2 + 2] annulation of benzylidenemalononitrile (1a) and
nitroalkene 2a.[a]
[a] The reaction was carried out with 1a (0.30 mmol), 2a
[a] The reaction was carried out with 1a (0.3 mmol), 2a (0.3 mmol),
and catalyst (0.15 mmol) in THF under ambient atmosphere.
[b] Isolated yields. [c] The reaction was carried out under argon.
[d] No reaction.
(0.15 mmol), and imidazole (0.075 mmol) in THF under ambient
atmosphere. [b] Isolated yield. [c] Imidazole (100 mol-%) was used.
[d] Imidazole (20 mol-%) was used. [e] The reaction was carried out
at 45 °C.
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X.-G. Liu, M. Shi
FULL PAPER
tion involved the use of 1a (2.0 equiv.) with 2a (1.0 equiv.) Table 3. Survey of (arylmethylidene)malononitriles 1 for the [2 + 2
+ 2] annulations with the nitroalkenes 2.[a]
in THF in the presence of imidazole (50 mol-%) as the pro-
moter at room temperature over 24 h.
With these optimized reaction conditions to hand, we
next turned our interest to the reaction generality. A variety
of (arylmethylidene)malononitriles 1 was examined under
these optimal conditions, and the results of these experi-
ments are shown in Entries 1–7 of Table 3. As summarized,
the reactions proceeded smoothly to produce cyclohexanes
3 in moderate to good yields, in each case as single dia-
stereoisomer regardless of whether an electron-withdrawing
or an electron-donating group was present on the benzene
ring of 1. Only in the case of (arylmethylidene)malono-
nitrile 1g, with a strongly electron-donating methoxy group
on the benzene ring, was a prolonged reaction time required
to give the corresponding cyclohexane 3g in 48% yield
(Table 3, Entry 6). Notably, a similar result was obtained
with the heterocyclic methylidenemalononitrile 1h, which
afforded the corresponding cyclohexane 3h in 44% yield
(Table 3, Entry 7).
Moreover, a variety of nitroalkenes 2 were also examined
under the optimized reaction conditions, and the results of
these experiments are summarized in Entries 8–12 of
Table 3. As can be seen, variation in the alkyl chain length
of the R2 group in 2 did not affect the yields of the corre-
[a] The reaction was carried out with 1 (0.30 mmol), 2 (0.15 mmol),
and imidazole (0.075 mmol) in THF under ambient atmosphere.
[b] Isolated yield. [c] 1-Nitropropene was used as a solution in di-
ethyl ether in a large excess. [d] The reaction was incomplete, and
the product was accompanied by some other unidentified byprod-
sponding products 3 in any instance, with the cyclohexanes
3i–3m being obtained in moderate to good yields (Table 3,
Entries 8–12). Use of an aromatic nitroalkene such as (E)-
(2-nitrovinyl)benzene (2e) as the substrate afforded the de- ucts, together with the recovery of 25% of the starting materials.
[e] Complex product mixtures were obtained.
sired product 3n in 13% yield along with some other un-
identified byproducts under the optimized reaction condi-
tions, accompanied by the recovery of 25% of the starting 1a with 2f in the presence of imidazole in THF (Scheme 1).
materials (Table 3, Entry 13). Furthermore, use of the alkyl- Moreover, when 2-(1-phenylethylidene)malononitrile (1j)
substituted methylidenemalononitrile 1i as the substrate was used as the substrate to react with (E)-1-nitrobut-1-ene
provided complex product mixtures within a very short (2a) in the presence of imidazole in THF at room tempera-
time (Table 3, Entry 14).
ture, it was found that the corresponding vinylogous
The scope and limitations of this reaction with regard to Michael addition product 4[15] and the dimerization product
the introduction of further substituents into the employed of 1j, which has been identified as compound 5,[16] were
(arylmethylidene)malononitriles 1 or the nitroalkenes 2 still formed in 21% and 9% yields, respectively, along with the
remained obscure, so (E)-2-nitropent-2-ene (2f) was synthe- recovery of the starting materials in 30% yield, suggesting
sized and utilized as the substrate to examine its reaction that the introduction of a substituent in 1 could change the
with 1a. However, no reaction occurred upon treatment of reaction pathway (Scheme 1).
Scheme 1. Lack of reaction between benzylidenemalononitrile (1a) and (E)-2-nitropent-2-ene (2b), together with the reaction between
(1-phenylethylidene)malononitrile (1j) and (E)-1-nitrobut-1-ene (2a).
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Eur. J. Org. Chem. 2008, 6168–6174

Highly Diastereoselective Synthesis of Multiply Substituted Cyclohexanes
It should be also noted that the reactions between diethyl
2-benzylidenemalonate (1Ј) or ethyl (E)-2-cyano-3-phenyl-
acrylate (1ЈЈ) and nitroalkene 2a did not take place under
the optimized reaction conditions, indicating that the
strongly electron-withdrawing dicyano groups in the sub-
strate 1 are essential for this imidazole-mediated reaction
(Scheme 2).[17]
Scheme 2. The absence of reactions between diethyl benzyl-
idenemalonate (1Ј) or ethyl (E)-2-cyano-3-phenylacrylate (1ЈЈ) and
nitroalkene 2a.
Figure 1. X-ray crystal structure of 3a.
The structures of these isolated cyclohexane products 3a–
1
3n were determined from their IR, H NMR, 13C NMR, transformation is outlined in Scheme 3. The zwitterionic in-
and HMRS spectroscopic data, as well as from microanaly- termediate 6 initially formed by nucleophilic attack of imid-
ses (see the Supporting Information). The diastereochemi- azole onto nitroalkene 2 is trapped by the (arylmethyl-
cal outcome in compounds 3 was assigned by single-crystal idene)malononitrile 1, leading to the formation of interme-
X-ray diffraction on 3a. This showed the ethyl group adja- diate 7 in an anti,anti configuration, presumably due to the
cent to C-3 in a cis configuration with respect to the nitro steric effect. The intermediate 7 can be further trapped by
group adjacent to C-2, whereas the phenyl groups adjacent another (arylmethylidene)malononitrile 1 to produce inter-
to C-1 and C-5 are in a trans configuration with respect to mediate 8, which undergoes an intramolecular SN2 cycliza-
the nitro group adjacent to C-2. The ORTEP drawing is tion through the sterically favored chair configuration of
shown in Figure 1.[18]
intermediate 9 to yield cyclohexane 3 and regenerates the
The mechanism of this novel imidazole-mediated cycliza- imidazole at the same time. The high electrophilicity of
tion reaction has not been unequivocally established, but (arylmethylidene)malononitrile 1 plays a key role in this re-
one straightforward and still reasonable mechanism for this action.
Scheme 3. A plausible reaction mechanism.
Eur. J. Org. Chem. 2008, 6168–6174
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X.-G. Liu, M. Shi
FULL PAPER
126 (38.7), 86 (73.1), 84 (100.0), 51 (48.5). HRMS (EI): calcd. for
C24H17Br2N5O2 [M]+ 564.9749; found 564.9735.
Conclusions
We have developed a quite simple, one-pot, three-compo-
nent synthesis of multiply substituted cyclohexanes in a
novel, imidazole-mediated [2 + 2 + 2] annulation process.
Moderate to good yields and high stereoselectivities, the use
of simple and cheap starting materials and catalyst, as well
as mild reaction conditions are the main advantages of this
method. In addition, the presented synthesis tolerates car-
bonitrile, aryl, and nitro functional groups. Further effort
will focus on expanding the versatility of this new [2 + 2 +
2] annulation as well as on performing the annulations in
an enantioselective manner.
2,4-Bis(3-bromophenyl)-6-ethyl-5-nitrocyclohexane-1,1,3,3-tetra-
carbonitrile (3c): M.p. 211–213 °C. 1H NMR (CDCl3, 300 MHz,
TMS): δ = 1.14 (t, J = 7.2 Hz, 3 H, CH3), 1.92–2.11 (m, 2 H, CH2),
3.33 (q, J = 4.2 Hz, 1 H, CH), 3.51 (s, 1 H, CH), 3.95 (d, J =
12.0 Hz, 1 H, CH), 5.73 (dd, J1 = 4.2, J2 = 12.0 Hz, 1 H, CH),
7.37 (t, J = 8.1 Hz, 1 H, Ar), 7.48 (t, J = 8.1 Hz, 2 H, Ar), 7.63–
7.67 (m, 2 H, Ar), 7.76 (d, J = 9.6 Hz, 1 H, Ar), 7.87–7.92 (m, 2
H, Ar) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.8, 20.3, 41.7,
44.5, 46.9, 47.3, 48.0, 81.0, 109.3, 110.9, 111.1, 111.8, 123.7, 124.1,
127.1, 131.1, 131.2, 131.8, 132.2, 132.8, 134.0, 135.1 ppm. IR
(CH Cl ): ν = 3052, 2978, 2940, 1664, 1567, 1479, 1367, 1265, 1079,
˜
2
2
738 cm–1. MS (EI): m/z = 569 [M + 4]+ (1.8), 567 [M + 2]+ (3.4),
565 [M]+ (1.8), 234 (43.6), 232 (45.7), 153 (100.0), 142 (44.1), 141
(19.8), 76 (18.2), 75 (19.7). HRMS (EI): calcd. for C24H17Br2N5O2
[M]+ 564.9749; found 564.9762.
Experimental Section
General Remarks: Melting points are uncorrected. 1H and 13C
NMR spectra were recorded at 300 and 75 MHz, respectively. MS
and HRMS data were recorded by EI methods. Organic solvents
used were dried by standard methods when necessary. Satisfactory
CHN microanalyses were obtained with an analyzer. Commercially
obtained reagents were used without further purification. All reac-
tions were monitored by TLC with silica gel coated plates. Flash
column chromatography was carried out with silica gel at increased
pressure.
2,4-Bis(4-chlorophenyl)-6-ethyl-5-nitrocyclohexane-1,1,3,3-tetra-
carbonitrile (3d): M.p. 211–213 °C. 1H NMR (CDCl3, 300 MHz,
TMS): δ = 1.14 (t, J = 7.5 Hz, 3 H, CH3), 1.92–2.14 (m, 2 H, CH2),
3.32 (q, J = 4.2 Hz, 1 H, CH), 3.55 (s, 1 H, CH), 3.98 (d, J =
12.0 Hz, 1 H, CH), 5.74 (dd, J1 = 4.2, J2 = 12.0 Hz, 1 H, CH),
7.44–7.50 (m, 4 H, Ar), 7.57 (d, J = 8.7 Hz, 2 H, Ar), 7.78 (d, J =
8.7 Hz, 2 H, Ar) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.8, 20.3,
41.7, 44.8, 46.9, 47.3, 48.0, 81.1, 109.5, 111.0, 111.4, 111.9, 127.5,
128.6, 130.1, 130.5, 130.6, 137.1, 138.4 ppm. IR (CH Cl ): ν =
˜
2
2
3059, 2979, 1900, 1704, 1597, 1567, 1496, 1099, 1015, 834 cm–1.
MS (EI): m/z = 477 [M]+ (4.2), 188 (64.6), 161 (22.3), 153 (70.7),
149 (32.4), 86 (68.0), 84 (100.0), 75 (22.5), 51 (40.7). HRMS (EI):
calcd. for C24H17Cl2N5O2 [M]+ 477.0759; found 477.0776.
Typical Reaction Procedure for the Imidazole-Mediated [2 + 2 + 2]
Annulation: The nitroalkene 2 (0.15 mmol) was added under ambi-
ent atmosphere to a mixture of the (arylmethylidene)malononitrile
1 (0.30 mmol) and imidazole (0.075 mmol) in solvent, and the reac-
tion mixture was stirred at room temperature for the required time
as indicated in the tables. After the reaction, the solution was con-
centrated under reduced pressure, and the residue was purified by
flash chromatography on silica gel (eluent: EtOAc/petroleum ether,
1:4) to afford the pure product 3.
4-Ethyl-5-nitro-2,6-bis(m-tolyl)cyclohexane-1,1,3,3-tetracarbonitrile
(3e): M.p. 209–211 °C. 1H NMR (CDCl3, 300 MHz, TMS): δ =
1.13 (t, J = 7.2 Hz, 3 H, CH3), 1.92–2.18 (m, 2 H, CH2), 2.39 (s, 3
H, CH3), 2.44 (s, 3 H, CH3), 3.28 (q, J = 4.5 Hz, 1 H, CH), 3.50
(s, 1 H, CH), 3.94 (d, J = 12.0 Hz, 1 H, CH), 5.78 (dd, J1 = 4.5,
J2 = 12.0 Hz, 1 H, CH), 7.25–7.40 (m, 5 H, Ar), 7.44 (t, J = 7.8 Hz,
1 H, Ar), 7.57 (s, 1 H, Ar), 7.67 (d, J = 7.2 Hz, 1 H, Ar) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 14.8, 20.3, 21.4, 21.5, 42.0, 45.0, 47.5,
48.0, 48.2, 81.5, 109.9, 111.3, 111.7, 112.3, 126.0, 129.3, 129.5,
4-Ethyl-5-nitro-2,6-diphenylcyclohexane-1,1,3,3-tetracarbonitrile
(3a): M.p. 214–216 °C. 1H NMR (CDCl3, 300 MHz, TMS): δ =
1.15 (t, J = 7.5 Hz, 3 H, CH3), 1.94–2.18 (m, 2 H, CH2), 3.30 (q,
J = 4.5 Hz, 1 H, CH), 3.56 (s, 1 H, CH), 4.00 (d, J = 12.0 Hz, 1
H, CH), 5.80 (dd, J1 = 4.5, J2 = 12.0 Hz, 1 H, CH), 7.48–7.63 (m,
8 H, Ar), 7.82–7.85 (m, 2 H, Ar) ppm. 13C NMR (CDCl3,
75 MHz): δ = 14.9, 20.4, 42.0, 45.1, 47.6, 48.0, 48.2, 81.4, 109.8,
111.2, 111.6, 112.2, 129.2, 129.3, 129.7, 130.2, 130.3, 130.7,
131.7 ppm. MS (EI): m/z = 409 [M]+ (19.1), 209 [M – 1]+ (42.2),
208 [M – 18]+ (61.7), 167 [M – 35]+ (43.3), 154 [M – 53]+ (54.9),
145 [M – 71]+ (57.7), 127 [M – 74]+ (41.5), 155 [M – 81]+ (20.9),
130.0, 130.2, 131.4, 132.5, 139.6, 140.1 ppm. IR (CH Cl ): ν =
˜
2
2
3037, 2978, 2926, 2874, 1708, 1608, 1566, 1493, 1464, 1367, 738,
702 cm–1. MS (EI): m/z = 437 [M]+ (55.7), 168 (100.0), 167 (55.5),
159 (50.5), 141 (67.9), 140 (65.1), 129 (51.7), 105 (66.1).
C26H23N5O2 (437.19): calcd. C 71.38, H 5.30, N 16.01; found C
71.39, H 5.51, N 16.00.
4-Ethyl-5-nitro-2,6-bis(p-tolyl)cyclohexane-1,1,3,3-tetracarbonitrile
(3f): M.p. 176–178 °C. 1H NMR (CDCl3, 300 MHz, TMS): δ =
1.13 (t, J = 7.5 Hz, 3 H, CH3), 1.93–2.19 (m, 2 H, CH2), 2.37 (s, 3
H, CH3), 2.42 (s, 3 H, CH3), 3.29 (q, J = 4.5 Hz, 1 H, CH), 3.53
(s, 1 H, CH), 3.97 (d, J = 12.0 Hz, 1 H, CH), 5.78 (dd, J1 = 4.5,
J2 = 12.0 Hz, 1 H, CH), 7.28 (d, J = 9.0 Hz, 2 H, Ar), 7.36 (d, J
= 7.8 Hz, 2 H), 7.41 (d, J = 7.8 Hz, 2 H), 7.71 (d, J = 9.0 Hz, 2 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.9, 20.3, 21.2, 21.3, 42.1,
45.4, 47.2, 47.7, 48.2, 81.5, 110.0, 111.4, 111.8, 112.3, 126.4, 127.3,
145 [M – 91]+ (10.1). IR (CH Cl ): ν = 3066, 3037, 2982, 2942,
˜
2
2
2883, 2244, 1562, 1497, 1458, 1366, 1299, 1004, 737, 701 cm–1
.
C24H19N5O2 (409.15): calcd. C 70.40, H 4.68, N 17.10; found C
70.24, H 4.76, N 17.16.
2,4-Bis(4-bromophenyl)-6-ethyl-5-nitrocyclohexane-1,1,3,3-tetra-
carbonitrile (3b): M.p. 204–206 °C. 1H NMR (CDCl3, 300 MHz,
TMS): δ = 1.15 (t, J = 7.2 Hz, 3 H, CH3), 1.93–2.12 (m, 2 H, CH2),
3.31 (q, J = 4.5 Hz, 1 H, CH), 3.51 (s, 1 H, CH), 3.96 (d, J =
11.7 Hz, 1 H, CH), 5.72 (dd, J1 = 4.5, J2 = 11.7 Hz, 1 H, CH),
7.39 (d, J = 8.7 Hz, 2 H, Ar), 7.64 (d, J = 8.7 Hz, 2 H, Ar), 7.68–
7.75 (m, 4 H, Ar) ppm. 13C NMR (CDCl3, 75 MHz): δ = 14.9,
20.3, 41.7, 44.6, 47.1, 47.5, 48.1, 81.1, 109.5, 111.0, 111.4, 111.9,
129.0, 130.3, 130.8, 140.8, 142.0 ppm. IR (CH Cl ): ν = 3034, 2977,
˜
2
2
2926, 2885, 1915, 1719, 1566, 1517, 823 cm–1. MS (EI): m/z = 437
[M]+ (15.6), 168 (100.0), 167 (34.9), 142 (37.0), 141 (59.5), 140
(46.9), 129 (39.0), 115 (37.4), 105 (35.5). HRMS (EI): calcd. for
C26H23N5O2 [M]+ 437.1852; found 437.1841.
125.4, 126.4, 128.0, 129.1, 130.7, 133.1, 133.6 ppm. IR (CH Cl ): ν
˜
2
2
= 3067, 2979, 2942, 1660, 1592, 1566, 1493, 1417, 1365, 1079, 1011,
830, 740 cm–1. MS (EI): m/z = 569 [M + 4]+ (3.8), 567 [M + 2]+
(6.0), 565 [M]+ (3.1), 234 (51.9), 232 (59.9), 153 (93.4), 142 (35.9),
4-Ethyl-2,6-bis(4-methoxyphenyl)-5-nitrocyclohexane-1,1,3,3-tetra-
carbonitrile (3g): M.p. 144–146 °C. 1H NMR (CDCl3, 300 MHz,
TMS): δ = 1.13 (t, J = 7.8 Hz, 3 H, CH3), 1.91–2.18 (m, 2 H, CH2),
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Eur. J. Org. Chem. 2008, 6168–6174

Highly Diastereoselective Synthesis of Multiply Substituted Cyclohexanes
3.25 (q, J = 4.2 Hz, 1 H, CH), 3.51 (s, 1 H, CH), 3.82 (s, 3 H, 4.00 (d, J = 11.7 Hz, 1 H, CH), 5.81 (dd, J1 = 4.5, J2 = 11.7 Hz, 1
OCH3), 3.86 (s, 3 H, CH3), 3.94 (d, J = 12.0 Hz, 1 H, CH), 5.72
(dd, J1 = 4.2, J2 = 12.0 Hz, 1 H, CH), 6.98 (d, J = 8.4 Hz, 2 H, NMR (CDCl3, 75 MHz): δ = 13.5, 22.1, 26.5, 32.3, 42.1, 45.1, 46.4,
Ar), 7.05 (d, J = 9.0 Hz, 2 H, Ar), 7.43 (d, J = 8.4 Hz, 2 H, Ar), 47.5, 48.0, 81.5, 109.8, 111.2, 111.6, 112.2, 129.2, 129.3, 129.7,
H, CH), 7.47–7.63 (m, 8 H, Ar), 7.83–7.86 (m, 2 H, Ar) ppm. 13C
7.75 (d, J = 9.0 Hz, 2 H, Ar) ppm. 13C NMR (CDCl3, 75 MHz): δ 130.2, 130.6, 131.7 ppm. IR (CH Cl ): ν = 3067, 3038, 2962, 2934,
˜
2
2
= 14.9, 20.3, 42.3, 45.8, 47.0, 47.4, 48.2, 55.3, 55.4, 81.6, 110.1, 2875, 1718, 1565, 1500, 737 cm–1. MS (EI): m/z = 437 [M]+ (14.9),
111.4, 111.9, 112.3, 115.0, 115.4, 121.1, 122.0, 130.6, 161.1, 236 (33.7), 155 (32.9), 154 (100.0), 128 (32.5), 127 (62.9), 115 (36.7),
161.8 ppm. IR (CH Cl ): ν = 2962, 2939, 2842, 1708, 1612, 1565,
103 (48.5), 91 (65.5). C26H23N5O2 (437.19): calcd. C 71.38, H 5.30,
N 16.01; found C 71.54, H 5.31, N 15.83.
˜
2
2
1517, 1464, 1288, 1262, 1186, 1031, 836 cm–1. MS (EI): m/z = 469
[M]+ (6.8), 239 (18.4), 185 (15.6), 184 (100.0), 179 (31.4), 174 (14.8),
149 (34.3), 141 (28.7), 114 (38.71). HRMS (EI): calcd. for
C26H23N5O4 [M]+ 469.1750; found 469.1760.
4-Butyl-5-nitro-2,6-bis(p-tolyl)cyclohexane-1,1,3,3-tetracarbonitrile
(3l): M.p. 125–127 °C. 1H NMR (CDCl3, 300 MHz, TMS): δ =
0.92 (t, J = 6.9 Hz, 3 H, CH3), 1.22–1.41 (m, 3 H, CH2), 1.45–1.59
(m, 1 H, CH2), 1.81–1.91 (m, 1 H, CH2), 1.98–2.08 (m, 1 H, CH2),
2.37 (s, 3 H, CH3), 2.42 (s, 3 H, CH3), 3.30 (q, J = 4.2 Hz, 1 H,
CH), 3.50 (s, 1 H, CH), 3.94 (d, J = 12.6 Hz, 1 H, CH), 5.77 (dd,
J1 = 4.2, J2 = 12.6 Hz, 1 H, CH), 7.27 (d, J = 9.0 Hz, 2 H, Ar),
7.35 (d, J = 8.1 Hz, 2 H), 7.40 (d, J = 8.1 Hz, 2 H), 7.71 (d, J =
9.0 Hz, 2 H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 13.5, 21.2,
21.3, 22.1, 26.5, 32.4, 42.2, 45.4, 46.5, 47.3, 47.8, 81.6, 109.9, 111.4,
111.8, 112.3, 126.4, 127.2, 129.1, 130.3, 130.8, 140.9, 142.1 ppm.
4-Ethyl-5-nitro-2-(pyridin-3-yl)-6-(pyridin-4-yl)cyclohexane-1,1,3,3-
tetracarbonitrile (3h): M.p. 170–172 °C. 1H NMR [(CD3)2SO,
300 MHz, TMS]: δ = 0.97 (t, J = 7.5 Hz, 3 H, CH3), 1.86–2.08 (m,
2 H, CH2), 4.03 (q, J = 4.2 Hz, 1 H, CH), 4.75 (s, 1 H, CH), 4.78
(d, J = 12.0 Hz, 1 H, CH), 6.41 (dd, J1 = 4.2, J2 = 12.0 Hz, 1 H,
CH), 7.54 (dd, J1 = 4.8, J2 = 7.8 Hz, 1 H, Ar), 7.75 (dd, J1 = 4.8,
J2 = 8.1 Hz, 1 H, Ar), 8.41 (d, J = 9.0 Hz, 1 H, Ar), 8.36–8.43 (m,
1 H, Ar), 8.66 (d, J = 4.5 Hz, 1 H, Ar), 8.84 (d, J = 4.8 Hz, 1 H,
Ar), 9.01 (d, J = 2.4 Hz, 1 H, Ar), 8.92–9.02 (m, 1 H, Ar) ppm.
13C NMR [(CD3)2SO, 75 MHz]: δ = 14.5, 20.4, 41.5, 42.1, 42.6,
45.0, 45.6, 81.1, 111.0, 112.2, 112.6, 112.7, 124.4, 125.2, 127.7,
IR (CH Cl ): ν = 3022, 2960, 2874, 1732, 1608, 1567, 1517,
˜
2
2
1365 cm–1. MS (EI): m/z = 465 [M]+ (16.5), 168 (100.0), 167 (41.6),
163 (39.5), 141 (49.7), 140 (45.8), 129 (40.5), 115 (35.3), 105 (61.5).
HRMS (EI): calcd. for C28H27N5O2 [M]+ 465.2165; found
465.2167.
129.3, 136.3, 151.2, 152.9 ppm. IR (CH Cl ): ν = 2904, 1712, 1560,
˜
2
2
1548, 1431, 1025, 713 cm–1. MS (EI): m/z = 411 [M]+ (3.5), 155
(100.0), 128 (48.3), 104 (57.5), 101 (34.4), 79 (23.0), 77 (15.7), 75
(22.0), 51 (16.6). HRMS (EI): calcd. for C22H17N7O2 [M]+
411.1444; found 411.1438.
4-Methyl-5-nitro-2,6-diphenylcyclohexane-1,1,3,3-tetracarbonitrile
(3m): M.p. 236–238 °C. 1H NMR (CDCl3, 300 MHz, TMS): δ =
1.61 (d, J = 7.2 Hz, 3 H, CH3), 3.61 (s, 1 H, CH), 3.65 (q, J =
4.5 Hz, 1 H, CH), 4.06 (d, J = 12.9 Hz, 1 H, CH), 5.87 (dd, J1 =
4.5, J2 = 12.9 Hz, 1 H, CH), 7.48–7.62 (m, 8 H, Ar), 7.84–7.87 (m,
2 H, Ar) ppm. 13C NMR (CDCl3, 75 MHz): δ = 11.1, 41.1, 41.9,
45.4, 46.4, 47.1, 82.0, 109.7, 111.1, 111.6, 112.2, 129.2, 129.3, 129.7,
5-Nitro-2,4-diphenyl-6-propylcyclohexane-1,1,3,3-tetracarbonitrile
(3i): M.p. 213–215 °C. 1H NMR (CDCl3, 300 MHz, TMS): δ =
0.98 (t, J = 6.9 Hz, 3 H, CH3), 1.28–1.43 (m, 1 H, CH2), 1.50–1.64
(m, 1 H, CH2), 1.80–1.92 (m, 1 H, CH2), 1.97–2.09 (m, 1 H, CH2),
3.34 (q, J = 4.2 Hz, 1 H, CH), 3.56 (s, 1 H, CH), 4.00 (d, J =
12.3 Hz, 1 H, CH), 5.81 (dd, J1 = 4.2, J2 = 12.3 Hz, 1 H, CH),
7.47–7.62 (m, 8 H, Ar), 7.83–7.86 (m, 2 H, Ar) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 13.4, 23.5, 28.7, 42.1, 45.1, 46.2, 47.5, 48.0,
81.5, 109.8, 111.3, 111.6, 112.2, 129.2, 129.4, 129.7, 130.2, 130.7,
130.1, 130.2, 130.7, 131.8 ppm. IR (CH Cl ): ν = 3204, 2963, 1736,
˜
2
2
1560, 1458, 1361, 1296, 1004, 734, 699 cm–1. MS (EI): m/z = 395
[M]+ (100.0), 349 (43.4), 195 (80.0), 194(56.6), 168 (42.6), 154
(67.8), 129 (49.4), 127 (41.4), 91 (50.0). HRMS (EI): calcd. for
C23H17N5O2 [M]+ 395.1382; found 395.1369.
131.7 ppm. IR (CH Cl ): ν = 3067, 2966, 2935, 2877, 1712, 1566,
˜
2
2
5-Nitro-2,4,6-triphenylcyclohexane-1,1,3,3-tetracarbonitrile (3n):
M.p. 132–134 °C. H NMR (CDCl3, 300 MHz, TMS): δ = 4.13 (s,
1458, 700 cm–1. MS (EI): m/z = 423 [M]+ (16.1), 222 (40.5), 155
(43.7), 154 (100.0), 128 (42.1), 127 (69.1), 115 (68.5), 103 (59.1), 91
(94.3). HRMS (EI): calcd. for C25H21N5O2 [M]+ 423.1695; found
423.1691.
1
1 H, CH), 4.49 (d, J = 12.9 Hz, 1 H, CH), 4.74 (d, J = 5.7 Hz, 1
H, CH), 6.09 (dd, J1 = 5.7, J2 = 12.9 Hz, 1 H, CH), 7.47–7.60 (m,
13 H, Ar), 7.87–7.89 (m, 2 H, Ar) ppm. 13C NMR (CDCl3,
75 MHz): δ = 42.2, 45.1, 47.7, 48.5, 52.4, 81.9, 109.9, 110.5, 111.9,
112.4, 128.4, 129.2, 129.4, 129.5, 129.7. 129.8, 130.1, 130.3, 130.7,
2,4-Bis(3-bromophenyl)-5-nitro-6-propylcyclohexane-1,1,3,3-tetra-
carbonitrile (3j): M.p. 185–187 °C. 1H NMR (CDCl3, 300 MHz,
TMS): δ = 0.98 (t, J = 7.2 Hz, 3 H, CH3), 1.32–1.42 (m, 1 H, CH2),
1.53–1.65 (m, 1 H, CH2), 1.80–2.01 (m, 2 H, CH2), 3.36 (q, J =
4.2 Hz, 1 H, CH), 3.50 (s, 1 H, CH), 3.94 (d, J = 12.6 Hz, 1 H,
CH), 5.73 (dd, J1 = 4.2, J2 = 12.6 Hz, 1 H, CH), 7.37 (t, J = 8.1 Hz,
1 H, Ar), 7.46–7.51 (m, 2 H, Ar), 7.63–7.67 (m, 2 H, Ar), 7.76 (d,
J = 7.5 Hz, 1 H, Ar), 7.88–7.93 (m, 2 H, Ar) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 13.4, 23.5, 28.6, 41.8, 44.5, 46.1, 47.0, 47.3,
81.1, 109.3, 110.9, 111.1, 111.8, 123.7, 124.1, 127.1, 131.1, 131.2,
131.4, 131.8 ppm. IR (CH Cl ): ν = 3065, 2922, 2852, 2357, 2320,
˜
2
2
1568, 1499, 1456, 1361, 737, 699 cm–1. MS (EI): m/z = 457 [M]+
(12.5), 410 (10.5), 256 (99.7), 191 (100.0), 155 (87.5), 127 (55.6),
115 (74.7), 91 (62.3). HRMS (EI): calcd. for C28H19N5O2 [M]+
457.1539; found 457.1541.
2-[3-(Nitromethyl)-1-phenylpentylidene]malononitrile (4): 1H NMR
(CDCl3, 300 MHz, TMS): δ = 0.92 (t, J = 7.2 Hz, 3 H, CH3), 1.25–
1.60 (m, 1 H, CH), 2.03–2.27 (m, 2 H, CH2), 3.11 (d, J = 6.9 Hz,
2 H, CH2), 4.24 (dd, J1 = 12.9, J2 = 8.1 Hz, 1 H, CH2), 4.35 (dd,
J1 = 12.9, J2 = 5.4 Hz, 1 H, CH2), 7.45–7.49 (m, 2 H, Ar), 7.52–
7.63 (m, 3 H, Ar) ppm. 13C NMR (CDCl3, 75 MHz): δ = 10.4,
23.9, 37.8, 39.1, 77.8, 86.7, 112.2, 112.3, 127.5, 129.6, 132.6, 133.6,
131.8, 132.1, 132.8, 134.1, 135.2 ppm. IR (CH Cl ): ν = 3067, 2966,
˜
2
2
2876, 1709, 1567, 1479, 1079, 736 cm–1. MS (EI): m/z = 582 [M +
4]+ (2.8), 581 [M + 2]+ (4.9), 579 [M]+ (2.2), 234 (45.3), 232 (46.7),
156 (22.1), 153 (100.0), 126 (36.1), 115 (20.5), 76 (20.5), 75 (20.5).
C25H19Br2N5O2 (578.99): calcd. C 51.66, H 3.29, N 12.05; found C
51.36, H 3.44, N 11.78.
178.6 ppm. IR (CH Cl ): ν = 2967, 2926, 2360, 2324, 2228, 1550,
˜
2
2
1381, 705 cm–1. MS (EI): m/z = 269 [M]+ (0.8), 239 (5.9), 223 (15.1),
193 (37.4), 183 (100.0), 179 (49.5), 155 (37.7), 91 (17.6). HRMS
(EI): calcd. for C15H15N3O2 [M]+ 269.1164; found 269.1166.
4-Butyl-5-nitro-2,6-diphenylcyclohexane-1,1,3,3-tetracarbonitrile
(3k): M.p. 180–182 °C. 1H NMR (CDCl3, 300 MHz, TMS): δ =
0.92 (t, J = 6.6 Hz, 3 H, CH3), 1.12–1.58 (m, 4 H, CH2), 1.83–2.09 2-Amino-6-methyl-4,6-diphenylcyclohexa-2,4-diene-1,1,3-tricarbo-
(m, 2 H, CH2), 3.34 (q, J = 4.5 Hz, 1 H, CH), 3.56 (s, 1 H, CH),
nitrile (5): A known compound.[16] 1H NMR (CDCl3, 300 MHz,
Eur. J. Org. Chem. 2008, 6168–6174
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6173

X.-G. Liu, M. Shi
FULL PAPER
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Acknowledgments
We thank the Shanghai Municipal Committee of Science and Tech-
nology (04JC14083, 06XD14005), the National Basic Research
Program of China [(973)-2009CB825300], and the National Natu-
ral Science Foundation of China (20472096, 20672127, and
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Received: September 4, 2008
Published Online: November 7, 2008
6174
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Eur. J. Org. Chem. 2008, 6168–6174