Aza-Henry reaction of ketoimines catalyzed by Na2CO3: An efficient way to β-nitroamines

Article abstract of DOI:10.1055/s-2008-1077952

A simple and efficient way to β-nitroamines via aza-Henry reaction of N-tosyl ketoimines and nitromethane has been developed. In the presence of only 5 mol% Na₂CO₃, most of the N-to-syl ketoimines can react to give products in good to excellent yields (up to 99%) in THF at room temperature.

Full text of DOI:10.1055/s-2008-1077952

LETTER
2075
Aza-Henry Reaction of Ketoimines Catalyzed by Na2CO3: An Efficient Way to
b-Nitroamines
S
c
y
nthesis of
b-N
i
itroa
m
w
ines ei Wang,a Cheng Tan,a Xiaohua Liu,a Xiaoming Feng*a,b
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064,
P. R. of China
Fax +86(28)85418249; E-mail: xmfeng@scu.edu.cn
State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, P. R. of China
d
Received 28 March 2008
in cyanosilylation of carbonyl compounds.11a Herein, we
wish to report a simple and efficient way for the catalytic
aza-Henry reaction of N-tosyl ketoimines catalyzed by in-
organic salts.
Abstract: A simple and efficient way to b-nitroamines via aza-
Henry reaction of N-tosyl ketoimines and nitromethane has been de-
veloped. In the presence of only 5 mol% Na2CO3, most of the N-to-
syl ketoimines can react to give products in good to excellent yields
(up to 99%) in THF at room temperature.
The initial studies were focused on the addition of ni-
tromethane to N-tosyl phenylmethylketoimine 1a.12 A se-
ries of inorganic salts were tested and the results are listed
in Table 1.
Key words: aza-Henry reaction, inorganocatalyst, ketoimines, ni-
tromethane, b-nitroamines
As can be seen from Table 1, the alkalinity of catalyst was
revealed to be an important parameter for the attainment
of high yield. The catalyst with exorbitant alkalinity
caused obvious decomposition of ketoimines, so that low
yields were obtained (Table 1, entries 4 and 5).8 On the
other hand, catalysts with insufficient alkalinity were not
active enough for the reaction, which provided much low-
The aza-Henry (or nitro-Mannich) reaction,1 that is, nu-
cleophilic addition of nitroalkanes to imines, provides
synthetically versatile b-nitroamines which can be easily
converted to 1,2-diamines by reduction of nitro group, a-
aminocarbonyl compounds by means of Nef reaction and
other reactions.2 Particularly, the 1,2-diamine structural
motif is of particular interest owing to its broad utility,
which involves the scopes of biologically active nature
products, medicinal chemistry, as well as employment as
ligands in organic synthesis.
Table 1 Screening of the Catalystsa
Ts
Ts
N
HN
Tremendous efforts have been devoted to develop catalyt-
ic aza-Henry reaction over the past decade. So far, both ra-
cemic and asymmetric methods for the reactions with
various nitroalkanes have been realized using metal
complexes1,3 and organocatalysts, such as thioureas,4
chiral proton catalysts,5 and cinchona alkaloids.6,7 How-
ever, most of them are known for aldimines, while a gen-
eral catalytic method for ketoimines is hardly accessible
due to their low reactivity and difficult preparation. To the
best of our knowledge, there are only two examples for
aza-Henry reactions of ketoimines reported to date. One is
diastereoselective aza-Henry reaction of N-tolylsulfi-
nylimines catalyzed by Yb(Oi-Pr)3 or TBAF in which
only two cases involving ketoimines were mentioned.8
The other is the organic base catalyzed aza-Henry reaction
of N-diphenylphosphinoyl ketoimines.9 However, this
method was ineffective for N-sulfonyl ketoimines which
are more commonly employed in other reactions because
of their superior stability.10 Therefore, the development of
an approach using N-sulfonyl ketoimines for such a reac-
tion is extremely necessary and potentially useful. We had
already reported inorganic salts as heterogeneous catalyst
cat.
MeNO2
THF, r.t.
NO2
1a
2a
Entry
Catalyst
Yield (%)b
c
1
2
3
4
5
6
7
8
Li2CO3
NaHCO3
Na2CO3
K2CO3
–
57
81
25
28
KO-tBu
HCOONa
NaOAc
KOAc
c
–
10
69
a All reactions were carried out with ketoimine 1a (0.2 mmol) and ni-
tromethane (10 equiv) in the presence of indicated catalyst (10 mol%)
and THF (0.29 mL) at r.t. for 24 h.
b Isolated yield.
c Not detected.
SYNLETT 2008, No. 13, pp 2075–2077
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x
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x
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Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077952; Art ID: W05108ST
© Georg Thieme Verlag Stuttgart · New York

2076
L. Wang et al.
LETTER
Table 2 Optimization of the Reaction Conditionsa
Table 3 Aza-Henry Reaction of N-Tosyl Ketoimines Catalyzed by
Na2CO3
a
Ts
N
Ts
HN
Ts
Ts
Na2CO3
MeNO2
NH
Na2CO3 (5 mol%)
THF, r.t.
N
MeNO2
R
NO2
solvent, r.t.
NO2
R
1
2
1a
2a
Entry
R
Time (h)
24
Yield (%)b
Entry
Cat (mol%) MeNO2
(equiv)
Solvent
Yield (%)b
1
2
Ph (1a)
86
86
99
90
88
94
92
77
37
80
86
1
2
20
10
5
10
10
10
5
THF
72
81
83
67
32
75
12
11
59
41
63
86
2-FC6H4 (1b)
4-FC6H4 (1c)
4-ClC6H4 (1d)
3-ClC6H4 (1e)
4-BrC6H4 (1f)
48
THF
3
48
3
THF
4
48
4
5
THF
5
48
5
5
1
THF
6
48
6c
7
5
20
10
10
10
10
10
10
–
7
3-MeOC6H4 (1g)
4-MeC6H4 (1h)
4-MeOC6H4 (1i)
1-naphthyl (1j)
48
48
48
48
72
5
CH2Cl2
toluene
MeCN
Et2O
8
8
5
9
9
5
10
11
10
11
12d
5
O
5
1,4-dioxane
THF
(1k)
5
12
13
72
96
75
45
a Unless otherwise noted, all reactions were carried out with keto-
imine 1a (0.2 mmol) and nitromethane in the presence of Na2CO3 and
indicated solvent (0.29 mL) at r.t. for 24 h.
b Isolated yields.
S
(1l)
c Nitromethane was used as solvent.
d Powdered Na2CO3 was used.
er yields (Table 1, entries 1, 6, and 7). Potassium acetate
could give moderate yield (Table 1, entry 8), but Na2CO3
was found to be the most promising one with 81% isolated
yield after 24 hours at room temperature (Table 1, entry
3).
(1m)
PhCH2CH2 (1n)
14
48
99
a Unless otherwise noted, all reactions were carried out with keto-
imines 1a–n (0.2 mmol) and nitromethane (10 equiv) in the presence
of Na2CO3 (5 mol%) and THF (0.29 mL) at r.t.
b Isolated yield.
Further improvement of the yield was obtained by optimi-
zation of other reaction conditions. As shown in Table 2,
increasing the loading of Na2CO3 caused a drop in yield
(Table 2, entry 1 vs. entry 2), while 83% isolated yield
was obtained when the catalyst loading was decreased to
5 mol% (Table 2, entry 3 vs. entry 1). Reducing the
amount of nitromethane led a dramatically decline in
yields, while using nitromethane as solvent could not pro-
vide a satisfied yield (Table 2, entries 4–6). Moreover,
some other solvents were also examined besides THF, but
no better results were obtained (Table 2, entries 7–11). Fi-
nally, with only 5 mol% powdered Na2CO3, the desired
product was obtained in 86% isolated yield after 24 hours
at room temperature (Table 2, entry 12).
aromatic ketoimines, introduction of both electron-with-
drawing and electron-donating groups at aromatic rings
could afford good to excellent yields (Table 3, entries 2–
8). However, the introduction of methoxy at the para po-
sition of the aromatic ring made the reaction much more
difficult, and only 37% isolated yield was obtained
(Table 3, entry 9). Meanwhile, both naphthalene and het-
erocyclic compounds gave good yields, but longer reac-
tion time was required (Table 3, entries 10–12). In
addition, the aliphatic ketoimines could also obtained
moderate to excellent yields (Table 3, entries 13 and
14).13,14
Under the optimized condition, a series of N-tosyl ke-
toimines 1a–n was reacted with nitromethane. As listed in
Table 3, most of the ketoimines afforded quaternary car-
bon products in good to excellent yields. For most of the
In conclusion, Na2CO3, which is a low-cost and environ-
mentally friendly reagent, was found to be an excellent
base catalyst for the aza-Henry reaction of N-tosyl ke-
toimines under mild conditions. Wide substrate scope,
Synlett 2008, No. 13, 2075–2077 © Thieme Stuttgart · New York

LETTER
Synthesis of b-Nitroamines
2077
(7) For other selected examples of enantioselective aza-Henry
reactions with nitromethane, see: (a) Bernardi, L.; Bonini,
B. F.; Capitò, E.; Dessole, G.; Comes-Franchini, M.; Fochi,
M.; Ricci, A. J. Org. Chem. 2004, 69, 8168. (b) Lee, A.;
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Halder, R.; Laso, A.; López, R. Angew. Chem. Int. Ed. 2006,
45, 117. (d) Gao, F.; Zhu, J.; Tang, Y.; Deng, M.; Qian, C.
Chirality 2006, 18, 741. (e) Handa, S.; Gnanadesikan, V.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129,
4900. (f) Trost, B. M.; Lupton, D. W. Org. Lett. 2007, 9,
2023.
mild conditions, and simple handling are advantages of
this procedure. Moreover, it provides a feasible direction
of asymmetric aza-Henry reaction for N-tosyl ketoimines.
Further investigations are under way in our laboratory for
the asymmetric catalytic aza-Henry reaction of keto-
imines.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(8) García Ruano, J. L.; Topp, M.; López-Cantarero, J.; Alemán,
J.; Remuiñán, M. J.; Belén Cid, M. Org. Lett. 2005, 7, 4407.
(9) Pahadi, N. K.; Ube, H.; Terada, M. Tetrahedron Lett. 2007,
48, 8700.
(10) (a) Huang, X.; Huang, J. L.; Wen, Y. H.; Feng, X. M. Adv.
Synth. Catal. 2006, 348, 2579. (b) Wang, J.; Hu, X. L.;
Jiang, J.; Gou, S. H.; Huang, X.; Liu, X. H.; Feng, X. M.
Angew. Chem. Int. Ed. 2007, 46, 8468.
Acknowledgment
The authors thank the National Nature Science Foundation of China
(Nos. 20732003 and 20702033) for financial support. We also thank
Sichuan University Analytical & Testing Center for NMR spectra
analysis and State Key Laboratory of Biotherapy for HRMS analy-
sis.
(11) (a) He, B.; Li, Y.; Feng, X. M.; Zhang, G. L. Synlett 2004,
10, 1776. (b) Prakash, G. K. S.; Vaghoo, H.; Panja, C.;
Surampudi, V.; Kultyshev, R.; Mathew, T.; Olah, G. A.
Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 3026.
(12) For the general procedure for the synthesis of N-tosyl
ketoimines, see: García Ruano, J. L.; Alemán, J.; Belén Cid,
M.; Parra, A. Org. Lett. 2005, 7, 179.
(13) To demonstrate that the size of R is important in terms of the
reactivity, some other examples, such as phenyl ethyl
ketimine, phenyl cyclic ketoimine, etc., were examined, but
no corresponding product was obtained. Meanwhile, some
other nitroalkanes, such as nitroethane and nitropropane,
were also examined; unfortunately, no corresponding
product was obtained by the present method.
References and Notes
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(14) General Procedure for aza-Henry Reaction of
Ketoimines
To a solution of 1a (0.2 mmol, 54.7 mg) with powdered
Na2CO3 (5 mol%, 1.1 mg) suspended in THF (0.29 mL) was
added MeNO2 (10 equiv, 0.11 mL) at r.t. and the mixture
was kept stirring for 24 h. The crude product was purified by
column chromatography on SiO2 (PE–EtOAc, 5:1) to give
the corresponding product 2a. By the general procedure,
compound 2a was obtained as a white solid in 86% isolated
yield. 1H NMR (400 MHz, CDCl3): d = 1.69 (s, 3 H), 2.42 (s,
3 H), 4.81 (d, J = 12.8 Hz, 1 H), 4.94 (d, J = 12.8 Hz, 1 H),
5.93 (s, 1 H), 7.22–7.33 (m, 7 H), 7.63 (d, J = 8.4 Hz, 2 H).
13 C NMR (100 MHz, CDCl3): d = 143.6, 139.7, 139.2,
129.6, 128.9, 128.4, 127.0, 125.3, 82.9, 60.1, 24.7, 21.5.
ESI-HRMS: m/z calcd for C16H18N2NaO4S [M + Na]:
357.0879; found: 357.0882.
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Synlett 2008, No. 13, 2075–2077 © Thieme Stuttgart · New York