Combinatorial synthesis of substituted thieno[3,2-b]pyridines and other annulated heterocycles via new SN2 → thorpe - ziegler → - thorpe - guareschi domino reactions

Full text of DOI:10.1021/cc9001372

J. Comb. Chem. 2010, 12, 9–12
9
Combinatorial Synthesis of Substituted
Thieno[3,2-b]pyridines and Other Annulated
Heterocycles via New SN2 f Thorpe-Ziegler
f Thorpe-Guareschi Domino Reactions
Anatoliy M. Shestopalov,* Lyudmila A. Rodinovskaya,
and Alexander A. Shestopalov
N.D. Zelinsky Institute of Organic Chemistry, Russian
Academy of Sciences, 119991 Moscow, Russian Federation
Figure 1. Possible approaches toward thieno[3,2-b]pyridines.
γ-aminobutyric acid receptor,13 immunomodulators,2,4,13 Ca
channel inhibitors,13,21 and herbicides.13
ReceiVed August 30, 2009
Considering the practical importance of thieno[3,2-b]py-
ridines and a limited number of methods available for their
synthesis, we decided to developed a new regioselective
protocol for preparation of these compounds based on a
domino-type reaction. The reaction includes the following
consecutive steps: the SN2 reaction f the Thorpe-Ziegler
reaction f the Thorpe-Guareschi reaction, and significantly
differs from the well-known domino pathways previously
described by Tietze.22
Thieno[3,2-b]pyridines were prepared by generating potas-
sium salts of 2-amino-2,2-dicyanoethylene-2-thiolate 3 from
isothiocyanates 1 and malonodinitrile (2) and reacting 3 with
4-chloroacetoacetic ester 4. We determined that the reaction
proceeds at elevated temperatures in the presence of potas-
sium ethoxide and gives thieno[3,2-b]pyridines 5a-h in high
yields (75-93%) after acidification of the reaction mixture
to pH ∼ 7 (Scheme 1).
Known methods of synthesis of thieno[3,2-b]pyridines are
significantly underrepresented compared to available infor-
mation on thieno[2,3-b]pyridines.1,2 Nevertheless, several
synthetic pathways toward thieno[3,2-b]pyridines have been
previously described in the literature.3-6
A thieno[3,2-b]pyridine structure can be approached via
several pathways (Figure 1), all of which require synthesis
or in situ generation of 3-aminothiophene. Pathway A was
developed by Gronowitz et al.7 It was successfully used to
prepare multiconjugated thieno[3,2-b]pyridines via the reac-
tion of ortho-halogenated pyridines with 3-tert-butoxycar-
bonylamino-2-trimethylstannylthiophene.8 Thieno[3,2-b]-
pyridines can also be synthesized via pathways B and C using
3-amino-2-carboxy thiophene and ꢀ-ethoxymethylene car-
bonyl compounds (derivatives of ethyl orthoformate and
malonodinitrile, acetoacetic ester, cyanoacetic ester, and
others).9-11 For example, the condensation of 3-amino
thiophene, triethyl orthoformate, and Meldrum’s acid was
used to prepare thieno[3,2-b]pyridines with anticancer activi-
ties.12 The reaction of 3-amino-2-carboxy thiophene and
4-fluorobenzoyl acetoacetic ester (pathway D) was employed
to obtain substituted thieno[3,2-b]pyridines, which were used
as intermediates in the synthesis of γ-aminobutyric acid
receptor modulators.13 Pathway E was used to synthesize
rare pyrrolothienopyridines by the reaction of 3-amidi-
nothiophene with maleic anhydride and the subsequent
oxidation of the Diels-Alder adduct.14
The IR spectra of compounds 5 contain a characteristic
absorption band of the conjugated cyano-group in the
2204-2216 cm-1 region. The NMR spectra of 5 show
corresponding R, NH, and OH signals, and includes a singlet
peak that corresponds to the C6H hydrogen atom in the
δ.5.15-6.06 ppm region. The IR spectra of 5 also demon-
strate an intense CONH absorption band in the 1612-1644
cm-1 region, which suggests that 5 also exist in a pyridine-
5(4H)-one tautomeric form, similar to pyridine-2(1H)-ones
[1].
Scheme 1
Thieno[3,2-b]pyridines can also be synthesized using an
alternative approach by attaching a thiophene ring to
pyridine.15-18 As such, they were prepared via a base
catalyzed reaction of 3-halogen-2-cyano(ethoxycarbonyl)-
methylene pyridine with heterocumulenes, isothiocyanates,
or carbon disulfide.16-18 Similarly, thieno[3,2-b]pyridines
annulated with pyridine or pyrimidine were prepared via a
one-step method using 3-cyanopyridine-2(1H)thiones (or
5-cyanopyridine-6(1H)thiones)and4-chloroacetoaceticester.19,20
Biological properties of thieno[2,3-b]pyridines are rela-
tively well studied. Very often, they tend to show higher
activities than isomeric thienopyridines.9,10,13 Substituted
thieno[3,2-b]pyridines are also known for their biologically
properties. Among them were found potential ligands for the
* Corresponding author. E-mail: shchem@dol.ru.
10.1021/cc9001372  2010 American Chemical Society
Published on Web 11/20/2009

10 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Reports
Scheme 2
The combinatorial potential of the described method is
determined by the number of available isothiocyanates and
derivatives of cyanoacetic acid (malonodinitrile, cyanothio-
acetamides). The potential of this reaction can be doubled
by substituting isothiocyanates with other heterocumulenes,
such as carbon disulfide. Moreover, the total possible
outcome of this method can be further expanded in geometric
progression by adding additional steps to the reaction

Reports
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 11
Scheme 3
sequence. Such a strategy opens new preparation pathways
not only toward substituted thieno[3,2-b]pyridines, but also
toward more complex multiconjugated heterocyclic systems
(Scheme 2).
Dipotassium 2,2,-dicyano-1,1-dithiolate (6a) or dipotas-
sium 2-cyano-2-carbamoyl-1,1-dithiolate (6b) were generated
in the ethanol solution by the reaction of malonodinitrile or
cyanothioacetamide (2b) with carbon disulfide in the pres-
ence of two equivalents of KOH (Scheme 2). Subsequently,
the reaction mixture was diluted with water (25% of total
volume) and slowly reacted with 1 equiv of 4-chloroac-
etoacetic ester under vigorous stirring at 10-12 °C. Under
such conditions, the SN2 reaction proceeds highly regiose-
lectively and gives intermediate 7 as the only product.
Consequently, KOH in the solution catalyzes the Thorpe-
Ziegler and Thorpe-Guareschi reactions and forms pyridine
ring 9.
To obtain compounds 12 and 13, the reaction mixture was
neutralized with 1 equiv of 48% HBr, filtered to remove an
inorganic salt, and diluted with ethanol. Subsequently, the
solution was divided into equal portions (up to 50 aliquots),
and each portion was reacted at room temperature with alkyl
halides 11a-x, 16 (method A). Intermediate 9 has several
nucleophilic centers, nonetheless, the reaction proceeds
highly regioselectively at the sulfur atom and forms thieno[3,2-
b]pyridine-5-ones 12, 13 in 38-93% yields. Similar selectiv-
ity was observed in the past for 2-amino-5-cyanopyrimidine-
6-thiolates,23 3-cyano-6-hydroxypyrimidine-2-thiolates,24
substituted 1,4-dihydropyridine-2-thiolates,20,25 and 1,2,3,4-
tetrahydro-2-oxopyridine-6-thiolates.26 Thieno[3′,2′:4,5]thi-
eno[3,2-b]pyridin-5(4H)-ones 14a,b were obtained without
initial acidification of the reaction mixture. As such, the
solution of 9 was reacted with R-halogen ketones 11b,c at
60-70 °C for 10 min and subsequently neutralized with an
excess of HCl. The formation of compounds 14 proceeds
via successive SN2 and the Thorpe-Ziegler reactions,
analogous to many other examples of the reactions between
cyanopyridine thiones and R-halogen ketones.1 New hetero-
cyclic systems 15 and 17 were obtained by reacting dipo-
tassium salt 9a with 4-chloroacetoacetic ester 4 or chloro-
acetyl urethane 16. Both of these reactions proceed via the
usual SN2 f Thorpe-Ziegler f Thorpe-Guareschi path-
way, which was supported by obtaining 17 upon refluxing
thieno[3,2-b]pyridine-5-one 12t in ethanol.
corresponding alkyl halogenides 11 to give compounds 18 in
good to high yields (73-92%, Scheme 3).
The structures of molecules 18 were supported by IR, 1H
NMR, 13C NMR, MS, and elemental analyses. The IR spectra
of 18 contain valent and deformation absorption bands of
the NH2-group at 1604-1632 and 3164-3428 cm-1, and
absorption bands of the COORs and conjugated CN-groups
at 1712-1740 and 2212-2218 cm-1. Probably, the CdO
group forms intramolecular hydrogen bond with the neigh-
boring NH2-group (Figure 2), which leads to the shift of the
CdO absorption band into the low region and its partial
overlap with the NH2 deformation band.
1
The H NMR spectra of compounds 18 contain charac-
teristic signals of Et, NH2, and Y-groups, and CH2(CO)
singlet signals at the 3.47-3.68 ppm. The 13C NMR spectra
show CdO signals at 151.62-155.25 ppm. This also
supports the hydrogen bond formation instead of the possible
enolization of the acetoacetic ester fragment.
Compounds 18a-d,f,g were converted into 12c,e-i in
62-75% yields via the Thorpe-Guareschi reaction under
refluxing in ethanol at the presence of a base (method B). When
compound 18g (Y ) COPh) was refluxed with an excess of a
base, it gave triannulated heterocycle 14b in a 70% yield.
Compound 5 has several reaction centers and, therefore,
can be further modified. Previously, we have demonstrated
that 4-hydroxypyridine-2(1H)-ones can be utilized in syn-
thesis of annulated 2-amino-4H-pyrans,20 some of which
have demonstrated an anticancer activity.27 Here, we utilized
compounds 5 in a similar reaction to prepare annulated
The structures of compounds 12, 13, 14, 15, and 17 were
confirmed by IR, NMR, and MS analyses (see the Supporting
Information). The IR spectra of 12 and 13 contain N4HC5dO
and CONH2 absorption bands in the 1584-1664 and
1
1640-1664 cm-1 regions. The H NMR spectra show a
broaden N4H signal at ∼11.9 ppm, which is characteristic
of all pyridine-2(1H)-thiones [1]. A 13C NMR signal of the
N4HC5dO fragment appears at 160-164 ppm, which sup-
ports the presence of the pyrimidone ring in 12 and 13.
By modifying the conditions, we confirmed to a certain extent
the sequence of reactions leading to compounds 12. As such,
when salt 6 was heated for several minutes with 4-chloroac-
etoacetic ester without the excess of KOH, the reaction stopped
at thienylacetoacetic ester 8a. Subsequently, the reaction mixture
was divided into several portions, which were reacted with
Figure 2. Intramolecular H-bond in ethyl 3-{3-amino-5-[R-meth-
ylenthio]-4-cyanothien-2-yl}-3-oxopropanoates.

12 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Reports
Scheme 4
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Most likely, this domino-type reaction proceeds via the
Knoevenagel f the Michael f and the Thorpe-Ziegler
steps. This is supported by the numerous examples of
stepwise pyrans syntheses, where unsaturated nitriles are first
prepared via the Knoevenagel reaction and then used in the
Michael reaction with 1,3-dicarbonyl compounds.20,27 Sub-
sequently, the resulting Michael adducts undergo cyclization
and 1,3-sigmatropic shift and form 2-amino-4H-pyrans 23.
The 1H NMR spectra of 23 contain NH2 and C6H singlets in
the 7.17-7.20 and 4.43-4.48 ppm regions. Similar to 5, 12,
14, 15, and 17, compounds 23 exist in a tautomeric form of
pyridine-5(1H)-ones. The 13C NMR spectra of 23 contain
characteristic C(O)NH signals at 158.25-158.77 ppm.
In conclusion, we have developed several domino-type
protocols: (1) SN2 reaction f Thorpe-Ziegler reaction f
Thorpe-Guareschi reaction, (2) double domino reaction SN2
reaction f Thorpe-Ziegler reaction f Thorpe-Guareschi
reaction, (3) SN2 reaction f Thorpe-Ziegler reaction, and
(4) Knoevenagel reaction f Michael reaction f hetero-
Thorpe-Ziegler reaction, which by themselves or in com-
binations significantly extend combinatorial potential for the
synthesis of new complex heterocycle systems.
Acknowledgment. This work was supported in part by
the Russian Foundation for Basic Research, grant no. 09-
03-00349. We are also grateful to Bruker Moscow for
providing us with a MicrOTOF II instrument for spectro-
metric measurements.
Supporting Information Available. Detailed experimen-
tal procedures and compound characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
CC9001372