Asymmetric direct vinylogous michael reaction of activated alkenes to nitroolefins catalyzed by modified cinchona alkaloids

Article abstract of DOI:10.1021/ol052283b

(Chemical Equation Presented) The first organocatalytic and asymmetric direct vinylogous Michael reaction that employs the electron-deficient vinyl malononitriles as the nucleophilic species has been reported. The novel transformations exhibit exclusive γ

Full text of DOI:10.1021/ol052283b

ORGANIC
LETTERS
2005
Vol. 7, No. 23
5293-5296
Asymmetric Direct Vinylogous Michael
Reaction of Activated Alkenes to
Nitroolefins Catalyzed by Modified
Cinchona Alkaloids
Dong Xue,†,‡ Ying-Chun Chen,*,§ Qi-Wei Wang,† Ling-Feng Cun,† Jin Zhu,† and
Jin-Gen Deng*,†,‡
Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan ProVince
and Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu 610041, China, Department of
Medicinal Chemistry, West China School of Pharmacy, Sichuan UniVersity, Chengdu
610041, China, and Graduated School of Chinese Academy of Sciences, Beijing, China
jgdeng@cioc.ac.cn; ycchenhuaxi@yahoo.com.cn
Received September 21, 2005
ABSTRACT
The first organocatalytic and asymmetric direct vinylogous Michael reaction that employs the electron-deficient vinyl malononitriles as the
nucleophilic species has been reported. The novel transformations exhibit exclusive -selectivity and high diastereo- and enantioselectivity
in the addition to nitroolefins, which give the multifunctional products with two vicinal chiral centers.
γ
The development of novel carbon-carbon bond construction
methods is very important to organic synthesis. However,
most of the usually applied protocols to generate the
nucleophilic carbanion are limited to the deprotonation of
an acidic C-H adjacent to one or more functional group-
(s).1 In 1935, Fuson2 formulated the principle of vinylogy
to provide a better understanding of the “anomalous”
reactivity of some unsaturated compound and recognized that
when a functional group is attached to an unsaturated moiety,
“the influence of (that) functional group might sometimes
be propagated along the chain and make itself apparent at
some remote point in the molecule”. Since then, fruitful
results have been reported in vinylogous aldol3 and Mannich4
reactions by employing previously masked dienol ethers
derived from γ-enolizable R,â-unsaturated carbonyl com-
pounds.
However, the direct vinylogous reactions would be more
desirable in regard to the development of green chemistry
and atom economy. It could be envisioned that the acidity
of γ-C-H might be greatly enhanced when strong electron-
withdrawing groups are attached to CdC bond, which allows
the easy generation of nucleophilic species by in situ
deprotonation under mild conditions. Indeed, in our recent
studies5 on the transfer hydrogenation of vinyl malononitriles
catalyzed by Noyori’s diamine-Ru(II) catalysts, it was found
that the γ-C-H of the vinyl malononitriles could be easily
(3) (a) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem.,
Int. Ed. 2005, 44, 4682. (b) Casiraghi, G.; Zanardi, F. Chem. ReV. 2000,
100, 1929.
(4) Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221.
(5) (a) Chen, Y.-C.; Xue, D.; Deng, J.-G.; Cui, X.; Zhu, J.; Jiang, Y.-Z.
Tetrahedron Lett. 2004, 45, 1555. (b) Xue, D.; Chen, Y.-C.; Cui, X.; Wang,
Q.-W.; Zhu, J.; Deng, J.-G. J. Org. Chem. 2005, 70, 3584.
† Chengdu Institute of Organic Chemistry.
‡ Graduated School of Chinese Academy of Sciences.
§ Sichuan University.
(1) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, 4th ed.;
Kluwer: New York, 2000; p 57.
(2) Fuson, R. C. Chem. ReV. 1935, 16, 1.
10.1021/ol052283b CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/08/2005

deuterated in the presence of NEt3. It is noteworthy that the
Hammett substituent constant for R,R-dicyanovinyl group
[-CHdC(CN)2] is even higher than that of nitro group
(σp ) 0.84 cf σp ) 0.78).6 Thus, as illustrated in Scheme 1,
not yet been applied to the vinylogous Michael reaction.8b
Thus, a series of chiral modified cinchona alkaloids were
investigated in the asymmetric reaction of vinyl malononitrile
1a to nitrostyrene. The results are shown in Table 1. The
Scheme 1. Regioselectivity in the C-C Bond Formation
Reaction of Vinyl Malononitrile under Mild Basic Conditions
Table 1. Optimization of Reaction Conditions for the
Vinylogous Michael Addition of Vinyl Malononitrile 1a with
Nitrostyrenea
facile deprotonation of 1a could occur to generate the
vinylogous carbanion under mild basic conditions. It is
interesting that high regioselectivity was observed for dif-
ferent C-C bond forming reactions.7,8 Only the R-alkylated
product 2 was detected in alkylation reaction (condition A).7a
However, the site selectivity completely changed to γ-posi-
tion using p-methoxynitrostyrene as the Michael addition
acceptor, with excellent diastereoselectivity (condition B).7b
Here we present for the first time an asymmetric direct
vinylogous Michael addition to nitrostyrenes with high regio-
and stereoselectivity, employing the electron-deficient vinyl
malononitriles as the vinylogous necleophiles.8,9
entry
catalyst
NEt3
quinine
quinidine
(DHQ)2AQN
(DHQD)2AQN
(DHQ)2PHAL
(DHQ)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
(DHQD)2PYR
T (h)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9d
10d,e
11d,f
12e,g
7
3
3
3
3
5
5.5
4
48
48
48
80
88
90
90
92
90
92
90
93
26
72
87
62
19
26
54
52
63
75
81
82
90
88
88
Chiral tertiary amines, especially Cinchona alkaloids and
their derivatives, have been successfully applied in various
organocatalytic asymmetric transformations,10,11 for example,
acting as chiral base catalysts.12 However, this concept has
a Reactions performed at 0.1 mmol scales. Method: 1.1 equiv nitrosty-
rene, in 0.5 mL of DCM at room temperature. b Isolated yield. c Determined
by chiral HPLC analysis. d At -40 °C. e 5 mol % catalyst. f 10 mol %
catalyst. g At -60 °C.
(6) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(7) (a) For selective monoalkylation of vinyl malononitrile, see: Gross-
man, R. B.; Varner, M. A. J. Org. Chem. 1997, 62, 5235. (b) For the self-
dimerization of vinyl malononitriles, see: Weir, M. R. S.; Hyne, J. B. Can.
J. Chem. 1964, 42, 1440 and references therein.
(8) For recent examples of vinylogous Michael reactions, see: (a)
Christoffers, J. Synlett 2001, 723 and references therein. (b) Zhang, F.-Y.;
Corey, E. J. Org. Lett. 2004, 6, 3397.
(9) During the preparation of this paper, a similar strategy was applied
by Jørgensen et al. in γ-amination reactions, see: Poulsen, T. B.; Alemparte,
C.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 11614.
(10) For recent reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Special issue, Houk, K. N.,
List, B., Eds.; Acc. Chem. Res. 2004, 37 (8).
(11) For reviews on modified cinchona alkaloids, see: (a) Tian, S.-K.;
Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004,
37, 621. (b) Kacprzak, K.; Gawron´ski, J. Synthesis 2001, 961.
(12) For recent examples, see: (a) Li, H.; Song, J.; Liu, X.; Deng, L. J.
Am. Chem. Soc. 2005, 127, 8948. (b) Li, H.; Wang, Y.; Tang, L.; Wu, F.;
Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005,
44, 105. (c) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 2896. (d) Saaby, S.; Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 8120. (e) Bella, M.;
Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 5672. (f) Papageorgiou, C.
D.; de Dios, M. A. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed.
2004, 43, 4641. (g) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem.
Soc. 2004, 126, 9906.
reaction exhibited high diastereoselectivity, and only the anti-
product was obtained in all reactions despite the various
catalysts used. Of the cinchona alkaloids and the derivatives
tested (for the structure of catalysts, see Supporting Informa-
tion), the commercially available [DHQD]2PYR proved to
be the most promising catalyst, giving the addition product
3a with 93% yield and 81% ee at room temperature (Table
1, entry 8). Several solvents have been investigated, and
DCM was selected as the best one. Temperature and catalyst
loading had obvious influence on enantioselectivity. The best
result (90% ee) was obtained with 5 mol % catalyst loading
at -40 °C (entry 10). Slightly low enantioselectivity was
afforded with higher catalyst loading at the same temperature
(entry 11). In addition, lower temperature also slightly
diminished the enantioselectivity with 5 mol % catalyst
loading (entry 12). With the optimized reaction conditions
in hand, the scope of the enantioselective vinylogous Michael
reaction was investigated (Table 2). A wide range of
5294
Org. Lett., Vol. 7, No. 23, 2005

istry of the two newly created stereocenters of 3c was
revealed to possess (10S,11R)-configuration as shown in
Figure 2.
Table 2. Enantioselective Vinylogous Michael Addition of
Vinyl Malononitriles 1a-e to Nitroolefins Catalyzed by
[DHQD]2PYRa
entry substrate
R
product yield (%)b ee (%)c
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1d
1e
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
87
90
91
90
93
91
85
93
93
95
89
91
95
90
90
90
91
94
93
91
94
70
86
81
76
66
p-CH3C6H4
p-ClC6H4
p-BrC6H4
p-CH3OC6H4
p-(CH3)2NC6H4
2-furanyl
2-thiophenyl
p-CH3OC6H4
Ph
9
10
11
12
13
3j
3k
3l
p-CH3OC6H4
Ph
Ph
3m
a Reactions performed at 0.068 mmol scales. Method: 1.0 equiv
nitroolefin, in 0.3 mL of DCM. b Isolated yield. c Determined by chiral
HPLC analysis.
Figure 2. X-ray Crystallographic Structure of 3c.
The scaling-up experiment verified the potential applica-
tion of this methodology (Scheme 2). Enantiopure 3e could
nitroolefins bearing aryl and heteroaryl groups were reacted
with vinyl malononitriles 1a-e (Figure 1) derived from
Scheme 2. Selective Transformation of the Addition Product
Figure 1. Structure of Vinyl Malononitriles.
corresponding ketones and malononitrile in CH2Cl2 at -40
°C in the presence of 5 mol % [DHQD]2PYR, and only the
anti-products were observed in all reactions. Reaction of aryl
and heteroaryl nitroalkenes with vinyl malononitrile 1a was
found to cleanly produce the corresponding adducts 3a-h
in high enantioselectivities (90-94% ee) and good yields
(85-93% range) (entries 1-8). High yield but decreased
enantioselectivity was obtained for 1b and 1c bearing
heteroatom (entries 9 and 10). For substrate 1d derived from
acyclic aromatic ketone, moderate enantioselectivities were
observed (entries 11 and 12). Cyclic aliphatic substrate 1e
also exhibited good reactivity, although the ee (66%) was
not satisfying (entry 13).
be obtained by a single recrystallization from EtOH. In
addition, chemo- and stereoselective reduction of the double
bond could be achieved using Hantzsch ester as the hydrogen
source, which gave compound 4 with continuous three chiral
carbon centers. The stereochemistry was determined to be
cis,trans-form by NMR analysis. Interestingly, enantiopure
nitrone compound 5 was accidentally obtained when NaBH4-
NiCl2 was used as the reductive reagent. Moreover, it should
be noted that 1-tetralone did not react with nitroolefins under
our conditions. This implies that malononitrile can serve as
a masking group7a,13 as well as an activating group.13
In summary, to the best our knowledge, this paper
represents the first organocatalytic and asymmetric direct
Enantiopure 3c (>99% ee), which contains a chlorine
atom, was obtained by crystallizing slowly from a mixture
of ethyl acetate and petroleum ether and the crystals were
suitable for X-ray structural analysis. Thus, the stereochem-
Org. Lett., Vol. 7, No. 23, 2005
5295

vinylogous Michael addition that employs the electron-
deficient vinyl malononitriles as the nucleophilic species. The
novel transformations exhibit exclusive γ-selectivity and high
diastereo- and enantioselectivity in the addition to nitroole-
fins, which give the multifunctional products with two vicinal
chiral centers. It is noticeable that vinyl malononitriles had
served as Michael acceptor for successful transfer hydroge-
nation of carbon-carbon double bonds catalyzed by Noyori’s
diamine-Ru(II) catalysts5 and in this work, vinyl malononi-
triles were applied as Michael donor for successful carbon-
carbon bond construction. Current studies are actively
underway to extend this strategy to alkyl-substituted ni-
troolefins and other asymmetric vinylogous reactions.
Acknowledgment. We are grateful for the financial
support of the National Science Foundation and Chinese
Academy of Sciences. Y.-C.C. thanks Sichuan University
for financial support.
Supporting Information Available: Experimental pro-
cedures, structural proofs, and spectral data for all new
compounds, including CIF files. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Zhang, B.; Zhu, X.-Q.; Lu, J.-Y.; He, J.; Wang, P. G.; Cheng, J.-P.
J. Org. Chem. 2003, 68, 3295.
OL052283B
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Org. Lett., Vol. 7, No. 23, 2005