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R.A. Irgashev et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 2. Previous and current synthetic strategies to construct thieno[3,2-b]indoles.
to report an alternative method for the preparation of 2-substi-
tuted thieno[3,2-b]indoles directly from 5-substituted methyl
3-aminothiophene-2-carboxylates through in situ formation of 3-
aminothiophenes, followed by their involvement in the Fischer
indole synthesis (Scheme 2). In turn, the required 3-aminothio-
phene-2-carboxylates were prepared in two steps starting from
the corresponding methyl ketones (Scheme 2, R = aryl, thien-2-yl
or styryl) by their sequential treatment with the Vilsmeier reagent
(POCl3-DMF complex) and hydroxylamine hydrochloride to form
3-substituted 3-chloroacrylonitriles [26], which further reacted
with methyl thioglycolate in the presence of NaOMe in a methanol
solution [27] according to the Fiesselmann method for thiophene
ring construction [28] (for experimental details see ESI).
Firstly, we studied behavior of 5-phenyl-3-aminothiophene
1aA, used as a model compound, in the Fischer reaction with
phenylhydrazine 2a. Amine 1aA is a known compound [19,22],
and it was prepared by us from 3-aminoester 1a in 95% yield via
its treatment with NaOH (4 equiv.) in i-PrOH-H2O (9:1, v/v) solu-
tion at reflux for 4 h, followed by neutralization of the reaction
mixture with acetic acid and its heating at 40 °C for 30 min to per-
form decarboxylation of the intermediate aminoacid. We found
that treatment of substrate 1aA with phenylhydrazine 2a (1.5
equiv.) in glacial acetic acid solution at reflux for 1 h give the
desired product 3a in 71% yield (Scheme 3), which confirmed our
assumption to use 3-aminothiophenes instead of thiophene-3
(2H)-ones to construct thieno[3,2-b]indoles via the Fischer
indolization. The presumable mechanism for this transformation
includes initial formation of iminium salt 1aB, its condensation
with 2a to give phenylhydrazone 1aC, and next Fischer indoliza-
tion to obtain the desired product 3a (Scheme 3).
isolation of the intermediate 3-aminothiophenes. To this end, ester
1a was saponified and the reaction mixture was concentrated
under reduced pressure. The obtained residue, containing sodium
salt of amino acid together with NaOH excess, was treated with
phenylhydrazine 2a (1.5 equiv.) in glacial acetic acid solution at
reflux for 1.5 h to afford compound 3a in 69% yield. In the same
manner, other 3-aminothiophene-2-carboxylates 1b-n, bearing
various aromatic as well as thien-2-yl fragments at C-5 position,
were successfully converted to 2-substituted thieno[3,2-b]indoles
3b-n in 50–77% yields (Scheme 4, Table 1). Thus, in comparison
with our previous protocol for the synthesis of thieno[3,2-b]indoles
3 from the thiophene-3(2H)-ones [25], the current approach pro-
vided us to obtain product 3a-c,e,n in higher yields (Table 1,
entries 1–3,5,14), while comparable yield was received for com-
pound 3d (Table 1, entry 4).
During this study, we also were able to synthesize 2-styryl-sub-
stituted thieno[3,2-b]indoles. To this end, 3-aminothiophene-2-
carboxylate 1o with styryl group at C-5 position was prepared
starting from benzylideneacetone in two steps similar to esters
1a-n (for experimental details see ESI). The standard saponification
of ester 1o, followed by treatment with phenylhydrazine 2a as well
as 4-carboxy- and 4-methylphenylhydrazines 2b and 2c afforded
2-styryl derivatives 3o-q in 42%, 40% and 44% yields, respectively
(Scheme 4, Table 1, entries 15–17). It should be noted, that all
thieno[3,2-b]indoles 3a-q, prepared using this approach, were iso-
lated in analytically pure form by filtration of the reaction mixtures
without any additional purification.
In summary, we have demonstrated new synthetic application
of 3-aminothiophenes as reagents for the preparation of thieno
The saponification of 3-aminoester 1a was carried out with
NaOH in aqueous i-PrOH instead of aqueous DMSO, which had
been previously used as a solvent to saponify the similar 3-hydrox-
ythiophene-2-carboxylate [25], since in that case a higher temper-
ature had been needed to proceed reaction due to initial formation
of the sodium 2-(methoxycarbonyl)thiophen-3-olate. In this con-
text, we decided to perform a direct transformation of 3-aminoth-
Scheme 4. Synthesis of 2-substituted thieno[3,2-b]indoles 3a-q.
iophene-2-carboxylates
1 to thieno[3,2-b]indoles 3 without
Scheme 3. Transformation of amine 1aA to thieno[3,2-b]indole 3a and its possible mechanism.
Please cite this article as: R. A. Irgashev, A. S. Steparuk and G. L. Rusinov, One-pot synthesis of 2-substituted thieno[3,2-b]indoles from 3-aminothiophene-
Irgashev, Roman A.
