Convenient and practical synthesis of 6-chloro-2-(chloromethyl)- thiazolo[5,4-b]pyridine

Article abstract of DOI:10.1080/00397911.2011.566408

(Chemical Equation Presented) A high-yielding and practical synthesis of 6-chloro-2-(chloromethyl)- thiazolo[5,4-b]pyridine starting from 2-amino-5-chloropyridine has been accomplished in a sequence of five steps. Copyright Taylor & Francis Group, LLC.

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Convenient and Practical Synthesis of 6-
Chloro-2-(chloromethyl)-thiazolo[5,4-
b]pyridine
Zi-Chun Ding a , Xiang Ma a b & Weicheng Zhou a
a State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key
Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry,
State Institute of Pharmaceutical Industry, Shanghai, China
b School of Pharmacy, Tongji Medical College, Huazhong University of
Science and Technology, Wuhan, Hubei Province, China
Accepted author version posted online: 14 Mar 2012.Version of
record first published: 29 May 2012.
To cite this article: Zi-Chun Ding, Xiang Ma & Weicheng Zhou (2012): Convenient and Practical
Synthesis of 6-Chloro-2-(chloromethyl)-thiazolo[5,4-b]pyridine, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:19, 2791-2796
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Synthetic Communications1, 42: 2791–2796, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.566408
CONVENIENT AND PRACTICAL SYNTHESIS
OF 6-CHLORO-2-(CHLOROMETHYL)-
THIAZOLO[5,4-b]PYRIDINE
Zi-Chun Ding,1 Xiang Ma,1,2 and Weicheng Zhou1
1State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab
of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry,
State Institute of Pharmaceutical Industry, Shanghai, China
2School of Pharmacy, Tongji Medical College, Huazhong University of
Science and Technology, Wuhan, Hubei Province, China
GRAPHICAL ABSTRACT
Abstract
A
high-yielding and practical synthesis of 6-chloro-2-(chloromethyl)-
thiazolo[5,4-b]pyridine starting from 2-amino-5-chloropyridine has been accomplished in
a sequence of five steps.
Keywords Antibacterial agents; sulfurization; thiazolo[54-b]pyridine
INTRODUCTION
Antibiotic-resistant strains of pathogenic bacteria are increasingly prevalent in
hospitals and the community. Novel agents that target mechanisms different from
those of currently approved antibiotics are urgently needed to combat these bacterial
pathogens to ensure future therapeutic success.[1] Recent studies reported a novel class
of small synthetic antibacterial agents, exemplified by PC190723 (1) (Fig. 1), which
inhibits a unique target FtsZ that prevents bacterial cell division.[2–4] PC190723, a
benzamide derivative with a thiazolo[5,4-b]pyridine fragment, holds great potential
to be developed into a new generation of antibacterial agents. One multistep procedure
for the preparation of PC190723 has been reported recently, of which the target
compound was easily obtained by an alkylation of a commercially available phenol
with 6-chloro-2-(chloromethyl)-thiazolo[5,4-b]pyridine (2) (Fig. 1).[5] However, the
procedure for the preparation of 6-chloro-2-(chloromethyl)-thiazolo[5,4-b]pyridine
Received January 4, 2011.
Address correspondence to Xiang Ma, School of Pharmacy, Tongji Medical College, Huazhong
University of Science and Technology, 13 Hangkong Road, Wuhan 430030, Hubei, China. E-mail:
maxwellcn@yahoo.com
2791

2792
Z.-C. DING, X. MA, AND W. ZHOU
Figure 1. Structures of PC 190723 (1) and 6-chloro-2-(chloromethyl)thiazolo[5,4-b]pyridine (2).
(2) was characterized by some disadvantages: The starting material
2,5-dichloropyridin-3-amine was not readily available and the final cyclization yield
was moderate with an unwanted side product.[5] Many other procedures have been
reported for the synthesis of the thiazolo[5,4-b]pyridine core structure, including
Pd-catalyzed thiol cross-coupling,[6] oxidative cyclization of N-methyl- and
N-benzoylpyridylthioureas,[7] 3-amino-2-chloropyridine with thioesters,[8] and con-
densation of chloronitropyridine with thioamides or thioureas.[9] However, these
methods also suffered from many disadvantages, such as poor yields, expensive
reagents, long reaction times, toxic organic solvents, strongly basic conditions, and
unsuitability for upscale preparation. Herein, the goal of the present work was to
develop a simple and convenient procedure for the practical synthesis of 6-chloro-2-
(chloromethyl)-thiazolo[5,4-b]pyridine (2).
RESULTS AND DISCUSSION
As mentioned earlier, Sorto and coworkers developed a strategy for the syn-
thesis of 6-chloro-2-(chloromethyl)-thiazolo[5,4-b]pyridine (2) using commercially
available but expensive 3-amino-2,5-dichloropyridine as a staring material.[5] How-
ever, it suffered from difficulties in the final ring closure, where an unwanted deha-
logenerated product was often obtained. The high temperature and long reaction
time of the sulfurization and ring closure process might account for this by-product.
We envisioned that using a relative more active 2-bromo substitituted pyridine[10]
instead of 2-chloro derivative could overcome the problem.
Therefore, in the initial study, we carried out the reaction for the preparation
of the 2-bromo-5-chloropyridin-3-amine (6), the key precursor, with an inexpensive
starting material, 2-amino-5-chloropyridine (3) (Scheme 1). Because of the electron-
donating effect of 2-amino group and the possible formation of 2-nitramino-5-chlor-
Scheme 1. Synthesis of 6-chloro-2-(chloromethyl)thiazolo[5,4-b]pyridine (2).

THIAZOLO[5,4-b]PYRIDINE SYNTHESIS
2793
opyridine intermediate, the direct 3-position nitration on the electron-deficient pyri-
dine ring was successful in converting 3 into 4 with concentrated nitric acid and sul-
furic acid at 60 ꢀC giving 68% yield. Diazotitation of 4 followed by bromination with
bromine proceeded smoothly to give 2-bromo-5-chloro-3-nitropyridine (5) in 60% yield.
The preparation of the amino derivative 6 by the catalytic hydrogenation of 3-nitropyr-
idine 5 had interesting facets. When either platinum or palladium were used at room
temperature with a constant hydrogen pressure of 5 bars, the reduction led exclusively
to 3-hydroxylamine derivative within 1 h. After further reaction under the same con-
ditions for 3 h, a debromination product was produced. The structures of these
unwanted compounds were confirmed using proton NMR and electrospray ioniza-
tion–mass spectrometry (ESI-MS). Ultimately the reduction was carried out using
reduced iron in acetic acid to convert 5 into 2-bromo-5-chloropyridin-3-amine (6) in
98% yield without any debromination by-product. The formation of 7 proceeded slowly
via acylation of 6 using chloroacetyl chloride in the present of triethylamine in moderate
yield (66%), and substituting the Hunig’s base (disopropylethyl amine, DIPEA) for
triethylamine only marginally increased the reaction yield. However, in the present of
pyridine, the acylation went efficiently with a much better yield of 88% to give 7.
The sulfurization and concomitant ring closure of 7 suffered the same problem
with dechlorination by-product using Lawesson’s reagents (LR) either in toluene or
p-xylene as in the previous report.[5] This suggested that more active 2-bromo substi-
tuted pyridine 7 was not superior to chloropyridine on the ring-closure process to
reduce the dechlorinated by-product. We attempted to solve the problem of dehalo-
genation by changing the sulfurization reagent into a common reagent, phosphorus
decasulfide (P4S10). P4S10 is among the oldest sulfurizating agents for organic com-
pounds, and it was used for the preparation of LR.[11] Although there is a general
conclusion that LR is superior to P4S10, particularly in terms of obtaining better
yields, there is no clearcut mechanism for understanding the difference between
the two reagents.[12] However, after many attempts, an optimal condition was
achieved when the sulfurization and ring closure took placed in P4S10=toluene system
at 110 ꢀC in only 0.5 h. The 6-chloro-2-(chloromethyl)-thiazolo[5,4-b]pyridine (7)
was obtained in 83% yield with only a trace amount of dechlorinated by-product
detected by thin-layer chromatography (TLC). In contrast to the reaction time of
12 h using LR, as in the previous report,[5] the current reaction using P4S10 was car-
ried out successfully in a much shorter reaction time (0.5 h vs. 12 h5) and a greater
yield (82.6% vs. 60.0%[5]). The shorter reaction time may help minimize the forma-
tion of the unwanted dechlorinated by-product and thus increase the yield.
In conclusion, we have demonstrated a practical synthesis of 6-chloro-2-
(chloromethyl)-thiazolo[5,4-b]pyridine (2) in good yields using low-cost materials
and a convenient reaction route. The finding paves the way for the synthesis of
PC190723 and future medicinal chemistry modification for the discovery of new
antibacterial agents to combat antibacterial drug resistance.
EXPERIMENTAL
Reagents and solvents were obtained from commercial sources and were used
without further purification. Thin-layer chromatography (TLC) was performed on
precoated silica-gel 60 F254 plates. Compounds were visualized using ultraviolet

2794
Z.-C. DING, X. MA, AND W. ZHOU
(UV) light (254 nm). Column chromatography refers to flash column chromato-
1
graphy on silica gel (200–300 mesh). H NMR spectra were recorded on a Varian
Inova 400-MHz spectrometer. Chemical shifts (d) are expressed in parts per million
(ppm) downfield by reference to tetramethylsilane (TMS) as the internal standard.
NMR data are presented in the following order: multiplicity (s, singlet; d, doublet;
t, triplet; q, quartet; and m, multiplet); coupling constance(s) in hertz, and number
of proton(s). The mass spectra were recorded on a Finnigan-MAT212 under electron
impact (EI) ionization condition or otherwise specified. Melting points were
obtained manually in open capillary tubes and are uncorrected.
2-Amino-5-chloro-3-nitropyridine (4)
2-Amino-5-chloropyridine (3) (38.6 g, 0.30 mol) was added in portions to 98%
sulfuric acid (150 mL), and the resulting solution was heated to 55 ꢀC. Through an
addition funnel, 65% nitric acid (22 mL, 0.32 mol) was added dropwise to the sol-
ution so as to maintain the internal temperature at 59 ꢁ 1 ꢀC. The resulting
brown=black solution was stirred at 59 ꢀC for 1 h and poured over ice (750 g). The
mixture was partially neutralized with 40% NaOH (300 mL). The precipitate was
filtered to leave a yellow=orange solid. This solid was washed by resuspension in
water (300 mL) and then was filtered and dried in the oven for 24 h to yield 35.5 g
(68.0%) of 4 as orange solid. Mp: 196–198 ꢀC. (lit.[13] 191–193 ꢀC); 1H NMR
(400 MHz, DMSO-d6): d 7.97 (br s, 2 H), 8.40 (d, J ¼ 2.4 Hz, 1 H), 8.43 (d,
J ¼ 2.4 Hz, 1H); MS (ESI): m=z 173.02 (M þ 1)þ.
2-Bromo-5-chloro-3-nitropyridine (5)
Compound 4 (56.0 g, 0.32 mol) was added to 40% HBr (235 mL, 1.60 mol) in
portions at 0 ꢀC with mechanical stirring. Bromine (55 mL, 1.07 mol) was added
dropwise to the solution, followed by a solution of NaNO2 (77.6 g, 1.12 mol) in water
(108 mL), while maintaining the internal temperature below ꢂ5 ꢀC. The resulting
red=brown mixture was stirred for another 45 min at 0 ꢀC, and then a solution of
NaOH (118 g, 2.95 mol) in water (168 mL) was added. The mixture was stirred below
20 ꢀC for an additional 1 h and then filtered. The cake was dried at room temperature
in vacuo for 6 h to give 67.6 g of the crude product. It was purified by recrystalliza-
tion from 95% ethanol (70 mL) to give 45.0 g (58.7%) of 5 as yellow prisms. Mp
1
77–79 ꢀC (lit.[13] 73–75 ꢀC); H NMR (400 MHz, CDCl3): d 8.13 (d, J ¼ 2.4 Hz, 1
H), 8.56 (d, J ¼ 2.4 Hz, 1 H); MS (ESI): m=z 236.94 (M þH)þ.
2-Bromo-5-chloropyridin-3-amine (6)
2-Bromo-5-chloro-3-nitropyridine (5) (6 g, 25.3 mmol) was added to glacial
acetic acid (34.5 mL, 59.8 mmol), and the solution was heated to 60 ꢀC with vigorous
stirring. Iron powder (6.91 g, 124.0 mmol) was added in portions. The resulting mix-
ture was cooled to room temperature and filtered. The solid was washed with diethyl
ether (2 ꢃ 50 mL) and ethyl acetate (2 ꢃ 50 mL). The organic phase was separated
and washed with water, saturated sodium bicarbonate solution, and brine. The
organic layer was then dried with magnesium sulfate and filtered. The solvent was

THIAZOLO[5,4-b]PYRIDINE SYNTHESIS
2795
evaporated in vacuo to afford 5.10 g (97.7%) of the title compound 6 as a light brown
solid. Mp: 143–145 ꢀC (lit.[14] 141–143 ꢀC); 1H NMR (400 MHz, CDCl3): d 4.19 (br s,
2 H), 6.98 (d, J ¼ 2.4 Hz, 1 H), 7.40 (d, J ¼ 2.0 Hz, 1 H); MS (EI): m=z 206 Mþ, 127
(M ꢂ HBr)þ.
N-(2-Bromo-5-chloropyridin-3-yl)-2-chloroacetamide (7)
2-Bromo-5-chloropyridin-3-amine (6) (5.19 g, 25.0 mmol) was dissolved in
CH2Cl2 (150 mL) and cooled to 0 ꢀC. Chloroacetyl chloride (3 mL, 37.7 mmol) was
added dropwise, followed by the addition of pyridine (3 mL, 37.2 mmol). The mix-
ture was stirred at room temperature for 1 h. The reaction was quenched by the
addition of water (150 mL). The organic layer was separated, washed with water
and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo
to afford 7.33 g of the crude product. It was purified by recrystallization from etha-
nol to yield 6.23 g (87.8%) of the title compound 7 as off-white prisms. Mp
1
135–137 ꢀC; H NMR (400 MHz, CDCl3): d 4.24 (s, 2 H), 8.13 (d, J ¼ 2.4 Hz, 1H),
8.76 (d, J ¼ 2.4 Hz, 1H), 8.95 (br s, 1 H); MS (EI): m=z 282 Mþ, 203 (M ꢂ HBr)ꢂ.
HRMS (EI) m=z calcd. for C7H5BrCl2N2O, Mþ 281.8962; found 281.8961.
6-Chloro-2-(chloromethyl)thiazolo[5,4-b]pyridine (2)
N-(2-Bromo-5-chloropyridin-3-yl)-2-chloroacetamide (7) (2.84 g, 10.0 mmol)
was dissolved in toluene (80 mL), and P4S10(1.33 g, 3.0 mmol) was added. The reac-
tion mixture was refluxed for 30 min at 110 ꢀC, then cooled to room temperature,
and evaporated in vacuo. Saturated sodium bicarbonate solution (120 mL) was
added, and the mixture was extracted by ethyl acetate (2 ꢃ 120 mL). The organic
layer was separated and evaporated in vacuo. The crude mixture was purified by col-
umn chromatography (10% ethyl acetate= petroleum ether) to yield 1.81 g (82.6%) of
1
2 as an amorphous white solid: Mp 89–90 ꢀC (lit.[5] 89–90 ꢀC); H NMR (400 MHz,
CDCl3): d 4.90 (s, 2 H), 8.30 (d, J ¼ 2.0 Hz, 1 H), 8.57 (d, J ¼ 2.0 Hz, 1 H); MS (ESI):
m=z 218.97 (M þH)þ.
ACKNOWLEDGMENT
This work was financially supported by The National Basic Research Program
of China (973 Program) (2010CB735601 and 2012CB724501).
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