Efficient synthesis of optically active 4-nitro-cyclohexanones via bifunctional thiourea-base catalyzed double-Michael addition of nitromethane to dienones

Article abstract of DOI:10.1039/c0cc05418f

Thiourea-modified cinchona alkaloids as bifunctional catalysts and a base could catalyze a stepwise [5+1] cyclization of divinyl ketones with nitromethane via double Michael additions, furnishing optically active 4-nitro- cyclohexanones with good yields,

Full text of DOI:10.1039/c0cc05418f

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COMMUNICATION
Efficient synthesis of optically active 4-nitro-cyclohexanones via
bifunctional thiourea-base catalyzed double-Michael addition of
nitromethane to dienonesw
Bin Wu, Guo-Gui Liu, Mei-Qiu Li, Yong Zhang, Shao-Yun Zhang, Jun-Ru Qiu,
Xiao-Ping Xu, Shun-Jun Ji* and Xing-Wang Wang*
Received 7th December 2010, Accepted 20th January 2011
DOI: 10.1039/c0cc05418f
Thiourea-modified cinchona alkaloids as bifunctional catalysts
and a base could catalyze a stepwise [5+1] cyclization of divinyl
ketones with nitromethane via double Michael additions, fur-
nishing optically active 4-nitro-cyclohexanones with good yields,
excellent diastereoselectivities (420 : 1) and high enantiomeric
ratios (up to 97 : 3).
that enantiomerically pure cyclohexanone derivatives can be
synthesized via organocatalyzed [4+2] two-component tandem
Michael–Michael or Michael–Aldol additions (eqn (i), Scheme 1).
Alternatively, Ramachary group has recently reported a L-proline
catalyzed one-pot [4+1+1] three-component cascade reaction
for the synthesis of chiral cyclohexanone derivatives (eqn (ii),
Scheme 1).8 In contrast, considerably less attention has been
paid to the investigation of a catalytic enantioselective synthesis
of cyclohexanone derivatives with divinyl ketones as acceptors
via [5+1] double Michael addition (eqn (iii), Scheme 1). This is
somewhat surprising as an actually non-asymmetric version of
the mode (iii) was reported as early as in 1924, when Kohler
and Helmkamp found that cyclohexanone derivatives could be
prepared by treatment of divinyl ketones with active methylene-
containing pronucleophiles in the presence of an equivalent of
sodium methylate or sodium hydroxide.9 Following this work
some other reagents such as KF/basic Al2O3,10 phase transfer
catalyst,11 or DBU12 have also been found to effectively
promote the [5+1] double Michael addition of divinyl ketones
with active methylene pronucleophiles for the synthesis of
cyclohexanones. We envisioned that the dienone and an active
methylene-containing Michael donor might be activated by
The construction of suitably functionalized cyclohexane
derivatives plays an important role in the synthesis of many
natural products with significant biological and pharmaceutical
activities.1 Besides the classic Diels–Alder reaction,2 some
enantioselective organocatalytic domino routes3 have been
successfully developed in recent years, including Michael–Aldol,
Michael–Mannich, Michael–Michael, etc.,4 thus allowing
facile access to a variety of functionalized cyclohexanes in
optically enriched forms. Despite this remarkable progress,
however, the organocatalytic preparation of enantiomerically
enriched cyclohexanones via an intermolecular process still
remains less explored. Three types of the organocatalytic
cascade reactions have been employed for the construction
of chiral cyclohexanone backbones, mostly with an intermolecular
Michael addition as the key step (Scheme 1). Jørgensen,5
Takemoto6 and Melchiorre7 groups have, respectively, disclosed
Scheme 1 The construction of functionalized cyclohexanones.
Key Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science, Soochow
University, Suzhou 215123, P. R. China.
E-mail: wangxw@suda.edu.cn
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 799931 (compound 3n). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0cc05418f
Scheme 2 Screened catalysts.
c
3992 Chem. Commun., 2011, 47, 3992–3994
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Table 1 Catalyst screeninga
Thus, catalyst IV turns out to be the optimal catalyst in terms
of both activity and selectivity for this transformation.
Further results on the optimization of the other parameters
for IV-catalyzed reaction of 1a and 2, including the reactant’s
molar ratio and the base used for the cyclization step, are
summarized in Table 2. Increasing the amount of nitro-
methane relative to that of dienone 1a was found to considerably
improve the yield of 3a, with the best result (86% yield and
96 : 4 er) being obtained when a large excess of nitromethane
(20 equiv.) was used in the reaction (entries 1–5). Under
solvent-free conditions, the yield could be further improved
to 90%, however accompanied by an appreciable loss in the
enantioselectivity (92 : 8 er, entry 6). Furthermore, the yield
of 3a decreased sharply dramatically to o10% when the
temperature was lowered to 0 1C (entry 7). With regard to
the base for the cyclization step, organic bases such as DBU
and TMG were also effective, albeit with er values somewhat
inferior to that with KOH (entries 8 and 9). In addition, we
also tested the direct addition of DBU or TMG into the
mixture after 48 hours of reaction without isolation of 4.
Unfortunately, in these cases the enantiomeric ratios dropped
significantly, though the yields were elevated to over 90%
(entries 10 and 11).
Entry
Catalyst
Time/h
Yieldb (%)
drc (3a/3a0)
erd
1
2
3
4
5f
6
7
I
II
96
96
72
48
48
48
48
o5e
—
—
58
38
—
—
—
420 : 1
420 : 1
—
—
—
—
95 : 5
97 : 3
—
III
IV
V
VI
VII
—
—
—
—
a
Reactions were performed with (i) 1a (0.25 mmol), 2 (0.30 mmol) and
catalysts (20 mol%), in toluene (1.0 mL) at rt; (ii) KOH (0.025 mmol),
b
c
EtOH (2.0 mL) at 0 1C for 2 hours. Isolated yields. Determined by
d
e
chiral HPLC and 1H NMR. Determined by chiral HPLC. Yield of 4.
f
With 2 (5.0 mmol).
using a proper enantiopure organocatalyst, thus affording
optically enriched cyclohexanone adducts via [5+1] double
Michael addition. Herein we report our preliminary results on
the facile synthesis of chiral 4-nitro-cyclohexanones via a
bifunctional thiourea-base catalyzed double-Michael addition
of nitromethane to dienones.
Having established the optimal reaction conditions, we
proceeded to explore the substrate scope and limitation of
the present protocol. As shown in Table 3, all the reactions
between divinyl ketones 1a–o and nitromethane (2) proceed
smoothly with the sequential catalytic actions of IV and
potassium hydroxide, affording the corresponding cyclization
products 3 in good yields with excellent enantioselectivities.
For the divinyl ketones with identical arms (1a–k, 1n), the
different substituents on phenyl groups of the divinyl ketones
demonstrated little effect on stereocontrol, albeit with a slight
variation in the reactivity as evidenced by the yields of the
corresponding cyclization products (entries 1–11, 14). Moreover,
divinyl ketones 1l–m containing heteroaromatic rings were
Initially, several common organocatalysts bearing
a
quinuclidine and/or a thiourea moiety13 were examined for
the catalysis of the Michael addition of 1,5-diphenylpenta-
1,4-dien-3-one (1a) and nitromethane (2) in toluene at rt under
a catalyst loading of 20 mol% (Scheme 2). As shown in
Table 1, the cinchona alkaloids I–III were found to be ineffective
for the reaction, affording essentially no or only trace amount
of the intermediate 4 after prolonged reaction times (3–4 days,
entries 1–3). To our delight, the reaction proceeded smoothly
in the presence of 20 mol% bifunctional thiourea-modified
(9-deoxy)-epi-cinchona alkaloid catalyst IV,14 to afford the
mono-Michael addition product 4 in good yield after 48 hours.
Flash column chromatographic purification of 4 followed by
subsequent KOH-promoted Michael addition–cyclization led
to the formation of cyclohexanone 3a in good overall yield
(58% for two steps) with excellent diastereoselectivity (dr 4
20 : 1 in favor of trans) and high enantioselectivity (95 : 5 er)
(entry 4). Purification of 4 to homogeneity was found to be
essential for this process, since otherwise the strong base
potassium hydroxide would catalyze the non-asymmetric direct
transformation of the residual 1a and 2 to 3a and thus degrade
the enantioselectivity. Quinine-derived thiourea catalyst V as a
pseudo-enantiomer of IV was also investigated for the reaction.
Surprisingly, though the enantioselectivity (97 : 3 er) remains
excellent in this case, a decrease in yield of 3a was observed
even when a large excess of nitromethane was used (entry 5),
suggesting the subtle influence of the catalyst structure on its
activity. Therefore, quinine derivative VI (an analogue of IV)
and thiourea catalyst VII were subsequently tested for this
transformation, but no reaction occurred after 48 h (entries 6–7).
Table 2 Optimization of reaction conditionsa
Entry
1a/2
Base
Yieldb (%)
drc (3a/3a0)
erd
1
2
3
4
1 : 1.2
1 : 2
1 : 5
1 : 10
1 : 20
—
1 : 20
1 : 20
1 : 20
1 : 20
1 : 20
KOH
KOH
KOH
KOH
KOH
KOH
KOH
DBU
TMGh
DBU
TMG
58
68
78
85
86
90
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
nd
420 : 1
420 : 1
420 : 1
420 : 1
95 : 5
94 : 6
95 : 5
95 : 5
96 : 4
92 : 8
nd
93 : 7
94 : 6
93 : 7
90 : 10
5
6e
7f
8
o10
84
88
9
10g
11g
92
90
a
Reactions were performed with (i) 1a (0.25 mmol), IV (20 mol%), in
toluene (1.0 mL) at rt for 48 hours; (ii) base (0.025 mmol) in EtOH
b
c
(2.0 mL) at 0 1C for 2 hours. Isolated yields. Determined by chiral
d
e
HPLC and 1H NMR. Determined by chiral HPLC. With
2
f
g
h
(2.0 mL). 0 1C for 3 days. One pot reaction. TMG = 1,1,3,3-
tetramethylguanidine.
c
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Chem. Commun., 2011, 47, 3992–3994 3993

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Table 3 Substrate scope in the reactiona
exploring other methylene pronucleophiles and the synthetic
application studies are underway in our laboratory.
We are grateful for the financial support from National
Natural Science Foundation of China (21072145), Foundation
for the Author of National Excellent Doctoral Dissertation of
PR China (200931), Natural Science Foundation of Jiangsu
Province of China (BK2009115). We also thank Professor Dr
Kuiling Ding and Dr Zheng Wang from Shanghai Institute of
Organic Chemistry for valuable discussion and amendments
on this paper.
Entry Products (3a–p)
Time/h Yieldb
(%)
drc erd
(3/30)
1
2
R1, R2 = Ph, 3a
R1, R2 = 3,5-(OMe)2C6H3, 3b 72
48
86
77
54
67
73
65
68
82
80
66
78
58
74
71
84
420 : 1 95 : 5
420 : 1 96 : 4
420 : 1 95 : 5
420 : 1 95 : 5
420 : 1 96 : 4
420 : 1 95 : 5
420 : 1 92 : 8
420 : 1 96 : 4
420 : 1 95 : 5
420 : 1 96 : 4
420 : 1 97 : 3
420 : 1 93 : 7
420 : 1 96 : 4
420 : 1 95 : 5
1.25 : 1 82 : 18
96 : 4e
3
4
5
6
7
8
9
10
11
12
13
14
15
R1, R2 = 4-MeC6H4, 3c
R1, R2 = 4-i-PrC6H4, 3d
R1, R2 = 4-FC6H4, 3e
R1, R2 = 2-ClC6H4, 3f
R1, R2 = 3-ClC6H4, 3g
R1, R2 = 4-ClC6H4, 3h
R1, R2 = 2-BrC6H4, 3i
R1, R2 = 4-BrC6H4, 3j
R1,R2 = 4-CF3C6H4, 3k
R1, R2 = 2-furyl, 3l
72
72
48
48
36
24
24
48
36
72
48
Notes and references
1 (a) T. L. Ho, Carbocycle Construction in Terpene Synthesis, Wiley-
VCH, Weinheim, Germany, 1988; (b) T. Bui and C. F. Barbas III,
Tetrahedron Lett., 2000, 41, 6951.
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Y. Liu, B. M. Foxman and L. Deng, J. Am. Chem. Soc., 2007, 129,
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R1, R2 = 2-thienyl, 3m
R1, R2 = 2,4-(Cl)2C6H3, 3n 48
R1 = Ph, R2 = 4-ClC6H4, 3o 36
16
R1, R2 = cyclohexyl, 3p
48
—
—
—
a
Unless specified, see the experimental section in the ESIw for reaction
conditions. Isolated yields. Determined by chiral HPLC and 1H
d
NMR. Determined by chiral HPLC. Minor diastereomer.
b
c
e
3 For selected publications: (a) C. Palomo and A. Mielgo, Angew.
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also suitable substrates for this reaction, with good yields and
high stereoselectivities being attained under the optimized
conditions (entries 12 and 13). Furthermore, non-symmetrical
divinyl ketone 1o provided the desired product in 84% yield,
albeit with a somewhat inferior diastereoselectivity (1.25 : 1)
and enantioselectivity (entry 15). We have examined the
reactivity of dienones with aliphatic residues for this reaction,
using a dicyclohexyl substituted divinyl ketone 1p as the model
substrate. Unfortunately, under our optimized conditions,
catalyst IV was found to be ineffective for the transformation
involving this compound (entry 16). Finally, we were fortunate
to obtain single crystals of compound 3n, which allows for an
unambiguous assignation of the trans configuration of C2 and
C6 stereocenters by X-ray crystallographic analysis (see ESIw).
The catalyst screening results discussed above provide some
useful hints for the mechanism of this reaction. In contrast
with the bifunctional catalysts IV and V, neither the basic
cinchona alkaloids I–III (and VI) nor the acidic thiourea VII
exhibited appreciable catalytic activity in the reaction, suggesting
that a co-activation of both reaction partners by the bifunctional
catalyst seems to be working for the first Michael addition to
intermediate 4. Catalyst IV, however, is not active enough for
the second step of the reaction, which necessitates a stronger
base such as KOH for the deprotonation and subsequent
Michael addition–cyclization.
9 E. P. Kohler and R. W. Helmkamp, J. Am. Chem. Soc., 1924, 46,
1267.
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catalysis: (a) M. S. Sigman and E. N. Jacobsen, J. Am. Chem. Soc.,
1998, 120, 4901; (b) P. R. Schreiner and A. Wittkopp, Org. Lett.,
2002, 4, 217; (c) O. Tomotaka, Y. Hoashi and Y. Takemoto,
J. Am. Chem. Soc., 2003, 125, 12672; (d) Y. Sohtome,
Y. Hashimoto and K. Nagasawa, Adv. Synth. Catal., 2005, 347,
1643; (e) J. Wang, H. Li, X. Yu, L. Zu and W. Wang, Org. Lett.,
2005, 7, 4293; (f) C.-L. Cao, M.-C. Ye, X.-L. Sun and Y. Tang,
Org. Lett., 2006, 8, 2901.
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Int. Ed., 2005, 44, 6367; (c) J. Ye, D. J. Dixon and P. S. Hynes,
Chem. Commun., 2005, 4481; (d) B. Li, L. Jiang, M. Liu, Y. Chen,
L. Ding and Y. Wu, Synlett, 2005, 603.
In summary, we have successfully developed a new route
to synthesize the enantiomerically enriched 4-nitrocyclo-
hexanones starting from divinyl ketones and nitromethane
by sequential use of a thiourea-modified cinchona alkaloid as
a bifunctional catalyst and a base, with good yields and excellent
diastereoselectivities as well as high enantioselectivities being
achieved for most symmetrical aryl- or heteroaryl divinyl
ketones. Further extension of the present protocol by
c
3994 Chem. Commun., 2011, 47, 3992–3994
This journal is The Royal Society of Chemistry 2011