Synthesis of substituted thiazolo[4,5-b]pyridines and other annulated heterocycles via SN2→Thorpe-Ziegler→Thorpe-Guareschi domino reactions

Article abstract of DOI:10.1016/j.tet.2010.09.045

A new combinatorial method for the preparation of substituted thiazolo[4,5-b]pyridines, which utilizes cyanoacetamide, heterocumulenes (isothiocyanates, carbon bisulfide), and ethyl-4-chloroacetoacetate in a new S_N2→Thorpe-Ziegler→Thorpe-Guareschi domino reactions has been developed. The obtained thiazolo[4,5-b]pyridines were then used together with aldehydes and malononitrile in another Knoevenagel reaction→Michael reaction→hetero-Thorpe-Ziegler domino reaction for the synthesis of substituted 4,6-dihydro-5H-pyrano[2,3-d]thiazolo[4,5-b]pyridines.

Full text of DOI:10.1016/j.tet.2010.09.045

Tetrahedron 66 (2010) 8945e8948
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Tetrahedron
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Synthesis of substituted thiazolo[4,5-b]pyridines and other annulated
heterocycles via SN2/ThorpeeZiegler/ThorpeeGuareschi domino reactions
*
Anatoliy M. Shestopalov , Liudmila A. Rodinovskaya, Alexander A. Shestopalov
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991, Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 July 2010
Received in revised form 22 August 2010
Accepted 13 September 2010
Available online 18 September 2010
A new combinatorial method for the preparation of substituted thiazolo[4,5-b]pyridines, which utilizes
cyanoacetamide, heterocumulenes (isothiocyanates, carbon bisulfide), and ethyl-4-chloroacetoacetate in
a new SN2/ThorpeeZiegler/ThorpeeGuareschi domino reactions has been developed. The obtained
thiazolo[4,5-b]pyridines were then used together with aldehydes and malononitrile in another Knoe-
venagel reaction/Michael reaction/hetero-ThorpeeZiegler domino reaction for the synthesis of
substituted 4,6-dihydro-5H-pyrano[2,3-d]thiazolo[4,5-b]pyridines.
Keywords:
Domino reactions
Ó 2010 Elsevier Ltd. All rights reserved.
Ethyl-4-chloroacetoacetate
Thiazolo[4,5-b]pyridines
5H-Pyrano[2,3-d]thiazolo[4,5-b]pyridines
1. Introduction
2. Results and discussion
Substituted thiazolo[2,3-b]pyridines represent an important
class of annulated heterocycles with diverse types of pharmaceu-
tical1 and pesticide2 activity. The practical significance of thiazolo
[4,5-b]pyridines stimulates the continuous development of syn-
thetic methods for the preparation of these compounds,3 including
combinatorial approaches via solution and solid-phase syntheses.4
The majority of known synthetic methods for substituted thia-
zolo[4,5-b]pyridines are two-stage protocols.2 As such, at the first
stage either the thiazole or pyridine cycle is constructed. The sec-
ond stage of the synthesis is usually the intermolecular cyclo-
condensation reaction, which forms the second pyridine or thiazole
ring. There are also examples of substituted thiazolopyridines
obtained from N-cyanoiminothiolate salts and polyfunctional halo-
alkanes, where the primary preparation of 5-substituted 4-amino-
thiazoles is followed by intramolecular cyclization, which forms the
second preannulated pyridine cycle.4,5 This approach also permits
synthesis of 2-R-amino(thio)thiazolopyridines from the corre-
sponding salts of N-cyanoiminothiolates and 4-bromoacetoacetic
ester without the isolation of intermediates.5 In general approaches
that rely on the preliminary synthesis and isolation of N-cyanoimi-
nothiolate salts usually restrict the variety of substituents in 2-R-
amino(thio)thiazolopyridines, result in the formation of by-products,
and have a low yield of the final thiazolopyridines.
In this study we describe a new one-pot method of synthesis of
substituted 7-hydroxy[1,3]thiazolo[4,5-b]pyridine-5(4H)-ones using
new SN2/ThorpeeZiegler/ThorpeeGuareschi domino reactions.
Several types of domino reactions (see works of Prof. L.F. Tietze6) are
very well described in literature and are routinely used in the syn-
thesis of various heterocyclic compounds, including some natural
products. However, the reactions presented in this study were not
previously described and their synthetic potential is not yet known.
We used cyanoacetamide 1, heterocumulenes (isothiocyanates
2, carbon bisulfide 3), and ethyl-4-chloroacetoacetate 4 as starting
reagents for our domino reactions. One of the distinctive features of
the proposed method is the direct generation of mercaptonitrile
salts 5 in the reaction mixture without their preliminary synthesis
and isolation (Scheme 1).
We discovered that high yield of the final products can be
achieved by introducing the starting reagents to the reaction
mixture in a specific sequence and by maintaining a certain tem-
perature regime (Scheme 1). As such, salt 5 was generated in EtOH
from equimolar amounts of compounds 1, 2 or 1, 3 and KOH at
20 ꢀC. Ethyl-4-chloroacetoacetate 4 was then added to the reaction
mixture, followed by an additional equimole of a KOH solution in
EtOH. Subsequently, the reaction mixture was refluxed for 30 min
to form 2-(R-amino)-7-hydroxy[1,3]thiazolo[4,5-b]pyridin-5(4H)-
ones (9), which were isolated in 70e82% yields after acidification of
the reaction mixture with HCl.
Under these conditions, the formation of compounds 9 proceeds
with high regioselectivity, which is a result of the specific sequence of
* Corresponding author. Tel.: þ7 499 135 8804; e-mail address: shchem@dol.ru
(A.M. Shestopalov).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.045

8946
A.M. Shestopalov et al. / Tetrahedron 66 (2010) 8945e8948
CN
EtOH, KOH,
20oC, 1 h
N
EtOH, KOH,
20oC, 1 h
H2N-CN + R-N=C=S
2a-g
H2N-CN + S=C=S
Z
SK
1
1
3
5
4
ClCH2COCH2COOC2H5 ( )
SN2
H
N
EtOH, KOH,
reflux,30 min
NH2
O
O
C
S
N
N
N
N
COOC2H5
Z
Z
COOC2H5
Thorpe-Ziegler
S
Z
S
O
OK
Thorpe-Guareschi
7
6
8
HBr
HCl
H
N
H
N
H
N
O
O
O
N
HN
R1-Hal (11)
N
K
R1S
S
S
S
RHN
S
OH
12a-j
OH
OH
10
9a-g
Scheme 1. Synthesis of substituted 7-hydroxy[1,3]thiazolo[4,5-b]pyridin-5(4H)-ones. Z¼NHR, SK. 2, 9: R¼CH3 (a); CH3CH2 (b); CH2CH]CH2 (c); C6H5 (d); 4-OCH3eC6H4 (e); 3-
CleC6H4 (f); 3-FeC6H4 (g). 11, 12: R1¼CH3 (a); CH3CH2 (b); CH2e3-C5H4N (c); CH2e2,6-Cl2eC6H3 (d); CH2e3,4-F2eC6H3 (e); CH2e3-CF3eC6H4 (f); CH2eCOe3,4-(OCH3)2eC6H3 (g);
CH2eCONHeAd1 (h); CH2eCONHe3,4-F2eC6H3 (i); CH2eCONHe2-CF3eC6H4 (j).
domino reactions: SN2 (intermediate 6)/ThorpeeZiegler reaction
(intermediate 7)/ThorpeeGuareschi reaction (intermediate 8).
A unique combinatorial aspect of the developed protocol is the
ability to prepare a solution of thiazolo[4,5-b]pyridine-2-thiolate 10
and, without isolating the intermediate, use it in the subsequent
SN2 reaction for the synthesis of pyridin-5(4H)-ones 12. This ap-
proach significantly simplifies the preparation of compounds 12
and avoids the isolation and purification of intermediates 5, 7.4,5
Moreover, an almost 2-fold increase in the yield of 2-(R-thio)-thio-
thiazolo[4,5-b]pyridinones 12 can probably be attributed to the
absence of the 2-alkylthiolate hydrolysis in molecules 12. Unlike
previously described protocols,4,5 in our method the alkylation
reaction was carried out at the end of the synthesis rather than at the
beginning.
Salt 5 (Z¼SK) was generated in ethanol from cyanoacetamide 1
and carbon bisulfide 3 in the presence of 2 mol of KOH. Salt 5 was
then reacted with ester 4 via the SN2 mechanism to form in-
termediate 6. The subsequent intramolecular ThorpeeZiegler and
ThorpeeGuareschi cyclizations proceeded via the formation of in-
termediate 7 to give di-potassium salt 8 (Z¼SK). This transition
from salt 5 to salt 8 forms the basis of our domino reaction. Then
the reaction mixture was acidified with HCl to obtain a solution of
salt 10, which was divided into equal volumes and equimolar
amounts of various R-Hal 11 were added to the solutions. The
formed precipitates of compounds 12 were isolated by filtration.
The high regioselectivity of the final alkylation reaction is probably
related to the higher nucleophilicity of the exocyclic sulfur atom
compared to the nitrogen or oxygen atoms. A similar behavior of
the conjugated thiolato heterocycles in SN2 reactions has been
observed in the past.7
10.85e11.88 ppm, respectively. In some cases NH protons were not
resolved due to deuterium exchange. The multiplicity and position
of the proton signals indicate that compounds 9 and 12 exist in
a DMSO solution in the same tautomeric form.
In the 13C NMR spectra, the presence of the characteristic signals
of the C2, C5, C6, and C7 atoms at
d 164.2e169.8, 162.9e167.7,
90.7e94.7, and 160.8e165.4 ppm, respectively, also confirms the
structures of 9 and 12.
Compounds 9 and 12 represent convenient building blocks for
the synthesis of previously unknown substituted 4,6-dihydro-5H-
pyrano[2,3-d][1,3]thiazolo[4,5-b]pyridines 18. The interest in new
synthetic pathways toward 2-amino-3-cyano-4H-pyranes is related
to their anticancer activity.8 We based a new synthetic method for
annulated pyranes on the domino reactions of the following type:
Knoevenagel reaction/Michael reaction/hetero-ThorpeeZiegler
reaction.
As such, compounds 18 were synthesizedin s singlereaction flask
by mixing equimolar amounts of starting compounds 9aed or 12a,
corresponding aldehyde 13, malononitrile 14, and Et3N as a catalyst
in DMF (Scheme 2). The reaction was carried out at 90e100 ꢀC for
w20 min.
All added reagents reacted with each other sequentially in
a domino process. Most likely, unsaturated nitrile 15 was formed
first in the Knoevenagel reaction. Subsequently, anion 16 reacted
with nitrile 15 in the Michael reaction to form adduct 17, which
cyclized to pyrane 18 via the ThorpeeZiegler mechanism. This re-
action sequence was partially confirmed by the use of unsaturated
nitriles 15 in the synthesis of pyranes, and by the isolation of
Michael adducts 17 and their subsequent cyclization into pyrans.5
The structures of compounds 18 were confirmed by NMR and
FTIR spectroscopy, and elemental analysis. A characteristic feature
of the IR spectra of heterocycles 18 is the presence of the high-in-
tensity stretching absorption bands of the C^N and NH2 groups at
2188e2204 and 3160e3452 cmꢁ1, respectively. Such absorption
bands are characteristic of the IR spectra of compounds containing
the conjugated enaminonitrile moiety (H2NeC]CeCN). The
bending absorption band of the NH2 group overlaps with the
absorption bands of the NH and C(O) groups.
The structures of the obtained compounds 9 and 12 were con-
firmed by NMR and FTIR spectroscopy, and elemental analysis. A
characteristic feature of the IR spectra of 9 and 12 is the presence of
stretching and bending absorption bands of the C(O)NH and NH
groups in the region 1612e1676 cmꢁ1 and 2980e3470 cmꢁ1. The
absence of characteristic absorption bands of the C^N, C]O, and
NH2 groups for intermediates 5e7 also indicates high regiose-
lectivity of the reaction. The 1H NMR spectra of compounds 9 and
12 contain, along with the proton signals of R and NH groups, the
signals of C6H, N4H, and OH protons at 5.14e5.77 ppm and
The 1H NMR spectra of compounds 18 show signals of NH2 and
C6H protons as singlets in the
d 6.95e7.319 and 4.28e4.70 ppm

A.M. Shestopalov et al. / Tetrahedron 66 (2010) 8945e8948
8947
H
N
4.2. 7-Hydroxy-2-(R-thio)[1,3]thiazolo[4,5-b]pyridin-5(4H)-
ones 12aej
DMF, Et3N,
O
90-100oC, 20 min
N
+
ArCHO
+
CH2(CN)2
14
R2
S
Knoevenagel
13a-i
Cyanoamide (1) (2.1 g, 0.05 mol) was added to a solution of 2.8 g
(0.05 mol) of KOH in 100 mL of EtOH with stirring at 20 ꢀC. Sub-
sequently, the reaction mixturewas quenched with3.0 mL (0.05 mol)
of carbon disulfide (3) after 2 min and a solution of 2.8 g (0.05 mol) of
KOH in 100 mL of EtOH after another 2 min. The reaction mixture was
stirred at 20 ꢀC for 1 h; then, 50 mL of water was added. Next, 6.7 mL
(0.05 mol) of chloroacetoacetic ester (4) was added dropwise at
a temperature of 10e12 ꢀC with intense stirring for 45 min. The
resulting solution was diluted with 20 mL of water and filtered
through a filter. A solution of 2.8 g (0.05 mol) of KOH in 100 mL of
EtOH was added to the filtered reactionmixture. Thereactionmixture
was refluxed for 30 min with stirring, it was then cooled down to
20 ꢀC, and 5.8 mL (0.05 mol) of hydrobromic acid (density of 1.49 g/
mL) was added. The reaction mixture was filtered again through
folded filter and a 40% aqueous ethanol solution was added to the
resulting solution to obtain 330 mL of the reaction mixture.
OH
9a-d,12a
H
H
N
N
O
O
NC
C
N
N
N
Ar
R2
S
R2
S
Ar
Michael
OH
O
17
15
16
C
N
CN
hetero-Thorpe-Ziegler
H
N
O
O
N
Ar
R2
S
CN
NH2
18a-q
The resulting solution of compound 10 was used in 10 different
syntheses with 30-mL portions placed in individual flasks. As such,
corresponding alkyl halide 11 (0.0045 mol) was added to each por-
tion at 20 ꢀC with stirring, and the reaction mixture was brought to
the boiling point. A precipitate was formed. The reaction mixture
was kept at 5 ꢀC overnight and the precipitate was filtered off and
sequentially washed with water (2ꢂ10 mL), ethanol (2ꢂ5 mL), and
hexane (2ꢂ10 mL). Compounds 12 were obtained in 98e100% purity.
Scheme 2. Synthesis of substituted 4,6-dihydro-5H-pyrano[2,3-d][1,3]thiazolo[4,5-b]
pyridines. 9: R2¼NHCH3 (a);NHCH2CH3 (b); NHCH2CH]CH2 (c); NHC6H5 (d).12: R2¼SCH3
(a).13: Ar¼C6H5 (a); 4-CleC6H4 (b); 4-BreC6H4 (c); 4-OCH3eC6H4 (d); 2,3-(OCH3)2eC6H3
(e); 4-COOCH3eC6H4 (f); 2-C4H3S (g); 3-C5H4N (h); 4-C5H4N (i). 18: R2¼NHCH3, Ar¼C6H5
(a); R2¼NHCH3, Ar¼2,3-(OCH3)2eC6H3 (b); R2¼NHCH3, Ar¼4-COOCH3eC6H4 (c);
R2¼NHCH3, Ar¼2-C4H3S (d); R2¼NHCH3, Ar¼4-C5H4N (e); R2¼NHCH2CH3, Ar¼4-CleC6H4
(f); R2¼NHCH2CH3, Ar¼4-OCH3eC6H4 (g); R2¼NHCH2CH3, Ar¼4-COOCH3eC6H4 (h);
R2¼NHCH2CH3, Ar¼2-C4H3S (i); R2¼NHCH2CH3, Ar¼3-C5H4N (j); R2¼NHCH2CH3, Ar¼4-
C5H4N (k); R2¼NHCH2CH]CH2, Ar¼4-COOCH3eC6H4 (l); R2¼NHCH2CH]CH2, Ar¼3-
C5H4N (m); R2¼NHC6H5, Ar¼4-BreC6H4 (n); R2¼NHC6H5, Ar¼4-OCH3eC6H4 (o);
R2¼SCH3, Ar¼3-C5H4N (p); R2¼SCH3, Ar¼4-C5H4N (q).
4.3. 8-Amino-6-aryl-7-cyano-5-oxo-4,6-dihydro-5H-pyrano
[2,3-d][1,3]thiazolo[4,5-b]pyridines 18aeq
regions. A characteristic feature of the 13C NMR spectra of com-
pounds 18 is the presence of signals of C6 and C^N carbons in the
A mixture of compounds 9aed or 12a (0.002 mol) was first
quenched with aldehydes 13 (0.002 mol) and malononitrile 14
(0.13 g, 0.002 mol) in 15 mL of DMF, and then with triethylamine
(0.5 mL). The reaction mixture was heated at 90e100 ꢀC for 20 min
and then filtered hot. Filtrate was cooled down and kept in a
refrigerator (5 ꢀC) overnight. The formed precipitate was filtered off
and washed with hot water (2ꢂ10 mL), ethanol (2ꢂ5 mL), and
hexane (2ꢂ15 mL). Compounds 18 were recrystallized from 1,4-
dioxane or nitromethane.
d
31.7e36.9 and 119.2e120.0 ppm regions. The position of the C8]
C7 carbon signals at 158.5e159.3 and 56.7e58.6 ppm indicates the
presence of a enaminonitrile moiety (H2NeC8]C7eCN) in 18 with
the p/d-electron conjugation.
3. Conclusions
In conclusion, we have developed several domino-type protocols:
(1) SN2 reaction/ThorpeeZiegler reaction/ThorpeeGuareschi re-
action and (2) Knovenagel reaction/Michael reaction/hetero-
ThorpeeZiegler reaction, which by themselves or in combinations
significantly extend combinatorial potential for the synthesis of new
complex heterocyclic systems.
Acknowledgements
This work was supported in part by the Russian Foundation for
Basic Research, grant no. 09-03-00349.
4. Experimental
Supplementary data
4.1. 2-(R-Amino)-7-hydroxy[1,3]thiazolo[4,5-b]pyridin-5(4H)-
ones 9aeg
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.09.045. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
Cyanoamide (1) (0.42 g, 0.01 mol) was added to a solution of
0.56 g (0.01 mol) of KOH in 20 mL of EtOH with stirring at 20 ꢀC,
and 0.01 mol of corresponding isothiocyanate 2 was added after
a minute. The reaction mixture was stirred at 20 ꢀC for 1 h; then,
1.37 mL (0.01 mol) of chloroacetoacetic ester (4) was added, and
a solution of 0.56 g (0.01 mol) of KOH in 20 mL of EtOH was added
after 5 min. The reaction mixture darkened, and its temperature
increased to w60 ꢀC. Next, the reaction mixture was refluxed with
stirring for 30 min; the mixture was cooled to 20 ꢀC with contin-
uous stirring for 3 h. Then,15 mL of water was added to the reaction
mixture, and the contents were acidified with a 10% solution of HCl
to pH 7. The resulting precipitate was filtered off, and successively
washed with water (2ꢂ15 mL), ethanol (2ꢂ10 mL), and hexane
(2ꢂ15 mL). Compounds 9 were recrystallized from ethanol or
nitromethane.
References and notes
1. (a) Lin, R.; Johnson, S. G.; Connolly, P. J.; Wetter, S. K.; Binnun, E.;
Hughes, T. V.; Murray, W. V.; Pandey, N. B.; Moreno-Mazza, S. J.; Adams, M.;
Fuentes-Pesquera, A. R.; Middleton, S. A. Bioorg. Med. Chem. Lett. 2009, 19,
2333e2337; (b) Kulkarni, S. S.; Newman, A. H. Bioorg. Med. Chem. Lett. 2007, 17,
2987e2991; (c) Komoriya, S.; Kobayashi, S.; Osanai, K.; Yoshino, T.; Nagata, T.;
Haginoya, N.; Nakamoto, Y.; Mochizuki, A.; Nagahara, T.; Suzuki, M.; Shimada, T.;
Watanabe, K.; Isobe, Y.; Furugoori, T. Bioorg. Med. Chem. 2006, 14, 1309e1330; (d)
Walczynski, K.; Zuiderveld, O. P.; Timmerman, H. Eur. J. Med. Chem. 2005, 40, 15e23.
2. Litvinov, V. P.; Dozenko, V. V.; Krivokolysko, S. G. The Chemistry of Thienopyr-
idines In. Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Elsevier Aca-
demic: Amsterdam, 2007; Vol. 93, pp 117e178.
3. (a) Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.; Morales, G. A.; Thomas, C. J.;
Zhang, W. J. Comb. Chem. 2009, 11, 739e790; (b) Dolle, R. E.; Le Bourdonnec, B.;
Goodman, A. J.; Morales, G. A.; Thomas, C. J.; Zhang, W. J. Comb. Chem. 2008, 10,

8948
A.M. Shestopalov et al. / Tetrahedron 66 (2010) 8945e8948
753e800; (c) Dolle, R. E.; Le Bourdonnec, B.; Goodman, A. J.; Morales, G. A.;
Salvino, J. M.; Zhang, W. J. Comb. Chem. 2007, 9, 855e902; (d) Lee, T.; Lee, D.;
7. Shestopalov, A. M.; Rodinovskaya, L. A.; Shestopalov, A. A. J. Comb. Chem. 2010,
12, 9e12.
Lee, I. Y.; Gong, Y. D. J. Comb. Chem. 2010, 11, 95e99.
8. (a) Wood, D. L.; Panda, D.; Wiernicki, T. R.; Wilson, L.; Jordan, M. A.; Sing, J. P.
Mol. Pharmacol. 1997, 52, 437e444; (b) Kasibhatla; Gourdeau, H.; Meerovitch, K.;
Drewe, J.; Reddy, L.; Qiu, H.; Zhang, F.; Bergeron, F.; Bbouffard, D.; Yang, Q.;
Herich, J.; Lamothe, S.; Cai, S. X.; Tseng, B. Mol. Cancer Ther. 2004, 3, 1365e1374;
(c) Gourdeau, H.; Leblond, L.; Hamelin, B.; Desputeau, C.; Dong, K.; Kianicka, I.;
Custeau, D.; Bondreau, C.; Geerts, L.; Cai, S.-X.; Drewe, J.; Labrecque, D.;
Kasibhatla, S.; Tseng, B. Mol. Cancer Ther. 2004, 3, 1375e1385; (d) Litvinov, Y. M.
Dissertation. Institute of Organic Chemistry, RAS: Moscow, 2009 [in Russian].
4. (a) Artemov, V. A.; Ivanov, V. L.; Shestopalov, A. M.; Litvinov, V. P. Tetrahedron
1997, 53, 13351e13360; (b) Ivanov, V. L.; Artemov, V. A.; Shestopalov, A. M.;
Nesterov, V. N.; Struchkov, Y. T.; Litvinov, V. P. Chem. Heterocycl. Compd. (NY)
1996, 413e419.
€
5. Walek, W.; Gotzschel, K. J. Prakt. Chem. 1979, 321, 260e269.
6. Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis;
Wiley-VCH : Weinheim, 2006; 617 p.