Simple Cyclohexanediamine-Derived Primary Amine Thiourea Catalyzed Highly Enantioselective Conjugate Addition of Nitroalkanes to Enones

Article abstract of DOI:10.1021/ol9010322

A highly enantioselective conjugate addition of nitroalkanes to enones has been developed. The process Is efficiently catalyzed by a simple chiral cyclohexanediamine-derived primary amine thiourea with a broad substrate scope.

Full text of DOI:10.1021/ol9010322

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2864-2867
Simple Cyclohexanediamine-Derived
Primary Amine Thiourea Catalyzed
Highly Enantioselective Conjugate
Addition of Nitroalkanes to Enones
Kui Mei,† Mei Jin,† Shilei Zhang,† Ping Li,† Wenjing Liu,† Xiaobei Chen,†
Fei Xue,† Wenhu Duan,*,†,‡ and Wei Wang*,†,§
Department of Pharmaceutical Science, School of Pharmacy, East China UniVersity of
Science & Technology, Shanghai 200237, People’s Republic of China, Shanghai
Institute of Materia Medica, Shanghai Institutes of Biological Sciences, Chinese
Academy of Sciences, Graduate School of the Chinese Academy of Sciences,
Shanghai 201203, People’s Republic of China, and Department of Chemistry and
Chemical Biology, UniVersity of New Mexico, Albuqueruqe, New Mexico 87131-0001
whduan@mail.shcnc.ac.cn; wwang@unm.edu
Received March 13, 2009
ABSTRACT
A highly enantioselective conjugate addition of nitroalkanes to enones has been developed. The process is efficiently catalyzed by a simple
chiral cyclohexanediamine-derived primary amine thiourea with a broad substrate scope.
Conjugate additions of carbon-centered nucleophiles to
electron-deficient alkenes are unrivaled in their power for
the formation of fundamental carbon-carbon bonds, whereby
a wide variety of substances that can serve as electrophiles
and nucleophiles and, consequently, a diverse array of
products can be generated.1-5 In the recent past, significant
and impressive progress has been made in the area of
organocatalysis.2-5 However, the use of nitroalkanes for
asymmetric conjugate addition to enones remains an unsolved
problem despite the fact that chiral versatile nitro carbonyl
adducts can be conveniently transformed into a variety of
valuable structures such as pyrrolidines,6 lactones,7 car-
bocycles,8 and amino acids9 in organic synthesis. To date,
† East China University of Science & Technology.
‡ Graduate School of the Chinese Academy of Sciences.
§ University of New Mexico.
(3) For recent reviews of nitro-Michael reactions, see: (a) Berner, O. M.;
Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 12, 1877. (b) Ballini,
R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105,
933.
(1) For reviews of conjugate addition reactions, see: (a) Perlmutter, P.
Conjugate Addition Reactions in Organic Synthesis; Pergamon: Oxford,
1992. (b) Sibi, M.; Manyem, S. Tetrahedron 2001, 56, 8033. (c) Christoffers,
J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688. (d) Ballini, R.; Bosica,
G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. ReV. 2007, 107, 933
(2) For recent reviews of organocatalyzed conjugate addition reactions,
(4) For recent reviews of asymmetric organocatalysis, see: (a) Berkessel,
A.; Groger, H. Asymmetric Organocatalysis-From Biomimetic Concepts to
Applications in Asymmetric Synthesis; Wiley-VCH Verlag GmbH & Co.
KGaA: Weinheim, Germany, 2005. (b) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138. (c) Special Issue on Asymmetric
Organocatalysis . Acc. Chem. Res. 2004, 37, 487.
.
see: (a) Almas¸i, D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry
2007, 18, 299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701
.
10.1021/ol9010322 CCC: $40.75
Published on Web 06/01/2009
 2009 American Chemical Society

among the reported methods, it is realized that generally good
enantioselectivity of the organocatalytic conjugate addition
processes are limited only to cyclic enones.10 Jørgensen11a
and Ley11b independently reported chiral pyrrolidine tetrazole
promoted the addition of 2-nitropropane to acyclic enone
with moderate to good enantioselectivity (70-89% ee). Soo´s
and co-workers described a cinchona alkaloid-derived thio-
urea catalyzed addition of nitromethane with high enanti-
oselectivity.12 Nevertheless, the method only applied for
chalcones as Michael acceptors. More recently, Liang, Ye
and co-workers disclosed an improved protocol and 73-86%
ee were obtained.13
reactions.14 However, their reactivity and selectivity toward
a reaction are strongly substrate-dependent. In some cases,
the subtle changes in the structure of a catalyst can sometimes
significantly improve catalytic activity and stereocontrol.
Accordingly, our attempts to identify an effective catalyst
for conjugate addition of nitromethane (1) to 4-phenylbut-
3-en-2-one (2a) were carried out in the presence of an
organocatalyst (15 mol %) in chloroform at rt (Figure 1).
Clearly, improving the enantioselectivity to a useful level
(g90% ee) of the conjugate addition of nitromethane to
acyclic enones is an important, but currently unmet goal.
Recently, we have initiated an effort on tackling the
challenging issue. Herein, we wish to report the results of
the investigation, which has led to a new simple primary
amine thiourea catalyzed highly enantioselective conjugate
addition of nitromethane to acyclic enones. Notably, high
to excellent (92-99%) enantioselectivities are achieved and
a wide array of R,ꢀ-unsaturated ketones can be exploited
for the process.
Figure 1. Structures of screened organocatalysts.
trans-Cyclohexane diamine derived bifunctional catalysts
have proved to be valuable promoters in Michel addition
(5) For selected examples of organocatalytic asymmetric Michael
additions of stabilized carbanions, see: Nitroalkanes: (a) Li, H.; Wang, Y.;
Tang, T.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906. (b) Okino, T.;
Hoashi, Y.; Furukawa, T.; Xu, X; Takemoto, Y. J. Am. Chem. Soc. 2005,
127, 119. (c) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005,
4481. Ketoesters: (d) Berkessel, A.; Cleemann, F.; Mukherjee, S. Angew.
Chem., Int. Ed. 2006, 45, 947. Diketones: (e) Zu, L.; Wang, W.; Wang, J.;
Li, H.; Duan, W.-H. Org. Lett. 2005, 7, 4713. (f) Malerich, J. P.; Hagihara,
K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416. Nitroesters: (g)
Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am. Chem. Soc. 2004,
126, 706. Dinitriles: (h) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem.,
Int. Ed. 2005, 44, 4032. Malonates: (i) Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li,
W.; Wang, Y.; Liang, S.; Ye, J. Org. Lett. 2009, 11, 753.
Widely used Takemoto’s catalysts I and II failed to promote
the process (Table 1, entries 1 and 2).15 Pyrrolidinesulfona-
Table 1. Asymmetric Michael Addition of Nitromethane (1) to
4-Phenylbut-3-en-2-one (2a)a
(6) (a) Cheruku, S. R.; Padmanilayam, M. P.; Vennerstrom, J. L.
Tetrahedron Lett. 2003, 44, 3701. (b) Halland, N.; Hazell, R. G.; Jørgensen,
K. A. J. Org. Chem. 2002, 67, 8331. (c) List, B.; Pojarliev, P.; Martin,
H. J. Org. Lett. 2001, 3, 2423.
entry
cat.
% yieldb
% eec
(7) Sil, D.; Sharon, A.; Maulikb, P. R.; Rama, V. J. Tetrahedron Lett.
2004, 45, 6273.
1
2
3
4
5
6
7
I
II
III
IV
V
0
0
NDd
NDd
58
59
37
(8) (a) Ballini, R.; Barboni, L.; Bosica, G.; Fiorini, D. Synthesis 2002,
2725. (b) Ballini, R. Synthesis 1993, 687.
(9) (a) Jiang, X.; Zhang, Y.; Chan, A. S. C.; Wang, R. Org. Lett. 2008,
11, 153. (b) Zhu, S. L.; Yu, S. Y.; Ma, D. W. Angew. Chem., Int. Ed.
2008, 47, 545. (c) Foresti, E.; Palmieri, G.; Petrini, M.; Profeta, R. Org.
Biomol. Chem. 2003, 1, 4275.
60
76
52
36
57
(10) (a) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975. (b) Tsogoeva,
S. B.; Jagtap, S. B.; Ardemasova, Z. A.; Kalikhevich, V. N. Eur. J. Org.
Chem. 2004, 4041. (c) Ooi, T.; Takada, S.; Fujioka, S.; Maruoka, K. Org.
Lett. 2005, 7, 5143. (d) Tsogoeva, S. B.; Jagtap, S. B.; Ardemasova, Z. A.
Tetrahedron: Asymmetry 2006, 17, 989. (e) Hanessian, S.; Shao, Z.; Warrier,
J. S. Org. Lett. 2006, 8, 4787. (f) Malmgren, M.; Granander, J.; Amedjkouh,
M. Tetrahedron: Asymmetry 2008, 19, 1934. (g) Szanto, G.; Bombicz, P.;
Grun, A.; Kadas, I. Chirality 2008, 20, 1120. (h) Suresh, P.; Pitchumani,
K. Tetrahedron: Asymmetry 2008, 19, 2037. For related selected examples
of organocatalytic addition of nitromethane to enals, see: (i) Palomo, C.;
Landa, A.; Mielgo, A.; Oiarbide, M.; Puente, A.; Vera, S. Angew. Chem.,
Int. Ed. 2007, 46, 8431. (j) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett.
2007, 9, 5307. (k) Zu, L.-S.; Xie, H.-X.; Li, H.; Wang, J.; Wang, W. AdV.
Synth. Catal. 2007, 349, 2660.
VI
VII
93
97
a Teaction was carried out with 0.1 mmol 2a and nitromethane (0.1
mL) in the presence of 15 mol % an organocatalyst in 0.2 mL of CHCl3 at
rt for 5 d. b Isolated yields. c Determined by HPLC analysis (Chirapak AS-H
column). d Not determined.
mide (III), first developed in our laboratory, displayed an
encouraging result (entry 3).16 It is well established that
thioureas with capability of affording two H-bonds generally
(11) (a) Prieto, A.; Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7,
3897, and ref 5b(b) Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem.
Commun. 2005, 5346. (c) Mitchell, C. E. T.; Brenner, S. E.; Garc´ıa-Fortanet,
J.; Ley, S. V. Org. Biomol. Chem. 2006, 4, 2039.
(14) For a review, see: Taylor, M. S.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 1520. and cited references therein.
(15) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672.
(12) Vakulya, B.; Varga, S.; Csa´mpai, A.; Soo´s, T. Org. Lett. 2005, 7,
1967.
(13) Liang, X.; Ye, J.; Li, P.; Wang, Y. Chem. Commun. 2008, 3302.
(16) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369.
Org. Lett., Vol. 11, No. 13, 2009
2865

give better catalytic efficiency.17 Therefore, catalysts IV and
V containing a thiourea moiety were explored (entries 4 and
5).18 Disappointingly, only marginal improvement in terms
of reaction yield and enantioselectivity was observed with
IV (entry 4). We then turned our attention to the primary
amine thioureas VI and VII although such catalysts had
never shown to be effective promoters for asymmetric
conjugate addition reactions.19,20 To our delight, a promising
result (93% ee) was achieved when VI was employed in
spite of low yield (entry 6). It is noted that the acidity of the
hydrogen bond donor motifs has a dramatic impact on their
catalytic activity. The activity of the catalyst improves as
the acidity of the hydrogen bond donor increases. This
observation was confirmed with catalyst VII (entry 7).
Notably, an excellent level of enantioselectivity (97% ee)
and an enhanced yield (57%) were obtained. Subsequently,
catalyst VII was selected for further reaction condition
optimization mainly aimed at improving yield of the
conjugate addition process without compromising the
enantioselectivity.
We are delighted to demonstrate the generality of this
highly enantioselective Michael reaction with a broad range
of acyclic enones 2 in significant structural variation. As
summarized in Table 3, the VII promoted conjugate addition
Table 3. Asymmetric Michael Addition of Nitromethane to
4-arylbut-3-en-2-one catalyzed by VIIa
entry
R1, R2, 3
Ph, Me, 3a
% yieldb
% eec
1
68
68
74
61
88
82
70
87
89
76
71
76
82
83
64
61
38
58
73
69
82g
98
98
97
97
92
95
95
99
99
96
94
95
93
95
97
97
96
94
98
97
94h
2d
3
p-CH3OC6H4, Me, 3b
p-N(CH3)2C6H4, Me, 3c
3,4-(OCH2O)C6H3, Me, 3d
p-NO2C6H4, Me, 3e
m-NO2C6H4, Me, 3f
o-NO2C6H4, Me, 3g
p-FC6H4, Me, 3h
p-BrC6H4, Me, 3i
o-IC6H4, Me, 3j
2-furanyl, Me, 3k
PhCH2, Me, 3 L
Ph(CH2)2, Me, 3m
n-Me(CH2)4, Me, 3n
trans-PhCHdCH, Me, 3o
Ph, Et, 3p
4
5
6
7
8
9
10
11
12
13
14d
15
16
17d
18
19
20e
21f
We first investigated the solvent effect on the Michael
addition. As shown in Table 2, the reaction yields were
Table 2. Effect of Solvents and Additives on the Asymmetric
Michael Addition of Nitromethane (1) to
4-Phenylbut-3-en-2-one (2a) catalyzed by VIIa
Ph, i-Pr, 3q
Ph, AcOCH2, 3r
Ph, PhCO2CH2, 3s
(CH2)4, 3t
entry
solvent
CH2Cl2
additive
% yieldb
% eec
Ph, Me, 3u
a Reaction conditions: unless specified, see footnote a in Table 1.
b Isolated yields. c Determined by chiral HPLC analysis (Chiralpak AS-H
or AD-H). d When reactions are carried out for 10 d, the yields are 68%
for 3b, 83% for 3n and 38% for 3q, respectively. e Reaction time: 4 d.
f Nitroethane as nucleophile with reaction time of 10 d. g Total yield for
both diastereomers. h 1:1.2 dr and 94% ee for both diastereoisomers, ee
determined by converting to corresponding acetal.
1
2
3
4
5
6
7
8
none
none
none
none
none
none
39
71
32
29
36
57
36
68
48
74
77
<5
97
94
92
89
95
98
99
98
93
89
93
NDd
THF
i-PrOH
DMSO
DMF
CHCl3
1,4-dioxane none
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
none
PhCO2H
AcOH
n-PrCO2H
CF3CO2H
reaction with aryl enones bearing electron-neutral (entry 1),
-donating (entries 2-4), or -withdrawing (entries 5-10)
substituents consistently proceeded in excellent enantiose-
lectivity (92-99% ee). Steric effect of substrates on the
conjugate addition was limited as well (entries 7 and 10).
Moreover, heteroaromatic furanyl derived enone effectively
engaged in the process (entry 11).
9
10
11
12
a Reaction conditions: unless specified, see footnote a in Table 1.
b Isolated yields. c Determined by HPLC analysis (Chirapak AS-H column).
d Not determined.
The VII catalyzed conjugate addition reactions not only
work out with aryl methyl enones, but also less reactive alkyl
systems at both ends with high efficiency (Table 3, entries
12-15). Moreover, the structural variation in switching of
the methyl group to other functionalities in the phenyl enones
can be tolerated (entries 16-19). High enantioselectivities
are obtained (94-98% ee). It is noted that in cases of 3b
(entry 2), 3n (entry 14), and 3q (entry 19), the low reaction
yields are due to slow conversion. Prolonging reaction times
improve their yields. In addition to acyclic enones, cyclic
enones such as cyclichexenone can effectively engage in the
solvent dependent whereas they had a limited impact on the
enantioselectivities. Among the solvents probed, it appeared
that ethyl acetate was the best one (entry 8). The effect of
acid additives was then surveyed. Acid additives such as
AcOH and n-C3H7CO2H improved the yield but with a
decrease in enantioselectivity (entries 10 and 11); PhCO2H
retarded this process and both yield and enantioselectivity
dropped (entry 9). It was found that stronger acid such as
CF3CO2H deteriorated this process significantly and no
product was obtained (entry 12).
2866
Org. Lett., Vol. 11, No. 13, 2009

reaction smoothly (69% yield and 97% ee, entry 20). Finally,
we probe the other nitroalkanes for the conjugate reaction.
It is realized that high yield (82%) and enantioselectivity
(94% ee for both diastereomers with 1:1.2 dr) are achieved
when nitroethane is used (entry 21).
a wide range of enones with a considerable degree of
structural variations. Significantly, high to excellent enan-
tioselectivities (92-99%) are achieved. Therefore, the pro-
tocol provides a useful catalytic approach to the preparation
of synthetic important highly enantiomertic enriched γ-nitro
ketones that are otherwise difficult to make by asymmetric
catalysis. Furthermore, the current study reveals that, slight
structural modification of an organocatalyst can create a more
efficient catalytic system for improving reaction efficiency
that cannot be achieved with existing promoters.
The absolute configuration of the Michael adducts 3a11c
was determined to be S by comparison of HPLC traces and
optical rotation value with those of the literatures reported
(see Supporting Information for detail).
The VII promoted highly enantioselective conjugate
addition of nitromethane to enones could be rationalized by
a proposed model A (Figure 2). The primary amine ef-
Acknowledgment. We are grateful for the financial
support from School of Pharmacy, East China University of
Science, the China 111 Project (Grant No. B07023), the
National Science Foundation of China (Nos. 03772648 and
30721005), and the Chinese National Programs for High
Technology Research and Development (Nos. 2006AA020602
and 2007AA02Z147).
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR and HRMS data for Experi-
Figure 2. Proposed transition state for VII catalyzed conjugate
addition of nitromethane to enones.
mental procedures and characterization of the products 3.
This material is available free of charge via the Internet at
http://pubs.acs.org.
fectively depronates the nitromethane and its small size
allows for accomdating R1 moeitey of the enone,21 while
the thiourea moiety interacts with the carbonyl moiety via
two H-bonds. Moreover, the enhanced acidity of the hydro-
gen bond donor motifs of the thiourea affords stronger
activity. Accordingly, such orientation directs nitronate for
Si face attack (assuming R2 ) Ar) and it is expected that
such synergistic activation delivers high enantioselectivity,
as demonstrated experimentally.
OL9010322
(19) Only two examples using catalysts VI and/or VII for reactions:
aldol reaction (ref 18): 6 and 5% ee, respectively; VII catalyzed nitro-
Mannich reaction, see: Han, B.; Liu, Q.-P.; Li, R.; Tian, X.; Xiong, X.-F.;
Deng, J.-G.; Chen, Y.-C. Chem.sEur. J. 2008, 14, 8094: 32% ee.
(20) (1S,2S)-2-Diaminocyclohexane is used for the preparation of catalyst
25
30
VII: [R]D ) +38.9 1, c ) 1.13, MeOH), [lit. [R]D ) +41.2 (c ) 1.0,
MeOH) Zhang, G.; Liao, Y.; Wang, Z.; Hiroyuki, N.; Takuji, H. Tetrahe-
dron: Asymmetry 2003, 14, 3297. ].
In summary, we have developed a simple primary amine
thiourea catalyzed enantioselective conjugate addition of
nitroalkanes to enones. The reaction allows employment of
(21) For recent reviews of primary amine catalyzed reactions, see: (a)
Xu, L.-W.; Lu, Y.-X. Org. Biomol. Chem. 2008, 6, 2047. (b) Chen, Y.-C.
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Chem. Soc. 2006, 128, 7170. (d) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N.
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S. B.; Wei, S. Chem. Commun. 2006, 1451. (g) Xie, J.-W.; Yue, L.; Chen,
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Org. Lett., Vol. 11, No. 13, 2009
2867