An efficient organocatalytic method for highly enantioselective michael addition of malonates to enones catalyzed by readily accessible primary amine-thiourea

Article abstract of DOI:10.1021/ol3019055

A practical and highly enantioselective Michael addition of malonates to enones catalyzed by simple and readily available bifunctional primary amine-thiourea derived from 1,2-diaminocyclohexane is reported. The addition of weak acids and elevated temperature (ca. 50 °C) improved the efficiency of the Michael reaction. This approach enables the efficient synthesis of 1,5-ketoesters with good yields, excellent enantioselectivities (up to 99% ee), and low loading (0.5-5 mol %) of simple chiral primary amine-thiourea catalysts, and is applicable in multigram scale synthesis.

Full text of DOI:10.1021/ol3019055

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
An Efficient Organocatalytic Method for
Highly Enantioselective Michael Addition of
Malonates to Enones Catalyzed by Readily
Accessible Primary Amine-Thiourea
ꢀ
Krzysztof Dudzinski, Anna M. Pakulska, and Piotr Kwiatkowski*
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
pkwiat@chem.uw.edu.pl
Received July 10, 2012
ABSTRACT
A practical and highly enantioselective Michael addition of malonates to enones catalyzed by simple and readily available bifunctional primary
amine-thiourea derived from 1,2-diaminocyclohexane is reported. The addition of weak acids and elevated temperature (ca. 50 °C) improved the
efficiency of the Michael reaction. This approach enables the efficient synthesis of 1,5-ketoesters with good yields, excellent enantioselectivities
(up to 99% ee), and low loading (0.5ꢀ5 mol %) of simple chiral primary amine-thiourea catalysts, and is applicable in multigram scale synthesis.
Asymmetric organocatalysis promoted by secondary
and primary amines (aminocatalysis) has been recognized
in the past decade as a very powerful tool in organic
synthesis.1 This approach has been successfully applied,
among others, to various asymmetric conjugate addition
reactions proceeding via an iminium activation mode.2
However, in contrast to catalysis with metal complexes,
application of aminocatalysis in the fine chemical industry
is still limited.3 The major drawback of many organocata-
lytic reactions is the requirement of a relatively high
catalyst loading (g10%) and long reaction times.
Currently, of particular interest are organocatalytic
reactions operating with low loadings (e5 mol %)4 of
easily accessible organic molecules, as well as the develop-
ment of more efficient organic catalysts. In some cases
simple modification of a chiral amine structure by the
introduction of, e.g., a thiourea moiety can significantly
improve the catalytic properties.5 In this communication
special attention is focused on catalysis with chiral bifunc-
tional primary amine-thioureas. This group of mole-
cules (e.g., 1aꢀe, Figure 1) was successfully introduced to
organocatalysis by Jacobsen6 and Tsogoeva7 and found
applications mostly in reactions operating via an enamine
intermediate.8 In recent years this type of catalyst was
(1) (a) Dalko, P. I., Ed. Enantioselective Organocatalysis; Wiley-VCH:
Weinheim, 2007. (b) List, B., Ed. Asymmetric Organocatalysis; Topics in
Current Chemistry, Vol. 291; Springer-Verlag, Berlin, 2009. (c) Barbas,
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M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(2) For reviews on asymmetric organocatalytic conjugate additions,
see: (a) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry
2007, 18, 299. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (c)
Zhang, Y.; Wang, W. Catal. Sci. Technol. 2012, 2, 42. (d) Vicario, J. L.;
Badıa, D.; Carillo, L.; Reyes, E. Organocatalytic Enantioselective Con-
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Synthesis of Complex Molecules; RSC Publishing: Cambridge, 2010.
(3) Ballini, R., Ed. Eco-Friendly Synthesis of Fine Chemicals; RSC:
Cambridge, 2009.
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Soc. Rev. 2012, 41, 2406.
(5) For selected reviews on bifunctional amine-thioureas, see:
(a) Siau, W.-Y.; Wang, J. Catal. Sci. Technol. 2011, 1, 1298. (b) Connon,
S. J. Chem.;Eur. J. 2006, 12, 5418.
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8964. (b) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170.
(c) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 6366.
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(b) Yalalov, D. A.; Tsogoeva, S. B.; Schmatz, S. Adv. Synth. Catal.
2006, 348, 826.
r
10.1021/ol3019055
XXXX American Chemical Society

also utilized in selected reactions of R,β-unsaturated car-
bonyl compounds based on iminium activation.9,10 Ye
and Liang10 intensively explored additions of various
nucleophiles to enones catalyzed by primary-tertiary amine-
thiourea catalysts of type 1j derived from 1,2-diaminocy-
clohexane and 9-amino-epi-cinchona alkaloids. This
catalytic system was also successfully applied in Michael
additions of malonates to enones.10b However, results
obtained by Duan and Wang9a indicated that the presence
of an additional tertiary amine is not essential for the
catalytic activity of primary amine-thiourea in the Michael
addition of nitromethane to enones.11
An enantioselective organocatalytic Michael addition
of malonates to enones can be realized using catalysts con-
taining secondary13 and tertiary14 amines as well as chiral
ammonium salts (phase-transfer catalysis).15 In recent years,
more attention has been paid to catalysis with primary
amines.16 Also this group of compounds was successfully
applied for the addition of malonates to enones.10b,17
In our studies we focused on the 1,4-conjugate addition
of malonates to enones in the presence of easily available
primary amine-thioureas derived from 1,2-diaminocyclo-
hexane of type 1aꢀc (Figure 1).
During our studies on Michael reactions catalyzed by
primary amines,12 we observed that simple and easily
available primary amine-thioureas derived from 1,2-di-
aminocyclohexane, e.g. 1a, were efficient catalysts for the
addition of malonates to various enones. Moreover, we
found that the addition of weak acids as cocatalysts and
elevated temperature (ca. 50 °C) significantly improved the
efficiency of the reaction.
(8) For selected examples, see: (a) Liu, K.; Cui, H.-F.; Nie, J.; Dong,
K.-Y.; Li, X.-J.; Ma, J.-A. Org. Lett. 2007, 9, 923. (b) Yalalov, D. A.;
Tsogoeva, S. B.; Shubina, T. E.; Martynova, I. M.; Clark, T. Angew.
Chem., Int. Ed. 2008, 47, 6624. (c) Uehara, H.; Barbas, C. F. Angew.
Chem., Int. Ed. 2009, 48, 9848. (d) Jiang, X.; Zhang, Y.; Chan, A. S. C.;
Wang, R. Org. Lett. 2009, 11, 153. (e) Zhang, X.; Liu, S.; Lao, J.; Du, G.;
Yan, M.; Chan, A. S. C. Tetrahedron: Asymmetry 2009, 20, 1451.
(f) Kokotos, C. G.; Kokotos, G. Adv. Synth. Catal. 2009, 351, 1355. (g) He,
T.; Qian, J.-Y.; Song, H.-L.; Wu, X.-Y. Synlett 2009, 3195. (h) Imashiro,
R.; Uehara, H.; Barbas, C. F. Org. Lett. 2010, 12, 5250. (i) Uehara, H.;
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Imashiro, R.; Hernandez-Torres, G.; Barbas, C. F. Proc. Natl. Acad.
Sci. U.S.A. 2010, 107, 20672. (j) Brown, A. R.; Kuo, W.-H.; Jacobsen,
E. N. J. Am. Chem. Soc. 2010, 132, 9286. (k) Xue, F.; Liu, L.; Zhang, S.;
Duan, W.; Wang, W. Chem.;Eur. J. 2010, 16, 7979. (l) Li, B.-L.; Wang,
Y.-F.; Luo, S.-P.; Zhong, A.-G.; Li, Z.-B.; Du, X.-H.; Xu, D.-Q. Eur. J.
Org. Chem. 2010, 656. (m) Yu, F.; Jin, Z.; Huang, H.; Ye, T.; Liang, X.;
Ye, J. Org. Biomol. Chem. 2010, 8, 4767. (n) Bai, J.-F.; Peng, L.; Wang,
L.; Wang, L.-X.; Xu, X.-Y. Tetrahedron 2010, 66, 8928. (o) Tsakos, M.;
Kokotos, C. G.; Kokotos, G. Adv. Synth. Catal. 2012, 354, 740.
(9) (a) Mei, K.; Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.; Xue, F.;
Duan, W.; Wang, W. Org. Lett. 2009, 11, 2864. (b) Galzerano, P.;
Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.;
Bartoli, G.; Melchiorre, P. Chem.;Eur. J. 2009, 15, 7846. (c) Dong, L.;
Du, Q.; Lou, C.; Zhang, J.; Lu, R.; Yan, M. Synlett 2010, 266. (d) Mei,
R.-Q.; Xu, X.-Y.; Li, Y.-C.; Fu, J.-Y.; Huang, Q.-C.; Wang, L.-X.
Tetrahedron Lett. 2011, 52, 1566. (e) Yang, J.; Huang, H.; Jin, Z.; Wu,
W.; Ye, J. Synthesis 2011, 1984.
(10) (a) Li, P.; Wang, Y.; Liang, X.; Ye, J. Chem. Commun. 2008,
3302. (b) Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang, Y.; Liang, X.; Ye,
J. Org. Lett. 2009, 11, 753. (c) Yang, J.; Li, W.; Jin, Z.; Liang, X.; Ye, J.
Org. Lett. 2010, 12, 5218. (d) Zhou, Y.; Li, X.; Li, W.; Wu, C.; Liang, X.;
Ye, J. Synlett 2010, 2357. (e) Wen, S.; Li, P.; Wu, H.; Yu, F.; Liang, X.;
Jinxing Ye, J. Chem. Commun. 2010, 4806. (f) Jin, Z.; Wang, X.; Huang,
H.; Liang, X.; Ye, J. Org. Lett. 2011, 13, 564. (g) Sun, X.; Yu, F.; Ye, T.;
Liang, X.; Ye, J. Chem.;Eur. J. 2011, 17, 430.
(11) The proposed transition state for nitromethane addition to
enones catalyzed by primary amine-thiourea in ref 9a is not correct
according to the literature and our observations.
(12) Kwiatkowski, P.; Dudzinski, K.; Lyzwa, D. Org. Lett. 2011, 13,
3624.
(13) (a) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem.,
Int. Ed. 1993, 32, 1176. (b) Kawara, A.; Taguchi, T. Tetrahedron Lett.
1994, 35, 8805. (c) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org.
Chem. 1996, 61, 3520. (d) Halland, N.; Aburel, P. S.; Joergensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 661. (e) Knudsen, K. R.; Mitchell,
C. E. T.; Ley, S. V. Chem. Commun. 2006, 66. (f) Wascholowski, V.;
Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem.ꢀEur. J. 2008, 14,
6155. (g) Prasetyanto, E. A.; Lee, S.-C.; Jeong, S.-M.; Park, S.-E. Chem.
Commun. 2008, 1995. (h) Pansare, S. V.; Lingampally, R. Org. Biomol.
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(j) Mase, N.; Fukasawa, M.; Kitagawa, N.; Shibagaki, F.; Noshiro, N.;
Takabe, K. Synlett 2010, 2340.
Figure 1. Organocatalysts examined in the Michael reaction.
As a model reaction we chose the addition of dimethyl
malonate to cyclohexenone (2a, Table 1).18 The product of
this reaction (3a) is a very interesting building block and
was utilized in the synthesis of several natural products,19
e.g., (ꢀ)-strychnine,19a,b tubifolidine,19c and (ꢀ)-gilbertine.19d
Typically Shibasaki’s BINOL/La catalyst20 was applied for
preparation of an optically pure product 3a.
(14) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W.
J. Am. Chem. Soc. 2006, 128, 12652.
(15) (a) Kim, D. Y.; Huh, S. C.; Kim, S. M. Tetrahedron Lett. 2001,
42, 6299. (b) Ooi, T.; Ohara, D.; Fukumoto, K.; Maruoka, K. Org. Lett.
2005, 7, 3195.
(16) For reviews on organocatalysis with primary amines, see:
(a) Jiang, L.; Chen, Y.-C. Catal. Sci. Technol. 2011, 1, 354. (b) Xu,
L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807. (c) Peng, F.; Shao, Z.
J. Mol. Catal. A: Chem. 2008, 285, 1. (d) Chen, Y.-C. Synlett 2008, 1919.
(17) (a) Yang, Y.-Q.; Zhao, G. Chem.;Eur. J. 2008, 14, 10888.
(b) Mao, Z.; Jia, Y.; Li, W.; Wang, R. J. Org. Chem. 2010, 75, 7428.
(c) Yoshida, M.; Narita, M.; Hara, S. J. Org. Chem. 2011, 76, 8513.
(18) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Symmetry 2011, 3, 84.
(19) (a) Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.;
Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14546. (b) Ohshima, T.; Xu,
Y.; Takita, R.; Shibasaki, M. Tetrahedron 2004, 60, 9569. (c) Shimizu, S.;
Ohori, K.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998, 63,
7547. (d) Jiricek, J.; Blechert, S. J. Am. Chem. Soc. 2004, 126, 3534.
(e) Zhu, L.; Lauchli, R.; Loo, M.; Shea, K. J. Org. Lett. 2007, 9, 2269.
(f) Haruta, Y.; Onizuka, K.; Watanabe, K.; Kono, K.; Nohara, A.;
Kubota, K.; Imoto, S.; Sasaki, S. Tetrahedron 2008, 64, 7211. (g) De
Buysser, F.; Verlinden, L.; Verstuyf, A.; De Clercq, P. J. Tetrahedron
Lett. 2009, 50, 4174.
(20) (a) Sasai, H.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1994,
116, 1571. (b) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima,
T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506.
B
Org. Lett., Vol. XX, No. XX, XXXX

During our preliminary investigations we observed that
readily available amino-thiourea 1a (5 mol %) can be a
very promising catalyst in the reaction of cyclohexenone
with dimethyl malonate (Table 1, entries 1ꢀ4). An addi-
tion of 5 mol % of benzoic acid as a cocatalyst and an
increaseoftemperatureto50°C improved thereactionrate
(conv >99%, entry 4). In the presence of stronger acids
(e.g., TFA) the yield was very low (entry 5). Among
various primary amines 1aꢀh (Figure 1) tested in the
presence of benzoic acid, the best results were observed
with thiourea derivatives 1aꢀe. Although conversions
were high (>88%), yields of expected product were lower
(51ꢀ77%) due to the formation of byproducts; among
them dimer 4 dominated.21 The highest enantioselectivity
(97ꢀ98% ee) wasobtainedwithcatalysts1aand 1d(entries
3, 4, and 8). Finally a more readily available catalyst1a was
used for further investigations.
the amount of byproducts. The reaction can be effectively
performed in different solvents as well as neat without loss
of enantioselectivity (entries 4ꢀ6). A higher temperature
(75 °C) lowered yields presumably due to catalyst decom-
position (entry 3). Moreover, we demonstrated that the
reaction is efficient and highly enantioselective (98% ee)
with the use of only 0.5 mol % of catalyst 1a 2BzOH and is
3
applicable in multigram scale synthesis (30 mmol, entry 8).
Inour opinion this isa veryattractive and practicalmethod
for the large-scale preparation of an optically pure com-
pound 3a. The advantages of this method are the need for
small amounts of catalyst (0.5ꢀ1 mol %), almost equimo-
lar amounts of reagents (1.05ꢀ1.2 equiv of dimethyl
malonate), a high concentration of the reaction mixture
(c = 2.5ꢀ3 mol/L), and a simple procedure.
Table 1. Catalyst Screening in the Model Reactiona
amine
acid
temp
yield
(conv) (%)b
ee
(%)c
entry
(5 mol %)
(5 mol %)
(°C)
1
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
none
20
50
20
50
50
50
50
50
50
50
50
50
50
42 (46)
66 (78)
71 (91)
68 (>99)
8 (25)
96 (R)
95 (R)
97 (R)
97 (R)
>95
2
none
3
BzOH
BzOH
TFA
4
5
6
BzOH
BzOH
BzOH
BzOH
BzOH
BzOH
BzOH
none
54 (98)
51 (>99)
77 (88)
61 (99)
18 (72)
40 (64)
40 (43)
<2
90 (R)
90 (R)
98 (R)
65 (R)
40 (R)
56 (R)
96 (R)
>90
7
8
Figure 2. Effect of BzOH additive on the reaction of enone 2a
and 2e with dimethyl malonate.
9
10
11
12
13
1g
1h
1i
Having established the optimal conditions for the reac-
tion of cyclohexenone (2a) with dimethyl malonate, we
extended investigations to other nucleophiles (Figure 3,
products 5, 6, and 7) and other cyclic enones (see products
3b, 3c, and 3d). In the case of cyclopentenone, an
acceptable yield was obtained when the reaction was
carried out in THF in the presence of 1 equiv of water
(product 3d). In all of the cases, good to very high
enantioselectivity was observed.
The reaction of benzylideneacetone (2e) and dimethyl
malonate is efficient with 2 mol % of 1a and a lower
concentration of benzoic acid (1 mol %) (Figure 2)22 and is
applicable in 10 mmol scale. This catalytic system (2ꢀ
5 mol %) is quite efficient for reactions of malonates with a
broad range of acyclic enones (Scheme 1). In most cases,
high enantioselectivity and good yields were achieved after
20 h (products 3eꢀ3i). For acyclic enones containing more
sterically demanding substituents, e.g. isopropyl or isobu-
tyl groups neighboring the carbonyl, the reaction time was
prolonged up to 5 days and products 3l and 3m were
isolated with good yields and high enantioselectivities.
a Reaction conditions: 2a (1 mmol, c = 1.0 mol/L), dimethyl mal-
onate (1.1ꢀ1.2 mmol), amine 1 (0.05 mmol), acid (0.05 mmol) in toluene
(ca. 0.75 mL), 20 or 50 °C, 20 h. b Determined by GC analysis with
internal standard. c Determined by GC analysis using CP-Chirasil-Dex
CB column.
We studied the influence of benzoic acid as an additive
in more detail in the reaction of dimethyl malonate
with cyclohexenone (2a) and benzylideneacetone (2e),
with 2 mol % of amine 1a at 50 °C (Figure 2). The best
results in terms of yield and enantioselectivity for Michael
addition to cyclohexenone were observed in the presence
of 2 equiv of benzoic acid vs 1a.22 Using these optimized
conditions with only 1ꢀ2 mol % of 1a we improved the
yield of 3a (>80%, Table 2, entries 2 and 7) and reduced
(21) When the reaction was carried out without dimethyl malonate
with 5 mol % of 1a BzOH at 50 °C, the conversion of 2a was ca. 60%
after 20 h.
(22) For more details, see Supporting Information.
3
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2. Model Reaction Optimization Studiesa
Scheme 1. Addition of Dimethyl Malonate to Acyclic Enones
1a 2BzOH
temp
conv
(%)b
yield
(%)b,c
ee
(%)d
3
entry
(mol %)
solvent
(°C)
1
2
3
4
5
6
2
2
2
2
2
1
toluene
toluene
toluene
THF
20
50
75
50
50
50
57
95
84
85
86
93
53
98
98
98
99
99
98
85 (82)
73
73
AcOEt
no
66
87
solvent
toluene
toluene
toluene
7e
8f
9g
1
50
50
50
96
80
48
88 (84)
75 (72)
46
98.5
98
0.5
0.2
99
a Reaction conditions: 2a (1 mmol, c = 1.0 mol/L), dimethyl mal-
onate (1.1ꢀ1.2 mmol), catalyst 1a 2BzOH in toluene (ca. 0.75 mL),
3
20ꢀ75 °C, 20 h. b Determined by GC analysis with internal standard.
c Numbers in parentheses refer to isolated yields. d Determined by GC
analysis using CP-Chirasil-Dex CB column. e 2a (20 mmol scale, c =
2.5 mol/L). f 2a (30 mmol scale, c = 2.9 mol/L), 72 h. g 48 h.
Figure 4. Proposed stereochemical model.
Figure 3. Products of Michael reaction with cyclic enones cat-
alyzed by 2ꢀ5 mol % of 1a 2BzOH (isolated yield given).
primary amine-thiourea catalysts and with a small excess
of dimethyl malonate (1.05ꢀ1.2 equiv) in a concentrated
solution. This method allows an efficient synthesis of
1,5-ketoesters with good yields (53ꢀ96%) and excellent
enantioselectivities up to 99% ee and is applicable for
multigram scale synthesis.
Moreover, our results confirmed that the presence of an
additional basic site (e.g., tertiary amine) in the primary
amine-thiourea catalyst structure is not essential for the
efficiency of this reaction.
3
The application of the catalyst (1R,2R)-1a resulted in
formations of, e.g., (R)-(þ)-3a, (R)-(þ)-3d, and (S)-(þ)-3e
products. Such a direction in asymmetric induction can be
explained by a simplified stereochemical model presented
in Figure 4, where cyclohexenone forms an iminium ion
with primary amine and malonate is stabilized via hydro-
gen bonds with a thiourea moiety.
In conclusion, we demonstrate practical and highly
enantioselective Michael additions of malonates to cyclic
and acyclic enones catalyzed by simple and readily avail-
able bifunctional primary amine-thiourea derived from
1,2-diaminocyclohexane. We observed that the addition
of weak acids (e.g., benzoic acid) and increasing the
temperature to 50 °C can significantly improve the effi-
ciency of the Michael reaction. This approach works
well with a low loading (0.5ꢀ5 mol %) of simple chiral
Acknowledgment. We are grateful to the Polish Ministry
of Science and Higher Education (Grant Iuventus Plus 2010
022170) for financial support.
Supporting Information Available. Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX