Epi-cinchona based thiourea organocatalyst family as an efficient asymmetric Michael addition promoter: Enantioselective conjugate addition of nitroalkanes to chalcones and α,β-unsaturated N-acylpyrroles

Article abstract of DOI:10.1021/jo702692a

(Chemical Equation Presented) A small set of easily available epi-cinchona based thiourea organocatalysts have been synthesized and tested in enantioselective Michael addition of nitroalkanes to chalcones. These bifunctional catalyst systems promoted the

Full text of DOI:10.1021/jo702692a

Epi-Cinchona Based Thiourea Organocatalyst Family as an Efficient
Asymmetric Michael Addition Promoter: Enantioselective Conjugate
Addition of Nitroalkanes to Chalcones and r,ꢀ-Unsaturated
N-Acylpyrroles
Benedek Vakulya,* Szilárd Varga, and Tibor Soós*
Institute of Biomolecular Chemistry, Chemical Research Center of Hungarian Academy of Sciences,
Budapest, Hungary P.O. Box 17, H-1525
tibor.soos@chemres.hu
ReceiVed December 18, 2007
A small set of easily available epi-cinchona based thiourea organocatalysts have been synthesized and
tested in enantioselective Michael addition of nitroalkanes to chalcones. These bifunctional catalyst systems
promoted the conjugate additions with high enantioselectivities and chemical yields. The extension of
this methodology was further explored to encompass R,ꢀ-unsaturated N-acylpyrroles, as a chalcone mimic.
Functionally, the N-acylpyrrole moiety in the adduct acts as an ester surrogate; therefore, it can easily be
transformed to various valuable and biologically relevant compounds. This approach allowed the concise
stereoselective synthesis of (R)-rolipram.
Introduction
synthesis. Moreover, a thrust of research in this area has also
been fueled by several practical and environmental issues.
The evolution of organocatalysis is tied to the effective
imitation of the enzyme catalytic cleft. Seizing the most
important feature, but not every detail of the catalytic center of
enzymes, it is possible to achieve “general organocatalysts” that
can be utilized for a specific type of reaction (e.g., Michael,
Diels–Alder, and aldol reactions) with a broad range of
substrates. Because acid–base cooperativity is generally invoked
in enzymatic catalysis,3 there is much interest in engineering
organocatalytic systems with properly arranged bifunctionality.4
It has generally been accepted that these catalyst systems are
able to “intramolecularise” the reactions via simultaneous
activation of two reaction partners.5
Catalyst developments for asymmetric reactions hold a
prominent position within organic chemistry.1 For many years,
only enzymes and chiral metal complexes have been employed
as catalysts to promote asymmetric transformations. However,
many reservations with these methodologies have been voiced
which prompted organic chemists to search for alternative
catalytic solution. Finally, enantioselective organocatalysis,
essentially a biomimetic approach, has been developed that
utilizes small chiral organic molecules as suitable catalysts.2
This field has witnessed tremendous developments due to its
efficiency and capacity to extend the scope of chiral organic
* To whom correspondence should be addressed. Phone: +3613257900/162.
(1) (a) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999. (b) Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000.
(2) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b)
Pellissier, H. Tetrahedron 2007, 63, 9267. (c) Berkessel, A.; Gröger, H.;
Asymmetric Organocatalysis, Wiley-VCH: New York, 2005. (d) Dalko, P. I.,
Ed. EnantioselectiVe Organocatalysis; Wiley-VCH: Weinheim, 2007.
(3) Selected examples: (a) Park, H.; Merz, K. M. J. Am. Chem. Soc. 2003,
125, 901. (b) Mazumder, D.; Kahn, K.; Bruice, T. C. J. Am. Chem. Soc. 2003,
125, 7553. (c) Cobucci-Ponzano, B.; Mazzone, M.; Rossi, M.; Moracci, M.
Biochemistry 2005, 44, 6331.
(4) Early examples of bifunctionality in small weight molecular organic
catalysis: (a) Swain, C. G.; Brown, J. F. J. Am. Chem. Soc. 1952, 74, 2534. (b)
Hine, J.; Cholod, M. S.; King, R. A. J. Am. Chem. Soc. 1974, 96, 835.
10.1021/jo702692a CCC: $40.75
Published on Web 04/01/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3475–3480 3475

Vakulya et al.
The enantioselective Michael addition reaction represents one
of the most important methods for the construction of optically
active compounds.6 As a result, considerable effort has been
directed to the development of the organocatalytic asymmetric
version7 of these processes, although the resulting catalysts were
mainly chiral secondary amines using enamine or iminium
activation pathways.
Results and Discussion
The conjugate addition of acidic nitroalkanes to R,ꢀ-unsatur-
ated carbonyl compounds is an important class of C-C bond
forming Michael addition reactions.11 The products of these
reactions are useful intermediates for a variety of natural and
non-natural products. Although several metal catalyzed and
organocatalyzed versions of these reactions exist, there is still
room for further improvement.12–14
Our group recently communicated the development of
bifunctional cinchona organocatalysts for catalyzing the asym-
metric Michael addition reaction of nitromethane to chalcones.8
We prepared several thiourea derived cinchona catalysts and
showed that they efficiently promoted the model reaction with
high level of enantioselectivity. The interest in this class of
catalysts was further heightened after several asymmetric
catalytic applications appeared in the literature with a remarkably
diverse combination of substrates.9,10
Due to the unique position in asymmetric chemistry, we
started to investigate the possible application of cinchona
alkaloids15 in asymmetric Michael addition reactions. The
reasons were evident: quinine has a large number of attributes
that fulfill many requirements sought by synthetic chemists.
Besides its availability and low price, it is endowed with unique
functional, stereochemical, and conformational features that lend
itself and its derivatives as efficient ligands16 or organocata-
lysts.17 Furthermore, over 20 years ago Wynberg and Hiemstra
demonstrated that natural cinchona alkaloids could function as
a bifunctional catalyst in Michael addition reactions. In their
seminal paper, they showed that the C-9 hydroxyl and quinu-
clidine groups are able to position and activate the nucleophiles
and electrophiles in conjugate thiol addition reactions.18 How-
ever, the natural cinchona catalyzed C-C Michael addition of
nitromethane to trans-chalcone proceeded only under 400 MPa
and afforded the adduct with modest enantioselectivity.19 This
result indicated that the exploration of more active bifunctional
cinchona derivatives might be the key to the development of
efficient catalytic processes.
The aim of the present study is to expand our preliminary
investigations in several ways. Further catalysts were prepared
and tested in catalytic asymmetric Michael addition reactions.
Then the substrate scope and limitation were investigated; the
scope of the nitroalkanes and chalcone structures also have been
evaluated. Finally, the stereoselective synthesis of rolipram has
been performed.
(5) Recent papers on bifunctional mechanism: (a) Hamza, A.; Schubert, G.;
Soós, T.; Pápai, I. J. Am. Chem. Soc. 2006, 128, 13151. (b) Bass, J. D.; Solovyov,
A.; Pascall, A. J.; Katz, A. J. Am. Chem. Soc. 2006, 128, 3737. (c) Hammar, P.;
Marcelli, T.; Hiemstra, H.; Himo, F. AdV. Synth. Catal. 2007, 349, 2537. (d)
Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 15872.
Following Wynberg’s proposal to have a more effective
catalyst system, Hatakeyama developed a chiral methodology
based on ꢀ-isocupreidine. Using a covalent linkage, this catalyst
(6) Recent reviews with extensive literature background: (a) Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033. (b) Krause, N.; Hoffmann-Röder, A.
Synthesis 2001, 171. (c) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003,
42, 1688.
(7) Recent reviews: (a) Almasi, D.; Alonso, D. A.; Najera, C Tetrahedron:
Asymmetry 2007, 18, 299. (b) Vicario, J. L.; Badía, D.; Carrillo, L. Synthesis
2007, 2065. (c) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(12) Selected examples using chiral metal complexes: (a) Yamaguchi, M.;
Igarashi, Y.; Reddy, R. S.; Shiraishi, T.; Hirama, M. Tetrahedron 1997, 53,
11223. (b) Funabashi, K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki,
M. Tetrahedron Lett. 1998, 39, 7557. (c) Sundararajan, G.; Prabagaran, N. Org.
Lett. 2001, 3, 389. (d) Lu, S.-F.; Du, D.-M.; Xu, J.; Zhang, S.-W. J. Am. Chem.
Soc. 2006, 128, 7418.
(8) Vakulya, B.; Varga, Sz.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7, 1967.
(9) Applicationofthioureabasedepi-quinineandepi-quinidineorganocatalysts:(a)
McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6370. (b)
Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron, 2006,
62, 375. (c) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am.
Chem. Soc. 2006, 128, 4932. (d) Song, J.; Wang, Y.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 6048. (e) McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org.
Chem. 2006, 71, 7494. (f) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L.
J. Am. Chem. Soc. 2006, 128, 8156. (g) Bode, C. M.; Ting, A.; Schaus, S. E.
Tetrahedron 2006, 62, 11499. (h) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Xie, H.;
Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652. (i) Gu, C.-L.; Liu,
L.; Sui, Y.; Zhao, J.-L.; Wang, D.; Chen, Y.-J. Tetrahedon: Asymmetry 2007,
18, 455. (j) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Mazzanti, A;
Sambri, L.; Melchiore, P. Chem. Comm. 2007, 722. (k) Song, J.; Shih, H.-W.;
Deng, L. Org. Lett. 2007, 9, 603. (l) Wang, B.; Wu, F.; Wang, Y.; Liu, X.;
Deng, L. J. Am. Chem. Soc. 2007, 129, 768. (m) Zu, L.; Wang, J.; Li, H.; Xie,
H.; Jiang, W.; Wang, W. J. Am. Chem. Soc. 2007, 129, 1036. (n) Wang, Y.; Li,
H.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007,
129, 6364. (o) Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2007,
129, 3830. (p) Wang, J.; Zu, L.; Li, H.; Xie, H.; Wang, W. Synthesis 2007,
2576. (q) Amere, M.; Lasne, M.-C.; Rouden, J. Org. Lett. 2007, 9, 2621. (r)
Dine´r, P.; Nielsen, M.; Bertelsen, S.; Niess, B.; Jorgensen, K. A. Chem. Comm.
2007, 3646. (s) Lubkoll, J.; Wennemers, H. Angew. Chem., Int. Ed. 2007, 46,
6841. (t) Pettersen, D.; Piana, F.; Bernardi, L.; Fini, F.; Fochi, M.; Sgarzani, V.;
Ricci, A. Tetrahedron Lett. 2007, 48, 7805. (u) Li, D. R.; Murugan, A.; Falck,
J. R. J. Am. Chem. Soc. 2008, 130, 46. (v) Peschiulli, A.; Gun’ko, Y.; Connon,
S. J. J. Org. Chem. 2008, 73, 2454. (w) Rho, H. S.; Oh, S. H.; Lee, J. W.; Lee,
J. Y.; Chin, J.; Song, C. E. Chem. Commun. 2008, 1208.
(13) Selected references using phase transfer catalysts: (a) Collona, S.;
Hiemstra, H.; Wynberg, H. J. Chem. Soc., Chem. Commun. 1978, 238. (b) Bakó,
P.; Szöllõsy, A.; Bombicz, P.; Tõke, L. Synlett 1997, 291. (c) Corey, E. J.; Zhang,
F.-Y. Org. Lett. 2000, 2, 4257. (d) Kim, D. Y.; Huh, S. C. Tetrahedron 2001,
57, 8933. (e) Bakó, T.; Bakó, P.; Keglevich, Gy.; Báthori, N.; Czugler, M.; Tatai,
J.; Novák, T.; Parlagh, Gy.; Tõke, L. Tetrahedron: Asymmetry 2003, 14, 1917.
(f) Ooi, T.; Takada, S.; Fujioka, S.; Maruoka, K. Org. Lett. 2005, 7, 5143.
(14) Selected references using organocatalysts: (a) Prieto, A.; Halland, N.;
Jorgensen, K. A. Org. Lett. 2005, 7, 3897. (b) Mitchell, C. E. T.; Brenner, S. E.;
Garcia-Fortant, J.; Ley, S. V. Org. Biomol. Chem. 2006, 4, 2039. (c) Hanessian,
S.; Shao, Z.; Warrier, J. S. Org. Lett. 2006, 8, 4787. (d) Linton, B. R.; Reutershan,
M. H.; Aderman, C. M.; Richardson, E. A.; Brownell, K. R.; Ashley, C. W.;
Evans, C. A.; Miller, S. J. Tetrahedron Lett. 2007, 48, 1993. (e) Hojabri, L.;
Hartikka, A.; Moghaddam, F. M.; Arvidsson, P. I. AdV. Synth. Catal. 2007, 349,
740. (f) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307. (g) Zu,
L.; Xie, H.; Li, H.; Wang, W. AdV. Synth. Catal. 2007, 349, 2660.
(15) For reviews, see: (a) Kacprzak, K.; Gawronski, J. Synthesis 2001, 961.
(b) Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem.
Res. 2004, 37, 621.
(16) Some selected reviews: (a) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. ReV. 1994, 94, 2483. (b) Burgi, T.; Baiker, A. Acc. Chem.
Res. 2004, 37, 909.
(17) Some recent examples of the organocatalytic application of cinchona
alkaloids or their derivatives: (a) Alema´n, J.; Jacobsen, C. B.; Frisch, K.;
Overgaard, J.; Jørgensen, K. A. Chem. Commun. 2008, 632. (b) Ricci, P.; Carlone,
A.; Bartoli, G.; Bosco, M.; Sambri, L.; Melchiorre, P. AdV. Synth. Catal. 2007,
350, 49. (c) Chen, W.; Du, W.; Duan, Y.-Z.; Wu, Y.; Yang, S.-Y.; Chen, Y.-C.
Angew. Chem., Int. Ed. 2007, 46, 7667. (d) Poisson, T.; Dalla, V.; Marsais, F.;
Dupas, G.; Oudeyer, S.; Levacher, V. Angew. Chem., Int. Ed. 2007, 46, 7090.
(e) Lopez-Cantarero, J.; Cid, M. B.; Poulsen, T. B.; Bella, M.; Ruano, J. L. G.;
Jorgensen, K. A. J. Org. Chem. 2007, 72, 7062. (f) Perdicchia, D.; Jorgensen,
K. A. J. Org. Chem. 2007, 72, 3565.
(10) Application of thiourea based epi-cinchonine and epi-cinchonidine
organocatalysts which were developed parallel by Chen et al.: (a) Li, B.-J.; Jiang,
L.; Liu, M.; Chen, Y.-C.; Ding, L.-S.; Wu, Y. Synlett 2005, 603. (b) Ye, J.;
Dixon, D. J.; Peter, S.; Hynes, P. S. Chem. Commun. 2005, 4481. (c) Tillman,
A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191. (d) Liu, T. Y.; Cui,
H. L.; Chai, Q.; Long, J.; Li, B. J.; Wu, Y.; Ding, L. S.; Chen, Y. C. Chem.
Commun. 2007, 2228. (e) Hynes, P. S.; Stranges, D.; Stupple, P. A.; Guarna,
A.; Dixon, D. J. Org. Lett. 2007, 9, 2107. (f) Jiang, L.; Zheng, H.-T.; Liu, T.-
Y.; Yue, L.; Chen, Y.-C. Tetrahedron 2007, 63, 5123.
(18) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417.
(19) Sera, A.; Takagi, K.; Katayama, H.; Yamada, H. J. Org. Chem. 1988,
53, 1157.
(11) An excellent review with extensive literature background: Ballini, R.;
Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105, 933.
3476 J. Org. Chem. Vol. 73, No. 9, 2008

Epi-Cinchona Based Thiourea Organocatalyst Family
TABLE 1. Asymmetric 1,4-Addition of Nitromethane to
trans-Chalcone (8a)a
entry
catalyst
t [h]
% yieldb
% eec, d
1
2
3
4
5
6
7
8
9
1a
1b
2a
2b
2c
3
4
5
6
7
99
99
99
99
99
99
99
99
99
99
4
0
93
71
6
42 (S)
-
96 (R)
95 (R)
96 (R)
-
86 (S)
89 (R)
n.d.
0
59
34
1
10
44
91
a The reactions were carried out with 8a (5 mmol), 3 equiv of
nitromethane (15 mmol) in toluene (3 mL) and catalysts 1–7 (10 mol %)
in capped vials at 25 °C. b Yield of isolated product after
chromatography. c Determined by HPLC using a Chiralpak AD column.
d Absolute configuration was determined by comparing the specific
rotation of 9a with that of literature data.26
from quinine, epi-quinine, and quinidine in an experimentally
simple and scalable two-step protocol.24
These novel bifunctional systems and their less acidic
precursors were screened for performance in enantioselective
1,4-addition reaction of trans-chalcone (8a, Table 1). As
expected from high pressure experiments, quinine (1a) showed
poor catalyst activity, and epi-quinine (1b) failed to accelerate
the model reaction. With the amide-functionalized catalyst 6
having a monodentate hydrogen bond donor system, the reaction
was sluggish (Table 1, entry 9). However, the epi-thiourea
derivative 2b and its pseudoenantiomer 4 gave promising results
and the enhanced catalytic activity was mirrored by a significant
increase in enantioselectivity (Table 1, entries 4 and 7). An
interesting feature of these bifunctional epi-thiourea-amine
systems is that the catalytic activity can be tuned without
affecting enantiocontrol via the modification of its Brønsted
basicity or Lewis acidity (Table 1, entries 3, 4, 5, and 8). This
bifunctional system, therefore, seems to be a dominant and
cooperative element which directs the two substrates of the
Michael addition toward a “bifunctional” pathway and the
possible competing, but less organized pathways (e.g., simple
amine catalysis) are not really operating. When we saturated
the vinyl group of the catalysts 2b to give 2a, it improved the
catalytic activity (Table 1, entry 4 vs entry 3). Interestingly,
we found that the modification of vinyl group in 2b to acetylene
in 2c severely impaired the catalytic activity (Table 1, entry 4
vs entry 5). It seems that the kinetics of the these conjugate
additions almost exclusively depends on the quinuclidine
basicity since the smallest possible modification in a relatively
remote group would not markedly alter the conformational
equilibrium of the catalyst or the steric hindrance of the catalytic
cleft. The less Lewis acidic cyclohexyl-thiourea derivative 5
gave the adduct 9a with lower yield but high enantioselectivity
(Table 1, entry 8). In contrast to the epi-thiourea derivatives,
the thiourea system 3 with natural configuration showed no
actiVity in this Michael addition (Table 1, entry 6). This rather
surprising observation in which epi-cinchona derivative proved
to be more efficient than the natural derivative revealed the
FIGURE 1. Bifunctional Lewis acid-amine systems.
has a well arranged spatial bifunctional system with a more
acidic 6′-phenolic group of the quinoline moiety.20 Instead of
covalent linkage, Deng and later Hiemstra used conformational
restricted derivatives as a key design element to have similar
properly arranged bifunctional cinchona systems.21
In search of new bifunctional cinchona catalysts, we assumed
that an effective and readily accessible organocatalyst family
could also be generated if the 9-hydroxyl group is replaced by
the more acidic thiourea group. On the basis of the recent
developments in chiral thiourea-catalysis,22,23 we predicted that
the thiourea moiety would not only be acidic but also would be
capable of forming two hydrogen bonds with the substrates.
Therefore, a set of catalyst candidates (Figure 1) was prepared
(20) Selected examples of ꢀ-isocupreidine catalyzed reactions: (a) Iwabuchi,
Y.; Nakatani, M.; Yokoyoma, N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121,
10219. (b) van Steenis, D. J. V. C.; Marcelli, T.; Lutz, M.; Spek, A. L.; van
Maarseveen, J. H.; Hiemstra, H. AdV. Synth. Catal. 2007, 349, 281.
(21) Excellent review on cupreines and cupreidines: (a) Marcelli, T.; van
Maarseveen, J. H.; Hiemstra, J. Angew. Chem., Int. Ed. 2006, 45, 7496. Selected
examples: (b) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc. 2004,
126, 9906. (c) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928.
(d) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H.
Angew. Chem., Int. Ed. 2006, 45, 929.
(22) Excellent reviews on urea and thiourea utilization in catalysis: (a)
Takemoto, Y.; Miyabe, H. Chimia 2007, 61, 269. (b) Doyle, A. G.; Jacobsen,
E. N. Chem. ReV. 2007, 107, 5713. (c) Connon, S. J. Chem.-Eur. J. 2006, 12,
5418. (d) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520.
(23) Most recent papers using thiourea catalysts: (a) Sohtome, Y.; Takemura,
N.; Takada, K.; Takagi, R.; Iguchi, T.; Nagasawa, K. Chem. Asian J. 2007, 2,
1150. (b) Pan, S. C.; Zhou, J.; List, B. Angew. Chem., Int. Ed. 2007, 46, 612.
(c) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129,
15110. (d) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am.
Chem. Soc. 2007, 129, 13404. (e) Sibi, M. P.; Itoh, K. J. Am. Chem. Soc. 2007,
129, 8064. (f) Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007,
129, 6686. (g) Kotke, M.; Schreiner, P. R. Synthesis 2007, 779.
(24) See Supporting Information.
J. Org. Chem. Vol. 73, No. 9, 2008 3477

Vakulya et al.
TABLE 2. Optimization of Reaction Conditions for Conjugate
Addition of Nitromethane to 8a Using Catalyst 2aa
TABLE 3. Enantioselective Michael Reaction of Nitroalkanes with
Enones 8a-h using 2aa
entry
solvent
T [°C] cat. load [mol %] t [h] % yieldb % eec
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Toluene
CH2Cl2
THF
25
25
25
25
25
25
25
25
50
50
50
50
50
75
100
10
10
10
10
10
10
10
10
5
3
2
1
0.5
110
110
110
110
110
110
110
48
19
27
45
91
94
84
38
31
35
41
77
95
97
95
94
94
82
94
68e
96
93
95
67
90
89
93
94
91
91
92
93
94
90
85
MeOH
CH3CN
Pyridine
Quinoline
entry
R1
R2
R3 R4 t [h] product % yieldb % eec, d
1
2
3
4
5
6
7
8
9
8b p-Cl Ph
8c p-F Ph
8d o-Me Ph
H
H
H
H
H
H
H
H
H
H
122
122
122
122
9b
9c
9d
9e
9f
9g
9h
9i
94
94
93
80
>90f
0
95 (R)d
d
-
98e
89e
96e
0
d
-
d
-
8e
8f
8g H
8h H
8a H
8a H
H
H
p-MeO-Ph H
H
OMe
Me
Ph
d
-
H
H
H
0.1
d
-
122
122
41
–
–
d
-
171
10
5
0
d
-
5
5
Me H
Me Me 192
56/38g, h 94/94e
d
-
Ph
9j
91g
92d
a The reactions were carried out with 9a (5 mmol) and 3 equiv of
nitromethane (15 mmol) in appropriate solvent (3 mL) in capped vials.
b Yield of product isolated after silica gel chromatography. c Determined
by HPLC by using Chiralpak AD column. d Neat reaction condition
without added solvent. e Catalyst finally decomposed at this temperature.
a The reactions were carried out with 8a-j (5 mmol), 5 equiv of
nitroalkane (25 mmol), and catalyst 2a (10 mol%) in toluene (3 mL) in
capped vials at 25 °C. b Yield of isolated product after chromatography.
c Determined by HPLC by using Chiralpak AD column. d Absolute
configuration of 9b was determined by comparing the specific rotation
with that of literature data.13c e Absolute configuration was not
determined. f 1,2-Henry type adduct formed. g Three equivalents of
nitroalkanes were used. h Diastereomers.
importance of the proper three-dimensional arrangement of the
functional groups in the catalytic cleft. Finally, the structurally
similar, but more rigid Takemoto’s catalyst25 7 was tested in
the Michael addition of nitromethane and showed reduced
activity although it furnished the product with high enantiose-
lectivity (Table 1, entry 10).
temperature without any additive (such as cosolvent, base or
molecular sieves) and technical grade reagents can be used with
no effort to exclude oxygen or moisture.
Experiments aimed at exploring the scope of the model
reaction are summarized in Table 3. Somewhat surprisingly,
chalcones having electron-withdrawing or electron-donating
groups showed similar reactivity in Michael addition reactions
and afforded the desired adducts with high level of enantiose-
lectivities (Table 3, entries 1–4). Furthermore, experiments were
run to evaluate the potential of other nitroalkanes in Michael
addition reactions. For the nitroethane and 2-nitropropane
examined, the conjugate addition gave the appropriate nitro
ketones with high yields and enantioselectivities (Table 3, entries
8, 9), however, there was no marked diastereoselectivity in case
of nitroethane. Although the scope of nitroalkanes addition to
chalcones was quite wide, we sought to expand this methodol-
ogy toward synthetically more valuable enone electrophiles.
Experiments that probed this opportunity were conducted. First,
the two structurally similar enone compounds, cinnamic ester
8g and benzylidene acetone (8h), failed to give any adduct in
the test reaction (Table 3, entries 6, 7). Furthermore, in a very
fast reaction, cinnamic aldehyde (8f) gave only racemic product
(Table 3, entry 5), although only the 1,2-adduct was formed
and no 1,4-addition occurred.
The above results led us to conclude that the application of
more reactive ester or enone surrogate is desirable to broaden
the substrate generality of our asymmetric thiourea based
organocatalysis, which was originally developed for chalcones.
Recent detailed investigation among ester surrogates by Shiba-
saki triggered us to investigate the application of R,ꢀ-unsaturated
N-acylpyrroles.27 These easily accessible and transformable
enones have very similar LUMO energy to chalcones due to
the delocalization of the nitrogen lone pair into the pyrrole ring.
Thus, we hypothesized that the chiral catalytic cleft appropriate
for chalcones would also be effective for unsaturated N-
acylpyrroles.
After selecting 2a as the most efficient catalyst, we proceeded
to investigate the influence of three experimental parameters:
solvent, temperature, and catalyst load (Table 2). Except for
the protic MeOH (Table 2, entry 4), the variation of the solvent
had no pronounced effect on the enantioselectivity. However,
the polarity of the solvent markedly influenced the rate of the
addition; the Michael reaction is generally more rapid in less
polar medium (Table 2, entry 1 vs entry 5). However, it seems
very difficult to assess how the medium effect, the specific and
nonspecific binding of the solvent to the catalytic cleft and
solvent induced conformational change of the catalyst indepen-
dently contribute to the observed rate inhibition. The more basic
but less apolar solvents, such as pyridine and quinoline, proved
to be less potent rate inhibitors than the more polar but less
basic CH3CN (Table 2, entries 6 and 7 vs entry 5). These results
would support the importance of medium effect; however, the
less basic and but apolar THF also exerted a very similar
influence on the addition rate (Table 2, entry 5 vs entry 3).
Therefore, we assume that both medium effect, specific coop-
erative binding of the solvent, and modified conformational
equilibrium of the catalyst may be involved in the rate inhibition.
When the model reaction was carried out in neat nitromethane,
an almost complete conversion was achieved in much shorter
time (Table 2, entry 8) which allowed to reduce the catalyst
load down to 0.5 mol% (Table 2, entry 13). Finally, we
recognized one of the most astonishing properties of the catalyst
2a: it maintains the high leVel of enantiocontrol oVer a
remarkable broad temperature range (even at 100 °C, Table 2,
entry 15). In addition to the high chemical yields and enanti-
oselectivity, it is worth emphasizing that our organocatalytic
method has several practical advantages: it runs at ambient
(25) Okino, T.; Hoashi, Y.; Takemoto, Y J. Am. Chem. Soc. 2003, 125,
12672.
(26) Botteghi, C.; Paganelli, S.; Schionato, A.; Boga, C.; Fava, A. J. Mol.
Catal. 1991, 66, 7.
(27) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J. Am.
Chem. Soc. 2004, 126, 7559.
3478 J. Org. Chem. Vol. 73, No. 9, 2008

Epi-Cinchona Based Thiourea Organocatalyst Family
TABLE 4. Asymmetric 1,4-Addition of Nitromethane to r,ꢀ-Unsaturated N-Acylpyrrolesa
entry
R1
cat. (mol%)
MeNO2 (equiv)
t [h]
% yieldb
% eec, e
1
2
3
4
5
6
7
8
9
10a
10b
10c
10d
10e
(E)-10f
(Z)-10f
10g
Ph
10
10
20
10
10
10
10
10
10
10
20
30
5
5
10
5
5
5
3
5
5
87
146
64
146
146
23
65
78
22
93
90
88
81
59
95
81
93
87
54
78
25
93
93
4-MeO-C6H4-
4-Cl-C6H4-
89
2-furyl-
93d
92
2-thienyl-
(E)-PhCH2CH2-
(Z)-PhCH2CH2-
cyclohexyl-
93
-34
94
90
94
93
82
10h
10i
10j
CH2dCH(CH2)8-
(E),(E)-C6H5CHdCH-
3-CpO-4-MeO-C6H3-
3-CpO-4-MeO-C6H3-f
10
11
12
10
10
100
139
183
72
12
a The reactions were carried out with 10a-j (1.0 mmol), 3–100 equiv of neat nitroalkane, and catalyst 2a (10–30 mol%) in capped vials at 25–50 °C.
b Yield of isolated product after chromatography. c Determined by HPLC by using Chiralpak AD column. d Determined by HPLC by using Chiralcel OD
column. e Absolute configuration was not determined. f Carbazole-containing substrate gave 13 adduct.
SCHEME 1. Synthetic Transformation of N-Acylpyrrole
To demonstrate the utility of unsaturated N-acylpyrroles,
Adducts and Concise Synthesis of (R)-Rolipram
various chalcone mimics were synthesized based on literature
procedure.27 The catalytic Michael addition to these substrates
proceeded smoothly under the selected reaction conditions with
high level of enantioselectivity and with no cleavage of the
pyrrole moiety, as summarized in Table 4. The reaction rate
was markedly faster when alkyl instead of aryl or heteroaryl
substituted N-acylpyrroles were used (Table 4, entries 6, 9 vs
entries 1–5). Interestingly, the stereochemistry around the double
bond in the substrate affected not only the reaction rate but also
the configuration of the product, because it gave the opposite
enantiomer (Table 4, entry 6 vs entry 7).28 This phenomenon
indicates that the face selectivity of the nucleophilic attack
remained the same, although less efficient in the (Z)-alkene 10f.
Furthermore, the Michael addition reaction showed exclusive
regioselectivity; when diene 10i was subjected for addition
reaction, no adduct in the δ-position was observed. Finally,
N-acylpyrrole 10j and its easily available N-acylcarbazole
analogue 12 were subjected to Michael additions. As might be
expected, the bulky carbazole moiety reduced the rate of addition
(Table 4, entry 11 vs entry 12).
The synthetic utility of the N-acylpyrroles adduct was
demonstrated by the subsequent elaboration of some selected
adducts (Scheme 1). Although the CO-N bond of N-acylpyrrole
proved to be robust under the catalytic conditions in 11a, it
can be cleaved with piperidine or MeOH to furnish the
corresponding amide 14 and ester 15 derivatives. Our goal was
to eliminate the usage of any Lewis acid or strong base additives
in these reactions to simplify the synthesis and to facilitate the
product isolation. As expected, the more nucleophilic piperidine
reacted at lower temperature (70 °C, capped vial, 24 h).
esterification proved to be a little sluggish, therefore addition
Recrystallization of this product twice from methylcyclohexane
of water was used to facilitate the reaction. The γ-nitro ester
16 was reduced at 23 °C with H2 with Pd/C give the
furnished 14 of >99% ee with good recovery (84%). Using
methanol as a nucleophile, more forcing conditions were
(R)-rolipram (17) after ring closure as a white solid with
necessary (130 °C, 2–3 h). The advantage of this approach was
that no formation of polymerized pyrrole was observed. Finally,
95% ee.29
we accomplished the enantioselective synthesis of (R)-rolipram
(17), using 11j as a key intermediate. In case of 11j, the
Conclusion
In summary, we have developed a readily tunable epi-
cinchona based thiourea organocatalyst family and demonstrated
its utility in asymmetric Michael additions of nitroalkanes to
(28) Recent organometallic examples: (a) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P.
J. Am. Chem. Soc. 2007, 129, 276. (b) Vuagnoux-d’ Augustin, M.; Alexakis, A
Eur. J. Org. Chem. 2007, 5852.
J. Org. Chem. Vol. 73, No. 9, 2008 3479

Vakulya et al.
6.29–6.26 (m, 2H); 4.80 (dd, J ) 12.6, 6.8 Hz, 1H); 4.66 (dd, J )
12.6, 7.7 Hz, 1H); 4.12 (br pseudo q, J ) 7.1 Hz, 1H); 3.76 (s,
3H); 3.28 (dd, J ) 14.5, 4.5 Hz, 1H); 3.22 (dd, J ) 14.5, 4.4 Hz,
1H) ppm; 13C NMR (CDCl3) δ 167.8, 159.4, 130.2, 128.6, 119.0,
114.7, 113.7, 79.5, 55.4, 39.0, 38.0 ppm; IR (KBr) ν 1717, 1557,
1539, 1470, 1380, 1329, 1249, 1115, 747 cm-1; HR-MS (EI) Exact
mass calculated for C15H16N2O4 [M]+ 288.1110; Found: 288.1110;
Anal. calcd for C15H16N2O4: C, 62.49; H, 5.59; N, 9.72; O, 22.20%.
chalcones and R,ꢀ-unsaturated N-acylpyrroles. Significantly, this
catalytic reaction maintained its high enantiocontrol over a
relatively broad range of temperature. This fact and the
simplicity of our methodologys no additives were required, it
is not sensitive to the air and moisture, and technical grade
reagents can be useds are highly advantageous for laboratory
and industrial applications. Finally, taking advantage of the
reactivity inherent to the N-acylpyrroles, the enantioriched
Michael addition products were easily transformed into interest-
ing building blocks. A synthesis of (R)-rolipram was developed
using one of these Michael adducts. Further studies on the
structure of the catalyst and the reaction mechanism are currently
underway in our laboratory.
25
Found: C, 62.19; H, 5.55; N, 9.63%; [R]D +22 (c 1.00, CHCl3,
93% ee).
3-(4-Chlorophenyl)-4-nitro-1-pyrrol-1-yl-butan-1-one (11c).
This product was purified by flash chromatography (hexane/EtOAc
1
) 5/1). Yellowish oil; H NMR (400 MHz, CDCl3) δ 7.34–7.18
(m, 6H), 6.31–6.27 (m, 2H), 4.82 (dd, J ) 12.8, 6.7 Hz, 1H), 4.68
(dd, J ) 12.8, 7.8 Hz, 1H), 4.16 (br pseudo q, J ) 7.0 Hz, 1H),
3.30 (dd, J ) 15.7, 5.6 Hz, 1H), 3.24 (dd, J ) 15.74, 5.52 Hz, 1H)
ppm; 13C NMR (CDCl3): δ 167.4, 136.8, 134.2, 129.5, 128.9, 119.0,
113.9, 79.0, 39.1, 37.7 ppm; IR (KBr) ν 1717, 1553, 1470, 1376,
1333, 1295, 1123, 830, 744 cm-1; HR-MS (EI) Exact mass
calculated for C14H13ClN2O3 [M]+ 292.0615; Found: 292.0608;
Experimental Section
Typical Procedure for Michael Addition of Nitromethane
to r,ꢀ-Unsaturated N-Acylpyrroles: Reaction of 3-Phenyl-1-
pyrrol-1-yl-propenone (10a) as a Representative. To a mixture
of nitromethane (305 mg, 5.0 mmol) and (2E)-3-phenyl-1-pyrrol-
1-yl-2-propen-1-one (10a, 197 mg, 1.0 mmol) was added thiourea
catalyst 2a (59.7 mg, 10 mol%) at ambient temperature. The mixture
was stirred in a capped vial for 87 h, and the volatiles were removed
in vacuo. The residue was purified by flash column chromatography
on silica gel (hexane/CHCl3 ) 4/3 as eluant) affording adduct 11a
(240 mg, 93%).
25
[R]D +21 (c 1.00, CHCl3, 89% ee).
3-(Furan-2-yl)-4-nitro-1-pyrrol-1-yl-butan-1-one (11d). This
product was purified by flash chromatography (hexane/EtOAc )
1
15/2). White solid; mp ) 36 °C; H NMR (400 MHz, CDCl3) δ
7.35 (dd, J ) 1.9, 0.7 Hz, 1H), 7.28 (br s, 2H); 6.32–6.29 (m, 3H);
6.21 (d, J ) 3.3 Hz, 1H); 4.83 (dd, J ) 12.9, 6.3 Hz, 1H); 4.77
(dd, J ) 12.9, 7.0 Hz, 1H); 4.29 (br pseudo q, J ) 6.7 Hz, 1H);
3.37 (dd, J ) 17.3, 6.4 Hz, 1H); 3.30 (dd, J ) 17.3, 7.3 Hz, 1H)
ppm; 13C NMR (CDCl3): δ 167.5; 151.1; 142.7; 119.1; 113.9; 110.7;
107.6; 77.0; 35.4; 33.6 ppm; IR (KBr) ν 1718, 1551, 1473, 1406,
1374, 1301, 1265, 1125, 751 cm-1; HR-MS (EI) Exact mass
calculated for C12H12N2O4 [M]+ 248.0797; Found: 248.0800; Anal.
calcd for C12H12N2O4: C, 58.06; H, 4.87; N, 11.29; O, 25.78%.
Found: C, 57.94; H, 4.83; N, 11.27%; [R]D25 +12 (c 1.00, CHCl3,
93% ee).
4-Nitro-3-phenyl-1-pyrrol-1-yl-butan-1-one (11a). This product
was purified by flash chromatography (hexane/CHCl3 ) 4/3). White
1
solid; mp ) 63 °C; H NMR (400 MHz, CDCl3) δ 7.37–7.22 (m,
7H); 6.29–6.27 (m, 2H); 4.84 (dd, J ) 12.7, 6.8 Hz, 1H); 4.71 (dd,
J ) 12.7, 7.6 Hz, 1H); 4.18 (br pseudo q, J ) 7.1 Hz, 1H);
3.35–3.23 (m, 2H) ppm; 13C NMR (CDCl3) δ 167.7, 138.4, 129.3,
128.3, 127.5, 119.0, 113.8, 79.3, 39.7, 37.8 ppm; IR (KBr) ν 1709,
1547, 1470, 1408, 1378, 1339, 1277, 1125, 750 cm-1; HR-MS
(EI) Exact mass calculated for C14H14N2O3 [M]+ 258.1004; Found:
258.1010; Anal. calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85;
Acknowledgment. We thank Ubichem Research Ltd. for
financial support. The grant 1/A/005/2004 NKFP MediChem2
and OTKA K-69086 is gratefully acknowledged. We gratefully
thank Ágnes Gömöry for running HRMS experiments and Gábor
Tárkányi for NMR measurements.
25
O, 18.58%. Found: C, 65.00; H, 5.43; N, 10.76%; [R]D +21 (c
1.00, CHCl3, 93% ee).
3-(4-Methoxyphenyl)-4-nitro-1-pyrrol-1-yl-butan-1-one (11b).
This product was purified by flash chromatography (CHCl3/hexane
1
) 2/1). White solid; mp ) 78 °C; H NMR (400 MHz, CDCl3) δ
Supporting Information Available: Complete experimental
procedures and characterization of novel compounds; Chiral
HPLC chromatograms for adducts and intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
7.28–7.22 (m, 2H); 7.20–7.14 (m, 2H); 6.88–6.83 (m, 2H);
(29) For recent asymmetric syntheses of rolipram, see: (a) Deng, J.; Duan,
Z.-C.; Huang, J.-D.; Hu, X.-P.; Wang, D.-Y.; Yu, S.-B.; Xu, X.-F.; Zheng, Z.
Org. Lett. 2007, 9, 4825. (b) Paraskar, A. S.; Sudalai, A. Tetrahedron 2006, 62,
4907. (c) Liu, W.-J.; Chen, Z.-L.; Chen, Z.-Y.; Hu, W.-H. Tetrahedron:
Asymmetry 2005, 16, 1693.
JO702692A
3480 J. Org. Chem. Vol. 73, No. 9, 2008