Aza-Henry reaction using DMSO as a solvent

Article abstract of DOI:10.1246/cl.141185

Using dimethyl sulfoxide (DMSO) under the influence of molecular sieves (MS) 4A the aza-Henry reaction of various N-tosylimines with nitroalkanes proceeded smoothly to afford β-nitroamines in high yields.

Full text of DOI:10.1246/cl.141185

Received: December 22, 2014 | Accepted: January 6, 2015 | Web Released: April 5, 2015
CL-141185
Aza-Henry Reaction Using DMSO as a Solvent
Toshihiro Isobe, Atsuki Kato, and Takeshi Oriyama*
Department of Chemistry, Faculty of Science, Ibaraki University, 2-1-1 Bunkyo, Mito, Ibaraki 310-8512
(E-mail: tor@mx.ibaraki.ac.jp)
Table 1. Effect of solventsa
Using dimethyl sulfoxide (DMSO) under the influence of
molecular sieves (MS) 4A the aza-Henry reaction of various
N-tosylimines with nitroalkanes proceeded smoothly to afford
β-nitroamines in high yields.
NTs
NHTs
MS 4A
+ MeNO2
NO2
Solvent, rt, 2 h
Ph
H
Ph
Entry
Solvent
Yield/%b
1
2
3
4
5
6
7
8
9
DMSO
DMF
MeCN
Et2O
79c
38c
17
1
7
14
0
2
9
3
13
The aza-Henry reaction is an important carbon-carbon
bond-forming reaction. The resulting β-nitroamines can be
converted to 1,2-diamines by reduction or α-amino acids by
Nef reaction. Various aza-Henry reactions have been reported;1
however, aza-Henry reactions of widely available and stable
N-tosylimines are yet to be appropriately explored. To date,
aza-Henry reactions of N-tosylimines have been conducted using
electrolysis,2 nanocrystalline MgO,3 Na2CO3,4 and rare earth
THF
1,4-dioxane
CH2Cl2
CHCl3
hexane
toluene
compound catalysts such as Yb(OiPr)3 and [(Me3Si)2N]3Y(μ-
5
10
11
Cl)Li(THF)3.6 In addition, Reformatsky-type aza-Henry reac-
tions using SmI2 and bromonitromethane,7 and asymmetric aza-
Henry reactions using metal complexes such as a binuclear zinc
complex8 and a chiral N,N¤-dioxide Cu(I) complex9 have been
reported. In these methods, electrolysis or an activator, such as a
metal catalyst or base, is needed for the reaction.
d
MeNO2
aAll reactions were performed in solvent (1 mL) using an imine
(0.30 mmol) and MeNO2 (1.5 mmol) in the presence of MS 4A
(50 mg). Yield was determined by H NMR analysis of crude
product. Isolated yield of purified product. 1 mL (63 equiv)
of MeNO2 were used.
b
1
c
d
Alternatively, we have reported many novel reactions using
dimethyl sulfoxide (DMSO) and molecular sieves (MS) 4A.10
For example, in DMSO with MS 4A, Henry reaction of alde-
hydes or α-ketoesters,10e Knoevenagel reaction of N-tosylimines
with active methylene compounds,10g and double Michael addi-
tion of dithiols to acetylenic carbonyl compounds10h proceeded
smoothly to produce the corresponding products without a metal
catalyst or base. Based on this research, here we describe the
aza-Henry reaction of various N-tosylimines with nitroalkanes to
afford corresponding β-nitroamines in DMSO with MS 4A.
Initially, we reacted N-benzylidene-4-methylbenzenesulfo-
namide (0.3 mmol) with 5 equiv of nitromethane in DMSO with
MS 4A (50 mg). As expected, the corresponding β-nitroamine
was obtained in good yield (Table 1, Entry 1). We subsequently
examined the effect of solvents (Entries 2-11). Other aprotic
polar solvents, such as DMF and MeCN, gave the desired
product in lower yields (Entries 2 and 3), while ether solvents
(Entries 4-6), halogenated solvents (Entries 7 and 8), and
hydrocarbon solvents (Entries 9 and 10) produced insufficient
yields. In the case of a MeNO2 solvent, the corresponding
product was obtained in only a 13% yield (Entry 11). Thus,
DMSO was determined to be the best solvent for this reaction.
We next investigated the reaction time (Table 2), obtaining
the best yield (91%) when the reaction was performed for 30 min
(Entry 2). For a reaction time longer than 30 min, a distinct
decrease in the yield was observed (Entries 3-6). This is because
aza-Henry product overreacts during a longer reaction time. In
fact, when the reaction was conducted for 48 h, 1,3-dinitro
compound was also obtained in a 13% yield (Entry 6). From the
above results, 30 min was determined to be an adequate reaction
time.
Table 2. Effect of reaction timesa
NTs
NHTs
MS 4A
+ MeNO2
NO2
DMSO, rt
Ph
H
Ph
Entry
Time
Yield/%b
1
2
3
4
5
6
5 min
30 min
1 h
70
91
84
2 h
79
24 h
48 h
75
70 (13)c
aAll reactions were performed in DMSO (1 mL) using an imine
(0.30 mmol) and MeNO2 (1.5 mmol) in the presence of MS
4A (50 mg). bIsolated yield of purified product. cYield of
1,3-dinitro compound.
NO2
NO2
Ph
The effect of additives was subsequently investigated
(Table 3). When the reaction was conducted in DMSO without
an additive, the corresponding β-nitroamine was obtained in an
83% yield (Entry 1). Upon adding 100 ¯L of H2O, the yield
decreased in comparison to that of no additive (Entry 2), while
adding 10 mg of MS 4A gave higher yield (Entry 3). Therefore,
it is a better choice to perform the reaction in the absolute
Chem. Lett. 2015, 44, 483–485 | doi:10.1246/cl.141185
© 2015 The Chemical Society of Japan | 483

Table 3. Effect of additivesa
Table 4. Aza-Henry reaction with various N-tosyliminesa
NTs
NHTs
NHTs
Additive
NTs
R2
MS 4A
+ MeNO2
NO2
NO2
+ MeNO2
R1
DMSO, rt, 30 min
Ph
H
Ph
R1
Entry R1
DMSO, rt
R2
Entry
Additive
Yield/%b
R2 MeNO2/equiv Time/h Yield/%b
1
2
3
4
5
6
7
8
9
none
83
75
89
92
91
90
89
85
84
91
75
52
1
2
3
4d
5
6
7
8
9
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
5
10
10
10
10
10
10
10
10
10
5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
3
92
H2O (100 ¯L)
MS 4A (10 mg)
MS 4A (30 mg)
MS 4A (50 mg)
MS 4A (70 mg)
MS 4A (100 mg)
MS 3A (30 mg)
MS 5A (30 mg)
MS 13X (30 mg)
MgSO4 (30 mg)
Drieriteμ (30 mg)
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
83c
84
76
82c
87
85c
99
1-naphthyl
2-naphthyl
2-furyl
cyclohexyl
sec-butyl
4-MeO2CC6H4
2-HOC6H4
2-TBSOC6H4
2-TIPSOC6H4
2-BnOC6H4
2-PMBOC6H4
2-PivOC6H4
2-BocOC6H4
2-MOMOC6H4
Ph
94
73
10
11
12
10
11
89
12
13
14
15
16
17d
18d
19
20
21
22
23g
5
3
0.5
5
76e
88
10
10
10
10
10
10
10
10
10
5
aAll reactions were performed in DMSO (1 mL) using an imine
(0.30 mmol) and MeNO2 (1.5 mmol) in the presence of
83f
82
1
b
additives. Isolated yield of purified product.
0.5
0.5
0.5
0.5
1
0.5
5
0.5
99
94
83c
98
dehydrative condition by using MS 4A. An examination of the
amount of MS 4A added (Entries 3-7) showed that using 30 mg
of MS 4A gave the highest yield, whereas the yields did not
increase further despite using more than 30 mg of MS 4A. Thus,
the reaction was then performed in the presence of 30 mg of
various additives (Entries 8-12). MS 13X gave a result
comparable to MS 4A; however, we chose MS 4A as it is most
commonly used.
92
92c
64
2-ClC6H4
10
94c
aAll reactions were performed in DMSO (1 mL) using an imine
(0.30 mmol) in the presence of MS 4A (30 mg). bYield of
isolated product after chromatographic purification. Yield of
c
With the optimized reaction conditions in hand, we
demonstrated aza-Henry reaction of various N-tosylimines
with nitromethane, as shown in Table 4.11 The reaction of N-
tosylimines containing electron-donating and electron-with-
drawing substituents at the para-position gave the corresponding
aza-Henry products in about 80% yields (Entries 2-5). Regard-
less of the substituent position, N-tosylimines derived from
ortho-, meta-, and para-chlorobenzaldehyde afforded the desired
product in greater than 80% yields (Entries 5-7). Treatment with
N-tosylimines, prepared from naphthaldehydes, gave the corre-
sponding β-nitroamines in excellent yields (Entries 8 and 9).
These reaction conditions were applicable to heteroarylimine
which was derived from furfural (Entry 10). By extending the
reaction time, aliphatic N-tosylimines afforded β-nitroamines in
good yields (Entries 11 and 12). Utilizing advantages of the mild
reaction conditions in this reaction, we performed the reaction
with imines which have various functional groups (Entries 13-
21). The reaction proceeded smoothly with N-tosylimines
containing benzoate (Entry 13), free hydroxy group (Entry 14),
silyl ethers (Entries 15 and 16), benzyl ethers (Entries 17 and
18), pivalate (Entry 19), carbonate (Entry 20), and acetal
(Entry 21), without damaging the functional groups. When the
reaction was performed with N-tosylketimine prepared from
acetophenone, the desired compound was obtained in a 64%
yield (Entry 22). A successful result was obtained from a gram-
scale reaction (Entry 23).
d
isolated product after recrystallization. 2 mL of DMSO were
used. e72:28 mixture of diastereomers was obtained. Yield
f
was determined by 1H NMR analysis. gReaction was per-
formed in DMSO (5 mL) using an imine (4.0 mmol, 1.2 g) in
the presence of MS 4A (100 mg).
Table 5. Aza-Henry reaction with various nitroalkanesa
NHTs
NTs
R2
NO2
MS 4A
NO2
+
R1
R1
DMSO, rt
R3
H
R2
R3
Entry R1
R2 R3 Time/h Yield/%b Drc
1
2
3
Ph
1-naphthyl Me
Ph
Me
H
H
0.5
1
95
80d
80d
85:15
85:15
®
Me Me
3
aAll reactions were performed in DMSO (1 mL) using an imine
(0.30 mmol) and nitroalkane (1.5 mmol) in the presence of MS
b
4A (30 mg). Yield of isolated product after chromatographic
purification. cDiastereomeric ratio (see below) was determined
by 1H NMR analysis.12 dYield of isolated product after
recrystallization.
We further evaluated the reaction with nitroethane or 2-
nitropropane, as summarized in Table 5. Surprisingly, the
reaction of N-tosylimines with nitroethane afforded the corre-
sponding product diastereoselectively in good yields (Entries 1
NHTs
NHTs
:
NO2
NO2
R1
R1
484 | Chem. Lett. 2015, 44, 483–485 | doi:10.1246/cl.141185
© 2015 The Chemical Society of Japan

and 2). In the case of 2-nitropropane, the desired compound was
obtained in an 80% yield (Entry 3).
8
9
F. Gao, J. Zhu, Y. Tang, M. Deng, C. Qian, Chirality 2006,
18, 741.
a) H. Zhou, D. Peng, B. Qin, Z. Hou, X. Liu, X. Feng,
J. Org. Chem. 2007, 72, 10302. b) C. Tan, X. Liu, L. Wang,
J. Wang, X. Feng, Org. Lett. 2008, 10, 5305.
In conclusion, a simple and convenient method for the aza-
Henry reaction was developed in DMSO, under the influence of
MS 4A. This reaction has the following synthetic advantages:
(1) in contrast to conventional methods, the present reaction
does not need electrolysis or an activator such as a metal catalyst
or base; (2) in addition to simple aromatic aldimines, a wide
range of N-tosylimines, including aliphatic imines, ketimine,
and imines which have a variety of functional groups, can be
employed; (3) the reaction can be performed with easy handling
and proceeds smoothly under mild reaction conditions; and (4)
when using nitroethane the desired products are obtained
diastereoselectively. Mechanistic studies and the application of
DMSO-promoted benign reactions in other efficient reactions are
currently being assessed in our laboratory.
10 For the catalyst-free reactions in DMSO developed by our
group, see: a) T. Watahiki, M. Matsuzaki, T. Oriyama, Green
Chem. 2003, 5, 82. b) T. Watahiki, S. Ohba, T. Oriyama,
Org. Lett. 2003, 5, 2679. c) K. Iwanami, Y. Hinakubo, T.
Oriyama, Tetrahedron Lett. 2005, 46, 5881. d) K. Iwanami,
T. Oriyama, Synlett 2006, 112. e) T. Oriyama, M. Aoyagi, K.
Iwanami, Chem. Lett. 2007, 36, 612. f) T. Kakinuma, R.
Chiba, T. Oriyama, Chem. Lett. 2008, 37, 1204. g) R. Chiba,
T. Oriyama, Chem. Lett. 2008, 37, 1218. h) T. Kakinuma, T.
Oriyama, Tetrahedron Lett. 2010, 51, 290. i) K. Buniuchi, T.
Oriyama, J. Synth. Org. Chem., Jpn. 2012, 70, 1041.
11 Typical experimental procedure is as follows: Nitromethane
(80 ¯L, 1.5 mmol) was added to a solution of N-benzylidene-
4-methylbenzenesulfonamide (78.6 mg, 0.30 mmol) in
DMSO (1 mL) in the presence of MS 4A (30 mg) at room
temperature under an argon atmosphere. After stirring for
30 min, the reaction mixture was quenched with saturated
aqueous NaHCO3. The organic materials were extracted with
AcOEt, washed with water, and dried over anhydrous
MgSO4. 4-Methyl-N-(2-nitro-1-phenylethyl)benzenesulfona-
mide (89.4 mg, 92%) was isolated by thin layer chromatog-
raphy on silica gel. Dehydrated DMSO was purchased
from Wako Pure Chemical Industries, Ltd. and used without
further purification.
Supporting Information is available electronically on J-STAGE.
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Chem. Lett. 2015, 44, 483–485 | doi:10.1246/cl.141185
© 2015 The Chemical Society of Japan | 485