Highly diastereo- and enantioselective organocatalytic michael addition of α-ketoamides to nitroalkenes

Article abstract of DOI:10.1021/ol102289g

The first organocatalytic enantio- and diastereoselective conjugate addition of α-ketoamides to nitroalkenes has been achieved using a bifunctional amino thiourea catalyst. In this new approach, the substrate amide proton plays a critical role in the form

Full text of DOI:10.1021/ol102289g

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5246-5249
Highly Diastereo- and Enantioselective
Organocatalytic Michael Addition of
r-Ketoamides to Nitroalkenes
Olivier Basle´, Wilfried Raimondi, Maria del Mar Sanchez Duque, Damien Bonne,*
Thierry Constantieux,* and Jean Rodriguez*
UMR CNRS 6263 iSm2, Aix-Marseille UniVersite´, Centre Saint Je´roˆme, serVice 531,
13397 Marseille, France
jean.rodriguez@uniV-cezanne.fr; thierry.constantieux@uniV-cezanne.fr;
damien.bonne@uniV-cezanne.fr
Received September 23, 2010
ABSTRACT
The first organocatalytic enantio- and diastereoselective conjugate addition of r-ketoamides to nitroalkenes has been achieved using a bifunctional
amino thiourea catalyst. In this new approach, the substrate amide proton plays a critical role in the formation of the Michael anti-adducts in
high yields and high stereoselectivities. To illustrate the high synthetic potential of this methodology, the diastereo- and enantioselective
synthesis of a hexasubstituted cyclohexane via a Michael-Michael-Henry cascade reaction is described.
Modern organic chemistry demands sustainable and selective
methods for the construction of carbon-carbon bonds.1 For
this purpose, the organocatalytic Michael addition of carbon-
centered nucleophiles to nitroalkenes represents a particularly
attractive approach,2 providing rapid access to versatile
building blocks with functional diversity and molecular
complexity in an atom-economical manner. In the past
decade, the development of small chiral organic molecules
mimicking enzyme activation has emerged as an appealing
strategy for catalytic asymmetric conjugate addition of
malonate derivatives or simple aldehydes and ketones on
various activated alkenes.3 Nevertheless, the search for more
elaborated pronucleophiles remains a research area of high
interest.4 In this context, systems of higher complexity and
broad synthetic value such as 1,2-dicarbonyl compounds (R-
ketoesters or R-ketoamides) were only occasionally explored
as pronucleophiles in organocatalysis.5 Their high electro-
philic character6 combined with their intrinsic potential for
(3) For recent reviews, see: (a) Palomo, C.; Oiarbide, M.; Lo´pez, R.
Chem. Soc. ReV. 2009, 38, 632. (b) Bertelsen, S.; Jørgensen, K. A. Chem.
Soc. ReV. 2009, 38, 2178. (c) Dondoni, A.; Massi, A. Angew. Chem., Int.
Ed. 2008, 47, 4638. (d) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli,
G. Angew. Chem., Int. Ed. 2008, 47, 6138. (e) Mukherjee, S.; Yang, J. W.;
Hoffmann, S.; List, B. Chem. ReV. 2007, 107, 5471. (f) Doyle, A. G.;
Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (g) Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 1701. (h) Sulzer-Mosse´, S.; Alexakis, A. Chem. Commun.
2007, 3123. (i) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis 2007, 2065.
(j) Almasi, D.; Alonso, D. A.; Na´jera, C. Tetrahedron: Asymmetry 2007,
18, 299. (k) Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem.,
Int. Ed. 2006, 45, 7496. (l) Taylor, M. S.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 1520.
(1) Li, C.-J.; Trost, B. M. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 13197.
(2) For selected recent examples, see: (a) Ban, S.; Du, D.-M.; Liu, H.;
Yang, W. Eur. J. Org. Chem. 2010, 5160. (b) Rodriguez-Llansola, F.;
Miravet, J. F.; Escuder, B. Chem.sEur. J. 2010, 16, 8480. (c) Balaguer,
A.-N.; Companyo´, X.; Calvet, T.; Font-Bard´ıa, M.; Moyano, A.; Rios, R.
Eur. J. Org. Chem. 2009, 199. (d) Alema´n, J.; Milelli, A.; Cabrera, S.;
Reyes, E.; Jørgensen, K. A. Chem.sEur. J. 2008, 14, 10958. (e) Zhou,
W.-M.; Liu, H.; Du, D.-M. Org. Lett. 2008, 10, 2817. (f) Liu, K.; Cui,
H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org. Lett. 2007, 9, 923. (g)
Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170.
(4) (a) Alonso, D. A.; Kitagaki, S.; Utsumi, N.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2008, 47, 4588. (b) Lubkoll, J.; Wennemers, H. Angew.
Chem., Int. Ed. 2007, 46, 6841.
10.1021/ol102289g  2010 American Chemical Society
Published on Web 10/25/2010

self-condensation7 and their considered lower acidity com-
pared to 1,3-dicarbonyl compounds,8 significantly limit their
use in intermolecular reactions.
Scheme 1
.
Asymmetric Conjugate Addition of 1,2-Dicarbonyl
Compounds to Nitroalkenes
Despite previous achievements,9,10 asymmetric conjugate
addition with 1,2-dicarbonyl compounds remained unsolved
until very recent examples from the Sodeoka and Shibasaki
groups. In these excellent reports, highly enantioselective 1,4-
addition of R-ketoesters or R-ketoamides to nitroalkenes by
mono- or dinuclear chiral nickel complexes were indepen-
dently developed with complementary diastereoselectivities.11
Our ongoing interest in ketoamide reactivity12 and organo-
catalytic conjugated additions to nitroalkenes13 prompted us
to investigate the unexplored and challenging asymmetric
Michael reaction of R-ketoamides with nitroalkenes (Scheme
1). Herein we present the first example of diastereo- and
enantioselective organocatalytic conjugate addition of 1,2-
dicarbonyl compounds as pronucleophiles.
acceptor, hydrogen bonding promoted by functionalized
thioureas largely leads the way with nitroolefins.15
In the past, success in the development of nucleophilic
addition of carbonyl compounds has been obtained with
chiral organocatalysts through different strategies. Transient
enamine formation from aldehydes or ketones provides a
widespread method for the catalytic generation of enolate
equivalents.3d A basic nitrogen center in the catalyst to aid
in the deprotonation of the carbonyl substrate and bind to
the resulting enolate intermediate represents another impor-
tant strategy.14 Concerning the activation of the Michael
Based on previous achievements in organocatalysis, we began
our investigation by testing the reaction between R-ketoamide
1a and nitrostyrene 2a in the presence of catalytic amounts of
a chiral organocatalyst. It is noteworthy that neither proline nor
proline derivatives showed any significant activity under
standard conditions (see the Supporting Information). Alterna-
tively, bifunctional amine-thiourea 4-7 was found to be more
appropriate for this transformation (Table 1) indicating that a
(5) For a cross-aldol example, see: Torii, H.; Nakadai, M.; Ishihara, K.;
Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983.
(6) For the use of 1,2-ketoesters and 1,2-ketoamides as electrophiles in
organocatalytic transformations, see: (a) Tokuda, O.; Kano, T.; Gao, W.-
G.; Ikemoto, T.; Maruoka, K. Org. Lett. 2005, 7, 5103. (b) Li, H.; Wang,
B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732. (c) Wang, F.; Xiong, Y.;
Liu, X.; Feng, X. AdV. Synth. Catal. 2007, 349, 2665. (d) Takada, K.;
Takemura, N.; Cho, K.; Sohtome, Y.; Nagasawa, K. Tetrahedron Lett. 2008,
49, 1623. (e) Li, Y.; Zhao, Z.-A.; He, H.; You, S.-L. AdV. Synth. Catal.
2008, 350, 1885. (f) Yang, J.; Wang, T.; Ding, Z.; Shen, Z.; Zhang, Y.
Org. Biomol. Chem. 2009, 7, 2208. (g) Xiang, J.; Li, B. Chin. J. Chem.
2010, 28, 617.
Table 1. Optimization of the Reaction Conditionsa
(7) Dambruoso, P.; Massi, A.; Dondoni, A. Org. Lett. 2005, 7, 4657.
For an application to Nazarov cyclization, see: Basak, A. K.; Shimada, N.;
Bow, W. F.; Vicic, D. A.; Tius, M. A. J. Am. Chem. Soc. 2010, 132, 8266.
(8) Bonne, D.; Coquerel, Y.; Constantieux, T.; Rodriguez, J. Tetrahe-
dron: Asymmetry 2010, 21, 1085.
(9) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem. Int. Ed
2001, 40, 2995. See also: Juhl, K.; Jørgensen, K. A. J. Am. Chem. Soc.
2002, 124, 2420
.
(10) (a) Lu, G.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2008, 47, 6847. (b) Xu, Y.; Lu, G.; Matsunaga, S.; Shibasaki,
M. Angew. Chem., Int. Ed. 2009, 48, 3353
.
(11) (a) Nakamura, A.; Lectard, S.; Hashizume, D.; Hamashima, Y.;
Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4036. (b) Nakamura, A.; Lectard,
S.; Shimizu, R.; Hamashima, Y.; Sodeoka, M. Tetrahedron: Asymmetry
2010, 21, 1682. (c) Xu, Y.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2010,
12, 3246. For a non-enantioselective conjugated addition of R-ketoesters
to nitroalkenes, see: Maeda, H.; Kraus, G. A. J. Org. Chem. 1997, 62, 2314.
(12) (a) Allais, C.; Constantieux, T.; Rodriguez, J. Synthesis 2009, 2523.
(b) Allais, C.; Constantieux, T.; Rodriguez, J. Chem.sEur. J. 2009, 15,
12945. (c) Sotoca, E.; Allais, C.; Constantieux, T.; Rodriguez, J. Org. Biomol.
Chem. 2009, 7, 1911. (d) Sotoca, E.; Constantieux, T.; Rodriguez, J. Synlett
2008, 1313. (e) Lie´by-Muller, F.; Allais, C.; Constantieux, T.; Rodriguez, J.
Chem. Commun. 2008, 4207. (f) Lie´by Muller, F.; Constantieux, T.;
Rodriguez, J. J. Am. Chem. Soc. 2005, 127, 17176.
entry
catalyst
solvent
yieldb (%)
drc
5:1
>20:1
>20:1
15:1
>20:1
>20:1
>20:1
>20:1
>20:1
eed (%)
1
2
3
4
5
6
7
8
9
4
5
5
5
5
5
5
6
7
toluene
toluene
THF
DCM
DCE
EtOAc
2-propanol
EtOAc
EtOAc
<10
89
85
85
80
83
82
40
44
nd
96
98
98
99
>99
90
60
(13) (a) Raimondi, W.; Lettieri, G.; Dulce`re, J.-P.; Bonne, D.; Rodriguez,
J. Chem. Commun 2010, 46, 7247. (b) Dumez, E.; Durand, A.-C.; Guillaume,
M.; Roger, P.-Y.; Faure, R.; Pons, J.-M.; Herbette, G.; Dulce`re, J.-P.; Bonne,
D.; Rodriguez, J. Chem.sEur. J. 2009, 15, 12470. (c) Bonne, D.; Salat, L.;
Dulce`re, J.-P.; Rodriguez, J. Org. Lett. 2008, 10, 5409.
41
a Ketoamide 1a (0.1 mmol), nitrostyrene 2a (0.11 mmol), solvent (0.2
mL). b Isolated yield after column chromatography. c Determined by 1H
NMR of the crude reaction product. d Determined by chiral HPLC analysis.
(14) For recent examples of soft enolization with organocatalyst, see:
(a) Kohler, M. C.; Yost, J. M.; Garnsey, M. R.; Coltart, D. M. Org. Lett.
2010, 12, 3376.
Org. Lett., Vol. 12, No. 22, 2010
5247

noncovalent hydrogen-bonding catalysis was probably required
for this transformation.
A wide range of aromatic and heteroaromatic nitroalkenes
underwent reaction with R-ketoamides in high yield, excel-
lent diastereoselectivities, and very good enantioselectivities
(dr >20:1, up to >99% ee). The absolute configuration and
the relative anti-selectivity were determined by X-ray
crystallographic analysis of 3e (Figure 1).17 Our findings
nicely complement the syn-selectivity observed when a
dinuclear nickel complex is used as catalyst.11c
While being efficient in the case of simple ketones via
enamine formation, the primary-amine thiourea catalyst 4
failed in producing the desired Michael adduct with syntheti-
cally useful yield and selectivity after 60 h at room
temperature (entry 1).2g To our delight, the Takemoto urea
catalyst (TUC, 5) with an appended tertiary amine15d
efficiently activates both substrates with strictly defined
conformation providing the desired product with high dia-
stereomeric ratio and 96% enantiomeric excess in toluene
(entry 2). This reaction was greatly product selective, and
only a minimal amount of byproduct (5-10%) due to
overreaction was isolated (Vide infra, Scheme 2).
After the reaction solvent was screened, the enantioselec-
tivity was further improved to >99% in ethyl acetate (entry
6). Surprisingly, the catalytic hydrogen-bonding activation
appeared to be also efficient in 2-propanol protic solvent,
although a lower enantioselectivity was obtained (entry 7).
Quinine-derived catalyst 6,16 in which either the quinoline
phenol or the C-9 alcohol can play the role of the thiourea
moiety, was also able to promote the formation of the
Michael adduct with the same high diastereoselectivity.
However, a moderate yield and a low enantioselectivity
resulted in this case (entry 8). Finally, since the more
elaborate thiourea-cinchonidine catalyst 7 afforded no ad-
vantage (entry 9), we selected the relatively simple and
commercially available thiourea 5 as the optimal catalyst.
Under the optimized reaction conditions, both the scope
and the generality of this new organocatalytic Michael addi-
tion of 1,2-dicarbonyl compounds were explored (Table 2).
Figure 1. X-ray structure of product 3e.
In order to achieve similar results with the highly reactive
R-ketoanilide 1c (Table 2, entries 9-13), reactions were run
at lower temperature (-35 °C, see the Supporting Informa-
tion). Importantly, R-ketoanilide 1c efficiently reacted with
the aliphatic nitroolefin 2g to afford the adduct 3m in high
yield and stereoselectivity (entry 13). The generally accepted
mechanism for Michael adduct formation with bifunctional
catalysts such as 5 involves electrophilic activation of the
nitroolefin via a bidentate H-bond interaction and concomi-
tant protonation of the tertiary amine basic center.15 The
resulting ion pair would adopt a multiple H-bonded transition
state. Therefore, a preferential approach of the Si face of
(Z)-enolate on the Re face of the nitroalkene could account
for the observed stereochemistry (Figure 2). Moreover, it is
Table 2. Thiourea-Catalyzed Conjugate Addition of
R-Ketoanilides to Nitroolefinsa
yieldc
drd
eee
entry
R1
2
1
product t (h) (%) syn/anti (%)
1
2
3
4
5
6
7
8
9
Ph
2a 1a
3a
3b
3c
3d
3e
3f
3g
3h
3i
60
60
60
48
60
60
60
60
16
16
16
16
40
83
73
71
76
67
93
75
73
94
93
82
93
92
>20:1 >99
4-MeOC6H4 2b 1a
>20:1
94
93
95
98
98
95
95
91
85
94
90
85
4-BrC6H4
4-FC6H4
2-thienyl
Ph
4-MeOC6H4 2b 1b
2-thienyl
Ph
2c 1a
2d 1a
2e 1a
2a 1b
14:1
10:1
13:1
Figure 2. Proposed transition state for the Michael addition.
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
important to highlight the critical role of the amide N-H
moiety in the described transformation. In fact, only trace
2e 1b
2a 1c
10 4-MeOC6H4 2b 1c
11 4-FC6H4 2d 1c
12 4-NO2C6H4 2f 1c
13 CH2CH2Ph 2g 1c
3j
3k
3l
(15) (a) Zhang, Z.; Schreiner, P. R. Chem. Soc. ReV. 2009, 38, 1187.
(b) Connon, S. J. Chem. Commun. 2008, 2499. (c) Hamza, A.; Schubert,
G.; Soo´s, T.; Pa´pai, I. J. Am. Chem. Soc. 2006, 128, 13151. (d) Okino, T.;
Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005,
127, 119. (e) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299.
(16) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004,
126, 9906.
3m
a Standard conditions: ketoanilide 1 (0.2 mmol), nitroolefin 2 (0.21
mmol) in ethyl acetate (0.4 mL). b Ketoanilide 1c (0.2 mmol), nitroolefin
2 (0.24 mmol) at -35 °C. c Isolated yield based on ketoanilides 1.
Determined by H NMR of the crude reaction product. e Determined by
d
1
(17) CCDC 790424 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
chiral HPLC analysis.
5248
Org. Lett., Vol. 12, No. 22, 2010

amounts of the desired product were detected in presence
of a tertiary amide substrate preventing an extra potential
cooperative H-bonding interaction.18
proton provided Michael adducts with broad generality in
high yield, excellent anti-selectivity and very good enantio-
selectivity. Such R-keto-δ-nitroamides have potential syn-
thetic usage as intermediates in polysubstituted pyrrolidines
preparation.11 Moreover, the described method nicely comple-
ments the syn-selective organometallic activation and finds
an interesting application in the diastereo- and enantiose-
lective synthesis of a densely functionalized cyclohexane via
a Michael-Michael-Henry type of cascade reaction where
six stereogenic carbons are created and controlled in one
single reaction. The mechanism and synthetic applications
of the described organocatalytic transformations are under
further investigation.
During the course of the reaction scope investigation, we
observed the high tendency of the fluorinated nitroalkene
2d to overreact with the 1,4-adduct and generate the densely
functionalized cyclic compound 8 in a Michael-Michael-
Henry type of cascade reaction.19,20 This potential was
exploited by reacting R-ketoanilide 1a with an excess of
nitroalkene 2d for 4 days. Impressively, the hexasubstituted
cyclohexane 8 was isolated in a remarkably excellent
stereoselectivity of 98% ee (Scheme 2).
Acknowledgment. This research was supported by the
French Research Ministry, The Agence Nationale pour la
Recherche (ANR-07-CP2D-06), the Universite´ Paul Ce´zanne,
and the CNRS (UMR 6263). We thank Dr. N. Vanthuyne
(iSm2-UMR 6263) for chiral HPLC analysis and M. Giorgi
(www.spectropole.fr) for the X-ray structure.
Scheme 2
.
Enantioselective Synthesis of Hexasubstituted
Cyclohexane 8 by an Asymmetric
Michael-Michael-Henry-Type Cascade Reaction
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL102289G
(19) For reviews on organocatalytic cascade reactions, see: (a) Alba,
A.-N.; Companyo´, X.; Viciano, M.; Rios, R. Curr. Org. Chem. 2009, 13,
1432. (b) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (c) Enders,
D.; Grondal, C.; Huˆttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570.
(d) Grondal, C.; Jeanty, M.; Enders, D. Nature Chem. 2010, 2, 167. For
very recent selected examples of organocatalytic cascade Michael-Michael
reaction, see: (e) Ma, A.; Ma, D. Org. Lett. 2010, 12, 3634, and references
therein. (f) McGarraugh, P. G.; Brenner, S. E. Org. Lett. 2009, 11, 5654.
For Michael-Henry reaction, see: (g) Tan, B.; Chua, P. J.; Li, Y.; Zhong,
G. Org. Lett. 2008, 10, 2437, and references cited therein. For TUC-
catalyzed Michael-Michael-type reactions, see: (h) Hoashi, Y.; Tabuta,
T.; Takemoto, Y. Tetrahedron Lett. 2004, 9185.
In conclusion, we developed the first efficient organocata-
lytic asymmetric conjugate addition of R-ketoamides to
nitroalkenes. The commercially available tertiary amine-
thiourea catalyst 5 with the cooperative effect of the amide
(18) Reaction in the presence of tertiary amide subtrate:
(20) For
a TUC-catalyzed Henry-type reaction, see: Okino, T.;
Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625.
Org. Lett., Vol. 12, No. 22, 2010
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