Synthesis of 2,5-dihalothiazole-4-carboxylates

Article abstract of DOI:10.1016/S0040-4039(02)01556-3

An efficient synthesis of 2,5-dihalothiazole-4-carboxylates has been described. Halogenation of aminothiazole carboxylate with NBS or NCS and subsequent diazotization with isoamyl nitrite and halogenation with CuBr₂, CuCl₂ or CH₂I₂ provided the corresponding diahalothiazole derivatives. The four-step process described is amenable to scale-up and requires no chromatographic purification in all the steps.

Full text of DOI:10.1016/S0040-4039(02)01556-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7051–7053
Synthesis of 2,5-dihalothiazole-4-carboxylates
John F. Okonya and Fahad Al-Obeidi*
Aventis Combinatorial Technologies Center, Selectide, 1580 E. Hanley Blvd., Tucson, AZ 85737, USA
Received 21 June 2002; accepted 26 July 2002
Abstract—An efficient synthesis of 2,5-dihalothiazole-4-carboxylates has been described. Halogenation of aminothiazole carboxy-
late with NBS or NCS and subsequent diazotization with isoamyl nitrite and halogenation with CuBr2, CuCl2 or CH2I2 provided
the corresponding diahalothiazole derivatives. The four-step process described is amenable to scale-up and requires no
chromatographic purification in all the steps. © 2002 Published by Elsevier Science Ltd.
Diverse biological activities have been derived from
thiazoles making them one of the most extensively
pursued heterocycles. For example, many compounds
containing the 2-aminothiazole moiety have been found
to display a wide range of biological activities including
anti-inflammatory, antiviral and antibacterial proper-
ties.1 Most recently, there has been a flurry of competi-
tive activity on the development of aminothiazole
derivatives as protein kinase inhibitors with potential
for treatment of cancer and cell proliferative disorders.2
Thiazoles have also found wide agricultural applica-
tions.3 Examples include photosystem II inhibiting her-
bicides,4 succinate dehydrogenase inhibiting thiazole
carboxanilide fungicides,5 and the recently intro-
closer look it became apparent to us that most of the
applications and synthesis of thiazoles are based on the
Hantzsch synthesis and related cyclocondensation reac-
tions.2f,7 Only a few examples describe substantial elab-
oration and manipulation of functionalities around a
thiazole template.5d,8 Consequently, the structural
diversity seen in thiazoles described in the literature
have, for the most part, been limited to those accessible
by the Hantzsch synthesis and related cyclocondensa-
tion reactions. With this in mind, we envisioned that
using dihalothiazole carboxylates as synthetic interme-
diates would offer differential and orthogonal reactivity
that would allow for elaboration to highly fucntional-
ized and diverse thiazole derivatives. A recent report by
Hodgett and Kershaw9 on selective reactivity of 2-
bromo-5-chlorothiazole-5-carboxylates in metal medi-
ated cross-coupling reactions has prompted us to
disclose some of our efforts in this regard. Herein, we
report the synthesis of a variety of 2,4-dihalothiazole-4-
carboxylates shown in the Scheme 1.
duced
aminothiazole
carboxamide
fungicide
(ethaboxam).6
Because of the importance of thiazoles and their ease of
synthesis, the literature and patents are rich in the
synthesis and applications of thiazoles. However, on a
Scheme 1. Preparation of 2,5-dihalothiazole-4-carboxylates.
* Corresponding author. E-mail: fahad.al-obeidi@aventis.com
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01556-3

7052
J. F. Okonya, F. Al-Obeidi / Tetrahedron Letters 43 (2002) 7051–7053
References
2,5-Dihalothiazole-4-carboxylates were readily prepared
in four steps (Scheme 1). The synthesis started with the
cyclocondensation of ethyl bromopyruvate (1) with
thiourea (2) in CH3CN by the standard Hantzsch reac-
tion. The reaction initially exothermic but was left to
run overnight at room temperature. The aminothia-
zole carboxylate was obtained as HBr salt which was freed
by treatment with a solution of NH3/MeOH in CH2Cl2.
Aminothiazole derivatives are highly electron rich at
the 5 or 4 position and, as a consequence, are readily
halogenated with the common halogenating reagents
like Br2, N-chlorosuccinimide (NCS) and N-bromosuc-
cinimide (NBS).8a,d Thus, treatment of 2-aminothiazole-
4-carboxylate (3) with NBS or NCS in CH2Cl2 or
CH3CN readily provided the 5-halogenated derivative
4. In the case of the reaction with NCS, it was neces-
sary to further treat the reaction mixture with Et3N for
at least 2 h to drive the reaction to completion. The
halogen at the 2-position was introduced by diazotiza-
tion of the 2-amino group and subsequent halogena-
tion. Several methods and examples of this
transformation are described in the literature.8b,c,10 We
noticed during our attempts to diazotize and halo-
genate the 2-amino group that the intermediate 2-diazo-
nium thiazole salt was very susceptible to reduction
generating prohibitive amounts of the reduced thiazole
derivative. We found that to avoid or minimize the
formation of the reduced thiazole derivative, the 2-
bromo or chlorothiazole derivatives were best prepared
by diazotization with isoamyl nitrite (i-AmONO) and
halogenation with CuBr2 or CuCl2 in CH3CN and that
it was helpful to run this reaction at low temperature
(0°C). The 2-iodo derivative was prepared by diazotiza-
tion with i-AmONO and halogenation with CH2I2. The
resulting 2,5-dihalothiazole-4-ethyl esters (5) were read-
ily hydrolyzed to the corresponding acids by treatment
with KOH in a 1:1 solution of THF/H2O. In order to
make the process amenable to scale-up, we devised a
method in which the halogenation in the second step
(Scheme 1) was run in CH3CN and the subsequent
diazotization/halogenation was run in one pot.11 The
dihalothiazole esters were then isolated by a simple
filtration through silica gel eluting with EtOAc/hexanes
(1:2). All these transformations were highly efficient
requiring no chromatographic purification in all the
steps. The dihalothiazole carboxylic acids were
obtained with an overall yield of 74% for the four steps.
Attempts to prepare the 2-florothiazole derivative by
diazotization and florination with tetrafloroboric acid
were unsuccessful in our hands, leading instead to
exclusive reduction at the 2-position.
1. (a) Sengupta, S.; Das, D. Synth. Commun. 1996, 26,
113–119 and references cited therein; (b) Kearney, P. C.;
Fernandez, M.; Flygare, J. A. J. Org. Chem. 1998, 63,
196–200 and references cited therein; (c) Bailey, N.;
Dean, A. W.; Judd, D. B.; Middlemiss, D.; Storer, R.;
Watson, S. P. Biorg. Med. Chem. Lett. 1996, 6, 1409–
1414 and references cited therein; (d) References cited in
2b.
2. (a) Pavia, P. P.; Codogno, R. A.; Lurago d’Erba; Vedano
al Lambro, B. S.; Brugherio, A. V.; Milan, M. V. US
Patent 6,114,365 (2000) [Pharmacia-Upjohn]; (b)
Pevarello, P.; Amici, R.; Traquandi, G.; Villa, M.;
Vulpetti, A.; Isacchi, A. PCT Int. Appl. 2000, WO
00626202 [Pharmacia-Upjohn]; (c) Das, J.; Padmanabha,
R.; Chen, P.; Norris, D. J.; Doweyko, A. M. P.; Barrish,
J. C.; Wityak, J. PCT Int. Appl. 2000, WO 0062778
[BMS]; (d) Rawlins, D. B.; Kimball, S. D.; Misra, R. N.;
Kim, K.; Webster, K. R. PCT Int. Appl. 1999, WO
99/65884 [BMS]; (e) Chong, W. K. M.; Chu, S. S.;
Duvadie, R. R.; Li, L.; Xiao, W.; Yang, Y. PCT Int.
Appl. 1999, WO 99/21845 [Agouron]; (f) Chu, S. S.;
Alegria, L. A.; Der, S. L.; Benedict, S. P.; Chardt, A. J.;
Kania, R. S.; Nambu, M. D.; Tempczyk-Russell, A. M.;
Sarshar, S. PCT Int. Appl. 1999, WO 00/75120 A1
[Agouron]; (g) Kimball, S. D.; Webster, K. R. Ann. Rep.
Med. Chem. 2001, 36, 139–148.
3. References cited in 2a and 2b.
4. Zjawiony, J. K.; Bowling, J. J.; Dayan, F. E.; Romangni,
J. G.; Vincent, A.; Duke, S. O.; Duke, M. V. Abstr.
Pap.-Am. Chem. Soc. 2000, 219th, AGRO-10.
5. (a) Tillett, T. C.; Decker, G. A. Eur. Pat. Appl. 1998,
EP846416 A1 19980610; (b) Phillips, W. G.; Rejda-
Heath, J. M. Pestic. Sci. 1993, 38, 1–7; (c) Alt, G. H.;
Pratt, J. K.; Phillips, W. G.; Srouji, G. H. Eur. Pat. Appl.
1990, EP371950 A2 19900606; (d) Phillips, W. G.; Rejda-
Heath, J. M. Pestic. Sci. 1993, 38, 1–7 and references
cited therein.
6. (a) Rew, Y. S. et al. Eur. Pat. Appl. 1995, EP 639574 A1
19950222; (b) Joe, G.-H.; Lee, J.-Y.; Lee, S.-Y.; Jae-
Hoon, J.; Kim, K.-T.; Cheon, H.-S. PCT Int. Appl. 2000,
WO 00118766 A1 20000406; (c) Rew, Y. S.; Choi, W. B.
Korean J. Med. Chem. 1995, 5, 72–75.
7. (a) Masquelin, T.; Obrecht, D. Tetrahedron 2001, 57,
153–156 and references cited therein; (b) Hantzch, A. R.;
Weber, J. H. Ber. 1887, 20, 3118.
8. (a) South, M. S.; Van Sant, K. A. J. Heterocyclic Chem.
1991, 28, 1017–1022 and references cited therein; (b) Ung,
A. T.; Pyne, S. G. Tetrahedron: Asymmetry 1998, 9,
1395–1407; (c) Abarbri, M.; Thibonnet, J.; Be´rillon, L.;
Dehmel, F.; Rottla¨nder, M.; Knochel, P. J. Org. Chem.
2000, 65, 4618–4634; (d) Tsuji, K.; Ogino, T.; Seki, N.;
Sawada, M.; Sudo, Y.; Nishigaki, F.; Manda, T.; Mat-
suo, M. Biorg. Med. Chem. Lett. 1998, 8, 2473–2478.
9. Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2002, 4,
1363–1365.
10. (a) Barton, A.; Breukelman, S. P.; Kaye, P. T.; Meakins,
G. D.; Morgan, D. J. J. Chem. Soc., Perkin 1 1982,
159–163; (b) Lee, L. F.; Schleppnik, F. M.; Howe, R. K.
J. Heterocyclic Chem. 1985, 22, 1621–1630; (c) Doyle, M.
P.; Siegfried, B.; Pellarin, J. F., Jr. J. Org. Chem. 1977,
42, 2426; (d) Li, P.; Xu, J. C. Tetrahedron Lett. 1999, 40,
8301–8304.
In conclusion, we have described an efficient synthesis
of dihalothiazoles carboxylates that is amenable to
scale-up. Exploiting the differential and orthogonal
reactivity provided by the halogen and carboxylate
functionality on thiazole should provide access to a
wide diversity of novel thiazole derivatives. An elegant
example demonstrating the sequential metal mediated
cross-coupling reactions of such a template has recently
been reported.8c,9 Our efforts in this regard are under-
way and will be reported in due course.

J. F. Okonya, F. Al-Obeidi / Tetrahedron Letters 43 (2002) 7051–7053
7053
11. Typical procedure for preparation of dihalothiazole from
amino thiazole is as follows. All compounds were charac-
terized by LC/MS, 1H and 13C NMR: a mixture of
aminothiazole (25.0 g, 144 mmol) and NCS (23.0 g, 173
mmol) in CH3CN (150 mL) was stirred overnight at rt.
The reaction mixture was cooled to 0°C and CuBr2 (38.45
g, 172 mmol) was added followed by dropwise addition
of isoamyl nitrite (26.6 g, 30.5 mL, 215 mmol). The
mixture was stirred for 2 h. The solvent was removed by
evaporation under reduced pressure and the residue was
extracted with EtOAc/hexane (1:2) and filtered through
silica gel. The combined filtrates were evaporated under
reduced pressure to provide a yellow solid. The product
was triturated with EtOAc/hexanes to provide the desired
2-bromo-4-carboethoxy-5-chlorothiazole as a yellow solid
(30 g, 77%).