Efficient and regioselective halogenations of 2-amino-1,3-thiazoles with copper salts

Article abstract of DOI:10.1021/jo802799c

Monohalo and dihalo 1,3-thiazole derivatives can be efficiently and selectively prepared under mild conditions from 2-amino-1,3-thiazoles. Halogenations proceed easily in the presence of copper(I) or copper(II) chlorides, bromides, or iodides directly in

Full text of DOI:10.1021/jo802799c

SCHEME 1.
Bromination of 4-((3-Fluorophenyl)ethynyl)-
Efficient and Regioselective Halogenations of
2-Amino-1,3-thiazoles with Copper Salts
thiazol-2-amine (1) under Sandmeyer Conditions
Fabrice G. Sime´on,* Matthew T. Wendahl, and
Victor W. Pike
Molecular Imaging Branch, National Institute of Mental
Health, National Institutes of Health, Building 10, Room
B3C346A, 10 Center DriVe, Bethesda, Maryland 20892-1003
simeonf@intra.nimh.nih.goV
ReceiVed December 23, 2008
Dibromo-1,3-thiazole has also been produced under harsher
conditions with phosphorus oxybromide.6 Although these
procedures give access to a variety of halo-1,3-thiazoles, only
a limited number are commercially available. Moreover, these
methods have seldom shown applicability to the syntheses of
more complex thiazole-containing molecules bearing further
functional groups. In the course of our research to produce new
improved radioligands for the molecular imaging of brain
mGluR5 in vivo with positron emission tomography (PET),7
we aimed to synthesize new 2-halo-1,3-thiazole derivatives with
various appendages in position 4. One such compound, the
2-bromo-1,3-thiazole derivative (2), had previously been ob-
tained in high yield from compound 1, copper(II) bromide, and
tert-butyl nitrite under Sandmeyer conditions (Scheme 1).8
Surprisingly, in our hands, this reaction led predominantly
to the 2,5-dibromo adduct 3 with the targeted monobromo
compound 2 as minor product (Scheme 1). Classically, the
Sandmeyer reaction involves diazotization of an arylamine
followed by reaction of the formed diazonium salt with
copper(II) halide (CuX2, X ) Cl, Br, or I). Although good yields
of haloarenes are generally obtained, this procedure is usually
complicated by numerous competing side reactions. The scope
and limitations of the Sandmeyer reaction have been widely
investigated with various arenes,9 but little was previously
known about this reaction for the halogenation of 2-amino-1,3-
thiazoles.
Monohalo and dihalo 1,3-thiazole derivatives can be ef-
ficiently and selectively prepared under mild conditions from
2-amino-1,3-thiazoles. Halogenations proceed easily in the
presence of copper(I) or copper(II) chlorides, bromides, or
iodides directly in solution or with supported copper halides.
1,3-Thiazole rings appear in many compounds that exhibit
important biological and pharmacological activities. For ex-
ample, these rings feature in all the potent
epothilones1used against multidrug-resistant tumor cell lines.
They are also found among pharmaceuticals for the treatment
of type 2 diabetes,2 antibiotic-like compounds,3 and metabo-
tropic glutamate receptor subtype 5 (mGluR5) antagonists.4
1,3-Thiazole rings are usually introduced into target molecules
by use of a monohalo thiazole in an organometal-catalyzed
coupling procedure (e.g., a Sonogashira, Heck, or Suzuki
reaction). Traditionally, the required monohalo thiazoles have
been synthesized from 1,3-thiazole or 2-bromo-1,3-thiazole in
two or three steps via stannyl or silyl intermediates.5 2,4-
To investigate the reasons for the formation of the dibromo
compound 3 from 1, we synthesized the des-fluoro analogue 4
and used it as a model in bromination reactions conducted with
CuBr2 and n-butyl nitrite in acetonitrile (Scheme 2).
The effects of order and method of addition of reagents, the
temperature, and the nitrite to copper bromide mole ratio on
the yield of the dibromo compound 6b were investigated.
(5) (a) Dondoni, A; Mastellari, A. R.; Medici, A.; Negrini, E.; Pedrini, P.
Synthesis 1986, 9, 757. (b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. J. Org. Chem. 1988, 53, 1748.
(1) Nicolaou, K. C.; King, N. P.; Finlay, M. R. V.; He, Y.; Roschangar, F.;
Vourloumis, D.; Vallberg, H.; Sarabia, F.; Ninkovic, S.; Hepworth, D. Bioorg.
Med. Chem. 1999, 7, 665.
(6) (a) Stanetty, P.; Schnuerch, M.; Mihovilovic, M. D. J. Org. Chem. 2006,
71, 3754. (b) Le Flohic, A.; Meyer, C.; Cossy, J. Tetrahedron 2006, 62, 9017.
(7) (a) Sime´on, F. G.; Brown, A. K.; Zoghbi, S. S.; Patterson, V. M.; Innis,
R. B.; Pike, V. W. J. Med. Chem. 2007, 50, 3256. (b) Brown, A. K.; Kimura,
Y.; Zoghbi, S. S.; Sime´on, F. G.; Liow, J.-S.; Kreisl, W. C.; Taku, A.; Fujita,
M.; Pike, V. W.; Innis, R. B. J. Nucl. Med. 2008, 49, 2042. (c) Shetty, H. U.;
Zoghbi, S. S.; Sime´on, F. G.; Liow, J. S.; Brown, A. K.; Kannan, P.; Innis,
R. B.; Pike, V. W. J. Pharmacol. Exp. Ther. 2008, 327, 727.
(8) Iso, Y.; Grajkowska, E.; Wroblewski, J. T.; Davis, J.; Goeders, N. E.;
Johnson, K. M.; Sanker, S.; Roth, B. L.; Tueckmantel, W.; Kozikowski, A. P.
J. Med. Chem. 2006, 49, 1080.
(9) (a) Doyle, M. P.; Siegfried, B.; Dellaria, J. F. J. Org. Chem. 1977, 42,
2426. (b) Kochi, J. K. J. Am. Chem. Soc. 1957, 79, 2942.
(2) Fyfe, F. M. C. T.; Gardner, L. S.; Nawano, M.; Procter, J. M.; Rasamison,
C. M.; Shofield, K. L.; Shah, V. K.; Yasuda, K. PCT Int. Appl. WO 2004/
072031, 26 August 2004; Chem. Abstr. 2004, 141, 225496.
(3) Kelly, T. R.; Lang, F. Tetrahedron Lett. 1995, 36, 5319.
(4) (a) Cosford, N. D. P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N. D.;
Anderson, J. J.; Bristow, L.; Brodkin, J.; Jiang, X. H.; McDonald, I.; Rao, S.;
Washburn, M.; Varney, M. A. J. Med. Chem. 2003, 46, 204. (b) Hamill, T. G.;
Krause, S.; Ryan, C.; Bonnefous, C.; Govek, S.; Seiders, T. J.; Cosford, N. D. P.;
Roppe, J.; Kamenecka, T.; Patel, S.; Gibson, R. E.; Sanabria, S.; Riffel, K.;
Eng, W.; King, C.; Yang, X.; Green, M. D.; O’Malley, S. S.; Hargreaves, R.;
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2578 J. Org. Chem. 2009, 74, 2578–2580 10.1021/jo802799c This article not subject to U.S. Copyright. Published 2009 by the American Chemical Society
Published on Web 02/20/2009

TABLE 2. Yields of Monohalo and Dihalo Derivatives of
1,3-Thiazol-4-arylacetylenes
SCHEME 2.
4-(Phenylethynyl)thiazol-2-amine (4)
Reactions of Copper Halides with
product
methoda
R
X1
Cl
Br
I
Cl
Br
NH2
NH2
I
X2
yieldb (%)
5a
5b
5c
6a
6b
7a
7b
8
I
I
I
II
II
III
III
III then I
III then I
I
H
H
H
H
H
H
H
H
H
H
H
Cl
Br
Cl
Br
Cl
Br
H
33
46
50
35
79
51
94
42
13
32
TABLE 1. Yields of Products from the Bromination of 4 with
Various Reagents under Sandmeyer Conditions
9
11
H
CN
Cl
Br
brominating agenta
5b (%)b
6b (%)b
7b (%)b
a See Scheme 2 and the Experimental Section for details. b Yields are
for isolated pure materials.
c
CuBr2
94
d
CuBr2
99
CuBrd
98
67
9
conversion was slow below 0 °C but became rapid and complete
at 60 °C. Thus, reaction of 4 with copper(II) bromide in the
presence of n-butyl nitrite rapidly gives 7b and is followed by
a second slower step, the diazotization of the amino group, and
bromine insertion. The latter reaction can be avoided by omitting
n-butyl nitrite, resulting in a high yield (94%) of 7b (Table 1).
The desired 2-bromo compound 5b was not observed in the
preceding temperature study. However, it reached almost 50%
yield when the reaction was run at a low temperature (between
-10 and 0 °C) with the molar ratio of copper(II) bromide to
nitrite decreased to 0.5. At room temperature, under these
conditions, yields of 5b never exceeded 30%.
CuBr
KBr
KBr-CuBr
Br2
Alumina-KCuBr2
4
77
58
90
a All reactions were performed overnight with n-butyl nitrite at room
temperature, unless otherwise indicated. b Yields are conversion of 4
determined by HPLC. c Performed in the absence of n-butyl nitrite.
d Performed at 85 °C for 15 min.
To obtain the initially targeted 2-bromothiazole 5b in
acceptable yield, we tested the reactivity of 4 with a variety of
brominating agents under Sandmeyer conditions (Table 1).
CuBr, KBr, KBr-CuBr, Br2, or alumina-supported-KCuBr2 was
added to a solution of 4 and n-butyl nitrite. Remarkably, near
quantitative yields of 5b were obtained with CuBr. KBr gave
an inextricable mixture of products in which 5b was found in
only low yield. A moderately high yield of 5b was obtained
with KBr-CuBr. Molecular bromine selectively gave the di-
bromo-derivative 6b in moderate yield.
FIGURE 1. Yield of products with temperature for the reaction of 4
with copper(II) bromide and n-butyl nitrite (mole ratio, 1:1.2:1.2).
The supported copper(I) complex, alumina-KCuBr2, is an
efficient reagent for halogen exchange in haloarenes.10 This
reagent gave 5b selectively and in very high yield at room
temperature after 24 h (Table 1). By contrast, reactions run with
CuBr without alumina at this temperature gave lower yields.
Technically, the use of a supported reagent is very attractive as
the protocol for product extraction is simple filtration. Also this
room temperature procedure might potentially allow the halo-
genation of more complex molecules that would either decom-
pose or racemize in solution at higher temperatures.
We also prepared other alumina-supported copper(I) halides
(alumina-KCuX2, X ) Cl or I). Reaction of these reagents or
of the available CuXn salts (X ) Cl or Br for n ) 1 or 2, or for
I, n ) 1) with 4 or the 3-cyanophenyl analogue 9 led to several
new halo-1,3-thiazoles (Table 2). Iodination of 4 with alumina-
supported-KCuI2 appeared to reach an equilibrium, since a
second addition of reagent significantly improved the yield of
Temperature played a critical role in product outcome. Above
room temperature, we found that 6b was almost always the
major product (>70%), independent of the stoichiometry of
reagents and other factors. Use of amyl, tert-butyl or n-butyl
nitrite gave the same results; therefore the latter was used in
the rest of this work. When the reaction was performed at 85
°C, 6b was formed rapidly, reaching 99% yield after 15 min
(Table 1).
The fact that the dibromo compound 6b was produced
suggested that the reaction occurred in two steps via a
monobromo intermediate. To verify this hypothesis, 4 was
submitted to a temperature study in which reaction progress
was monitored by HPLC with the temperature rising by 10 °C
at intervals of 30 min ((5 min) (Figure 1). Initially, after 10
min of reaction at - 40 °C, 5-bromo-4-(phenyl)ethynyl-1,3-
thiazol-2-amine (7b) appeared in solution, showing bromination
to occur first at position 5. The ratio of 7b to 4 increased with
temperature. At - 10 °C, 7b was the only product. Above -10
°C, 7b converted into the dibromo compound, 6b. This
(10) Clark, J. H.; Jones, C. W.; Duke, C. V. A.; Miller, J. M. J. Chem. Res.
(S) 1989, 238.
J. Org. Chem. Vol. 74, No. 6, 2009 2579

Method II: Synthesis of Dihalo 1,3-Thiazoles 6a and 6b. The
2-aminothiazole 4 (40 mg, 0.20 mmol) and CuX2 (X ) Cl or Br;
0.30 mmol) were dissolved in acetonitrile (2 mL). This reaction
mixture was stirred at room temperature for 15 to 120 min (gentle
heating at 40 °C is necessary when using CuCl2 as the reaction
proceeds at a slower rate). Reaction was monitored by TLC. After
all starting material had been consumed, n-butyl nitrite (35 µL,
0.30 mmol) was added and the reaction was stirred for an additional
15 min at 65 °C. The reaction mixture was then cooled and the
acetonitrile evaporated off in vacuo. The residue was dissolved in
ethyl acetate (20 mL) and washed with ammonia solution (0.1 M;
2 × 50 mL). The organic layer was collected, dried over MgSO4,
and evaporated to dryness in vacuo. The residue was purified by
chromatography on silica gel (hexane-ethyl acetate; 97: 3, v/v).
This procedure gave 6a and 6b in 35% and 79% yield, respectively.
Method III: Synthesis of 2-Amino-5-halo-1,3-thiazolarylacety-
lenes 7a and 7b. 2-Aminothiazole derivative 4 (52 mg, 0.26 µmol)
and CuX2 (X ) Cl or Br; 0.26 µmol) were dissolved in acetonitrile
(2.5 mL). This reaction mixture was stirred at rt for 10 h. The
reaction mixture was then evaporated to dryness in vacuo, and the
residue was dissolved in ethyl acetate (20 mL) and washed with
aqueous ammonia (0.1 M; 2 × 50 mL). The organic layer was
dried over MgSO4 then evaporated to dryness in vacuo. The residue
was purified by chromatography on silica gel (hexane-ethyl acetate;
70: 30, v/v). This procedure gave 7a and 7b in 51% and 94% yield,
respectively.
General Procedure for the Halogenation of 4 on Supported
Copper(I) Salts. Potassium halide (1 mmol) and copper(I) halide
(1 mmol) were mixed in a flask containing neutral aluminum oxide
(3 g). A solution of water (0.1% v/v) in acetonitrile (5 mL) was
added and the mixture was stirred in an open vessel until solvent
had completely evaporated off. The residue was placed in an oven
at 100 °C for 24 h and stored at room temperature before use.
2-Aminothiazole 4 (25 µmol) was dissolved in acetonitrile (3.5 mL)
with n-butyl nitrite (30 µmol) at room temperature. The reaction
mixture was stirred for 15 min and then a supported copper(I) halide
(0.5 g) was added. The reaction mixture was stirred overnight at
room temperature. Then acetonitrile was filtered off and the residue
was rinsed with ethyl acetate. The organic solutions were combined
and solvent evaporated off. The residue was purified by chroma-
tography on silica gel. This procedure produced compounds 5a,
5b, and 5c in 56%, 83%, and 62% yield, respectively.
5c. Having demonstrated the regioselectivity of these reactions,
we speculated that it would be possible to introduce different
halogens selectively in two steps at two different positions. The
synthesis of 2-iodo-5-chlorothiazole derivative 8 and 2-chloro-
5-bromothiazole derivative 9 demonstrated that this was indeed
possible with these versatile procedures. The methods are only
limited by the availabilities of the halogenation reagents;
therefore no 5-iodo analogue could be produced as unstable CuI2
is not commercially available.
It has been established that the Sandmeyer reaction proceeds
via formation of radical species.11 Nevertheless, in the case of
the 2-amino-1,3-thiazole derivative 4, addition of the radical
trap TEMPO or of the radical initiator AIBN failed to modify
the yields of reaction or the ratios of the products 5b, 6b, and
7b, suggesting that the reactions proceeded according to ionic
mechanisms.
In conclusion, we have shown that halo-1,3-thiazole deriva-
tives can be prepared regioselectively and efficiently with a
variety of simple reagents. Regioselective halogenation in
position 5 of 2-amino-1,3-thiazoles was achieved at room
temperature by reaction with CuX2 (X ) Cl or Br) in
acetonitrile. Dibromination was realized in high yield with
n-butyl nitrite and CuX2 at temperatures above 65 °C and
halogenation in position 2 was achieved selectively by using
an alumina-supported copper(I) material or CuX (X ) Cl, Br,
or I). The methods we described here for selective halogenations
of 2-amino-1,3-thiazole derivatives were mild and were suc-
cessfully used on variously substituted compounds and led to
several new iodo, bromo, and chloro derivatives. These are
especially interesting as potential intermediates for new mGluR5
ligands, and could lead to the development of new PET
radioligands by radiofluorination12 or new SPECT radioligands
by radioiodination.13
Experimental Section
Method I: Synthesis of 2-Halo-1,3-thiazolarylacetylenes 5a-c.
The 2-aminothiazole 4 (182 mg, 0.91 mmol) and CuX (1.39 mmol,
X ) Cl, Br, or I) were dissolved in acetonitrile (8 mL) at room
temperature. n-Butyl nitrite (162 µL, 1.39 mmol) was added with
stirring, and the solution was heated to 60 °C. The reaction was
complete after 15 min, as monitored by TLC. The reaction mixture
was then evaporated to dryness in vacuo. The residue was dissolved
in ethyl acetate (20 mL) and washed with ammonia solution (0.1
M; 2 × 50 mL). The organic layer was dried over MgSO4 and
evaporated to dryness in vacuo. The residue was purified by
chromatography on silica gel (hexane-ethyl acetate; 97: 3, v/v).
This procedure gave 5a, 5b, and 5c in 33%, 46%, and 50% yield,
respectively.
In the case of the Al2O3-KCuI2, the reaction was incomplete
after 24 h at room temperature. Addition of more supported reagent
(0.5 g) led to reaction completion after a further 12 h. The mixture
was filtered and the filtrate was washed with sodium metabisulfate
and dried over magnesium sulfate. Finally, solvents were evaporated
off and product purified with chromatography.
Acknowledgement. This work was supported by the Intra-
mural Research Program of the National Institutes of Health
(NIMH).
(11) Friedman, L.; Chlebowski, J. F. J. Org. Chem. 1968, 33, 1633.
(12) (a) Sime´on, F. G.; Pike, V. W. J. Labelled Compd. Radiopharm. 2005,
48 (1), S158. (b) Cai, L.; Lu, S. Y.; Pike, V. W. Eur. J. Org. Chem. 2008, 17,
285.
(13) See: (a) Kabalka, G. W.; Gooch, E. E.; Sastry, K. A. R. J. Nucl. Med.
1981, 22, 908. (b) Dewanjee, M. K. Radioiodination: Theory, Practice, and
Biomedical Application, DeVelopments in Nuclear Medicine; Kluwer Academic
Publishers: Dordrecht, The Netherlands, 1992.
Supporting Information Available: Other experimental
procedures, characterization data for compounds 4-11, and
copies of 1H and 13C spectra of new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO802799C
2580 J. Org. Chem. Vol. 74, No. 6, 2009