Chiral bifunctional thiourea-catalyzed enantioselective michael addition of ketones to nitrodienes

Article abstract of DOI:10.1021/jo901991v

"Chemical Equation Presented" Simple bifunctional thioureas, derived from the commercially available saccharides and chiral diamines, have been shown tunably to promote Michael-type addition of ketones to α,β-γ, (δ-nitrodienes. The Michael adducts were ob

Full text of DOI:10.1021/jo901991v

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Chiral Bifunctional Thiourea-Catalyzed Enantioselective Michael
Addition of Ketones to Nitrodienes
Hai Ma, Kun Liu, Fa-Guang Zhang, Chuan-Le Zhu, Jing Nie, and Jun-An Ma*
Department of Chemistry, Tianjin University, Tianjin 300072, China
majun_an68@tju.edu.cn
Received October 13, 2009
Simple bifunctional thioureas, derived from the commercially available saccharides and chiral
diamines, have been shown tunably to promote Michael-type addition of ketones to R,β-γ,
δ-nitrodienes. The Michael adducts were obtained in good yields albeit with high enantioselectivites
(84-99% ee). Furthermore, these products can be readily transformed into more useful molecules.
Introduction
addition reactions.5 For example, the asymmetric Michael
addition of various carbon nucleophiles to nitrolefins is proving
a particularly attractive target, due largely to (a) the ready
availability and high reactivity of nitroalkenes, (b) the ability
Michael addition is one of the most important carbon-
carbon bond-forming reactions in organic synthesis.1 Over the
past decades, considerable efforts have been made to achieve
asymmetric catalytic versions of the process.2 More recently, the
need for environmentally friendly and metal-free reactions has
led to great progress in the organocatalyst-mediated Michael
addition.3,4 Of the developed organocatalysts, chiral bifunc-
tional amine-thioureas have been proven to be powerful and
have been applied successfully in asymmetric catalytic Michael
(5) For reviews on chiral thiourea promoted organocatalytic reactions:
(a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (b) Connon, S. J.
Chem.;Eur. J. 2006, 12, 5418. (c) Taylor, M. S.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 1520. (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713. (e) Chen, Y.-C. Synlett 2008, 1919. (f) Xu, L.-W.; Luo, J.;
Lu, Y. Chem. Commun. 2009, 1807.
(6) Results of organocatalytic Michael addition reactions reported by
Jacobsen’s group, see: (a) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc.
2006, 128, 7170. (b) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 6366.
(7) Results of organocatalytic Michael addition reactions reported by
Takemoto’s group, see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am.
Chem. Soc. 2003, 125, 12672. (b) Okino, T.; Nakamura, S.; Furukawa, T.;
Takemoto, Y. Org. Lett. 2004, 6, 625. (c) Okino, T.; Hoashi, Y.; Furukawa,
T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (d) Hoashi, Y.;
Okino, T.; Takemoto, Y. Angew. Chem., Int. Ed. 2005, 44, 4032. (e) Xu, X.;
Yabuta, T.; Yuan, P.; Takemoto, Y. Synlett 2006, 137. (f) Hoashi, Y.;
Yabuta, T.; Yuan, P.; Miyabe, H.; Takemoto, Y. Tetrahedron 2006, 62, 365.
(8) For the results of organocatalytic Michael addition reactions reported
by the Tsogoeva’s group, see: (a) Tsogoeva, S. B.; Yalalov, D. A.; Hateley,
M. J.; Weckbecker, C.; Huthmacher, K. Eur. J. Org. Chem. 2005, 4995.
(b) Tsogoeva, S. B.; Hateley, M. J.; Yalalov, D. A.; Meindl, K.; Weckbecker,
C.; Huthmacher, K. Bioorg. Med. Chem. 2005, 13, 5680. (c) Tsogoeva, S. B.;
Wei, S.-W. Tetrahedron: Asymmetry 2005, 16, 1947. (d) Tsogoeva, S. B.; Wei,
S.-W. Chem. Commun. 2006, 1451. (e) Yalalov, D. A.; Tsogoeva, S. B.;
Schamtz, S. Adv. Synth. Catal. 2006, 348, 826. (f) Wei, S.; Yalalov, D. A.;
Tsogoeva, S. B.; Schmatz, S. Catal. Today 2007, 121, 151.
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: Oxford, 1992. (b) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.;
Petrini, M. Chem. Rev. 2005, 105, 933.
(2) For reviews of asymmetric Michael addition reactions, see: (a)Tomioka,
K.; Nagaoka, Y.; Yamaguchi, M. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999;
€
Vol. III, Chapters 31.1 and 31.2, pp 1105-1139. (b) Krause, N.; Hoffmann-Roder,
A. Synthesis 2001, 171. (c) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877. (d) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42,
1688. (e) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354.
(3) For selected reviews of organocatalysis, see: (a) Dalko, P. I.; Moisan,
L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) List, B. Synlett 2001, 1675.
(c) List, B. Tetrahedron 2002, 58, 5573. (d) Jarvo, E. R.; Miller, S. J.
Tetrahedron 2002, 58, 2481. (e) List, B. Acc. Chem. Res. 2004, 37, 548.
(f) Notz, W.; Tanaka, F.; Barbas, C. F. III. Acc. Chem. Res. 2004, 37, 580.
(4) For reviews of organocatalytic Michael addition reaction, see:
(a) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (b) Enders, D.; Grondal,
€
C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
1402 J. Org. Chem. 2010, 75, 1402–1409
Published on Web 02/05/2010
DOI: 10.1021/jo901991v
r
2010 American Chemical Society

Ma et al.
JOCArticle
FIGURE 1. Saccharide-derived bifunctional thiourea catalysts.
of the nitro functionality to accept hydrogen bonds from suitably
designed catalyst systems, and (c) the high synthetic utility of
the nitroalkane adducts.6-9 In contrast, little progress has
been made in the development of nitrodienes as Michael
acceptors.10,12h-12j
Efforts from our laboratory have focused on the design
and synthesis of a new class of bifunctional amine-thiourea
catalysts based on saccharides.11 These simple organic
molecules have been shown to be excellently enantioselective
for direct Michael addition of ketones and malonates to
nitroolefins. Furthermore, the saccharide-derived thiourea
seemed to be an interesting backbone for the design of new
organocatalysts for asymmetric synthesis. Herein, we report
that saccharide-derived bifunctional thioureas tunably pro-
mote catalytic asymmetric addition reactions of ketones to
nitrodienes, providing very useful adducts in high yields and
stereoselectivities. Such studies would be of immense benefit
for expanding the scope of application of these conjugate
reactions in organic synthesis.
(9) Other chiral thiourea-catalyzed Michael addition reactions; selected
examples: (a) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005,
44, 6367. (b) Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005, 7,
4713. (c) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
(d) McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org. Chem. 2006, 71, 7494.
(e) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901.
(f) Cao, Y.-Y.; Lu, H.-H.; Lai, Y.-Y.; Lu, L.-Q.; Xiao, W.-J. Synthesis 2006,
3795. (g) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
(h) Wang, J.; Li, H.; Zu, L. S.; Jiang, W.; Xie, H. X.; Duan, W. H.; Wang, W.
J. Am. Chem. Soc. 2006, 128, 12652. (i) Jiang, L.; Zheng, H.-T.; Liu, T.-Y.;
Yue, L.; Chen, Y.-C. Tetrahedron 2007, 63, 5123. (j) Cao, Y.-J.; Lai, Y.-Y.;
Wang, X.; Li, Y.-J.; Xiao, W.-J. Tetrahedron Lett. 2007, 48, 21. (k) Wang, Y.;
Li, H. M.; Wang, Y. Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc.
2007, 129, 6364. (l) Zu, L. S.; Wang, J.; Li, H.; Xie, H. X.; Jiang, W.; Wang,
W. J. Am. Chem. Soc. 2007, 129, 1036. (m) McCooey, S. H.; Conon, S. J. Org.
Lett. 2007, 9, 599. (n) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J.
Chem. Commun. 2008, 1431. (o) Han, B.; Liu, Q. P.; Li, R.; Tian, X.; Xiong,
X. F.; Deng, J.-G.; Chen, Y.-C. Chem.;Eur. J. 2008, 14, 8094. (p) Jiang, X.;
Zhang, Y.; Chan, A. S. C.; Wang, R. Org. Lett. 2009, 11, 153. (q) Kokotos,
C. G.; Kokotos, G. Adv. Synth. Catal. 2009, 351, 1355. (r) Bui, T.; Syed, S.;
Barbas, C. F. III. J. Am. Chem. Chem. 2009, 131, 8758. (s) Nodes, W. J.; Nutt,
D. R.; Chippindale, A. M.; Cobb, A. J. A. J. Am. Chem. Soc. 2009, 131,
16016. (t) Guo, L.; Chi, Y.; Almeida, A. M.; Guzei, I. A.; Parker, B. K.;
Gellman, S. H. J. Am. Chem. Soc. 2009, 131, 16018.
Results and Discussion
At the beginning of this work, we have started our
investigation with the addition of acetophenone to phenyl-
nitrodiene 2a in the presence of the simplest thiourea 1a
(Figure 1). The results were listed in Table 1. Interestingly, no
trace of 1,6-addition adduct has ever been observed during
the preliminary optimization study. Only 1,4-addition
occurred with perfect control of the regioselectivity for the
(10) Recently, Alexakis and co-workers provided an excellent example of
the diphenylprolinol-catalyzed additions of aldehydes to nitrodienes: Belot,
S.; Massaro, A.; Tenti, A.; Mordini, A.; Alexakis, A. Org. Lett. 2008, 10,
4557.
(11) (a) Liu, K.; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org.
Lett. 2007, 9, 923. (b) Li, X.-J.; Liu, K.; Ma, H.; Nie, J.; Ma, J.-A. Synlett
2008, 3242.
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TABLE 1. Enantioselective Addition of Acetophenone to Phenylnitro-
diene 2aa
TABLE 2. Enantioselective Addition of Aromatic Ketones to Nitrodiene
2a
catalyst
(mol %)
additive
(mol %)
yieldb
(%)
eec
(%)
entry
solvent
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (15)
1a (20)
1b (15)
1c (15)
1d (15)
1e (15)
23
33
41
40
20
28
97
98
97
98
98
98
2
AcOH (15)
H2O (20)
3
4
PhCO2H (15)
TsOH (15)
5
6
4-NO2PhCO2H (15)
CF3CO2H (15)
PhCO2H (10)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
PhCO2H (5)
7
8
50
55
36
10
30
41
24
15
60
70
78
60
60
98
98
97
94
96
88
99
99
92
97
98
95
64
9
10
11
12
13
14 d
15 e
16
17
18
19
20
Et2O
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
aThe reaction was conducted with phenylnitrodiene (0.2 mmol),
ketone (2.0 mmol), catalyst (0.03 mmol), additives, and solvent. bIso-
lated yield (average of two runs). cThe ee values were determined by
HPLC. dThe reaction was conducted at 0 °C. eThe reaction was
conducted at -20 °C.
adduct 3aa with excellent enantioselectivity (97% ee). How-
ever, the product yield was low (23%), despite the cleanness
of the reaction (entry 1). Subsequently, a screen of weak
Bronsted acid additives was undertaken.4a,9e-9q,12 In most
cases an increase of yields was observed by using these
additivies, while the enantioselectivity was basically main-
tained (entries 2-6). However, no product was obtained in
the presence of CF3CO2H (entry 7). The basis for this
intriguing difference in reactivity is not well understood at
this stage. With decreasing the loading of the additive of
PhCO2H, the catalyst 1a provided the adduct in modest
yields (entries 8 and 9). Variation of other standard reaction
parameters (solvent, temperature, and catalyst loading)
failed to increase the reaction rate and enantioselectivity.
Subsequently, several new thiourea catalysts (1b-e) were
prepared by a simple modification of substituents on the
saccharide backbone. The catalysts 1b and 1c with bulky
substituents at the saccharide scaffold appeared to be more
aIsolated yield (average of two runs). bDetermined by chiral HPLC.
active than the simple compounds 1a (entries 17 and 18).
When replacing of ester moiety with ether protecting groups,
a decrease of both yields and the ee values of the product was
observed (entries 19 and 20). Among them, catalyst 1c with
four pivaloyl groups gave the highest yield (78%), while the
enantioselectivity was maintained (98% ee).
A series of aromatic ketone substrates was probed next. It
was found that the 1c-catalyzed conjugate addition processes
were also applicable to various aromatic ketones in good to
high yields (70-90%) with excellent enantioselectivities (up
to 97% ee) (Table 2, entries 1-7). Good to excellent stereo-
selection was also observed with heteroaromatic ketones
(84-98% ee) (Table 2, entries 8-12). The major enantiomer
(12) Weak Bronsted acids as additives in asymmetric organocatalytic
Michael Addition; see a recent review (ref 4a). Selected recent examples:
(a) Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611. (b) Andrey, O.;
Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559. (c) Andrey, O.;
Alexakis, A.; Tomassini, A.; Bernardinelli, G. Adv. Synth. Catal. 2004, 346,
ꢀ
1147. (d) Marigo, M.; Schulte, T.; Franzen, J.; Jorgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 15710. (e) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem.
Soc. 2006, 128, 10354. (f) Luo, S.; Mi, X.; Zhang, L.; Liu, S.; Xu, H.; Cheng,
J.-P. Angew. Chem., Int. Ed. 2006, 45, 3093. (g) Luo, S.; Zhang, L.; Mi, X.;
Qiao, Y.; Cheng, J.-P. J. Org. Chem. 2007, 72, 9350. (h) Lu, A.; Gao, P.; Wu,
Y.; Wang, Y.; Zhou, Z.; Tang, C. Org. Biomol. Chem. 2009, 7, 3141. (i) Chua,
P. J.; Tan, B.; Zeng, X.; Zhong, G. Bioorg. Med. Chem. Lett. 2009, 19, 3915.
(j) Zeng, X.; Zhong, G. Synthesis 2009, 1545.
(13) CCDC 733670 contains the supplementary crystallographic data for
the product 3ad. These data can also be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
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FIGURE 2. Crystal structure of the adduct 3ad.
single-crystal X-ray diffraction analysis (see the Supporting
Information).14 Probably, the flexibility of catalyst 1g allows
the thiourea group and the primary amine moiety to be
involved in the catalytic addition process of aliphatic ketones
to nitroalkenes with both activation of the nucleophile and
the electrophile, while the rigidity of catalyst 1a or 1c appears
to be suitable to aromatic ketones. A bifunctional catalytic
mechanism was suggested in which a thiourea moiety inter-
acts through hydrogen bonding with a nitro group of the
nitrodienes and enhances their electrophilicity while the
neighboring primary amine activates ketones involving an
iminium ion A and an enamine intermediate B promoted by
acid additive. Subsequently, the C-nucleophile attacks the
si-face of the β-carbon at the nitrodiene to give the imine
intermediate C. Finally, the regeneration of the catalyst
through hydrolysis of the imine C is facilitated by water
(Scheme 1).8e
As noted above, both thioureas 1c and 1g proved to be
efficient catalysts in the conjugate addition to phenylnitro-
dienes with aromatic ketones and (a)cyclic aliphatic ketones,
respectively. Nitrodienes substituted with electron-poor
and -rich arenes (2b and 2c) were also tested (Table 4). The
desired 1,4-adducts were obtained in 48-98% yields with
good to excellent enantioselectivities (84-99% ee) (Table 4,
entries 1-6). When we attempted the enantioselective con-
jugate addition of ketones to aliphatic nitrodiene (1-nitro-
hexa-1,3-diene), no desired product was formed, but some
insoluble polymeric material was observed. Notably, it was
also found that the 1,4-conjugate addition of ketones to
phenylnitroeneyne 2d gave the adducts in high yields and
enantioselectivities (Table 4, entries 7-9).
FIGURE 3. TS structures for the formation of the R and S
enantiomers.
for the adduct 3ad was recrystallized in the enantiomerically
pure form (ee >99.9%) by using dichloromethane/hexane
mixture. The absolute configuration was determined to be
€
S by X-ray measurement and Rontgen diffraction studies
(Figure 2).13 The results show that the si-face of the β-carbon
at the nitrodiene was predominantly approached by the
enamine intermediate generated from ketone and the pri-
mary amine group of the bifunctional catalyst. The attack of
the enamine to the re-face of the nitrodiene was restricted by
the thiourea scaffold of the catalyst (Figure 3).
It is noteworthy that the thioureas 1a-e did not catalyze the
conjugate addition of cyclohexanone to phenylnitrodiene 2a at
all. Accordingly, further modifications of modular organoca-
talyst 1c have been made by simple replacement of cyclohex-
ane-1,2-diamine moiety with chiral 1,2-diphenylethane-1,2-
diamine to give a series of new thiourea-amine catalysts
1f-j (Figure 1). The experimental results showed that the
addition reaction of cyclohexanone to phenylnitrodiene 2a
took place in the presence of these new thioureas and additives
(PhCO2H) in toluene (Table 3, entries 1-5). The bifunctional
thiourea 1g as a highly enantioselective catalyst afforded the
syn-Michael adduct in 93% ee. The yields were further
improved when H2O was used as the coadditive (Table 3,
entries 6 and 7). The water might accelerate the reaction by
facilitating the interconversion of the different intermediates of
the catalytic cycle. Having this new organocatalyst system at
hand, we examined other cyclic ketone substrates. The corre-
sponding products 3am-ar were obtained in excellent yields
(92-98%) with high enantioselectivities (88-99% ee) (Table 3,
entries 8-10). In addition, the addition reaction of acetone to
phenylnitrodiene 2a also afforded the desired product in good yield
(75%) and high enantioselectivity (95% ee), while the more steri-
cally demanding methyl isopropyl ketone gave completely linear
product in 44% yield and 93% ee (Table 3, entries 11 and 12).
The three-dimensional molecular structures of both
modular organocatalysts 1a and 1g were determined by
These 1,4-conjugate addition products 3 are versatile
building blocks for further modifications. For example, the
adducts 3aa and 3aq could easily undergo a simple one-
pot reduction/intramolecular cyclization, followed by pro-
tection, separation of diastereoisomers, oxidation, and
recrystallization to give trans- and cis-(3R)-5-substituted
3-pyrrolidinecarboxylic acids (Scheme 2). (3R,5R)-5-Meth-
yl-3-pyrrolidinecarboxylic acid proved to be an efficient
organocatalyst for anti-Mannich-type reactions.15
Conclusion
We have developed enantioselective organocatalytic con-
jugate addition of a series of ketones to R,β-γ,δ-unsaturated
(14) CCDC 698374 and CCDC 695685 contain the supplementary crys-
tallographic data for the products 1a and 1g. These data can also be obtained
free of charge from the Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_ request/cif.
(15) Mitsumori, S.; Zhang, H.; Cheong, P. Y.-Y.; Houk, K. N.; Tanaka,
F.; Barbas, C. F. III. J. Am. Chem. Soc. 2006, 128, 1040.
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TABLE 3. Enantioselective Addition of Aliphatic Ketones to Nitrodiene 2a
aIsolated yield (average of two runs). bDetermined by 1H NMR or HPLC of crude product. cDetermined by chiral HPLC on the syn adduct.
SCHEME 1. Plausible Mechanism for Bifunctional Thiourea-Amine Catalysis
nitro compounds using bifunctional amine-thiourea cata-
lysts easily prepared from saccharides and chiral diamines.
In all cases, only 1,4-addition occurred without any trace of
the 1,6-adduct. The reaction proceeds well for a great
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TABLE 4. Enantioselective Addition of Ketones to Nitrodienes and Nitroeneynea
aFor aromatic ketones: 1c (15 mol %) and PhCO2H (5 mol %). For alphatic ketones: 1g (15 mol %), PhCO2H (5 mol %), and H2O (200 mol %).
bIsolated yield (average of two runs). cDetermined by 1H NMR or HPLC of crude product. dDetermined by chiral HPLC on the syn adduct.
SCHEME 2. Synthetic Transformations of Adducts 3aa and 3aq
diversity of nucleophilic carbonyl compounds and nitro-
dienes with high enantioselectivties (84-99% ee). Further-
more, this process provides some synthetically useful
intermediates which can easily be transformed into
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JOCArticle
trans- and cis-(3R)-5-substituted 3-pyrrolidinecarboxylic
acids.
(0.4 mmol) were placed in a 5 mL vial equipped with a Teflon-
coated stir bar. The solvent (1 mL) was added under air. The vial
was capped with a white polyethylene stopper, and the resulting
mixture was stirred at room temperature for the stated time.
Then the reaction solution was concentrated in vacuo, and the
crude was purified by flash chromatography to afford the
product. The compounds 3am-as, 3bb, 3bc, 3cb, 3cc, 3db, and
3dc were prepared according to this procedure.
Experimental Section
General Procedure for the Synthesis of Catalysts. To a solu-
tion of 1,2-cyclohexyldiamine (3.6 mmol) in dichloromethane
(20 mL) was added the corresponding saccharide-derived iso-
thiocyanates (3 mmol). The mixture was stirred at room tem-
perature for 3-24 h (TLC) and concentrated. The resulting
residue was purified by flash chromatography with the eluent
(AcOEt/Et3N 100/1) to give the crude solid. The crude solid was
dissolved in a minimal amount of dichloromethane and slowly
precipitated from solution by the addition of petroleum at
0 °C. Filtration afforded the desired thiourea products 1b. The
catalysts of 1c-j were prepared by this similar procedure.16,17
2-(1-Nitro-4-phenylbut-3-en-2-yl)cyclohexanone (3am): yield
1
94%; mp 111-112 °C; [R]20 -1.1 (c 1.0, CH2Cl2); H NMR
D
(500 MHz, CDCl3) δ 1.40-1.52 (m, 1H, cyclohexanone-H),
1.60-1.71 (m, 4H, cyclohexanone-H), 2.05-2.12 (m, 2H, cyclo-
hexanone-H), 2.44-2.47 (m, 1H, cyclohexanone-H), 2.53-2.58
(m, 1H, cyclohexanone-H), 3.33-3.39 (m, 1H, CH), 4.56-4.60
(dd, J = 12.0 Hz, 8.5 Hz, 1H, CHNO2), 4.66-4.71 (m, 1H,
CHNO2), 6.00-6.05 (dd, J = 16.0 Hz, 10.5 Hz, 1H, =CH),
6.46-6.51 (m, 1H, =CH), 7.23-7.36 (m, 5H, Ph-H); 13C NMR
(500 MHz, CDCl3) δ 211.5, 136.5, 135.1, 134.6, 128.8, 128.2,
126.7, 125.9, 78.3, 51.9, 42.9, 32.8, 28.3, 25.3; IR (KBr) ν 3080,
2952, 2871, 1699, 1552, 1494, 1384, 966, 743, 691 cm-1; MS
(ESI) m/z 274.62 (M þ 1)þ; HRMS (EI) found m/z 296.1259
[M þ Na]þ, calcd for C16H19NO3þNa 296.1257; 95% ee, 70/30
dr, determined by HPLC analysis Daicel Chirapak AS-H,
i-PrOH/hexane (20/80), 254 nm, 0.8 mL/min, tR = 21.5 min
(minor), 13.5 min (major).
1
1b: yield 56%; [R]20 þ46.8 (c 0.5, CH2Cl2); H NMR (500
MHz, CDCl3) δ 1.18-D1.28 (m, 6H, cyclohexyl-H), 1.62 (br, 1H,
NH), 1.89 (br, 1H, NH), 2.05-2.16 (m, 2H, cyclohexyl-H), 3.31
(br, 2H NHC(S)NH), 3.70-3.74 (m, 1H, cyclohexyl-H),
4.10-4.15 (m, 1H, cyclohexyl-H), 4.31-4.33 (m, 1H, CH2),
4.46-4.49 (m, 1H, pyranosyl-H), 4.59-4.61 (m, 1H, CH2),
5.57-5.59 (m, 1H, pyranosyl-H), 5.71-5.75 (m, 1H, pyranosyl-
H), 6.00-6.03 (m, 1H, pyranosyl-H), 6.21-6.23 (m, 1H, pyrano-
syl-H), 7.25-8.07 (m, 20H, Ph-H); 13C NMR (125 MHz, CDCl3)
δ179.7, 166.2, 133.5, 133.2, 130.1, 129.9, 129.7, 129.5, 128.8, 128.7,
128.4, 128.2, 83.4, 73.9, 71.4, 69.5, 63.0, 58.7, 58.2, 53.5, 34.5, 33.4,
31.6, 29.7, 28.1, 24.5, 24.4, 22.9, 18.4, 14.2; IR (KBr) ν 2930, 2855,
1731,1558, 1532, 1470, 1441, 1268, 1093, 1069, 708 cm-1; MS
(ESI) m/z 752.20 [M þ 1]þ; HRMS (EI) found m/z 752.2633
[M þ 1]þ, calcd for C41H41N3O9S þ H 752.2636.
Procedure for the Transformation of Compounds 3aa and 3aq.
(i) To a solution of (S)-3aa 500 mg (2.1 mmol) in 20 mL of AcOH
was added zinc powder (4.2 g, 30 equiv) in portions at 55 °C. The
resultant mixture was stirred for 4 h at 65 °C (monitored by
TLC). After zinc powder was filtered off, the filtrate was cooled
to 0 °C. The filtrate was diluted with ethyl acetate and neutra-
lized by the addition of sodium hydrogen carbonate (70%
saturated aqueous). The mixture was extracted with dichloro-
methane (30 mL ꢀ 4), washed with brine, and dried with
magnesium sulfate. The solvent was removed under reduced
pressure to afford 4 (418 mg, 99%) as a colorless oil, and the
residue was directly used to next step without purified.
Procedure for the Thiourea-Promoted Michael Addition of
Ketones to Nitrodienes. Procedure A. The nitrodiene (0.2 mmol),
aryl ketone (2.0 mmol), PhCO2H (0.01 mmol), and catalyst 1c
(0.03 mmol) were placed in a 5 mL vial equipped with a Teflon-
coated stir bar. The solvent (1 mL) was added under air. The vial
was capped with a white polyethylene stopper, and the resulting
mixture was stirred at room temperature for the stated time.
Then the reaction solution was concentrated in vacuo, and the
crude was purified by flash chromatography to afford the
product. The compounds 3aa-al, 3ba, 3ca, and 3da were pre-
pared according to this procedure.
3-(Nitromethyl)-1,5-diphenylpent-4-en-1-one (3aa): yield 78%;
mp 105-107 °C; [R]20D þ1.0 (c 1.0, CH2Cl2);1H NMR (500 MHz,
CDCl3) δ 3.30-3.31 (d, J=6.5 Hz, 2H, COCH2), 3.72-3.80 (m,
1H, CH), 4.60-4.64 (dd, J = 12.0 Hz, 7.5 Hz, 1H, CHNO2),
4.71-4.74 (dd, J=12.0 Hz, 6.0 Hz, 1H, CHNO2), 6.15-6.20 (dd,
J = 16.0 Hz, 9.0 Hz, 1H, dCH), 6.56-6.60 (d, J = 16.0 Hz,
1H, dCH), 7.23-7.27 (m, 1H, Ph-H), 7.29-7.34 (m, 4H, Ph-H),
7.48-7.51 (m, 2H, Ph-H), 7.59-7.62 (m, 1H, Ph-H), 7.96-7.97
(d, J=7.5 Hz, 2H, Ph-H); 13C NMR (500 MHz, CDCl3) δ 197.3,
136.7, 136.4, 133.9, 133.7, 129.0, 128.9, 128.3, 128.2, 126.8, 126.7,
79.0, 40.6, 37.5; IR (KBr) ν 3031, 2907, 1680, 1542, 1450, 1218, 969
907, 758, 691 cm-1; MS (ESI) m/z 296.48 [M þ 1]þ; HRMS (EI)
found m/z 318.1098 [M þ Na]þ, calcd for C18H17NO3 þ Na
318.1101; 98% ee, determined by HPLC analysis Daicel Chirapak
AD-H, i-PrOH/hexane (10/90), 254nm, 1.0mL/min,tR=16.8 min
(minor), 14.7 min (major).
4: 1H NMR (500 MHz, CDCl3) δ 1.81-1.89 (m, 1H, pyrro-
lidine-H), 2.15-2.20 (m, 1H, pyrrolidine-H), 2.91-2.96 (m, 1H,
pyrrolidine-H), 3.11-3.19 (m, 1H, pyrrolidine-H), 3.45-3.50
(m, 1H, pyrrolidine-H), 4.39-4.46 (m, 1H, pyrrolidine-H,
pyrrolidine-H), 5.57 (s, 1H, NH), 6.20-6.27 (m, 1H, dCH),
6.46-6.51 (m, 1H, dCH), 7.22-7.34 (m, 10H, Ph-H); 13C NMR
(100 MHz, CDCl3) δ 142.5, 132.1, 131.5, 130.2, 129.6, 127.4,
127.3, 127.0, 126.3, 126.1, 61.8, 52.6, 42.3, 40.5; IR (KBr) ν 3414,
3138, 2933, 2836, 2112, 1651, 1494, 1443, 1387, 1320, 1198, 970,
750, 702 cm-1
.
(ii) To a solution of 4-nitrobenzoyl chloride (0.47 g, 2.6 mmol)
and Et3N (0.82 mL, 6.0 mmol) in dry CH2Cl2 (10 mL) was added
dropwise a solution of 4 (418 mg, 1.7 mmol) in dry CH2Cl2
(10 mL) at 0 °C. After the mixture was stirred for 24 h
(monitored by TLC), solvent was removed under reduced
pressure. After column chromatography on silica gel (eluent,
ethyl acetate/hexane 1/4), the product 5a (trans) (98% ee) and 5b
(cis) (92% ee) as a white solid was isolated in 37% yield and 23%
yield.
(iii) Ozone was passed through a solution of 5a (142 mg,
0.36 mmol) in dry CH2Cl2 (1.5 mL) at -78 °C for 2 h. Argon gas
was passed through the mixture. The mixture was concentrated
at 0 °C and was added to a mixture of formic acid (90%, 1.5 mL)
and hydrogen peroxide (30%, 0.75 mL). The mixture was stirred
at 40 °C for 1 h and at 70 °C for 1 h and then concentrated. To the
solution of the residue in acetone (12 mL) was added a solution
of KMnO4 (150 mg) in water (6 mL) at room temperature. After
the mixture was stirred for 1 day, concentrated HCl was added
to the mixture until a clear solution was obtained. The mixture
was extracted with CHCl3 (30 mL ꢀ 3). The organic layer was
washed with water and then dried over MgSO4. Concentration,
Procedure B. The nitrodiene (0.2 mmol), ketone (2.0 mmol),
catalyst 1g (0.03 mmol), PhCO2H (0.01 mmol), and H2O
(16) (a) Mbadugha, B. N. A.; Menger, F. M. Org. Lett. 2003, 5, 4041.
~
(b) Velarde, S.; Urbina, V. J.; Pena, M. R. J. Org. Chem. 1996, 61, 9541.
(c) Tiwari, P.; Misra, A. K. Tetrahedron Lett. 2006, 47, 3573. (d) Egusa, K.;
Kusumoto, S.; Fukase, K. Eur. J. Org. Chem. 2003, 3435.
(17) (a) Ishikawa, T.; Fletcher, H. G. J. Org. Chem. 1969, 34, 563.
(b) Muskat, I. E. J. Am. Chem. Soc. 1934, 56, 693. (c) Jensen, H. H.;
Nordstrm, L. U.; Bols, M. J. Am. Chem. Soc. 2004, 126, 9205. (d) Bihovsky,
R.; Selick, C.; Giusti, I. J. Org. Chem. 1988, 53, 4026.
1408 J. Org. Chem. Vol. 75, No. 5, 2010

Ma et al.
JOCArticle
flash chromatography (eluent, ethyl acetate/hexane 1/6 to
MeOH/ethyl acetate 1/4), and recrystallization (dichloro-
methane/hexane) afforded 6a as white solid with an overall yield
of 18%. In the same manner, 6b was obtained in yield of 11%.
Starting from (S)-3aq, 9a (trans) and 9b (cis) were attained with
an overall yield of 21% and 12%.
pyrrolidine-H), 3.63-3.67 (m, 1H, pyrrolidine-H), 3.96-4.00
(t, J=10.5 Hz, 1H, pyrrolidine-H), 5.11-5.14 (t, J=8.0 Hz, 1H,
pyrrolidine-H), 7.05-7.07 (d, J=6.5 Hz, 1H, Ph-H), 7.20-7.23
(t, J=7.0 Hz, 1H, Ph-H), 7.31-7.34 (t, J=7.5 Hz, 3H, Ph-H),
7.38-7.40 (d, J=7.5 Hz, 2H, Ph-H), 7.88-7.89 (d, J=7.5 Hz,
2H, Ph-H); 13C NMR (100 MHz, DMSO-d6) δ 173.4, 167.2,
148.7, 143.6, 142.9, 129.4, 128.8, 127.2, 126.1, 124.1, 61.4, 55.4,
52.9, 43.2; IR (KBr) ν 3433, 3012, 2897, 2344, 1699, 1577, 1505,
1433, 1320, 855, 693 cm-1; MS (ESI) m/z 339.14 (M - H)-;
HRMS (EI) found m/z 363.0954 [M þ Na]þ, calcd for
C18H16N2O5 þ Na 363.0951.
6a: yield 18%; mp 139-140 °C; [R]20D -52.6 (c 1.0, CH2Cl2);
1H NMR (500 MHz, DMSO-d6) δ 2.00-2.04 (m, 1H, pyrroli-
dine-H), 2.58-2.62 (m, 1H, pyrrolidine-H), 3.06-3.11 (m, 1H,
pyrrolidine-H), 3.61-3.64 (dd, J=10.5 Hz, 4.5 Hz, 1H, pyrro-
lidine-H), 3.92-3.96 (dd, J=10.5 Hz, 7.0 Hz, 1H, pyrrolidine-
H), 5.20-5.23 (t, J=7.0 Hz, 1H, pyrrolidine-H), 6.99-7.00 (d,
J=7.0 Hz, 1H, Ph-H), 7.23-7.26 (m, 1H, Ph-H), 7.36-7.38 (m,
3H, Ph-H), 7.84-7.85 (d, J=8.5 Hz, 2H, Ph-H), 8.30-8.31 (d,
J=8.5 Hz, 2H, Ph-H); 13C NMR (125 MHz, CDCl3) δ 177.0,
169.2, 148.4, 142.3, 142.1, 129.3, 128.2, 127.9, 125.6, 123.5, 63.5,
53.7, 39.3, 18.5; IR (KBr) ν 3427, 3054, 2908, 2350, 1724, 1587,
1514, 1428, 1338, 871, 729 cm-1; MS (ESI) m/z 339.12 [M - 1]-;
HRMS (EI) found m/z 363.0953 [M þNa]þ, calcd for
C18H16N2O5 þ Na 363.0951.
Acknowledgment. We gratefully appreciate the National
Natural Science Foundation of China (No. 20772091 and
20972110) and Tianjin Municipal Science & Technology
Commission (No. 07JCDJC04700) for financial support.
Supporting Information Available: Experimental details for
the preparation of organocatalysts 1c-j, the adducts 3ab-al,
3ba, 3ca, 3da, 3an-as, 3bb, 3bc, 3cb, 3cc, 3db, and 3dc, the
intermediate 7, and the products 9a and 9b; 1H and 13C NMR
spectra for all of the new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
6b: yield 11%; mp 136-138 °C; [R]20D -40.0 (c 0.5, CH2Cl2);
1H NMR (500 MHz, DMSO-d6) δ 1.87-1.94 (m, 1H, pyrroli-
dine-H), 2.68-2.74 (m, 1H, pyrrolidine-H), 3.11-3.18 (m, 1H,
J. Org. Chem. Vol. 75, No. 5, 2010 1409