Preparation of 5-nitro-2-amino[b]thiophenes and 1-(2-amino-5-nitrophenyl) ethanones via microwave irradiation

Article abstract of DOI:10.1002/jhet.88

(Chemical Equation Presented) 1-(2-Chloro-5-nitrophenyl)ethanone) reacts with various amines in the presence of sulfur under microwave radiation to give the corresponding 2-aminobenzo[b]-thiophenes 3a-f in good yields. The yields of 3a-f are vastly superi

Full text of DOI:10.1002/jhet.88

July 2009
Preparation of 5-Nitro-2-amino[b]thiophenes and 1-(2-Amino-5-
nitrophenyl)ethanones via Microwave Irradiation
599
Afsha Rais, Haribabu Ankati, and Ed Biehl*
Department of Chemistry, Southern Methodist University, Dallas, Texas 75275
*E-mail: ebiehl@mail.smu.edu
Received October 2, 2008
DOI 10.1002/jhet.88
Published online 30 June 2009 in Wiley InterScience (www.interscience.wiley.com).
1-(2-Chloro-5-nitrophenyl)ethanone) reacts with various amines in the presence of sulfur under micro-
wave radiation to give the corresponding 2-aminobenzo[b]-thiophenes 3a–f in good yields. The yields
of 3a–f are vastly superior to those obtained using conventional heating. Additionally, 1-(2-amino-5-
nitrophenyl)ethanones 4a–f were also obtained. A mechanism is proposed in which 2-amino thiophenes
3a–f are formed by a SNAr mechanism involving an intramolecular addition of sulfur of the intermedi-
ate thioamide to the 2-substituted carbon to give a Meisenheimer complex, which collapses to 2-amino-
thiophenes 3a–f, and 2-amino ketones (4a–f) are formed by a parallel pathway involving nucleophilic
addition amine to the 2-chloro position of 1 to form a Meisensheimer complex, which collapses to the
amino ethanones.
J. Heterocyclic Chem., 46, 599 (2009).
INTRODUCTION
To see if these yields could be increased, we subjected
the reactions to microwave irradiation and report the
results herein.
In our continuing research on microwave-assisted syn-
thesis of heterocycles [1], we directed our attention to
preparing 2-aminobenzo[b]-thiophenes. Our interest in
these heterocycles was piqued by their extensive use in
the chemical and pharmaceutical industries. For example,
2-aminothiophenes are important precursors or intermedi-
ates in the preparation of coumarin dyes, biologically
active chemicals, other fused heterocycles, etc. [2–4].
Before this study, 2-aminothiophenes were prepared
primarily by the Gewald reaction [5], which involves
treating an activated ketone, an activated nitrile and sul-
fur in the presence of morpholine as catalyst. Recently,
the Gewald reaction was carried out using KF-alumina
as catalyst [6] and microwave irradiation for heating.
Cyclohexanone and cyclopentanone gave 2-amino prod-
ucts in very good yields (85–92%), whereas other cyclic
ketones and various acyclic ketones gave modest yields
(55–66%). All reactions were completed in 3.5–8.0 min.
On the other hand, when the reactions were carried out
using conventional heating (CH), the 2-aminothiphenes
were obtained in comparable yields but a much longer
time (3.5–7 h) was required [6].
RESULTS AND DISCUSSION
Equation (1) outlines the microwave-assisted reactions
carried out in our laboratories for preparation of several
5-nitro-2-amino-benzo[b]thiophenes (3a–f). As shown,
the reaction 5-nitro-1-(2-chlorophenyl)ethanone (1) with
the appropriate amine (2a–f), elemental sulfur, NaOAc
and DMF using microwave irradiation at 90–100ꢀC for
10 min yielded thiophene analogs (3a–f) as major prod-
ucts along with minor amounts of 2-amino-5-nitroetha-
nones (4a–f). The microwave yields as well as the
yields of 3a–f reported previously using CH [7] are
listed in Table 1.
Considering first the relative yields of 3a–f using
microwave radiation (MV) versus CH, one sees that the
yields from the former are significantly higher than
those of the latter. For example, the ratio of the yields
of 3b and 3d (entries 2 and 4) using MV versus CH
was 60:14 and 52:19, respectively. Additionally, the ra-
tio of the yields of the morpholino derivative 3f was
essentially the same (10 vs. 12%) (entry 6) in DMF.
However, the MW reaction using NMM (entry 7)
increased to 45%.
Neckers and coworkers [7] reported a one-pot synthe-
sis of 5-nitro-2-aminobenzo[b]thiophenes via a Willger-
odt–Kindler (W-K) [8] using CH. Although the thio-
phenes were formed quickly (6–20 min), the yields were
generally mediocre (4–47%). Furthermore, 2-chlorophe-
nyl)ethanones that lacks a 5-nitro group failed to react.
A possible mechanism for the formation of 3 and 4 is
shown in Scheme 1. As shown, there are two parallel
C
V
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600
A. Rais, H. Ankati, and E. Biehl
Vol 46
Table 1
Reaction conditions and yields of compound 3a–f and 4a–f.
Yield (%)
2-Aminothiophene
2-Aminoethanone
MWa Conventionalb
Ketone
1
Amine
2
3
MWa
Conventionalb
4
1
a
a
a
a
a
a
a
b
c
a
b
c
d
e
e
e
a
a
a
b
c
d
e
f
f
g
h
71
60
62
52
65
10
45c
0
36 (8, 60)
14 (10,60)
30 (10, 60)
19 (6, 35)
31 (15, 60)
12 (20, 100)
–
a
b
c
d
e
f
f
g
h
60
62
52
65
10
48
25c
0
31 (8, 60)
2
3
4
5
6
7
8
9
30 (10, 60)
52 (10, 60)
65 (6, 35)
12 (15, 60)
10 (20, 100)
0
0
0
0
0
0
a DMF used as solvent unless indicated otherwise. MW reactions were carried out at 90ꢀC for 10 min.
b Respective time (minutes) and temperature (ꢀC) for conventional reactions are given in parenthesis and ranged between 6 and 20 min and 35 and
100ꢀC.
c NMM used as solvent.
pathways to the two products. One involves the reaction
of 5-nitro-2-chloro ketone (1), amine (2), and sulfur pro-
ceeds via a W-K reaction to give the corresponding thi-
oamide (5). Compound 5 then undergoes a substitution
nucleophilic aromatic (SNAr) intramolecular addition of
sulfur to the 2-chloro-substituted carbon to give a Mei-
senheimer complex 6, which then collapses to 3. How-
ever, the starting ketone 1 can also proceed via a SNAr
pathway in which amine 2 adds intramolecularly to the
2-chloro carbon atom of 1 to form the resonance-stabi-
lized Meisenheimer complex 7 and 8. The complex then
collapses to 4. The stability of this complex probably
allows this pathway to compete successfully with the
addition of amine 2 to the C¼¼O group in 1 giving an
enamine, which is most likely the first step in the W-K
mechanism [8,9].
vent. As shown in Table 2, compounds 4a–f were
obtained in excellent yields (93–97%) using microwave
irradiation at 90ꢀC for only 5 min.
An added feature of this reaction is that various 2-
aminoacetophenones are excellent precursors to various
Scheme 1
In support of our proposed mechanism, the starting
acetophenones 1b and Ic (entries 8 and 9), which lack a
5-nitro group, failed to react by either pathway. Further,
we were able to isolate the direct amination products
4a–f by carrying out microwave-assisted reactions of 1a
with the amines 2a–f in the absence of sulfur and sol-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Preparation of 5-Nitro-2-amino[b]thiophenes and 1-(2-Amino-5-nitrophenyl)ethanones
via Microwave Irradiation
601
Table 2
ing, the reaction mixture was worked up as described in the
1
general procedure for the preparation of 3a–f. The H and 13C
Microwave-assisted synthesis of 5-nitro-2-aminoacetophenones (4a–f)
using primary and secondary amines.a
NMR, IR spectral data, and elemental analyses for these novel
compounds are shown later.
1-(2-(n-Butylamino)-5-nitrophenyl)ethanone (4a). This com-
pound was obtained as light yellow solid, mp (46.8–48.3ꢀC);
IR: 637.1, 748.2, 904.3, 953.4, 1213.8, 1322.2, 1496.8, 1608.9,
;
1633.8, 2960.6, 3284.9 cmꢁ1 1H NMR (deuteriochloroform):
d 0.96 (t, J ¼ 7.45 Hz, 3H, CH3), 1.42–1.49 (m, 2H, CH2),
1.64–1.71 (m, 2H, CH2), 2.63 (s, 1H, CH3), 3.26–3.30 (m, 2H,
CH2), 6.68 (d, J ¼ 9.75 Hz, 1H, aromatic), 8.17 (dd, J ¼ 2.3
Hz, 9.15 Hz, 1H, aromatic), 8.70 (d, J ¼ 2.5 Hz, 1H,
aromatic), 9.63 (br, 1H, NH). 13C NMR (deuteriochloroform):
d 13.8 (CH3), 20.2 (CH2), 27.8 (CH3), 30.8 (CH2), 42.8
(CH2), 111.5 (C), 115.7 (CH), 130.0 (CH), 130.1 (CH),
135.1 (C), 154.7 (C), 200.5 (CO). Anal. Calcd. for
C12H16N2O3: C, 61.00; H, 6.83; N, 11.86. Found: C, 60.86; H,
7.01; N, 12.05.
Entry
Amine
Products [yield (%)]b
1
2
3
4
5
6
n-Butylamine (2a)
Isopropylamine (2b)
Benzylamine (2c)
Cyclohexylamine (2d)
Pyrrolidine(2e)
4a (93)
4b (97)
4c (92)
4d (94)
4e (97)
4f (93)
1-(2-(Isopropylamino)-5-nitrophenyl)ethanone
(4b). This
Morpholine (2f)
compound was obtained as light orange solid, mp (68.3–
71.4ꢀC); IR: 676.1, 634.8, 831.2, 1172.3, 1114.5, 1236.4,
1338.0, 1440.3, 1486.9, 1527.8, 1580.9, 1604.4, 1642.7,
;
1690.2, 1708.9, 2973.5, 3249.2 cmꢁ1 1H NMR (deuterio-
a Reaction mixtures were subjected to microwave radiation at 90ꢀC for
5 min.
b Product yields were determined by gravimetric analysis. Products
were identified by NMR, IR, and elemental analyses.
chloroform): d 1.29 (d, J ¼ 6.30 Hz, 6H, ACH3 X 2), 2.61 (S,
3H, CH3), 3.78–3.82 (m, 1H, CH), 6.68 (d, J ¼ 9.15 Hz, 1H,
aromatic), 8.13 (dd, J ¼ 2.3 Hz, 9.15 Hz, 1H, aromatic), 8.67
(d, J ¼ 2.3 Hz, 1H, aromatic), 9.60 (br, 1H, NH). 13C NMR
(deuteriochloroform): d 22.5 (CH3), 27.9 (CH3), 44.2 (CH),
111.8 (CH), 126.3 (C), 129.9 (CH), 130.3 (CH), 132.0 (CH),
153.8 (C), 200.4 (CO). Anal. Calcd. for C15H14N2O3: C,
59.45; H, 6.35; N, 10.36. Found: C, 60.86; H, 5.27; N, 10.45.
1-(2-(Benzyl)-5-nitrophenyl)ethanone (4c). This compound
was obtained as light yellow solid, mp (89.1–91.5ꢀC); IR:
696.7, 746.4, 819.7, 965.4, 1118.4, 1224.9, 1326.0, 1493.7,
biologically important compounds, such as azines [10],
heterocyclic compounds [10], and repaglinide and
related hypoglycemic benzoic acid derivatives [11].
EXPERIMENTAL
The 1H and 13C NMR were recorded on a 500 MHz Joel
multinuclear NMR spectrometer; chemical shifts were refer-
enced to TMS as internal standard. Microwave experiments
were carried out in CEM-Driver microwave. All chemicals
were purchased from Aldrich Chemicals and were used with-
out further purification. Elemental analyses were performed by
the SMU Analytical Services.
1579.0, 1605.7, 1643.7, 3068.7, 3280.9 cmꢁ1 1H NMR (deu-
;
teriochloroform): d 2.69 (s, 3H, CH3), 4.54 (d, J ¼ 5.65 Hz,
1H, CH2), 6.68 (d, J ¼ 9.20 Hz, 1H, aromatic), 7.28–7.37 (m,
5H, aromatic), 8.15 (d, J ¼ 9.75 Hz, 1H, aromatic), 8.73 (d, J
¼ 2.25 Hz, 1H, aromatic), 10.0 (br, 1H, NH). 13H NMR (deu-
teriochloroform): d 27.9 (CH3), 47.1 (CH2), 112.2 (CH), 116.3
(C), 127.0 (CH), 127.9 (CH), 129.1 (CH), 129.9 (CH), 130.0
(CH), 135.7 (C), 136.7 (C), 154.6 (C), 200.7 (CO). Anal.
Calcd. for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found:
C, 66.86; H, 5.27; N, 10.45.
General procedure for the preparation of 5-nitro-2-ami-
no[b]thiophenes (3a–f). In a typical experiment, 1-(2-chloro-
5-nitrophenyl)-ethanone (1) (1 equiv) was mixed with amine 2
(2 equiv), sulfur (3 equiv), DMF or N-methylpyrrolidine as
solvent, and base (sodium acetate or methylpyrrolidine) in a
microwavable test tube. The tube was then capped and charged
into a CEM microwave instrument, and the mixture was irradi-
ated with 250 psi pressure and at a temperature for several
minutes (see Table 1 for conditions). After cooling, the reac-
tion mixture was dissolve in ethyl acetate and then washed
with brine. The ethyl acetate layer was separated, dried over
sodium sulfate, and evaporated under reduced pressure. The
crude reaction mixture was purified by column chromatogra-
phy using ethyl acetate–hexane (9:1, v/v) as eluent, and the
1-(2-Cyclohexylamino-5-nitrophenyl)ethanone
(4d). This
compound was obtained as light yellow solid, mp (124.3–
126.1ꢀC); IR: 654.97, 757.7, 834.5, 907.4, 953.2, 1115.3,
1225.0, 1315.7, 1442.2, 1492.5, 1529.5, 1579.4, 1603.7,
;
1649.2, 1708.0, 2852.8, 2927.2, 3254.1 cmꢁ1 1H NMR (deu-
teriochloroform): d 1.31–1.46 (m, 5H, CH2), 1.63–1.65 (m,
1H, CH2), 1.78–1.79 (m, 2H, CH2), 1.99–2.03 (m, 2H, CH2),
2.65 (s, 3H, CH3), 3.51–3.52 (m, 1H, CH), 6.71 (d, J ¼ 9.70
Hz, 1H, aromatic), 8.15 (dd. J ¼ 2.90 Hz, 9.70 Hz, 1H, aro-
matic), 8.71 (d, J ¼ 2.90 Hz, 1H, aromatic), 9.75 (br, 1H,
NH). 13C NMR (deuteriochloroform): d 24.4 (CH2), 25.5
(CH2), 27.9 (CH3), 32.4 (CH2), 51.1 (CH2), 111.8 (CH), 115.6
(C), 129.9 (CH), 130.4 (CH), 134.8 (C), 153.8 (C), 200.5
(CO). Anal. Calcd. for C14H18N2O3: C, 64.10; H, 6.92; N,
10.68. Found: C, 64.16; H, 6.77; N, 10.48.
1
compounds were identified by comparison of their H and 13C
NMR spectral data with those previously reported [7].
General procedure for the preparation of 1-(2-amino-5-
nitrophenyl)ethanones (4a–f). In
a typical experiment, 1
equiv 1-(2-chloro-5-nitrophenyl)ethanone (1) and 2 equiv of
the appropriate amine 2a–f were placed in a microwavable test
tube and then capped. The mixture was then placed in a CEM-
driven microwave and heated at 90ꢀC for 10 min. After cool-
1-(5-Nitro-2-(pyrrolidin-1-yl)phenyl)ethanone (4e). This
compound was obtained as a colorless solid, mp (149.8–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

602
A. Rais, H. Ankati, and E. Biehl
Vol 46
151.8ꢀC); IR: 747.9, 802.1, 867.4, 914.7, 955.2, 1113.4,
1229.2, 1266.8, 1300.6, 1369.1, 1447.1, 1481.8, 1501.9,
REFERENCES AND NOTES
1563.2, 1556.1, 1682.4, 2851.6 cmꢁ1 1H NMR (deuterio-
;
[1] See, for example: (a) Kamila, S; Biehl, E. R. J Heterocycl
Chem 2007, 44, 407; (b) Kamila, S.; Biehl, E. R. J Heterocycl Chem
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chloroform): d1.97ꢁ2.0 (m, 4H, NCH2 X 2), 2.62 (s, 3H,
CH3) 3.17ꢁ3.19 (m, 4H, NCH2 X 2), 6.70 (d, J ¼ 9.75 Hz,
1H, aromatic), 8.08 (dd, J ¼ 2.3 Hz, 9.2 Hz, 1H, aromatic),
dd, J ¼ 2.3 Hz, 1H, aromatic). 13C NMR (deuteriochloro-
form): d 25.8 (NCH2), 29.0 (CH3), 52.3 (OCH2), 113.7 (CH),
124.2 (C), 126.8 (CH), 127.3 (CH), 135.6 (C), 150.8 (C),
198.4 (CO). Anal. Calcd. for C14H12N2O3: C, 61.53; H, 6.02;
N, 11.96. Found: C, 61.63; H, 6.07; N, 11.89.
[2] For an excellent review on 2-aminothiophenes see: Sabnis,
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1-(2-Morpholino)-5-nitrophenyl)ethanone (4f). This com-
pound was obtained as light yellow solid, mp (61.1–63.6ꢀC);
IR: 601.3, 653.7, 739.2, 905.3, 931.3, 1263.7, 1043.5, 1107.8,
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1229.4, 1342.6, 1452.6, 1503.8, 1576.2, 1598.0, 1684.7 cmꢁ1
;
2859.5 1H NMR (deuteriochloroform): d 2.63 (s, 3H, CH3)),
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X
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2), 2.63 (s, 3H, CH3), 7.03 (d, J ¼ 9.2 Hz, 1H, aromatic), 8.22
(dd, J ¼ 2.4 Hz, 9.2 Hz, 1H, aromatic), 8.31 (d, J ¼ 2.4 Hz,
1H, aromatic). 13C NMR (deuteriochloroform): d 28.7 (CH3),
52.4 (NCH2), 66.4 (OCH2), 117.6 (CH), 127.2 (CH), 127.5
(CH), 131.8 (C), 141.0 (C), 155.3 (C), 200.7 (CO). Anal.
Calcd. for C12H14N2O4: C, 57.59; H, 5.64; N, 11.19. Found:
C, 57.86; H, 5.67; N, 11.25.
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Acknowledgments. The authors thank the Robert Welch Foun-
dation for partial funding of this work and Mr. Alan Humason for
running elemental analyses.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet