Syntheses of 4- and 6-substituted thiazolo[4,5-c]pyridines

Article abstract of DOI:10.1016/j.tetlet.2010.03.070

A general synthetic approach to 4,6-substituted thiazole[4,5-c]pyridines, involving a novel one-pot thiol deprotection-cyclization key step, is described.

Full text of DOI:10.1016/j.tetlet.2010.03.070

Tetrahedron Letters 51 (2010) 2800–2802
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Syntheses of 4- and 6-substituted thiazolo[4,5-c]pyridines
a
a
a
Yuhua Huang a, Frank Bennett a, , Vinay Girijavallabhan , Carmen Alvarez , Tze-Ming Chan ,
*
Rebecca Osterman a, Mary Senior a, Cecil Kwong b, Namita Bansal b, F. George Njoroge a, Malcolm MacCoss a
a Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
b Department of Medicinal Chemistry, Southern Research Institute, 2000 Ninth Avenue South, Birmingham, AL 35205, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A general synthetic approach to 4,6-substituted thiazole[4,5-c]pyridines, involving a novel one-pot thiol
deprotection-cyclization key step, is described.
Received 22 February 2010
Revised 15 March 2010
Accepted 16 March 2010
Available online 21 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Heterocycles continue to play an increasingly important role in
medicinal chemistry. For example, Haginoya et al. described a syn-
thesis of thiazole[4,5-c]pyridine 1a, and its application as an inter-
mediate in the construction of factor Xa (fXa) inhibitors.1
the amino thiol 7 proceeded smoothly to the pyridylthiazole 1a,
presumably via an intermediate, the vicinally substituted thiol-
formamide 8, although it was never observed during the course
of the reaction.
We reasoned if we could generate the same disposition of func-
tional groups, in situ, from the cleavage of a suitable thiol-protect-
ing group in an acid media, then ring closure would follow. This
would avoid problems commonly associated with aryl mercaptans
(e.g., oxidation to the disulfide). To this end, we were particularly
attracted to the p-methoxybenzyl group (PMB) 9 which could
release the thiol 10 in refluxing TFA.3 Subsequent dehydration
would thus generate the desired substituted pyridyl thiazole 11.
R4
N
N
2
S
R6
1a; R4=R6=H
Having incorporated 1a into a successful medicinal chemistry
program we wanted to further expand the SAR of our active enti-
ties by incorporating alkyl groups at the 4- and 6-positions of the
pyridylthiazole ring. In the preceding paper a general synthesis
of 4-alkyl mono-substituted derivatives is described (Scheme 1).2
Treatment of compound 1a with mCPBA provided the N-oxide 2
in good yield. Subsequent exposure to refluxing phosphorus oxy-
chloride provided the corresponding 4-substituted chloride 3,
exclusively. Finally, alkyl groups were introduced using an appro-
priate triakylaluminum in the presence of tetrakis(triphenylphos-
phine)palladium(0) in acceptable yields (1b–1f; 70–80%).
Surprisingly, we could not find any literature reference to these rel-
atively simple compounds.
To progress the project further and expand on the range of this
class of heterocycle by introducing functionality at the 6-position,
we decided to devise and execute the syntheses of pyridylthiazoles
4, 5, and 6 (Diagram 1). Analogue 4 is the 6-methyl homologue of
1b. Compound 5 should lead to the 6-positional analogues of 1b–
1f, whereas, the chloride 6, provides the flexibility to obtain the
corresponding 6-methyl analogues of 1c–1f.
Cl
O
N
b
a
N
N
N
N
N
S
S
S
2
3
1a
R4
c
N
1b;R4=Me;75%; 1c;R4=Et;80%
1d;R4=n-Pr;72%; 1e;R4=iPr;70%
1f;R4=cyclopropyl ;75%
N
S
Scheme 1. Reagents: (a) mCPBA, CH2Cl2, 95%; (b) POCl3, 50%; (c) R3Al, Pd(PPh3)4,
AcOH.
Cl
We based our synthetic strategy toward compounds 4–6
around the formylation-condensation final step in Haginoya’s syn-
thesis of 1a (Scheme 2).1 When exposed to refuxing formic acid,
N
N
S
N
N
S
N
N
S
Cl
4
5
6
* Corresponding author.
E-mail address: frank.bennett@spcorp.com (F. Bennett).
Diagram 1. 6-Substituted pyridylthiazoles 4, 5 and 6.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.070

Y. Huang et al. / Tetrahedron Letters 51 (2010) 2800–2802
2801
NO2
NO2
Cl
NO2
NH2:HCl
SH
N
N
NHCHO
SH
N
(a)
(c)
N
N
(b)
(a)
(b)
N
1a
Cl
SPMB
HO
HO
19
17
18
7
9
8
NO2
NH2
NHCHO
SPMB
N
N
(d)
N
(e)
R4
R4
R4
SPMB
SPMB
NHCHO
S
NHCHO
SH
Cl
N
Cl
Cl
N
N
22
20
21
5
R6
S
R6
R6
(f)
N
S
N
11
10
SPMB
Cl
OMe
Scheme 4. Reagents and conditions: (a) KOtBu, tBuOOH, NH3, THF 91%; (b) 4-
methoxy- -toluenethiol, NaH, THF, 91%; (c) POCl3, reflux, 100%; (d) SnCl2/2H2O,
Scheme 2. Reagents: (a) HCO2H, reflux, 90%; (b) TFA, reflux.
a
HCl, Et2O, H2O, 97%; (e) AFA, ice bath; (f) AgBF4, TFA, 61% from 21.
Me
Me
Me
NO2
Cl
NO2
N
(a), (b)
Me
N
(c)
refluxing formic acid, the amine 21 largely decomposed. However,
treatment with cold acetic-formic anhydride (AFA) generated the
desired formamide 22, usually in less than 1 h. It was necessary
to manipulate this reaction as soon as the reaction was determined
to be complete. If allowed to warm to room temperature overnight,
the formamide 22 proceded to the diformyl imide 23. Following
work-up, the crude formamide 22 is treated with silver tetrafluoro-
borate in TFA to give the pyridylthiazole 5.10
N
(d)
OH
Me
SPMB
Me
12
Me
13
14
Me
Me
NH2
N
S
NHCHO
SPMB
N
(e)
N
N
SPMB
Me
Me
Me
N(CHO)2
N
4
15
16
SPMB
Cl
23
Scheme 3. Reagents: (a) HNO3, H2SO4, 93%; (b) POCl3, DMF, toluene, 69%; (c) 4-
methoxy- -toluenethiol, NaH, THF, 96%; (d) SnCl2/2H2O, HCl, Et2O, H2O, 100%; (e)
a
The synthesis of our last example, compound 6, is shown in
Scheme 5. Beginning with commercially available 4-hydroxy-6-
methyl-3-nitro-2-pyridone 24, the 4-hydroxyl was transformed
selectively into the chloride 25 by formation of the cyclohexyl-
amine salt and subsequent treatment with phosphoryl chloride.11
The protected thiol functional group was installed as previously
described, albeit in lower yield. The resulting sulfide 26 was
exposed to additional phosphorous oxychloride to provide the 2-
chloropyridine 27. Reduction and formylation of the amine 28 pro-
vided the formamide 29, which was treated, in crude form, with
silver tetrafluoroborate in TFA to give the pure 4-chloro-6-methyl-
pyridylthiazole 6 following silica gel column chromatography.12
In summary, a general synthetic approach to 4- and 6-mono and
di-substituted thiazole[4,5-c]pyridines was successfully executed.
We hope that this methodology will be helpful in the construction
HCO2H, reflux, followed by TFA, AgBF4, 100%.
With this in mind, our synthesis of the, 4,6-dimethylpyridyl thi-
azole 4 is shown in Scheme 3. Thus, commercially available 2,6-di-
methyl-4-hydroxypyridine 12 was converted, via
a two-step
process, to the nitrate 13, using previously reported procedures.4,5
The protected thiol functionality was introduced, in good isolated
yield, by nucleophilic chloro displacement with the anion gener-
ated from 4-methoxybenzylthiol at room temperature. Reduction
of the nitro 14 was achieved, efficiently, using tin(II) chloride dihy-
drate. Formylation of the resulting amine 15 proceeded smoothly
to the formamide 16, in refluxing, neat, formic acid. The reaction
was generally complete within 3 h. Rather than isolating the amide
16, TFA (threefold volume relative to formic acid) was added to the
mixture, and heating resumed for a further 24 h. LCMS analysis re-
vealed an approximate 50% conversion to the desired pyridylthiaz-
ole 4, which could easily be separated from the starting material 16
using silica gel column chromatography. Similar results were
achieved by refluxing in neat TFA in the absence or presence of
o-cresol.6 Satisfactory reaction conditions were finally achieved
by adding an equal volume of TFA to 16 in the formylation media
and adding silver tetrafluoroborate7 (20 mol %) at ambient temper-
ature. The one-pot deprotection and ring closure were complete,
without warming, within 1 h, providing an excellent yield of the
desired bicycle 4.8
O
O
O
NO2
OH
NO2
Cl
NO2
HN
Me
HN
Me
HN
Me
(a)
(c)
(b)
SPMB
26
24
25
Cl
Cl
Cl
NO2
NH2
NHCHO
SPMB
N
N
(d)
N
(e)
SPMB
SPMB
Me
Me
Me
Me
With the fundamental chemistry in place, we next turned our
attention to the 6-chloro intermediate 5 (Scheme 4).
29
27
28
Cl
Our starting material 18 with the desired substitution pattern
for the synthesis of the chloride 5 was obtained from inexpensive
4-chloro-3-nitropyridine 17 via hydroperoxide vicarious nucleo-
philic substitution.9 As shown previously (Scheme 3), the chloride
18 was transformed into thioether 19, followed by conversion of
the 2-pyridone functionality to the chloropyridine 20 with phos-
phorous oxychloride. Reduction of the nitro group proceeded
smoothly to the corresponding amine 21. When exposed to
(f)
N
S
N
6
Scheme 5. Reagents and conditions: (a) cyclohexylamine, MeOH, room tempera-
ture, then POCl3, room temperature, 80 h, 81%; (b) 4-methoxy- -toluenethiol, NaH
a
(2.2 equiv), THF, 53%; (c) POCl3, reflux, 75%; (d) SnCl2/2H2O, HCl, Et2O, H2O, 100%;
(e) AFA, ice bath; (f) AgBF4, TFA, 45% from 28.

2802
Y. Huang et al. / Tetrahedron Letters 51 (2010) 2800–2802
aqueous phase was separated and further extracted with CH2Cl2 (Â3). The
combined organic phases were dried (MgSO4) and the solvent was removed in
vacuo. The crude reaction product was purified by silica gel column
chromatography using EtOAc/hexanes (2:3) as an eluent to give the desired
pyridylthiazole 4 (2.39 g; 100%), as a light-brown solid. Data for compound 4
1H NMR (500 MHz, CDCl3) d 8.88 (1H, s), 7.55 (1H, s), 2.97 (3H, s), 2.64 (3H, s);
13C NMR (125 MHz, CDCl3) d 153.90, 152.50, 152.21, 146.72, 144.33, 113.30,
24.41, 21.48. HRMS calcd for C8H935ClN3S [M+H]+: 165.0486, found 165.0481.
9. Stavenger, R. A.; Cui, H.; Dowdell, S. E.; Franz, R. G.; Gaitanopoulos, D. E.;
Goodman, K. B.; Hilfiker, M. A.; Ivy, R. L.; Leber, J. D.; Marino, J. P., Jr.; Oh, H.-J.;
Viet, A. Q.; Xu, W.; Ye, G.; Zhang, D.; Zhao, Y.; Jolivette, L. J.; Head, M. S.; Semus,
S. F.; Elkins, P. A.; Kirkpatrick, R. B.; Dul, E.; Khandekar, S. S.; Yi, T.; Jung, D. K.;
Wright, L. L.; Smith, G. K.; Behm, D. J.; Doe, C. P.; Bently, R.; Chen, Z. X.; Hu, E.;
Lee, D. J. Med. Chem. 2007, 50, 2.
of other thiazole-containing systems. The application of pyridyl-
thiazoles 4, 5, and 6 in the preparation of biologically active mole-
cules will be presented elsewhere.
References and notes
1. Haginoya, N.; Komoriya, S.; Osanai, K.; Yoshino, T.; Nagata, T.; Nagamochi, M.;
Muto, R.; Yamaguchi, M.; Nagahara, T.; Kanno, H. Hetrocycles 2004, 63, 1555.
2. Girijavallabhan, V. et al Tetrahedron Lett. 2010. preceding article.
3. Akabori, S.; Sakakibara, Y.; Shimonishi, Y.; Nobuhara, Y. Bull. Chem. Soc. Jpn.
1964, 37, 433.
4. Reich, M. F.; Fabio, P. F.; Lee, V. J.; Kuck, N. A.; Testa, R. T. J. Med. Chem. 1989, 32,
2474.
5. Almansa, C.; de Arribal, A.; Cavalcanti, F. L.; Gomez, L. A.; Miralles, A.; Merlos,
M.; Garcia-Rafanell, J.; Forn, J. J. Med. Chem. 2001, 44, 350.
6. Tayor, A. W.; Dean, D. Tetrahedron Lett. 1988, 29, 1845.
7. Yoshida, M.; Tatsumi, T.; Fujiwara, Y.; Iiunuma, S.; Kimura, T.; Akaji, K.; Kiso, Y.
Chem. Pharm. Bull. 1990, 38, 1551.
8. One-pot deprotection-cyclization with TFA-formic acid. A solution of the amine 15
(4.00 g; 14.6 mmol) in formic acid (40 ml) was heated to reflux, under an
atmosphere of nitrogen, for 2 h. After cooling, TFA (40 ml) was added followed
by silver tetrafluoroborate (0.56 g; 2.9 mmol) and the resulting mixture was
stirred at room temperature for 1 h. The volatiles were removed under reduced
pressure and the residue partitioned between CH2Cl2 and satd aq NaHCO3. The
10. Data for compound 5. 1H NMR (500 MHz, DMSO-d6) d 9.53 (1H, s), 9.19 (1H, d,
J = 2 Hz), 8.43 (1H, d, J = 2 Hz); 13C NMR (125 MHz, DMSO-d6) d 159.63, 149.36,
145.21, 144.69, 144.32, 117.62. HRMS calcd for C8H735ClN3S [M+H+ACN]+:
212.00492, found 212.00496.
11. Dzierba, C. D.; Takvorian, A. G.; Rafalski, M.; Kasireddy-Polam, P.; Wong, H.;
Molski, T. F.; Zhang, G.; Li, Y.-W.; Snjezana, L.; Peng, Y. J.; McElroy, J. F.; Zaczek,
R. C.; Taub, R. A.; Combs, A. P.; Gilligan, P. J.; Trainor, G. L. J. Med. Chem. 2004,
47, 2.
12. Data for compound 6. 1H NMR (400 MHz, DMSO-d6) d 9.48 (1H, s), 8.10 (1H, q,
J = 2 Hz), 2.58 (1H, d, J = 2 Hz); HRMS calcd for C7H535ClN2S [M+H]+: 184.99347,
found 184.99355.