Palladium(II)-catalyzed oxidative Heck coupling of thiazole-4-carboxylates

Article abstract of DOI:10.1016/j.tetlet.2011.08.088

Oxidative Heck coupling of thiazole-4-carboxylates via palladium(II)- catalyzed C-H bond activation has been achieved in moderate to good yields. No ligand, and no acidic additive were used in the reaction. The results showed that this protocol tolerated

Full text of DOI:10.1016/j.tetlet.2011.08.088

Tetrahedron Letters 52 (2011) 5643–5647
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Tetrahedron Letters
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Palladium(II)-catalyzed oxidative Heck coupling of thiazole-4-carboxylates
Ziyuan Li a,c, Ling Ma a,c, Changhua Tang a,c, Jinyi Xu a, Xiaoming Wu b,c, Hequan Yao a,c,
⇑
a Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
b Center for Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China
c State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2011
Revised 28 July 2011
Accepted 16 August 2011
Available online 22 August 2011
Oxidative Heck coupling of thiazole-4-carboxylates via palladium(II)-catalyzed C–H bond activation has
been achieved in moderate to good yields. No ligand, and no acidic additive were used in the reaction. The
results showed that this protocol tolerated a series of substitutions on the thiazole ring. A preliminary
attempt of direct arylation with p-xylene via Pd(II)-catalyzed C–H bond activation has also been done.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Thiazole-4-carboxylate
C–H bond activation
Oxidative Heck-coupling
Alkenylation
Direct arylation
Thiazole is among the most significant moieties in many natural
products and synthetic molecules with potent biological activities.
During the past decades, natural and synthetic thiazole-based mol-
ecules have drawn increasing attentions and interests due to their
miscellaneous applications in pharmaceutical sciences and mate-
rial chemistry. Among them, a variety of compounds featured with
5-vinylthiazole-4-carboxylate moiety1 (Fig. 1a) and other 5-alkyl-
thiazole-4-carboxylate moiety (Fig. 1b),2 which could be derived
from 5-vinyl substituted ones, have been reported to possess con-
siderable biological activities. Thus, developing an efficient meth-
odology on the alkenylation of thiazole-4-carboxylates is desirable.
During the last few decades, major progress has been achieved
in transition-metal-catalyzed C–C bond-formation where one or
both of the carbon atoms are required to be preactivated,3 such
as Mizoroki–Heck reaction and Suzuki–Miyaura coupling. More re-
cently, direct C–C bond formation via palladium(II) catalyzed C–H
bond cleavage of both substrates has been becoming an exceed-
ingly valuable process in contemporary organic synthesis,4 allow-
ing concise and economical routes to be applied to the
preparation of natural or synthetic compounds with biological
activities. In light of the advances in this area, several groups have
independently reported the cross-coupling reactions of thiazoles at
5-postion5 with organic halides or acrylates. For example, Liegault
and Fagnou et al.5c,d developed elegant palladium-catalyzed
hetereoarene benzylation and heteroaromatic direct arylation,
respectively. More recently, Miura et al. successfully achieved in
5-alkenylation of 2-substituted or 2,4-disubstituted thiazoles via
Pd(II)-catalyzed C–H bond activation, in which EtCOOH or PivOH
was used to accelerate the reaction.6 Although their results shed
some lights on direct C–H functionalization at 5-position of thia-
zoles, the direct alkenylation of thiazole-4-carboxylates at 5-posi-
tion remains unexplored so far. As a continuation of our research
on azoles,7 hererin, we wish to report an acidic additive free
palladium(II)-catalyzed oxidative Heck coupling of thiazole
-4-carboxylates.
We began our investigation using 1a as the model substrate.
The results were summarized in Table 1. Initial attempts to evalu-
ate different combinations of catalysts and oxidants indicated that
a catalytic amount (20 mol %) of Pd(OAc)2 with 2 equiv of AgOAc
and olefin 2 (6 equiv) in DMF/DMSO (10:1, v/v) at 100 °C for 48 h
could afford the desired alkenylation product 3a in moderate yield
(entry 1). Cu(OAc)2 could also be used as an oxidant, but significant
amount of homocoupling product 3a0 was found as a side product
(entry 2). Changing the oxidant or catalyst dramatically decreased
the yields of 3a (entries 3–5). The unsatisfactory yields were
caused either by incomplete consumption of 1a or generation of
3a0. We then carefully screened the reaction conditions in order
to improve the yields of 3a. Very interestingly, the yield of 3a
was improved when the reaction was carried out at 110 °C with
lower loading of Pd(OAc)2 (10 mol %) (entry 6). Further tests on
the reaction temperature revealed that an excellent yield of 3a
could be achieved when the reaction was performed at 115 °C (en-
try 7). Elevating temperature provided no better result (entry 8).
⇑
Corresponding author. Tel.: +86 25 83271402; fax: +86 25 83301606.
E-mail address: hyao@cpu.edu.cn (H. Yao).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.088

5644
Z. Li et al. / Tetrahedron Letters 52 (2011) 5643–5647
S
N
(a)
HN
N
HOOC
R
O
S
N
O
S
N
Ph
H
N
N
HO
N
O
n-Bu-O2C
HO
R = methyl or phenyl
O
EtOOC
H
S
N
NHPh
Ph
N
O
S
N
(b)
HOOC
HN
N
O
HO
S
O
Ph
H
N
S
N
N
N
HO
O
N
O
n-Bu-O2C
HO
OH
OH
N
OH OH
F
O
S
N
H2N
O
Figure 1. Representive biologically active compounds: (a) 5-vinylthiazole-4-carboxylates; (b) 5-alkylthiazole-4-carboxylates.
The excellent yield could also be maintained when the loading of 2
was gradually decreased to 1.5 equiv (entries 10–12), but remark-
ably dropped when the loading was declined to 1 equiv (entry 13).
Thus, a condition of 1.5 equiv of 2, 10 mol % of Pd(OAc)2, 2 equiv of
AgOAc at 115 °C in DMF/DMSO (10:1, v/v) was selected for further
investigation of the substrate compatibility. Very gratifyingly, the
formation of byproduct 3a0 was suppressed under this optimized
condition.
With the established condition in hand, we then examined a ser-
ies of thiazole-4-carboxylates to demonstrate the substrate scope as
shown in Table 2. Generally, all substrates reacted smoothly to pro-
vide the desired cross-coupling products in moderate to excellent
yields within 48 h. Different substitutions on the thiazole ring were
well tolerated, and some patterns were observed. For 2-phenyl sub-
strates, the substrates with electron-donating group and halogen on
the benzene ring afforded the product in good yields (3a–3e, 3h–3l),
while the ones with electron-withdrawing substituents gave the
moderate yields due to incomplete consumption of the substrates
(3f–3g). Only trace amount of the homocoupling byproducts could
be observed for all 2-phenyl substrates, while more homocoupling
byproducts for 2-alkyl and 2-carbonyl substituted substrates were
obtained, leading to the relatively lower yields of the corresponding
cross-coupling products (3m–3o).
tolerated (4a–4f), affording the desired products in moderate to
good yields, although small amount of substrates remained uncon-
sumed even after 48 h. More bulky a-methylacrylates afforded the
products only in lower yields and more homocoupling byproducts
were isolated (4e–4f), suggesting that bulky olefins might be more
difficult to couple with the thiazole substrates.
In addition, a preliminary attempt to couple thiazole-4-carbox-
ylate with arene was conducted, since many compounds bearing
5-arylthiazole scaffold have been reported to have considerable
pharmaceutical values. We successfully coupled methyl 2-phenyl-
thiazole-4-carboxylate (1a) with p-xylene to afford the arylation
product 5 in 35% yield. Most of 1a was homocoupled to afford
the byproduct 3a0 (Scheme 1). To the best of our knowledge, this
is the first example that 5-arylation of thiazole via C–H bond cleav-
age of both substrates is ever reported. Further research focusing
on the direct arylation is now undergoing in our group.
In conclusion, we have developed a general protocol for alkeny-
lation of thiazole-4-carboxylates with good tolerance in moderate
to excellent yields via Pd(OAc)2-catalyzed C–H bond activation.
The reaction demonstrated broad substrate and olefin scope. No
pre-activation and no ligand or additive was required. This work
could offer a route to the synthesis of 5-vinylthiazole-4-carboxyl-
ate scaffold-based biologically active compounds and other func-
tional chemicals. Further application of this protocol to the
synthesis of 5-vinylthiazole-4-carboxylate-based active com-
Next, the effective condition was extended to a variety of olefins
as shown in Table 3. Acrylates, acrylamide and styrene were well

Z. Li et al. / Tetrahedron Letters 52 (2011) 5643–5647
5645
Table 1
Screening of reaction conditiona,8
COOnBu
CO2Me
S
N
2
n-Butyl Acrylate ( )
3a
H
S
N
Catalyst
+
Oxidant
DMF/DMSO
(10:1, v/v)
CO2Me
MeO2C
S
N
S
1a
N
CO2Me
3a'
b
Entry
Catalyst (mol %)
Oxidant (equiv)
2 (equiv)
Temp (°C)
Time (h)
Yields of 3a/3a0 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd(OAc)2 (20)
Pd(OAc)2 (20)
Pd(OAc)2 (20)
PdCl2 (20)
AgOAc (2)
Cu(OAc)2 (2)
Ag2CO3 (2)
AgOAc (2)
Cu(OAc)2 (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
AgOAc (2)
6
6
6
6
6
6
6
6
6
4
2
1.5
1
100
100
100
100
100
110
115
120
115
115
115
115
115
48
48
48
36
36
48
48
48
48
48
48
48
48
71/trace
74/13
48/tracec
55/4d
PdCl2 (20)
56/15
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
84/trace
90/trace
75/trace
86/trace
90/trace
88/trace
90/trace
78/19
a
b
c
Reaction conditions: methyl 2-phenylthiazole-4-carboxylate (1a, 0.5 mmol), n-butyl acrylate (2), catalyst and oxidant in solvent (1.5 ml DMF with 0.15 ml DMSO).
Isolated yield.
42% of 1a was recovered.
37% of 1a was recovered.
d
Table 2
Investigation on the substrate scopea
2
n-Butyl Acrylate ( , 1.5 equiv)
COOnBu
H
S
S
N
Pd(OAc)2 (10 mol%)
R
R
AgOAc (2.0 equiv)
DMF/DMSO (10:1, v/v)
N
CO2Me
CO2Me
3a-3o
1a-1o
115 °C, 48 h
COOnBu
S
COOnBu
CO2Me
COOnBu
CO2Me
COOnBu
CO2Me
S
S
N
MeO
MeO
MeO
N
N
CO2Me
3a
3b
S
(90%)
(86%)
3c
(87%)
S
COOnBu
CO2Me
COOnBu
CO2Me
S
N
O2N
N
N
MeO
F3C
OMe
3d
b
3e
3f
3i
(87%)
(71% )
(84%)
S
COOnBu
CO2Me
COOnBu
CO2Me
COOnBu
CO2Me
S
N
S
N
F
Cl
Br
N
b
3g
(65% )
3h
(82%)
(85%)
S
COOnBu
CO2Me
Cl
Cl
COOnBu
CO2Me
COOnBu
CO2Me
S
S
N
N
N
3l
(81%)
3j
(86%)
3k
(79%)
(continued on next page)

5646
Z. Li et al. / Tetrahedron Letters 52 (2011) 5643–5647
Table 2 (continued)
COOnBu
CO2Me
COOnBu
CO2Me
COOnBu
S
O
S
N
S
N
N
CO2Me
d
c
3n
e
(50% )
3m
(61% )
3o
(61% )
a
Reaction conditions: methyl 2-substituted thiazole-4-carboxylate (1a–1o, 0.5 mmol), n-butyl acrylate (2, 0.75 mmol, 1.5 equiv), Pb(OAc)2 (0.05 mmol, 10 mol%) and
AgOAc (1 mmol, 2.0 equiv) in solvent (1.5 ml DMF with 0.15 ml DMSO) at 115 °C for 48 h. Isolated yields.
Substrates incompletely consumed.
With 30% of the homocoupling byproduct.
With 38% of the homocoupling byproduct.
With 32% of the homocoupling byproduct.
b
c
d
e
Table 3
Investigation on the olefin scopea
R1
H
2a 2f
- , 1.5 equiv)
(
R2
R1
H
S
S
Pd(OAc)2 (10 mol%)
R2
CO2Me
AgOAc (2.0 equiv)
DMF/DMSO (10:1, v/v)
115 °C, 48 h
N
N
CO2Me
4a-4f
1a
CO2Me
CO2Et
CONHBn
CO2Me
S
N
S
N
S
N
CO2Me
CO2Me
4a
4b
4c
(83%)
(80%)
(76%)
COOnBu
CO2Et
S
N
S
N
S
N
CO2Me
CO2Me
CO2Me
b
c
4e
(46% )
4f
(54% )
4d
(82%)
b
c
With 49% of the homocoupling byproduct.
With 38% of the homocoupling byproduct.
a
Reaction conditions: methyl 2-phenylthiazole-4-carboxylate (1a, 0.5 mmol), olefins (2a–2f, 0.75 mmol, 1.5 equiv), Pb(OAc)2 (0.05 mmol, 10 mol%) and AgOAc (1 mmol,
2.0 equiv) in solvent (1.5 ml DMF with 0.15 ml DMSO) at 115 °C. Isolated yields.
S
N
CO2Me
Pd(OAc)2 (10 mol%)
AgOAc (2.0 equiv)
H
5 (35%)
S
N
+
p-xylene/DMSO (10:1, v/v)
CO2Me
MeO2C
N
115 °C, 24 h
1a
Not optimized
S
N
S
CO2Me
3a' (54%)
Scheme 1. A preliminary 5-arylation of 1a via palladium catalyzed C–H bond cleavage of both substrates.
pounds as potential leads is undergoing in our laboratory and will
Supplementary data
be reported in due course.
Supplementary data (1H NMR and 13C NMR spectra of 3a–3o,
4a–4f) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.08.088.
Acknowledgments
Financial support from the Program for New Century Excellent
Talents in University (NCET 2008) by the Ministry of Education of
China, Fok Ying Tong Education Foundation (121040) and Funda-
mental Research Funds for the Central Universities (JKZ2009002
for H.Y.) is highly appreciated.
References and notes
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8. Typical procedure for palladium(II)-catalyzed oxidative Heck coupling of thiazole-4-
carboxylate:
A reaction tube was charged with methyl 4-phenylthiazole-4-
carboxylate (1a, 0.5 mmol), olefin 2 (0.75 mmol, 1.5 equiv), Pd(OAc)2 (11 mg,
0.05 mmol, 10 mol%), AgOAc (167 mg, 1 mmol, 2.0 equiv), DMF (1.5 ml) and
DMSO (0.15 ml). The mixture was vigorously stirred at 115 °C (oil temperature).
After stirring for 48 h, the mixture was cooled to room temperature, diluted
with ethyl acetate and filtered. The filtrate was washed with saturated NaHCO3,
water and brine, dried over Na2SO4, and concentrated in vacuo to give dark
residue, which was purified by flash chromatography on silica gel to afford the
cross coupling product 3a (155 mg, 90%) as off-white solid; mp 91–93 °C; 1H
NMR (300 MHz, CDCl3) d 6.58 (d, 1H, J = 15.9 Hz), 7.96–8.00 (m, 2H), 7.46–7.49
(m, 3H), 6.36 (d, 1H, J = 15.9 Hz), 4.24 (t, 2H, J = 6.7 Hz), 4.02 (s, 3H), 1.66–1.74
(m, 2H), 1.39–1.49 (m, 2H), 0.97 (t, 3H, J = 7.3 Hz); 13C NMR (75 MHz, CDCl3) d
167.1, 165.7, 162.2, 144.9, 141.3, 133.6, 132.2, 131.4, 129.1, 127.1, 124.4, 64.9,
52.7, 30.7, 19.2, 13.7; IR (KBr) 2957, 2924, 2872, 2852, 1723, 1627, 1494, 1463,
1440, 1335, 1308, 1221, 1182, 1021, 973, 856, 769, 688, 643 cmꢀ1; HRMS (ESI)
calcd for [C18H19NO4S+H]+ 346.1113, found 346.1117.
4. (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Rev. 2001, 34, 633; (b) Shilov, A.
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