Synthesis of 5-arylthiazoles. Comparative study between Suzuki cross-coupling reaction and direct arylation

Article abstract of DOI:10.1016/j.tet.2009.05.013

A facile synthetic route to the new thiazol-5-ylboronic acid pinacol ester was described herein. Its reactivity toward Suzuki cross-coupling reaction was studied to provide various 5-arylthiazoles. A comparative study between Suzuki cross-coupling reactio

Full text of DOI:10.1016/j.tet.2009.05.013

Tetrahedron 65 (2009) 5739–5746
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Tetrahedron
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Synthesis of 5-arylthiazoles. Comparative study between Suzuki cross-coupling
reaction and direct arylation
,
Nicolas Primas a, Alexandre Bouillon b, Jean-Charles Lancelot a, Hussein El-Kashef c, Sylvain Rault a
*
a Centre d’Etudes et de Recherche sur le Me´dicament de Normandie, U.F.R des Sciences Pharmaceutiques, Universite´ de Caen Basse-Normandie,
boulevard Becquerel, 14032 Caen Cedex, France
b BoroChem S.A.S., Immeuble Emergence, 7 rue Alfred Kastler, 14000 Caen, France
c Department of Chemistry, Faculty of Science, Assiut University, 71516 Assiut, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthetic route to the new thiazol-5-ylboronic acid pinacol ester was described herein. Its re-
activity toward Suzuki cross-coupling reaction was studied to provide various 5-arylthiazoles. A com-
parative study between Suzuki cross-coupling reactions and palladium-catalyzed C5–H direct arylation
on thiazole ring was achieved.
Received 18 March 2009
Received in revised form 6 May 2009
Accepted 7 May 2009
Available online 13 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Thiazole
Boronic ester
Suzuki cross-coupling
Direct arylation
Aryl halides
1. Introduction
Regarding the Suzuki coupling, only one paper described a thiazole
carrying the boronic function,11 the other arylthiazoles were synthe-
The thiazole ring is a widespread heterocycle found in various
biologically active natural products like thiamine (vitamin B1) and
penicillins,1 and also in many naturally based peptides and pepto-
lides isolated from marine organisms such as fungi, algae, etc.2 Some
thiazole derivatives were evaluated for their cyclin-dependent ki-
nase 5/p25 inhibitors as a potential treatment for Alzheimer’s dis-
ease,3 and others showed antimicrobial activity.4 Certain thiazoles
are used as pharmaceuticals, agrochemicals,5 and as potent and se-
lective human adenosine A3 receptor antagonists.6 Aryl-substituted
thiazoles are important organic functional materials such as fluo-
rescent dyes7a,b and liquid crystals.7b,c Thiazole orange is used as
fluorescent intercalator for determining DNA binding affinity and
sequence selectivity of small molecules.8
sized from the halogenothiazoles.12 Metal-catalyzed direct hetero-
cycle C–H arylation15 was also used to synthesize arylthiazole
derivatives. The first direct C–H arylation in C-5 position of unsub-
stituted thiazole was described by Ohta et al. in 1990.15a Since this
discovery, numerous improvements of palladium-catalyzed direct
arylationwere achieved by using ligand-free palladium catalyst15b and
very recently by using low ligand-free catalyst loading;15d however
there are few examples of direct arylation on C-2 unsubstituted thi-
azole. Most of examples are described with C-2 position blocked.15,16
Therefore, the search for new regioselective methods for the
preparation of new thiazole derivatives is always a matter of in-
terest. We wish to describe herein a facile synthetic route to the
new boronic ester namely thiazol-5-ylboronic acid pinacol ester 2,
which is hereby described and prepared for the first time. Its ability
to be engaged in Suzuki cross-coupling reactions to furnish 5-
arylthiazoles was studied. A comparative study with palladium-
catalyzed C5–H direct arylation method was then achieved. This
work is also a part of a project aiming to compare boronic species in
the imidazole,17 thiazole, and oxazole18 series.
Thiazoles have traditionally been synthesized by Hantzsch syn-
thesis,9a which consists of a cyclocondensation between
a-halo-
ketones and thioamides.9a–e Several other methods have been
described.10 Recently, powerful methods involving palladium medi-
ated coupling processes such as Suzuki coupling,11,12 Stille reaction,13
and Negishi coupling14 have been emerged, allowing the facile in-
troduction of various aryl or alkenyl groups into the thiazole nucleus.
2. Discussion and results
In the light of the above biological activities of thiazole com-
pounds, and in continuation of our recent work17 on the synthesis
* Corresponding author. Tel.: þ33 (0)2 31 56 68 01; fax: þ33 (0)2 31 56 68 03.
E-mail address: sylvain.rault@unicaen.fr (S. Rault).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.013

5740
N. Primas et al. / Tetrahedron 65 (2009) 5739–5746
i or ii
sequence in THF using 5 (direct ortho-metalation) or 6 (halogen–
N
N
N
O
O
metal exchange), followed by transesterification with pinacol gave
the corresponding 5-pinacol boronate ester 7 in a good yield (Table
1, entry 3). It is worthy mentioning that the TIPS group of 7 could
not be cleaved without affecting the boronic ester function. Thus
when 7 was engaged in a Suzuki cross-coupling reaction with
4-iodoanisole under standard aqueous conditions (cf. Scheme 3),
the reaction product was identified as 5-(4-methoxyphenyl)th-
iazole 8b where the silyl group was cleaved during the purification
step on silica gel (Scheme 3). Although the cross-coupling reaction
occurred with satisfactory yield (51%), yet this approach was costly
due to the expensive triisopropylsilyl chloride.
B
B
B
Cl
S
N
S
O
O
2
1
N
i
O
O
B
Cl
82%
N
O
O
THP
THP
4
3
Scheme 1. Investigated reaction and homology with previous works. Reagents and
conditions: (i) H2, Pd/C, MeOH, 0 ꢁC to rt, 2 h and (ii) Zn, AcOH, heating.
Since we found that the lithiation–boronation sequence of 5 (or 6)
did not afford the expected boronic ester 7 in ether using LDA (Table
1; entry 4), we have re-investigated several boronation reactions
starting from 2-TST. Finally we found that the boronation of 2-tri-
methylsilylthiazole using n-BuLi in THF gave a rather higher yield of
2 (70%) in comparison with that (15%) obtained in ether using LDA
(Table 1, entry 5). The neopentylglycol ester 9 was synthesized
similarly in 59% yield. It was also possible to obtain, but in a rather
modest yield the acid derivative 10 by acidic hydrolysis step instead
of the transesterification (Scheme 4). Although the acid 10 was
a coupling partner in the Suzuki cross-coupling reaction (with 4-
iodoanisole); the difficulties encountered during the purification
process of 10 let us to abandon this synthetic methodology.
The reactivity of the two boronic esters 2 and 9 toward Suzuki
cross-coupling reactions was studied. Thus, the ester 2 was firstly
reacted with 4-iodoanisole under standard Suzuki reaction condi-
tions (boronic ester 1.1 equiv; Na2CO3 2.5 equiv; Pd(PPh3)4 5 mol %;
dioxane/water; 80 ꢁC) and the reaction furnished 8b with a satis-
factory yield of 61% (Table 2, entry 1). Using 2 equiv of 2 was found
to raise the yield of 8b to 80% (entry 1a). The use of a stronger base
such as Cs2CO3 gave a lower yield (36%, entry 2). The use of
PdCl2(dppf) instead of Pd(PPh3)4 in the same conditions that used
in entry 1 gave a lower yield (49%, entry 3). When the neo-
pentylglycol ester 9 was used (entry 4) instead of the pinacol ester 2
in the same conditions as in entry 1, the yield decreased notably.
Consequently, we have chosen to continue this study with the more
reactive ester 2. Since heteroarylboronic derivatives are known to
be prone to deboronation under aqueous conditions,20 therefore
we tried the reaction conditions reported in our previous work
(boronic ester 1.1 equiv; CsF 2.5 equiv; CuI 0.1 equiv; Pd(PPh3)4
5 mol %; dry DMF; 80 ꢁC), described for sensitive boronic ester17
where the coupling occurred with 54% yield (Table 1, entry 5). The
use of K3PO4 instead of CsF/CuI in DMF gave almost the same yield
(entry 6). However, the use of PdCl2(dppf) as catalyst in DMF raised
the yield to 68% (entry 7).
of 4(5)-arylimidazoles using the imidazolylboronic ester 4 via
Suzuki cross-coupling reaction, it deemed of interest to synthesize
the title compounds using the same methodology.
Firstly, we focused our attention on the synthesis of the key
thiazolylboronic species 2. Similar to the synthetic strategy that we
have reported for the synthesis of the imidazolylboronic ester 415
(Scheme 1), we prepared the 2-chlorothiazol-5-yl boronic ester 1,
following the method described by Stanetty et al.11 with the aim to
dechlorinate it to gave 2. Stanetty reported that 1 was sensitive to
aqueous conditions and was a poor coupling partner in Suzuki
cross-coupling reactions. However, in our hands all attempts to
carry out the dechlorination reaction of 1 either via catalytic hy-
drogenation in the presence of Pd/C as a catalyst or by using Zn/
acetic acid reduction failed to proceed.
Consequently, we tried another strategy to protect C-2 position
of the thiazole ring. This could be achieved following the method
described by Dondoni et al.,19 which consists of a C-5 regioselective
lithiation of 2-trimethylsilylthiazole (2-TST) in ether since the 5-
lithio derivative was found to be unstable in THF at ꢀ78 ꢁC.14c Thus,
starting with 2-TST (purchased or easily prepared19 from the
readily available 2-bromothiazole, Scheme 2), a C-5 lithiation was
carried out followed by boronation using triisopropyl borate.
Transesterification of the intermediate obtained was achieved by
treatment with pinacol followed by adjusting the pH to 5 using
acetic acid. The reaction led directly to the corresponding stable
pinacol ester 2 where the trimethylsilyl group was cleaved during
the last stage work-up. Nevertheless, the yield obtained was very
poor: 15% (Scheme 2; Table 1, entry 1).
It seems to us that the trimethylsilyl group was too labile under
these reaction conditions. Substitution of this group by a triethyl-
silyl one did not improve the yield. This encouraged us to look for to
other silyl protecting groups more resistant to hydrolysis such as triiso
propylsilyl (TIPS) group. Thus starting with either 2-triisopropylsi-
lylthiazole 5 or 5-bromo-2-triisopropylsilylthiazole 6, previously
reported by Stangeland and Sammakia,13c a lithiation–boronation
2.1. Suzuki cross-coupling reactions
N
N
N
i
ii
O
Having secured good access to 8b, then we examined the scope
and limitations of our thiazolylboronic ester 2. Thus, 2 was coupled
with a variety of aryl halides using standard aqueous reaction
conditions but using 2 equiv of boronic ester in order to rise up the
yield (conditions A: boronic ester 2 2 equiv; aryl halide 1 equiv;
Na2CO3 2.5 equiv; Pd(PPh3)4 5 mol %; dioxane/water 3/1; 80 ꢁC) or
using the water free protocol for the aryl halides bearing sensitive
groups (conditions B: boronic ester 2 2 equiv; CsF 2.5 equiv; CuI
0.1 equiv; Pd(PPh3)4 5 mol %; dry DMF; 80 ꢁC). The yields were
satisfactory and our methodology using the new thiazol-5-ylboronic
pinacol ester allows the synthesis of 5-arylthiazoles bearing sen-
sitive groups such as nitriles, esters or aldehydes positioned in any
position of the phenyl group (Table 3). The electron-deficient 3-
bromobenzaldehyde was found to be less reactive, and afforded 8i
in a poor yield (Table 2, entry 9). Heteroaryl bromides were also
suitable reactants in the Suzuki cross-coupling. 3-Bromopyridine
Br
B
SiMe3
2-TST
95%
S
S
S
2
O
15%
Scheme 2. Synthesis of 5-thiazolylboronic esters 2 and 5. Reagents and conditions: (i)
n-BuLi 1.05 equiv, Me3SiCl 1 equiv, ether, ꢀ78 ꢁC and (ii) LDA 1.2 equiv, B(Oi-Pr)3
1.2 equiv, pinacol 1 equiv, AcOH pH 5, ether, ꢀ78 ꢁC to rt.
Table 1
Lithation–boronation sequence optimization starting from 2-TST or 5
Entry
SiR3
Base
Solvent
Yielda (%)
1
2
3
4
5
SiMe3
SiMe3
Si-i-Pr3
Si-i-Pr3
SiMe3
LDA (1.2 equiv)
LDA (1.2 equiv)
n-BuLi
LDA (1.2 equiv)
n-BuLi
Ether
THF
THF
Ether
THF
15
0
74a
0
70
a
Obtained from 5 (83% from 6).

N. Primas et al. / Tetrahedron 65 (2009) 5739–5746
5741
N
N
TIPS
TIPS
S
S
5
i
N
N
ii
O
B
TIPS
S
S
MeO
O
51%
7
8b
74% from 5
83% from 6
i
Br
6
Scheme 3. Synthesis of 2-TIPS-5-thiazolylboronic ester 7 and Suzuki cross-coupling. Reagents and conditions: (i) n-BuLi 1.2 equiv, B(Oi-Pr)3 1.2 equiv, pinacol 1 equiv, AcOH pH 5,
THF, ꢀ78 ꢁC to rt and (ii) boronic ester 1.1 equiv, 4-iodoanisole 1 equiv, Na2CO3 2.5 equiv, Pd(PPh3)4 5 mol %, 80 ꢁC, dioxane/water.
N
O
2
B
8 and 12). During our study an other ligand-free protocol using
Pd(OAc)2 was described by Roger et al.15d (conditions E). Although
this procedure seems to be the most efficient with electron-de-
ficient aryl bromides such as 4-bromobenzonitrile, which
conducted to 8d in 72% yield (Table 3, entry 4), this latter did not
permit to obtain better yields than Bold’s conditions with other
electron-deficient aryl bromides (Table 3, entries 7,11, and 14).
Electron-donating aryl halides like 4-iodoanisole were found to be
unreactive toward conditions E (Table 3, entry 2). It must be
pointed out that direct arylation was not suitable in the case of 4-
bromoaniline were no coupling product was isolated (Table 3, entry
3). The direct arylation gave in general lower yield than the Suzuki
procedure except in the case of 2-bromobenzonitrile and chlor-
imine substrates (Table 3, entries 5 and 3).
70%
S
O
i
N
N
O
ii
9
B
SiMe3
2-TST
S
59%
S
O
iii
N
HO
10
B
S
22%
HO
Scheme 4. Synthesis of 5-thiazolylboronic derivatives 2, 9, and 10. Reagents and
conditions: (i) n-BuLi 1.2 equiv, B(Oi-Pr)3 1.2 equiv, pinacol 1 equiv, AcOH pH 5, THF,
ꢀ78 ꢁC to rt; (ii) n-BuLi 1.2 equiv, B(Oi-Pr)3 1.2 equiv, neopentylglycol 1 equiv, AcOH pH
5, THF, ꢀ78 ꢁC to rt and (iii) n-BuLi 1.2 equiv, B(OMe)3 1.2 equiv, NaOH 4 N, HCl 3 N,
THF, ꢀ78 ꢁC to rt.
2.3. Discussion and conclusion
The Suzuki cross-coupling reaction afforded in all cases the
expected compounds in 50–90% yield except for the 3-carbox-
aldehyde compound (entry 9), which was obtained only with 35%
yield. This was probably due to the partial degradation of the 3-
bromobenzaldehyde. The electron withdrawing or donating char-
acter of the substrate does not affect notably the yield, however, the
comparison of entries 1,3, and 4 shows that the results obtained
with aryl bromides bearing an electron withdrawing group seem to
be better (p-benzonitrile 91%) than those obtained with substrates
bearing an electron-donating group (p-aniline 63%) and the result
obtained with bromobenzene is situated at an average value
(phenyl 79%).
and 5-bromofurfural gave, respectively, 8k and 8n in good yields.
Moreover, it must be pointed out that it was possible to perform
cross-coupling with chlorimine, which was a pharmacological
interest molecule precursor21 (Table 3, entry 13). Furthermore, the
4-amino derivative 8c (Table 3, entry 3) was obtained with an ac-
ceptable yield.
2.2. Direct C5–H arylation
For the C5–H direct arylation of unsubstituted thiazole, we have
chosen the conditions described by Bold et al.15h using 5 equiv of
thiazole,1 equiv of halide, 3 equiv of KOAc, and 5 mol % of Pd(PPh3)4
in DMA at 150 ꢁC in a sealed tube (conditions C). The ligand-free
conditions described by Parisien et al.15b using Pd(OH)2/C as cata-
lyst (conditions D) lead to the same or lower yields (Table 3, entries
On the other hand, the influence of the substituent position
cannot be clearly established. The good correlation found for the
nitrile (para 91%, meta 55%, ortho 50%) was not verified with the
carboxaldehyde. It must be also pointed out that the mild conditions
Table 2
Cross-coupling reaction optimization of 2 and 9 with 4-iodoanisole
Base
N
S
I
2
or
9
Catalyst
+
Solvent
80 °C
MeO
MeO
8b
Entry
Boronic (equiv)
Base
Catalyst (5 mol %)
Solvent
Yielda (%)
1
1a
2
3
4
2 (1.1 equiv)
2 (2 equiv)
2 (1.1 equiv)
2 (1.1 equiv)
9 (1.1 equiv)
2 (1.1 equiv)
Na2CO3 (2.5 equiv)
Na2CO3 (2.5 equiv)
Cs2CO3 (2.5 equiv)
Na2CO3 (2.5 equiv)
Na2CO3 (2.5 equiv)
CsF (2.5 equiv)
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2(dppf)
Pd(PPh3)4
Pd(PPh3)4
Dioxane/H2O 3/1
Dioxane/H2O 3/1
Dioxane/H2O 3/1
Dioxane/H2O 3/1
Dioxane/H2O 3/1
DMF
61
80
36
49
32
5
5
CuI (0.1 equiv)
6
7
2 (1.1 equiv)
2 (1.1 equiv)
K3PO4 (2.5 equiv)
CsF (2.5 equiv)
Pd(PPh3)4
PdCl2(dppf)
DMF
DMF
54
68
CuI (0.1 equiv)
a
Isolated yield.

5742
N. Primas et al. / Tetrahedron 65 (2009) 5739–5746
Table 3
Suzuki cross-coupling reactions of ester 2 or direct C5–H arylation oh thiazole with various (het)halides
Conditions A or
Conditions B
N
N
N
Direct C-H arylation
O
(Het)Ar-X
(Het)Ar-X
+
+
B
(Het)Ar
S
S
S
O
2
8
Entry
1
Halide
Product
Suzuki Conditions
Suzuki yield (%)
Direct arylation conditions
Direct arylation
yield (%)
N
Br
8a
A
79
C
63
S
N
I
C
E
36
0
2
3
8b
A
B
80
63
S
MeO
H2N
MeO
H2N
N
Br
Br
8c
C
Traces
S
N
C
E
59
4
5
6
8d
8e
8f
B
B
B
91
50
55
72a
S
NC
NC
N
Br
C
C
63
45
S
CN
Br
CN
N
NC
S
CN
N
Br
C
E
45b
34
7
8
8g
8h
B
B
54
67
S
OHC
OHC
N
Br
C
D
50
25
S
CHO
CHO
Br
N
OHC
9
8i
8j
B
B
35
65
C
C
27
43
S
CHO
I
N
10
S
COOEt
COOEt
N
S
Br
C
E
35
34
11
12
8k
8l
A
B
67
57
N
N
N
I
S
C
D
49
48
NO2
NO2

N. Primas et al. / Tetrahedron 65 (2009) 5739–5746
5743
Table 3 (continued )
Entry
Halide
Product
Suzuki Conditions
Suzuki yield (%)
Direct arylation conditions
Direct arylation
yield (%)
N
N
N
N
13
8m
8n
A
54
74
C
60
EtO
N
EtO
Br
Cl
S
C
E
28
18
N
14
B
S
CHO
O
O
OHC
Conditions A: boronic ester 2 equiv; aryl halide 1 equiv; Na2CO3 2.5 equiv; Pd(PPh3)4 5 mol %; dioxane/water 3/1; 80 ꢁC.
Conditions B: boronic ester 2 equiv; aryl halide 1 equiv; CsF 2.5 equiv; CuI 0.1 equiv; Pd(PPh3)4 5 mol %; dry DMF; 80 ꢁC.
Conditions C (direct arylation): thiazole 5 equiv; aryl halide 1 equiv; KOAc 3 equiv; Pd(PPh3)4 5 mol %; DMA; 150 ꢁC in sealed tube.
Conditions D (direct arylation): thiazole 1 equiv; aryl halide 3 equiv; KOAc 3 equiv; Pd(OH)2/C 0.1 equiv; DMA; 145 ꢁC in sealed tube.
Conditions E (direct arylation): thiazole 2 equiv; aryl halide 1 equiv; KOAc 2 equiv; Pd(OAc)2 0.4 mol %; DMA; 130 ꢁC in sealed tube.
a
Described as 88%.15d
b
Described as 61%.15h
of the Suzuki reaction allow a high yield with 5-bromofurfural,
which is known to be a fragile substrate.
n-BuLi (2.5 M) (27.5 mL, 68.7 mmol, 1.2 equiv) over a period of
20 min. After 15 min of stirring at this temperature was added
triisopropyl borate (15.8 mL, 68.7 mmol, 1.2 equiv). The resulting
mixture was allowed to react at this temperature for 1.5 h and then
left to warm to room temperature over a course of 45 min. After an
additional stirring for 30 min at room temperature, a solution of
pinacol (6.76 g, 57.2 mmol, 1 equiv) in THF (20 mL) was added and
after 10 min, glacial acetic acid was added dropwise until the pH
reached 5. The mixture was diluted with ether, filtered, and the
filtrate was concentrated to one-third of its volume. This was di-
luted with cyclohexane and concentrated under vacuum three
times to eliminate the excess of AcOH. The resulting residue was
then triturated with n-hexane. The solid precipitate was filtered to
afford 2 as a white powder (8.46 g, 70%). Mp 98 ꢁC. IR (KBr): 3060,
Using the direct arylation procedures C and E, the yield rarely
exceed 60%. The drastic conditions conjugated with the presence of
sensitive groups such as aldehydes lead to poor yields (25–45%). It is
noteworthy that the direct arylation procedure is not suitable for
substrate bearing a free amino group (entry 3), and finally, we con-
firm that direct arylation, particularly in E conditions is not suitable
for substrates bearing an electron-donating group (entry 2).15d
In conclusion, we have performed an efficient synthesis of the 5-
thiazolylboronic acid pinacol ester 2. This latter is stable in the Suzuki
cross-couplingreactions and permits inmildconditions thesynthesis
of 5-arylthiazoles variously substituted. The comparison of the re-
sults of the Suzuki cross-coupling reaction with the straightforward
direct arylation procedures indicate that the former method must be
preferred with sensitive substrate even if it needs the preparation of
the thiazol-5-ylboronic acid pinacol ester. Finally, these two pro-
cedures remain complementary. We are now studying the usefulness
of 2 in Chan-Lam C-heteroatom cross-coupling reactions.
2968, 1537, 1383, 1127, 713, 653. 1H NMR (CDCl3):
(s, 1H), 1.33 (s, 12H). 13C NMR (CDCl3):
158.3, 152.6, 84.5, 24.6 (the
d 9.02 (s, 1H), 8.36
d
boron-carrying C-5 did not appear). HRMS (EI) m/z calcd: 211.0838,
found: 211.0837. Anal. Calcd for C9H14BSNO2: C, 51.21; H, 6.69; N,
6.64. Found: C, 51.59; H, 7.01; N, 6.60.
3. Experimental
3.3. 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-
triisopropylsilylthiazole (7)
3.1. General procedures
To a stirred solution under nitrogen of 2-triisopropylsilylthi-
azole13c (2.21 g, 9.16 mmol) in dry THF (100 mL) cooled to ꢀ78 ꢁC was
added n-BuLi (2.5 M) (4.4 mL, 11.0 mmol, 1.2 equiv) over a period of
20 min. After 40 min of stirring at this temperature was added trii-
sopropyl borate (2.5 mL, 11.0 mmol,1.2 equiv). The resulting mixture
was allowed to react at this temperature for 1.5 h and then left to
warm to room temperature over a course of 1 h. After an additional
stirring for 30 min at room temperature, a solution of pinacol (1.08 g,
9.16 mmol,1 equiv) inTHF (10 mL) was added and after 5 min, glacial
acetic acid was added until the pH reached 5. After 45 min of stirring
atroomtemperature,themixturewasdilutedwithether, filtered,and
concentrated. The ethereal solution was washed with a saturated
aqueous solution of NaHCO3. The organic layer was dried over MgSO4
and concentrated to obtain 7 (2.50 g, 74%) as a yellow oil. 1H NMR
Commercial reagents were used as received without additional
purification. Melting points were determined on a Ko¨fler melting
point apparatus and are uncorrected. IR spectra were taken with
a Perkin Elmer Spectrum BX FT-IR System spectrometer. 1H NMR
(400 MHz) and 13C NMR (100 MHz) wererecorded on a JEOL Lambda
400 Spectrometer. Chemicals shifts are expressed in parts per mil-
lion downfield from tetramethylsilane as an internal standard. The
mass spectra (MS) weretaken on a JEOLJMS GCMatespectrometerat
a ionizing potential of 30 eV. Thin layer chromatographies (TLC)
were performed on 0.2 mm precoated plates of silica gel 60F-264
(Merck). Visualization was made with ultraviolet light (234 nm) or
by iodine. Column chromatographies were carried out using silica
gel 60 (0.063–0.2 mm) (Merck). Elemental analyses for new com-
pounds wereperformed at the ‘Institut de Recherche en Chimie Fine’
(Rouen). 2-TST was prepared according to the literature.19
(CDCl3):
d
8.56 (s, 1H), 1.48 (sept, J¼7.8 Hz, 3H), 1.36 (s, 12H), 1.13 (d,
J¼7.8 Hz, 18H). 13C NMR (CDCl3):
d 176.3, 154.2, 145.3, 84.4, 24.7, 18.4,
11.6. HRMS (EI) m/z calcd: 367.21726,found: 367.21720.
3.2. 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-
thiazole (2)
3.4. 5-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)thiazole (9)
To a stirred solution under nitrogen of 2-trimethylsilylthiazole
(9.0 g, 57.2 mmol) in dry THF (150 mL) cooled to ꢀ78 ꢁC was added
This compound was obtained following the same procedure
described for 2 using 2-TST (5.85 g) and neopentylglycol (3.87 g).

5744
N. Primas et al. / Tetrahedron 65 (2009) 5739–5746
White solid 4.26 g (59%). Mp 82 ꢁC. 1H NMR (CDCl3):
8.12 (s, 1H), 3.61 (s, 4H), 0.90 (s, 6H). 13C NMR (CDCl3):
72.4, 32.1, 21.9 (the boron-carrying C-5 did not appear). HRMS (EI)
d
8.83 (s, 1H),
157.6, 151.2,
0.1 equiv) in dimethyl acetamide (5 mL) were degassed and then
heated in a sealed tube for 24 h at 145 ꢁC. The dark suspension was
filtered and concentrated. The resulting mixture was redissolved in
water and extracted three times with EtOAc. The organic layers were
washed with brine, dried (MgSO4), and concentrated. Column
chromatography (silica gel, cyclohexane/EtOAc) afforded 5-
arylthiazole.
d
m/z calcd: 197.06817, found: 197.06815.
3.5. 5-thiazolylboronic acid (10)
To a stirred solution under nitrogen of 2-trimethylsilylthiazole
(2.0 g, 12.7 mmol) in dry THF (80 mL) cooled to ꢀ78 ꢁC was added
n-BuLi (2.5 M) (6.10 mL, 15.3 mmol, 1.2 equiv) over a period of
20 min. After 30 min of stirring at this temperature was added
trimethylborate (1.59 mL, 14.0 mmol, 1.1 equiv). The resulting
mixture was allowed to react at this temperature for 30 min and
then left to warm to room temperature over a course of 45 min. The
solution was quenched with HCl 1 N until pH 2. The mixture was
extracted three times with EtOAc, dried over MgSO4, and concen-
trated. The residue was triturated with ether and filtered to give 10
as a white solid (360 mg, 22%). Mp>250 ꢁC. 1H NMR (DMSO-d6):
3.10. Typical procedure E for the C–H direct arylation
Thiazole (500 mg, 5.9 mmol, 2 equiv), aryl halide (2.9 mmol,
1 equiv), KOAc (5.9 mmol, 2 equiv), and Pd(OAc)2 (2.6 mg,
0.01 mmol, 0.004 equiv) in dimethyl acetamide (5 mL) were
degassed and then heated in a sealed tube for 24 h at 130 ꢁC. The
dark suspension was filtered and concentrated. The resulting
mixture was redissolved in water and extracted three times with
EtOAc. The organic layers were washed with brine, dried (MgSO4),
and concentrated. Column chromatography (silica gel, cyclohex-
ane/EtOAc) afforded 5-arylthiazole.
d
9.20 (s, 1H), 8.44 (br s, 2H), 8.31 (s, 1H). 13C NMR (DMSO-d6):
d
158.3, 151.1 (the boron-carrying C-5 did not appear). MS (ESIþ)
calcd for C3H4BO2NS [MꢀHþ] 129.88.
3.10.1. 5-Phenylthiazole (8a)13b,15b
White solid using bromobenzene as a halocompound. Mp
3.6. Typical procedure A for the cross-coupling reaction
45 ꢁC. 1H NMR (CDCl3):
5H). 13C NMR (CDCl3):
128.6.
d
8.70 (s, 1H), 8.05 (s, 1H), 7.65–7.20 (m,
152.0, 138.9, 139.3, 131.0, 129.1, 126.9,
d
To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
thiazole 2 (500 mg, 2.4 mmol, 2 equiv), aryl halide (1.2 mmol,
1 equiv) in a mixture of dioxane and water 3/1 (20 mL) under argon
were added Na2CO3 (314 mg, 3.0 mmol, 2.5 equiv) and Pd(PPh3)4
(68 mg, 0.06 mmol, 0.05 equiv). The reaction mixture was heated at
80 ꢁC and the consumption of halocompound was followed by TLC.
The reaction mixture was then diluted with EtOAc and filtered
through a pad of CeliteÒ. The filtrate was washed three times with
brine. The organic layer was dried on MgSO4, filtered, and evapo-
rated under vacuum. The crude product was purified using column
chromatography on silica gel (cyclohexane/EtOAc 7/3).
3.10.2. 5-(4-Methoxyphenyl)thiazole (8b)10l,15b,i
White solid using 4-iodoanisole as halocompound. Mp 92 ꢁC. 1H
NMR (CDCl3):
d
8.70 (s, 1H), 7.98 (s, 1H), 7.50 (d, J¼8.8 Hz, 2H), 6.94
(d, J¼8.8 Hz, 2H), 3.84 (s, 3H). 13C NMR (CDCl3):
d 159.8, 151.2, 139.2,
138.1, 128.3, 123.6, 114.5, 55.4. HRMS (EI) m/z calcd: 191.04048,
found: 191.04038.
3.10.3. 4-(Thiazol-5-yl)aniline (8c)14c
Yellow solid using 4-iodoaniline as halocompound. Mp 149 ꢁC.
1H NMR (CDCl3):
d
8.65 (s, 1H), 7.93 (s, 1H), 7.38 (d, J¼6.8 Hz, 2H),
3.7. Typical procedure B for the cross-coupling reaction
6.71 (d, J¼8.7 Hz, 2H), 3.83 (br s, 2H). 13C NMR (CDCl3):
d 150.5,
146.8, 139.8, 137.3, 128.2, 121.3, 115.3. HRMS (EI) m/z calcd:
To a mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
thiazole 2 (500 mg, 2.4 mmol, 2 equiv), aryl halide (1.2 mmol,
1 equiv) in dry DMF (20 mL) under argon were added CsF (450 mg,
3.0 mmol, 2.5 equiv), CuI (23 mg, 0.12 mmol, 0.1 equiv), and
Pd(PPh3)4 (68 mg, 0.06 mmol, 0.05 equiv). The reaction mixture was
heated at 80 ꢁC and the consumption of halocompound was fol-
lowed by TLC. The reaction mixturewas then diluted with EtOAc and
filtered through a pad of CeliteÒ. The filtrate was washed three times
with brine. The organic layer was dried on MgSO4, filtered, and
evaporated under vacuum. The crude product was purified using
column chromatography on silica gel (cyclohexane/EtOAc 7/3).
176.04081, found: 176.04095.
3.10.4. 4-(Thiazol-5-yl)benzonitrile (8d)
White solid using 4-bromobenzonitrile as halocompound. Mp
102 ꢁC. IR (KBr): 2221, 1603, 1417, 1119, 829, 538. 1H NMR (CDCl3):
d
8.86 (s, 1H), 8.19 (s, 1H), 7.71 (s, 4H). 13C NMR (CDCl3):
d 153.7,
140.7, 135.6, 132.9, 127.3, 118.4, 111.8 (a quaternary carbon’s signal
did not appear). HRMS (EI) m/z calcd: 186.02516, found: 186.02513.
Anal. Calcd for C10H6N2S: C, 64.49; H, 3.25; N, 15.04. Found: C,
64.22; H, 3.09; N, 14.81.
3.10.5. 2-(Thiazol-5-yl)benzonitrile (8e)
3.8. Typical procedure C for the C–H direct arylation
White solid using 2-bromobenzonitrile as halocompound. Mp
92 ꢁC. 1H NMR (CDCl3):
d
8.92 (s, 1H), 8.30 (s, 1H), 7.79 (d, J¼7.8 Hz,
Thiazole (500 mg, 5.9 mmol, 5 equiv), aryl halide (1.2 mmol,
1 equiv), KOAc (3.5 mmol, 3 equiv), and Pd(PPh3)4 (124 mg,
0.06 mmol, 0.05 equiv) in dimethyl acetamide (5 mL) were
degassed and then heated in a sealed tube for 24 h at 150 ꢁC. The
dark suspension was filtered and concentrated. The resulting
mixture was redissolved in water and extracted three times with
EtOAc. The organic layers were washed with brine, dried (MgSO4),
and concentrated. Column chromatography (silica gel, cyclohex-
ane/EtOAc) afforded 5-arylthiazole.
1H), 7.68–7.61 (m, 2H), 7.49 (t, J¼7.8 Hz, 1H). 13C NMR (CDCl3):
d
154.1,142.7,134.4,134.2,133.1,130.3,130.0,128.6,118.0,110.9. HRMS
(EI) m/z calcd: 186.02516, found: 186.02509. Anal. Calcd for
C10H6N2S: C, 64.49; H, 3.25; N, 15.04. Found: C, 64.30; H, 3.02; N,
14.91.
3.10.6. 3-(Thiazol-5-yl)benzonitrile (8f)
White solid using 3-iodobenzonitrile as halocompound. Mp
91 ꢁC. 1H NMR (CDCl3):
d 8.80 (s, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.76
(d, J¼7.8 Hz, 1H), 7.59 (d, J¼6.8 Hz, 1H), 7.50 (t, J¼7.8 Hz, 1H). 13C
3.9. Typical procedure D for the C–H direct arylation
NMR (CDCl3): d 153.2, 140.0, 136.7, 132.2, 131.4, 130.8, 130.0, 129.8,
117.9, 113.2. HRMS (EI) m/z calcd: 186.02516, found: 186.02514.
Anal. Calcd for C10H6N2S: C, 64.49; H, 3.25; N, 15.04. Found: C,
64.28; H, 2.99; N, 14.78.
Thiazole (200 mg, 2.4 mmol, 1 equiv), aryl halide (7.1 mmol,
3 equiv), KOAc (7.1 mmol, 3 equiv), and Pd(OH)2 (34 mg, 0.24 mmol,

N. Primas et al. / Tetrahedron 65 (2009) 5739–5746
5745
3.10.7. 4-(Thiazol-5-yl)benzaldehyde (8g)15h
found: 295.07845. Anal. Calcd for C16H13N3OS: C, 65.06; H, 4.44; N,
14.23. Found: C, 64.87; H, 4.42; N, 13.99.
Yellow solid using 4-bromobenzaldehyde as halocompound. Mp
79 ꢁC. 1H NMR (CDCl3):
d 10.04 (s, 1H), 8.86 (s, 1H), 8.23 (s, 1H), 7.94
(d, J¼7.8 Hz, 2H), 7.76 (d, J¼7.8 Hz, 2H). 13C NMR (CDCl3):
d 191.2,
Acknowledgements
153.5, 140.5, 137.9, 136.8, 135.8, 130.5, 127.2. HRMS (EI) m/z calcd:
189.02484, found: 189.02479.
´
This work was supported by the ‘Conseil Regional de Basse-
´
Normandie’ and BoroChem S.A.S. We thank Dr. Remi Legay for high
3.10.8. 2-(Thiazol-5-yl)benzaldehyde (8h)
resolution mass spectrometry analyses.
Yellow solid using 2-bromobenzaldehyde as halocompound. Mp
85 ꢁC. 1H NMR (CDCl3):
d
10.15 (s, 1H), 8.95 (s, 1H), 8.02 (d, J¼7.8 Hz,
References and notes
1H), 7.87 (s, 1H), 7.67 (t, J¼7.8 Hz, 1H), 7.59–7.51 (m, 2H). 13C NMR
1. (a) Dondoni, A. In Comprehensive Heterocyclic Chemistry II; Shinkai, I., Ed.;
Pergamon: Glasgow, 1996; Vol. 3, p 373; (b) Kalgutkar, A. S.; Crews, B. C.;
Marnett, L. J. Biochem. 1996, 35, 9076; (c) Hutchinson, I.; Stevens, M. F. G.;
Westwell, A. D. Tetrahedron Lett. 2000, 41, 425.
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Prod. Rep. 1998, 15, 113; (c) Ogino, J.; Moore, R. E.; Patterson, G. M. L.; Smith, C.
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Wipf, P. Chem. Rev. 1995, 95, 2115.
(CDCl3):
d 190.9, 154.3, 143.7, 134.4, 133.8, 133.7, 133.5, 131.9, 129.2,
128.3. HRMS (EI) m/z calcd: 189.02484, found: 189.02481. Anal.
Calcd for C10H7NOS: C, 63.47; H, 3.73; N, 7.40. Found: C, 63.24; H,
3.49; N, 7.17.
3.10.9. 3-(Thiazol-5-yl)benzaldehyde (8i)
Pale yellow solid using 3-bromobenzaldehyde as halo-
3. Shiradkar, M. R.; Akula, K. C.; Dasari, V.; Baru, V.; Chiningiri, B.; Gandhi, S.;
Kaure, R. Bioorg. Med. Chem. 2007, 15, 2601.
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2006, 14, 3859.
5. (a) Dunkel, R.; Elbe, H.-L.; Greul, J. N.; Hartmann, B.; Gayer, H.; Seitz, T.; Wa-
chendorff-Neumann, U.; Dahmen., P.; Kuck, K.-H. WO 2006061215, 2006; Chem.
Abstr. 2006, 145, 62881; (b) Murakami, H.; Takii, S.; Mizuno, M. JP 200466855,
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2003029249, 2003; (d) Doemling, A.; Kolb, J. DE 10134478, 2008.
compound. Mp 61 ꢁC. 1H NMR (CDCl3):
d 10.07 (s, 1H), 8.83 (s, 1H),
8.17 (s, 1H), 8.07 (s, 1H), 7.87–7.83 (m, 2H), 7.60 (t, J¼6.8 Hz, 1H). 13C
NMR (CDCl3):
d 191.5, 152.7, 139.7, 137.7, 136.9, 132.4, 132.0, 129.8,
129.6, 127.3. HRMS (EI) m/z calcd: 189.02484, found: 189.02478.
Anal. Calcd for C10H7NOS: C, 63.47; H, 3.73; N, 7.40. Found: C, 63.27;
H, 3.55; N, 7.28.
6. Bhattacharya, P.; Leonard, J. T.; Roy, K. Bioorg. Med. Chem. 2005, 13, 1159.
7. (a) Schwander, H. In Ullman’s Encyclopedia of Industrial Chemistry; VCH:
Weinheim, 1988; Vol. A11, p 279; (b) Mori, A.; Sekiguchi, A.; Masui, K.; Shimada,
T.; Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125,
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In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: New York, NY, 1984; Vol. 6, pp 235–332; (c) Aguilar, E.; Meyers, A. I.
Tetrahedron Lett.1994, 35, 2473; (d) Varma, R. S. Pure Appl. Chem. 2001, 73,193; (e)
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68, 7887.
3.10.10. Ethyl 2-(thiazolyl-5-yl)benzoate (8j)
Yellow oil using ethyl 2-iodobenzoate as halocompound. 1H
NMR (CDCl3):
d
8.84 (s, 1H), 7.87 (d, J¼7.8 Hz, 1H), 7.77 (s, 1H), 7.55–
7.43 (m, 3H), 4,20 (q, J¼6.8 Hz, 2H), 1.16 (t, J¼6.8 Hz, 3H). 13C NMR
(CDCl3):
d 167.5, 152.9, 141.5, 136.7, 132.1, 131.8, 131.2, 130.5, 130.0,
128.7, 61.3, 13.8. HRMS (EI) m/z calcd: 233.05105, found: 233.05101.
Anal. Calcd for C12H11NO2S: C, 61.78; H, 4.75; N, 6.00. Found: C,
61.57; H, 4.55; N, 6.21.
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P. W.; Matteucci, M.; McDonald, E. Synlett 2006, 460.
3.10.11. 3-(Thiazol-5-yl)pyridine (8k)13d
Yellow oil using 3-bromopyridine as halocompound. 1H
NMR (CDCl3):
(s, 1H), 7.90 (dd, J¼2.0 and 8.8 Hz, 1H), 7.39 (dd, J¼4.9 and
8.8 Hz, 1H). 13C NMR (CDCl3):
153.1, 149.4, 147.7, 140.0, 135.5,
d
8.87–8.83 (m, 2H), 8.60 (d, J¼4.9 Hz, 1H), 8.15
d
134.0, 127.3, 123.8. HRMS (EI) m/z calcd: 162.02516, found:
162.02473.
3.10.12. 5-(2-Nitrophenyl)thiazole (8l)
11. Stanetty, P.; Schnuerch, M.; Mihovilovic, M. D. J. Org. Chem. 2006, 71, 3754.
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Fujitaki, J. M.; van Poelje, P. D.; Huang, J.; Lipscomb, W. N.; Erion, M. D. J. Am.
Chem. Soc. 2007, 129, 1549; (b) Vachal, P.; Toth, L. M. Tetrahedron Lett. 2004, 45,
7157; (c) Feuerstein, M.; Doucet, H.; Santelli, M. J. Organomet. Chem. 2003, 687,
327; (d) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302.
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A.; Borsato, G.; Brussolo, S.; Frascella, P.; Lucchini, V. Tetrahedron Lett. 2007, 49,
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Quintero, L. Tetrahedron Lett. 1999, 40, 5701.
Orange solid using 2-iodonitrobenzene as halocompound. Mp
70 ꢁC; 1H NMR (CDCl3):
d
8.90 (s, 1H), 7.91 (d, J¼6.8 Hz, 1H), 7.88 (s,
1H), 7.65 (t, J¼8.8 Hz, 1H), 7.59–7.53 (m, 2H). 13C NMR (CDCl3):
d
154.3, 149.2, 142.4, 142.3, 132.9, 132.4, 129.7, 125.1, 124.3. HRMS
(EI) m/z calcd: 206.01500, found: 206.01485. Anal. Calcd for
C9H6N2O2S: C, 52.42; H, 2.93; N, 13.58. Found: C, 52.19; H, 2.68; N,
13.70.
3.10.13. 5-(Thiazol-5-yl)furan-2-carbaldehyde (8m)13b
Yellow solid using 5-bromofurfural as halocompound.
Mp<50 ꢁC. 1H NMR (CDCl3):
d
9.67 (s, 1H), 8.86 (s, 1H), 8.30 (s, 1H),
7.33 (s, 1H), 6.79 (s, 1H). 13C NMR (CDCl3):
d
176.4,153.7, 152.0, 151.4,
141.6, 127.1, 123.1, 109.5. HRMS (EI) m/z calcd: 179.00410, found:
14. (a) Sapountzis, I.; Dube, H.; Lewis, R.; Gommermann, N.; Knochel, P. J. Org.
Chem. 2005, 70, 2445; (b) Lipshutz, B. H.; Frieman, B.; Birkedal, H. Org. Lett.
2004, 6, 2305; (c) Jensen, J.; Skjaerbaek, N.; Vedsø, P. Synthesis 2001, 1, 128.
15. (a) Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.; Gohma, K.;
Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J.; Honma, R.; Akita, Y.; Ohta, A.
Heterocycles 1992, 33, 257; (b) Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem.
2005, 70, 7578; (c) Derridj, F.; Roger, J.; Geneste, F.; Djebbar, S.; Doucet, H.
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Chem. 2009, 74, 1179; (e) Pozgan, F.; Roger, J.; Doucet, H. ChemSusChem 2008, 1,
404; (f) Gottumukkala, A. L.; Doucet, H. Eur. J. Inorg. Chem. 2007, 23, 3626; (g)
Kondo, Y.; Komine, T.; Sakamoto, T. Org. Lett. 2000, 2, 3111; (h) Bold, G.; Faessler,
A.; Capraro, H.-G.; Cozens, R.; Klimkait, T.; Lazdins, J.; Mestan, J.; Poncioni, B.;
Roesel, J.; Stover, D.; Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.;
179.00433.
3.10.14. 7-Ethoxy-4(thiazol-5-yl)pyrrolo[1,2-a]quinoxaline (8n)
Yellow solid. Following typical procedure using 4-chloro-7-
ethoxypyrrolo[1,2-a]quinoxaline21 as halocompound. Mp 175 ꢁC.
1H NMR (CDCl3):
d 8.97 (s, 1H), 8.70 (s, 1H), 7.95 (s, 1H), 7.79 (d,
J¼8.8 Hz, 1H), 7.42 (d, J¼2.9 Hz, 1H), 7.22–7.14 (m, 2H), 6.93 (m, 1H),
4.16 (q, J¼6.8 Hz, 2H), 1.49 (t, J¼6.8 Hz, 3H). 13C NMR (CDCl3):
d
156.7, 155.1, 145.3, 143.0, 138.3, 136.6, 123.6, 121.2, 118.0, 114.6,
114.5, 114.1, 111.5, 107.1, 64.0, 14.8. HRMS (EI) m/z calcd: 295.07791,

5746
N. Primas et al. / Tetrahedron 65 (2009) 5739–5746
Eschbach, M.; Huerlimann, T.; Masso, E.; Roussel, S.; Ucci-Stoll, K.; Wyss, D.;
Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.; Osakada, K.; Kawamoto, M.;
Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700; (i) Pivsa-Art, S.; Satoh, T.; Kawamura,
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