Regiospecific substitution of the 4-nitro group in 3-amino-4,6-dinitrobenzo[b]thiophene-2-carboxylates: Unexpected activating effect of the amino group

Article abstract of DOI:10.1016/S0040-4039(01)01833-0

The cyclocondensation of 2,4,6-trinitrobenzonitrile with the esters of thioglycolic acid results in the formation of 3-amino-4,6-dinitrobenzo[b]thiophene-2-carboxylates 3. The interaction of 3 with anionic nucleophiles RO^- (R=CF₃CH₂, CH≡CCH₂), RS^- (R=Ph, PhCH₂, (CH₃)₂CHCH₂), N₃^- in NMP or DMF leads to the substitution of only the 4-NO₂ group. The replacement of the electron-donating NH₂ group in 3 with hydrogen unexpectedly and significantly hampers nucleophilic substitution of the nitro group. It is assumed that increased reactivity of the 4-NO₂ in 3 is connected with the twist of this group with respect to the plane of the aromatic ring under the influence of the NH₂ group as indicated by semi-empirical quantum chemical calculations.

Full text of DOI:10.1016/S0040-4039(01)01833-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8539–8541
Regiospecific substitution of the 4-nitro group in
3-amino-4,6-dinitrobenzo[b]thiophene-2-carboxylates: unexpected
activating effect of the amino group
Svyatoslav A. Shevelev,* Igor L. Dalinger and Tatyana I. Cherkasova
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospekt, 47, 119991 Moscow, Russia
Received 11 January 2001; revised 14 September 2001; accepted 28 September 2001
Abstract—The cyclocondensation of 2,4,6-trinitrobenzonitrile with the esters of thioglycolic acid results in the formation of
3-amino-4,6-dinitrobenzo[b]thiophene-2-carboxylates 3. The interaction of 3 with anionic nucleophiles RO− (R=CF3CH2,
CHꢀCCH2), RS− (R=Ph, PhCH2, (CH3)2CHCH2), N3 in NMP or DMF leads to the substitution of only the 4-NO2 group. The
−
replacement of the electron-donating NH2 group in 3 with hydrogen unexpectedly and significantly hampers nucleophilic
substitution of the nitro group. It is assumed that increased reactivity of the 4-NO2 in 3 is connected with the twist of this group
with respect to the plane of the aromatic ring under the influence of the NH2 group as indicated by semi-empirical quantum
chemical calculations. © 2001 Elsevier Science Ltd. All rights reserved.
The interaction of 2,4,6-trinitrobenzonitrile (TNBN)1
with the esters of thioglycolic acid 1 in the presence of
KOH in CH3CN/H2O (4:1) at 25°C leads to the forma-
tion of ortho-nitro group substitution products—
sulphides 2—which undergo cyclisation in situ with
the formation of the corresponding 3-amino-4,6-
dinitrobenzo[b]thiophene-2-carboxylic acid 32 (Scheme
1).3
place, giving previously unknown 4-substituted esters of
3-amino-6-nitrobenzo[b]thiophenecarboxylic acid 4–94
(Scheme 2).
Nucleophiles RO− and RS− were generated in situ,
using the mixture of ROH or RSH with powdered
K2CO3 (molar ratio of dinitrobenzothiophene 3/ROH
(RSH)/K2CO3=1:1:2). For azidation, an equimolar
amount of NaN3 has been used. Reactions were main-
tained at 25°C in the case of RSH and NaN3, and at
80–90°C for ROH until full conversion of the starting
material was achieved. The yields of isolated nitroben-
We have found, that dinitrobenzothiophenes 3 possess
an interesting feature in that they react with anionic O-,
S- and N-nucleophiles (Nu−): RO− (R=CF3CH2, CHꢀ
CCH2), RS− (R=Ph, PhCH2, (CH3)2CHCH2), N3 in
zothiophenes 4 were 80–90%. According to H NMR
−
1
1-methyl-2-pyrrolidone (NMP) or DMF in such a way
that selective substitution of the 4-NO2 group takes
data, the 6-NO2 group does not undergo substitution,
making this reaction regiospecific.
CN
CN
NO2
NH2
O2N
NO2
O2N
SCH2CO2R
KOH
HSCH2CO2R
50-55%
CO2R
S
O2N
NO2
NO2
TNBN
1
3
2
R = Me (3a), Et (3b)
Scheme 1.
Keywords: benzo[b]thiophenes; nitro group; aromatic nucleophilic substitution; regiospecificity; deamination.
* Corresponding author. Fax: +7(095) 135 5328; e-mail: shevelev@ioc.ac.ru
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01833-0

8540
S. A. She6ele6 et al. / Tetrahedron Letters 42 (2001) 8539–8541
NO2
Nu
NO2
N3
NH2
CO2R
NH2
CO2R
NaN3
NMP, 25ºC
Nu
CO2Et
CO2Et
NMP (DMF)
S
S
S
S
O2N
O2N
O2N
O2N
13
12
3
4-9
Scheme 4.
Scheme 2. R=Me (a), Nu=PhS (4a), PhCH2S (5a),
(CH3)2CHCH2 (6a); R=Et (b), Nu=PhS (4b), PhCH2S (5b),
(CH3)2CHCH2S (6b), CF3CH2O (7b), CHꢀCCH2O (8b), N3
(9b).
As is seen, in going from 3b to 12 the selectivity for the
nucleophilic substitution of 4-NO2 is the same, but the
reactivity considerably decreases.
We have also found that the reduction of a nitro group
in 3 is regioselective as well: under the action of hydra-
zine hydrate in the presence of FeCl3, only the 4-NO2
group in 3b can be reduced thus giving 3,4-diamino-6-
nitrobenzo[b]thiophene-2-ethylcarboxylate 105 and the
6-NO2 group is left intact even when a reducing agent is
used in excess (Scheme 3). The ease of nucleophilic
substitution of the 4-NO2 group in dinitrobenzothio-
phenes 3, despite the p-excessive character of thiophene
and meta positioned nitro groups is notable. In this
respect, dinitrobenzothiophenes 3 considerably surpass,
for example, 1,3-dinitrobenzene, which does not react
with NaN3 or CF3CH2OH+K2CO3 under the same
conditions.
Here, we observed an unexpected activating effect of
the amino group during nucleophilic substitution,
despite its +M and +I effects.8
It is safe to assume that in this case steric hindrance is
the controlling factor. Recent reports have shown that9
the twist in the plane of the nitro group, with respect to
the aromatic ring under the influence of a neighbouring
substituent speeds up the formation of a Meisenheimer
ipso-complex and therefore facilitates the process of
nucleophilic substitution of this nitro group. Most
probably, the significant disruption of the coplanarity
between the nitro group and the aromatic ring pro-
motes alteration of the hybridisation of the ipso-carbon
atom from sp2 to sp3 upon formation of the Meisen-
heimer ipso-complex, because the twist of the nitro
group decreases its conjugation with the aromatic ring
in the starting material. According to quantum-chemi-
cal calculations (AM1), owing to the steric influence of
the NH2, the 4-NO2 group is turned by an angle of
ꢁ56° and the 6-NO2 group lies within the plane of the
aromatic ring. At the same time, in dinitrobenzothio-
phene 12, the angle of rotation of the 4-NO2 group is
just 9°.
The reactivity of the nitro group in nucleophilic substi-
tution reactions would be expected to increase on
replacement of the electron-donating amino group in 3
with hydrogen.
With this in mind, we performed diazotization on 3b
using NO+BF4 . Diazonium salt 11 was then treated
−
with EtOH in the presence of Cu2O to form 4,6-dini-
trobenzo[b]thiophene-2-ethylcarboxylate 12,6 Scheme 3.
We have found that despite our expectations, replace-
ment of the amino group in 3b by hydrogen signifi-
cantly hampers nucleophilic substitution of the nitro
group. Thus, 12 does not react with CF3CH2OH+
K2CO3 under the same conditions as 3b. It was
observed that the reaction of 12 with NaN3 is much
slower compared to 3b. Full conversion of 3b upon
interaction of NaN3 in NMP (25°C) takes 3 h whereas,
under the same conditions, azidation of 12 requires 17
h giving ethyl 4-azido-6-nitrobenzo[b]thiophene car-
boxylate 13 (60%),7 Scheme 4.
It is felt that the present calculations adequately reflect
the tendency of dihedral angle alteration between NO2
and the aromatic ring in 3b and 12. In support of this
conjecture, it is important to note the comparison of
calculated and X-ray10 data for the twist of the NO2
group caused by peri-interaction in 1,5-dinitronaph-
thalene (calculated angle 31°, found 48.7°) and 9-
nitroanthracene (calculated angle 51°, found 85°). The
structures of all the new products were established from
1
microanalysis, mass-spectrometry and H NMR spec-
tra, which showed all the expected signals.
NH2
NH2
CO2Et
S
O2N
10
NO2
NH2
CO2Et
S
O2N
N2+BF4
NO2
-
NO2
3b
EtOH
Cu2O
CO2Et
CO2Et
S
S
O2N
O2N
11
12
Scheme 3.

S. A. She6ele6 et al. / Tetrahedron Letters 42 (2001) 8539–8541
8541
Acknowledgements
Compound 6b: 81%, mp 117°C (PriOH); 1H NMR (d6-
DMSO): l 1.02 (d, 6H, J=2.5 Hz Me2), 1.31 (t, 3H,
J=2.5 Hz, CH3), 1.87 (m, 1H, CH), 3.05 (d, 2H, J=3.0
Hz, CH2), 4.29 (q, 2H, J=2.0 Hz, OCH2), 7.24 (s, 2H,
NH2), 7.99 (s, 1H, H-5), 9.60 (s, 1H, H-7).
We thank the International Science and Technology
Center (Project c419) for financial support.
Compound 7b: 86%, mp 195°C (PriOH); 1H NMR (d6-
DMSO): l 1.32 (t, 3H, J=3.0 Hz, CH3), 4.35 (q, 2H,
J=2.0 Hz, OCH2), 5.21 (q, 2H, J=2.0 OCH2), 6.78 (s,
2H, NH2), 7.83 (s, 1H, H-5), 8.53 (s, 1H, H-7).
References
Compound 8b: 78%, mp 150°C (PriOH); 1H NMR (d6-
DMSO): l 1.29 (t, 3H, J=3.0 Hz, CH3), 3.78 (s, 1H,
CH), 4.28 (q, 2H, J=2.0 Hz, OCH2), 5.19 (s, 2H, OCH2),
6.98 (br s, 2H, NH2), 7.69 (s, 1H, H-5), 8.50 (s, 1H, H-7).
1. Sitzman, M. F.; Dacons, J. C. J. Org. Chem. 1973, 38,
4363.
2. Dalinger, I. L.; Cherkasova, T. I.; Khutoretskii, V. M.;
Shevelev, S. A. Mendeleev Commun. 2000, 72.
3. Dinitrobenzothiophene 3b described in Ref. 2. 3a: mp
1
Compound 9b: 90%, mp 180°C, H NMR (d6-DMSO): l
1
196–198°C (PriOH); H NMR (d6-DMSO): l 3.9 (s, 3H,
1.30 (t, 3H, J=2.5 Hz, CH3), 4.28 (q, 2H, J=3.0 Hz
OCH2), 7.02 (s, 2H, NH2), 7.84 (s, 1H, H-5), 8.63 (s, 1H,
H-7).
CH3), 6.6 (br s, 2H, NH2), 8.7 (s, 1H, H-7) 9.4 (s, 1H,
H-5).
4. Substitution in 3. General procedure
5. Synthesis of 10: A mixture of 3b (0.95 g, 3 mmol), 10
mmol of N2H4·H2O, FeCl3·6H2O and Cact was refluxed
for 4 h in 18 mL of MeOH. Precipitated solid was
collected by filtration washed with acetone and the com-
bined filtrates were evaporated. 62%, mp 228°C, 1H
NMR (d6-DMSO): l 1.30 (t, 3H, J=3.0 Hz CH3), 4.27
(q, 2H, J=3.0, OCH2), 6.18 (s, 2H, NH2), 6.82 (s, 2H,
NH2), 7.37 (s, 1H, H-5), 7.84 (s, 1H, H-7).
6. Synthesis of 12: A mixture of 3b (0.3 g, 1 mmol) and 1.5
mmol of NOBF4 was stirred for 2 h at 25°C in 10 mL of
CHCl3. The precipitated salt was collected by filtration
and washed with CHCl3. The solid obtained was dis-
solved in 3 mL of EtOH, Cu2O was added in one portion
(0.15 g, 1 mmol) and the mixture was left to stand at
20°C for 20 h. Precipitated solid was collected by filtra-
tion and recrystallised. 55%, mp 145°C (EtOH), 1H NMR
(d6-DMSO): l 1.38 (t, 3H, J=2.5 Hz, CH3), 4.41 (q, 2H,
J=2.5 Hz, OCH2), 8.47 (s, 1H, H-3), 8.87 (s, 1H, H-7),
9.54 (s, 1H, H-5).
7. Synthesis of 13: A mixture of 12 (0.5 g, 1.7 mmol) and
NaN3 (0.11 g, 1.7 mmol) was stirred at 25°C in 15 mL of
NMP until full conversion of the starting material. The
solution was poured into 30 mL of water, acidified with
25% HCl (pH 1) and the precipitated solid washed with
water and recrystallised. 60%, mp 115° (EtOH), 1H NMR
(d6-DMSO): l 1.35 (t, 3H, J=3.0 Hz, CH3), 4.39 (q, 2H,
J=2.0 Hz, OCH2), 7.93 (s, 1H, H-3), 7.97 (s, 1H, H-5),
8.91 (s, 1H, H-7).
Synthesis of 4a, 5a, 6a and 4b, 5b, 6b. A mixture of
K2CO3 (0.56 g, 4 mmol), 2 mmol of NuH and 3a (0.62 g,
2 mmol) or 3b (0.59 g, 2 mmol) was stirred at 25°C in 15
mL of NMP (DMF). The resultant solution was poured
into 30 mL of water, acidified with 25% HCl (pH 1),
washed with water. The precipitated solid was collected
by filtration and recrystallised.
Synthesis of 7b and 8b was performed at 80–90°C
Synthesis of 9b: A mixture of NaN3 (0.13 g, 2 mmol), 3b
(0.62 g, 2 mmol) was stirred in 15 mL of NMP at 25°C.
The resultant solution was poured into 30 mL of water
and acidified with 25% HCl (pH 1). The precipitated solid
was collected by filtration and washed with water and
acetone.
Compound 4a: 95%, mp 235°C (PriOH), 1H NMR (d6-
DMSO): l 3.82 (s, 3H, OMe), 7.22 (br s, 2H, NH2), 7.42
(m, 5H, Ph), 7.89 (s, 1H, H-5), 8.92 (s, 1H, H-7).
Compound 4b: 84%, mp 157°C (PriOH); 1H NMR (d6-
DMSO): l 1.28 (t, 3H, J=3.0 Hz, CH3), 4.28 (q, 2H,
J=3.0, OCH2), 7.15 (br s, 2H, NH2), 7.39 (m, 5H, Ph),
7.84 (s, 1H, H-5), 8.86 (s, 1H, H-7).
Compound 5a: 88%, mp 186°C (PriOH); 1H NMR (d6-
DMSO): l 3.83 (s, 3H, OMe), 4.38 (s, 2H, CH2), 7.21 (br
s, 2H, NH2), 7.27 (m, 5H, Ph), 7.94 (s, 1H, H-5), 8.75 (s,
1H, H-7).
Compound 5b: 98%, mp 156°C (PriOH); 1H NMR (d6-
DMSO): l 1.32 (t, 3H, J=2.5 Hz, CH3), 4.29 (q, 2H,
J=2.5 Hz, OCH2), 4.38 (s, 2H, CH2), 7.18 (br s, 2H,
NH2), 7.23 (m, 5H, Ph), 7.91 (s, 1H, H-5), 8.70 (s, 1H,
H-7).
8. Hansch, C.; Loo, A.; Taft, R. W. Chem. Rev. 1991, 91,
165.
9. Benedetti, F.; Marshall, D. R.; Stirling, C. J. M.; Leng, J.
L. Chem. Commun. 1982, 918.
10. Balakrishnan, P.; Boykin, D. W. J. Org. Chem. 1985, 50,
3663.
Compound 6a: 90%, mp 127°C (PriOH); 1H NMR (d6-
DMSO): l 1.02 (d, 6H, J=2.0 Hz, Me2), 1.86 (m, 1H,
CH), 3.05 (d, 2H, J=2.0 Hz, CH2), 3.82 (s, 3H, OMe),
7.26 (br s, 2H, NH2), 8.00 (s, 1H, H-5), 8.75 (s, 1H, H-7).