A versatile approach for the synthesis of 8H-thieno[2,3-b]indoles and N-[2-(2-N-(R1,R2)-2-Thioxoacetyl)-phenyl]acetamides from 1-acetyl-1,2-dihydro-3H-indol-3-one (Acetylindoxyl) and its derivatives: A novel synthesis of intermediate (1-acetyl-1h-indol-3-yl)malononitrile/cyanoacetates

Article abstract of DOI:10.1002/jhet.960

We report on two approaches for the synthesis of new 2-amino-3-cyano/ alkoxycarbonyl-8H-thieno[2,3-b]indoles and another one for the synthesis of 2-N,N-dialkylamino-3-cyano/aryl-8H-thieno[2,3-b]indoles, based either on acetylindoxyl and (1-acetyl-1H-indol-3-yl)malononitrile/cyanoacetates or 2-bromoacetylindoxyl transformations. A new, simple, rapid, and efficient method for the synthesis of valuable key intermediate malononitrile/cyanoacetates based on acetylindoxyl condensation with malononitrile or cyanoacetates in the presence of triethylamine has been developed. A number of synthetic procedures for the preparation of thioacetamides, 1-acetylthioisatin, and 2,2-disubstituted indoxyls have been elaborated during the synthesis of thieno[2,3-b]indoles. Thioacetamides have been shown as novel agents active against Mycobacterium tuberculosis H₃₇Rv, the cause of tuberculosis, with minimal inhibitory concentration values ranging between 5 and 21 μg/mL.

Full text of DOI:10.1002/jhet.960

Month 2013
A Versatile Approach for the Synthesis of 8H‐Thieno
[2,3‐b]indoles and N‐[2‐(2‐N‐(R1,R2)‐2‐Thioxoacetyl)‐
phenyl]acetamides from 1‐Acetyl‐1,2‐dihydro‐3H‐indol‐3‐one
(Acetylindoxyl) and Its Derivatives: A Novel Synthesis of
Intermediate (1‐Acetyl‐1H‐indol‐3‐yl)malononitrile/cyanoacetates
a
a
Valeriya S. Velezheva,a,b Alexander Yu. Lepyoshkin, Konstantin F. Turchin,
*
a
a
c
*
Irina N. Fedorova, Alexander S. Peregudov, and Patrick J. Brennan
aA.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
119991 GSP‐1 Moscow, Russia
bAll‐Russian Chemical Pharmaceutical Research Institute, 119815, Moscow, Russia
cDepartment of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins,
Colorado 80523‐1682
*
E-mail: vel@ineos.ac.ru or patrick.brennan@colostate.edu
Received November 16, 2010
DOI 10.1002/jhet.960
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
We report on two approaches for the synthesis of new 2‐amino‐3‐cyano/alkoxycarbonyl‐8H‐thieno
[2,3‐b]indoles 5 and another one for the synthesis of 2‐N,N‐dialkylamino‐3‐cyano/aryl‐8H‐thieno[2,3‐b]
indoles 16, based either on acetylindoxyl 1 and (1‐acetyl‐1H‐indol‐3‐yl)malononitrile/cyanoacetates 14
or 2‐bromoacetylindoxyl 2 transformations. A new, simple, rapid, and efficient method for the synthesis
of valuable key intermediate malononitrile/cyanoacetates 14 based on acetylindoxyl 1 condensation with
malononitrile or cyanoacetates in the presence of triethylamine has been developed. A number of synthetic
procedures for the preparation of thioacetamides 6, 1‐acetylthioisatin 8, and 2,2‐disubstituted indoxyls 13
have been elaborated during the synthesis of thieno[2,3‐b]indoles. Thioacetamides 6 have been shown as
novel agents active against Mycobacterium tuberculosis H37Rv, the cause of tuberculosis, with minimal
inhibitory concentration values ranging between 5 and 21 μg/mL.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
2, 2‐aminoacetylindoxyl, as well as 2‐arylidene‐1,2‐
dihydro‐3H‐indol‐3‐ones, were used [8,5]. It is noteworthy
that acetylindoxyl derivatives were also used for the synthe-
sis of such hetero[b]fused indoles as alkaloids ellipticine [11]
and quindoline [12] and other fused indoles [13–15]. Thus,
they demonstrated the capability of serving as key intermedi-
ates for annulations of nitrogen, oxygen, and sulfur–nitrogen
rings onto the existing indole or indoline cores.
Among the products resulting from the annulation of
sulfur heterocycles to [b]indole or indoline cores, thienoin-
doles being analogs of biologically important naturally
occurring pyrroloindoles offer a prospective class of com-
pounds for drug discovery. The heterocyclic systems of
pyrrolo[2,3‐b]indoles as well as their O‐ and S‐isoelectronic
analogs, furo[2,3‐b]indoles and thieno[2,3‐b]indoles, do
represent structural cores of bioactive molecules, alkaloids
In the course of our ongoing studies of the chemical and
biological properties of linear hetero[b]fused indoles [1–4],
we have developed effective and simple methods for the
synthesis of pharmacologically interesting pyridazino[4,3‐
b]indoles [5], pyrano[3,2‐b]indoles [6], pyrrolo[3,2‐b]
indoles [7], imidazo[4,5‐b]indoles, thiazolo[5,4‐b]indoles
[8], and some of their analogs [9,10]. A number of repre-
sentatives of these series displayed antituberculosis, mono-
amine oxidase inhibiting, antiviral, antihypoxic, and
hepatoprotective activities some of which may be attrib-
utable to monoamine oxidase inhibition. In the syntheses
of such fused indoles, available starting materials, 1‐
acetyl‐1,2‐dihydro‐3H‐indol‐3‐one (1) (acetylindoxyl)
and some of its derivatives, such as 2‐bromoacetylindoxyl
© 2013 HeteroCorporation

V. S. Velezheva, A. Y. Lepyoshkin, K. F. Turchin, I. N. Fedorova, A. S. Peregudov,
and P. J. Brennan
Vol 50
physostigmine, physovenine, madindoline, and thiophyso-
RESULTS AND DISCUSSION
venin [16]. In particular, a series of thienoindoles have been
investigated as potential depressants of central nervous sys-
tem activities [17], inhibitors of acetylcholine esterase and
butyrylcholine esterase [18], as well as anti‐inflammatory
[1] and antituberculosis agents [2]. In particular, thienodo-
lin (6‐chlorothieno[2,3‐b]indole‐2‐carboxamide) isolated
from the culture broth of Streptomyces albogriseolus [3]
and characterized by Japanese researches has proved to
have plant‐growth‐regulation activity. The parent thieno
[2,3‐b]indole also demonstrated antifungal activity [4].
Several syntheses of thieno[2,3‐b]indoles have been
reported, some in recent years [19–24]. However, the num-
ber of publications is less than those describing the prepara-
tion of fused indoles with five‐membered nitrogen and
oxygen rings reflecting the relative difficulty in obtaining
the starting compounds. Thieno[2,3‐b]indoles with alkyl‐
or aryl‐substituents in the thiophene ring were obtained by
the Paal‐Knorr reaction between 3‐(2‐oxoalkyl)‐oxoindoles
and phosphorus pentasulfide [25]. Thieno[2,3‐b]indoles
were also synthesized by cyclization of 3‐indolylthioalca-
noic acid [26] and by the interaction of 2‐chloroindole‐3‐
carbaldehyde with methyl thioglycolate [27]. The first
examples of C═S‐induced Pauson–Khand‐type reactions
were described involving conversion of 2‐alkynylphenyl
isothiocyanates to 3‐substituted‐2H‐thieno[2,3‐b]indol‐2‐
ones in the presence of a stoichiometric amount of Mo
(CO)6 or Co2(CO)8, or a catalytic amount of Rh catalyst
[28]. A simple and effective method was also elaborated
for the synthesis of the thieno[2,3‐b]indole ring system
based on the electrophilic recyclization of 2‐alkyl‐5‐(2‐
isothiocyanoaryl)furans in the presence of anhydrous
AlCl3 [29]. A number of thieno[3,2‐b]indoles have been
regioselectively synthesized in 85–90% yield by the tan-
dem cyclization of 1‐acetyl‐3‐(4′‐aryloxybut‐2′‐ynylthio)
indoles on treatment with 1 equiv of m‐CPBA in CH2Cl2
at room temperature (RT) for 1 h. The latter were in turn
prepared from indole via the formation of thiuronium salt
and subsequent reaction with 1‐aryloxy‐4‐chlorobut‐2‐
yne and acetylation by acetyl chloride [30]. The synthe-
sis of 4,5,6,7‐ tetrahydro‐8H‐thieno[2,3‐b]indoles was
performed by the Fisher reaction from corresponding
thienylhydrazines and cyclohexanone [31].
As further examples of the application of acetylindoxyl 1
and its derivatives for fused indole synthesis, we report on the
straightforward preparation of 2‐amino‐ and 2‐N,N‐dialkyla-
mino‐3‐cyano/alkoxycarbonyl/aryl‐8H‐thieno[2,3‐b]indoles.
The presence of the vicinal amino, nitrile, or alkoxycarbonyl
groups, in particular, provides the background for further
functionalization of the molecules.
We first decided on the synthesis of some thienoindoles
that could be obtained in a single step by a simple reaction
earlier offered by Gewald [32]. The method was success-
fully used for the preparation of 2‐amino‐3‐cyano/carbalk-
oxythiophenes. Acetylindoxyl 1 and malononitrile 3a were
taken as the ketone and the active‐hydrogen nitrile, respec-
tively. When these compounds were refluxed in alcohol so-
lution in the presence of elemental sulfur and a secondary
amine 4a or 4b as a base, the reaction occurring was sup-
posed to furnish 2‐amino‐8‐acetyl‐3‐cyano‐8H‐thieno[2,3‐
b]indole (5a). However, although 5a may arise from the
Gewald reaction, it has not been described so far.
Contrary to our expectations, thienoindole 5a was iso-
lated only in low yield (8–9%). Both in the presence and
the absence of malononitrile, acetylindoxyl 1 underwent
ring opening to afford the corresponding thioamides 6a,b
as the main products when secondary amines were used.
Thus, acetylindoxyl 1, when refluxed with malononitrile,
elemental sulfur, and morpholine 4a or piperidine 4b in
isopropanol for 3 h, gave thioamides 6a,b in yields of 61
and 55%, respectively (Scheme 1). Without malononitrile
the yields of thioamides 6a,b turned out to be even higher
(76 and 67%).
Under the same conditions, a primary amine, butylamine
4c, also induces acetylindoxyl ring opening to give the
Schiff base 7 but in 35% yield only (Scheme 2).
It is worth noting that thioamides 6a,b were obtained in
the above yields when the reactions were carried out in air,
while under argon they were formed in such small amounts
that their presence in the reaction mixture could be
revealed by TLC only. Since the yields of compounds 6a,
b turned out to be less when malononitrile was present
and compound 5a was among the products, a question to
be considered was whether 5a could be formed from 6a
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 A Versatile Approach for the Synthesis of 8H‐Thieno[2,3‐b]indoles and N‐[2‐(2‐N‐(R1R2)‐2‐Thioxoacetyl)‐
phenyl]acetamides from 1‐Acetyl‐1,2‐dihydro‐3H‐indol‐3‐one (Acetylindoxyl) and Its Derivatives
Scheme 2
under the action of malononitrile. However, no transforma-
tion of thioamide 6a into thienoindole 5a occurred when
the former was treated with malononitrile under the reac-
tion conditions. Again, 5a should not be an intermediate
that malononitrile converts into 6a since the latter is
formed without malononitrile, and moreover, 5a did not
furnish 6a when specially treated with malononitrile and
morpholine.
On the contrary, the ring opening of isatin under the ac-
tion of various nucleophiles was reported to be facile [33].
The same should obviously be characteristic of 2‐thioisatin
derivative 8. It means that a reaction pathway involving
compound 8 or its hydrodimer 9 as an intermediate seems
plausible.
Unlike 2‐thioisatin and indoxyl disulfide lacking substi-
tuents at the ring nitrogen, their 1‐acetyl derivatives 8 and 9
have not been described so far. So, we purposefully pre-
pared indoxyl disulfide 9 and thioisatin 8 in 45 and 72%
yields, respectively, by interaction of bromoacetylindoxyl
2 with sodium thiosulfate. The reaction proceeded via
Bunte salt 10 that further reacted with iodine at RT in the
molar ratio of 0.5/1. The conversion of disulfide 9 into
thioisatin 8 was spontaneous in these media (Scheme 3).
Taking into account the above facts, we suggest the fol-
lowing scheme for the transformation of acetylindoxyl 1
into thioamides 6 (Scheme 3). The first step, α‐thiolation
of acetylindoxyl 1 to thiol 11, seems rather obvious since
ketones are known to react in such a manner in the pres-
ence of bases [34]. For comparison, acetylindoxyl 1 is
readily brominated at position 2; bromoacetylindoxyl 2
was obtained by us previously in quantitative yield by
heating 1 with bromine in methylene chloride for several
minutes [7]. The presence of a base (amine) is essential
for the formation of thiol 11 as shown by the lack of the lat-
ter when acetylindoxyl 1 and sulfur were reacted without
amine producing unidentified polymeric materials instead.
Thiol 11 can undergo the second thiolation to furnish
dithiol 12 since the ketone bisthiolation was shown to
occur in the Gewald reaction with malononitrile, e.g., bis
(5‐amino‐3‐methyl‐4‐cyanoethyl)sulfide is formed from
acetone [35]. Dithiol 12 should be unstable producing
thioisatin 8 after elimination of hydrogen sulfide [36].
However, there is a possibility for 8 to be formed via
oxidation of thiol 11 in light of the well‐known fact that in-
doxyl and its 2‐substituted derivatives are prone to oxida-
tion by air oxygen [37] and is in line with the finding
mentioned above that the reaction studied proceeds
smoothly and with good yields only in air. Moreover, the
oxidation may proceed via disulfide 9 since the latter was
shown to undergo the transformation into thioisatin 8 when
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. S. Velezheva, A. Y. Lepyoshkin, K. F. Turchin, I. N. Fedorova, A. S. Peregudov,
and P. J. Brennan
Vol 50
Scheme 5
standing in air in the presence of small amounts of a base
(Scheme 4). The ring opening occurs by means of an amine
attack on the resulting C═S bond of 8.
In fact, thioamides 6a–e were shown to be formed by the
interaction of either 1‐acetyl‐2‐thioisatin 8 or acetylindoxyl
disulfide 9 with amines 4a–e, morpholine, piperidine,
N‐methylpiperazine, butylamine, and isopropylamine, re-
spectively (Schemes 3 and 4). The reactions occurred in
dioxane, isopropanol, or acetone at RT. The nature of the
solvent did not markedly affect the yields of thioamides
6a–e. The highest yields of thioamides 6a–e (91–87%)
were achieved when thioisatin 8 was used as the starting
compound, whereas 6a,b were obtained from disulfide 9
in somewhat lower yields (78 and 70%, respectively). As
in the case of the reactions of acetylindoxyl 1 with sulfur
and amines (vide supra), the yields of thioamides 6a,b
were less in the presence of malononitrile. Under the reac-
tion conditions, thioisatin 8 and disulfide 9 were shown not
to react with malononitrile and, thus, are not precursors of
thienoindole 5a.
It is interesting to note that thioamides 6a,b undergo
cyclization to 2,2‐disubstituted indoxyls 13a,b in 52 and
45% yields upon alkylation with methyl iodide in the pres-
ence of potassium hydroxide (Scheme 5). This cyclocon-
densation of thioamides 6a,b and their analogs opens a
simple way to 2,2‐disubstituted indoxyls with different
substituents in position 2, which are difficult to obtain by
other methods.
the protons of the CH2 groups in equal positions but on
different sides relative to the nitrogen. These differences
achieve 0.6 and 0.7 ppm for the CH2 groups in the
α‐position relative to the nitrogen atom of morpholine
and piperidine residues, respectively, and are probably as-
sociated with the hindered rotation of the ring around the
thioamide bond. The 13C‐NMR spectra confirm the pres-
ence of the thioamide and amide bonds and the conjugated
carbonyl in compounds 6a, the carbon atoms of which have
the signals at 192.4, 169.1, and 190.1 ppm. As well as in the
1H‐NMR spectra, the 13C‐NMR spectra differ markedly by
the chemical shifts for the α‐carbons of the amine moiety,
which occupy opposite positions relative to the nitrogen
atom: Δδc = 4.9 ppm. The structures of 13a and 13b are
1
confirmed by the H‐NMR spectra and by the 13C‐NMR
spectrum for 13a, in which there are the signals for the con-
jugated ketone and amide carbonyls at δ 195.6 and 171.1,
respectively, the signal at δ 89.1 corresponding to the qua-
ternary sp3‐hybridized carbon atom C2.
The thioamides 6a–e were evaluated for their in vitro ac-
tivity against Mycobacterium tuberculosis H37Rv accord-
ing to protocols developed at the Tuberculosis
Antimicrobial Acquisition and Coordinating Facility (cour-
tesy of Dr. Anne Lenaerts), Colorado State University
(http:://www.mrl.coloradostate.edu), with minimal inhibi-
tory concentration (MIC) values ranging between 5 and
21 μg/mL.
The spectral data (IR, NMR, mass spectrometry) were
used to prove the structures of thioamides 6a–e. In the IR
spectra of 6a–e, the groups NCOCH3, CO, and NH are ob-
served at 1640–1660, 1675–1700, and 3000–3300 cm−1,
respectively. For indoxyls 13a,b, the bands associated with
the NCOMe and CO groups have the frequencies of 1675,
1680, and 1720 cm−1, respectively. The 1H‐ and 13C‐NMR
data are in accord with the structures of compounds 6a
1
(Table 1). The H‐NMR spectra of these compounds indi-
cate nonequivalence of the edges of the cyclic amine resi-
due, which manifests itself in different chemical shifts for
Scheme 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 A Versatile Approach for the Synthesis of 8H‐Thieno[2,3‐b]indoles and N‐[2‐(2‐N‐(R1R2)‐2‐Thioxoacetyl)‐
phenyl]acetamides from 1‐Acetyl‐1,2‐dihydro‐3H‐indol‐3‐one (Acetylindoxyl) and Its Derivatives
Table 1
N‐[2‐(2‐N‐(R1, R2)‐Thioxoacetyl)‐phenyl]acetamides (6a–e).
Comp.
6a
3‐H
4‐H
5‐H
6‐H
N‐Ac
NH
R1, R2
7.68 (d)
7.70 (d)
7.70 (d)
7.06 (t)
7.19 (t)
7.20 (t)
7.56 (t)
7.66 (t)
7.65 (t)
8.75 (d)
8.53 (d)
8.36 (d)
2.22 (s)
2.18 (s)
2.16 (s)
11.28 (s)
11.02 (s)
10.92 (s)
3.57 (m, 2H, CH2), 3.67 (m, 2H, CH2),
3.88 (m, 2H, CH2), 4.29 (m, 2H, CH2)
1.52 (m, 2H, CH2), 1.70 (m, 4H, CH2),
3.59 (t, 2H, CH2), 4.18 (t, 2H, CH2)
0.92 (t, 3H, CH3), 1.37 (m, 2H, CH2), 1.64
(m, 2H, CH2), 3.65 (br, 2H, CH2),11.05
(br d, 1H, NH)
6b
6c
6d
6e
7.72 (d)
7.69 (d)
7.21 (t)
7.20 (t)
7.68 (t)
7.65 (t)
8.52 (d)
8.40 (d)
2.19a(s)
2.17 (s)
11.00 (s)
10.95 (s)
2.23a(s, 3H, CH3), 2.35 (br, 2H, CH2),
2.51b(2H, CH2), 3.62 (br, 2H, CH2),
4.21 (br, 2H, CH2)
1.26 (d, 6H, 2CH3), 4.58 (m, 1H, CH),
10.99 (br d, 1H, NH)
aAn alternative assignment of the signals is possible.
bThe signal merges with that of the solvent (DMSO‐d6).
Thus, acetylindoxyl 1 has been successfully used for the
convenient preparation of thioamides 6; this was possible
since the competitive Gewald reaction leading to thienoin-
doles apparently proceeds slower under the described con-
ditions. Nevertheless, the latter reaction afforded
thienoindole 5a in low yield in the presence of a secondary
amine (vide supra). That is why we decided to use a ter-
tiary amine as a base in this process instead of a secondary
one believing that it would provide more favorable condi-
tions for the formation of both thienoindole 5a and its an-
alog 5b containing a COOEt group at position 3. In fact,
when triethylamine was used instead of morpholine or pi-
peridine, thienoindole 5a was obtained in 52% yield com-
pared to only 10% yield for 5b (Scheme 6).
The reactions were carried out by refluxing a mixture of
acetylindoxyl 1, malononitrile 3a, or ethyl cyanoacetate 3b,
elemental sulfur, and excess of triethylamine in isopropanol
or acetonitrile. Resinification of the reaction mixture was
observed, which was especially noticeable in the case of
5b. The use of cyanoacetamide as the less active‐hydrogen
component under the same conditions did not give the
corresponding thienoindole at all. Such relatively low reac-
tivity of acetylindoxyl 1 in the Gewald reaction is akin to
that of cyclopentanone [32]. We assumed that desired
thienoindole should readily be formed only in the case
when the condensation of acetylindoxyl 1 with active‐
hydrogen nitrile would occur before the interaction with sul-
fur. So, we decided to use 1‐acetyl‐3‐indolylmalononitrile
14a and 3‐indolylcyanoacetates 14c–e with the COMe/
COOEt/H moiety at the ring nitrogen (N‐1), respectively,
instead of acetylindoxyl 1 and the corresponding active‐
hydrogen nitriles. The first can be considered as one of syn-
thetic equivalents of the Knoevenagel reaction products
between acetylindoxyl 1 and activated nitriles. Among
malononitrile derivatives only ylidenemalononitriles are
known to be successfully used in the Gewald reaction
instead of ketones [32], whereas, as far as we know, such
type of fully heteroaromatic nitriles as 14 has not been
tested in the reaction. We already reported the synthesis of
3‐indolylmalononitrile 14a that was obtained by condensation
of acetylindoxyl 1 with malononitrile in DMSO in the pres-
ence of sodium hydride [38]. In this work, we showed that
the condensation proceeded more readily in acetonitrile or iso-
propanol in the presence of triethylamine. By application of
this protocol, we prepared 1‐acetyl‐3‐indolylmalononitrile
14a in 88% yield. In the series of 3‐indolylcyanoacetates,
their 1‐carbalkoxy derivatives are the most available. 3‐
Indolylcyanoacetates bearing a substituent at the position
1 are formed in yields from 30 to 92% upon the interaction
of 3‐indolylacetonitriles with dialkylcarbonates in the pres-
ence of sodium hydride, yields depending on the nature of
the substituent at positions 1 or 5 [39]. In some cases, 3‐
indolylcyanoacetates with the unsubstituted ring nitrogen
atom were isolated as a byproduct in low (8–12%) yields.
It is not surprising since this species as well as its
benzene‐substituted derivatives, as a rule, are not easily
available even via the Fischer reaction because of side pro-
cesses [40]. It should also be noted that Nenitzescu and
Raileanu attempted to obtain 1‐acetyl‐3‐indolylcyanoacetic
acid by condensation of acetylindoxyl 1 with cyanoacetic
acid but failed; they also did not observe the formation of
Scheme 6
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V. S. Velezheva, A. Y. Lepyoshkin, K. F. Turchin, I. N. Fedorova, A. S. Peregudov,
and P. J. Brennan
Vol 50
3‐indolylcyanoacetic acid [41]. 1‐Acetyl‐3‐indolylacetonitrile
was obtained instead probably due to the fact that the reac-
tion was carried out under severe conditions and was there-
fore accompanied by decarboxylation. We managed to
implement the condensation between acetylindoxyl 1 and
methyl cyanoacetate 3c in the presence of triethylamine that
furnished methyl 1‐acetyl‐3‐indolylcyanoacetate 14c in
72% yield using acetonitrile or isopropanol as solvents
(Scheme 7). The same reaction, when allowed to proceed
in methanol, resulted 14e in 62% yield (Scheme 7). To all
appearance, lacking of the acetyl group in the primarily
formed 14c occurs by its methanolysis under these condi-
tions. In reality, 14c gradually transforms into NH‐cyanoester
14e at 20°C in methanol in the presence of an equivalent of
triethylamine, the transformation being complete in 24 h.
TLC of the reaction mixture showed that only partial split-
ting out of the acetyl group occurred if the reaction was
carried out in ethanol for 24 h as well. The method is distin-
guished by its preparative potentialities and apparent general-
ity that it can be used for the preparations of the corresponding
3‐indolylmalononitriles and 3‐indolylcyanoesters bearing
various substituents at the benzene ring. The latter are known
to be applied in the syntheses of biologically active com-
pounds [40]. Ethyl cyanoacetate 14d bearing 1‐NCOOEt sub-
stituent was obtained from 3‐indolylacetonitrile and
diethylcarbonate by the method given in ref. 39.
spectrum of 14a showed both the CH3 and CH aliphatic
signals at 2.70 and 6.76 ppm, respectively, and the chemi-
cal shifts (δ C 24.3 and 20.10) correspond with the carbons
at methyl and methine groups, respectively. HMBC experi-
ments showed methine CH proton correlations to the ring
C‐3 and C‐2 carbons as well as CN groups.
We used 3‐indolylmalononitrile 14a and 3‐indolylcya-
noesters 14c,d for the synthesis of thienoindoles 5a,c,d
with various substituents in positions 3 and 8 of the ring
system (Scheme 8). The yields of thienoindoles 5a,c,d
were in the range from high for 5a (80%) to low for
5c (25%) and 5d (33%) and depended mainly on the na-
ture of the substituent in position 3 of the ring system.
Thienoindole 5e lacking the substituent at the ring nitrogen
was isolated in the lowest (5%) yield but it should be
obtained in higher yield in future work from thienoindole
5c by hydrolysis of its 1‐N‐acetyl group.
Thienoindoles 5a,c,d were prepared by refluxing nitriles
14a,c,d and sulfur in isopropanol or ethanol in the presence
of the excess of triethylamine. Thienoindole 5a is formed
rather readily, for 1 h, while the synthesis of thienoindoles
5c,d takes not less than 10 h. Under similar conditions,
thienoindole 5c was isolated only in low yield (1–2%)
due to strong resinification of the reaction mixture. We
managed to increase the yield of thienoindole 5c up to
25% by heating cyanoester 14c and sulfur in DMSO at 75°C
for 5 h as well as by performing the reaction in DMF or ace-
tonitrile at 20°C for 10 days. All thienoindoles 5 obtained
were purified without using any chromatographic methods.
The structures of 14a,c,e were assigned on the basis of
elemental analysis, mass, 1H, 13C, and 1D and 2D (COSY,
HSQC, and HMBC) NMR spectral data (Table 2). The 1H
Scheme 7
Table 2
(1‐R2‐1H‐Indol‐3‐yl)‐R1‐acetonitriles (14a,c,e).
Comp.
2‐H
4‐H
5‐H
6‐H
7‐H
CH
R1
R2
14a
14c
14e
8.17 (br s)
8.03 (br s)
7.55 (d)
7.78 (d)
7.62 (d)
7.62 (d)
7.50a
7.50a
8.44 (d)
8.37 (d)
7.48 (d)
6.80 (br s, 1H, CH)
5.99 (br s, 1H, CH)
5.81 (s, 1H, CH)
–
2.74 (br s, 3H, CH3)
2.68 (br s, 3H, CH3)
11.36 (br s, 1H, NH)
7.38a
7.38a
3.76 (br s, 3H, CH3)
3.71 (s, 3H, CH3)
7.08b(t)
7.16b(t)
aComplex overlapping signals.
bAn alternative assignment of the signals is possible.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 A Versatile Approach for the Synthesis of 8H‐Thieno[2,3‐b]indoles and N‐[2‐(2‐N‐(R1R2)‐2‐Thioxoacetyl)‐
phenyl]acetamides from 1‐Acetyl‐1,2‐dihydro‐3H‐indol‐3‐one (Acetylindoxyl) and Its Derivatives
Scheme 8
We suppose that in the case of thienoindole 5 synthesis
from the heteroaryl‐ activated nitrile 14 and sulfur, the
starting nitrile is deprotonated followed by the thiolation
in position 2 of the indole ring with subsequent intramolec-
ular cyclization via intermediates 15A,B. On the other
hand, the reason of the decrease in the yields of thienoin-
doles 5c–e can also be the competitive thiolation of 3‐indo-
lylcyanoesters at the active α‐position.
We have also studied the preparation of 2‐N,N‐dialkyla-
minothienoindoles 16a–d through the condensation of
bromoacetylindoxyl 2 with cyclic (morpholino‐ or piperi-
dino‐) thioamides of arylacetic acids 17a–c (where
Ar = Ph, 4‐CH3-C6H4-, 4‐O2N-C6H4-) and cyanoacetic
acid 17d (Scheme 9). N,N‐Disubstituted thioamides are
known to react with α‐halo ketones in ambiguous fashion
depending on the reaction conditions and the nature of
components. In 1970, Eschenmoser described the transfor-
mation of thiolactams into its vinylogs that occurs under
the action of such α‐halo ketones as phenacyl bromides
in the presence of a base [42] and involves the formation
of sulfur‐bridged intermediate of the thiirane 18 type
(Scheme 9). According to [43, 44], N,N‐dialkylthioamides
also react with some α‐halo ketones, in particular, phena-
cylbromides in the presence of a base but affording 2‐ami-
nothiophenes. The data for similar interactions of α‐halo
ketones with cyanoacetic acid thioamides 17a–d were lack-
ing. So, it was impossible to decide a priori what would be
a real route for the interaction of thioamides 17a–d with
bromoacetylindoxyl 2. We carried out the reaction between
bromoacetylindoxyl 2 and thioamides 17a–d by short
heating of the components in isopropanol and obtained
thienoindoles 16a–d in yields from 28 to 50%. Thus, the
annulation of the thiophene ring took place in all the
cases considered.
We ascertained that in the presence of a base where pro-
duction of 2‐aminothiophenes occurred [43], phenylacetic
acid thiomorpholide 17a afforded 2‐morpholinothienoindole
16a both in the presence and absence of triethylamine but in
low yield. The reaction was accompanied by resinification
that was especially obvious in the presence of a base. When
Scheme 9
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. S. Velezheva, A. Y. Lepyoshkin, K. F. Turchin, I. N. Fedorova, A. S. Peregudov,
and P. J. Brennan
Vol 50
Table 3
3‐R1‐8‐R2‐2‐Amino‐8H‐thieno[2,3‐b]indoles (5a–e).
Comp.
4‐H
5‐H
6‐H
7‐H
8‐R2
2‐NH2
3‐R1
5a
5b
7.64 (br)
8.32 (d)
7.35 (m)
7.30 (m)
7.35 (m) 7.85 (m)
7.30 (m) 7.90 (m)
2.79 (br s, 3H, CH3)
2.81 (s, 3H, CH3)
7.36 (br s, 2H, NH2)
7.41 (br s, 2H, NH2)
–
1.41 (t, 3H, CH3),
4.37 (dd, 2H, CH2)
3.89 (s, 3H, CH3)
1.42 (m, 3H, CH3),
4.37 (m, 2H, CH2)
3.88 (s, 3H, CH3)
5c
5d
8.27 (br)
8.24 (d)
7.33 (m)
7.29 (m)
7.33 (m) 7.89 (m)
7.29 (m) 8.08 (m)
2.83 (s, 3H, CH3)
1.42 (m, 3H, CH3),
4.48 (br, 2H, CH2)
7.52 (br s, 2H, NH2)
7.53 (br s, 2H, NH2)
b
5e
8.05 (br)
7.00a(br)
7.07a(t)
7.38 (d) 11.23 (br, 1H, NH)
–
aAn alternative assignment of signals is possible.
bThe signal merges with that of the solvent (DMSO‐d6).
Table 4
8‐Acetyl‐2‐N‐(R2,R3)‐3‐R1‐8H‐thieno[2,3‐b]indoles (16a–d).
Comp.
4‐H
7.48a
5‐H
6‐H
7‐H
8‐Ac
2‐N‐R2,R3
3‐R1
16a
7.15 (t)
7.28 (t)
7.90 (m)
2.83 (s, 3H, CH3)
2.94 (m, 4H, 2CH2), 3.68 (m,
4H, 2CH2)
7.66 (d, 2H, 2′,6′‐Ph),
7.48a(t, 2H, 3′5′‐Ph),
7.38 (t, 1H, 4′‐Ph)
16b
7.51 (d)
7.15 (t)
7.27 (t)
7.90 (m)
2.80 (s, 3H, CH3)
2.93 (m, 4H, 2CH2), 3.69 (m,
4H, 2CH2)
2.44 (s, 3H, CH3), 7.56 (d,
2H, 2′,6′‐Ph), 7.28 (d, 2H,
3′5′‐Ph)
16c
16d
7.44 (d)
7.64 (m)
7.23(t)
7.26a
7.36 (t)
7.29a
8.09 (d)
7.81 (m)
2.86 (s, 3H, CH3)
1.53 (m, 2H, CH2), 1.55 (m, 4H, 7.94 (d, 2H, 2′,6′‐Ph), 8.38
2CH2), 2.88 (t, 4H, 2CH2)
1.47 (m, 2H, CH2), 1.56 (m, 4H,
2CH2), 3.37 (t, 4H, 2CH2)
(d, 2H, 3′5′‐Ph)
2.70 (br s, 3H, CH3)
–
aThe complex overlapping signals.
the same reaction was performed on short heating in an
isopropanol solution of the same species, thienoindole 16a
was isolated in 33% yield. Under the same conditions,
thienoindoles 16b–d were obtained in 28, 39, and 50% yields,
respectively (Scheme 9).
and 1650–1660 cm−1, respectively. The N‐acetyl groups
in aminothienoindoles 5a–c manifest themselves at
1660–1670 cm−1; those in N,N‐dialkylaminothienoindoles
16a–c, 16d and the NCOOEt group in thienoindole 5d have
higher frequencies, 1660 and 1740 cm−1, respectively. The
1H‐ and 13C‐NMR data are in accord with the structures of
thienoindoles 5 and 16 (Tables 3 and 4).
It is obvious that the first step of the process is S‐alkylation
of a thioamide with bromoacetylindoxyl 2 to afford the
corresponding α‐thioiminoketone salts 19A,B (Scheme 9).
The salt undergoes cyclization to give hydroxydihy-
drothienoindole 20 followed by both dehydration of the
latter and splitting of HBr to furnish thienoindole 16. This
is in line with our earlier findings that cyclic hydroxy‐
containing intermediates of 20 type are readily formed
in the course of the synthesis of thiazolo[5,4‐b]indoles
and imidazo[4,5‐b]indoles from bromoacetylindoxyl 2
[8,45,46]. The above process takes place when the reac-
tion is conducted in the absence of a base. The compet-
itive formation of the Eschenmoser‐type thiirane 18
followed by its further transformations seems more likely
in the presence of a base.
A general peculiarity of the 1H‐NMR spectra of
N‐acetylthienoindoles 16a–d (Table 3) measured at RT is
a remarkable broadening of the signals of the indole protons,
which lie at about 200 Hz for the 7‐H of the compound 16b
(T = 25°C). Upon increasing the temperature, the signals be-
come narrower indicating that this broadening is associated
with a dynamic process, hindered rotation of the acetyl group
about the N8‐CAc amide bond.
CONCLUSIONS
It is of considerable general preparative interest that
secondary/primary amines in the presence of elemental
sulfur induce the ring opening of acetylindoxyl 1 in a single
step, under mild conditions, affording pharmacologically
interesting thioamides of 2‐acetylaminophenylglyoxylic
acid 6 or 7 and, as a rule, in good yields. The pathway of
The IR spectra of thienoindoles 5a–e show absorption
bands in the range of 3200–3420 cm−1 associated with
the NH2 groups. The nitrile and ester groups of thienoin-
doles 5a–e have typical stretching modes at 2195–2200
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 A Versatile Approach for the Synthesis of 8H‐Thieno[2,3‐b]indoles and N‐[2‐(2‐N‐(R1R2)‐2‐Thioxoacetyl)‐
phenyl]acetamides from 1‐Acetyl‐1,2‐dihydro‐3H‐indol‐3‐one (Acetylindoxyl) and Its Derivatives
and 150.93 (13C) MHz in DMSO‐d6 solutions. Chemical shifts
this process was shown to involve the formation of inter-
mediates 1‐acetyl‐2‐thioisatin 8 and/or 1‐acetyl‐indoxyldi-
sulfide 9. Thioamides 6a,b were demonstrated to undergo
are given in ppm from residual proton signals from deuterated
solvent as the internal standard (1H‐2.54, 13C‐40.45 ppm). IR
spectra were recorded on a Perkin‐Elmer 457 apparatus. Elemen-
cyclization to 2,2‐disubstituted indoxyls 13a,b in moderate
tal analyses were performed with a Perkin‐Elmer recorder.
yields upon their alkylation with methyl iodide in the pres-
ence of potassium hydroxide. This cyclocondensation also
shows possibilities of thioamides 6a–e to serve as the key
N‐[2‐(2‐N‐(R1,R2)‐Thioxoacetyl)‐phenyl]acetamides (6a–e),
8‐acetyl‐2‐amino‐8H‐thieno[2,3‐b]indole‐3‐carbonitrile (5a),
and N‐[2‐(butylimino‐butylthiocarbamoyl‐methyl)‐phenyl]
intermediates in the synthesis of various derivatives of in-
doxyl and indole series. The thioamides 6a–e are under
study at the Colorado State University as potential antitu-
berculosis drugs. Already some have displayed appreciable
antituberculosis activity against Mycobacterium tuberculo-
sis H37Rv with the MIC values ranging between 5 and
21 μg/mL. A novel method for 1‐acetyl‐3‐indolylmalononitrile
14a and methyl 1‐acetyl‐3‐indolylcyanoacetate 14c,e
syntheses based on acetylindoxyl 1 condensation with
malononitrile or cyanoacetates is offered. It is rather simple
and the process proceeds under mild conditions in high‐to‐
good yields. The protocol may be used for the synthesis of
a variety of the compounds of this series. In some key aspects,
these protocols are more advantageous than current ones.
We also report on a method for the synthesis of thienoin-
doles 5 in a single step from fully heteroaromatic activated
nitriles such as 3‐indolylmalononitrile 14a and the
corresponding 3‐indolylcyanoacetates, 14c or 14e. 2‐Ami-
nothienoindoles 5 bearing COMe/COOEt substituent in
position 1 of the ring system were prepared from nitriles
14 by means of a novel modification of the Gewald reac-
tion with elemental sulfur in the presence of a tertiary
amine in low‐to‐high yields (80–25%). Although the yield
of thieno[2,3‐b]indoles from this modification of the
Gewald aminothiophene synthesis is somewhat low, the
simplicity of the method makes it suitable for preparative
purposes. Besides, purification of all fused indoles
obtained does not require any chromatographic procedures.
The approach offers advantages for application in the syn-
thesis of other sulfur‐containing compounds of this series.
We also offer a simple, quick, and high‐ to satisfactory‐
yielding syntheses of 2‐N,N‐dialkylaminothienoindoles 16
from bromoacetylindoxyl 2 (available starting material)
and demonstrate their potential as intermediates in the syn-
thesis of other sulfur heterocycles.
acetamide (7) (Tables 1 and 3). Method A. A mixture of
acetylindoxyl 1 (1.75 g, 10 mmol), sulfur (0.48 g, 15 mmol),
malononitrile 3a (1.0 g, 15 mmol), and morpholine 4a (1.31 g,
15 mmol) was boiled in 2‐propanol (20 mL) for 3 h. After
cooling, the crystals were filtered off and washed with
dichloromethane (5 mL) and toluene (20 mL). Thienoindole 5a
(0.23 g) was obtained in a yield of 9%, mp 276–278°C
(decomp.); IR: 1665 (COMe), 2200 (CN), 3200, 3400 (NH2) cm−1;
13C‐NMR: δ 24.7, 72.0, 115.2, 116.2, 117.7, 120.3, 123.0, 123.6,
124.0, 136.7, 165.0, 167.3 ppm; ms: m/z 255 (M+). Anal. Calcd. for
C13H9N3OS: C, 61.16; H, 3.55; N, 16.46; S, 12.56. Found: C,
61.21; H, 3.54; N, 16.50; S, 12.64.
The filtrate was concentrated by evaporation, and the residue is
crystallized from toluene. Thioamide 6a (1.78 g, 61%) was
obtained, mp 192–194°C; IR: 1640 (COMe), 1695 (CO), 3290
(NH) cm−1 13C‐NMR: δ 25.0, 47.1, 52.0, 65.5, 65.8, 118.8,
;
120.7, 123.0, 133.3, 136.0, 141.6, 169.1, 190.1, 192.4 ppm; ms:
m/z 292 (M+). Anal. Calcd. for C14H16N2O3S: C, 57.52; H, 5.52;
N, 9.58; S, 10.97. Found: C, 57.55; H, 5.47; N, 9.60; S, 10.93.
The use of piperidine 4b (1.28 g, 15 mmol) gave 5a (0.22 g,
8%) and thioamide 6b (55%), mp 157–159°C; IR: 1640 (COMe),
1690 (CO), 3300 (NH) cm−1; ms: m/z 290 (M+). Anal. Calcd. for
C15H18N2O2S: C, 62.04; H, 6.25; N, 9.65; S, 11.04. Found: C,
62.11; H, 6.18; N, 9.69; S, 11.09.
Method B. A mixture of acetylindoxyl 1 (1.75 g, 10 mmol),
sulfur (0.48 g, 15 mmol), and morpholine 4a (1.74 g, 20 mmol)
was boiled in 2‐propanol (20 mL) for 3 h. After cooling, the
crystals were filtered off and recrystallized from toluene.
Thioamide 6a (2.21 g, 76%) was obtained.
The use of piperidine 4b (1.70 g, 20 mmol) gave 6b (1.94 g,
67%). The use of butylamine 4c (1.46 g, 20 mmol) results in 7
(1.17 g, 35%), mp 147–149°C; IR: 1660 (COMe), 3160
(NH) cm−1 1H‐NMR: δ 0.92* (3H, CH3), 0.92* (3H, CH3),
;
1.36 (m, 2H, CH2), 1.44 (m, 2H, CH2), 1.63 (m, 2H, CH2),
1.72 (m, 2H, CH2), 2.11 (s, 3H, COCH3), 3.18, 3.55 (t, 2H,
CH2), 3.68 (br, 2H, CH2), 7.09 (t, 1H, 4‐H), 7.42* (1H, 3‐H),
7.42* (1H, 5‐H), 8.59 (d, 1H, 6‐H), 10.88 (br d, 1H, NH),
13.21 ppm (s, 1H, NH) *complex overlapping signals; 13C‐
NMR: δ 13.8, 13.9, 20.0, 20.4, 25.2, 29.3, 32.7, 44.0, 51.7,
119.1, 119.6, 122.2, 131.3, 140.7, 167.9, 168.7, 192.5 ppm; ms:
m/z 333 (M+). Anal. Calcd. for C18H27N3OS: C, 64.83; H, 8.16;
N, 12.60; S, 9.61. Found: C, 64.78; H, 8.08; N, 12.59; S, 9.57.
When the reaction was run in an argon atmosphere, compounds
6a–c were chromatographically detected using Silufol UV‐254
plates and chloroform–acetone (20:1) mixture as an eluent.
Method C. A mixture of 9 (2.05 g, 5 mmol) and morpholine
4a (1.04 g, 12 mmol) was boiled in dioxane (10 mL) for 2 h. The
solvent was removed in vacuo, and the residue was crystallized
from an ethanol–water mixture. 6a (2.28 g, 78%) was obtained.
Thus, acetylindoxyl 1 and some of its derivatives have
been successfully used as available and versatile starting
materials in the synthesis of pharmacologically interesting
thieno[2,3‐b]indoles and “opened” thioamides.
EXPERIMENTAL
Melting points are uncorrected. Mass spectra of all compounds
except 9 and 13 were recorded on a Finnigan Polaris Q apparatus
(70 eV). FAB mass spectra of compounds 9 and 13 were recorded
on a Jeol JMS DX300 in a matrix of meta‐nitrobenzilic alcohol
The use of piperidine 4b (1.02 g, 12 mmol) gave 6b (2.03 g,
70%). When the reaction was run in the presence of the equimolar
amount of malononitrile 3a, the yields of compounds 4a,b were
78 and 70%, respectively.
1
using xenon as an ionizing gas. H‐ and 13C‐NMR spectra were
recorded on a Bruker Avance‐600 spectrometer at 600.22 (1H)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

V. S. Velezheva, A. Y. Lepyoshkin, K. F. Turchin, I. N. Fedorova, A. S. Peregudov,
and P. J. Brennan
Vol 50
Method D. A mixture of 8 (2.05 g, 10 mmol) and morpholine
4a (1.04 g, 12 mmol) was mixed for 20 min in dioxane (10 mL) at
RT. The solvent was removed in vacuo, and the residue was
recrystallized from an ethanol–water mixture. 6a (2.65 g, 91%)
was obtained.
SCH3), 2.90 (br, 4H, 2CH2), 3.62 (m, 4H, 2CH2), 7.18 (t, 1H,
5‐H), 7.64 (t, 1H, 6‐H), 7.69 (d, 1H, 4‐H), 8.53 ppm (d, 1H, 7‐H);
13C‐NMR: δ 12.2, 25.4, 47.0, 66.7, 89.1, 118.0, 122.0, 123.8,
125.1, 138.9, 152.4, 171.1, 195.6 ppm; ms: (FAB) m/z 306 (M+).
Anal. Calcd. for C15H18N2O3S: C, 58.80; H, 5.92; N, 9.14; S,
10.47. Found: C, 58.80; H, 5.89; N, 9.12; S, 10.41.
The use of piperidine 4b (1.02 g, 12 mmol) gave 6b (2.51 g,
87%). The use of n‐butylamine 4c (0.88 g, 12 mmol) results in
6c (2.50 g, 90%), mp 149–151°C; IR: 1650 (COMe), 1675
(CO), 3050, 3200, 3300 (NH) cm−1; ms: m/z 278 (M+). Anal.
Calcd. for C14H18N2O2S: C, 60.41; H, 6.52; N, 10.06; S, 11.52.
Found: C, 60.46; H, 6.46; N, 10.02; S, 11.45.
The use of 6b (1.45 g, 5 mmol) yielded 13b (0.68 g, 45%),
1
mp 89–91°C; IR: 1675 (COMe), 1720 (CO) cm−1; H‐NMR: δ
1.37 (m, 2H, CH2), 1.45 (m, 4H, 2CH2), 1.84 (s, 3H, COCH3),
2.61 (s, 3H, SCH3), 2.73 (br, 4H, 2CH2), 7.28 (t, 1H, 5‐H),
7.70 (d, 1H, 4‐H), 7.77 (t, 1H, 6‐H), 8.43 ppm (d, 1H, 7‐H);
ms: (FAB) m/z 304 (M+). Anal. Calcd. for C16H20N2O2S: C,
63.13; H, 6.62; N, 9.20; S, 10.53. Found: C, 63.19; H, 6.55; N,
9.17; S, 10.48.
The use of N‐methylpiperazine 4d (1.20 g, 12 mmol) yields in
6d (2.68 g, 88%), mp 176–179°C; IR: 1640 (COMe), 1700 (CO),
3280 (NH) cm−1
;
ms: m/z 305 (M+). Anal. Calcd. for
8‐Acetyl‐2‐amino‐8H‐thieno[2,3‐b]indole‐3‐carbonitrile (5a).
Method B. A mixture of acetylindoxyl 1 (1.75 g, 10 mmol), sulfur
(0.48 g, 15 mmol), malononitrile 3a (1.0 g, 15 mmol), and
triethylamine (1.5 g, 15 mmol) was boiled in 2‐propanol (20 mL)
for 1 h. Dichloromethane (5 mL) was added to the cooled reaction
mixture, and the crystals were filtered off and washed with toluene.
5a, 1.34 g (52%) was obtained.
Method C. A mixture of 14a (0.5 g, 2.2 mmol), sulfur (0.11 g,
3.4 mmol), and triethylamine (0.33 g, 3.3 mmol) was boiled in
2‐propanol (5 mL) for 1 h. The crystals precipitated were filtered
off and washed with toluene. 5a, 0.45 g (80%) was obtained. The
use of morpholine as a base gave 5a, 0.45 g (80%).
Ethyl 8‐acetyl‐2‐amino‐8H‐thieno[2,3‐b]indole‐3‐carboxylate
(5b). A mixture of acetylindoxyl 1 (1.75 g, 10 mmol), sulfur
(0.64 g, 20 mmol), 3b (2.26 g, 20 mmol), and triethylamine
(2 g, 20 mmol) was boiled in 2‐propanol (15 mL) for 3 h. The
reaction mixture was cooled and kept overnight. The crystals
precipitated were filtered off and recrystallized from
toluene and then from dioxane. The yield was 10% (0.3 g), mp
220–222°C (decomp.); IR: 1660 br (COMe, COOEt), 3300,
3420 (NH); ms: m/z 302 (M+). Anal. Calcd. for C15H14N2O3S:
C, 59.59; H, 4.67; N, 9.27; S, 10.60. Found: C, 59.65; H,
4.61; N, 9.30; S, 10.63.
C15H19N3O2S: C, 58.99; H, 6.27; N, 13.76; S, 10.50. Found: C,
58.92; H, 6.20; N, 13.79; S, 10.44.
The use of isopropylamine 4e (0.70 g, 12 mmol) gave 6e (2.38
g, 90%), mp 212–214°C; IR: 1660 (COMe), 1670 (CO), 3200,
3300 (NH) cm−1
;
ms: m/z 264 (M+). Anal. Calcd. for
C13H16N2O2S: C, 59.07; H, 6.10; N, 10.60; S, 12.13. Found: C,
59.12; H, 6.03; N, 10.61; S, 12.10.
When the reaction was run in the presence of the equimolar
amount of malononitrile 3a, the yields of compounds 6a,b were
91 and 87%, respectively.
1‐Acetyl‐2‐thioxo‐1,2‐dihydro‐3H‐indol‐3‐one (8). A solution
of Na2S2O3 pentahydrate (2.0 g, 8.0 mmol) in water (10 mL) was
added to a solution of bromoindoxyl 2 (2.0 g, 7.9 mmol) in
dioxane (20 mL). The reaction mixture was stirred at RT for
20 min. Sodium acetate (0.66 g, 8 mmol) and iodine (2.10 g,
8.3 mmol) were added to the reaction mixture. The mixture was
stirred for 40 min, diluted with water (15 mL), and the
precipitated crystals were filtered off. The yield was 72%
(1.17 g), mp 182–184°C (decomp.); IR: 1690 (COMe), 1730
(CO) cm−1; ms: m/z 205 (M+). Anal. Calcd. for C10H7NO2S: C,
58.52; H, 3.44; N, 6.82; S, 15.62. Found: C, 58.47; H, 3.40; N,
6.81; S, 15.65.
2,2′‐Dithiobis(1‐acetyl‐1,2‐dihydro‐3H‐indol‐3‐one) (9). A
solution of Na2S2O3 pentahydrate (2.0 g, 8.0 mmol) in water
(10 mL) was added to a solution of bromoindoxyl 2 (2.0 g,
7.9 mmol) in dioxane (20 mL). The reaction mixture was stirred
at RT for 20 min. Sodium acetate (0.33 g, 4.0 mmol) and iodine
(1.05 g, 4.1 mmol) were added to the reaction mixture. The
mixture was stirred for 20 min, and the precipitated crystals were
filtered off and recrystallized from dioxane. The yield was 45%
(0.73 g), mp 212–214°C (decomp.); IR: 1685 (COMe), 1720
(CO) cm−1; ms: (FAB) m/z 412 (M+). Anal. Calcd. for
C20H16N2O4S2: C, 58.24; H, 3.91; N, 6.79; S, 15.55. Found: C,
58.30; H, 3.88; N, 6.73; S, 15.58.
(1‐Acetyl‐1H‐indol‐3‐yl)malononitrile (14a). A mixture of
acetylindoxyl 1 (1.75 g, 10 mmol), triethylamine (1.5 g, 15 mmol),
and malononitrile 3a (0.99 g, 15 mmol) was boiled in acetonitrile
(20 mL) for 1 h. Then, acetic acid (2.0 mL) and water (15 mL)
were added to the reaction mixture. After cooling, the crystals
were filtered off. The yield was 88% (1.96 g). The yield in
2‐propanol was 73% (1.63 g), mp 164–166°C; 13C‐NMR: δ 20.1,
24.3, 107.4, 113.2, 116.9, 118.8, 124.7, 126.6, 126.7, 127.8,
135.6, 170.2 ppm; ms: m/z 223 (M+). Anal. Calcd. for
C13H9N3O: C, 69.95; H, 4.06; N, 18.82. Found: C, 69.82; H,
4.05; N, 18.89.
Methyl (1‐acetyl‐1H‐indol‐3‐yl)cyanoacetate (14c). A
mixture of acetylindoxyl 1 (1.75 g, 10 mmol), triethylamine (1.5 g,
15 mmol), and 3c (1.49 g, 15 mmol) was boiled in acetonitrile
(20 mL) for 5 h. Acetic acid (2.0 mL) was added to the
reaction mixture. The solvent was removed in vacuo. The
residue was recrystallized from a 2‐propanol–water mixture.
The yield was 72% (1.84 g). The yield in 2‐propanol was
67% (1.72 g), mp 124–126°C; IR: 1720 (COMe), 1750
(COOMe), 2260 (CN) cm−1; ms: m/z 256 (M+). Anal. Calcd.
for C14H12N2O3: C, 65.62; H, 4.72; N, 10.93. Found: C,
65.65; H, 4.70; N, 10.91.
1‐Acetyl‐2‐(methylthio)‐2‐morpholin‐1‐yl‐1,2‐dihydro‐
3H‐indol‐3‐one (13a) and 1‐acetyl‐2‐(methylthio)‐2‐
piperidin‐1‐yl‐1,2‐dihydro‐3H‐indol‐3‐one (13b). A solution
of KOH (0.7 g, 12.5 mmol) in methanol (10 mL) was added to a
solution of thioamide 6a (1.46 g, 5 mmol) and methyl iodide
(1.42 g, 10 mmol) in dimethylformamide (15 mL). The reaction
mixture was stirred at RT for 30 min and poured into water
(50 mL). The reaction product was extracted with dichloromethane
(3 × 10 mL); the extract was washed with water and dried over
Na2SO4. Dichloromethane was evaporated, and the residue was
recrystallized from a benzene–petroleum ether mixture. The yield
of 13a was 52% (0.80 g), mp 121–122°C; IR: 1680 (COMe),
Methyl (1H‐indol‐3‐yl)cyanoacetate (14e). Method A. A
mixture of acetylindoxyl 1 (1.75 g, 10 mmol), triethylamine
(1.5 g, 15 mmol), and 3c (1.49 g, 15 mmol) was boiled in
1
1720 (CO) cm−1; H‐NMR: δ 1.88 (s, 3H, COCH3), 2.71 (s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 A Versatile Approach for the Synthesis of 8H‐Thieno[2,3‐b]indoles and N‐[2‐(2‐N‐(R1R2)‐2‐Thioxoacetyl)‐
phenyl]acetamides from 1‐Acetyl‐1,2‐dihydro‐3H‐indol‐3‐one (Acetylindoxyl) and Its Derivatives
methanol (20 mL) for 5 h. A solution of acetic acid (2.0 mL) in
water (40 mL) was added to the reaction mixture. After cooling,
Methyl 2‐amino‐8H‐thieno[2,3‐b]indole‐3‐carboxylate
(5e). A mixture of 14e (0.43 g, 2 mmol), sulfur (0.25 g,
7.8 mmol), and triethylamine (0.37 g, 3.6 mmol) in
dimethylformamide (2.5 mL) was stirred at RT for 5 days.
The sulfur residue was filtered off, a benzene–petroleum ether
(1:1) mixture (5 mL) was added to the filtrate, and the
reaction mixture was diluted with water (15 mL). The crystals
precipitated were filtered off and recrystallized twice from a
benzene–petroleum ether mixture. The yield of 5e was 5%
(0.025 g), mp 179–181°C; IR: 1660 (COOMe), 3290, 3400
(NH, NH2) cm−1; ms: m/z 246 (M+). Anal. Calcd. for
C12H10N2O2S: C, 58.52; H, 4.09; N, 11.37; S, 13.02. Found:
C, 58.61; H, 4.07; N, 11.42; S, 13.07.
the crystals were filtered off and recrystallized from
a
methanol–water mixture. The yield was 62% (1.33 g), mp 122–
124°C; IR: 1740 (COOMe), 2260 (CN), 3420 (NH) cm−1; ms:
m/z 214 (M+). Anal. Calcd. for C12H10N2O2: C, 67.28; H, 4.71;
N, 13.08. Found: C, 67.25; H, 4.70; N, 13.02.
Method B. A solution of 14c (0.5 g, 2.0 mmol) and
triethylamine (0.20 g, 2.0 mmol) in methanol (5 mL) was kept
at RT for 24 h. Then, acetic acid (0.3 mL) and water (15 mL)
were added to the reaction mixture. The crystals precipitated
were filtered off and recrystallized from a methanol–water
mixture. The yield was 21% (0.09 g).
Ethyl (1‐carboethoxy‐1H‐indol‐3‐yl)cyanoacetate (14d).
Compound 14d (mp 71–73°C) was obtained from 3‐
indolylacetonitrile and diethylcarbonate by the method given in
ref. 38.
8‐Acetyl‐2‐N‐(R3,R4)‐3‐R2‐8H‐thieno[2,3‐b]indoles (16a–d)
(Table 4). Bromoindoxyl 2 (2.54 g, 10 mmol) was added to a
boiling solution of a corresponding thioamide 17a–d (10 mmol)
in 2‐propanol (40 mL), and the mixture was boiled for 7 min.
After cooling, the product was crystallized for several hours. The
crystals precipitated were filtered off and washed with
isopropanol. The yield of 16a was 33% (1.24 g), mp 182–184°C;
IR: 1675 (COMe) cm−1; ms: m/z 376 (M+). Anal. Calcd. for
C22H20N2O2S: C, 70.19; H, 5.35; N, 7.44; S, 8.52. Found: C,
70.25; H, 5.32; N, 7.41; S, 8.50.
Methyl 8‐acetyl‐2‐amino‐8H‐thieno[2,3‐b]indole‐3‐carboxylate
(5c). Method A. A mixture of 14c (1.0 g, 3.9 mmol), sulfur (0.5 g,
15.6 mmol), and triethylamine (0.73 g, 7.2 mmol) was boiled in
2‐propanol (7 mL) for 10 h. The solvent was removed in vacuo.
The reaction product obtained was recrystallized from toluene
and then from a toluene–dioxane mixture. 5c (0.022 g, 2%)
was obtained, mp 236–238°C (decomp.); IR: 1650 (COMe),
1670 (COOMe), 3310, 3440 (NH2) cm−1; ms: m/z 288 (M+).
Anal. Calcd. for C14H12N2O3S: C, 58.32; H, 4.20; N, 9.72; S,
11.12. Found: C, 58.34; H, 4.16; N, 9.69; S, 11.18.
The yield of 16b was 28% (1.09 g), mp 164–166°C; IR: 1680
(COMe) cm−1; ms: m/z 390 (M+). Anal. Calcd. for C23H22N2O2S:
C, 70.74; H, 5.68; N, 7.17; S, 8.21. Found: C, 70.82; H, 5.63; N,
7.20; S, 8.19.
Method B. Sulfur (0.5 g, 15.6 mmol) and triethylamine (0.73 g,
7.2 mmol) were added to a solution of 14c (1.0 g, 3.9 mmol) in
DMSO (7 mL). The reaction mixture was stirred at 75°C for 5 h.
Triethylamine was removed in vacuo, unreacted sulfur was
filtered off, then benzene (10 mL) was added to the filtrate, and
the reaction mixture was diluted with water (15 mL). The
mixture was stirred for 30 min, and the crystals precipitated were
filtered off, washed with methanol, and recrystallized from
dioxane. The yield was 20% (0.22 g).
The yield of 16c was 39% (1.63 g), mp 204–206°C; IR: 1680
(COMe) cm−1; ms: m/z 419 (M+). Anal. Calcd. for C23H21N3O3S:
C, 65.85; H, 5.05; N, 10.02; S, 7.64. Found: C, 65.86; H, 4.99; N,
9.97; S, 7.69.
The yield of 16d was 50% (1.62 g), mp 212–215°C; IR: 1720
(COMe), 2195 (CN) cm−1; ms: m/z 323 (M+). Anal. Calcd. for
C18H17N3OS: C, 66.85; H, 5.30; N, 12.99; S, 9.91. Found: C,
66.89; H, 5.26; N, 13.03; S, 10.00.
Method C. A mixture of 14c (0.5 g, 2 mmol), sulfur (0.25 g,
7.8 mmol), and triethylamine (0.37 g, 3.6 mmol) in
dimethylformamide (2.5 mL) was stirred at RT for 10 days, the
sulfur residue was filtered off, benzene (5 mL) was added to
the filtrate, and the reaction mixture was diluted with water
(10 mL). The mixture was stirred for 30 min, and the crystals
precipitated were filtered off and washed with methanol. The
yield was 21% (0.12 g).
Acknowledgments. This research was partially supported by a
grant (RB2‐2032) from the U.S. Civilian Research and
Development Foundation (CRDF).
REFERENCES AND NOTES
Method D. A mixture of 14c (0.5 g, 2 mmol), sulfur (0.25 g,
7.8 mmol), and triethylamine (0.37 g, 3.6 mmol) in acetonitrile
(2.5 mL) was stirred at RT for 10 days. The reaction mixture
was diluted with water (3 mL), and the crystals precipitated
were filtered off, washed with methanol, and put into boiling
toluene (10 mL). The suspension was boiled for 5 min, cooled,
and the product obtained was filtered off. The yield was 25%
(0.14 g).
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