Intermediate as catalyst: Catalytic asymmetric conjugate addition of nitroalkanes to α,β-unsaturated thioamides

Article abstract of DOI:10.1021/ol202898e

Catalytic asymmetric conjugate addition of nitroalkanes to α,β-unsaturated thioamides is promoted by a mesitylcopper/(R)-DTBM- Segphos precatalyst, affording γ-nitrothioamides in moderate to high syn-selectivity and excellent enantioselectivity. The inter

Full text of DOI:10.1021/ol202898e

ORGANIC
LETTERS
2012
Vol. 14, No. 1
110–113
Intermediate as Catalyst: Catalytic
Asymmetric Conjugate Addition of
Nitroalkanes to r,β-Unsaturated
Thioamides
Takanori Ogawa,† Shinsuke Mouri,† Ryo Yazaki,†,‡ Naoya Kumagai,*,† and
Masakatsu Shibasaki*,†
Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021,
Japan, and Graduate School of Pharmaceutical Sciences, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
nkumagai@bikaken.or.jp; mshibasa@bikaken.or.jp
Received October 27, 2011
ABSTRACT
Catalytic asymmetric conjugate addition of nitroalkanes to R,β-unsaturated thioamides is promoted by a mesitylcopper/(R)-DTBM-Segphos
precatalyst, affording γ-nitrothioamides in moderate to high syn-selectivity and excellent enantioselectivity. The intermediate Cu-thioamide enolate
functions as a soft Lewis acid/hard Brønsted base cooperative catalyst to drive the catalytic cycle efficiently under proton transfer conditions.
Catalytic enantioselective conjugate addition of carbon
nucleophiles offers a robust methodology for the produc-
tion of optically active building blocks via CÀC bond
formation.1 Nitroalkanes are widely used pronucleo-
philes in organic synthesis due to the facile formation
of active nitronates and the masked amine nature of nitro
functionality.2 Although nitroalkanes 1 have been suc-
cessfully applied in catalytic asymmetric 1,2-addition
reactions,3 their use in catalytic asymmetric conjugate
addition is relatively less explored.4 Both metallic catalysts
and organocatalysts allow for enantioselective conjugate
addition of nitroalkanes 1 to R,β-unsaturated ketones,5
(4) For a review, see: Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.;
Petrini, M. Chem. Rev. 2005, 105, 933.
(5) Recent selected examples: (a) Yamaguchi, M.; Shiraishi, T.; Igar-
ashi, Y.; Hirama, M. Tetrahedron Lett. 1994, 35, 8233. (b) Funabashi,
K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki, M. Tetrahedron
Lett. 1998, 39, 7557. (c) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2,
4257. (d) Hanessian, S.; Pharm, V. Org. Lett. 2000, 2, 2975. (e) Halland,
N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331.
(f) Tsogoeva, S. B.; Jagtap, S. B.; Ardemasova, Z. A.; Kalikhevich,
V. N. Eur. J. Org. Chem. 2004, 4014. (g) Vakulya, B.; Varga, S.;
† Institute of Microbial Chemistry.
‡ The University of Tokyo.
(1) For general reviews of catalytic asymmetric conjugate addition, see:
€
(a) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171. (b) Yamaguchi,
M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Hiedelberg, Germany, 2003; Suppl. 1, pp 151.
(c) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221. (d) Christoffers,
J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688. (e) Tsogoeva, S. B. Eur. J.
Org. Chem. 2007, 1701.
(2) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York,
2001.
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Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967. (h) Mitchell, C. E. T.;
Brenner, S. E.; Ley, S. V. Chem. Commun. 2005, 5346. (i) Preito, A.;
Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897. (j) Choudary,
B. M.; Ranganath, K. V. S.; Pal, U.; Kantam, M. L.; Sreedhar, B. J. Am.
Chem. Soc. 2005, 127, 13167. (k) Taylor, M. S.; Zalatan, D. N.;
Lerchner, A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313.
(l) Palomo, C.; Pazos, R.; Oiarbide, M.; Garcıa, J. M. Adv. Synth. Catal.
2006, 348, 1161. (m) Dijk, E. W.; Boersma, A. J.; Feringa, B. L.; Roelfes,
(3) For general review of catalytic asymmetric nitroaldol and nitro-
Mannich reactions, see: (a) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua,
N. C. Tetrahedron: Asymmetry 2006, 17, 3315. (b) Palomo, C.; Oiarbide,
M.; Laso, A. Eur. J. Org. Chem. 2007, 2561. (c) Westermann, B. Angew.
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G. Org. Biomol. Chem. 2010, 8, 3868. (n) Manzano, R.; Andres, J. M.;
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Alvarez, R.; Muruzabal, M. D.; de Lera, A. R.; Pedrosa, R. Chem.;
Eur. J. 2011, 17, 5931. (o) Maltsev, O. V.; Chizhov, A. O.; Zlotin, S. G.
Chem.;Eur. J. 2011, 17, 6109.
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Chem., Int. Ed. 2003, 42, 151. (d) Marques-Lopez, E.; Merino, P.; Tejero,
T.; Herrera, R. P. Eur. J. Org. Chem. 2009, 2401.
r
10.1021/ol202898e
Published on Web 11/23/2011
2011 American Chemical Society

CÀC bond formation of soft Lewis basic substrates
under proton transfer conditions.11 A major drawback
to this strategy, however, is the tedious catalyst preparation.
A prototype catalyst required separate preparation of chiral
bisphosphine ligand/[Cu(CH3CN)4]PF6 (soft Lewis acid)
and LiOAr (hard Brønsted base) just before use. Mechanistic
studies revealed that {phosphine/Cu-OAr and LiPF6}, gen-
erated in equilibrium with {phosphine/CuPF6 and LiOAr},
also acts as a soft Lewis acid and a hard Brønsted base
cooperative catalyst.12 On the basis that a phosphine/Cu-base
fragment can deprotonate the pronucleophile, which is an
initial step to trigger proton transfer CÀC bond formation,
we focused on the use of the reaction intermediate as a
catalyst to simplify the catalytic system (Scheme 1). In the
reaction using nitroalkane 1 and thioamide 2, the intermedi-
ate is a chiral phosphine/Cu-thioamide enolate 4, in which
the Cu and thioamide enolate would function as a soft Lewis
acid and a hard Brønsted base, respectively. Nitroalkane 1
and the precatalyst comprising a chiral phosphine ligand/
mesitylcopper13 generated Cu-nitronate via irreversible de-
protonation with concomitant generation of mesitylene, and
the subsequent coordination of thioamide 2 delivered com-
plex 5. This is an entry point to the following catalytic cycle, in
which enantioselective CÀC bond formation through 5
generates the intermediate 4 that promotes proton exchange
with nitroalkane 1 to regenerate 5. By this catalytic cycle, the
entry to 4
Scheme 1. Catalyst Design and Application to the Reaction of
Nitroalkanes and R,β-Unsaturated Thioamides
aldehydes,6 and nitroalkenes.7 The analogous catalytic
asymmetric addition to R,β-unsaturated carboxylic acid
derivatives, however, is limited due to their low electro-
philicity, and to date, only one successful example using
R,β-unsaturated acylpyrazoles and nitromethane (1a) un-
der Ni complex/2,2,6,6-tetramethylpiperidine catalyst has
been reported.8 Our recent research focused on the use of
R,β-unsaturated thioamide 2 as a viable electrophile in the
carboxylic acid oxidation state that is chemoselectively
activated by a soft Lewis acid catalyst to overcome the
intrinsic low reactivity.9 In this context, we envisioned to
develop a catalytic asymmetric conjugate addition of
nitroalkanes 1 to R,β-unsaturated thioamides 2, promoted
by a soft Lewis acid/hard Brønsted base cooperative
catalyst.10 Divergent transformation of the thioamide
functionality of the product 3 highlights the synthetic
utility of the present protocol.
initiates an efficient proton transfer CÀC bond-forming
catalysis, and this methodology would be applicable to
other carbon pronucleophiles bearing an acidic proton. An
(R)-DTBM-Segphos/mesitylcopper precatalyst quickly
emerged as a suitable precatalyst for the reaction of nitro-
methane(1a) andN,N-dimethylthiocinnamide (2a), afford-
ing γ-nitrothioamide 3aa in 93% yield and 99% ee after 1 h
of stirring at room temperature in toluene (eq 1). Initially,
mesitylcopper deprotonated 1a with a concomitant
The soft Lewis acid/hard Brønsted base cooperative cata-
lyst offers a particularly effective strategy for stereoselective
(6) Recent selected examples: (a) Hojabri, L.; Hartikka, A.; Moghaddam,
F. M.; Arvidson, P. I. Adv. Synth. Catal. 2007, 349, 740. (b) Zu, L.; Xie,
H.; Li, H.; Wang, J.; Wang, W. Adv. Synth. Catal. 2007, 349, 2660.
(c) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307.
(d) Enders, D.; Wang, C.; Bats, J. W. Synlett 2009, 1777. (e) Gotoh,
H.; Okamura, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11,
4056. (f) Zhong, C.; Chen, Y.; Petersen, J. L.; Akhmedov, N. G.; Shi,
X. Angew. Chem., Int. Ed. 2009, 48, 1279. (g) Anwar, S.; Chang, H.-J.;
Chen, K. Org. Lett. 2011, 13, 2200. Examples using preformed silyl
nitronate as active nucleophile: (h) Ooi, T.; Doda, K.; Maruoka, K.
J. Am. Chem. Soc. 2003, 125, 9022.
(7) Rabalakos, C.; Wulff, W. D. J. Am. Chem. Soc. 2008, 130, 13524.
(8) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394.
(9) (a) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2010, 132, 10275. (b) Yanagida, Y.; Yazaki, R.; Kumagai, N.; Shibasaki,
M. Angew. Chem., Int. Ed. 2011, 50, 7910.
(10) Recent reviews on cooperative catalysis: (a) Ma, J.-A.; Cahard,
D. Angew. Chem., Int. Ed. 2004, 43, 4566. (b) Yamamoto, H.; Futatsugi,
K. Angew. Chem., Int. Ed. 2005, 44, 1924. (c) Ikariya, T.; Murata, K.;
Noyori, R. Org. Biomol. Chem. 2006, 4, 393. (d) Paull, D. H.; Abraham,
C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem. Res.
2008, 41, 655. (e) Lee, J.-K.; Kung, M. C.; Kung, H. H. Top. Catal. 2008,
49, 136. (f) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41,
222. (g) Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50,
4760.
(11) (a) Suzuki, Y.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Angew.
Chem., Int. Ed. 2009, 48, 5026. (b) Yazaki, R.; Kumagai, N.; Shibasaki,
M. J. Am. Chem. Soc. 2010, 132, 5522. (c) Iwata, M.; Yazaki, R.; Chen,
I.-H.; Sureshkumar, D.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2011, 133, 5554.
(12) Yazaki, R.; Kumagai, N.; Shibasaki, M. Chem. ;Asian J. 2011,
6, 1778.
(13) Tsuda, T.; Yazawa, T.; Watanabe, K.; Fujii, T.; Saegusa, T.
J. Org. Chem. 1981, 46, 192.
(14) Experiments were conducted with mesitylcopper prepared from
the reported procedure (ref 13). Mesitylcopper is commercially available
from Strem Chemicals Inc., and purchased mesitylcopper exhibited
comparable catalytic performance in the present reaction: the reaction
of 1b and 2a (Table 2, entry 1) under otherwise identical conditions, 3ba
was obtained in 89% yield syn/anti = 80/20, 99% ee (syn).
Org. Lett., Vol. 14, No. 1, 2012
111

Table 1. Catalytic Asymmetric Conjugate Addition of Nitro-
methane (1a) to R,β-Unsaturated Thioamides 2a
Table 2. Catalytic Asymmetric Conjugate Addition of Ni-
troalkane 1 to R,β-Unsaturated Thioamides 2a
nitroalkane
1
thioamide 2
thioamide 2
time yieldb syn/ ee (%)
product (h) (%) antic (syn)
entry
R1
R2
product yieldb (%) ee (%)
entry R3
R1
R2
1
2
3
4
5
6
Me Ph
2a
2b
2c
3aa
3ab
3ac
3ad
3ae
3af
95
93
92
82
75
97
99
99
99
99
98
99
Me 4-MeC6H4
Me 4-ClC6H4
1
2
3
4
5
Me
Et
1b Me Ph
1c Me Ph
2a 3ba
2a 3ca
2a 3da
1
1
95 81/19 99
96 93/7 99
Me 4-MeOC6H4 2d
allyl 1d Me Ph
2
95 89/11 99
94 88/12 99
90 88/12 99
81 84/16 99
45 86/14 99
63 84/16 99
Me Me
Bn Ph
2e
2f
allyl 1d Me 4-MeC6H4 2b 3db
allyl 1d Me 4-ClC6H4 2c 3dc
2
2
6d allyl 1d Me 4-ClC6H4 2c 3dc
7e allyl 1d Me 4-ClC6H4 2c 3dc
6
a 1a: 2.0 mmol, 2: 0.4 mmol. b Isolated yield.
20
6
8
allyl 1d Me 4-
MeOC6H4
allyl 1d Me 2-furyl
2d 3dd
liberation of mesitylene, and subsequent enantioselective
addition to 2a activated by the (R)-DTBM-Segphos/Cu
complex through a softÀsoft interaction gave 4, which
drove the following catalytic cycle. Both mesitylcopper
and (R)-DTBM-Segphos are commercially available.14
The scope of the catalytic asymmetric addition of nitro-
methane (1a) to R,β-unsaturated thioamides 2 is summar-
ized in Table 1. A n-hexane/toluene binary solvent system
proved best to produce maximum catalyst efficiency, com-
pleting the reaction in 1 h with 5 mol % of catalyst loading,
and affording 3aa in 95% yield and 99% ee (entry 1). The
electronic nature of the β-substituent of thioamides had
only a marginal impact on reactivity, and excellent enan-
tioselectivity was observed (entries 2À4). Thioamide bear-
ing a β-methyl substituent was also applicable, exhibiting
high enantioselectivity (entry 5). The catalytic efficiency
was not relevant to the substituent on the nitrogen, and N,
N-dibenzylthioamide 2f served as a suitable substrate to give
the corresponding product 3af with high enantioselectivity
(entry 6), and the thioamide functionality can be regarded as
a masked primary amine and is of synthetic value.
9
2g 3dg
2
2
2
91 75/25 99
72 72/28 99
89 80/20 99
10 allyl 1d Me 2-thienyl 2h 3dh
11 allyl 1d Me (E)-CHd 2i 3di
CHCH3
12 allyl 1d Me Me
13 allyl 1d Bn Ph
2e 3de
2f 3df
1
1
1
1
91 81/19 99
90 79/21 99
86 80/20 99
90 77/23 98
14 allyl 1d Bn 4-ClC6H4 2j 3dj
15 allyl 1d Bn Me 2k 3dk
a 1: 2.0 mmol, 2: 0.4 mmol. b Isolated yield. c Determined by 1H NMR
of the crude mixture. d 2.0 equiv of 1d was used. e 2 mol % of catalyst was
used.
Our next focus was diastereoselectivity (Table 2), which
remained a formidable challenge in this important trans-
formation.15 In the reaction using nitroethane (1b) and
thioamide 2a, the use of n-hexane as a solvent enhanced
the catalytic efficiency, and high yield and enantioselec-
tivity were observed, albeit with moderate syn-selectiv-
ity. An inverted configuration at the R-carbon of the
nitro group in the minor anti-isomer, as well as the
transition state model depicted in Figure 1, suggested that
the steric bulk of nitroalkane is a dominant factor for
diastereoselectivity in thiscatalytic system. Consistent with
Figure 1. Proposed transition state model for diastereo- and
enantioselectivity.
this assumption, bulkier nitroalkanes 1c and 1d exhibited
higher diastereoselectivity (entries 2 and 3). The reaction
with 4-nitro-1-butene (1d) and various R,β-unsaturated
thioamides 2 provided a series of products bearing a
pendant allyl group (entries 4À15). The amount of 1d
(15) Examples with low diastereoselectivity (dr e3/1), see: refs 5d, 5e,
5h, 5i, 5k, 6aÀ6c, and 6f. Examples exhibiting moderate to high
diastereoselectivity using silyl nitronate (ref 6h), nitroethanol (ref 6e),
and homochiral nitroalkane (ref 6g) are reported; however, there is no
example of general diastereo- and enantioselective addition of nitroalk-
anes to R,β-unsaturated carbonyl compounds.
112
Org. Lett., Vol. 14, No. 1, 2012

could be reduced to 2.0 equiv with an extended reaction
time (entry 6), whereas the reaction with 2 mol % of
catalyst loading resulted in a significantly decreased reac-
tion efficiency (entry 7). Thioamides bearing a heteroaro-
matic ring produced lower diastereoselectivity, albeit with
excellent enantioselectivity (entries 9 and 10). Exclusive
1,4-addition was observed with the diene-conjugated
thioamide 2i (entry 11). The reaction with β-methyl-sub-
stituted R,β-unsaturated thioamide proceeded smoothly to
afford a yield and stereoselectivity comparable to those
obtained with β-aryl substrates (entry 12). The substituent
on the thioamide nitrogen was not relevant to either the
reactivity or stereoselectivity, and N,N-dibenzylthioamides
also served as suitable substrates (entries 13À15).
(Scheme 3). The product 3df was transformed into the
corresponding amide 9 by treatment with TFAA.16
S-Methylation with MeOTf followed by hydride reduc-
tion in acidic medium allowed desulfurization to give
dibenzyl-protected amine 10.17 Thioamide moiety of the
product 3ac was converted to thioester 11 by MeI with
TFA in wet THF.18 The subsequent hydrolysis delivered
the corresponding carboxylic acid, which can be trans-
formed to (R)-baclofen in a single step, a therapeutically
useful GABAB receptor agonist.19,20
Scheme 3. Transformation of the Products
The chemoselective nature of the present catalysis was
evidenced by the following competition experiments
(Scheme 2). In the reaction of nitroethane (1b) with thioa-
mide 2a in the presence of R,β-unsaturated amide 6, ester 7,
and even R,β-unsaturated ketone 8, which exhibits intrinsi-
cally higher electrophilicity than the corresponding thioa-
mide 2a, only 3ba was produced and 6À8 were recovered
unchanged. The high fidelity in chemoselectivity was ex-
ploited for the sequential conjugate addition using 2l, where
the enantioselective conjugate addition of 1a, followed by
the intramolecular conjugate addition of Cu-thioamide
enolate 4 to unsaturated ester, furnished indane derivative
3al having three consecutive stereogenic centers as a single
diastereomer in 75% yield and 99% ee (eq 2).
In summary, we developed a catalytic asymmetric con-
jugate addition of nitroalkanes to R,β-unsaturated thioa-
mides promoted by mesitylcopper/(R)-DTBM-Segphos
precatalyst. The intermediate Cu-thioamide enolate func-
tioned as a soft Lewis acid/hard Brønsted base cooperative
catalyst to drive the catalytic cycle via efficient proton
transfer between substrates. Divergent transformation of
the thioamide functionality is advantageous for further
manipulations. Studies of the application of the present
mesitylcopper/chiral phosphine catalysis to other pronu-
cleophiles are currently underway.
Scheme 2. Competitive Reaction: Highly Chemoselective Con-
jugate Addition to R,β-Unsaturated Thioamide 2a
Acknowledgment. This work was financially supported
by KAKENHI (20229001 and 23590038) from JSPS. N.K.
thanks the Sumitomo Foundation for financial support.
R.Y. thanks JSPS predoctral fellowship.
Supporting Information Available. Characterization of
new compounds and experimental procedures. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
ꢀ
(19) (a) Olpe, H.-R.; Demieville, H.; Baltzer, V.; Bencze, W. L.;
The divergent transformation of the thioamide func-
tionality is useful for further synthetic manipulations
Koella, W. P.; Wolf, P.; Haas, H. L. Eur. J. Pharmacol. 1978, 52, 133.
(b) Bowery, N. G. Trends Pharmacol. Sci. 1982, 3, 400.
(20) Recent selected examples of catalytic asymmetric synthesis of
(16) Masuda, R.; Hojo, M.; Ichi, T.; Sasano, S.; Kobayashi, T.;
Kuroda, C. Tetrahedron Lett. 1991, 32, 1195.
(17) Sundberg, R. J.; Walters, C. P.; Bloom, J. D. J. Org. Chem. 1981,
46, 3730.
(18) Harrowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron
1999, 55, 1187.
~
baclofen via atom-economical approach: (a) Camps, P.; Munoz-Torrero,
ꢀ
D.; Sanchez, L. Tetrahedron: Asymmetry 2004, 15, 2039. (b) Okino, T.;
Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005,
127, 119. (c) Paraskar, A. S.; Sudalai, A. Tetrahedron 2006, 62, 4907. (d)
Nemoto, T.; Jin, L.; Nakamura, H.; Hamada, Y. Tetrahedron Lett. 2006,
47, 6577. See also refs 5c, 6a, and 6c.
Org. Lett., Vol. 14, No. 1, 2012
113