Catalytic enantioselective synthesis of β-trifluoromethyl pyrrolines

Article abstract of DOI:10.1039/c2cc18049a

Enantioselective synthesis of β-trifluoromethylated pyrrolines has been developed by the organocatalyzed-conjugated addition of nitromethane to β-trifluoromethylated enones, followed by a nitro-reduction/cyclization/ dehydration sequence in a one-pot procedure with 97-98% ees.

Full text of DOI:10.1039/c2cc18049a

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COMMUNICATION
Catalytic enantioselective synthesis of b-trifluoromethyl pyrrolineswz
Hiroyuki Kawai,a Takashi Kitayama,a Etsuko Tokunaga,a Takashi Matsumoto,b
Hiroyasu Sato,b Motoo Shirob and Norio Shibata*a
Received 23rd December 2011, Accepted 9th February 2012
DOI: 10.1039/c2cc18049a
Enantioselective synthesis of b-trifluoromethylated pyrrolines
has been developed by the organocatalyzed-conjugated addition
of nitromethane to b-trifluoromethylated enones, followed by a
nitro-reduction/cyclization/dehydration sequence in a one-pot
procedure with 97–98% ees.
The trifluoromethyl group is one of the most attractive functional
groups for medicinal chemists to design novel biologically active
molecules due to its extremely unique properties.1 In particular,
Scheme 1 Enantioselective organocatalytic synthesis of 2.
heterocycles containing a trifluoromethyl unit constitute a major
without any additional substituent in the b-position are very
rare (2, R = H).9 Billard and co-workers reported the racemic
synthesis of 2 (R = H) via the conjugated addition of
nitromethane to b-(trifluoromethyl)enones followed by reductive
cyclization using TiCl3/HCl in moderate yields.9c However, the
asymmetric synthesis of 2 (R = H) has not yet been reported.
Herein we disclose the first enantioselective synthesis of target
b-trifluoromethylated pyrrolines 2 by a cinchona alkaloid-
catalyzed enantioselective conjugated addition of nitromethane
to b-trifluoromethylated enones 3, followed by an iron-mediated
reduction/cyclization/dehydration sequence in excellent yields
with excellent enantioselectivities up to 98% ee in a one-pot
procedure (Scheme 1). Cinchona-alkaloid-thiourea derivatives
are very effective for this transformation and either enantiomer
of 2 was obtained in high yields with excellent enantiomeric
excesses depending on the choice of catalyst. Our success is not
only the first example of asymmetric synthesis of the target
compounds 2 (R = H), but also the chemical yields in this
methodology are a vast improvement on those of a previously
reported-racemic synthesis of 2 by the use of an iron-mediated
reduction/cyclization/dehydration sequence instead of the
TiCl3/HCl system.
contributing nucleus in pharmaceuticals and agrochemicals on the
market.2 Thus the development of efficient and flexible methods
to construct
a trifluoromethylated heterocyclic system has
received much attention.3 Recently, trifluoromethyl-substituted
4,5-dihydro-isoxazoles, i.e., 2-isoxazolines, have emerged as an
important class of drug candidates including an antiparasitic drug
(1 in Fig. 1).4 We recently reported the catalytic asymmetric
synthesis of biologically important 5-trifluoromethyl-2-isoxazo-
lines 1 using chiral ammonium salts of cinchona alkaloids.5 The
expeditious synthesis of 1 based on the direct introduction of
a trifluoromethyl group into aromatic isoxazoles was also
disclosed.6 As part of our ongoing research programs directed
at the development of efficient methodologies for the construc-
tion of trifluoromethylated heterocyclic frameworks,7 we became
interested in the synthesis of the carbon variant of 1, trifluoro-
methylated 3,4-dihydro-2H-pyrrole, i.e., b-trifluoromethyl pyrro-
lines 2 as a potential drug candidate.
The target b-trifluoromethyl pyrrolines 2 are well reported
in the literature;8 however, the b-trifluoromethyl pyrrolines
The enantioselective conjugated addition of nitroalkanes to
a,b-unsaturated carbonyl compounds is one of the most practical
and important carbon–carbon bond formation reactions in
organic synthesis.10 Tremendous efforts have been devoted to
the development of a new catalytic system for this transformation
in past decades and recently high enantioselectivities have been
achieved by the use of chiral organocatalysts,11a–f phase-transfer
catalysts,11g–i and metal complexes.11j–l However, none of the
examples of the enantioselective conjugated addition of nitro-
alkanes to b-trifluoromethylated enones 3 have been reported. We
started our investigation with the reaction of (E)-4,4,4-trifluoro-
1-phenylbut-2-en-1-one (3a) with nitromethane (5.0 equiv.)
in the presence of a catalytic amount of cinchona alkaloid in
Fig. 1 Structures of biologically attractive trifluoromethylated
2-isoxazolines 1 and b-trifluoromethyl D1-pyrrolines 2.
a Department of Frontier Materials, Graduate School of Engineering,
Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya 466-8555, Japan. E-mail: nozshiba@nitech.ac.jp;
Fax: +81-52-735-5442
b Rigaku Corporation, 3-9-12 Mastubara-cho, Akishima,
Tokyo 196-8666, Japan
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available. CCDC
866120 and 859930. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc18049a
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4067–4069 4067

Table 1 Optimization of reaction conditions
Table 2 Generality of substrates
Entry Catalyst
Solvent
Time/h Yield (%) ee (%)
Entry
3
Ar
4
Time/h
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
Cinchonine
Toluene
Toluene
Toluene
Toluene
Toluene
16
16
16
16
11
11
11
21
14
14
14
18
45
88
64
Trace
64
48
19
93
96
92
70
96
94
84
77
77
96
93
98
98
72 (S)
75 (S)
5 (S)
n.d.
9 (S)
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
20
70
48
48
70
71
72
90
72
83
98
95
96
96
88
99
92
94
97
95
97
98
96
97
97
97
98
97
97
98
Quinidine
Cupreidine
b-ICD
(DHQD)2AQN
(DHQD)2PHAL Toluene
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
2-Naphthyl
2-Furanyl
0
(DHQD)2PYR
Toluene
Toluene
Toluene
Toluene
Toluene
PhCF3
o-Xylene 18
Benzene
THF
CH2Cl2
MeNO2
Toluene
Toluene
Toluene
8 (R)
97 (S)
97 (S)
98 (R)
97 (R)
97 (S)
97 (S)
97 (S)
95 (S)
95 (S)
93 (S)
97 (S)
97 (S)
97 (S)
5
6
7
8
7
7
7
7
7
7
7
7
7
9
10
11
12
13
14
15
16
17
18a
19b
20c
3j
4j
to establish the generality of the process. Using a catalytic
amount of 7, all cases afforded excellent yields with excellent
enantioselectivities independent of the nature of functional
groups on the aromatic ring (electron-donating, withdrawing,
halides, etc.), and position (Table 2). Namely, a series of
b-trifluoromethylated enone derivatives 3a–h with substituents
at their aromatic rings, such as methyl, methoxy, fluoro,
chloro, bromo, and nitro, were nicely converted to desired
4a–h in excellent yields with 96–98% ee (entries 1–8). Sterically
demanding naphthyl substituted enone 3i was also compatible
under the same reaction conditions affording 4i in 97% yield
with an ee value of 97% (entry 9). The heteroaromatic
substrate bearing a furanyl group 3j was also a suitable
substrate for this transformation, and provided desired 4j in
95% yield with 98% ee (entry 10). The absolute stereochemistry
of (S)-4i was clearly determined by X-ray analysis (CCDC
866120, Fig. S1 (ESIz)) and all the other products were
tentatively assigned by analogy with 4i.
18
24
24
12
20
20
60
a
b
c
5 mol% of 7 was used. 2 mol% of 7 was used. 0.5 mol% of
7 was used.
toluene at ambient temperature (Table 1). We first examined the
reaction in the presence of natural cinchona alkaloids, cinchonine
and quinidine; the desired product 4a was obtained in moderate to
good yields with 72% and 75% enantioselectivities, respectively
(entries 1 and 2). While natural cinchona alkaloids tend to show
poor activities during the asymmetric conjugated addition of
nitroalkanes to chalcones,11b,f rather nice results were obtained
in our case. This indicates that b-trifluoromethylated enone 3a has
a much higher reactivity than non-fluorinated enones due to the
strong electron-withdrawing effect of the b-CF3 group.7d
Preliminary results encouraged us to screen the cinchona
alkaloid derivatives that would further improve the yield and
enantioselectivity of 4a. We attempted the reaction with
cupreidine and b-ICD, both catalysts giving unsuccessful
results (entries 3 and 4). Commercially available bis-cinchona
alkaloids, (DHQD)2AQN, (DHQD)2PHAL and (DHQD)2PYR
provided nitromethane adduct 4a in moderate yields with miserable
ees (entries 5–7). Gratifyingly, cinchona-alkaloid-thiourea
derivatives 5 and 6 derived from cinchonine and quinidine
showed higher reactivities with a much improved ee value of
97% (entries 8 and 9).11b,12 The opposite (R) stereochemistry was
obtained by using the pseudoenantiomeric thiourea derivatives
7 and 8 with excellent enantioselectivities (entries 10 and 11).
A subsequent solvent survey revealed that the ee values were
almost independent of the solvent used (entries 12–17). The effect
of catalyst loading was further examined. It should be noted that
0.5 mol% of thiourea 7 gave a comparable result without any loss
of enantioselectivity; although a slightly longer reaction time was
required (entry 20). Catalyst loading of 2 mol% was chosen as the
preferred reaction time (entry 19) for the following experiments.
With optimal reaction conditions established, the scope of
the conjugated addition of nitromethane to b-trifluoromethylated
enones 3 was explored with a variety of substrates selected in order
With the enantiomerically enriched conjugated adducts 4
obtained, the transformation of 4 to b-trifluoromethylated
pyrrolines 2 was carried out. Billard and co-workers reported
the reduction of the nitro moiety of 4a into b-trifluoromethylated
pyrroline 2a by the use of the Nef reaction conditions, namely
TiCl3 in acidic media.9c However, the yields were moderate. In
contrast, we have found an efficient nitro-reduction/cyclization/
dehydration sequence using iron in the presence of acetic acid in
excellent yield without any loss of enantioselectivity (Scheme 2).
Integration of chemical reactions enhances the power and
speed of organic synthesis,13 which is classified into three types
including: (a) time and space integration, (b) time integration,
and (c) space integration. One-pot sequential synthesis has recently
attracted much attention as time integration of chemical reactions.
In this context, we finally examined the one-pot synthesis of
enantiomerically pure b-trifluoromethylated pyrrolines 2 from
b-trifluoromethylated enones 3. Gratifyingly, excellent yields
and enantioselectivities were obtained for all cases in the one-pot
procedure. Halogens on the aromatic ring were well tolerated
Scheme 2 Iron-mediated cyclization of 4a to 2a.
c
4068 Chem. Commun., 2012, 48, 4067–4069
This journal is The Royal Society of Chemistry 2012

Table 3 One-pot synthesis of b-trifluoromethylated pyrrolines 2
R. Aggarwal and S. P. Singh, J. Fluorine Chem., 2006, 127, 880;
(c) P. Bravo, L. Bruche, M. Crucianelli, A. Farina, S. V. Meille,
A. Merli and P. Seresini, J. Chem. Res., Synop., 1996, 348.
5 K. Matoba, H. Kawai, T. Furukawa, A. Kusuda, E. Tokunaga,
S. Nakamura, M. Shiro and N. Shibata, Angew. Chem., Int. Ed.,
2010, 49, 5762.
6 H. Kawai, K. Tachi, E. Tokunaga, M. Shiro and N. Shibata,
Angew. Chem., Int. Ed., 2011, 50, 7803.
Entry
3
Ar
2
Yield (%)
ee (%)
7 (a) N. Shibata, H. Fujimoto, S. Mizuta, S. Ogawa, Y. Ishiuchi,
S. Nakamura and T. Toru, Synlett, 2006, 3484; (b) S. Ogawa,
N. Iida, E. Tokunaga, M. Shiro and N. Shibata, Chem.–Eur. J.,
2010, 16, 7090; (c) S. Ogawa, T. Nishimine, E. Tokunaga and
N. Shibata, Synthesis, 2010, 3274; (d) Y. Huang, E. Tokunaga,
S. Suzuki, M. Shiro and N. Shibata, Org. Lett., 2010, 12, 1136.
8 For examples, see: (a) A. W. Moradi, T. N. Mueller, T. Murata,
M. Hatazawa, P. Bruechner, E. Shimojo, T. Ichihara, M. Ataka,
K. Shibuya and U. Goergens, PCT Int. Appl., WO 2011128299,
2011; (b) T. Murata, M. Ataka, Y. Yoneta, H. Watanabe,
E. Shimojo, K. Shibuya and T. Ichihara, PCT Int. Appl. WO
2011054871, 2011; (c) H. Ihara and K. Kumamoto, PCT Int. Appl.
WO 2010090344, 2010; (d) T. Mita, E. Ikeda, H. Takahashi and
M. Komoda, PCT Int. Appl. WO 2009072621, 2009.
9 (a) V. Kameswaran and V. M. Kamhi, Eur. Pat. Appl. EP 481182,
1992; (b) E. N. Shaitanova, I. I. Gerus and V. P. Kukhar,
Tetrahedron Lett., 2008, 49, 1184; (c) O. Marrec, C. Christophe,
T. Billard, B. Langlois, J.-P. Vors and S. Pazenok, Adv. Synth.
Catal., 2010, 352, 2825.
10 (a) M. P. Sibi and S. Manyem, Tetrahedron, 2000, 56, 8033;
(b) R. Ballini, G. Bosica, D. Fiorini, A. Palmieri and M. Petrini,
Chem. Rev., 2005, 105, 933.
11 For selected examples, see: (a) S. Hanessian and V. Pham,
Org. Lett., 2000, 2, 2975; (b) B. Vakulya, S. Varga, A. Csampai
and T. Soos, Org. Lett., 2005, 7, 1967; (c) A. Prieto, N. Halland
and K. A. Jorgensen, Org. Lett., 2005, 7, 3897; (d) X. Liang, J. Ye,
P. Li and Y. Wang, Chem. Commun., 2008, 3302; (e) K. Mei,
M. Jin, S. Zhang, P. Li, W. Liu, X. Chen, F. Xue, W. Duan and
W. Wang, Org. Lett., 2009, 11, 2864; (f) W. Yang and D.-M. Du,
Org. Lett., 2010, 12, 5450; (g) E. J. Corey and F. Y. Zhang, Org.
Lett., 2000, 2, 4257; (h) D. Y. Kim and S. C. Huh, Tetrahedron,
2001, 57, 8933; (i) M.-Q. Hua, H.-F. Cui, L. Wang, J. Nie and
J.-A. Ma, Angew. Chem., Int. Ed., 2010, 49, 2772; (j) K. Funabashi,
Y. Saida, M. Kanai, T. Arai, H. Sasai and M. Shibasaki,
Tetrahedron Lett., 1998, 39, 7557; (k) M. S. Taylor,
D. N. Zalatan, A. M. Lerchner and E. N. Jacobsen, J. Am. Chem.
Soc., 2005, 127, 1313; (l) L. Wang, Q. Zhang, X. Zhou, X. Liu,
L. Lin, B. Qin and X. Feng, Chem.–Eur. J., 2010, 16, 7696.
12 For selected reviews, see: (a) A. G. Doyle and E. N. Jacobsen,
Chem. Rev., 2007, 107, 5713; (b) S. J. Connon, Chem.–Eur. J.,
2006, 12, 5418; For selected examples of a cinchona alkaloid-
derived chiral thiourea catalyzed reaction, see: (c) S. H. McCooey
and S. J. Connon, Angew. Chem., Int. Ed., 2005, 44, 6367;
(d) J. Song, Y. Wang and L. Deng, J. Am. Chem. Soc., 2006,
128, 6048; (e) J. Wang, H. Li, L. Zu, W. Jiang, H. Xie, W. Duan
and W. Wang, J. Am. Chem. Soc., 2006, 128, 12652;
(f) G. Dickmeiss, V. De Sio, J. Udmark, T. B. Poulsen,
V. Marcos and K. A. Jørgensen, Angew. Chem., Int. Ed., 2009,
48, 6650; (g) X. Han, J. Luo, C. Liu and Y. Lu, Chem. Commun.,
2009, 2044; (h) T. Yang, A. Ferrali, F. Sladojevich, L. Campbell
and D. J. Dixon, J. Am. Chem. Soc., 2009, 131, 9140;
(i) W. J. Nodes, D. R. Nutt, A. M. Chippindale and A. J.
A. Cobb, J. Am. Chem. Soc., 2009, 131, 16016; (j) H. Zhang,
S. Syed and C. F. Barbas III, Org. Lett., 2010, 12, 708;
(k) W. Zhang, S. Zheng, N. Liu, J. B. Werness, I. A. Guzei and
W. Tang, J. Am. Chem. Soc., 2010, 132, 3664; (l) R. G. Arrayas
and J. C. Carretero, Chem. Commun., 2011, 47, 2207–2211.
13 S. Suga, D. Yamada and J. Yoshida, Chem. Lett., 2010, 404.
1
2
3
4
3a
3c
3d
3f
3g
3h
3i
Ph
2a
2c
2d
2f
2g
2h
2i
89
92
97
94
91
85
95
98
98
98
98
98
98
97
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
2-Naphthyl
5
6a
7
a
4-(3-(Trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl)aniline (2h, Ar =
4-NH2C6H4) was obtained.
under the second reductive cyclization step using Fe/CH3CO2H
(Table 3, entries 1–7). It should be noted that the nitro group on
the aromatic ring of 3h was spontaneously reduced under a
reduction step, affording aniline product 2h (entry 6). The
structure of 2 was confirmed based on the X-ray crystallo-
graphic analysis of racemic 2g (CCDC 859930, Fig. S2 (ESIz)).
In summary, we have developed the first enantioselective
synthesis of b-trifluoromethylated pyrrolines 2 via the asymmetric
conjugated addition of nitromethane to b-trifluoromethylated
enones 3, followed by a nitro-reduction/cyclization/dehydration
sequence mediated by iron in the presence of acetic acid. Catalyst
loading can be reduced from 2.0 mol% to 0.5 mol% without
any loss of enantioselectivity and yield. The one-pot sequential
protocol provides enantiomerically enriched b-trifluoromethylated
pyrrolines 2 for all cases, which adds an additional advantage
of this method based on time integration. Biological activities
such as antitumor activity and antiparasitic activity of a series of
b-trifluoromethylated pyrrolines 2 are now under investigation.
This study was financially supported in part by Grants-in-Aid
for Scientific Research from MEXT (Ministry of Education,
Culture, Sports, Science and Technology) (21390030, 22106515,
Project No. 2105: Organic Synthesis Based on Reaction
Integration). We also thank the Asahi Glass Foundation for
support in part. E.T. acknowledges Grants-in-Aid for Scientific
Research for financial support from MEXT (23915014).
Notes and references
1 J. Nie, H.-C. Guo, D. Cahard and J.-A. Ma, Chem. Rev., 2011,
111, 455.
2 Fluorinated Heterocyclic Compounds: Synthesis, Chemistry, and
Applications, ed. V. A. Petrov, Wiley, Hoboken, New Jersey, 2009.
3 (a) V. M. Muzalevskiy, A. V. Shastin, E. S. Balenkova, G. Haufe
and V. G. Nenajdenko, Synthesis, 2009, 3905; (b) A. W. Erian,
J. Heterocycl. Chem., 2001, 38, 793; (c) P. Lin and J. Jiang,
Tetrahedron, 2000, 56, 3635; (d) M. J. Silvester, Adv. Heterocycl.
Chem., 1994, 59, 1; (e) J. T. Welch, Tetrahedron, 1987, 43, 3123.
4 For examples, see: (a) M. L. Quan, C. D. Ellis, A. Y. Liauw,
R. S. Alexander, R. M. Knabb, G. Lam, M. R. Wright, P. C. Wong
and R. R. Wexler, J. Med. Chem., 1999, 42, 2760; (b) V. Kumar,
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 4067–4069 4069