On the reactivity of 3-bromo-2-nitrobenzo[b]thiophene with nucleophiles: Elucidation of the base-catalysed mechanism with rearrangement

Article abstract of DOI:10.1016/S0040-4020(01)00875-4

The reactivity of 3-bromo-2-nitrobenzo[b]thiophene (1) with several (anionic and neutral) nucleophiles has been examined. Only with neutral, weak nucleophiles (as anilines) 1 gives, in the presence of non-nucleophilic bases (triethylamine or potassium car

Full text of DOI:10.1016/S0040-4020(01)00875-4

TETRAHEDRON
Pergamon
Tetrahedron 57 *2001) 8903±8911
On the reactivity of 3-bromo-2-nitrobenzo[b]thiophene
with nucleophiles: elucidation of the base-catalysed mechanism
with rearrangement
Barbara Cosimelli,a,p Liliana Lamartinab and Domenico Spinellia
aDipartimento di Chimica Organica `A. Mangini', Via S. Donato 15, I-40127Bologna, Italy
bDipartimento di Chimica e Tecnologie Farmaceutiche, Via Archira® 32, I-90123 Palermo, Italy
Received 13 June 2001; revised 25 July 2001; accepted 23 August 2001
AbstractÐThe reactivity of 3-bromo-2-nitrobenzo[b]thiophene *1) with several *anionic and neutral) nucleophiles has been examined. Only
with neutral, weak nucleophiles *as anilines) 1 gives, in the presence of non-nucleophilic bases *triethylamine or potassium carbonate),
together with the `expected' 3-amino-2-nitrobenzo[b]thiophenes *3) also the `unexpected' 2-amino-3-nitrobenzo[b]thiophenes *4). The
composition of the ®nal isomeric mixture depends on the base added *nature and quantity) and on the solvent used. The results demonstrate
the relevance of base-catalysis and support a reaction pathway involving the formation of an anionic intermediate *B) which undergoes
addition of a second molecule of nucleophile to give *C) in which migration of the nitro group occurs through a three membered ring *D or E)
formed by loss of bromide ion. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
we studied the behaviour of the 13C-labelled 1 at C-2,
collecting proof in favour of a reaction pathway involving
a base-catalysed nitro group migration.6
In the framework of our interest in aromatic nucleophilic
substitutions,1±4 we have recently studied the behaviour of
3-bromo-2-nitrobenzo[b]thiophene *1) with nucleophiles,
observing `unexpected' results in the reaction with some
amines.5,6 Thus we observed, for example, that by re¯uxing
in DMF for 15 min in the presence of Et3N *a non-nucleo-
philic base in the experimental conditions employed) 1 and
3-*tri¯uoromethyl)aniline *2a) gave a mixture of the
isomeric 3-amino-2-nitro- *3a) and 2-amino-3-nitro-
benzo[b]thiophene *4a) *i.e. the `expected' and
`unexpected' product, respectively; *Scheme 1)) in the
85:15 relative ratio.5 To enlighten the course of the reaction
The mechanistic study above originates from a drug-design
project linked to the observation that N-substituted
3-amino-2-nitrobenzo[b]thiophenes show analgesic, anti-
exudative and anti-in¯ammatory properties7,8 together
with very low mutagenicity9 as measured through the
Ames test: thus a way to a new potential class of drugs
seems to have been disclosed.
The reactivity of 1 has already been investigated with some
anionic *sodium hydroxide10 and methoxide11,12) and
Scheme 1.
Keywords: 3-bromo-2-nitrobenzo[b]thiophene; nucleophiles; aromatic nucleophilic substitutions.
Corresponding author. Tel.: 139-051243218; fax: 139-051244064; e-mail: cosimel@ms.fci.unibo.it.
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020*01)00875-4

8904
B. Cosimelli et al. / Tetrahedron 5712001) 8903±8911
neutral nucleophiles *ammonia,10 diethylamine,10 aniline,10
cyclohexylamine,11 piperidine,11,13 morpholine,13,14 and
several other aliphatic and aromatic amines7,8). In every
case the exclusive formation of the expected ipso-substitu-
tion products had been claimed.
tron donor ability; solvatochromic solvent polarity [a good
estimate of hydrogen-bond donor character *HBD): normal-
ized constant, ETN]. The relevant values for DMF are bp
1538C, e 36.71, DNN 0.69, ET 0.404.
N
The solvents tested were toluene [bp 110.68C, with a low
dielectric constant *2.38) and a low ETN *0.099)], 2-butanol
[2-BuOH, bp 99.58C, a protic polar solvent *e 16.56, ET
To gain further insight into the reaction and with the aim of
®nding experimental conditions favourable to the synthesis
of 4a and structurally similar compounds we have examined
the in¯uence of several factors on the reactivity of 1 towards
nucleophiles.
N
0.506)], hexa¯uoroisopropanol [HFiP, bp 598C, a protic
solvent with signi®cant acidic character *pKA 9.31, e
16.7,18 ET 1.068)], and two further dipolar solvents as
N
DMSO *bp 1898C, e 46.45, DNN 0.77, ETN 0.444) and aceto-
nitrile *ACN, bp 828C, e 35.94, DNN 0.36, ETN 0.460). The
last two solvents have different properties relative to the
proton `af®nity', the ®rst favouring and the second dis-
favouring *because of its protophobicity) proton transfer
reactions.
2. Results
First we con®rmed8 that, in the absence of non-nucleophilic
bases, 1 reacts with 2a in re¯uxing DMF to give exclusively
the `normal' substitution product 3a, thus suggesting that
the formation of 4a *the `unexpected' product) requires
catalysis by a base *e.g. Et3N, pKB 2.99)15a stronger than
the nucleophile itself *2a, pKB 10.51).15b To verify this
hypothesis, by using our standard conditions5 *substrate/
nucleophile/added baseˆ1:3:1.8) we have carried out the
reaction in the presence of pyridine *pKB 8.75) or potassium
carbonate *pKB 3.75), i.e. two possible catalysts of much
weaker *the former) or comparable basicity *the latter)
with respect to Et3N: in the ®rst instance only 3a was
obtained while, in contrast, a signi®cant yield of 4a *3a/
4aˆ62:38) was observed with the carbonate. This result
clearly indicates the signi®cance of the added base, con®rm-
ing the occurrence of some kind of base-catalysis for the
formation of 4a.
All the experiments *Table 1) have been carried out in the
standard conditions for a short time *15 min) as well as until
complete disappearance of 1. Both series of data evidence a
reactivity sequence *DMSO.DMF.2-ButOHùHFiP.to-
lueneùACN) wherein high-boiling aprotic dipolar solvents
rank highest, as expected for a nucleophilic substitution. In
every case very good overall yields *$90%) have been
obtained.
We have also ascertained that no interconversion between
3a and 4a occurs in the reaction conditions: thus no
rearrangement was observed by re¯uxing, even for long
times, pure 3a or 4a in the presence of 2a and Et3N.
Concerning the isomeric *3a/4a) product composition, we
can comment as follows: *a) in HFiP only 3a could be
obtained probably because of the acidic character of the
For a better understanding of the factors that could affect the
course of this peculiar kind of nucleophilic substitution we
have examined in more detail the in¯uence of the nature of
solvent, added base *as well as its concentration), nucleo-
phile16 and substrate *extending with this aim the study to
3-bromo-5-chloro-2-nitrobenzo[b]thiophene).
N
solvent *see the reported pKA value and the ET value,
monitoring a high HBD character), which prevents the
effect of the base added *cf. the results obtained in DMF
in the absence of Et3N); *b) in ACN only a trace amount
*3%) of 4a has been observed, probably because of the
protophobicity of the solvent; *c) in toluene as well as in
2-BuOH, both of low polarity and non-HBA*hydrogen-
bond acceptor) solvents *hence of low ef®ciency both in
promoting nucleophilic substitutions and in stabilizing
polar intermediates) low absolute yields of 4a have been
2.1. In¯uence of the solvent
In order to collect information on the role of the solvent we
have chosen a set of solvents with relatively high boiling
points *as a matter of fact the reaction occurred very slowly
in low-boiling solvents such as methanol or ethanol) and
with different properties17a such as: relative permittivity
*dielectric constant, e) for the pure liquid at 258C; donicity
*normalized donor number, DNN), i.e. an estimate of elec-
Table 2. Results for the reaction of 1 with 2a in DMF in the presence of
variable amounts of different non-nucleophilic bases, until disappearance of
1
Entry
Base
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
C5H5N
K2CO3
K2CO3
K2CO3
K2CO3
1/2a/base *molar ratio)
3a:4a *%)
Yield *%)
Table 1. Results of the reaction of 1 with 2a *3 mol. equiv.) by re¯uxing in
the presence of Et3N *1.8 mol. equiv.) for 15 min *columns 1 and 2) or until
disappearance of 1 *columns 4, 5, and 6) in various solvents *column 3)
1
2
3
4
5
6
7
8
1:3:3
1:3:1.8
1:3:1
1:3:0.5
1:3:0.33
1:3:0
1:3:1.8
1:3:3
1:3:1.8
1:3:1
1:3:0.5
60:40
75:25
87:13
91:9
100:0
100:0
100:0
50:50
62:38
57:43
63:37
85
90
95
98
76
82
82
68
66
84
95
3a/4a *%) Yield *%)
Solvent
3a/4a *%) Yield *%)
Time
85:15
80:20
95:5
82
92
19
28
22
5
DMF
DMSO
Toluene
75:25
80:20
93:7
90
92
90
92
90
95
2 h
15 min
24 h
16 h
16 h
24 h
a
a
a
a
92:8
100:0
2-ButOH 88:12
100:0
97:3
9
10
11
HFiP
ACN
a
±
All the reactions were carried out on a 1.5 mmol scale.
The isomeric ratio could not be evaluated.
All the reactions were carried out on a 1.5 mmol scale.
Solubilized in 0.5 mL of H2O.
a
a

B. Cosimelli et al. / Tetrahedron 5712001) 8903±8911
8905
Table 3. Results for the reaction of 1 with 2b in DMF in the presence of Et3N or K2CO3, until disappearance of 1
Entry
Base
1/2b/base *molar ratio)
3b/4b *%)
Yield *%)
Time *min)
1
2
3
4
5
6
Et3N
Et3N
Et3N
K2CO3
K2CO3
K2CO3
1:3:1.8
1:3:3
1:3:10
1:3:3
1:3:5
100:0
100:0
80:20
80:20
75:25
75:25
90
98
86
90
92
83
45
45
15
30
15
15
a
b
c
1:3:10
All the reactions were carried out on a 1.5 mmol scale.
K2CO3 was solubilized in 0.5 mL of H2O.
a
b
K2CO3 was solubilized in 0.6 mL of H2O.
K2CO3 was solubilized in 2.3 mL of H2O.
c
observed *6 and 11%, respectively); *d) best yields of 4a,
together with overall highest reactivity, have been found in
DMSO and DMF, two aprotic *following Reichardt's
recommendation17b this term should be more correctly
replaced with nonhydroxylic or non-HBD) dipolar solvents
both able to promote bimolecular nucleophilic substitutions,
to solvate polar intermediates and to behave as HBA
solvents: accordingly DMF has been chosen for all the
experiments hereinafter.
Scheme 2.
2.2. In¯uence of base concentration and strength
Table 4. Results for the reaction of 1 with aliphatic amines in DMF in the
presence of Et3N or K2CO3, until disappearance of 1
The in¯uence of the base concentration on the reaction
outcome is well evidenced in entries 1±6 of Table 2,
which show a direct dependence of the formation of 4a on
the quantity of Et3N.
Entry Amine Base 1/amine/base *molar ratio) Product *yield %)
1
2
3
4
5
5
6
7
Et3N
Et3N
Et3N
K2CO3 1:3:3
K2CO3 1:3:3
1:3:1.8
1:3:1.8
1:3:1.8
9 *96)
10 *93)
11 *76)
11 *73)
12 *78)
The base strength proves in turn to be a very important
factor, as 3a is the only reaction product in the presence
of pyridine *Table 2; entry 7). On the other hand, with
K2CO3 we observed that the relative percentage of 3a and
4a is only moderately affected by the quantity of the salt
*entries 8 and 9).
a
7
8b
a
All the reactions were carried out on a 1.5 mmol scale.
K2CO3 was solubilized in 0.5 mL of H2O.
Dimethylamine hydrochloride, neutralized with K2CO3.
a
b
Compounds 9,11 1010 and 1111,13 were already known and
their structures were assigned by comparison with literature
data: these, as well as unknown compounds, have been fully
characterized by 1H and 13C NMR and mass spectra.
2.3. In¯uence of nucleophile19
A. Neutral nucleophiles: We have tested several aliphatic
and aromatic amines. With aniline *2b; pKB 9.37), which is
signi®cantly more nucleophilic than 2a, in the presence of
1.8±3.0 mol equiv. of Et3N only the expected N-*2-nitro-
benzo[b]thiophene-3-yl)aniline *3b) was formed *Table 3,
entries 1 and 2), whereas in the presence of 3 equiv. of
K2CO3 *Table 3, entry 4) we obtained *Scheme 1) a 80:20
mixture of 3b and of the `unexpected' isomer N-*3-nitro-
benzo[b]thiophene-2-yl)aniline *4b), in excellent overall
yield *90%).
On the other hand with the arylaliphatic N-methylaniline
*2c; pKB 9.15; Scheme 1) in the presence of K2CO3 as
catalyst *1/2c/K2CO3ˆ1:3:5) a 66:34 mixture of the
isomeric 3c and 4c in a good overall yield *65%) was
obtained.
B. Anionic nucleophiles: We have also tested the reactivity
of 1 with some oxygen and sulphur anionic nucleophiles:
sodium phenoxide *13), benzenethiolate *14) and benzen-
sul®nate *15). In every case we obtained exclusively the
`expected' product of reaction *Scheme 3). Of course,
considering the anionic nature of such nucleophiles, the
addition of bases *as Et3N or K2CO3) has no meaning.
Moreover we observed that Et3N decomposes 2-nitro-
benzo[b]thiophen-3-yl phenyl sulfone *18) on re¯uxing in
DMF.
Asigni®cant formation of 4b in the presence of Et3N was
observed only with a large *tenfold) excess of the catalyst
*Table 3, entry 3). On the other hand, a further excess of
K2CO3 *Table 3, entries 5 and 6) causes no signi®cant effect
on the 3b/4b ratio.
When employing even stronger nucleophiles, *such as
cyclohexylamine *5), diethylamine *6), piperidine *7) or
dimethylamine *8), i.e.aliphatic amines in the 3±4 pKB
range) only the `expected' 3-amino-2-nitrobenzo[b]thio-
phenes were observed in the presence of Et3N as well as
of K2CO3 *Scheme 2 and Table 4).
2.4. In¯uence of substrate
Finally, we estimated the effect of a substituent in the

8906
B. Cosimelli et al. / Tetrahedron 5712001) 8903±8911
First of all, it must be recalled that in SNAr processes on
benzene derivatives, the intermediate s-adduct can either
lose the nucleophile *going back to the starting materials)
or the leaving group *giving the substitution product): in
both cases the driving force is the regeneration of the
aromatic ring and its resonance stabilization. The situation
can be signi®cantly different in heteroaromatic systems and
especially in ®ve-membered rings: as a matter of fact the
lower resonance stabilization energy and the presence of a
weak heteroatom±carbon bond discloses the way to new
reaction pathways which are unavailable to `true' aromatic
systems.20 The situation can be envisaged as even more
complex in benzocondensed derivatives, as, for example,
the thiophene ring can hardly be considered aromatic in
benzo[b]thiophenes:21 the reactivity of nitrobenzo[b]thio-
phene derivatives24 could thus be best related to that of
nitroalkenes *or of arylnitroalkenes),25 i.e. 1 behaving as a
nitroalkene-like system.
Scheme 3.
benzene ring of the substrate using the reaction between
3-bromo-5-chloro-2-nitrobenzo[b]thiophene *19) and the
aniline 2a under experimental conditions *19/2a/
Et3Nˆ1:3:3) similar to those reported for compound 1
*entry 1 of Table 2). The resulting 45:55 mixture of the
isomeric 5-chloro-2-nitro-N-[3-*tri¯uoromethyl)phenyl]-
benzo[b]thiophen-3-amine *20) and 5-chloro-3-nitro-N-[3-
*tri¯uoromethyl)phenyl]benzo[b]thiophen-2-amine
*21)
*65% overall yield) only shows a small, although signi®-
cant, in¯uence of the substituent on the reaction.
Concerning the mechanism of nucleophilic substitutions
on 3-bromo-2-nitrobenzo[b]thiophene *1), we previously
supposed5 *Scheme 4) that the formation of the `unex-
pected' substitution products could essentially depend on:
3. Discussion
*a) the formation of an intermediate in which C-2 and C-3
become equivalent with respect to the sulphur atom *i.e.
through some kind of skeletal rearrangement of the
thiophene ring), or
*b) a base-catalysed addition of the nucleophile at both
C-2 and C-3 with formation of a cyclic intermediate26
and, eventually, a nitro-group shift from C-2 to C-3.
On account of the results obtained the overall conclusion
can be drawn that the nucleophilic substitution on 3-bromo-
2-nitrobenzo[b]thiophene *1) gives `unexpected' substitu-
tion products only with neutral weak nucleophiles such as
anilines and in the presence of a base *e.g. Et3N or K2CO3)
stronger than the nucleophile itself. This clearly indicates
the need for base-catalysis for the occurrence of the
`unexpected' substitution pathway, and K2CO3 appears
especially effective in this respect.
The results obtained with 1 13C-labeled at C-2 allowed us to
exclude hypothesis *a) providing instead evidence for a
nitro-group shift *hypothesis b).6
Adeeper analysis of the data and some further considera-
tions were necessary in order to ensure a complete under-
standing of the results obtained.
Acritical examination of the new results herein can help in
the understanding of the reactivity of 1. As a matter of fact
we have studied four kinds of reactions: *1) reaction with
Scheme 4.

B. Cosimelli et al. / Tetrahedron 5712001) 8903±8911
8907
Scheme 5.
anionic *strong) nucleophiles; *2) reaction with strong
neutral nitrogen nucleophiles *pKB,4); *3) reaction with
weak neutral nitrogen nucleophiles *pKB.9); *4) reaction
with the previous weak neutral nitrogen nucleophiles in the
presence of non-nucleophilic strong bases *pKB,4). As
indicated above, the experimental data indicate that the
formation of the `unexpected' products of substitution
occurs only in the last case, i.e. with weak nucleophiles
and in the presence of non-nucleophilic strong bases.
a rationalization 2a leads to `unexpected' product more
easily and hence with higher yields than 2b *estimated
DpKa ca. 1).
4. Conclusion
Adetailed study of the peculiar reactivity of 1 with several
nucleophiles has been carried out: the high purity of 1
*.98%) allows us to exclude the possibility that compounds
4a±c could derive from 2-bromo-3-nitrobenzo[b]thiophene
formed as by-product during the nitration of 3-bromo-
benzo[b]thiophene. Moreover we did not obtain 4-like
products in every instance, but only with anilines observing
3/4 ratios which depend on the experimental conditions
*solvent, nature and quantity of the added base). However
it is known13 that 2-bromo-3-nitrobenzo[b]thiophene is not
able to give 2-amino-3-nitrobenzo[b]thiophenes 4 by the
action of amines.
Actually, cases 1 and 2 resemble the usual activated
aromatic nucleophilic substitution,1±3,27 with a fast and
`early'28 s-adduct formation followed by bromide ion
elimination to the normal ipso-substitution product. In
contrast, with weak nucleophiles *cases 3 and 4) the
s-adduct *A) formation should be `late'.28 In case 3 the
base is weak *i.e. the excess nucleophile itself) and
the formation of the anionic intermediate B is unfavoured
and/or too slow to affect the course of the reaction: therefore
the only product obtained is the `normal' one after bromine
loss from A. In case 4, however, *Scheme 5) the strong
catalytic base present can be responsible for a fast proton
abstraction. Here, though, because of the low contribution
of the thiophene ring to the total resonance stabilization
energy of the benzo[b]thiophene system, the following
expulsion of the leaving group from B *restoring the thio-
phene ring and leading directly to 3) can be in competition
with the addition of a second molecule of the nucleophile at
the carbon±nitrogen double bond, thus leading to the
anionic intermediate C. The contemporary presence of
two negative charges on the nitro group, making its nitrogen
atom a strong nucleophilic centre, could well force C to
evolve through an anchimerically assisted loss of bromide
ion giving the cyclic intermediates D or E,26 and hence 3
and 4, respectively.
In conclusion the obtained results prove that 1 gives also the
`unexpected' 4a±c only with neutral, weak nucleophiles
*e.g. anilines) and in the presence of added non-nucleophilic
strong bases. Therefore we feel that enlighting the role of
base-catalysis for the occurrence of the `unexpected' path-
way we have been able to give proof in favour of the forma-
tion of a three-membered ring intermediate26 capable of
rationalizing the C-2 to C-3 nitro-group shift.
5. Experimental
5.1. General
NMR spectra were recorded on a Varian Gemini 300 Instru-
ment in the Fourier transform mode at 21^0.58C in DMSO-
1
d6. H *300.07 MHz, 0.02 M) and 13C *75.43 MHz, 0.1 M)
The formation of B from A by proton abstraction *the key
step to the `unexpected' product) can be related to the acidic
character of the proton in the ±NH21±Ar residue. As a
matter of fact the intermediate A obtained from 2a±c is
much more acidic than the corresponding ones from
the primary and secondary aliphatic amines *estimated
DpKa 6±8), and accordingly only with 2a±c the formation
chemical shifts *d) are in ppm relative to TMS as secondary
internal reference; coupling constants are in Hz. Mass
spectra were recorded on a VG70 70E apparatus. Melting
points were measured using a Ko¯er apparatus and are
uncorrected. Solvents were removed under reduced
pressure. TLC: precoated silica gel *Merck F254) or
aluminum oxide neutral *Merck art. 5550) plates. Flash
chromatography: silica gel 60 *ICN Silica 32±63) or
aluminum oxide neutral *Merck art. 1097). Compound 1
of
B
is effective,29 resulting in the formation of
appreciable amounts of 3-nitro-2-arylaminobenzo[b]thio-
phenes; furthermore, as foreseable on the grounds of such

8908
B. Cosimelli et al. / Tetrahedron 5712001) 8903±8911
was obtained in 98% purity according to a literature
procedure.30
in 0.8 mL of H2O) were successively added to a solution of
1 *0.400 g, 1.55 mmol) in DMF *7 mL) and the mixture kept
at 1208C until disappearance of 1 *30 min). The mixture was
then cooled to room temperature, poured into ice/water and
extracted with toluene *4£60 mL). The extracts were dried
over Na2SO4 and concentrated in vacuum, and the residue
was puri®ed by ¯ash chromatography on silica gel *ethyl
acetate/petroleum etherˆ1:9 v/v as eluant). The faster
running band afforded compound 3c *0.19 g), the slower
running band afforded compound 4c *0.09 g) for an overall
65% yield.
5.1.1. General procedure for the evaluation of solvent's
in¯uence 4Table 1). Method A: 2a *0.6 mL, 4.65 mmol) and
Et3N *0.4 mL, 2.88 mmol) were successively added to a
solution of 1 *0.400 g, 1.55 mmol) in the proper solvent
*4.5 mL) and re¯uxed for 15 min. The mixture was cooled
to room temperature, poured into ice/water and the precipi-
tate was ®ltered and dried under vacuum. Compounds 3a
and 4a were puri®ed and separated from residual 1 by ¯ash-
chromatography on silica gel *toluene/cyclohexaneˆ4:1 v/v
as eluant) and identi®ed as reported.5
Compound 3c: Garnet red crystals from EtOH; mp 115±
1
3
1168C; H NMR d 8.09 *d, Jˆ8.1 Hz, 1H, H-7), 7.64
3
3
4
Method B: The mixture was re¯uxed until disappearance of
1, quantities and operating procedures being otherwise as
described above.
*ddd, Jˆ8.1 Hz, Jˆ6.7 Hz, Jˆ1.6 Hz, 1H, H-6), 7.44±
7.37 *m, 2H, H-5 and H-4), 7.25 *m, 2H, H-30 and H-50),
6.94±6.89 *m, 3H, H-20, H-40 and H-60), 3.45 *s, 3H, CH3);
13C NMR d 146.36 *C-3), 141.52 *C-10), 140.03 *C-2),
135.94 *C-7a), 133.86 *C-3a), 130.04 *C-6), 129.23 *C-30
and C-50), 125.77 *C-4 or C-5), 125.65 *C-5 or C-4), 123.96
*C-7), 120.83 *C-40), 116.14 *C-20 and C-60), 40.08 *N±
CH3); M/S m/z *%) 284 *M1, 69), 267 *5), 255 *11), 237
*100), 223 *43), 210 *14), 161 *4), 146 *9), 134 *16), 121
*19), 119 *12), 104 *13), 91 *10), 89 *15), 77 *68), 63 *12),
51 *44); HRMS: 284.06158, C15H12N2O2S requires
284.06195. [Found: C, 63.15; H, 4.26; N, 8.81.
C15H12N2O2S requires C, 63.36; H, 4.25; N, 8.95].
5.1.2. General procedure for the evaluation of the effect
of base concentration and strength. Compound 2a
*0.6 mL, 4.65 mmol) and the base *amounts as in Table 2)
were successively added to a solution of 1 *0.400 g,
1.55 mmol) in DMF *4.5 mL) and the mixture was heated
and kept at 1208C until disappearance of 1. After cooling to
room temperature and pouring into ice/water; the precipitate
was ®ltered, dried under vacuum and then treated as
described in method Ain Section 5.1.1.
5.1.3. General procedure for the reactions of 1 with
aniline 42b). Aniline *0.4 mL, 4.65 mmol) and the base
*amounts as in Table 3) were successively added to a solu-
tion of 1 *0.400 g, 1.55 mmol) in DMF *4.5 mL). The
mixture was heated and kept at 1208C until disappearance
of 1, then cooled to room temperature and poured into ice/
water; the precipitate was ®ltered and dried under vacuum.
Crystallization from EtOH gave compound 3b. The mother
liquor furnished, by ¯ash-chromatography on aluminum
oxide *ethyl acetate/petroleum etherˆ1:7 v/v as eluant),
the remaining 3b and 4b, in order of elution.
Compound 4c: Yellow needles from EtOH; mp 99±1008C;
1H NMR d 8.18 *d, 3Jˆ8.1 Hz, 1H, H-4), 7.89 *d,
3Jˆ8.0 Hz, 1H, H-7), 7.45 *t, Jˆ8.1 Hz, Jˆ8.1 Hz, 1H,
H-5), 7.48±7.32 *m, 5H, H±Ar), 7.24 *dd, 3Jˆ8.1 Hz,
3Jˆ8.0 Hz, 1H, H-6); 13C NMR d 160.53 *C-2), 146.79
*C-10), 131.72 *C-3a), 129.69 *C-30 and C-50), 127.36
*C-7a), 126.71 *C-5), 125.97 *C-40), 124.81 *C-6), 124.56
*C-3), 122.42 *C-7), 122.11 *C-20 and C-60), 121.29 *C-4),
44.98 *N±CH3); M/S m/z *%) 284 *M1, 51), 267 *34), 255
*19), 237 *100), 223 *31), 210 *4); 161 *17), 146 *12), 134
*18), 120 *12), 119 *12), 104 *11), 91 *21), 89 *9), 77 *41),
63 *7), 51 *26); HRMS: 284.06163, C15H12N2O2S requires
284.06195. [Found: C, 63.21; H, 4.33; N, 8.79.
C14H10N2O2S requires C, 63.36; H, 4.25; N, 8.95].
3
3
Compound 3b: Orange crystals from toluene; mp 218±
1
2198C *lit.8,10 222±223 and 210±2118C, respectively); H
and 13C NMR8,31 as well as mass32 spectra have been already
reported. HRMS: 270.04676, C14H10N2O2S requires
270.04630.
5.1.5. General procedure for the reactions of 1 with
aliphatic amines 5±8. The amine *4.65 mmol) and the
base *amounts as in Table 4) were successively added to a
solution of 1 *0.400 g, 1.55 mmol) in DMF *4.5 mL) and the
mixture kept at 1208C until disappearance of 1. The mixture
was then cooled to room temperature, poured into ice/water
and the precipitate ®ltered, dried under vacuum and puri®ed
by crystallization or ¯ash-chromatography on silica gel.
Compound 4b: Orange crystals from toluene; mp 156±
1578C; H NMR d 11.28 *s, exch., 1H, NH), 8.32 *dd,
1
4
3
3Jˆ8.1 Hz, Jˆ0.6 Hz, 1H, H-4), 7.78 *d, Jˆ8.1 Hz, 1H,
3
H-7), 7.61±7.45 *m, 5H, H±Ar), 7.44 *pt, Jˆ8.1 Hz, 1H,
H-5), 7.31 *pt, Jˆ8.1 Hz, 1H, H-6); 13C NMR d 162.42
3
*C-2), 139.23 *C-10), 130.94 *C-3a), 129.66 *C-30 and
C-50), 127.68 *C-40), 126.69 *C-5), 125.02 *C-7a), 124.74
*C-6), 124.60 *C-20 and C-60), 122.34 *C-7), 121.23 *C-4),
119.94 *C-3); M/S m/z*%) 270 *M1, 100), 237 *12), 236
*29), 235 *37), 223 *14), 222 *25), 221 *11), 145 *10), 121
*11), 120 *13), 76 *29), 50 *18); HRMS: 270.04662,
C14H10N2O2S requires 270.04630. [Found: C, 62.32; H,
3.81; N, 10.24. C14H10N2O2S requires C, 62.21; H, 3.73;
N, 10.36].
Compound 9: Orange crystals from cyclohexane; mp 139±
1418C *lit.11 139±1408C); 1H NMR d 9.53 *d, exch.
3
4
3Jˆ8.1 Hz, 1H, NH), 8.19 *dd, Jˆ8.4 Hz, Jˆ0.8 Hz, 1H,
H-4), 7.92 *dd, 3Jˆ8.1 Hz, 4Jˆ1.0 Hz, 1H, H-7), 7.68 *ddd,
3Jˆ8.1 Hz, Jˆ7.3 Hz, Jˆ0.8 Hz, 1H, H-6), 7.49 *ddd,
3
4
3Jˆ8.4, Jˆ7.3 Hz, Jˆ1.0 Hz, 1H, H-5), 4.41±4.34 *m,
1H, CH), 2.12±1.21 *m, 10H, 5£CH2); 13C NMR d
147.49 *C-3), 138.39 *C-7a), 131.61 *C-6), 127.74 *C-3a),
127.69 *C-4), 125.67 *C-5), 124.07 *C-7), 119.55 *C-2),
52.69 *CH), 32.87 *2£CH2), 24.72 *CH2), 23.50 *2£CH2);
M/S m/z *%) 276 *M1, 84), 242 *20), 241 *14), 194 *48), 178
3
4
5.1.4. Reaction of 1 with N-methylaniline 42c). N-Methyl-
aniline *0.5 mL, 4.65 mmol) and K2CO3 *1.07 g, 7.75 mmol

B. Cosimelli et al. / Tetrahedron 5712001) 8903±8911
8909
*35), 177 *11), 164 *25), 161 *22), 160 *19), 149 *12), 148
*73), 147 *15), 146 *20), 136 *25), 135 *46), 134 *62), 121
*30), 103 *18), 102 *13), 99 *12), 89 *16), 83 *11), 81 *21),
77 *16), 76 *14), 55 *100); HRMS: 276.09356, C14H16N2O2S
requires 276.09325.
144.66 *C-3), 137.30 *C-2), 134.86 *C-7a), 130.64 *C-6),
130.54 *C-3a), 130.07 *C-20 and C-60), 126.36 *C-5),
124.07 *C-4 and C-7), 123.75 *C-40), 115.81 *C-30 and
C-50); M/S m/z *%) 271 *M1, 10), 224 *12), 179 *10), 178
*100), 162 *12), 152 *13), 136 *29), 134 *38), 121 *12), 120
*20), 108 *12), 106 *10), 104 *11), 77 *30), 76 *15), 69 *11),
65 *15), 51 *30), 50 *14); HRMS: 271.02984, C14H9NO3S
requires 271.03031. [Found: C, 61.85; H, 3.52; N, 5.07.
C14H9NO3S requires C, 61.98; H, 3.34; N, 5.16].
Compound 10: Orange crystals from EtOH; mp 538C *lit.10
548C) from ¯ash-chromatography *cyclohexane/benzeneˆ
1:4 v/v as eluant); 1H NMR d 8.05 *dd, 3Jˆ8.3 Hz,
3
4
4Jˆ1.1 Hz, 1H, H-4), 7.89 *dd, Jˆ8.1 Hz, Jˆ1.1 Hz, 1H,
H-7), 7.60 *ddd, 3Jˆ8.1 Hz, 3Jˆ7.2 Hz, 4Jˆ1.1 Hz 1H,
H-6), 7.45 *ddd, 3Jˆ8.3 Hz, 3Jˆ7.2 Hz, 4Jˆ1.1 Hz 1H,
5.1.7. 2-Nitro-3-phenylsulfanylbenzo[b]thiophene 417).
Sodium benzenethiolate *14) *0.614 g, 4.65 mmol) was
added to a solution of 1 *0.400 g; 1.55 mmol) in dioxane
*25 mL); the resulting solution was stirred at room tempera-
ture for 24 h and then concentrated in vacuum. The residue
was treated with water and the solid ®ltered off and dried.
By crystallization from MeOH 2-nitro-3-phenylsulphanyl-
benzo[b]thiophene *17) was obtained *yield 80%): yellow
needles, mp 95±968C; 1H NMR d 8.17 *m, 1H, H-4 or H-7),
7.63 *m, 1H, H-5 or H-6), 7.48±7.34 *m, 7H, H±Ar); 13C
NMR d 148.41 *C-2), 137.19 *C-7a), 136.47 *C-10), 132.75
*C-3a), 130.24 *C-3), 130.14 *C-20 and C-60), 129.75 *C-40),
129.63 *C-30 and C-50), 128.04, 126.11, 125.99, 123.92;
M/S m/z *%) 287 *M1, 93), 241 *23), 240 *82), 223 *24),
222 *42), 208 *18); 195 *13), 194 *32), 165 *15), 164 *10),
152 *13), 146 *100), 136 *41), 121*19), 120 *53), 108 *16),
93 *10), 77 *35), 69 *19), 51 *20); HRMS: 287.00688,
C14H9NO2S2 requires 287.01084. [Found: C, 58.48; H,
3.27; N, 4.76. C14H9NO2S2 requires C, 58.52; H, 3.16; N,
4.87].
3
3
H-5), 3.61 *q, Jˆ7.1 Hz, 4H, 2£CH2), 1.09 *t, Jˆ7.1 Hz,
6H, 2£CH3); 13C NMR d 146.58 *C-3), 136.02 *C-7a),
134.30 *C-3a), 131.59 *C-2), 129.97 *C-6), 126.27 *C-4),
125.30 *C-5), 123.56 *C-7), 46.95 *2£CH2), 13.62
*2£CH3); M/S m/z *%) 250 *M1, 16), 223 *13), 207 *14),
189 *16), 175 *14), 163 *17), 162 *17), 161 *100), 160 *20),
148 *14), 147 *15), 135 *27), 134 *72), 133 *14), 103 *12),
102 *11), 89 *31), 77 *10), 76 *16), 71 *15), 70 *10), 69 *42),
63 *14); HRMS: 250.07714, C12H14N2O2S requires
250.07760.
Compound 11: Orange crystals from EtOH; mp 119±1218C
*lit.13 118±1208C); 1H NMR d 8.07 *m, 1H, H-4), 7.90 *m,
1H, H-7), 7.62 *m, 1H, H-6), 7.47 *m, 1H, H-5), 3.56±3.52
*m, 4H, 2£CH2), 1.77±1.68 *m, 6H, 3£CH2); 13C NMR d
147.39 *C-3), 136.37 *C-7a), 133.04 *C-3a), 130.10 *C-6),
128.58 *C-2), 126.43 *C-4), 125.31 *C-5), 123.66 *C-7),
53.40 *2£NCH2), 26.18 *CH2), 23.38 *2£CH2); M/S m/z
*%) 262 *M1, 49), 245 *100), 228 *21), 227 *30), 217
*45), 214 *13), 200 *14), 190 *11), 188 *19), 187 *13), 186
*26), 175 *26), 174 *13), 173 *13), 163 *22), 162 *19), 161
*37), 160 *47), 149 *20), 148 *41), 147 *33), 146 *14), 135
*21), 134 *47), 133 *25), 121 *15), 116 *15), 102 *11), 89
*45), 85 *14), 69 *11), 67 *22), 57 *23), 55 *26); HRMS:
262.07743, C13H14N2O2S requires 262.07760.
5.1.8. 2-Nitrobenzo[b]thiophen-3-yl phenyl sulfone 418).
Asolution of 1 *0.400 g; 1.55 mmol) in EtOH *60 mL) was
added of sodium benzenesul®nate *15) *0.327 g,
2.01 mmol) and warmed to 608C for 15 min. On cooling,
yellow crystals of 18 from EtOH/dioxane *mp 1948C; yield
95%) were obtained; 1H NMR d 8.58 *m, 1H, H-4 or H-7),
8.28 *m, 1H, H-7 or H-4), 8.14 *m, 2H, H-20 and H-60),
7.81±7.68 *m, 5H, H-5, H-6, H-30, H-40 and H-50); 13C
NMR d 153.47 *C-2), 139.35 *C-7a), 135.27 *C-10),
134.74 *C-40), 131.76 *C-3a), 129.80 *C-30), 129.00 *C-6),
128.37 *C-3), 127.81 *C-4), 127.27 *C-20), 125.29 *C-5),
123.99 *C-7); M/S m/z *%) 319 *M1, 100), 226 *34), 208
*22), 165 *16), 162 *18), 136 *17), 134 *27), 125 *30), 91
*10), 77 *26), 51 *12); HRMS: 318.99799, C14H9NO4S2
requires 318.99730. [Found: C, 52.78; H, 2.98; N, 4.31.
C14H9NO4S2 requires C, 52.65; H, 2.84; N, 4.39].
Compound 12: Yellow crystals from EtOH; mp 107±1098C;
1H NMR d 8.27 *m, 1H, H-4), 7.89 *m, 1H, H-7), 7.61 *m,
1H, H-6), 7.44 *m, 1H, H-5), 3.31 *s, 6H, 2£CH3); 13C NMR
d 148.28 *C-3), 136.45 *C-7a), 132.53 *C-3a), 130.08 *C-6),
127.24 *C-4), 126.02 *C-2), 125.02 *C-5), 123.55 *C-7),
44.60 *2£CH3); M/S m/z *%) 222 *M1, 89), 205 *16), 193
*16), 177 *23), 176 *39), 175 *38), 174 *13), 163 *19), 162
*16), 161 *100), 160 *44), 150 *55), 149 *30), 148 *60), 147
*27), 146 *17), 135 *18), 134 *63), 133 *22), 121 *45), 117
*12), 116 *11), 102 *10), 90 *12), 89 *44), 76 *10), 69 *14),
67 *14), 62 *11); HRMS: 222.04590, C10H10N2O2S requires
222.04630. [Found: C, 54.12; H, 4.51; N, 12.50.
C10H10N2O2S requires C, 54.04; H, 4.53; N, 12.60].
5.1.9. Reaction of 19 with 3-tri¯uoromethylaniline 42a).
2a *0.6 mL, 4.65 mmol) and Et3N *0.4 mL, 4.65 mmol)
were successively added to a solution of 19 *0.456 g,
1.55 mmol) in DMF *8 mL). The resulting solution was
kept at 1208C until disappearance of 19 *45 min). Then
the mixture was cooled at room temperature and poured
onto ice water; the precipitate was ®ltered and dried under
vacuum *yield 65%). Using ¯ash-chromatography on silica
gel *cyclohexane/tolueneˆ1:4 v/v as eluant), compounds 20
and 21 were isolated in a 45:55 ratio *65% overall yield).
5.1.6. 2-Nitro-3-phenoxybenzo[b]thiophene 416). Sodium
phenoxide trihydrate *13) *0.790 g, 4.65 mmol) was added
to a solution of 1 *0.400 g; 1.55 mmol) in dioxane *25 mL);
the resulting solution was stirred at room temperature for
33 h and then poured into ice/water. The precipitate was
®ltered, dried under vacuum *yield 71%) and identi®ed as
2-nitro-3-phenoxybenzo[b]thiophene *16): yellow needles
from EtOH/dioxane; mp 132±1348C; 1H NMR d 8.18
*m, 1H, H-7), 7.73 *m, 1H, H-6), 7.62 *m, 1H, H-4), 7.50
*m, 1H, H-5), 7.41±7.36 *m, 2H, H-30 and H-50), 7.19±7.10
Compound 20: Orange needles from EtOH; mp 183±1858C;
1H NMR d 10.37 *br s, exch., 1H, NH), 8.07*d, 3Jˆ8.5 Hz,
3
4
1H, H-7), 7.73 *dd, Jˆ8.5 Hz, Jˆ1.9 Hz, 1H, H-6), 7.67
13
4
*m, 3H, H-20, H-40 and H-60); C NMR d 156.63 *C-10),
*d, Jˆ1.9 Hz, 1H, H-4), 7.58 *m, 1H, H-50), 7.52 *m, 1H,

8910
B. Cosimelli et al. / Tetrahedron 5712001) 8903±8911
H-20), 7.51 *m, 1H, H-40), 7.41 *m, 1H, H-60); 13C NMR d
140.99 *C-10), 138.02 *C-3), 135.35 *C-7a), 132.24 *C-5),
130.68 *C-6), 130.03 *C-3a), 129.99 *C-50), 129.59 *C-30),
129.34 *C-2), 125.77 *C-7), 124.72 *C-60), 124.70 *C-4),
123.99 *CF3), 120.54 *C-40), 117.59 *C-20); M/S m/z *%)
372 *M1, 100), 338 *26), 325 *23), 313 *13), 292 *14), 291
*68), 290 *14), 271 *18), 257 *29), 222 *13), 189 *13), 168
*10), 145 *43), 133 *13), 125 *17), 119 *11), 95 *23), 75 *25),
69 *43), 63 *15); HRMS: 371.99400, C15H8ClF3N2O2S
requires 371.99471. [Found: C, 48.27; H, 2.30; N, 7.12.
C15H8ClF3N2O2S2 requires C, 48.33; H, 2.16; N, 7.52].
Caruso, A.; Leone, M. G.; Felice, A. Il Farmaco 1990, 45,
29±38.
Á
8. Guerrera, F.; Salerno, L.; Sarva, M. C.; Siracusa, M. A.;
Lamartina, L.; Caruso, A.; Cutuli, V. Il Farmaco 1992, 47,
1149±1160.
9. Hrelia, P.; Fimognari, C.; Maffei, F.; Spinelli, D.; Lamartina,
Á
L.; Sarva, M. C.; Cantelli Forti, G. Chem.-Biochem. Interact.
1999, 118, 99±111.
10. Van Zyl, G.; Bredeweg, C. J.; Rynbrandt, R. H.; Neckers, D. C.
Can. J. Chem. 1966, 44, 2283±2289.
11. Lampert, B. B. PhD Dissertation, Northwestern University,
1951, quoted in Harthough, H. D.; Meisel, S. L. Compounds
with Condensed Thiophene Rings; Interscience: New York,
1954 p 52.
Compound 21: Yellow needles from EtOH; mp 160±1618C;
1H NMR d 11.39 *br s, exch., 1H, NH), 8.28 *d, 4Jˆ2.1 Hz,
1H, H-4), 8.03 *m, 1H, H-20), 7.95 *m, 1H, H-60), 7.86 *d,
3Jˆ8.5 Hz, 1H, H-7), 7.80±7.78 *m, 2H, H-40 and H-50),
12. De Santis, F.; Stegel, F. Gazz. Chim. Ital. 1973, 103, 649±655.
13. Chippendale, K. E.; Iddon, B.; Suschitzky, H.; Taylor, D. S.
J. Chem. Soc., Perkin Trans. 1 1974, 1168±1172.
14. Van Zyl, G.; De Jongh, D. C.; Heasley, V. L.; Van Dyke, J. W.
J. Org. Chem. 1961, 26, 4946±4949.
3
4
7.39 *dd, Jˆ8.5 Hz, Jˆ2.1 Hz, 1H, H-6); 13C NMR d
162.64 *C-2), 139.99 *C-10), 132.40 *C-3a), 131.85 *C-5),
130.90 *C-50), 130.35 *C-30), 128.87 *C-60), 124.53 *C-6),
124.26 *C-40), 124.10 *C-7), 123.57 *C-7a), 123.56 *CF3),
121.90 *C-20), 120.39 *C-4), 119.76 *C-3); M/S m/z *%) 372
*M1, 100), 342 *19), 341 *12), 340 *18), 339 *26), 338 *26),
291 *24), 271 *20), 257 *15), 256 *11), 180 *18), 172 *12),
171 *21), 170 *11), 169 *20), 168 *15), 156 *12), 155 *20),
154 *15), 145 *49), 142 *10), 133 *16), 125 *16), 119 *29), 95
*17), 76 *10), 75 *22), 69 *22), 63 *11); HRMS: 371.99429,
C15H8ClF3N2O2S2 requires 371.99471. [Found: C, 48.39; H,
2.28; N, 7.35. C15H8ClF3N2O2S2 requires C, 48.33; H, 2.16;
N, 7.52].
15. *a) pKB Values from Handbook of Chemistry and Physics;
74th ed.; CRC: Boca Raton, 1993±1994 if not otherwise indi-
cated. *b) Roberts, J. D.; Webb, R. L.; McElhill, E. A. J. Am.
Chem. Soc. 1950, 72, 408±411.
16. The importance of the nature of the solvent and of the basic
strength of the nucleophile has been well evidenced by Hirst,
J.; Onyido, I. J. Chem. Soc., Perkin. Trans. 2 1984, 711±715 in
their studies of catalysis in aromatic nucleophilic substitu-
tions.
17. *a) Physical constant values are from Reichardt, C. Solvents
and Solvent Effects in Organic Chemistry; 2nd ed.; VCH:
Weinheim, 1988 if not otherwise indicated. *b) See Ref.
17a, p 16 and references therein.
Acknowledgements
18. Murto, J.; Kivinen, A.; Kivimaa, S.; Laasko, R. Suom. Kemis-
tilehati B 1967, 40, 250±257.
We thank CNR, MURST and the University of Bologna
*Funds for selected research topics) for ®nancial support.
19. The nucleophilicity of a reagent can be measured in terms of
its reactivity versus a reference electrophile and is determined
by a number of factors, such as basicity, polarizability and
solvation *in this respect HBD or non-HBD character of the
used solvent is usually an important factor, especially with
anionic nucleophiles). It is impossible to establish a simple
general nucleophilicity order, as it appears to be strongly
dependent on the nature of the electrophile, of the solvent,
and so on: Bunnett, J. F. Nucleophilic reactivity. Ann. Rev.
Phys. Chem. 1963, 14, 271±290 indicated no less than seven-
teen factors affecting nucleophilicity.
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*b) Gronowitz, S. Some recent work on nonbenzenoid thio-
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benzo[b]thiophene range around 53 kcal mol21 22
. Considering
the benzene contribution *36 kcal mol21), the increase deter-
mined by the condensed thiophene ring appears much lower
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4. *a) Frenna, V.; Macaluso, G.; Consiglio, G.; Guernelli, S.;
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Á
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Á
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29. This situation recalls that observed in acetonitrile in connec-
tion with the occurrence of base-catalysis in aromatic nucleo-
philic substitution by J. Hirst and I. Onyido.16
25. *a) Perekalin, V. V.; Lipina, E. S.; Berestovitskaya, V. M.;
Efremov, D. A. Nitroalkenes, Conjugated Nitro Compounds;
Wiley: New York, 1994. *b) Williams, D. L. H. In Supplement
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Groups; Patai, S., Ed.; Wiley: New York, 1996; pp. 144±
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30. Boswell, D. E.; Brennan, J. A.; Landis, P. S.; Rodewald, P. G.
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Á
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26. The formation of three-membered ring intermediates has been
supposed and/or evidenced in several organic transformations,
e.g. see: Lucchini, V.; Modena, G.; Pasquato, L. J. Am. Chem.