A novel synthesis of N-arylamides from nitroarenes via reductive N-acylation with red phosphorus and iodine

Article abstract of DOI:10.1055/s-2006-947334

A series of N-arylamides and imides were synthesized via reductive N-acylation of nitroarenes with red phosphorus and carboxylic acids, catalyzed by iodine or iodides; an I /I° redox cycle was proposed to promote the reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-947334

LETTER
1953
A Novel Synthesis of N-Arylamides from Nitroarenes via Reductive
N-Acylation with Red Phosphorus and Iodine
N
ovel Synthesis of
i
N
-Ary
a
lamides ohua Du, Mei Zheng, Sheng Chen, Zhenyuan Xu*
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Catalytic Hydrogenation Research Center,
Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, P. R. of China
Fax +86(571)88320066; E-mail: chrc@zjut.edu.cn
Received 18 February 2006
Red phosphorus and iodine had been employed to reduce
arylsulfonyl chlorides,8 where hydroiodic acid was con-
sidered as the reducing agent. For example, refluxing
with two equivalents of red phosphorus and a catalytic
amount of iodine in acetic acid, 2-chloro-4-fluoro-5-
nitrobenzenesulfonyl chloride was converted to S-(2-
chloro-4-fluoro-5-nitrophenyl)ethanethioate. In this reac-
tion, the nitro group was unchanged. Interestingly, how-
ever, we found that if four equivalents of red phosphorus
were used in the above reaction, besides the chloro-
sulfonyl group being reduced, the nitro group was also re-
duced and acylated to form an amide.9 This result inspired
us to investigate the reductive N-acylation of nitroarenes
with the red phosphorous/iodine system (Scheme 1).
Abstract: A series of N-arylamides and imides were synthesized
via reductive N-acylation of nitroarenes with red phosphorus and
carboxylic acids, catalyzed by iodine or iodides; an I–/I0 redox cycle
was proposed to promote the reaction.
Key words: N-arylamide, nitroarene, reductive N-acylation, red
phosphorus, iodine
N-Arylamides are widely useful compounds as pharma-
ceuticals, pesticides, dyes, and intermediates. A widely
practical method of amide synthesis is the acylation of
primary or secondary amines with an acylating agent,
such as acyl chloride, acyl bromide, ester, acyl anhydride,
or carboxylic acid, etc.1 On the other hand, several at-
tempts have been made in order to synthesize amides from
nitro compounds, so-called reductive N-acylations. This
direct synthesis of amides is an advantageous method of
saving a single step, the reduction of nitro compounds to
amines. These reductive acylations were attained by em-
ploying various reducing agents. Ho2 used excess molyb-
denum hexacarbonyl (2.0 equiv) as the reducing agent,
giving 46–85% yield of anilides. Nahmed et al.3 used
methyl formate or formic acid as the supply of hydrogen,
NO2
+
NHCOR'
P/I2
R
R
R'CO2H
1
2
3
O
NO2
+
N
P/I2
HO2C(CH2)3CO2H
O
Cl
Cl
Cl
Cl
1h
4
5
catalyzed by
a
ruthenium carbonyl compound
[Ru3(CO)12]. Matsuda et al.4 claimed that reacting
nitrobenzene with a large excess of acetic acid at 250 °C
gave 97% acetanilide. Kajimoto et al.5 reduced nitro-
benzene at 310 °C with carbon monoxide in acetic acid or
propionic acid in the presence of transition-metal-carbon-
yl catalyst [for example Ni(CO)4] to give anilides in
moderate yields. Watanable et al.6 utilized an alternative
catalytic system, PtCl2(PPh3)2 combined with tin(IV)
chloride for reductive acylation with carbon monoxide.
For example, acetanilide was obtained in 91% yield from
nitrobenzene at 180 °C and 60 atm of carbon monoxide
pressure for four hours. Choudary et al.7 accomplished a
reductive N-acylation of nitroarenes with a stoichiometric
amount of sodium iodide, catalyzed by Fe(III)-exchanged
montmorillonite.
Scheme 1 Substituents: 1a: R = H; 1b: R = 2,3-Me2; 1c: R = 2-Cl;
1d: R = 3-Cl; 1e: R = 4-Cl; 1f: R = 4-F; 1g: R = 2-Cl-4-CF3; 1h:
R = 3,4-Cl2. 2a: R¢ = Me; 2b: R¢ = Et; 2c: R¢ = n-Pr; 2d: R¢ = n-Hex;
2e: R¢ = Ph.
Firstly, 3,4-dichloronitrobenzene (1h) was selected as a
model compound and reacted with two equivalents of red
phosphorus and 0.04 equivalents of iodine in various
carboxylic acids.10 The reaction was kept at reflux for six
hours for acetic acid and 140 °C for other acids whose
boiling points were higher than 140 °C. As shown in
Table 1, N-arylamides of the tested aliphatic acids,
benzoic acid, and dicarboxylic acid were synthesized in
moderate to good yields. For aliphatic acids (Table 1,
entry 1–4), good conversions and selectivity were
obtained. Although the conversion in benzoic acid
(Table 1, entry 5) was high, the selectivity was remark-
ably lower than for aliphatic acids. For glutaric acid (4), a
dicarboxylic acid, N-heterocyclodione (N-glutarimide)
was obtained (Table 1, entry 6) with high conversion and
selectivity.
Here, we wish to report a novel catalytic reductive N-
acylation of nitroarenes promoted by red phosphorus and
iodine or iodides.
SYNLETT 2006, No. 12, pp 1953–1955
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1
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8
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Advanced online publication: 24.07.2006
DOI: 10.1055/s-2006-947334; Art ID: W03606ST
© Georg Thieme Verlag Stuttgart · New York

1954
X. Du et al.
LETTER
Table 1 Reductive Acylation of 3,4-Dichloronitrobenzenea,10
conversion and selectivity were 76.1% and 89.4%, respec-
tively. When the amount of iodine was increased to 0.03
equivalents (Table 3, entry 4), 1h reacted nearly com-
pletely in six hours, but the selectivity was only 92.8%.
The best selectivity was obtained with 0.04 equivalents of
iodine (Table 3, entry 5). Further increasing the amount of
iodine (Table 3, entry 6) was not obviously beneficial to
the reaction. When iodine was replaced by potassium
iodide (Table 3, entry 7), sodium iodide (Table 3, entry 8),
or KI3 (Table 3, entry 9), no obvious change in the conver-
sion and selectivity occurred.
NO2
NHCOR'
P/I2
+
R'CO2H
Cl
Cl
Cl
Cl
1h
2
3
Entry
Products
R¢
Conversion
(%)b
Selectivity
(%)c
1
2
3
4
5
6
3a
3b
3c
3d
3e
5
Me
82.4
98.1
97.8
87.4
99.3
94.2
96.7
97.2
95.6
91.2
85.4
96.9
Et
Table 3 Effects of Catalyst on the Reductive Acylation of
3,4-Dichloronitroarenes with Propionic Acid
n-Pr
n-Hex
Ph
Entry
Catalyst
Amount
(mol)a
Conversion
(%)
Selectivity
(%)
1
2
3
4
5
6
7
8
9
none
I2
0
–
–
a Reactions carried out at 140 °C, except for 3a which reacted at
110 °C.
0.01
0.02
0.03
0.04
0.05
0.08
0.08
0.03
76.1
96.9
99.8
100
89.4
90.8
92.8
95.6
95.1
94.8
93.7
95.3
b The conversion of 3,4-dichloronitrobenzene.
c Analyzed by GC and calculated with area normalization.
I2
I2
I2
Secondly, seven nitroarenes were utilized to investigate
the applicability of this reaction.11 At this time, propionic
acid (2b) was used as the acylating agent. As shown in
Table 2, all nitroarenes were reductively acylated, giving
N-arylpropionamides with high selectivity.
I2
100
KI
NaI
KI3
99.4
98.9
99.7
Table 2 Reductive Acylation of Nitroarenes with Propionic Acid
a Per mol of dichloronitrobenzene.
NO2
NHCOEt
P/I2
R
+
R
EtCO2H
A preliminary mechanism was proposed in Scheme 2.
Since KI and NaI showed the same catalytic effects
(Table 3, entries 7–9) as iodine in this reaction, there must
exist an I–/I0 redox cycle in the reaction. During this redox
cycle, the nitro group was reduced to an amino group and
phosphorus was oxidized from P(0) to P(V); PI5 was a
possible intermediate, which promoted the acylation of
the amino group with a carboxylic acid. Further research
is going on to disclose the reaction mechanism.
1
2b
3
Entry
Products
R
Conversion Selectivity
(%)
(%)
1
2
3
4
5
6
7
3f
3g
3h
3i
H
54.1
33.2
32.4
58.4
91.2
48.8
58.3
98.3
90.7
97.8
98.2
99.0
96.7
98.3
2,3-Me2
2-Cl
3-Cl
4-Cl
4-F
I–
ArNO2
P(V)
3j
3k
3l
PI5
RCO2H
2-Cl-4-CF3
I0
ArNH2
ArNHCOR
P(0)
Scheme 2 A preliminary hypothesis
Thirdly, the effects of catalysts were investigated, using
the reaction of 3,4-dichlooronitrobenzene (1h) with
propionic acid (2b) to give N-(3,4-dichlorophenyl)pro-
pionamide (3b) as the model reaction.12 According to the
results shown in Table 3, for reductive N-acylation of 1h
As the reducing agent in the reaction, each phosphorus
atom contributed 5 electrons. Considering its atomic
weight was 31, the reducing equivalent of phosphorus was
with red phosphorus in 2b the amount of catalyst was an only 6.2, which was much more atom economical than
important factor. Both the conversion and selectivity other literature reported2–7 reducing agents (metal-carbo-
dropped as the amount of iodine decreased. In the absence nyl compounds, formic acid, acetic acid, carbon monox-
of iodine (Table 3, entry 1), the conversion was less than ide, sodium iodide, etc.). In addition, red phosphorus was
readily available, inexpensive, and suitable to industrial
scale application.
0.5% even with prolonged reaction times of 24 hours;
with 0.01 equivalents of iodine (Table 3, entry 2), the
Synlett 2006, No. 12, 1953–1955 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of N-Arylamides
1955
3c: Mp 69–71 °C. IR (KBr): 3310, 3098, 2961, 1671, 1589,
1522, 1466, 1382, 818 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.77 (s, 1 H), 7.34–7.38 (m, 3 H), 2.33 (t, 2 H, J = 7.2
Hz), 1.69–1.78 (m, 2 H), 0.98 (t, 3 H, J = 7.2 Hz). MS (70
eV): m/z = 231 (M+), 161.
3d: Oil. IR (KBr): 3309, 2928, 1666, 1590, 1522, 1470,
1382, 815 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.76 (s, 1
H), 7.57 (s, 1 H), 7.32–7.34 (m, 2 H), 2.34 (t, 2 H, J = 7.2
Hz), 1.68–1.73 (m, 2 H), 1.29–1.34 (m, 6 H), 0.88 (t, 3 H,
J = 6.4 Hz). MS (70 eV): m/z = 273 (M+), 161.
In summary, the reductive N-acylation of nitroarenes
promoted by P/I2 was a useful method for the synthesis of
N-arylamides. It has several advantages such as atom
economy, readily available and inexpensive raw materi-
als, and relatively mild reaction conditions.
Acknowledgment
This work was financially supported by the National Basic
Research Program of China (2003CB114400).
3e: Mp 134–136 °C. IR (KBr): 3298, 1652, 1582, 1511,
1381, 813, 714 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.91
(s, 1 H), 7.84–7.90 (m, 3 H), 7.41–7.60 (m, 5 H). MS (70
eV): m/z = 265 (M+), 105.
References and Notes
5: Mp 182–184 °C. IR (KBr): 3086, 2961, 1729, 1684, 1468,
1365, 1256, 1135, 832, 760 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.53 (d, 1 H, J = 8.4 Hz), 7.26 (s, 1 H), 6.97 (d,
1 H, J = 8.4 Hz), 2.82 (t, 4 H, J = 6.4 Hz), 2.11 (dd, 2 H, J =
6.4, 6.4 Hz). MS (70 eV): m/z = 257 (M+), 229, 187, 161.
(11) Following the same procedure described above, 1h was
replaced by nitroarenes 1a–g, and propionic acid (2b) was
employed to give 3f–l.
(1) Weininger, S. J.; Stermitz, F. R. Organic Chemistry;
Academic Press Inc.: New York, 1984, 653.
(2) Ho, T.-L. J. Org. Chem. 1977, 42, 3755.
(3) Nahmed, E. M.; Jenner, G. Tetrahedron Lett. 1991, 32,
4917.
(4) Matsuda, F.; Ogiya, N.; Kato, T. Japan Kokai JP75-82025,
1975; Chem. Abstr. 1975, 83, 205977.
(5) Kajimoto, T.; Tsuji, J. Bull. Chem. Soc. Jpn. 1969, 42, 827.
(6) Watsnabe, Y.; Tsuji, Y.; Kondo, T.; Takeuchi, R. J. Org.
Chem. 1984, 49, 4451.
(7) Choudary, B. M.; Kantam, M. L.; Ranganath, K. V. S.; Rao,
K. K. Angew. Chem. Int. Ed. 2005, 44, 322.
(8) (a) Yamashita, H.; Takahashi, Y. Japan Kokai JP 49-25255,
1974; Chem. Abstr. 1974, 83, 9476. (b) Kawahara, K.
Yakugaku Zasshi 1957, 77, 959; Chem. Abstr., 1957, 52,
15650.
(9) S-(5-Acetylamino-2-chloro-4-fluorophenyl)ethane-
thioate: To a solution of 2-chloro-4-fluoro-5-nitrobenzene-
sulfonyl chloride (0.55 g, 2.0 mmol) in AcOH (5 mL) was
added red phosphorus (0.25 g, 8.0 mmol) and I2 (5.0 mg,
0.04 mmol). The mixture was stirred and heated to reflux at
110 °C for 6 h. After cooling to r.t., the mixture was filtered.
The filtrate was poured into ice-water and extracted with
EtOAc (3 ×10 mL). The extracts were combined and dried
over anhyd Na2SO4. After evaporating the solvent 0.49 g
(94%) the desired product was obtained; mp 143–145 °C. IR
(KBr): 3315, 3143, 3096, 1705, 1676, 1599, 1521, 1472,
1371, 1103, 957, 881, 706 cm–1. 1H NMR (400 MHz,
CDCl3): d = 8.55 (1 H, d, J = 7.6 Hz), 7.43 (1 H, s), 7.28 (1
H, d, J = 10.8 Hz), 2.45 (3 H, s), 2.20 (3 H, s). MS (70 eV):
m/z = 261 (M+), 219 (M+ – CH2CO), 177 (219 – CH2CO),
142 (177 – Cl).
(10) General Procedure. A 50-mL three-necked flask was
charged with 3,4-dichloronitrobenzene (1h, 1.92 g, 10
mmol), red phosphorus (0.62 g, 20 mmol), I2 (0.1 g, 0.4
mmol), and an organic acid (2a–e or 4a, 40 mmol). The
mixture was stirred at 140 °C (110 °C for AcOH) for 6 h.
After cooling to r.t., the mixture was decanted onto ice-water
and extracted with EtOAc (3 ×10 mL). The extracts were
combined and dried over anhyd Na2SO4. The solvent was
evaporated to give product 3a–e and 5.
3f: Mp 84–86 °C. IR (KBr): 3255, 1666, 1603, 1541, 750
cm–1. 1H NMR (400 MHz, CDCl3): d = 7.62–7.64 (m, 2 H),
7.30–7.32 (m, 2 H), 7.21 (s, 1 H), 7.08– 7.12 (m, 1 H), 2.43
(q, 2 H, J = 7.2 Hz), 1.26 (t, 2 H, J = 7.2 Hz). MS (70 eV):
m/z = 149 (M+), 93.
3g: Mp 79–81 °C. IR (KBr): 3280, 2935, 1659, 1529, 1457,
782, 720 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.81 (s, 1
H), 6.85–7.11 (m, 3 H), 2.45 (q, 2 H, J = 7.2 Hz), 2.33 (s, 3
H), 2.29 (s, 3 H), 1.26 (t, 2 H, J = 7.2 Hz). MS (70 eV):
m/z = 177 (M+), 121, 106.
3h: Mp 91–93 °C. IR (KBr): 3288, 3032, 1664, 1587, 1526,
1285, 754 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.40–8.42
(m, 1 H), 7.64 (s, 1 H), 7.36–7.37 (m, 1 H), 7.26 –7.29 (m, 1
H), 7.02–7.05 (m, 1 H), 2.48 (q, 2 H, J = 7.2 Hz), 1.28 (t, 2
H, J = 7.2 Hz). MS (70 eV): m/z = 183 (M+), 148, 127.
3i: Mp 74–75 °C. IR (KBr): 3248, 2977, 1668, 1596, 1532,
1415, 1307, 879, 774 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.74 (s, 1 H), 7.50–7.52 (m, 1 H), 7.36–7.42 (m, 1 H),
7.20–7.26 (m, 1 H), 7.06–7.08 (m, 1 H), 2.39 (q, 2 H, J = 7.2
Hz), 1.24 (t, 3 H, J = 7.2 Hz). MS (70 eV): m/z = 183 (M+),
127.
3j: Mp 123–124 °C. IR (KBr): 3299, 2976, 1666, 1605,
1542, 1492, 823 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.48
(d, 2 H, J = 8.0 Hz), 7.28 (d, 2 H, J = 8.0 Hz), 7.14 (s, 1 H),
2.39 (q, 2 H, J = 7.4 Hz), 1.25 (t, 3 H, J = 7.4 Hz). MS (70
eV): m/z = 183 (M+), 127.
3k: Mp 105–107 °C. IR (KBr): 3272, 3089, 1663, 1556,
1507, 1212, 830 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.47–7.48 (m, 2 H), 7.22 (s, 1 H), 6.99–7.02 (m, 2 H),
2.37 (q, 2 H, J = 7.2 Hz), 1.24 (t, 3 H, J = 7.2 Hz). MS (70
eV): m/z = 167 (M+), 111.
3l: Mp 75–77 °C. IR (KBr): 3270, 2987, 1670, 1532, 1424,
1333, 1121, 820 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.80
(s, 1 H), 7.72 (s, 1 H), 7.49 (d, 1 H, J = 8.0 Hz), 7.29 (d, 2 H,
J = 8.0 Hz), 2.50 (q, 2 H, J = 7.4 Hz), 1.29 (t, 3 H, J = 7.4
Hz). MS (70 eV): m/z = 251 (M+), 195.
3a: Mp 110–113 °C. IR (KBr): 3297, 3181, 1669, 1592,
1528, 1470, 1379, 812 cm–1. 1H NMR (400 MHz, CDCl3):
d = 7.75 (s, 1 H), 7.31–7.38 (m, 3 H), 2.18 (s, 3 H). MS (70
eV): m/z = 203 (M+), 161.
3b: Mp 86–88 °C. IR (KBr): 3304, 3097, 1667, 1588, 1522,
1466, 1380, 815 cm–1. 1 H NMR (400 MHz, CDCl3):
d = 7.77 (s, 1 H), 7.26–7.35 (m, 3 H), 2.39 (q, 2 H, J = 7.2
Hz), 1.24 (t, 3 H, J = 7.2 Hz). MS (70 eV): m/z = 217 (M+),
161.
(12) Compound 3b was synthesized by the same procedure as
described above, except the amount of catalyst and
composition were changed.
Synlett 2006, No. 12, 1953–1955 © Thieme Stuttgart · New York