Highly anti-selective asymmetric nitro-mannich reactions catalyzed by bifunctional amine-thiourea-bearing multiple hydrogen-bonding donors

Article abstract of DOI:10.1021/ja803538x

Highly anti-selective and enantioselective nitro-Mannich reactions have been achieved for a broad spectrum of substrates catalyzed by chiral bifunctional multiple hydrogen-bonding-donor amine-thioureas. Multiple hydrogen-bonding donors play a significant

Full text of DOI:10.1021/ja803538x

Published on Web 06/13/2008
Highly anti-Selective Asymmetric Nitro-Mannich Reactions Catalyzed by
Bifunctional Amine-Thiourea-Bearing Multiple Hydrogen-Bonding Donors
Chun-Jiang Wang,* Xiu-Qin Dong, Zhi-Hai Zhang, Zhi-Yong Xue, and Huai-Long Teng
College of Chemistry and Molecular Sciences, Wuhan UniVersity, P.R. China 430072
Received May 12, 2008; E-mail: cjwang@whu.edu.cn
Table 1. Screening Studies of Oganocatalytic Asymmetric
Nitro-Mannich Reaction of N-Boc Aldimine 2a and
Nitromethane 3aa
The addition of nitroalkanes to imines, known as the nitro-
Mannich (or aza-Henry) reaction is a highly valuable carbon-carbon
bond-forming process in organic synthesis.1 Synthetically versatile
ꢀ-nitro amines formed in this way can be readily converted to 1,2-
diamines,2 R-aminocarbonyl compounds.3 Since the pioneering
work of Shibasaki,4 much attention has been paid to developing
enantioselective catalytic protocols for this reaction over the past
decade. Enantio- and diastereoselective nitro-Mannich reactions
have been reported using chiral metal complexes5 and organocata-
lysts, such as chiral thiourea,6 chiral proton catalysts,7 and chiral
phase transfer catalysts.8 Most recently, Shibasaki and co-workers
reported a heterobimetallic Cu-Sm-Shiff base complexes cata-
lyzed nitro-Mannich reactions with excellent syn-selectivity (>20:
1) and enantioselectivity (83-98%).9 For anti-selective nitro-
Mannich reaction, however, such high diastereoselectivity and
enantioselectivity have not been obtained so far. Among numerous
literature examples, to our knowledge, there are only few organo-
catalytic asymmetric nitro-Mannich reactions reported which can
afford both excellent enantioselectivity and high antiselectivity of
greater than 10:1 for a broad scope of the reaction partners.6b,f
Therefore, there is substantial room for improvement in terms of
both selectivity and substrate scope for organocatalytic nitro-
Mannich reaction.
entry
catalyst
solvent
MS (4Å)
temp (°C)
t (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1d
1e
1d
1d
1d
1d
1d
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Et2O
+
+
+
+
-
+
+
+
+
+
+
rt
rt
rt
rt
rt
rt
rt
rt
0
5
5
5
5
5
48
5
5
8
10
15
92
95
93
95
89
20
94
95
95
97
95
75
80
78
96
96
11
94
95
98
99
99
DCM
9
MeCN
MeCN
MeCN
10
-20
-20
11d
a Unless otherwise noted, the reactions was carried out with 0.2
mmol of 2, 1 mmol of 3, and 50 mg powered 4Å molecular sieves in
0.5 mL of solvent; rt
)
room temperature. b Isolated yield.
c Enantiomeric excesses were determined by chiral HPLC analysis.
d Run using 5 mol % catalyst.
the corresponding product was obtained in 20% yield with only
11% ee even in 48 h (Table 1, entry 6). This indicates that the
third NH of sulfonamide on the 1,2-diphenylethenediamine moiety
indeed plays a significant role in this nitro-Mannich reaction. The
current system showed remarkable improvement over the previous
organocatalyst nitro-Mannich reaction in terms of enantioselectivity
and reactivity.6b,d,f
Recently, we reported a new class of bifunctional amine-thiourea
catalysts 1 bearing multiple hydrogen bonding donors, which
showed excellent performance in catalytic asymmetric addition of
acetylacetone to nitroolefins.10 Extending the interest of these
organocatalysts in asymmetric catalysis, herein we report that
catalyst 1d results in high anti-selectivities (93:7-99:1) and
excellent enantioselectivities (96-99%) in the asymmetric nitro-
Mannich reaction for a broad scope of substrates.11
Our initial study began with the reaction of N-Boc aldimine 2a
with nitromethane 3a in which only one stereogenic center was
formed, and the representative results are summarized in Table 1.
Gratifyingly, the nitro-Mannich reaction proceeded readily at room
temperature in the presence of 10 mol % of catalyst 1 under different
conditions, and the desired product 4a was obtained in high yields
after 5 h. Among the catalysts tested, (1R,2R,1′R,2′R)-1d bearing
two electron-withdrawing CF3 groups on the aromatic ring of
sulfonamide NHSO2Ar emerged as the most effective catalyst
(Table 1, entry 4). A study of the reaction with 1d at room
temperature in various solvents identified dichloromethane and ether
as suitable alternatives to acetonitrile (Table 1, entries 4, 7, and 8).
The addition of 4A molecular sieves was taken to avoid the
decomposing of the aldimine during the reactions (Table 1, entries
4 and 5). Reducing the temperature to -20 °C in acetonitrile or
dichloromethane led to completed reaction with 99% ee in less than
10 h (Table 1, entry 10). Catalyst loading was successfully reduced
to 5 mol % without any loss of enantioselectivity (Table 1, entry
11). Using methylated (1R,2R,1′R,2′R)-1e as the catalyst under the
optimized reaction condition, the reaction became sluggish, and
Encouraged by this result, we next investigated the nitro-Mannich
reaction of various N-Boc aldimines with nitromethane under the
optimized experimental conditions. Representative results are
summarized in Table 2.12 A variety of imines, which bear electron-
rich, electron-neutral, or electron-deficient groups, reacted with
nitromethane smoothly to afford the corresponding products (4a-
j) in high yields (85-99%) and excellent enantioselectivities
(96-99% ee) at -20 °C with 10-15 h (Table 2, entries 1-10). It
appears that the position and the electronic property of the
substituents on the aromatic rings have a very limited effect on the
enantioselectivities. Noticeably, up to 99% ee was still obtained
even for the challenging ortho-substituted substrates6b,d (2d and
2f) and 1-naphthyl N-Boc aldimines6f (2j) (Table 2, entries 4, 6
and 10). The best literature report for 2f is only 92% ee in 42 h
using thiourea catalyst derived from R-D-glucose.6d Another at-
tractive features of this methodology is the remarkable tolerance
for heteroaryl and alkyl N-Boc aldimines (Table 2, entries 11-13).
9
8606 J. AM. CHEM. SOC. 2008, 130, 8606–8607
10.1021/ja803538x CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Nitro-Mannich Reaction of N-Boc Aldimines 2
with Nitromethane 3a Using Oganocatalyst 1da
2-naphthyl N-Boc aldimine (2i), and heteroaryl aldimines (2k and
2l) is noteworthy (Table 3, entries 7, 9, 10, and 11), as such N-Boc
aldimines were shown to be relatively challenging substrates in
previous studies involving chiral metal complexes9 and organo-
catalysts6b,f Alkyl N-Boc aldimine also works well in this reaction
leading to 93:7 dr and 97% ee (Table 3, entry 16).
entry
R
product
yield (%)b
ee (%)c
In conclusion, we have developed highly anti-selective (93:7-99:
1) and excellent enantioselective (96-99% ee) nitro-Mannich
reactions catalyzed by chiral bifunctional thiourea catalyst bearing
multiple hydrogen-bonding donors that perform well over a broad
scope of substrates. This methodology presented herein is the best
result for organocatalytic asymmetric nitro-Mannich reactions
reported so far, and nicely complements the highly syn-selective
version using a herterobimetallic Cu-Sm-Shiff base complex.
Further investigations into the mechanism and applications of the
present bifunctional thiourea catalysts in other catalytic asymmetric
reactions are underway in our laboratory.
1
2
3
4
Ph (2a)
4a
4b
4c
4d
4e
4f
4g
4h
4i
97
88
85
94
93
90
91
96
89
98
99
91
99
99
99
99
99
99
99
99
99
97
99
96
99
98
p-Me-Ph (2b)
p-MeO-Ph (2c)
o-MeO-Ph (2d)
p-Cl-Ph (2e)
o-Cl-Ph (2f)
5
6
7d
8
p-F-Ph (2g)
p-CF3-Ph (2h)
2-Naphthyl (2i)
1-Naphthyl (2j)
2-Furyl (2k)
3-Pyridyl (2l)
iBu (2m)
9
10
11
12
13
4j
4k
4l
4m
Acknowledgment. This work was supported by National
Natural Science Foundation of China (20642005, 20702039) and
the startup fund from Wuhan University.
a See Table 1. b See Table 1. c See Table 1. d Reaction was performed
at -50 °C in 0.5 mL DCM in 12 h; 95% ee was achieved in acetonitrile
at -20 °C.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Table 3. High anti-Selective Catalytic Asymmetric Nitro-Mannich
Reactions of N-Boc Aldimines with Nitroalkanesa
References
(1) For recent advances on this reaction, see: (a) Westermann, B. Angew. Chem.,
Int. Ed. 2003, 42, 151. (b) Ting, A.; Schaus, S. E. Eur. J. Org. Chem.
2007, 5797.
yieldb
(%)
drc
(anti:syn) (%)
eed
(2) (a) Bernadi, L.; Bonini, B. F.; Capito, I, E.; Dessole, G.; Comes-Franchini,
M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69, 8168. (b) Lloyd, D. H.;
Nichols, D. E. J. Org. Chem. 1986, 51, 4294. (c) Barrett, A. G. M.; Spilling,
C. D. Tetrahedron Lett. 1988, 29, 5733. (d) Sturgess, M. A.; Yarberry,
D. J. Tetrahedron Lett. 1993, 34, 4743. (e) Adams, H.; Anderson, J. C.;
Peace, S.; Pennell, A. M. K. J. Org. Chem. 1998, 63, 9932.
(3) (a) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017. (b) Foresti, E.;
Palmieri, G.; Petrini, M.; Profeta, R. Org. Biomol. Chem. 2003, 1, 4275.
(4) (a) Yamada, K.-I.; Harwood, S. J.; Groger, H.; Shibasaki, M. Angew. Chem.,
Int. Ed. 1999, 38, 3504. (b) Yamada, K.-I.; Moll, G.; Shibasaki, M. Synlett
2001, 980.
(5) (a) Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2001, 40, 2992. (b) Knudsen, K. R.; Risgaard, T.; Nishiwaki,
N.; Gothelf, K. V.; Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843.
(c) Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362.
(d) Anderson, J. C.; Blake, A. J.; Howell, G. P.; Wilson, C. J. J. Org.
Chem. 2005, 70, 549. (e) Anderson, J. C.; Howell, G. P.; Lawrence, R. M.;
Wilson, C. J. J. Org. Chem. 2005, 70, 5665. (f) Palomo, C.; Oiarbide, M.;
Halder, R.; Laso, A.; Lo´ıpez, R. Angew. Chem., Int. Ed. 2006, 45, 117. (g)
Trost, B. M.; Lupton, D. W. Org. Lett. 2007, 9, 2023. (h) Gao, F.; Zhu, J.;
Tang, J. Y.; Deng, M.; Qian, C. Chirality 2006, 18, 741. (i) Lee, A.; Kim,
W.; Lee, J.; Hyeon, T.; Kim, B. M. Tetrahedron: Asymmetry 2004, 15,
2595.
entry
R
R′
catalyst product
1
2
3
4
5
6
7
8
9
Ph (2a)
Ph (2a)
Ph (2a)
p-Me-Ph (2b)
p-MeO-Ph (2c) Me (3b)
p-Cl-Ph (2e)
o-Cl-Ph (2f)
p-CF3-Ph (2g) Me (3b)
2-naphthyl (2i) Me (3b)
Me (3b)
Me (3b)
Me (3b)
Me (3b)
1a
1b
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
5ab
5ab
5ab
5bb
5cb
5eb
5fb
5gb
5ib
5kb
5lb
5ac
5bc
5cc
5ad
5mb
88
90
92
90
95
88
93
97
91
93
88
94
99
93
95
93
80:20
93:7
97:3
96:4
98:2
97:3
96:4
97:3
97:3
94:6
96:4
99:1
97:3
99:1
99:1
93:7
76
87
99
98
98
99
96
99
97
96
99
99
99
98
99
97
Me (3b)
Me (3b)
10 2-furyl (2k)
11 3-pyridyl (2l)
12 Ph (2a)
13 p-Me-Ph (2b)
14 p-MeO-Ph (2c) Et (3c)
Me (3b)
Me (3b)
Et (3c)
Et (3c)
15 Ph (2a)
Bn (3d)
Me (3b)
16 iBu (2m)
(6) (a) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem. Soc. 2007,
129, 15110. (b) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005,
44, 466. (c) Palomo, C.; Oiarbide, M.; Halder, R.; Laso, A.; Lopez, R.
Angew. Chem., Int. Ed. 2006, 45, 117. (d) Wang, C.; Zhou, Z.; Tang, C.
Org. Lett. 2008, 10, 1707. (e) Okino, T.; Nakamura, A.; Furukawa, T.;
Takemoto, Y. Org. Lett. 2004, 6, 625. (f) Xu, X. N.; Furukawa, T.; Okino,
T.; Miyabe, H.; Takemoto, Y. Chem.sEur. J. 2006, 12, 466.
(7) (a) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004,
126, 3418. (b) Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am.
Chem. Soc. 2007, 129, 3466. (c) Singh, A.; Johnston, J. N. J. Am. Chem.
Soc. 2008, 130, 5866.
(8) (a) Palomo, C.; Oiarbide, M.; Laso, A.; Lo´ıpez, R. J. Am. Chem. Soc. 2005,
127, 17622. (b) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernadi,
L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975. (c) Bernardi, L.; Fini,
F.; Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62, 375. (d)
Bode, C. M.; Ting, A.; Schaus, S. E. Tetrahedron 2006, 62, 11499.
(9) Handa, S.; Gnanadesikan, V.; Matsunag, S.; Shibasaki, M. J. Am. Chem.
Soc. 2007, 129, 4900.
a See Table 1. b See Table 1. c Diastereomeric ratio was determined
by HPLC analysis. Minor syn-isomer was not detected on the crude 1H
NMR. d Enantiomeric excesses were determined by chiral HPLC
analysis.
Having succeeded in the enantioselective nitro-Mannich reaction
of N-Boc aldimine with nitromethane, we then investigate the nitro-
Mannich reaction of N-Boc aldimine with other nitroalkanes that
can result in the generation of two contiguous nitrogen-bearing
stereogenic centers. The scope of the reaction of nitroalkanes 3
with N-Boc aldimines 2 is summarized in Table 3.11,12 Indeed, all
tested nitroalkanes and various N-Boc aldimines have proven to
be excellent substrates with respect to diastereo-/enantioselectivity
and reactivity using 1d as the catalyst. Nitroethane 3b and
nitroalkanes 3c and 3d showed the same reactivity as nitromethane
3a, and the corresponding products were obtained in high yields
and excellent diastereo-/enantioselectivities (93:7-99:1 dr; 96-99%
ee). The consistently excellent diastereo-/enantioselectivity obtained
with the sterically hindered ortho-substituted N-Boc aldimine (2f),
(10) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chem. Commun. 2008,
1431.
(11) ꢀ-nitroamine 5 was named as anti-isomer according to Shibasaki’s paper.
(12) The absolute configurations of the known products were assigned by HPLC
and optical rotation comparisons with the reported data (see refs 6b, 6d,
and Supporting Information), and those of other adducts were deduced on
the basis of these results.
JA803538X
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J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8607