A single-step preparation of thiazolo[5,4-b]pyridine- and thiazolo[5,4-c]pyridine derivatives from chloronitropyridines and thioamides, or thioureas

Article abstract of DOI:10.1002/jhet.185

(Chemical Equation Presented) A one-step synthesis of thiazolo[5,4-b] pyridines from an appropriately substituted chloronitropyridine and thioamide, or thiourea, is presented. In particular, the reaction was used to prepare a large number of 6-nitrothiazo

Full text of DOI:10.1002/jhet.185

November 2009
A Single-Step Preparation of Thiazolo[5,4-b]pyridine- and
Thiazolo[5,4-c]pyridine Derivatives from Chloronitropyridines
and Thioamides, or Thioureas
1125
Kiran P. Sahasrabudhe, M. Angels Estiarte, Darlene Tan,
Sheila Zipfel, Matthew Cox, Donogh J. R. O’Mahony,
William T. Edwards, and Matthew A. J. Duncton*
Evotec, Two Corporate Drive, South San Francisco, California 94080
*E-mail: mattduncton@yahoo.com
Received January 12, 2009
DOI 10.1002/jhet.185
Published online 27 October 2009 in Wiley InterScience (www.interscience.wiley.com).
A one-step synthesis of thiazolo[5,4-b]pyridines from an appropriately substituted chloronitropyridine
and thioamide, or thiourea, is presented. In particular, the reaction was used to prepare a large number
of 6-nitrothiazolo[5,4-b]pyridine derivatives, bearing hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl,
heteroaryl, and amine substituents at the 2-position. The reaction could also be extended to produce a
thiazolo[4,5-c]pyridine derivative and thiazolo[5,4-b]pyridines with alternative substituents on the
pyridinoid ring.
J. Heterocyclic Chem., 46, 1125 (2009).
INTRODUCTION
as tin(II) chloride, thiocyanate salts, thiophosgene,
organometallics, or bromine [14–18].
The thiazolo[5,4-b]pyridine nucleus is of interest to
those working in the agrochemical, pharmaceutical, and
materials industries [1]. For instance, compounds con-
taining a thiazolo[5,4-b]pyridine substructure have been
described as ligands, or modulators, of leukotriene A4
[2], VEGFR-2 [3], p38 MAP kinase [4], CCR3 [5], IAP
[6], PPAR [7], D4 [8], ubiquitin ligase [9], glucokinase
[10], JAK3 [11], and sirtuin [12] amongst others [13].
A number of methods to prepare thiazolo[5,4-b]pyridines
have been documented in the literature [1]. For example,
methods that construct the bicycle by formation of a
thiazole ring, include condensations of 3-amino-2-halo-
pyridine, or 3-amino-2-pyridone derivatives, with thio-
cyanates, thioamides, or thioesters [14], the oxidative
ring-closure of 3-aminopyridine thioamides or thioureas
[15], condensations with 3-aminopyridin-2-thiones [16],
and reactions of N-(2-pyridone-3-yl)acetamides with
phosphorous pentasulfide [17]. Recently, a cross-cou-
pling/cyclization sequence starting from N-(2-bromopyri-
din-3-yl)acetamide was also detailed [18]. In this article,
we would like to disclose a new, single-step synthesis of
the thiazolo[5,4-b]pyridine and thiazolo[4,5-c]pyridine
nuclei. The approach is based upon the reaction of a thi-
oamide, or thiourea, with an appropriately substituted
chloronitropyridine to give a number of interesting
thiazolopyridines in up to 60% yield (Fig. 1) [19].
In contrast to many literature methods of thiazolopyri-
dine synthesis, our method does not use reagents such
RESULTS AND DISCUSSION
Our initial interest in compounds based around
thiazolo[5,4-b]pyridines was stimulated by an examina-
tion of their potential use as modulators of ion-channel
activity [20]. Toward this end, we required access to a
number of 2-substituted-6-nitrothiazolo[5,4-b]pyridines.
Our first attempts targeted the preparation of ethyl 6-
nitrothiazolo[5,4-b]pyridine-2-carboxylate (3a). Fusing
2-chloro-3,5-dinitropyridine (1) with ethyl 2-amino-2-
thioxoacetate (2a) in a 1:2 ratio at 70ꢀC, then diluting
with xylene and heating at 140ꢀC gave the desired
product (3a) in a moderate yield after column chroma-
tography (Scheme 1). Subsequently, we found that the
reaction could be performed using sulfolane as a solvent
without any loss in efficiency (20% isolated yield). Sul-
folane was chosen as similar reactions have used this
solvent to give benzothiazole derivatives [21].
To investigate the scope of this ring-forming process,
a diverse set of thioamides was reacted with 2-chloro-
3,5-dinitropyridine to provide a range of thiazolo[5,4-
b]pyridines that would be of interest to the medicinal
chemist (Table 1). For example, it was found that this
method could give compounds with substituted alkyl
groups at the 2-position. The reaction was tolerant of a
number of functional groups in the alkyl side chain,
C
V
2009 HeteroCorporation

1126
K. P. Sahasrabudhe, M. A. Estiarte, D. Tan, S. Zipfel, M. Cox, D. J. R. O’Mahony,
W. T. Edwards, and M. A. J. Duncton
Vol 46
Scheme 1. Synthesis of ethyl 6-nitrothiazolo[5,4-b]pyridine-2-carboxy-
late. i. Fuse 70ꢀC, then dilute with xylene and heat to 140ꢀC (20%).
resulted in a comparable conversion compared with the
reference transformation (entry 1). Significantly, other
model transformations noticed that the use of heating
under microwave irradiation resulted in a reduced reac-
tion time, with no loss in isolated yield (Table 3,
entry 1). Indeed, the use of 4 equivalents of thioamide
starting material, together with microwave irradiation
resulted in an enhanced conversion compared to the
thermal conditions used previously (Table 3, entries 2–5
cf. Table 1 entries 3, 6, 7, and 15, respectively). This
improvement in yield was most likely due to a combina-
tion of factors, including a rapid initial reaction under
microwave conditions, resulting in a transient overshoot
in temperature, particularly when reactions were run at
high concentrations (ca. 1M; entry 5). In general, the
microwave reactions also gave cleaner mixtures, with
fewer by-products, which facilitated the purification pro-
cess of final compounds.
Figure 1. Some approaches to thiazolo[5,4-b]pyridines.
such as ester, ether, thioether, nitrile, and sulfone
(entries 1–7). Branching on the alkyl chain was also tol-
erated as demonstrated by the successful reaction to pro-
duce compounds (3i)–(3k) (entries 8–10). 2-Aryl and
heteroaryl derivatives were also accessible (entries 11–
13), as was the 2-amino thiazolopyridine (entry 14). The
parent hydrido compound (3o) was also produced (entry
15), although in this instance the final compound was
synthesized by reacting 2-chloro-3,5-dinitropyridine with
neat N,N-dimethylthioformamide at 60ꢀC, then diluting
with xylenes and refluxing overnight [22]. Yields for the
synthesis of 2-substituted-6-nitrothiazolo[5,4-b]pyridines
ranged from the moderate (ca. 40%) to the modest (10–
20%). Although the reactions seemed to progress
smoothly when followed by analytical techniques such
as LC/MS, obtaining material with acceptable purity
proved to be problematic in a number of cases. As
such, at least part of the lower isolated yield may be
attributable to difficulties with purification for many
compounds, since preparative high-performance liquid
chromatography, or repeated trituration, had to be used.
Nevertheless, the above one-step process could be used
to make compounds on a gram-scale, without any
reduction in yield, for a number of final compounds
(e.g., 3b and 3c).
Table 1
Synthesis of 6-nitrothiazolo[5,4-b]pyridines.
Entry
Product
R1
% Yielda
1
2
3
4
3a
3b
3c
3d
CO2Et
Me
20
43b
36
16
CH2OC(O)C(Me)3
CH2OC6H4OMe
(4-methoxy isomer)
CH2SPh
5
6
3e
3f
14
7
CH2CN
Attempts to optimize a model transformation, (2–3k),
by variation in solvent, or additives, did not result in
any improvement in conversion as measured by high-
performance liquid chromatography (Table 2). For
example, changing from sulfolane to a similarly polar
solvent such as DMF, DMSO, or NMP resulted in a
marked retardation in the formation of desired product
(entries 3–5) [23]. The use of diphenylether, ethanol, or
1,4-dioxane (entries 6–8) resulted in a moderate amount
of thiazolo[5,4-b]pyridine formation, although efficien-
cies were lower than for sulfolane. We next investigated
the influence of a small selection of additives on the
amount of product formation (entries 9–14), finding that
only the inclusion of scandium(III) triflate (entry 11)
7
8
3g
3h
3i
3j
3k
3l
3m
3n
3o
CH2SO2C(Me)3
CH(Me)OC(O)C(Me)3
CH(Ph)2
9
35
7
9
10
11
12
13
14
15
Cyclopropyl
Ph
2-Thienyl
4
20
20
6
3-Pyridyl
NH2
15
11c
H
a Performed using 1 equiv of compound (1) and 2 equiv of thioamide
(or thiourea) (2a)–(2n) in sulfolane at 100ꢁ110ꢀC.
b Performed using 1 equiv of compound (1) and 4 equiv of thioamide
(2b) in sulfolane at 100ꢀC.
c Performed using 1 equiv of compound (1) and 4.6 equiv of N,N-
dimethylthioformamide at 60ꢀC and then diluted with xylene and
refluxed.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009 A Single-Step Preparation of Thiazolo[5,4-b]pyridine- and Thiazolo[5,4-c]pyridine
Derivatives from Chloronitropyridines and Thioamides, or Thioureas
1127
Table 2
Table 4
Effect of solvent/additives on conversion for a model transformation.
Synthesis of thiazolo[5,4-b]pyridines.
Entry
Solvent
Additive
% Conversiona
Entry
Thioamide
Product
R1
% Yielda
1
2
Sulfolane
Sulfolane
DMF
None
None
None
44
20b
10
0
1
2
3
4
2b
2k
2n
2o
5a
5b
5c
5d
Me
Ph
49
26
46/10b
26
3
NH2
H
4
5
DMSO
NMP
None
None
4
a Reaction of (4) using 4 equiv of appropriate thioamide at 135ꢀC
under microwave irradiation.
6
7
Ph2O
EtOH
None
None
12
12
24
0
b Reaction performed using 2 equiv of thioamide (2n) at 130ꢀC (no
microwave irradiation).
8
9
1,4-Dioxane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
None
iPrNEt
DDQ
10
11
12
13
14
4
Sc(OTf)3
NaOAc
K2CO3
KI
39
0
absence of a nitro-group in the pyridinoid ring seemed
to be slightly beneficial in terms of isolated yield.
0
21
Reactions with substituted 2-chloro-3-nitropyrid-
ines. As a further extension of the reaction, we sought
to investigate the use of pyridine starting materials in
which a substituent other than nitro, or hydrogen, was
present. As can be seen from Table 5, a number of
interesting derivatives were prepared. The mildness of
the technique was illustrated in the preparation of thia-
zolo[5,4-b]pyridines incorporating a halogen (7a)–(7c)
(entries 1–3). The synthesis of such compounds is some-
what sparse in the chemical literature, and our approach
to the bromo- and iodo-analogues (entries 2 and 3) is
significant, as some thiazolopyridine syntheses may not
be able to provide such compounds (e.g., methods
involving metal-mediated approaches). Our methodology
is therefore attractive, as halogenated thiazolopyridines
are potentially useful building blocks for medicinal
chemistry libraries. For instance, compounds (7b) and
(7c) possess a halo- and amine handle for derivatization
(e.g., palladium-mediated reactions for halo-substituent;
a Reaction performed using 2 equiv of (2k). Conversion to (3k) was
based upon integration of peak area in LC/MS trace after 4 h at
100ꢀC.
b Reaction performed using 1 equiv of (2k).
Reactions with 2-chloro-3-nitropyridine. To explore
the potential of our method in providing thiazolo[5,4-
b]pyridines with only hydrogen substituents on the pyri-
dinoid ring, 2-chloro-3-nitropyridine (4) was reacted
with a representative selection of thioamides (2b, 2k,
2o) and with thiourea (2n) to provide cyclized products
(Table 4). Either thermal or microwave conditions could
be used to give thiazolo[5,4-b]pyridines (5a)–(5d) in up
to 49% yield. As can be seen when comparing the
entries in Table 4 to their counterparts in Table 1, the
Table 3
Microwave-assisted synthesis of 6-nitrothiazolo[5,4-b]pyridines.
Table 5
Synthesis of 2-aminothiazolo[5,4-b]pyridines.
Entry
Product
R1
% Yielda
1
2
3
4
5
3a
3c
3f
3g
3o
CO2Et
CH2OC(O)C(Me)3
CH2CN
CH2SO2C(Me)3
H
26
36b
16
18
50
Entry
Nitropyridine
Product
R1
% Yielda
1
2
3
4
5
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
6-Cl
6-Br
48
62
39
19
8
6-I
6-Me
5-OMe
a Reaction of (1) using 4 equiv of appropriate thioamide at 110–130ꢀC
under microwave irradiation.
b Reaction performed using 2 equiv of thioamide (2c) at 110–130ꢀC
under microwave irradiation (4 equiv of (2c) not performed).
a Reaction of (6a)–(6e) using 4 equiv of appropriate thioamide at
135ꢀC under microwave irradiation for 45 min.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1128
K. P. Sahasrabudhe, M. A. Estiarte, D. Tan, S. Zipfel, M. Cox, D. J. R. O’Mahony,
W. T. Edwards, and M. A. J. Duncton
Vol 46
Scheme 2. Preparation of 2-amainothiazolo[4,5-c]pyridine. i. Sulfo-
lane, 135ꢀC, microwave, 75 min (22%).
Scheme 3. Reaction with piperidine-1-carbothioamide. i. Sulfolane,
100ꢀC (9% 12 and 6% 3n).
amide, urea, and reductive alkylation reactions for the
amine group). Thus, chemical libraries with two points
of diversity could be envisaged around these scaffolds.
Compounds with alternative substituents on the pyridi-
noid ring, such as the 6-methyl and 5-methoxy deriva-
tives (7d) and (7e) (entries 4–5), were also prepared.
However, the reaction to give (7e) was particularly low
yielding (8%), which may be as a result of the
methoxy-group also being activated toward nucleophilic
substitution by the thiourea starting material.
related reductions with sulfur reagents, such as sulfides
(Zinin reduction), sodium dithionite, elemental sulfur,
and thiourea S,S-dioxide, have been used frequently
[24–27]. Of note in the reduction step is an apparent se-
lectivity in nitro-reduction for the postulated intermedi-
ates (10a)–(10o). Although some low yields encountered
in our synthesis meant that we cannot exclude the possi-
bility that both nitro groups in (10a)–(10o) are reduced,
the observed selectivity in reduction of (10a)–(10o) is
consistent with that seen for other 2-substituted-3,5-dini-
tropyridines, such as the reduction of 2-amino-3,5-dini-
tropyridine with sodium sulfide [28,29]. Evidence for
the type of reaction described earlier, as opposed to one
involving displacement of the nitro group from
intermediate (10a)–(10o), is provided in the preparation
of parent hydrido derivative (3o) using N,N-dimethylth-
ioformamide (Table 1, entry 15), and the formation of
both (12) and (3n) when 2-chloro-3,5-dinitropyridine (1)
is reacted with piperidine-1-carbothioamide (11)
(Scheme 3).
Reaction with 4-chloro-3-nitropyridine. As demon-
strated, thiazolo[5,4-b]pyridines can be synthesized with
diverse substituents on both the thiazole and pyridine
rings. To probe the utility of the reaction in providing
other isomeric thiazolopyridines, a synthesis of 2-amino-
thiazolo[4,5-c]pyridine (9) from 4-chloro-3-nitropyridine
(8) and thiourea (2n) was devised (Scheme 2). Heating
at 135ꢀC under microwave irradiation gave the desired
product (9) in 22% yield after column chromatography.
Thus, we believe that the reaction may have the poten-
tial to access other thiazolo[4,5-c]pyridine derivatives,
such as those with an alkyl- or aryl-group at the 2-posi-
tion, or those with substituents other than hydrogen on
the pyridinoid ring. However, investigations toward such
molecules were beyond the scope of our studies and
will await further experimentation. In addition, it would
also be desirable to explore the potential of forming
thiazolo[5,4-c]pyridines from 3-chloro-4-nitropyridine
precursors.
CONCLUSIONS
In conclusion, we have developed an expeditious new
single-step synthesis of the thiazolo[5,4-b]pyridine and
thiazolo[4,5-c]pyridine nuclei by condensing an appro-
priately substituted chloronitropyridine with a thioamide
or thiourea. The use of such conditions is complemen-
tary to existing techniques to thiazolopyridines and may
offer advantages in terms of scope, speed of synthesis,
and availability of starting materials. The single-step na-
ture of the reaction is particularly noteworthy, as many
established thiazolopyridine syntheses use multistep
routes, and frequently resort to toxic reactants, or
reagents requiring special handling conditions, to pre-
pare suitable starting materials or final products. Addi-
tionally, our method tolerates sensitive functionality in
the coupling partners, may be accelerated by the use of
microwave irradiation and is operationally simple to
perform, giving final products in moderate yield. The
synthesis outlined in this article will be of particular
interest to those in the medicinal, agrochemical, materi-
als, and heterocyclic fields, where thiazolo[5,4-b]- and
thiazolo[4,5-c]pyridines have found many uses.
The reaction pathway. Currently, we believe that
the reaction proceeds by an initial displacement of the
chloro-group followed by nitro-group reduction and
concomitant cyclization. For example, with 2-chloro-
3,5-dinitropyridine (1), displacement with an appropriate
thioamide gives intermediates (10a)–(10o) (Fig. 2).
Reductive cyclization of (10a)–(10o), on exposure to
excess thioamide in the reaction mixture, provides the
desired thiazolopyridines (3a)–(3o). Although nitro-
group reductions with thioamides, or thiourea, have not
been detailed extensively in the chemical literature,
Figure 2. Proposed reaction pathway.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009 A Single-Step Preparation of Thiazolo[5,4-b]pyridine- and Thiazolo[5,4-c]pyridine
Derivatives from Chloronitropyridines and Thioamides, or Thioureas
1129
1
(3f). H
EXPERIMENTAL
2-(6-Nitrothiazolo[5,4-b]pyridin-2-yl)acetonitrile
NMR (400 MHz; d6-DMSO) d 9.46 (d, J ¼ 2.4 Hz, 1H), 9.27
(d, J ¼ 2.4 Hz, 1H), 4.94 (s, 2H); 13C NMR (100 MHz; d6-
DMSO) d 165.9, 163.2, 144.4, 143.5, 142.7, 125.5, 115.9,
23.7; m/z ¼ 219.0 (M – 1).
All reagents except 1-amino-1-thiooxopropan-2-yl pivalate
and cyclopropanecarbothioamide were purchased from com-
mercial sources and used without further purification. 1-
Amino-1-thiooxopropan-2-yl pivalate (example 3h) and cyclo-
propanecarbothioamide (example 3j) were synthesized by
GVK Biosciences Private (Hyderabad, India). All microwave-
assisted reactions were performed with a CEM Discover S-
Class microwave with 48-position autosampler. Temperature
during microwave reactions was monitored by a vertically
sensored infrared temperature sensor, which comes as a stand-
ard feature of the CEM Discover S-Class system. All NMR
spectra are quoted in ppm relative to a tetramethylsilane inter-
nal standard, or by referencing on the chemical shift of the
deuterated solvent.
2-(tert-Butylsulfonylmethyl)-6-nitrothiazolo[5,4-b]pyridine
1
(3g). H NMR (400 MHz; d6-DMSO) d 9.41 (d, J ¼ 2.4 Hz,
1H), 9.28 (d, J ¼ 2.4 Hz, 1H), 5.35 (s, 2H), 1.42 (s, 9H); 13C
NMR (100 MHz; d6-DMSO) d 163.5, 163.3, 144.1, 143.4,
142.8, 125.8, 60.8, 51.7, 22.8; m/z ¼ 316.3 (M þ 1).
1
1-(6-Nitrothiazolo[5,4-b]pyridin-2-yl)ethyl pivalate (3h). H
NMR (400 MHz; d6-DMSO) d 9.45 (d, J ¼ 2.4 Hz, 1H), 9.21
(d, J ¼ 2.4 Hz, 1H), 6.16–6.21 (q, J ¼ 6.6 Hz, 1H), 1.70 (d,
J ¼ 6.6 Hz, 3H), 1.24 (s, 9H); 13C NMR (100 MHz; d6-
DMSO) d 176.6, 176.3, 162.5, 144.6, 143.4, 142.5, 125.6,
70.0, 38.3, 26.7, 19.9; m/z ¼ 310.4 (M þ 1).
1
General procedure for preparation of thiazolo[5,4-b]pyri-
dines under thermal conditions.
2-Benzhydryl-6-nitrothiazolo[5,4-b]pyridine (3i). H NMR
(400 MHz; d6-DMSO) d 9.40 (d, J ¼ 2.0 Hz, 1H), 9.17 (d,
J ¼ 2.0 Hz, 1H), 7.37–7.43 (m, 11H), 7.31–7.33 (m, 2H), 6.29
(s, 1H); 13C NMR (100 MHz; d6-DMSO) d 179.7, 164.0,
146.1, 144.2, 143.0, 141.6, 129.9, 129.8, 129.0, 128.5, 128.4,
126.2, 56.0; m/z ¼ 348.2 (M þ 1).
Preparation of (6-nitrothiazolo[5,4-b]pyridin-2-yl)methyl
pivalate (3c). A mixture of 2-chloro-3,5-dinitropyridine (1)
(5.1 g, 25 mmol) and 2-amino-2-thioxoethylpivalate (2c) (8.8
g, 50 mmol) in sulfolane (50 mL) was heated to 100–110ꢀC
under a nitrogen atmosphere and stirred for 2 h. After allowing
to cool to room temperature, the mixture was poured into
EtOAc (150 mL), and the organic layer was washed with H2O
(3 ꢂ 200 mL) and brine (1 ꢂ 100 mL). The organic layer was
dried (MgSO4), filtered, and the solvent removed under vac-
uum to leave a crude oil. The oil was purified by filtration
through a plug of silica eluting with EtOAc/hexanes (1:9–1:4)
to give a solid (ca. 6–7g). The solid was then triturated with
MeOH (ca. 20 mL) and filtered to give the desired product
(2.17g). Further product was obtained by concentrating the fil-
trate under vacuum and purifying by column chromatography
on silica gel using EtOAc/hexanes (0:1–1:4) as eluent to give
a solid (1.1 g). The solid was triturated with MeOH to give
further product (0.5g). Total yield 2.67 g (36%). 1H NMR
(400 MHz; CDCl3) d 9.46 (d, J ¼ 2.4 Hz, 1H), 9.00 (d, J ¼
2.4 Hz, 1H), 5.54 (s, 2H), 1.32 (s, 9H); 13C NMR (100 MHz;
CDCl3) d 177.4, 172.6, 163.6, 145.2, 143.1, 142.3, 125.1, 63.4,
38.9, 27.1; m/z ¼ 296.5 (M þ 1).
1
2-Cyclopropyl-6-nitrothiazolo[5,4-b]pyridine (3j). H NMR
(400 MHz; d6-DMSO) d 9.34 (d, J ¼ 2.4 Hz, 1H), 8.97 (d,
J ¼ 2.4 Hz, 1H), 2.66–2.72 (m, 1H), 1.34–1.39 (m, 2H), 1.25–
1.29 (m, 2H); 13C NMR (100 MHz; d6-DMSO) d 179.2,
162.6, 145.2, 143.2, 141.1, 123.6, 15.8, 12.9; m/z ¼ 222.1
(M þ 1).
1
6-Nitro-2-phenylthiazolo[5,4-b]pyridine (3k). H NMR (400
MHz; d6-DMSO) d 9.44 (d, J ¼ 2.0 Hz, 1H), 9.22 (d, J ¼ 2.0
Hz, 1H), 8.18–8.21 (m, 2H), 7.65–7.68 (m, 3H); 13C NMR
(100 MHz; d6-DMSO) d 158.3, 147.9, 142.0, 141.9, 141.5,
132.6, 129.4, 129.4, 127.5, 124.8; m/z ¼ 259.0 (M þ 1).
1
(3l). H
6-Nitro-2-(thiophen-2-yl)thiazolo[5,4-b]pyridine
NMR (400 MHz; CDCl3) d 9.37 (d, J ¼ 2.0 Hz, 1H), 8.95 (d,
J ¼ 2.0 Hz, 1H), 7.78–7.79 (m, 1H), 7.66–7.67 (m, 1H), 7.22–
7.23 (m, 1H); 13C NMR (100 MHz; d6-DMSO) d 146.4,
141.7, 136.1, 132.0, 131.0, 128.7, 124.0; m/z ¼ 263.0 (M – 1).
1
(3m). H
6-Nitro-2-(pyridin-3-yl)thiazolo[5,4-b]pyridine
NMR (400 MHz; d6-DMSO) d 9.47 (d, J ¼ 2.4 Hz, 1H), 9.36
(dd, J ¼ 2.0 and 0.8 Hz, 1H), 9.27 (d, J ¼ 2.4 Hz, 1H), 8.85
(dd, J ¼ 4.8 and 1.5 Hz, 1H), 8.55 (ddd, J ¼ 8.0, 2.0 and 1.5
Hz, 1H), 7.69 (ddd, J ¼ 8.0, 4.8 and 0.8 Hz, 1H); 13C NMR
(100 MHz; d6-DMSO) d 154.1, 149.2, 143.6, 136.2, 129.1,
126.4, 125.6, 100.5; m/z ¼ 259.2 (M þ 1).
1
Ethyl 6-nitrothiazolo[5,4-b]pyridine-2-carboxylate (3a). H
NMR (400 MHz; CDCl3) d 9.59 (d, J ¼ 2.4 Hz, 1H), 9.23 (d,
J ¼ 2.4 Hz, 1H), 4.62 (q, J ¼ 7.0 Hz, 2H), 1.53 (t, J ¼ 7.0
Hz, 3H); 13C NMR (100 MHz; CDCl3) d 164.0, 163.2, 159.4,
145.5, 144.6, 143.5, 127.7, 64.1, 14.2.
1
1
2-Methyl-6-nitrothiazolo[5,4-b]pyridine (3b). H NMR (400
6-Nitrothiazolo[5,4-b]pyridine-2-amine (3n). H NMR (400
MHz; d6-DMSO) d 9.38 (d, J ¼ 2.3 Hz, 1H), 9.25 (d, J ¼ 2.3
Hz, 1H), 2.91 (s, 3H); 13C NMR (100 MHz; CDCl3) d 172.4,
164.5, 145.7, 142.9, 141.5, 124.0, 21.4; m/z ¼ 196.2 (M þ 1).
2-(4-Methoxyphenoxymethyl)-6-nitrothiazolo[5,4-b]pyridine
MHz; d6-DMSO) d 8.93 (d, J ¼ 2.5 Hz, 1H), 8.34 (br. s, 2H),
8.26 (d, J ¼ 2.5 Hz, 1H); 13C NMR (100 MHz; d6-DMSO) d
168.0, 161.8, 147.0, 143.3, 136.5, 116.7; m/z ¼ 195.1 (M – 1).
6-Nitrothiazolo[5,4-b]pyridine (3o) [22]. A mixture of 2-
chloro-3,5-dinitropyridine (1) (8.0 g, 39 mmol) and N,N-dime-
thylthioformamide (14.5 mL, 178 mmol) was heated at 60ꢀC
for 3 h (a yellow precipitate was formed). Xylene (20 mL)
was added, and the mixture was heated to reflux for 4 h, then
stirred at room temperature for 18 h. The mixture was diluted
with EtOH (12 mL), filtered, and the solid recrystallized from
1
(3d). H NMR (400 MHz; d6-DMSO) d 9.45 (d, J ¼ 2.4 Hz,
1H), 9.21 (d, J ¼ 2.4 Hz, 1H), 7.07–7.09 (m, 2H), 6.90–6.92
(m, 2H), 5.64 (s, 2H), 3.71 (s, 3H); 13C NMR (100 MHz;
CDCl3) d 174.9, 163.7, 154.9, 151.4, 145.2, 142.9, 142.1,
124.9, 116.0, 114.8, 68.8, 55.6.
1
6-Nitro-2-(phenylthiomethyl)thiazolo[5,4-b]pyridine (3e). H
1
NMR (400 MHz; d6-DMSO) d 9.38 (d, J ¼ 2.0 Hz, 1H), 9.09
(d, J ¼ 2.0 Hz, 1H), 7.42–7.45 (m, 2H), 7.29–7.33 (m, 2H),
7.21–7.23 (m, 1H), 4.89 (s, 2H); 13C NMR (100 MHz; d6-
DMSO) d 175.7, 163.3, 144.8, 143.3, 142.2, 133.7, 129.3,
129.0, 127.0, 125.0, 35.6; m/z ¼ 302.2 (M – 1).
EtOH to give the product (800 mg, 11%) as a solid. H NMR
(400 MHz; d6-DMSO) d 9.82 (s, 1H), 9.49 (d, J ¼ 2.4 Hz,
1H), 9.27 (d, J ¼ 2.4 Hz, 1H); 13C NMR (100 MHz; d6-
DMSO) d 162.4, 161.8, 144.7, 143.1, 142.6, 125.8; m/z ¼
182.2 (M þ 1).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1130
K. P. Sahasrabudhe, M. A. Estiarte, D. Tan, S. Zipfel, M. Cox, D. J. R. O’Mahony,
W. T. Edwards, and M. A. J. Duncton
Vol 46
1
(12). H
1
6-Nitro-2-piperidin-1-yl-thiazolo[5,4-b]pyridine
6-Methylthiazolo[5,4-b]pyridin-2-amine (7d). H NMR (400
MHz; d6-DMSO) d 7.94 (d, J ¼ 1.2 Hz, 1H), 7.74 (br. s, 2H),
7.45 (d, J ¼ 1.2 Hz, 1H), 2.30 (s, 3H); 13C NMR (100 MHz;
d6-DMSO) d 165.8, 152.4, 146.7, 142.0, 130.4, 124.0, 17.8; m/
z ¼ 166.3 (M þ 1).
NMR (400 MHz; d6-DMSO) d 8.94 (d, J ¼ 2.3 Hz, 1H), 8.34
(d, J ¼ 2.3 Hz, 1H), 3.66–3.70 (m, 4H), 1.61–1.66 (m, 6H);
13C NMR (100 MHz; d6-DMSO) d 166.7, 159.5, 145.3, 141.9,
134.8, 115.7, 23.3, 21.9; m/z ¼ 264.8 (M þ 1). Separately, 6-
nitrothiazolo[5,4-b]pyridin-2-amine (3n) (13 mg, 6%) was also
isolated.
1
5-Methoxythiazolo[5,4-b]pyridin-2-amine (7e). H NMR
(400 MHz; CDCl3) d 7.69 (d, J ¼ 8.6 Hz, 1H), 6.72 (d, J ¼
8.6 Hz, 1H), 5.52 (br. s, 1H), 5.39 (br. s, 1H), 3.94 (s, 3H);
13C NMR (100 MHz; CDCl3) d 163.3, 160.6, 151.4, 140.2,
128.7, 108.8, 54.0; m/z ¼ 182.2 (M þ 1).
General procedure for reactions using microwave-
assisted synthesis.
Preparation of 6-nitrothiazolo[5,4-b]pyridine (3o). A 5-mL
microwave vial was charged with 2-chloro-3,5-dinitropyridine
(1) (0.41 g, 2.0 mmol), N,N-dimethylthioformamide (0.69 mL,
8.0 mmol), and sulfolane (2 mL). The mixture was heated
under microwave irradiation with a target temperature of
110ꢀC (CARE: the reaction displayed a significant exotherm
on heating and reached 130ꢀC within 25 s). After 2 min the
mixture had cooled to 110ꢀC, and heating was continued at
this temperature for 40 min. After cooling to room tempera-
ture, the mixture was diluted with MeOH (5 mL) and EtOAc
(60 mL) and then washed with brine (50 mL, 3 ꢂ 20 mL) and
saturated NaHCO3 (20 mL). The organic layer was dried
(Na2SO4), filtered, and the solvent removed under vacuum to
leave a crude solid (1.08 g). Purification by column chroma-
tography on silica gel (dry-loaded on 4.5 g of silica) using
EtOAc/hexanes (1:9–3:2) as eluent gave the product (183 mg,
50%) as a solid.
1
2-Aminothiazolo[4,5-c]pyridine (9). H NMR (400 MHz;
CDCl3) d 8.55 (d, J ¼ 0.9 Hz, 1H), 8.13 (d, J ¼ 5.4 Hz, 1H),
7.79 (br. s, 2H), 7.75 (dd, J ¼ 0.9, 5.4 Hz, 1H); 13C NMR
(100 MHz; CDCl3) d 167.0, 149.8, 140.4, 139.5, 138.4, 116.3;
m/z ¼ 152.0 (M þ 1).
Acknowledgments. The authors thank Michael Kelly and John
Kincaid for their support and encouragement throughout this
study.
REFERENCES AND NOTES
[1] For reviews see (a) El-Gaby, M. S. A.; Al-Schemi, A. G.;
Mohamed, Y. A.; Ammar, Y. A.; Phosphorus Sulfur Silicon 2006,
181, 631; (b) Ulrich, H. Sci Synth 2002, 11, 835.
[2] Young, R. N.; Xiang, Y. B.; Labelle, M.; Lau, C. K.;
Leblanc, Y.; Dufresne, C.; Gareau, Y. Eur. Pat. 604114 (1994); Chem
Abstr 1994, 122, 10021.
1
2-Methylthiazolo[5,4-b]pyridine (5a). H NMR (400 MHz;
CDCl3) d 8.54 (d, J ¼ 4.6 Hz, 1H), 8.19 (d, J ¼ 8.2 Hz, 1H),
7.42 (dd, J ¼ 8.2, 4.6 Hz, 1H), 2.87 (s, 3H); 13C NMR (100
MHz; CDCl3) d 162.3, 159.2, 146.7, 146.6, 129.4, 121.2, 21.1;
m/z ¼ 151.2 (M þ 1).
[3] Yoon, S. H.; Joo, H. W.; Jeong, U.; Kim, Y. K.; Koo, S.-
Y.; Yang, S. Y.; Kim, K.-H.; Hwang, J.; Heung, S.; Choi, H. G.; Lim,
D.; Song, S. J.; Yoon, H.-S.; Hong, S.-Y.; Kim, M.-J.; Choi, S.; Jo,
K.; Kim, M.-H.; Kim, J.; Kim, J. I.; Park, T. K. WO Pat. 2007058482
(2007);Chem Abstr 2007, 147, 9919.
1
2-Phenylthiazolo[5,4-b]pyridine (5b). H NMR (400 MHz;
d6-DMSO) d 8.64 (dd, J ¼ 4.5, 1.5 Hz, 1H), 8.46 (dd, J ¼
8.2, 1.5 Hz, 1H), 8.15–8.12 (m, 2H), 7.64–7.61 (m, 4H); 13C
[4] Almansa, R. C.; Virgili, B. M.; Grima, P.; Pedro, M. WO
Pat. 2006013095 (2006); Chem Abstr 2006, 144, 212773.
[5] (a) Nagy, L. T.; Pappne, B. A.; Kapui, Z.; Aranyi, P.;
Batori, S.; Bartane, B. V.; Varga, M.; Ferenczy, G.; Mikus, E.; Urban-
Szabo, K.; Vargane, S. J.; Walcz, E.; Susan, E. WO Pat. 2007034252
(2007); Chem Abstr 2007, 146, 379984; (b) Nagy, L. T.; Pappne, B.
A.; Kapui, Z.; Aranyi, P.; Batori, S.; Bartane, B. V.; Varga, M.; Fer-
enczy, G.; Mikus, E.; Urban-Szabo, K.; Vargane, S. J.; Szabo, T.;
Walcz, E. WO Pat. 2007034251 (2007); Chem Abstr 2007, 146,
379996.
NMR (100 MHz; d6-DMSO)
d
167.5, 157.5, 147.6,
146.5, 135.5, 132.0, 130.2, 129.4, 127.3, 122.2; m/z ¼ 213.4
1
2-Aminothiazolo[5,4-b]pyridine (5c). H NMR (400 MHz;
(M þ 1).
d6-DMSO) d 8.09 (dd, J ¼ 1.6, 4.6 Hz, 1H), 7.79 (br. s, 2H),
7.62 (dd, J ¼ 1.6, 7.9 Hz, 1H), 7.24 (dd, J ¼ 4.6, 7.9 Hz,
1H); 13C NMR (100 MHz; d6-DMSO) d 165.5, 155.4, 146.8,
141.6, 123.4, 121.1; m/z ¼ 152.2 (M þ 1).
1
Thiazolo[5,4-b]pyridine (5d). H NMR (400 MHz; CDCl3)
[6] Koehler, M. F. T.; Gazzard, L. J.; Tsui, V. H.-W. WO Pat.
2007106192 (2007); Chem Abstr 2007, 147, 386251.
d 9.18 (s, 1H), 8.66 (m, H), 8.37 (m, 1H), 7.48 (dd, J ¼ 8.3,
4.6 Hz, 1H); 13C NMR (100 MHz; CDCl3) d 157.4, 155.4,
147.9, 145.8, 131.0, 121.3; m/z ¼ 137.2 (M þ 1).
[7] (a) Bebernitz, G. R. WO Pat. 2004050645 (2004); Chem
Abstr 2004, 141, 54350; (b) Conner, S. E.; Mantlo, N. B.; Zhu, G.
WO Pat. 2004063155 (2004); Chem Abstr 2004, 141, 157107; (c) Itai,
A.; Muto, S. R.; Fukazawa, H.; Ohara, T.; Kato, T. WO Pat.
2007023882 (2007); Chem Abstr 2007, 146, 295907.
1
6-Chlorothiazolo[5,4-b]pyridin-2-amine (7a). H NMR (400
MHz; d6-DMSO) d 8.12 (d, J ¼ 2.2 Hz, 1H), 8.06 (br. s, 2H),
7.74 (d, J ¼ 2.2 Hz, 1H); 13C NMR (100 MHz; d6-DMSO) d
167.4, 153.8, 147.9, 139.4, 128.6, 122.8; m/z ¼ 186.2 (M þ 1
for 35Cl).
[8] (a) Cowart, M. D. WO Pat. 2003101994 (2003); Chem
Abstr 2003, 140, 27845; (b) Cowart, M. D.; Latshaw, S. P.; Nelson, S.
L.; Stewart, A. O. WO Pat. 2006172995 (2006); Chem Abstr 2006,
145, 1889916.
1
6-Bromothiazolo[5,4-b]pyridin-2-amine (7b). H NMR (400
MHz; d6-DMSO) d 8.19 (d, J ¼ 2.1 Hz, 1H), 8.06 (br. s, 2H),
7.86 (d, J ¼ 2.1 Hz, 1H); 13C NMR (100 MHz; d6-DMSO) d
167.1, 154.1, 148.3, 141.5, 125.4, 117.1; m/z ¼ 230.1/232.1
(M þ 1).
[9] Parlati, F.; Ramesh, U. V.; Singh, R.; Payan, D. G.; Lowe,
R.; Look, G. C. WO Pat. 2005037845 (2005); Chem Abstr 2005, 142,
430262.
[10] (a) Nishimura, T.; Iino, T.; Nagata, T.; Eiki, J. WO Pat.
20030800585 (2003); Chem Abstr 2003, 139, 261302; (b) Bebernitz,
G. R. WO Pat. 2004050645 (2004); Chem Abstr 2004, 141, 54350; (c)
Iino, T.; Hashimoto, N.; Nakashima, H.; Takahashi, K.; Nishimura, T.;
Eiki, J. WO Pat. 2004076420 (2004); Chem Abstr 2004, 141, 260754;
(d) Mitsuya, M.; Bamba, M.; Sakai, F.; Watanabe, H.; Sasaki, Y.;
1
6-Iodothiazolo[5,4-b]pyridin-2-amine (7c). H NMR (400
MHz; d6-DMSO) d 8.27 (d, J ¼ 1.9 Hz, 1H), 8.01 (br. s,
2H), 7.97 (d, J ¼ 1.9 Hz, 1H); 13C NMR (100 MHz; d6-
DMSO) d 166.5, 154.5, 148.6, 146.4, 130.8, 90.1; m/z ¼
277.9 (M þ 1).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009 A Single-Step Preparation of Thiazolo[5,4-b]pyridine- and Thiazolo[5,4-c]pyridine
Derivatives from Chloronitropyridines and Thioamides, or Thioureas
1131
Nishimura, T.; Eiki, J. WO Pat. 2004081001 (2004); Chem Abstr
2004, 141, 296024; (e) Mitsuya, M.; Bamba, M.; Sasaki, Y.; Nishi-
mura, T.; Eiki, J.; Arakawa, K. WO Pat. 2005090332 (2005); Chem
Abstr 2005, 143, 347192; (f) Bebernitz, G. R.; Gupta, R. C.; Jagtap,
V. V.; Mandhare, A. B.; Tuli, D. WO Pat. 2005095417 (2005); Chem
Abstr 2005, 143, 387021; (g) Bebernitz, G. R.; Gupta, R. C.; Jagtap,
V. V.; Mandhare, A. B.; Tuli, D. WO Pat. 2005095418 (2005); Chem
Abstr 2005, 143, 387022; (h) Sugawara, K.; Matsudaira, T.; Sugama,
H.; Nawano, M.; Ohashi, R. WO Pat. 2007007886 (2007); Chem Abstr
2007, 146, 163098; (i) Bebernitz, G. R. WO Pat. 2007041365 (2007);
Chem Abstr 2007, 146, 421973; (j) Bebernitz, G. R.; Kirman, L. WO
Pat. 2007041366 (2007); Chem Abstr 2007, 146, 401962; (k) Aicher,
T. D.; Lee, W.-M.; Hinklin, R. J.; Chicarelli, M. J.; Boyd, S. A.; Con-
droski, K. R. WO Pat. 2007053345 (2007); Chem Abstr 2007, 146,
501037.
[15] (a) Okafor, C. O. J Org Chem 1973, 26, 4383; (b) Kram-
berger, L.; Lorencak, P.; Polanc, S.; Vercek, B.; Stanovnik, B.; Tisler,
M.; Povazanek, F. J Heterocycl Chem 1975, 12, 337; (c) Tsuruoka,
A.; Kaku, Y.; Kakinuma, H.; Tsukada, I.; Yanagisawa, M.; Nara, K.;
Naito, T.Chem Pharm Bull 1998, 46, 623; (d) Castro, A.; Martinez, A.
J Heterocycl Chem 1999, 36, 991; (e) Jouve, K.; Bergman, J. J Hetero-
cycl Chem 2003, 40, 261; (f) Zavarzin, I. V.; Smirnova, N. G.; Yaro-
venko, V. N.; Krayushkin, M. M. Russ J Org Chem 2006, 42, 273.
[16] (a) Bednyagina, N. P.; Gulemina, N. N.; Lipunova, G. N.;
Saloutina, L. V. Khim Geterotsiklicheskikh Soedin 1975, 7, 925; (b)
Mylari, B. L.; Scott, P. J.; Zembrowski, W. J. Synth Commun 1989,
19, 2921.
[17] For cyclization of pyridone-analoges using sulfur reagents
see (a) Oklobdzija, M.; Comisso, G.; Decorte, E.; Fajdiga, T.; Grat-
ton, G.; Moimas, F.; Toso, R.; Sunjic, V.
J Heterocycl Chem
[11] Hemmerling, M.; Klingstedt, T. WO Pat. 2004099204
(2004); Chem Abstr 2004, 141, 424193.
1983, 20, 1329; For cyclization of chloro-analoges using sulfur
reagents see (b) Couture, A.; Grandclaudon, P. Heterocycles 1984,
22, 1383.
[12] Nunes, J. J.; Milne, J.; Bemis, J.; Xie, R.; Vu, C. B.; Ng, P.
Y.; Disch, J. H.; Salzmann, T.; Armistead, D. WO Pat. 2007019346
(2007); Chem Abstr 2007, 146, 274349.
[18] Itoh, T.; Mase, T. Org Lett 2007, 9, 3687.
[19] For some alternative synthesis of thiazolo[5,4-b]pyridines
not detailed in Figure 1 see (a) Koren, B.; Stanovnik, B.; Tisler, M.
Monatsh F Chem 1988, 119, 333; (b) Yarovenko, V. N.; Polushina, A.
V.; Zavarzin, I. V.; Krayushkin, M. M.; Kotovskaya, S. K.; Charushin,
V. N. Russ J Org Chem 2007, 43, 429.
[13] A substructure search of the thiazolo[5,4-b]pyridine core
yields over two hundred papers and patents (applied and granted)
describing the medicinal action of such compounds. The following are
some examples taken from the primary literature (a) Gayral, P.; Bour-
dais, J.; Lorre, A.; Abenhaim, D.; Dusset, F.; Pommies, M.; Fouret, G.
Eur J Med Chem 1978, 13, 171; (b) Kulkarni, D. G.; Lokhande, S. R.;
Khadse, B. G. Ind J Pharm Sci 1981, 43, 37; (c) Couture, A.; Huguerre,
E.; Grandclaudon, P. Synth Commun 1989, 19, 713; (d) Mylari, B. L.;
Larson, E. R.; Beyer, T. A.; Zembroski, W. J.; Aldinger, C. E.; Dee, M.
F.; Siegel, D. H.; Singleton, D. H. J Med Chem 1991, 34, 108; (e) Ter-
nansky, R. J.; Draheim, S. E.; Pike, A. J.; Bell, F. W.; West, S. J.; Jor-
dan, C. L.; Wu, C. Y. E.; Preston, D. A.; Alborn, W.; Kasher, J. S.;
Hawkins, B. L. J Med Chem 1993, 36, 1971; (f) Uchikawa, O.; Fakatsu,
K.; Suno, M.; Aono, T.; Doi, T.Chem Pharm Bull 1996, 44, 2070; (g)
Tsushima, M.; Iwamatsu, K.; Tamura, A.; Shibahara, S. Bioorg Med
Chem 1998, 6, 1009; (h) Tsushima, M.; Kano, Y.; Umemura, E.; Iwa-
matsu, K.; Tamura, A.; Shibahara, S. Bioorg Med Chem 1998, 6, 1641;
(i) Kolasa, T.; Gunn, D. E.; Bhatia, P.; Woods, K. W.; Gane, T.; Stew-
art, A. O.; Bouska, J. B.; Harris, R. R.; Hulkower, K. I.; Malo, P. E.;
Bell, R. L.; Carter, G. W.; Brooks, C. D. W. J Med Chem 2000, 43,
690; (j) Das, J.; Lin, J.; Moquin, R. V.; Shen, Z.; Spergel, S. H.; Wityak,
J.; Doweyko, A. M.; DeFex, H. F.; Fang, Q.; Pang, S.; Pitt, S.; Shen, D.
R.; Schieven, G. L.; Barrish, J. C. Bioorg Med Chem Lett 2003, 3,
2145; (k) Borthwick, A. D.; Davies, D. E.; Ertl, P. F.; Exall, A. M.;
Haley, T. M.; Hart, G. J.; Jacksom, D. L.; Parry, N. R.; Patikis, A.; Triv-
edi, N.; Weingarten, G. G.; Woolven, J. M. J Med Chem 2003, 46,
4428; (l) Tanaka, J.; Iida, H.; Abe, M.; Yuda, Y.; Inoue, S.; Okabe, S.
Arzneim Forsch 2004, 54, 221; (m) Walcznski, K.; Zuiderveld, O. P.;
Timmerman, H. Eur J Med Chem 2005, 40, 15; (n) Boros, E. E.; Johns,
B. A.; Garvey, E. P.; Koble, C. S.; Miller, W. H. Bioorg Med Chem
Lett 2006, 16, 5668.
[20] Kelly, M. G.; Kaub, C. J.; Kincaid, J.; Janagani, S.; Wu,
G.; Wei, Z.-L.; Sahasrabudhe, K.; Duncton, M.; Upasani, R. B.; Fang,
Y.; Cox, M. WO Pat. 2007100758 (2007); Chem Abstr 2007, 147,
343795.
[21] Hamprecht, R. DE 3337859 (1984); Chem Abstr 1984, 101,
211131.
[22] Performed using a similar procedure for preparation of 5-
nitrobenzothiazole. See (a) Hosojima, S.; Takido, T.; Itabashi, K. Yuki
Gosei Kagaku Kyokaishi 1984, 42, 170; (b) Fletcher, S. R.; Holling-
worth, G. J.; Jones, B. A.; Moyes, C. R.; Rogers, L. WO Pat.
2005028445 (2005); Chem Abstr 2005, 142, 336366.
[23]
A completely different material was synthesized when
DMF, DMSO or NMP were used as solvents. The identity of this
compound, which was also formed in ca. 20% when using sulfolane,
is unknown to us at this time. Data for unknown compound: 1H
NMR (400 MHz; d6-DMSO) d 8.33–8.31 (m, 1H), 8.14–8.12 (m,
1H), 7.65–7.57 (m, 4H); 13C NMR (100 MHz; d6-DMSO) d 187.0,
171.8, 131.5, 131.1, 129.7, 128.7, 128.6, 128.0, 126.9, 126.4; m/z ¼
239.5.
[24] Porter, H. K. Org React 1973, 20, 455.
[25] (a) Joshi, G. G.; Shah, N. M. Curr Sci 1949, 18, 73; (b)
Khurana, J. M.; Singh, S. J Ind Chem Soc 1996, 73, 487.
[26] McLaughlin, M. A.; Barnes, D. M. Tetrahedron Lett 2006,
47, 9095, and references cited therein.
[27] (a) Gore, P. H.Chem Ind 1954, 1355; (b) Gu, S.-X.; Yao,
K.-L.; Hou, Z.-J.; Wu, J.-G. Youji Huaxue 1988, 18, 157.
[28] (a) Tomasik, P.; Skrowaczewska, Z. Roczniki Chemii 1966,
40, 637; (b) Kai, S. X.; Huang, J.-C.; Espitia, S. L.; Tran, M.; Ilyin,
V. I.; Hawkinson, J. E.; Woodward, R. M.; Weber, E.; Keana, J. F. W.
J Med Chem 1997, 40, 3679.
[14] (a) Altland, H. W.; Molander, G. A. J Heterocycl Chem
1977, 14, 129; (b) Couture, A.; Grandclaudon, P. Synthesis 1985, 533;
(c) Couture, A.; Grandclaudon, P.; Huguerre, E. J Heterocycl Chem
1987, 24, 1765; (d) Singh, B.; Pennock, P. O.; Lesher, G. Y.; Bacon,
E. R.; Page, D. F. Heterocycles 1993, 36, 133; (e) Yoon, J. H.; Song,
H.; Kim, S. W.; Han, G.; Choo, H.-Y. P. Heterocycles 2005, 65, 2729;
(f) Zhu, L.; Zhang, M.; Dai, M. J Heterocycl Chem 2005, 42, 727.
[29] Preferential reduction of a nitro group ortho- to an oxygen
or nitrogen substituent in dinitroarenes has also been reported previ-
ously. See ref 24 and Terpko, M. O.; Heck, R. F. J Org Chem 1980,
45, 4992.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet