9096
M. A. McLaughlin, D. M. Barnes / Tetrahedron Letters 47 (2006) 9095–9097
NH2
NO2
attributed to the absence of N-alkylated and S-extruded
byproducts formed during the Raney nickel reduction.
9
S8, NaHCO3 (3 equiv)
DMF, 130 o
ð1Þ
C
CN
CN
7d
8d
NH2
NO2
S8 (3 equiv)
NH2
NH2
Further study of the reduction showed that sulfur might
be used to reduce a variety of nitro arenes to the corres-
ponding anilines. The influence of base, solvent and
reagent equivalents was investigated to determine stan-
dard conditions for the reduction. A screen of amine
and inorganic bases including propylamine, NaHCO3,
Na CO , NaOH, and K HPO with sulfur in formamide
NaHCO3 (3 equiv)
N
N
DMF, 130oC, 5.5 h
ð2Þ
93 %
N
N
S
S
6
4
2
3
2
4
at 100 °C showed NaHCO to provide the best conver-
3
With the optimized reaction conditions in hand, the
effect of the nature of the base was revisited. Using 2-
nitrobiphenyl (7a) and 3 equiv of sulfur in DMF we
found that a variety of bases provided clean conversion
to 2-aminobiphenyl (8a). Primary, secondary, and ter-
tiary amine bases (benzylamine, morpholine and Hu-
nig’s base) all showed good conversion, with Hunig’s
base proving optimal (96% conversion by HPLC area
sion while minimizing side product formation. A pro-
duct mixture containing aniline and formylated aniline
byproducts, however, complicated these reactions.
Attempts to drive the reaction completely to the formyl-
ated product by extending the reaction time were
unsuccessful, but a change of solvent from formamide
to dimethylformamide eliminated this side product for-
mation. Next, it was shown that 3 equiv each of S8
and NaHCO3 gave the best conversion to product.
Using 3-nitrobenzonitrile (7d, Eq. 1), the conversion at
1
1
%
). Other inorganic bases also provided comparable re-
sults to NaHCO . The reaction showed similar conver-
3
sion with K CO and a faster reaction with NaOH.
1
0
2
3
2
2
h was 96% with 3 equiv of S8 versus 64% with
equiv, and 40% with 1 equiv. Investigation of the reac-
Unfortunately, as with NaHCO , Hunig’s base did not
3
cleanly provide a reduced product when attempted on
tion temperature showed that elevated temperatures
130 °C) were typically required for the reduction.
Therefore, optimal conditions were the nitroarene
1 equiv), sulfur (3 equiv), and NaHCO3 (3 equiv) in
3
-bromo-nitrobenzene.
(
In conclusion, we report a method for the conversion of
functionalized nitroarenes to the corresponding anilines
with sulfur and base in moderate to high yields. This
method does not require the use of transition metals
or hydrogen gas and highlights the capacity of sulfur
(
DMF at 130 °C.
The scope of the reaction was examined using various
substituted nitroarenes (Table 1). The reaction was
found to tolerate a range of functionalities on the aro-
matic ring including nitrile, ester, amide, and chloride
substituents. However, attempts to reduce both 3- and
1
2
as an inexpensive 2-electron reductant. The conditions
are also notable for their compatibility with a range of
functional groups and use of a mild base.
4
-bromo-nitrobenzene resulted in significant decomposi-
General method for synthesis of substituted anilines.
Biphenyl-2-amine (8a). To a flask equipped with reflux
condenser were added 2-nitrobiphenyl (2.0 g, 10.0
mmol), sulfur (0.96 g, 30.1 mmol), NaHCO3 (2.53 g,
tion. The yield of these latter reactions was not im-
proved at 100 °C. Finally, reduction of nitropyrimidine
4
ford aniline 6 in 93% yield. The higher yield relative to
the reaction run under previous conditions (76%) is
(Eq. 2) proceeded cleanly under these conditions to af-
3
0.1 mmol) and DMF (20 mL) and the suspension was
heated to 130 °C. (Note: Reaction shows gas evolution.)
The reaction was stirred for 18 h and cooled to room
temperature. The dark brown reaction mixture was par-
titioned between MTBE (50 mL) and water (50 mL) and
the aq extracted with MTBE (50 mL). The combined
organics were washed with water (50 mL) and brine
8
Table 1. S Reduction of functionalized nitroarenes
NO2
NH2
sulfur (3 equiv)
NaHCO3 (3 equiv)
(
25 mL), dried over Na SO , and concentrated to 1.8 g
2 4
o
DMF, 130 C
yellow oil. The crude material was chromatographed
with 10% isopropyl acetate/heptane and dried in vacuo
at room temperature overnight to yield 1.5 g (88%)
R
R
7a-g
8a-g
1
a
Substrate
R
Time Yield (8a–g)
yellow solid 8a. Mp = 53–54 °C; H NMR (400 MHz,
(
h)
(%)
DMSO-d ): d 4.73 (s, 2H), 6.63 (td, J = 7.34, 1.23 Hz,
6
1
7
H), 6.75 (dd, J = 8.03, 1.17 Hz, 1H), 6.97 (dd, J =
7
7
7
7
7
7
7
a
b
c
d
e
f
2-Phenyl
3-CF
4-OEt
3-CN
3-Cl
18
18
3
2
6
88
73
64
87
96
72
87
.48, 1.58 Hz, 1H), 7.04 (ddd, J = 7.99, 7.24, 1.65 Hz,
3
1
3
1H), 7.30–7.35 (m, 1H), 7.38–7.46 (m, 4H) ppm;
NMR (100 MHz, DMSO-d ): d 114.8, 116.3, 125.6,
126.2, 127.7, 128.1, 128.2, 129.5, 139.1, 144.3 ppm; MS
C
6
3-CO
2
Et
1
2
(DCI+) m/z 170.0 (M+1). Anal. Calcd for C H N:
12 11
g
3-Morpholine carboxamide
C, 85.17; H, 6.55; N, 8.28. Found C, 85.01; H, 6.78;
N, 8.24.
a
Isolated yield of purified product.