Regiocontrolled Synthesis of Substituted Thiazoles

Article abstract of DOI:10.1021/ol025688u

(Formula Presented) The regiocontrolled synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl 2-bromo-5-chloro-4-thiazolecarboxylate 1 using sequential palladium-catalyzed coupling reactions is described.

Full text of DOI:10.1021/ol025688u

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1363-1365
Regiocontrolled Synthesis of
Substituted Thiazoles
Kevin J. Hodgetts* and Mark T. Kershaw
Neurogen Corporation, 35 Northeast Industrial Road, Branford, Connecticut 06405
khodgetts@nrgn.com
Received February 7, 2002
ABSTRACT
The regiocontrolled synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thiazoles from ethyl 2-bromo-5-chloro-4-thiazolecarboxylate 1 using
sequential palladium-catalyzed coupling reactions is described.
Thiazoles occupy a prominent position among heterocycles.
In nature, the thiazolium ring is the chemically active center
in the coenzyme derived from vitamin B (thiamin). A large
number of thiazoles obtained from microbial and marine
origins exhibit important biological effects such as antitumor,
antifungal, antibiotic, and antiviral activities.1 Synthetic
thiazoles have also been shown to exhibit a wide variety of
biological activity,2 while others have found application as
liquid crystals3 and cosmetic sunscreens.4
The classical method for the synthesis of thiazoles is the
Hantzsch process, in which an R-haloketone is condensed
with a thioamide.5 This method gives excellent yields for
simple thiazoles; however, for some substituted examples
low yields have been reported as a result of dehalogenation
of the R-haloketone during the reaction.4,6 Notwithstanding
the Hantzsch process and other methods,7 we required a
flexible route that would give high yielding and rapid access
to a series of alkyl-, alkenyl-, alkynyl-, and aryl-substituted
thiazoles. A method involving a sequence of regioselective
palladium-catalyzed coupling reactions based upon a thiazole
scaffold was identified as an attractive possibility.8 The
previously unreported ethyl 2-bromo-5-chloro-4-thiazole-
carboxylate 1 was identified as a potential precursor. It was
anticipated that a palladium-catalyzed coupling reaction9
would be selective for the more electron-deficient 2-position
and that the C-2 substituent could be introduced first. A
second cross-coupling reaction could then be utilized for the
installation of the second substituent at C-5. The carboxylic
functionality could finally be exploited by a range of
synthetic maneuvers leading to the installation of a variety
of C-4 substituents (Figure 1).
(1) Lewis, J. R. Nat. Prod. Rep. 1996, 13, 435.
(2) Metzger, J. V. Thiazole and its DeriVatiVes; John Wiley & Sons:
New York, 1979, and references therein.
(3) Kiryanov, A. A.; Sampson, P.; Seed, A. J. J. Org. Chem. 2001, 66,
7925.
Figure 1.
(4) Bach, T.; Heuser, S. Tetrahedron Lett. 2000, 41, 1707.
(5) (a) Hantzch, Ber. Dtsch. Chem. Ges. 1888, 21, 942. (b) Wiley, R.
H.; England, D. C.; Behr, L. C. In Organic Reactions; John Wiley: 1951;
Vol. 6, p 367.
(6) Carter, J. S.; Rogier, D. J.; Graneto, M. J.; Seibert, K.; Koboldt, C.
M.; Zhang, Y.; Talley, J. J. Biorg. Med. Chem. Lett. 1999, 9, 1167.
(7) Metzger, J. V. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: Elmsford, Oxford, 1984; Vol. 6, p
235.
The synthesis of ethyl 2-bromo-5-chloro-4-thiazole-
carboxylate 1 is shown in Scheme 1. The commercially
available thiazole 310 was chlorinated at the 5-position by
treatment with N-chlorosuccinimide in refluxing aceto-
nitrile.11 The 2-amino substituent was then converted, under
10.1021/ol025688u CCC: $22.00 © 2002 American Chemical Society
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considerably longer (entry 2). The less hindered 4-methoxy-
phenylboronic acid proved significantly more reactive and
gave a much shorter reaction time (entry 3). Indeed, this
coupling could be accomplished in 16 h at room temperature
(entry 4). The Stille coupling reaction was investigated next.14
Using standard conditions and 1 equiv of vinyltributyltin,
exclusive coupling at the 2-position was observed, affording
4d in 91% isolated yield (entry 5). The Negishi coupling
reaction of 1 with 2-pyridylzinc bromide in THF at reflux
also gave exclusive coupling at C-2, producing 4e in 74%
yield (entry 6).15 Sonogashira reaction of 1 with phenyl-
acteylene gave 4f as the major-coupled product; however,
the yield was low and a large amount of resinous material
was formed during the reaction (entry 7).16 Low yields for
the Sonogashira and Heck reaction of 2-bromothiazoles have
previously been reported, and this was attributed to ring
cleavage of the thiazole following palladation at the 2-posi-
tion.17 In summary, the Suzuki, Stille, and Negishi reactions
were all regioselective for the electron-deficient 2-position,
and any byproducts (<5% yield) were due to dehalogenation
of the starting material 1 and product 4.
Scheme 1a
a Reaction conditions: (i) NCS, CH3CN, reflux, (91%); (ii)
tBuONO, CuBr2, CH3CN, 80 °C, (82%).
modified Sandmeyer conditions, to the 2-bromothiazole 1
in 82% yield. The synthesis of 1 was performed on a
multigram scale and required no chromatography.
The regioselectivity of palladium-catalyzed cross-coupling
reactions of 1 with a variety of organometallic reagents was
examined. Under standard Suzuki conditions12 and 1 equiv
of phenylboronic acid, exclusive coupling at the more
electron-deficient 2-position was observed, affording the
major product 4a in 81% isolated yield (entry 1, Table 1).
Under controlled conditions and 1 equiv of the organo-
metallic, there was no coupling at the 5-position during the
palladium-catalyzed coupling reaction. The next step, how-
ever, was to study the reactivity of the 5-chlorothiazole 4a
in a variety of coupling reactions (Scheme 2).
Table 1. Palladium-Catalyzed Coupling Reactions of 1
Scheme 2a
entry
R
conditionsa time (h) product yield (%)
1
2
3
4
5
6
7
Ph
i
i
i
ii
iii
iv
v
4
16
1
16
12
12
4
4a
4b
4c
4c
4d
4e
4f
81
76
92
88
91
74
19
2-MeOPh
4-MeOPh
4-MeOPh
vinyl
2-Pyridyl
CCPh
a Reaction conditions: (i) Pd(Ph3P)4, PhB(OH)2, aq. K2CO3,
PhMe, 80 °C, 16 h; (ii) Pd(Ph3P)2Cl2, CH2CHSnBu3, dioxane, 100
°C, 24 h; (iii) Pd(Ph3P)4, 2-pyridylzinc bromide, THF, 65 °C, 24
h; (iv) Pd(Ph3P)2Cl2, CuI, phenyl acteylene, Et3N, 80 °C, 24 h.
a Reaction conditions: (i) Pd(Ph3P)4, RB(OH)2, aq. K2CO3, PhMe, 80
°C; (ii) Pd(Ph3P)4, RB(OH)2, aq. K2CO3, PhMe, 20 °C; (iii) Pd(Ph3P)2Cl2,
CH2CHSnBu3, dioxane, 100 °C; (iv) Pd(Ph3P)4, 2-pyridylzinc bromide, THF,
65 °C; (v) Pd(Ph3P)2Cl2, CuI, phenyl acteylene, Et3N, 80 °C.
No coupling at the 5-position was observed. Two minor
byproducts (<5% yield) were formed during the reaction:
debromination of the starting material 1 and dechlorination
of the product 4a.13 Under the same conditions 2-methoxy-
phenylboronic acid gave exclusive coupling at the 2-position
although the reaction time for this hindered example was
As expected, longer reaction times and an excess of the
organometallic proved necessary to drive the reaction to
completion. In the Suzuki coupling, 4a required 2 equiv of
phenylboronic acid and a 16 h reaction time for complete
conversion at 80 °C, affording 5a in 87% yield. The Stille
and Negishi coupling reactions both required 3 equiv of the
organometallic and prolonged reaction times for complete
(8) For recent reviews of this general strategy, see: (a) Collins, I. J.
Chem. Soc., Perkin Trans. 1 2000, 2845. (b) Snieckus, V. Med. Res. ReV.
1999, 19, 342 and references therein.
(9) Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry;
Pergamon: Elmsford, Oxford, 2000; Chapter 7, p 297.
(10) (a) Maybridge Chemical Company, Trevillet, Tintagel, Cornwall,
PL34 OHW, U.K. (b) Plouvier, B.; Houssin, R.; Bailly, C.; Henichart, J.-
P. J. Heterocycl. Chem. 1989, 26, 1643.
(11) South, M. S. J. Heterocycl. Chem. 1991, 28, 1003.
(12) (a) Miyaura, N.; Suzuki, A. Chem ReV. 1995, 95, 2457. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147.
(14) (a) Stille, J. K. Angew. Chem. 1986, 98, 504. (b) Stille, J. K. Pure
Appl. Chem. 1985, 57, 1771.
(15) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42,
1821.
(16) (a) Cassar, L. J. Organomet. Chem. 1975, 93, 253. (b) Dieck, H.
A.; Heck, R. F. J. Organomet. Chem. 1975, 93, 259. (c) Sonogashira, K.;
Tohda, Y.; Nagihara, N. Tetrahedron Lett. 1975, 4467. (d) Takahashi, S.;
Kuroyama, Y.; Sonogashira, K.; Nagihara, N. Synthesis 1980, 627.
(17) Sakamoto, T.; Nagata, H.; Kondo, Y.; Shiraiwa, M.; Yamanaka,
H. Chem. Pharm. Bull. 1987, 35, 823.
(13) Kim, H.; Kwon, I.; Kim, O. J. Heterocycl. Chem. 1995, 32, 937.
1364
Org. Lett., Vol. 4, No. 8, 2002

consumption of the starting material, affording 5b and 5c in
72% and 70% yield, respectively. The Sonogashira reaction,
which was problematic with the 2-bromothiazole 1, gave a
cleaner reaction, affording 5d in 56% yield. In general, the
palladium-catalyzed coupling reactions of the 5-chloro-
thiazole 4a gave good yields of the expected 5-substituted
thiazole, although 2-3 equiv of the organometallic and
longer reaction times were required for complete conversion.
Sequential regioselective palladium coupling reactions
facilitated the installation of a variety of substituents at first
the C-2 and then the C-5 position of the thiazole. To extend
the usefulness of this process, a one-pot Suzuki coupling
procedure was investigated (Scheme 3). Using standard
Scheme 4a
a Reaction conditions: (i) NaOH, EtOH, rt, (92%); (ii) DMF-
H2O (1:1), 150 °C, (74%).
boronic acid, the 4-bromothiazole proved to be reactive,
affording after 2 h 10a in 94% yield. Standard Stille
conditions and 2 equiv of vinyltributyltin gave 10b in 81%
yield. Negishi coupling with 2-pyridylzinc bromide gave 10c
in 75% yield, and Sonogashira reaction with phenylacteylene
gave 10d in 61% yield (Scheme 5).
Scheme 3a
Scheme 5a
a Reaction conditions: (i) Pd(Ph3P)4 (5 mol %), 1 equiv of
4-MeOPhB(OH)2, aq. K2CO3, toluene, 80 °C, 1 h; (ii) Pd(Ph3P)4
(5 mol %), 2 equiv of PhB(OH)2, 80 °C, 16 h (72%).
Suzuki conditions the thiazole 1 was treated with 1 equiv of
4-methoxyphenylboronic acid at 80 °C. After 1 h no starting
material remained by TLC, and a further 5 mol % of
Pd(Ph3P)4 and 2 equiv of phenylboronic acid were added.
The reaction was reheated to 80 °C for a further 16 h and
following flash chromatography thiazole 6 was isolated in
72% yield. The structure of 6 was confirmed by treating the
5-chlorothiazole 4c with phenylboronic acid, which gave a
compound with spectral and physical properties identical to
those of 6. It was necessary to add the second 5 mol % of
Pd(Ph3P)4 to the reaction; failure to do so resulted in no
coupling at the 5-position and the intermediate 4c was
isolated as the major product.
The synthetic utility of the carboxylic functionality at C-4
could now be exploited by a variety of transformations. For
example, hydrolysis of the ester 5a with sodium hydroxide
in ethanol gave the acid 7 in 92% yield. Heating of the acid
6 in aqueous DMF at 150 °C for 18 h resulted in clean
decarboxylation and gave the 2,5-diphenyl thiazole 8 in 74%
yield (Scheme 4), thereby providing a route to 2,5-disubsti-
tuted thiazoles.
a Reaction conditions: (i) KOH, AgNO3, H2O; (ii) Br2, CCl4,
75 °C, (71%); (iii) Pd(Ph3P)4, PhB(OH)2, aq. K2CO3, PhMe, 80
°C, 2 h; (iv) Pd(Ph3P)2Cl2, CH2CHSnBu3, dioxane, 100 °C, 8 h;
(v) Pd(Ph3P)4, 2-pyridylzinc bromide 0.5 M, THF, 65 °C, 8 h; (vi)
Pd(Ph3P)2Cl2, CuI, phenyl acteylene, Et3N, 80 °C, 4 h.
The readily available ethyl 2-bromo-5-chloro-4-thiazole-
carboxylate 1 proved to be a versatile template for the
synthesis of 2,5-disubstituted and 2,4,5-trisubstituted thi-
azoles. Regioselective Suzuki, Stille, and Negishi coupling
reactions were used to install substituents at the C-2 thiazole
position. A second palladium-catalyzed coupling reaction was
then used to install substituents at the C-5 position. It was
also possible to combine two successive Suzuki coupling
reactions into a one-pot procedure. The carboxylic function-
ality at C-4 was decarboxylated and gave a 2,5-disubstituted
thiazole or was converted to the corresponding bromide. The
bromide was then exploited in a third palladium-catalyzed
coupling reaction to introduce substituents at C-4. The wide
range of compatible organometallic reagents offers consider-
able flexibility for the synthesis of substituted thiazoles.
Alternatively, a Hunsdiecker reaction18 was used to intro-
duce a halogen at the C-4 position that proved suitable for
further functionalization via palladium-catalyzed processes.
The acid 7 was converted to the corresponding silver salt
by treatment with silver nitrate and potassium hydroxide in
water. Heating the silver salt in the presence of 1 equiv of
bromine gave the 4-bromothiazole 9 in 71% yield.18 Under
standard Suzuki conditions and with 1 equiv of phenyl-
Acknowledgment. The authors gratefully thank Dr. Dario
Doller and Professor Rich Carter for helpful discussions.
Supporting Information Available: Spectroscopic data
for compounds 1, 4a-f, 5a-d, 6-9 and 10a-d. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) For a review, see: Johnson, R. G.; Ingham, R. K. Chem. ReV. 1956,
56, 219.
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