Halogenated 2′-chlorobithiazoles via Pd-catalyzed cross-coupling reactions

Article abstract of DOI:10.1021/jo0601009

Halogenated bithiazoles allow facile further functionalization and are, therefore, suitable intermediates for the synthesis of compounds with interesting biological activity or material science properties. The applicability of three coupling methods (Negi

Full text of DOI:10.1021/jo0601009

Halogenated 2′-Chlorobithiazoles via Pd-Catalyzed Cross-Coupling
Reactions
Peter Stanetty,* Michael Schnu¨rch, and Marko D. Mihovilovic
Institute of Applied Synthetic Chemistry, Vienna UniVersity of Technology, Getreidemarkt 9/163-OC,
A-1060 Vienna, Austria
peter.stanetty@tuwien.ac.at
ReceiVed January 18, 2006
Halogenated bithiazoles allow facile further functionalization and are, therefore, suitable intermediates
for the synthesis of compounds with interesting biological activity or material science properties. The
applicability of three coupling methods (Negishi, Suzuki, and Stille) for the synthesis of the title compounds
was compared. The Negishi method proved to be troublesome, and side reactions were predominant.
The synthesis of the first thiazoleboronic acid ester offered a new method for the formation of bithiazoles,
not generally applicable so far. The lower toxicity compared to that of tin organyls make this method an
approach with interesting perspectives. The Stille coupling proved to be superior to the other methods
and enabled the synthesis of the title compounds with diverse connectivity.
Introduction
complex molecules, as an important contribution to this field
of research. Additionally, starting materials should be cheap and
readily available, either from commercial sources or via well-
established transformations. Two principle methods for the
synthesis of bithiazoles are reportedscyclization strategies and
cross-coupling protocolsswhereby the first method is predomi-
nating. In the cases of I, II, IV, and V, cyclization strategies
were applied, although I was also prepared via cross-coupling
methods, as was the case for the bithiazole motif in III.
In contrast to cyclization reactions, palladium-catalyzed cross-
coupling reactions3 offer the possibility to prepare a wide range
of compounds from a small number of selected starting
materials. Cross-coupling reactions are, nowadays, a well-
established method for the formation of C-C and even C-X
(X ) N, O, S) bonds. Especially, cross-coupling reactions to
biphenyl compounds are extensively investigated, and a still-
growing number of efficient catalysts with various ligands are
available for these transformations.4 Heterocyclic substrates on
The bithiazole motif can be found in a number of molecules
with interesting properties. Besides compounds with biological
activities in various fields,1 a number of compounds with
attractive qualities in material sciences were reported in the
literature (Figure 1).2 We, therefore, consider the availability
of versatile methods for the efficient synthesis of bithiazole
building blocks, which can further be functionalized to more
* Corresponding author. Fax: +43-1-58801-15499.
(1) Selected examples: (a) Ojika, M.; Suzuki, Y.; Tsukamoto, A.;
Sakagami, Y.; Fudou, R.; Yoshimura, T.; Yamanaka S. J. Antibiot. 1998,
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D.; MacDonald, D. PCT Int. Appl. WO 2004096220, 2004; Chem. Abstr.
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WO 2005033288, 2005; Chem. Abstr. 142:367707. (d) Riego, E.; Hernandez,
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H.; Inoue, Y.; Tokito, S.; Yamashita, Y. J. Am. Chem. Soc. 2005, 127,
14996-14997. (b) Cao, J.; Kampf, J. W.; Curtis, M. D. Chem. Mater. 2003,
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10.1021/jo0601009 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/11/2006
3754
J. Org. Chem. 2006, 71, 3754-3761

Cross-Coupling Reactions toward Bithiazoles
FIGURE 1. Selected bithiazole compounds with interesting biological activity or material science properties.
the other hand are by far less represented in the literature, and
hardly any systematic studies of various ring-systems are
available.5 Often, efficient reaction conditions for biphenyl
formation give lower or unsuccessful results on heterocyclic
systems. Cross-coupling reactions leading to biheteroaryl com-
pounds are even less investigated.6
We, therefore, embarked in a systematic research program
focused on the formation of such biheteroaryl systems and
started with the synthesis of bithiazole compounds. Dondoni
and co-workers7 reported the formation of all possible bithiazole
compounds via a Stille reaction, but this work was limited with
one exception only to the parent systems bearing no substituents
for subsequent functionalizations. Additionally, the Negishi8 and
Stille9 reactions already proved to be efficient in the synthesis
of selected functionalized bithiazole systems.10,11 In this study,
we compared three cross-coupling methodologies (Negishi,
Stille, and Suzuki-Miyaura12) in the formation of bithiazoles.
For Suzuki-Miyaura reactions, we had to establish thiazole-
boronic acids or esters as cross-coupling partners, a compound
class not known in the literature, so far. Although 2-thiazole-
boronic acid was claimed in patents, its actual preparation
remains doubtful.13 The only nonpatent reference indirectly
claimed the formation of 2-thiazoleboronic acid, but no prepara-
tion procedure is given.14
As starting material, we chose 2-chlorothiazole (1), because
it is readily available from commercial 2-aminothiazole via a
Sandmeyer reaction.15 The formation of the metal organyl in
(8) (a) King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc., Chem.
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Chem. 1977, 132, C17-C19. (c) Dai, C.; Fu, G. C. J. Am. Chem. Soc.
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1996, 473-474. (e) Knochel, P.; Jones, P., Eds. Organozinc Reagents;
Oxford University Press: Oxford, U.K., 1999.
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3638. (b) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508-524. (c) Farina,
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Chemistry, 2nd ed.; John Wiley & Sons: Chichester, U.K., 2004.
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3185. (b) Shao, J.; Panek, J. S. Org. Lett. 2004, 6, 3083-3085. (c) Bach,
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Chem., Int. Ed. 2005, 44, 1199-1201.
(12) (a) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979,
866-867. (b) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979,
3437-3440. (c) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-
2483. (d) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168. (e) Kotha,
S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633-9695. (f) Martin,
A. R.; Yang, Y. Acta Chem. Scand. 1993, 47, 221-230. (e) Suzuki, A.
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(4) (a) Stanforth, S. P. Tetrahedron 1998, 54, 263-303. (b) Anctil, E.
J.-G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150-160. (c) Zhang,
Z.; Mao, J.; Wang, R.; Wu, F.; Chen, H.; Wan, B. J. Mol. Catal. A: Chem.
2006, 243, 239-243. (d) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. ReV. 2002, 102, 1359-1469.
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Marsais, F.; Queguiner, G. Can. J. Chem. 2001, 79, 1754-1761. (b) Li, J.
J.; Gribble, G. W. Palladium in Heterocyclic Chemistry - A Guide for the
Synthetic Chemist; Pergamon Press: Elmsford, NY, 2000. (c) Schro¨ter, S.;
Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245-2267. (d) Chinchilla, R.;
Najera, C.; Yus, M. Chem. ReV. 2004, 104, 2667-2722.
(6) Selected examples: (a) Sandosham, J.; Undheim, K. Acta Chem.
Scand. 1989, 43, 684-689. (b) Thompson, A. E.; Batsanov, A. S.; Bryce,
M. R.; Saygili, N.; Parry, P. R.; Tarbit, B. Tetrahedron 2005, 61, 5131-
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2004, 2, 852-857. (d) Kaae, B. H.; Krogsgaard-Larsen, P.; Johansen, T.
N. J. Org. Chem. 2004, 69, 1401-1404. (e) Stanetty, P.; Hattinger, G.;
Schnu¨rch, M.; Mihovilovic, M. D. J. Org. Chem. 2005, 70, 5215-5220.
(f) Stanetty, P.; Schnu¨rch, M.; Mihovilovic, M. D. Synlett 2003, 1862-
1864. (g) Seley, K. L.; Salim, S.; Zhang, L.; O’Daniel, P. I. J. Org. Chem.
2005, 70, 1612-1619. (h) Collins, I.; Castro, J. L.; Street, L. J. Tetrahedron
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SanMartin, R. Eur. J. Org. Chem. 2002, 2126-2135.
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P. Synthesis 1986, 757-760. (b) Dondoni, A.; Fogagnolo, M.; Medici, A.;
Negrini, E. Synthesis 1987, 185-186. (c) Dondoni, A.; Fantin, G.;
Fogagnolo, M.; Medici, A.; Pedrini, P. J. Org. Chem. 1988, 53, 1748-
1761.
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Sikorski, J. A. PCT Int. Appl. WO 2003053368, 2003; Chem. Abstr. 139:
85160. (b) Wallace, O. B.; Wang, T.; Yeung, K.; Pearce, B. C.; Meanwell,
N. A.; Qiu, Z.; Fang, H.; Xue, Q. M.; Yin, Z. U.S. Pat. Appl. US
2003069245, 2003; Chem. Abstr. 138:304300. (c) Wallace, O. B.; Wang,
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Weber, A. E. Bioorg. Med. Chem. Lett. 2005, 15, 2533-2536.
J. Org. Chem, Vol. 71, No. 10, 2006 3755

Stanetty et al.
FIGURE 2. Applied cross-coupling strategy for the formation of bithiazoles and possible further transformations.
SCHEME 1. Negishi Attempts toward Bithiazolesa
a (i)n-BuLi, ZnI2, THF, -80 °C; (ii) iodobenzene, Pd(PPh3)4, THF, 120 °C, mw; (iii) 2-bromothiazole, Pd(PPh3)4, THF, 170 °C, mw.
the 5-position and subsequent cross-coupling with various
halothiazoles should give the desired bithiazoles, maintaining
the chlorine and the introduced thiazole ring for various
subsequent transformations (Figure 2).
Nevertheless, 2-bromothiazole (3) was also applied to Negishi
cross-coupling conditions with 1a, and the conversion was
monitored by GC-MS analysis. We found that under reflux
conditions no conversion was observed. Initial microwave
experiments (130 °C, 20min) gave the same results. When the
temperature was raised to 170 °C (15bar, 20min), three different
products were formed besides starting material 3 as the major
component, indicating a slow cross-coupling process (Scheme
1). The new compounds included the desired bithazole 4,
however, in the lowest amount of all reaction products. The
major new compound was 2,2′-bithiazole (5),8b,16 derived from
a homo coupling of 3. 2,2′-Dichloro-5,5′-bithiazole (6) was
detected as another homocoupling product derived from the
organozinc intermediate 1a. As a result of their similar proper-
ties, the three compounds could not be separated on preparative
scale, but their relative ratio was determined by GC-MS analysis
(Scheme 1). The structures of compounds 5 and 6 were assigned,
because GC-MS data of the pure compounds were available in
our laboratory. Significant hydrolysis of 1a could be ruled out,
because additional heating under the same conditions gave
further conversion to the three initially observed compounds.
Obviously, high temperatures are required for a successful cross-
coupling, but then side reactions leading to homocoupling
products are dominant. We, therefore, did not investigate the
Negishi method further.
Results and Discussion
Initially, we investigated the Negishi protocol, because it gave
excellent results in the formation of 2,4′-bithiazoles in the
synthesis of cystothiazoles.10,11 Additionally, toxicity is less
problematic compared to that of the Stille reaction, and
preparation of the organometal species should be less elaborate
as was expected for thiazoleboronic acids. In a test reaction,
the metal organyl was prepared from 1 via lithiation at the
5-position with LDA and subsequent quenching with ZnI2.
Cross-coupling with iodobenzene under thermal conditions and
Pd(PPh3)4 catalysis gave no conversion to the desired 2-chloro-
5-phenylthiazole (2). When the cross-coupling reaction was
performed under microwave conditions (120 °C, THF, 10 min)
25% of 2a was formed (Scheme 1) and only minor amounts of
1 were recovered as a result of its volatility. This is consistent
with the literature to a certain extent, because Bach reported
successful Negishi reactions only for 4-thiazolyl zinc reagents
bearing alkyl substituents in the 2-position. This is, of course,
the case for cystothiazoles with an isopropyl group in that
position, but even phenyl or alkynyl substituents in the 2-position
did not give any conversion.10b
As a result of the high toxicity of the tin compounds, we
decided to investigate the Suzuki-Miyaura reaction next. The
(15) (a) Bowden, M. C. U.K. Pat. Appl. GB 2323595, 1998; Chem. Abstr.
130:52410. (b) Vernin, G.; Metzger, J. Bull. Soc. Chim. Fr. 1963, 2504-
2508.
(16) Erlenmeyer, H.; Schmid, E. H. HelV. Chim. Acta 1939, 22, 698-
700.
3756 J. Org. Chem., Vol. 71, No. 10, 2006

Cross-Coupling Reactions toward Bithiazoles
SCHEME 2. Formation of Bithiazoles via Suzuki-Miyaura or Stille Reactionsa
a (i) (1) LDA, B(O-iPr)3, THF, -80 °C to room temperature; (2) pinacol, CH3COOH. Cross-coupling conditions: halide, dry dioxane, Pd(PPh3)4, Cs2CO3,
mw or thermal.
formation of bithiazoles via this method initially required a
protocol for the formation of the corresponding thiazoleboronic
acid or ester. Therefore, 2-chlorothiazole 1 was added to a
mixture of LDA and B(O-iPr)3 at -80 °C. Via this method, the
initially lithiated species should be trapped by the boron
electrophile in the moment of formation. Nevertheless, isolation
of the resulting boronic acid proved to be impossible due to
the very limited stability of this species. A workup protocol
developed for the formation of 2-pyridineboronic acid,17 which
is sensitive to deboronation, failed in our hands, and only starting
material 1 was recovered. This result indicated a strong tendency
of initially formed 5-thiazoleboronic acid to decompose in a
deboronation reaction. We, therefore, decided to synthesize the
corresponding 5-thiazoleboronic acid pinacol ester (1b), for
which a higher stability was expected, by adding a transesteri-
fication step to the reaction protocol. After aqueous workup and
purification by Kugelrohr distillation, 1b was obtained in 30%
yield (Scheme 2). In scale-up experiments, considerably lower
yields (<10%) were obtained independent of concentration
effects. A modification of the workup procedure toward a water-
free protocol18 drastically improved the result. A simple filtration
of the reaction mixture through a pad of Celite and evaporation
of the solvent gave 1b in excellent 86% yield after Kugelrohr
distillation. This is also an indication for the very low stability
of thiazoleboronic acids under aqueous conditions. To the best
of our knowledge, 1b is the first successfully synthesized and
characterized thiazoleboronic acid ester.
mixture was heated under microwave conditions to 150 °C for
30 min, but no conversion to the desired product was observed.
When the temperature was increased to 170 °C for 120 min,
again no product was formed, but 1b obviously decomposed.
We changed the base and followed a literature reference19 to
identify Cs2CO3 as an efficient base to give a cross-coupling
reaction with iodobenzene to compound 2a. Elevated temper-
atures facilitated the transformation, and the best results were
obtained using microwave irradiation (130 °C, dioxane, Pd-
(PPh3)4), providing efficient conversion and minimizing the
decomposition of 1b under the reaction conditions. GC-MS
analysis after 20 min of microwave irradiation indicated that
1b has either reacted to the product or is decomposed to 1.
Compound 2a was isolated in 56% yield. Thoroughly dried
dioxane (over Na) and Cs2CO3 (160 °C, drying pistol) improved
the stability of 1b considerably in the reaction mixture. We
found that the boronic ester was now stable for several hours
at high temperatures but, interestingly, reacted at lower rates
than in the presence of traces of water. Instead of 20 min at
130 °C, now almost 3 h at 170 °C were necessary to obtain
78% (GC-MS) conversion to 2a. Similar results indicating a
catalytic effect of trace amounts of water have been reported in
the literature.20
Further attempts to improve the cross-coupling yield were
performed. The addition of ionic liquids to the reaction mixture
to increase the temperature only led to the fast deboronation of
1b, and no cross-coupling product 2a was observed. Using
graphite, another good microwave absorber, instead gave about
50% conversion to 2a after 20 min, according to GC-MS
analysis, but decomposition of the remaining 1b to 2-chlo-
rothiazole, therefore, did not lead to an improvement in the yield.
As a result of the instability of 1b under aqueous conditions,
a water-free cross-coupling protocol was required. First we used
solid Na2CO3 in DME and Pd(PPh3)4 as catalyst. The reaction
(17) (a) Bouillon, A.; Lancelot, J.-C.; de Oliveira Santos, J. S.; Collot,
V.; Bovy, P. R.; Rault, S. Tetrahedron 2003, 59, 10043-10049.
(18) Coudret, C. Synth. Commun. 1996, 26, 3543-3547.
(19) Boykin, D. W.; Tao, B. J. Org. Chem. 2004, 69, 4330-4335.
(20) Dallas, A. S.; Gothelf, K. J. Org. Chem. 2005, 70, 3321-3323.
J. Org. Chem, Vol. 71, No. 10, 2006 3757

Stanetty et al.
TABLE 1. Cross-Coupling Results of 1b and 1c with Various
Halothiazoles under Microwave Irradiation
product. Because only small amounts were detected, no further
investigations into this direction were undertaken. Minor
amounts of 4-bromothiazole (9) were detected, which must be
formed by the reduction of the administered halide in the
2-position. The least reactive bromothiazole 9 gave the lowest
yield (9%). In this case, dry conditions did not give any
conversion, and only in the presence of traces of water was
conversion achieved (entry 10). Under such conditions, 1b has
a very limited stability and, therefore, the yield could not be
improved. When Et3N was used as the homogeneous base
instead of Cs2CO3, no conversion was observed at all (entry
11). Based on the poor yields even for the most reactive
bromothiazoles and as a result of the side reactions encountered,
we moved on to investigate the Stille reaction as a final
alternative.
T
time
yield
entry halide
method
Suzuki (1b) Cs2CO3 170
Suzuki (1b) KOAc 170
Suzuki (1b) Cs2CO3 130
base
(°C) (min) product (%)
1
2
3
3
20
70
4
4
37a
32a
19c
6b
3
3
20
4
4
5
6
3
3
3
Stille (1c)
Stille (1c)
Stille (1c)
170
170
170
110
150
20
4
4
4
44c
56a
17a
69b
81a
7
8
9
10
11
12
13
14
15
16
7
7
7
9
9
9
12
12
13
17
Suzuki (1b) Cs2CO3 170
40
20
20
60
60
120
30
60
120
30
10
10
10
11
11
11
4
14
15
15
Stille (1c)
Stille (1c)
170
170d
Suzuki (1b) Cs2CO3 170
9a,e
Suzuki (1b) NEt3
Stille (1c)
Stille (1c)
Stille (1c)
Stille (1c)
170
125
170
170
125
170
0a
36a
14a
36c
52a
33a
The starting material, 2-chloro-5-tributylstannylthiazole (1c)
was prepared in 96% yield from 1 via lithiation with LDA at
-70 °C in dry THF and subsequent quenching with Bu3SnCl.
Again, cross-coupling with iodobenzene was used as the test
reaction under microwave conditions (170 °C, benzene, Pd-
(PPh3)4, 20 min) and afforded 2a in a promising 82% yield.
However, when 3 was used as the halide, only 6% of product
4 was obtained under the same reaction conditions (entry 4).
The yield could be improved to 44% by using a different catalyst
(PdCl2(PhCN)2; entry 5). When freshly prepared Pd(PPh3)4 was
used, even better results (56% of 4, entry 6) were obtained,
which confirmed our experience that commercially available
Pd(PPh3)4 is of varying quality. A similar trend was observed
with thiazole halide 7. With commercially available Pd(PPh3)4,
69% of 10 was obtained (Table 1, entry 8), whereby the freshly
prepared catalyst gave 81% of 10 even under reflux conditions
without microwave irradiation (entry 9)
Stille (1c)
a Freshly prepared Pd(PPh3)4. b Commercially available Pd(PPh3)4.
c PdCl2(PhCN)2. d Alternatively under reflux. e Traces of water present.
Attempts to improve the yields by switching to other catalytic
entities are currently under way in our laboratory.
Additionally, we investigated the influence of electron-
donating and electron-withdrawing substituents on the outcome
of the Suzuki-Miyaura cross-coupling reaction. Therefore,
4-iodoanisole, 4-iodonitrobenzene, and 4-iodobenzonitrile were
tested as halides. We found that in all three cases similar results
were obtained. With 4-iodonitrobenzene and 4-iodobenzonitrile,
32% (2d) and 27% (2c) of the cross-coupling product were
isolated. 4-Iodoanisole gave only 13% of the desired compound
2b, accompanied by another 13% of 2a, derived from a ligand
exchange from Pd(PPh3)4, a phenomenon already described in
the literature.21 Therefore, also in this case, 26% of cross-
coupling products were obtained, which lies within the range
of the other two investigated halides. The results remained the
same, no matter if the boronic acid ester or the halide were
used in excess. Because with Cs2CO3 a heterogeneous base was
used, we also added, in one experiment (4-iodonitrobenzene as
halide), 2 equiv of EDTA to the reaction mixture to get the
base in solution through complexation. In this case, no cross-
coupling product 2d was detected, and only starting material
was recovered.
Optimized cross-coupling reaction conditions were then
applied to conversions of 1b with several bromothiazoles (Table
1). The best yield (37%) was obtained using 2-bromothiazole
(3) at 170 °C. At 130 °C, only 19% of 4 was obtained. Again,
2,2′-bithiazole (5), derived from a homocoupling of the applied
halide, was isolated as byproduct (13%; entry 1). When the
weaker base KOAc was used instead of Cs2CO3, slightly lower
yields (32%) were obtained, but no 5 was formed (entry 2).
Dibromide 7 gave even lower yields (17%) of the desired
product 10 (entry 7), and a number of additional side reactions
were observed. Surprisingly, 4-bromo-2-chlorothiazole (8) was
formed as a byproduct, according to GC-MS analysis. To prove
the structure of compound 8, it was alternatively synthesized
from 7 via a lithiation with n-BuLi in the 2-position and
subsequent quenching with hexachloroethane (see experimental
part). Eventually, reductive elimination from a Pd species
formed in the course of the reaction can proceed to this side
Subsequently, other halothiazoles were submitted to the cross-
coupling conditions (Table 1). The least-reactive 4-bromothia-
zole 9 gave 36% of the cross-coupling product (entry 12). 2,5-
Dibromothiazole (12) was converted to the desired cross-
coupling product 14 in 36% yield under PdCl2(PhCN)2 catalysis
(entry 14). When Pd(PPh3)4 was used, dehalogenated product
4 and 2,5-bis-coupled compound 17 were obtained instead of
the desired product (entry 13 and Scheme 3). It seems that Pd-
(PPh3)4 is reactive enough to insert into the C-Br bond in the
5-position of the initially cross-coupled product with subsequent
cross-coupling to 16 (4%) or debromination to 4 (14%), and
byproducts were not observed under PdCl2(PhCN)2 catalysis.
This is in contrast to Dondonis work, who reported that Pd-
(PPh3)4-catalyzed Stille cross-coupling of 12 with 2-trimethyl-
silyl-4-trimethylstannylthiazole gave 4-bromo-2′-trimethylsilyl-
2,4′-thiazole in 76% yield without this side reaction.8b A similar
result was obtained when 2-bromo-5-iodothiazole (17) was used
(entry 16 and Scheme 3). In this case, the initial cross-coupling
took place in the 5-position, followed by a second cross-coupling
in the 2-position to give 16 (9%) or dehalogenation to 15 (33%).
Desired 5-bromo-2′-chloro-2,5′-bithiazole was not observed. In
the reaction with 17, a homocoupling product 6 (28%), derived
from 1c, was also obtained. This was not observed in any other
case. Finally, 5-bromothiazole (13) was cross-coupled to 15 in
52% yield (entry 15) without any side reactions.
In the cases of halides 9 and 13 (entries 11 and 14), lower
temperatures proved to be superior, whereby in all other
examples, higher temperatures gave the best results. This might
be due to a limited stability of 1c in the presence of a Pd catalyst.
(21) Segelstein, B. E.; Butler, T. W.; Chenard, B. L. J. Org. Chem. 1995,
60, 12-13.
3758 J. Org. Chem., Vol. 71, No. 10, 2006

Cross-Coupling Reactions toward Bithiazoles
SCHEME 3. Byproduct Formations in Stille Cross-Coupling
Reactions of 1ca
Experimental Section
General Cross-Coupling Procedures. Stille: The stannane 1c
(1 equiv), the halide (1 equiv), and the catalyst (0.05 equiv) were
dissolved in benzene or toluene and heated in a CEM Explorer
PLS microwave unit under nitrogen. The temperature in all
microwave experiments was measured with an external IR sensor.
Alternatively, in the case of iodobenzene, refluxing overnight gave
similar results.
Suzuki-Miyaura: Boronic acid ester 1b (1 equiv) and the
corresponding halide (1 equiv) were heated in thoroughly dried
dioxane (distilled from Na) with the corresponding catalyst (0.05
equiv, Table 1) and Cs2CO3 as base (2 equiv) to 170 °C under
microwave conditions until complete consumption of 1b, according
to GC-MS analysis.
General Workup Procedure for Cross-Coupling Reactions:
The reaction mixture was filtered, the solvent evaporated, and the
residue purified by MPLC (LP/EtOAc, 15:1). The product fractions
were united, and the solvent was evaporated. In the case of Stille
examples, the residue was then treated with light petroleum (LP)
to remove the remaining stannane fragments.
2-Chloro-5-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)thia-
zole (1b): To a solution of LDA (1.1 equiv, 9.20 mmol) and B(O-
i-Pr)3 (1.3 equiv, 2.04 g, 10.87 mmol) in dry diethyl ether (100
mL) 1 (1 equiv, 1.0 g, 8.36 mmol) was added at -90 °C. The
reaction mixture was slowly warmed to room temperature before
pinacol (1.4 equiv, 1.38 g, 11.71 mmol) in diethyl ether (10 mL)
was added. After 15 min, AcOH (1.1 equiv, 0.55 g, 9.20 mmol) in
0.5 mL of diethyl ether was added, and the reaction mixture was
immediately filtered through Celite. The solvent was evaporated,
and the crude material was purified by Kugelrohr distillation to
give 86% (1.76 g, 7.16 mmol) of 1b as a colorless liquid: bp 100
°C (0.15 mbar). Compound 1b decomposes on silica gel and
a Conditions: halide, benzene or toluene, Pd(PPh3)4, 125 °C, mw.
In a blind experiment, 1c was heated in benzene to 170 °C for
20 min without addition of the halide and catalyst. GC-MS
analysis showed that no decomposition occurred, and thermal
instability could be ruled out. In contrast, complete decomposi-
tion was observed after 20 min when the experiment was
repeated in the presence of the Pd catalyst (without any coupling
partner). It seems that considerable decomposition takes place
in the presence of the Pd catalyst, besides cross-coupling. While
the reaction rate increases at high temperatures, the stability of
the reagent is decreased. At lower temperatures, the stability of
1c is increased, on the other hand, but the reaction is consider-
ably slower. We found 125 °C to be the optimum temperature
in these two cases. Other solvents (DMF, acetone) were used
but gave considerably lower conversion, or no conversion at
all, in Stille cross-coupling attempts.
1
alumina. H NMR (DMSO, 200 MHz): δ 1.33 (s, 12H), 7.96 (s,
1H). 13C NMR (DMSO, 50 MHz): δ 24.7 (q), 84.8 (s), 150.7 (d),
157.5 (s). The boron-carrying C5 did not appear. MS (EI) m/z
(relative intensity): 245.2 (33); 230.1 (47); 210.2 (100); 146.1 (39);
85.1 (36).
2-Chloro-5-(tributylstannyl)thiazole (1c): To a stirred solution
of DIPA (1.2 equiv, 0.71 g, 7.03 mmol) in dry THF (50 mL) under
argon n-BuLi (1.2 equiv, 2.90 mL, 7.03 mmol, 2.42M in hexane)
was added at -80 °C. The reaction mixture was warmed to 0 °C
and stirred at that temperature for 20 min. Then 1 (1 equiv, 0.70 g,
5.85 mmol) was added dropwise at -80 °C, and the reaction
mixture was stirred for 30 min and allowed to warm to -50 °C.
Subsequently, Bu3SnCl (1.3 equiv, 2.48 g, 7.61 mmol) was added
dropwise at -80 °C. The reaction solution was warmed to room
temperature and diluted with diethyl ether, and the organic layer
was washed with 2 N HCl, water, and brine, dried over Na2SO4,
filtered, and evaporated. The crude material was purified by
Kugelrohr distillation to give 95% (2.27 g, 5.5 mmol) of 1c as a
Conclusion
According to the data obtained in this comparative study, the
Stille reaction represents the superior cross-coupling method
for obtaining bithiazoles. It was successful for the cross-coupling
of 1c with a series of halothiazoles to bithiazoles. Here, side
reactions were only detected when dihalides with two positions
of similar reactivity were applied. In summary, new bithiazoles
were formed in moderate to good yields (36-81%) in three
steps starting from 2-aminothiazole. These bithiazoles can be
easily further functionalized and might be useful in the synthesis
of interesting compounds. Reactions applying a Negishi cross-
coupling protocol suffered from substantial side reactions,
leading to an inseparable mixture of products. Within this study,
we have synthesized the first thiazoleboronic acid ester and
successfully demonstrated its principal applicability for cross-
coupling reactions. These results may open up a potential
alternative to existing strategies, although the procedures have
to be optimized and much more has to be learned about the
behavior of this new compound class in cross-coupling reactions
to gain general applicability. In light of the toxicity of tin
organyls, further research toward a Suzuki-Miyaura strategy
in thiazole chemistry may prove highly desirable and is currently
addressed in our laboratory.
1
colorless liquid: bp 190 °C (0.2 mbar). H NMR (CDCl3, 200
MHz): δ 0.93 (t, J ) 7.1 Hz, 9H), 1.17 (m, 6H), 1.35 (sext, J )
7.1 Hz, 6H), 1.55 (m, 6H), 7.47 (s, 1H). 13C NMR (CDCl3, 50
MHz): δ 10.9 (t), 13.5 (q), 27.1 (t), 28.8 (t), 132.1 (s), 147.8 (d),
156.1 (s). MS (EI) m/z (relative intensity): 352.4 (100), 350.4 (70),
296.2 (81), 240.0 (78), 238.0 (70).
2-Chloro-5-phenylthiazole (2a):22 Compound 2a was prepared
according to the general Stille procedure. Reaction parameters: 20
min; 175 °C; Pd(PPh3)4; benzene. Yield: 82% (79 mg, 0.40 mmol)
colorless solid; mp 40-42 °C. Compound 2a was alternatively
prepared according to the general Suzuki-Miyaura procedure in
1
56% yield. H NMR (CDCl3, 200 MHz): δ 7.34-7.55 (m, 5H),
7.71 (s, 1H). 13C NMR (CDCl3, 50 MHz): δ 126.6 (d), 128.9 (d),
129.2 (d), 130.4 (s), 136.5 (d), 141.4 (s), 150.3 (s). MS (EI) m/z
(22) Hafez, E. A. A.; Abed, N. M.; Elsakka, I. A. J. Heterocycl. Chem.
1983, 20, 285-288.
J. Org. Chem, Vol. 71, No. 10, 2006 3759

Stanetty et al.
(relative intensity): 197.09 (33), 195.07 (100), 160.11 (24), 134.03
(76), 89.07 (18).
was added dropwise. After 1 h, a solution of hexachloroethane (1.1
equiv, 536 mg, 2.26 mmol) in diethyl ether (5 mL) was added, and
the reaction mixture was slowly warmed to room temperature. The
reaction solution was then washed with 2 N HCl, water, and brine,
and the aqueous phases were re-extracted with diethyl ether. The
combined organic layers were dried over Na2SO4. Filtration and
evaporation of the solvent gave 8 without further purification in
95% (0.39 g, 1.97 mmol) yield as colorless crystals; mp 59-60
°C. 1H NMR (CDCl3, 200 MHz): δ 7.15 (s, 1H). 13C NMR (CDCl3,
50 MHz): δ 118.9 (d), 123.1 (s), 152.5 (s).
2-Chloro-5-(4-methoxyphenyl)thiazole (2b): Compound 2b was
prepared according to the general Suzuki-Miyaura procedure (170
°C, 20 min). Purification: MPLC (LP/EtOAc, 25:1). Yield: 13%
(18 mg, 0.08 mmol) beige solid; mp 82-84 °C. 1H NMR (CDCl3,
200 MHz): δ 3.84 (s, 3H), 6.93 (d, J ) 8.9 Hz, 2H), 7.40 (d, J )
8.9 Hz, 2H), 7.59 (s, 1H). 13C NMR (CDCl3, 50 MHz): δ 55.4 (t),
114.6 (d), 123.0 (s), 127.9 (d), 135.3 (d), 139.0 (d), 141.3 (s), 149.3
(s), 160.1 (s). MS (EI) m/z (relative intensity): 227.1 (34), 225.1
(100), 210.0 (70), 207.0 (33), 181.9 (31).
4-Bromothiazole (9): Starting material 7 (1 equiv, 3.33 g, 13.71
mmol) was dissolved in dry diethyl ether (100 mL) and cooled to
0 °C. Subsequently, i-PrMgCl (1.2 equiv, 8.22 mL, 16.45 mmol)
was added at that temperature as a 2 M solution in dry THF. During
the addition, a colorless precipitate was formed. After complete
addition of the Grignard reagent, the reaction mixture was allowed
to warm to room temperature overnight. The organic layer was
washed with 2 N HCl solution, water, and brine, dried over Na2-
SO4, and filtered, and the solvent mixture was evaporated. The crude
material was purified by Kugelrohr distillation to give 73% (1.65
g, 10.06 mmol) of 9 as colorless liquid; bp 189-190 °C (lit.:7a
29% yield, bp 188-190 °C). 1H NMR (CDCl3, 200 MHz): δ 7.29
(d, J ) 2.2 Hz, 1H), 8.73 (d, J ) 2.2 Hz, 1H). 13C NMR (CDCl3,
50 MHz): δ 116.8 (d), 126.5 (s), 153.7 (d). MS (EI) m/z (relative
intensity): 165.0 (100), 163.0 (95), 137.9 (33), 135.9 (31), 57.1
(44).
4-Bromo-2′-chloro-2,5′-bithiazole (10): Compound 10 was
prepared according to the general Stille procedure. Reaction
parameters: overnight, reflux, Pd(PPh3)4, benzene (thermal) or 20
min, 170 °C, Pd(PPh3)4, benzene (microwave). Yield: 81% (112
mg, 0.40 mmol) yellow solid. Compound 10 was alternatively
prepared according to the general Suzuki-Miyaura procedure in
17% yield; mp 125-127 °C. 1H NMR (CDCl3, 200 MHz): δ 7.23
(s, 1H), 7.93 (s, 1H). 13C NMR (CDCl3, 50 MHz): δ 116.8 (d),
126.3 (s), 133.7 (s), 139.8 (d), 154.0 (s), 158.2 (s). MS (EI) m/z
(relative intensity): 282.0 (100), 280.0 (67), 137.6 (48), 135.6 (46),
56.6 (52). Anal. Calcd for C6H2BrClN2S2: C, 25.59; H, 0.72; N,
9.95. Found: C, 25.82; H, 1.00; N, 9.87.
4-(2-Chlorothiazol-5-yl)benzonitrile (2c): Compound 2c was
prepared according to the general Suzuki-Miyaura procedure (170
°C, 20 min). Purification: MPLC (LP/EtOAc, 10:1). Yield: 27%
(37 mg, 0.17 mmol). 1H NMR (CDCl3, 200 MHz): δ 7.59 (d, J )
8.5 Hz, 2H), 7.71 (d, J ) 8.9 Hz, 2H), 7.82 (s, 1H). 13C NMR
(CDCl3, 50 MHz): δ 112.3 (s), 118.2 (s), 126.9 (d), 133.0 (d),
134.8 (s), 138.3 (d), 139.2 (s), 152.4 (s). MS (EI) m/z (relative
intensity): 222.1 (27), 221.1 (10), 220.0 (80), 158.8 (100), 113.8
(14).
2-Chloro-5-(4-nitrophenyl)thiazole (2d): Compound 2d was
prepared according to the general Suzuki-Miyaura procedure (170
°C, 20 min). Purification: MPLC (LP/EtOAc, 20:1). Yield: 32%
(47 mg, 0.20 mmol) yellow solid; mp 140-143 °C. 1H NMR
(CDCl3, 200 MHz): δ 7.65 (d, J ) 8.9 Hz, 2H), 7.87 (s, 1H), 8.28
(d, J ) 8.9 Hz, 2H). 13C NMR (CDCl3, 50 MHz): δ 124.7 (d),
127.0 (d), 131.1 (s), 136.6 (s), 138.7 (d), 147.6 (s), 152.8 (s). MS
(EI) m/z (relative intensity): 240.1 (100), 210.0 (44), 207.0 (44),
132.6 (62), 88.7 (78).
2′-Chloro-2,5′-bithiazole (4): Compound 4 was prepared ac-
cording to the general Stille procedure. Reaction parameters: 20
min; 175 °C; Pd(PPh3)4; benzene. Yield: 56% (70 mg, 0.35 mmol)
pale yellow solid; mp 78-80 °C. Compound 4 was alternatively
prepared according to the general Suzuki-Miyaura procedure in
1
32% yield. H NMR (CDCl3, 200 MHz): δ 7.35 (d, J ) 3.2 Hz,
1H), 7.81 (d, J ) 3.2 Hz, 1H), 7.91 (s, 1H). 13C NMR (CDCl3, 50
MHz): δ 119.3 (d), 134.9 (s), 139.2 (d), 143.7 (d), 153.2 (s), 157.4
(s). MS (EI) m/z (relative intensity): 204.0 (22), 202.0 (55), 167.1
(29), 58.1 (100).
2′-Chloro-4,5′-bithiazole (11): Compound 11 was prepared
according to the general Stille procedure. Reaction parameters: 120
min, 125 °C, Pd(PPh3)4, benzene. Yield: 36% (41 mg, 0.20 mmol)
pale yellow solid; mp 78-81 °C. Compound 11 was alternatively
prepared according to the general Suzuki-Miyaura procedure in
2,2′-Dichloro-5,5′-bithiazole (6): Compound 6 was obtained as
a byproduct during the formation of 4 (via a Negishi reaction, not
isolated) and 16 (from 1c and 18 via the general Stille procedure).
Yield: 28% (106 mg, 0.447 mmol) pale yellow solid; mp 103-
1
105 °C. H NMR (CDCl3, 200 MHz): δ 7.58 (s, 2H). 13C NMR
1
9% yield. H NMR (CDCl3, 200 MHz): δ 7.47 (d, J ) 2.0 Hz,
(CDCl3, 50 MHz): δ 129.1 (s), 139.1 (d), 151.9 (s). MS (EI) m/z
(relative intensity): 237.9 (82), 235.9 (100), 200.8 (33), 174.7 (43),
139.7 (34).
1H), 7.88 (s, 1H), 8.84 (d, J ) 2.0 Hz, 1H). 13C NMR (CDCl3, 50
MHz): δ 113.6 (d), 135.2 (s), 137.4 (d), 146.7 (s), 151.2 (s), 153.6
(d). MS (EI) m/z (relative intensity): 204.0 (39), 202.0 (100), 166.9
(51), 113.8 (28), 68.7 (33). Anal. Calcd for C6H3ClN2S2: C, 35.56;
H, 1.49; N, 13.82. Found: C, 35.63; H, 1.65; N, 13.56.
2,4-Dibromothiazole (7): 2,4-Thiazolidinedione (1 equiv, 5.38
g (90% from Aldrich), 41.33 mmol) was mixed with POBr3 (7.6
equiv, 100.0 g, 349 mmol) and refluxed for 1.5 h. The reaction
mixture was then cooled, poured onto ice water, and neutralized
with solid Na2CO3. The aqueous phase was extracted three times
with EtOAc. The combined organic layers were washed with water
and brine, dried over Na2SO4, and filtered, and the solvent was
evaporated. The crude material was dissolved in light petroleum,
and the remaining solid was removed by filtration. Evaporation of
the solvent and subsequent Kugelrohr distillation gave 7 as colorless
crystals in 99% (9.94 g, 40.9 mmol) yield; mp 79-80 °C; (lit.:23
2,5-Dibromothiazole (12): 2-Bromothiazole 3 (1 equiv, 1.35 g,
8.23 mmol) was stirred in a mixture of water (10 mL) and 48%
aqueous HBr (10 mL). Then Br2 (4.7 equiv, 6.22 g, 38.9 mmol)
was added, and the reaction mixture was refluxed for 3 h. The
formed precipitate (the hydrobromide of 12) was removed by
filtration, dissolved in diethyl ether, and neutralized with satd.
NaHCO3 solution. The organic layer was washed with water and
brine, dried over Na2SO4, and filtered, and the solvent was
evaporated to give 12. By extracting the initial filtrate with diethyl
ether and repeating the washing procedure for the precipitate, a
second fraction of 12 was obtained after Kugelrohr distillation.
Overall yield: 55% (1.10 g, 4.53 mmol) as a colorless, slow
crystallizing liquid; mp 45-47 °C (lit.:24 40% yield, mp 46-47
1
60% yield; mp 82 °C). H NMR (CDCl3, 200 MHz): δ 7.20 (s,
1H). 13C NMR (CDCl3, 50 MHz): δ 120.7 (d), 124.3, (s), 136.3
(s). MS (EI) m/z (relative intensity): 244.9 (66), 242.9 (100), 240.9
(60), 137.9 (50), 57.1 (68).
4-Bromo-2-chlorothiazole (8): A solution of n-BuLi (1.05
equiv, 0.91 mL, 2.16 mmol, 2.37 M in hexane) in dry diethyl ether
(100 mL) was cooled to -80 °C, and a solution of 2,4-dibro-
mothiazole (1 equiv, 0.5 g, 2.06 mmol) in diethyl ether (5 mL)
1
°C). H NMR (CDCl3, 200 MHz): δ 7.51 (s, 1H).25 13C NMR
(CDCl3, 50 MHz): δ 110.7 (s), 135.8 (s), 144.0 (d). MS (EI) m/z
(24) Erlenmeyer, H.; Kiefer, H. HelV. Chim. Acta 1945, 28, 985-991.
(25) Kerdesky, F. A. J.; Seif, L. S. Synth. Commun. 1995, 25, 4081-
4086.
(23) Reynaud, P.; Robba, M.; Moreau, R. C. Bull. Soc. Chim. Fr. 1962,
1735-1738.
3760 J. Org. Chem., Vol. 71, No. 10, 2006

Cross-Coupling Reactions toward Bithiazoles
(relative intensity): 244.9 (40), 243.0 (74), 241.0 (35), 164.0 (100),
162.0 (92), 57.1 (77).
130.0 (s), 138.8 (d), 141.4 (d), 151.3 (s), 153.0 (d). MS (EI) m/z
(relative intensity): 203.8 (65), 201.8 (100), 174.8 (39), 113.6 (29),
68.5 (33).
5-Bromothiazole (13): Substrate 12 (1 equiv, 683 mg, 2.81
mmol) was cooled to -40 °C in dry diethyl ether (50 mL). At that
temperature, i-PrMgCl (1.1 equiv, 1.97 mL in dry THF, 3.09 mmol)
was added dropwise. After 30 min, the reaction mixture was
quenched with MeOH, warmed to room temperature, and washed
with 2 N HCl. The organic layer was concentrated, and the crude
material was purified by MPLC (first light petroleum, then LP/
EtOAc, 10:1) to give 20% (91 mg, 0.55 mmol) of 13 as colorless
liquid; bp 70 °C at 20 mbar (lit.:7a 16% yield, bp 80-81 °C at 18
Torr).1H NMR (CDCl3, 200 MHz): δ 7.82 (s, 1H), 8.77 (s, 1H).
13C NMR (DMSO-d6, 50 MHz): δ 109.1 (s), 144.6 (d), 156.3 (d).26
MS (EI) m/z (relative intensity): 164.7 (100), 162.8 (95), 85.7 (16),
83.7 (90), 56.6 (76).
2,2′′-Dichloro-5,2′:5′,5′′-terthiazole (16): Compound 16 was
obtained as a byproduct during the formation of 4 (from 1c and
12; 4%) and 15 (from 1c and 17; 9% (67 mg, 0.21 mmol)); pale
1
yellow solid; mp 188-190 °C. H NMR (CDCl3, 200 MHz): δ
7.66 (s, 1H), 7.79 (s, 1H), 7.93 (s, 1H). 13C NMR (CDCl3, 50
MHz): δ 127.5 (s), 129.5 (s), 134.2 (s), 139.0 (d), 139.8 (d), 141.3
(d), 151.7 (s), 154.0 (s), 157.1 (s).
2-Bromo-5-iodothiazole (17): 2-Bromothiazole 3 (1 equiv, 1.0
g, 6.10 mmol) in diethyl ether (10 mL) was added dropwise to a
solution of LDA (1.1 equiv, 6.70 mmol) in dry diethyl ether (200
mL) at -80 °C. The reaction mixture was kept at that temperature
for 30 min before I2 (1.2 equiv, 1.86 g, 7.32 mmol) in diethyl ether
(20 mL) was added dropwise. The reaction mixture was slowly
warmed to room temperature and subsequently washed with
aqueous satd. Na2S2O5, water, and brine. All aqueous phases were
re-extracted with diethyl ether. The combined organic layers were
dried over Na2SO4 and filtered, and the solvent was evaporated.
MPLC (LP/EtOAc, 10:1) gave 17 in 74% (1.30 g, 4.48 mmol) yield
as a yellow solid; mp 108-110 °C (lit.:7a 35% yield; mp 110-112
°C). 1H NMR (CDCl3, 200 MHz): δ 7.65 (s, 1H). 13C NMR
(CDCl3, 50 MHz): δ 72.3 (s), 139.4 (s), 150.6 (d).
5-Bromo-2′-chloro-2,5′-bithiazole (14): Compound 14 was
prepared according to the general Stille procedure. Reaction
parameters: 60 min, 170 °C, Pd(PPh3)2Cl2, benzene. Yield: 36%
(50 mg, 0.178 mmol) pale yellow solid; mp 113-115 °C. 1H NMR
(CDCl3, 200 MHz): δ 7.68 (s, 1H), 7.85 (s, 1H). 13C NMR (CDCl3,
50 MHz): δ 109.4 (s), 134.4 (s), 139.4 (d), 144.8 (d), 153.7 (s),
158.5 (s). MS (EI) m/z (relative intensity): 281.9 (65), 280.0 (44),
203.0 (33), 201.0 (81), 57.0 (100). Anal. Calcd for C6H2BrClN2S2:
C, 25.59; H, 0.72; N, 9.95. Found: C, 25.86; H, 0.91; N, 9.73
Acknowledgment. This project was supported by Syngenta
Crop Protection, Basel, Switzerland. The contributions from
Johanna Ha¨mmerle and Markus Holzweber in their short courses
are gratefully acknowledged. Thanks are given to Vienna
University of Technology for providing the infrastructure.
2-Chloro-5,5′-bithiazole (15): Compound 15 was prepared
according to the general Stille procedure. Reaction parameters: 120
min, 125 °C, Pd(PPh3)4, benzene. Yield: 52% (26 mg, 0.128 mmol)
from 13 and 33% (156 mg, 0.77 mmol) from 17; pale yellow solid;
mp 82-84 °C. 1H NMR (CDCl3, 200 MHz): δ 7.64 (s, 1H), 7.95
(s, 1H), 8.80 (s, 1H). 13C NMR (CDCl3, 50 MHz): δ 127.2 (s),
Supporting Information Available: 1H, 13C, and DEPT (where
of importance) NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(26) Faure, R.; Galy, J.-P.; Vincent, E.-J.; Elguero, J. Can. J. Chem.
1978, 56, 46-55.
JO0601009
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