Efficient palladium(II)-catalyzed homocoupling of thiazole-4-carboxylic or oxazole-4-carboxylic derivatives

Article abstract of DOI:10.1016/j.tet.2011.05.123

An efficient Pd(OAc)₂-catalyzed homocoupling of thiazole-4-carboxylic or oxazole-4-carboxylic derivatives is described. It represents a facile and practical methodology to prepare bis-5,5′-thiazole (oxazole)-4,4′-dicarboxylic derivatives in goo

Full text of DOI:10.1016/j.tet.2011.05.123

Tetrahedron 67 (2011) 5550e5555
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Efficient palladium(II)-catalyzed homocoupling of thiazole-4-carboxylic
or oxazole-4-carboxylic derivatives
,
,
,
,
,c,
*
Ziyuan Li a c, Yiyun Wang a c, Yue Huang a c, Changhua Tang a c, Jinyi Xu a, Xiaoming Wu b
,
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:
An efficient Pd(OAc)2-catalyzed homocoupling of thiazole-4-carboxylic or oxazole-4-carboxylic
derivatives is described. It represents a facile and practical methodology to prepare bis-5,50-thiazole
(oxazole)-4,40-dicarboxylic derivatives in good to excellent yields. This protocol tolerates a series of
substitutions on the thiazole (oxazole) rings, including alkyl, carbonyl, and electron-withdrawing/donating
group substituted phenyl groups.
Received 25 March 2011
Received in revised form 23 May 2011
Accepted 31 May 2011
Available online 2 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Homocoupling
Palladium(II)-catalyzed
CeH bond activation
Thiazole
Oxazole
1. Introduction
synthetic compounds bearing the scaffold of bis-5,50-thiazole or
bis-5,50-oxazole have been reported to have miscellaneous phar-
Over past decades, significant progress has been achieved in
transition-metal-catalyzed CeC bond formation where one or both
of the carbon atoms are required to be pre-activated, such as the
MizorokieHeck, Kumada, Stille, Negishi, SuzukieMiyaura, Hiyama
coupling, and TsujieTrost allylation.1 More recently, direct conver-
sion2 of CeH bond to CeC bond via palladium (II) catalysis has been
becoming an exceedingly valuable process in contemporary organic
synthesis, allowing concise, economical, and environmental-benign
routes to be applied to the synthesis of many useful functional
chemicals or organic compounds with biological activities.
In light of the advances in this area, our interest in the synthesis
of the biologically leads, such as new CDC25 inhibitors, inspired us
to explore a general protocol for the direct 5-arylation of thia-
zoles.3,4 When we treated methyl 2-phenylthiazole-4-carboxylate
(1a) with 4 equiv of anhydrous toluene in DMF/DMSO using
Pd(OAc)2 as a catalyst (Scheme 1), however, only trace amount of
the desired 5-aryl substituted product 2 was observed, and
a homocoupling byproduct 3a was acquired in very good yield.
Encouraged by the promising result, we then turned our attention
to this homocoupling reaction. As we know, many natural or
maceutical applications or to be used as functional materials.5
Ph
S
Desired
Arylation Product
N
Yield: trace
CO2Me
PhMe (4.0 equiv)
Ph
Pd(OAc)2 (0.2equiv)
S
5
2
AgOAc (2.0 equiv)
H
N
4
+
DMF / DMSO (10:1)
120 oC, 24 h
CO2Me
MeO2C
1a
4'
Ph
Undesired
S
5
N
Homocoupling Product
Yield 89%
N
5'
S
Ph
4
CO2Me
3a
Scheme 1. Palladium catalyzed homocoupling of thiazole-4-carboxylate.
Previous methods to implement the preparationof bis-5,50-azoles
usually required participation of halogen atoms,6 which makes this
conversion not economical and environmental-benign. Oxidative
cross-coupling was also reported as an efficient method to achieve
bis-5,50-azoles, inwhich a strong base like n-BuLi was usually used to
dissociate the hydrogen atom on the coupling site before the cross-
coupling takes place.5b,7 Recently, Mori and co-workers provided
an example of the homocoupling of 2-(p-methoxyl)phenylthiazole
* Corresponding authors. Tel.: þ86 25 83271042; fax: þ86 25 83301606 (H.Y.);
tel.: þ86 25 83271501; fax: þ86 25 83301606 (X.W.); e-mail addresses: xmwu@
cpu.edu.cn (X. Wu), hyao@cpu.edu.cn (H. Yao).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.123

Z. Li et al. / Tetrahedron 67 (2011) 5550e5555
5551
using a PdCl2(dppb)/AgOAc catalytic system when they focused on
the homocoupling of thiophenes.8 In addition, other examples of
Pd(II)-catalyzed homocoupling of heteroarene have also been
reported in the literatures.9 Although various approaches have been
developed for the preparation of bis-5,50-azoles so far, no general
catalytic system was reported for the homocoupling of thiazole-4-
carboxylic or oxazole-4-carboxylic derivatives. Herein, we wish to
describe a general reaction system for the homocoupling of various
thiazole (oxazole)-4-carboxylic derivatives with wide compatibility
via Pd(OAc)2 catalyzed CeH bond activation.
species B. B undergoes a reductive elimination to afford the
homocoupling product 3. The Pd(II) catalyst is regenerated via an
oxidation of Pd(0) to complete the catalytic cycle.
MeO2C
N
H
R
S
1
Ag(0) or Cu(I)
Ag(I) or Cu(II)
Pd(II)
C-H Bond
Activation
HOAc
2. Results and discussion
MeO2C
Pd(0)
N
We began our investigation using 1a as the model substrate. The
results were summarized in Table 1. An initial attempt under
a similar condition to that in Scheme 1 without toluene was suc-
cessful within a remarkably shorter time even when a smaller
catalyst loading (0.1 equiv) was tried (entry 1). Further attempts to
evaluate reaction temperature and different combinations of cata-
lysts and oxidants provided no better results (entries 2e9). Lower
loading of Pd(OAc)2 resulted in poorer yields of the desired product
3a (entries 10 and 11). Replacing the metal oxidants with more
cost-effective oxidants, such as BQ and O2 were also detrimental to
the yield (entries 12e18). Reactions without any palladium (II)
catalyst provided no or only trace amount of 3a (entries 19e21)
suggesting the plausible mechanism of this conversion as illus-
trated in Fig. 1.8 Electrophilic CeH substitution of Pd(II) catalyst
with 1, followed by disproportionation gives bis-thiazolepalladium
A
AcO
MeO2C
Pd
R
S
N
S
R
MeO2C
R
S
N
N
MeO2C
CO2Me
3
H
R
S
N
S
R
1
Pd
R
S
HOAc
N
CO2Me
B
Fig. 1. Plausible mechanism of Pd(OAc)2-catalyzed homocoupling.
With the established condition in hand, we embarked on the
investigation of the substrate scope. Compatibility of the estab-
lished condition on various thiazole-4-carboxylic substrates was
first examined, and the results were summarized in Table 2. All
thiazole-4-carboxylate substrates were completely consumed
within 12 h, and the homocoupling proceeded smoothly to give
the corresponding products in good to excellent yields (3aep). For
those 2-substituted phenylthiazole-4-carboxylate substrates, the
electronic property of the group on the benzene ring had some
influences on the homocoupling reaction (3aej, 3nep). Generally,
strong electron-donating group substituted substrates provided
the desired products in relatively lower yields (3b and 3d). On the
contrary, substrates with strong electron-withdrawing group or
halogen atom on the benzene ring afforded the homocoupling
products in higher yields (3eej, 3o, and 3p), and much less ad-
verse products were observed. This substitution effect on thia-
zoles could be explained by the fact that the Pd induced CeH bond
activation process might be originated from the CeH acidity at 5-
position of thiazoles.8 Good results were also achieved for the
substrates with akyl or benzoyl groups (3kem). Although pro-
longed reaction time was required for the thiazole-4-formamide
substrates to be fully consumed under this condition, but all
provided the homocoupling products (3qeu) in good yields after
36 h. It is noteworthy that the homocoupling of a 2-monosubstituted
substrate favored at the relatively electrophile-susceptible 5-position
to afford the bis-5,50-thiazole (3v) in excellent yield under the
optimized condition.6a
Applications of the established protocol to the homocoupling of
oxazole-4-carboxylic derivatives were also explored and the results
showed similar patterns comparing to the thiazole substrates
(Table 3). The homocoupling of all carboxylate substrates pro-
ceeded smoothly to afford the desired products in moderate to
good yields within 12 h (5aeg). Among them, the yields of the
homocoupling of 2-phenyloxazole-4-carboxylates with halo or
electron-withdrawing group substitution on phenyl group were
remarkably higher than that of other types of substitution, same as
the thiazole substrates. Small amount of the oxazole-4-formamide
substrates remained unconsumed even after a prolonged reaction
time (36 h), resulting in relatively lower yields (5h and 5i). To the
Table 1
The screening of the reaction conditionsa
Entry
Catalyst
Oxidant
3a (1a) (%)b
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(OAc)2
PdCl2
Pd(OAc)2
PdCl2
AgOAc
Ag2CO3
Cu(OAc)2
AgOAc
Ag2CO3
Cu(OAc)2
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
BQ
91
74
26(67)
88
5
40(51)
82(7)
84(8)
62(31)
31(67)
77(17)
27(66)
47(47)
21(68)
trace
32(64)
17(75)
68(21)
24(58)
0
6
7c
8d
9e
10f
11g
12
13
14
15h
16h
17h
18h
19
20
21
O2
O2
AgOAc/O2
AgOAc/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
AgOAc
CuCl2
None
None
None
0
Cu(OAc)2
Trace
a
Reaction conditions unless otherwise specified: 1a (0.5 mmol), Pd(II) catalyst
(0.05 mmol, 0.1 equiv), and oxidant (1.0 mmol, 2.0 equiv) in 1.5 ml DMF and 0.15 ml
DMSO.
b
Isolated yield.
c
Conducted at 100 ꢀC.
d
Conducted at 80 ꢀC.
Conducted at 60 ꢀC.
Pd(OAc)2 (0.05 equiv) was used.
Pd(OAc)2 (0.01 equiv) was used.
e
f
g
h
AgOAc or Cu(OAc)2 (0.1 equiv) was used as a co-oxidant besides O2.

5552
Z. Li et al. / Tetrahedron 67 (2011) 5550e5555
Table 2
Table 3
,c
Homocoupling of thiazole-4-carboxylic derivativesa,b
Homocoupling of oxazole-4-carboxylic derivativesa,b
a
Reaction conditions: oxazole substrate (0.2 mmol), Pd(OAc)2 (0.1 equiv), and
oxidant (2.0 equiv) in 1 ml DMF and 0.1 ml DMSO.
b
Isolated yield.
3. Conclusion
We have developed a general protocol of homocoupling of thia-
zole-4-carboxylic or oxazole-4-carboxylic derivatives in good to ex-
cellent yields via palladium (II)-catalyzed CeH bond activation. The
reaction demonstrated broad substrate scope and good substitution
tolerance. No ligand, acidic or basic additive was needed. This work
provides a general route to the preparation of bis-5,50-azole scaffold-
based biologically active compounds and other functional chemicals.
Further work to apply this protocol to the synthesis of bis-5,50-azole-
based active compounds as potential leads is undergoing in our
laboratory and will be reported in due course.
4. Experimental section
4.1. General experimental
All solvents were distilled prior to use unless otherwise noted.
NMR spectra were recorded for 1H NMR at 300 MHz and for 13C
NMR at 75 MHz. For 1H NMR, tetramethylsilane (TMS) served as
internal standard (
d
¼0) and data are reported as follows: chemical
shift, integration, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, br¼broad), and coupling constant in
hertz. For 13C NMR, TMS (
d¼0) or CDCl3
(d¼77.25) was used as in-
ternal standard and spectra were obtained with complete proton
decoupling. HRMS data were obtained using ESI ionization. Mp data
were measured with micro melting point apparatus. IR spectra
were recorded on an FT-IR spectrometer (KBr).
a
Reaction conditions: thiazole substrate (0.5 mmol), Pd(OAc)2 (0.1 equiv), and
oxidant (2 equiv) in 1.5 ml DMF and 0.15 ml DMSO.
b
Isolated yield.
Conducted at 100 ꢀC.
c
4.2. General procedures for the homocoupling of thiazole-4-
carboxylic or oxazole-4-carboxylic derivatives
best of our knowledge, this is the first example that the homo-
coupling of oxazole derivatives to afford bis-5,50-oxazole de-
rivatives via direct CeH bond activation is ever reported.
A Schlenk tube was charged with the substrate (0.5 mmol),
Pd(OAc)2 (11 mg, 0.1 equiv), AgOAc (167 mg, 2.0 equiv), DMF

Z. Li et al. / Tetrahedron 67 (2011) 5550e5555
5553
(1.5 ml), and DMSO (0.15 ml). After vigorously stirring at 115 ꢀC (oil
temperature) for 12 or 36 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 corre-
sponding homocoupling product.
161.6, 144.7, 135.3, 133.8, 132.9, 131.2, 130.4, 126.9, 125.1, 52.6; IR
(KBr) 3091, 3068, 2991, 2956, 1725, 1571, 1475, 1448, 1347, 1275,
1242, 1205, 1171, 1022, 988, 931, 888, 782, 745, 683, 648 cmꢁ1
;
HRMS calcd for [C22H14Cl2N2O4S2þH]þ 504.9850, found 504.9849.
4.2.8. Dimethyl
carboxylate (3h). Yield: 91%; Yellow powder; mp: 161.5e163 ꢀC; 1H
NMR (300 MHz, CDCl3) 8.39e8.43 (m, 2H), 7.40e7.54 (m, 6H), 3.86
(s, 6H); 13C NMR (75 MHz, CDCl3)
163.7, 161.9, 143.2, 133.7, 132.1,
2,20-di-(2-chlorophenyl)-bis-5,50-thiazole-4,40-di-
d
4.2.1. Dimethyl 2,20-diphenyl-bis-5,50-thiazole-4,40-dicarboxylate (3a).
Yield: 91%; Off-white powder; mp: 170e170.5 ꢀC; 1H NMR
d
131.4, 131.1, 130.7, 130.6, 127.3, 52.5; IR (KBr) 2956, 1713, 1480, 1437,
1360, 1296, 1266, 1218, 1064, 1002, 968, 763, 671, 642 cmꢁ1; HRMS
(ESI) calcd for [C22H14Cl2N2O4S2þH]þ 504.9850, found 504.9843.
(300 MHz, CDCl3)
d
7.98e8.02 (m, 4H), 7.47e7.49 (m, 6H), 3.86 (s,
168.6, 161.8, 144.5, 132.7, 132.3,
6H); 13C NMR (75 MHz, CDCl3)
d
131.2, 129.1, 127.0, 52.5; IR (KBr) 2950, 2923, 2852, 1716, 1458, 1441,
1322, 1237, 1211, 1005, 778, 763, 689, 636 cmꢁ1; HRMS (ESI) calcd
for [C22H16N2O4S2þH]þ 437.0630, found 437.0628.
4.2.9. Dimethyl
carboxylate (3i). Yield: 87%; White powder; mp: 255e256 ꢀC; 1H
2,20-di-(4-bromophenyl)-bis-5,50-thiazole-4,40-di-
NMR (300 MHz, CDCl3)
d
7.87 (d, 4H, J¼8.5 Hz), 7.62 (d, 4H,
4.2.2. Dimethyl 2,20-di-(4-methoxylphenyl)-bis-5,50-thiazole-4,40-di-
J¼8.5 Hz), 3.86 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 166.9, 161.1,
carboxylate (3b). Yield: 79%; Yellow powder; mp: 212e214 ꢀC; 1H
144.2, 132.1, 131.8, 130.7, 127.8, 125.2, 52.1; IR (KBr) 2920, 2851, 1721,
1456, 1396, 1319, 1242, 1210, 1179, 1070, 1006, 972, 831, 775,
642 cmꢁ1; HRMS (ESI) calcd for [C22H14Br2N2O4S2þH]þ 592.8840,
found 592.8847.
NMR (300 MHz, CDCl3)
d
7.94 (d, 4H, J¼8.8 Hz), 6.98 (d, 4H,
J¼8.8 Hz), 3.88 (s, 6H), 3.84 (s, 6H); 13C NMR (75 MHz, CDCl3)
d
168.4, 162.0, 161.9, 144.2, 131.9, 128.6, 125.2, 114.4, 55.5, 52.5; IR
(KBr) 2962, 2921, 2844, 1723, 1608, 1576, 1462, 1309, 1260, 1176,
1035, 1012, 838, 777, 692, 641 cmꢁ1; HRMS (ESI) calcd for
[C24H20N2O6S2þH]þ 497.0841, found 497.0828.
4.2.10. Dimethyl 2,20-di-(4-trifluoromethylphenyl)-bis-5,50-thiazole-
4,40-dicarboxylate (3j). Yield: 87%; White powder; mp: 153e154 ꢀC;
1H NMR (300 MHz, CDCl3)
d
8.13 (d, 4H, J¼8.1 Hz), 7.75 (d, 4H,
4.2.3. Dimethyl 2,20-di-(4-methylphenyl)-bis-5,50-thiazole-4,40-dicarbox-
J¼8.1 Hz), 3.88 (s, 6H); 13C NMR (CDCl3, 75 MHz)
d 166.8, 161.5,
ylate (3c). Yield: 93%; Yellow powder; mp: 175.5e176 ꢀC; 1H NMR
145.0, 135.3, 133.2, 133.0, 132.6, 127.2, 126.2, 126.1, 126.0, 125.5,
52.6; IR (KBr) 2951, 1727, 1616, 1457, 1329, 1248, 1216, 1159,
1126, 1070, 1011, 848, 781, 642 cmꢁ1; HRMS (ESI) calcd for
[C24H14F6N2O4S2þH]þ 573.0377, found 573.0375.
(300 MHz, CDCl3)
d
7.89 (d, 4H, J¼8.1 Hz),
d
7.27 (d, 4H, J¼8.1 Hz),
3.85 (s, 6H), 2.42 (s, 6H); 13C NMR (75 MHz, CDCl3)
d
168.7, 161.8,
144.3,141.6,132.2,129.7,127.2,126.9, 52.4, 21.5; IR (KBr) 3021, 2942,
2920, 2850, 1725, 1608, 1457, 1336, 1247, 1200, 1179, 1158, 1011, 964,
821, 793, 773, 648 cmꢁ1; HRMS (ESI) calcd for [C24H20N2O4S2þH]þ
465.0943, found 465.0944.
4.2.11. Dimethyl 2,20-diphenylethyl-bis-5,50-thiazole-4,40-dicarbox-
ylate (3k). Yield: 83%; White powder; mp: 158e159 ꢀC; 1H NMR
(300 MHz, CDCl3)
d 7.21e7.34 (m, 10H), 3.82 (s, 6H), 3.38 (t, 4H,
4.2.4. Dimethyl 2,20-di-(3,4-dimethoxylphenyl)-bis-5,50-thiazole-4,40-
J¼8.5 Hz), 3.14 (t, 4H, J¼8.5 Hz); 13C NMR (75 MHz, CDCl3)
d 171.0,
dicarboxylate (3d). Yield: 71%; Yellow powder; mp: 192.5e194 ꢀC;
161.6,143.0, 140.0, 133.0,128.7,128.5,126.6, 52.4, 35.7, 35.3; IR (KBr)
2950, 1729, 1475, 1384, 1337, 1322, 1240, 1197, 1172, 1004, 933, 781,
753, 708 cmꢁ1; HRMS (ESI) calcd for [C26H24N2O4S2þH]þ 493.1256,
found 493.1247.
1H NMR (300 MHz, CDCl3)
d
7.57 (s, 2H), 7.50 (d, 2H, J¼8.3 Hz), 6.92
(d, 2H, J¼8.3 Hz), 4.00 (s, 6H), 3.95 (s, 6H), 3.85 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 168.5, 161.9, 151.7, 149.4, 144.2, 131.9, 125.4, 120.5,
111.0, 109.4, 56.2, 56.0, 52.5; IR (KBr) 2945, 2838, 1727, 1716, 1524,
1465, 1449, 1438, 1419, 1268, 1248, 1166, 1148, 1020, 800, 761,
651 cmꢁ1; HRMS (ESI) calcd for [C26H24N2O8S2þH]þ 557.1052,
found 557.1050.
4.2.12. Dimethyl 2,20-di-n-propyl-bis-5,50-thiazole-4,40-dicarboxylate
(3l). Yield: 78%; Yellow oil; 1H NMR (300 MHz, CDCl3)
d 3.82 (s, 6H),
3.05 (t, 4H, J¼7.7 Hz),1.86 (q, 4H, J¼7.7 Hz),1.06 (t, 6H, J¼7.7 Hz); 13C
NMR (75 MHz, CDCl3)
d 172.3, 161.7, 142.8, 132.9, 52.3, 35.5, 23.4,
4.2.5. Dimethyl 2,20-di-(4-fluorophenyl)-bis-5,50-thiazole-4,40-di-
carboxylate (3e). Yield: 88%; White powder; mp: 199e201 ꢀC; 1H
13.6; IR (neat) 2957, 2926, 2872, 1725, 1457, 1340, 1314, 1202, 1160,
1000, 765, 749 cmꢁ1; HRMS (ESI) calcd for [C16H20N2O4S2þH]þ
369.0943, found 369.0939.
NMR (300 MHz, CDCl3)
d
8.00 (dd, 4H, J¼8.5 Hz), 7.17 (t, 4H,
J¼8.5 Hz), 3.86 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 167.4, 166.2,
162.8, 161.7, 144.5, 132.5, 129.1, 129.0, 128.7, 128.6, 116.4, 116.1, 52.5;
IR (KBr) 2949, 1720, 1594, 1516, 1465, 1328, 1232, 1156, 1100, 1015,
973, 840, 780, 689, 639, 579, 510 cmꢁ1; HRMS (ESI) calcd for
[C22H14F2N2O4S2þH]þ 473.0441, found 473.0438.
4.2.13. Dimethyl 2,20-dibenzoyl-bis-5,50-thiazole-4,40-dicarboxylate
(3m). Yield: 96%; Light yellow needle; mp: 180e181 ꢀC; 1H NMR
(300 MHz, CDCl3)
d
8.58 (d, 4H, J¼7.3 Hz), 7.70 (t, 2H, J¼7.3 Hz), 7.58
(t, 4H, J¼7.3 Hz), 3.87 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 183.0,
167.9, 161.3, 145.1, 138.4, 134.4, 134.0, 131.4, 128.7, 52.7; IR (KBr)
2954, 1735, 1644, 1470, 1444, 1285, 1213, 1180, 996, 918, 855, 709,
663 cmꢁ1; HRMS (ESI) calcd for [C24H16N2O6S2þH]þ 493.0528,
found 493.0525.
4.2.6. Dimethyl 2,20-di-(4-chlorophenyl)-bis-5,50-thiazole-4,40-
dicarboxylate (3f). Yield: 91%; White powder; mp: 230e231 ꢀC; 1H
NMR (300 MHz, CDCl3)
d
7.94 (d, 4H, J¼8.6 Hz), 7.46 (d, 4H,
J¼8.6 Hz), 3.86 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 167.3, 161.6,
144.7, 137.4, 132.6, 130.7, 129.4, 128.2, 52.6; IR (KBr) 3090, 3056,
2988, 2945, 2841, 1722, 1595, 1457, 1322, 1242, 1212, 1179, 1092,
4.2.14. Di-n-butyl 2,20-diphenyl-bis-5,50-thiazole-4,40-dicarboxylate
(3n). Yield: 93%; Light yellow oil; 1H NMR (300 MHz, CDCl3)
1008, 973, 834, 775, 643 cmꢁ1
;
HRMS (ESI) calcd for
[C22H14Cl2N2O4S2þH]þ 504.9850, found 504.9844.
d
7.99e8.03 (m, 4H), 7.47e7.50 (m, 6H), 4.22 (t, 4H, J¼6.6 Hz),
1.50e1.56 (m, 4H), 1.18e1.26 (m, 4H), 0.81 (t, 6H, J¼7.4 Hz); 13C
4.2.7. Dimethyl 2,20-di-(3-chlorophenyl)-bis-5,50-thiazole-4,40-di-
NMR (75 MHz, CDCl3) d 168.4, 161.3, 145.3, 132.3, 131.1, 129.1, 126.9,
carboxylate (3g). Yield: 86%; White powder; mp: 180e181 ꢀC; 1H
65.5, 30.4, 19.1, 13.6; IR (KBr) 2955, 2926, 2867, 1724, 1459, 1325,
1238, 1204, 995, 763, 689, 639 cmꢁ1; HRMS (ESI) calcd for
[C28H28N2O4S2þH]þ 521.1563, found 521.1563.
NMR (300 MHz, CDCl3)
d
8.04 (s, 2H), 7.85 (d, 2H, J¼7.3 Hz),
7.38e7.48 (m, 4H), 3.87 (s, 6H); 13C NMR (75 MHz, CDCl3)
d
167.0,

5554
Z. Li et al. / Tetrahedron 67 (2011) 5550e5555
4.2.15. Di-n-butyl 2,20-di-(4-fluorophenyl)-bis-5,50-thiazole-4,40-di-
carboxylate (3o). Yield: 88%; White needle; mp: 129e131 ꢀC; 1H
J¼7.4 Hz), 7.58 (s, 2H), 7.36e7.46 (m, 4H), 3.38 (q, 4H, J¼7.4 Hz), 1.61
(p, 4H, J¼7.4 Hz), 1.36e1.44 (m, 4H), 0.94 (t, 6H, J¼7.4 Hz); 13C NMR
(75 MHz, CDCl3) d 165.9, 160.9, 146.5, 135.1, 134.2, 130.7, 130.4, 130.1,
NMR (300 MHz, CDCl3)
d
7.98e8.03 (m, 4H), 7.17 (t, 4H, J¼8.5 Hz),
126.5, 124.9, 39.2, 31.7, 20.2, 13.8; IR (KBr) 3340, 2956, 2930, 2870,
1670, 1658, 1530, 1245, 1078, 791, 746, 684, 640 cmꢁ1; HRMS (ESI)
calcd for [C28H28Cl2N4O2S2þH]þ 587.1109, found 587.1104.
4.22 (t, 4H, J¼6.6 Hz), 1.49e1.57 (m, 4H), 1.18e1.27 (m, 4H), 0.82 (t,
6H, J¼7.4 Hz); 13C NMR (75 MHz, CDCl3)
d 167.2, 166.1, 162.8, 161.2,
145.3, 132.2, 129.0, 128.9, 128.7, 128.6, 116.4, 116.1, 65.5, 30.4, 19.0,
13.6; IR (KBr) 2959, 2921, 2873, 1719, 1600, 1451, 1219, 1185, 846,
4.2.22. 2,20-Diphenyl-bis-5,50-thiazole (3v)6a. Yield: 89%; Light yel-
low powder; mp: 182e183 ꢀC; 1H NMR (300 MHz, CDCl3)
639, 515 cmꢁ1
557.1375, found 557.1387.
;
HRMS (ESI) calcd for [C28H26F2N2O4S2þH]þ
d
7.94e7.98 (m, 6H), 7.45e7.49 (m, 6H); 13C NMR (75 MHz, CDCl3)
4.2.16. Di-n-butyl 2,20-di-(3-chlorophenyl)-bis-5,50-thiazole-4,40-di-
d
167.6, 141.1, 133.1, 130.4, 129.1, 128.4, 126.5.
carboxylate (3p). Yield: 89%; Light yellow powder; mp:
99.5e101 ꢀC; 1H NMR (300 MHz, CDCl3)
d 8.04 (s, 2H), 7.86 (d,
4.2.23. Di-n-butyl 2,20-diphenyl-bis-5,50-oxazole-4,40-dicarboxylate
(5a). Yield: 67%; White oil; 1H NMR (300 MHz, CDCl3)
8.20 (d, 4H,
d
2H, J¼7.4 Hz), 7.39e7.49 (m, 4H), 4.23 (t, 4H, J¼6.6 Hz), 1.50e1.59
(m, 4H), 1.19e1.27 (m, 4H), 0.83 (t, 6H, J¼7.4 Hz); 13C NMR
J¼7.6 Hz), 7.49e7.54 (m, 6H), 4.30 (t, 4H, J¼7.4 Hz), 1.61 (p, 4H,
J¼7.4 Hz), 1.23e1.32 (m, 4H), 0.82 (t, 6H, J¼7.4 Hz); 13C NMR
(75 MHz, CDCl3)
d 166.8, 161.0, 145.5, 135.3, 133.8, 132.6, 131.1,
(75 MHz, CDCl3) d 162.6, 160.7, 141.1, 134.6, 131.8, 128.9, 127.3, 125.9,
130.4, 126.8, 125.1, 65.6, 30.4, 19.0, 13.6; IR (KBr) 2957, 2920,
2873, 1713, 1569, 1443, 1240, 1191, 1022, 938, 896, 789, 741,
683 cmꢁ1; HRMS (ESI) calcd for [C28H26Cl2N2O4S2þH]þ 589.0784,
found 589.0787.
65.6, 30.5, 19.0, 13.5; IR (neat) 2958, 2926, 2872, 1740, 1606, 1554,
1450, 1303, 1193, 1086, 1074, 1024, 944, 715, 689 cmꢁ1; HRMS (ESI)
calcd for [C28H28N2O6þH]þ 489.2026, found 489.2018.
4.2.24. Di-n-butyl 2,20-di-(4-methoxylphenyl)-bis-5,50-oxazole-4,40-
4.2.17. N,N0-Di-n-butyl 2,20-diphenyl-bis-5,50-thiazole-4,40-diforma-
dicarboxylate (5b). Yield: 74%; Light yellow oil; 1H NMR (300 MHz,
mide (3q). Yield: 81%; White powder; mp: 106e107 ꢀC; 1H NMR
CDCl3)
d
8.13 (d, 4H, J¼8.3 Hz), 7.01 (d, 4H, J¼8.3 Hz), 4.28 (t, 4H,
(300 MHz, CDCl3)
d 7.93e7.95 (m, 4H), 7.62 (s, 2H), 7.44e7.46 (m,
J¼7.4 Hz), 3.89 (s, 6H), 1.57e1.63 (m, 4H), 1.25e1.29 (m, 4H), 0.82 (t,
6H), 3.38 (q, 4H, J¼7.2 Hz), 1.58 (p, 4H, J¼7.2 Hz), 1.37 (m, 4H), 0.94
6H, J¼7.4 Hz); 13C NMR (75 MHz, CDCl3)
d 162.4, 160.9, 140.7, 134.3,
(t, 6H, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3)
d 167.5, 161.1, 146.3,
132.7, 129.1, 118.5, 114.4, 65.5, 55.5, 30.5, 19.0, 13.6; IR (neat) 2958,
132.6, 130.7, 129.7, 129.0, 126.7, 39.1, 31.7, 20.2, 13.8; IR (KBr) 3360,
2956, 2926, 2870, 1737, 1683, 1510, 1440, 1286, 1270, 1248, 782,
736 cmꢁ1; HRMS (ESI) calcd for [C28H30N4O2S2þH]þ 519.1888,
found 519.1881.
2926, 2853, 1737, 1610, 1498, 1259, 1172, 1024, 840, 764, 749 cmꢁ1
;
HRMS (ESI) calcd for [C30H32N2O8þH]þ 549.2237, found 549.2224.
4.2.25. Dimethyl 2,20-di-(4-methoxylphenyl)-bis-5,50-oxazole-4,40-
4.2.18. N,N0-Di-n-butyl 2,20-di-(4-nitrophenyl)-bis-5,50-thiazole-4,40-
dicarboxylate (5c). Yield: 72%; Yellow powder; mp: 200e204 ꢀC; 1H
diformamide (3r). Yield: 83%; Yellow powder; mp: 194e197 ꢀC; 1H
NMR (300 MHz, CDCl3)
d
8.13 (d, 4H, J¼8.8 Hz), 7.01 (d, 4H,
J¼8.8 Hz), 3.91 (s, 6H), 3.89 (s, 6H); 13C NMR (75 MHz, CDCl3)
NMR (300 MHz, CDCl3)
d
8.34 (d, 4H, J¼8.6 Hz), 8.13 (d, 4H,
J¼8.6 Hz), 7.56 (s, 2H), 3.39 (q, 4H, J¼7.3 Hz), 1.61 (p, 4H, J¼7.3 Hz),
d
162.5, 161.3, 140.8, 133.8, 129.1, 118.5, 114.4, 55.5, 52.5; IR (KBr)
1.37e1.47 (m, 4H), 0.95 (t, 6H, J¼7.3 Hz); 13C NMR (75 MHz, CDCl3)
2924, 2855, 1719, 1618, 1501, 1253, 1214, 1173, 1145, 1015, 837, 806,
739 cmꢁ1; HRMS (ESI) calcd for [C24H20N2O8þNa]þ 487.1112, found
487.1122.
d
164.8, 160.6, 149.0, 147.3, 137.9, 131.2, 127.4, 124.4, 39.2, 31.7, 20.2,
13.8; IR (KBr) 3315, 2957, 2930, 2856, 1665, 1598, 1522, 1466, 1384,
1346, 1249, 1111, 851, 754, 690 cmꢁ1; HRMS (ESI) calcd for
[C28H28N6O6S2þH]þ 609.1590, found 609.1588.
4.2.26. Dimethyl 2,20-di-(4-ethoxylphenyl)-bis-5,50-oxazole-4,40-di-
carboxylate (5d). Yield: 69%; Yellow powder; mp: 216e218 ꢀC; 1H
4.2.19. N,N0-Di-n-butyl 2,20-di-(4-trifluorophenyl)-bis-5,50-thiazole-
4,40-diformamide (3s). Yield: 87%; White powder; mp: 150e151 ꢀC;
NMR (300 MHz, CDCl3)
J¼8.5 Hz), 4.12 (q, 2H, J¼6.9 Hz), 3.91 (s, 3H), 1.46 (t, 3H, J¼6.9 Hz);
13C NMR (75 MHz, CDCl3)
162.6, 161.9, 161.3, 140.7, 133.8, 129.1,
118.3, 114.8, 63.8, 52.5, 29.7, 14.7; IR (KBr) 2925, 1721, 1616, 1501,
1385, 1277, 1254, 1212, 1175, 1146, 1014, 804 cmꢁ1; HRMS (ESI) calcd
for [C26H24N2O8þNa]þ 515.1425, found 515.1436.
d
8.12 (d, 4H, J¼8.5 Hz), 7.00 (d, 4H,
1H NMR (300 MHz, CDCl3)
d
8.06 (d, 4H, J¼8.1 Hz), 7.72 (d, 4H,
d
J¼8.1 Hz), 7.61 (s, 2H), 3.39 (q, 4H, J¼7.3 Hz), 1.60 (p, 4H, J¼7.3 Hz),
1.34e1.44 (m, 4H), 0.94 (t, 6H, J¼7.3 Hz); 13C NMR (75 MHz, CDCl3)
d
165.8, 160.8, 146.8, 135.6, 132.6, 132.2, 130.5, 126.9, 126.1, 126.0,
125.6, 121.9, 39.2, 31.7, 20.2, 13.8; IR (KBr) 3321, 2957, 2925, 2854,
1730, 1657, 1617, 1526, 1460, 1323, 1274, 1261, 1170, 1128, 1069, 1001,
847, 764, 750 cmꢁ1; HRMS (ESI) calcd for [C30H28F6N4O2S2þH]þ
655.1636, found 655.1625.
4.2.27. Di-n-butyl 2,20-di-(4-bromophenyl)-bis-5,50-oxazole-4,40-di-
carboxylate (5e). Yield: 89%; Light yellow powder; mp: 111e112 ꢀC;
1H NMR (300 MHz, CDCl3)
d
8.05 (d, 4H, J¼8.6 Hz), 7.66 (d, 4H,
J¼8.6 Hz), 4.30 (t, 4H, J¼7.3 Hz), 3.89 (s, 6H), 1.61 (p, 4H, J¼7.3 Hz),
4.2.20. N,N0-Di-n-butyl
4,40-diformamide (3t). Yield: 89%; Off-white powder; mp:
152e153 ꢀC; 1H NMR (300 MHz, CDCl3)
2,20-di-(4-fluorophenyl)-bis-5,50-thiazole-
1.24e1.33 (m, 4H), 0.84 (t, 6H, J¼7.4 Hz); 13C NMR (75 MHz, CDCl3)
d
161.8, 160.5, 141.1, 132.3, 128.7, 126.7, 124.7, 65.7, 30.5, 19.0, 13.6; IR
d
7.94 (t, 4H, J¼8.6 Hz), 7.59
(KBr) 2955, 2929, 2873, 1732, 1602, 1480, 1402, 1276, 1216, 1144,
1010, 830, 729 cmꢁ1; HRMS (ESI) calcd for [C28H26Br2N2O6þH]þ
645.0236, found 645.0240.
(s, 2H), 7.15 (t, 4H, J¼8.6 Hz), 3.37 (q, 4H, J¼7.3 Hz), 1.59 (p, 4H,
J¼7.3 Hz), 1.35e1.44 (m, 4H), 0.94 (t, 6H, J¼7.3 Hz); 13C NMR
(75 MHz, CDCl3)
d 166.34, 165.9, 162.6, 161.0, 146.4, 129.6, 129.0,
4.2.28. Dimethyl 2,20-di-(4-trifluorophenyl)-bis-5,50-oxazole-4,40-di-
carboxylate (5f). Yield: 84%; White powder; mp: 193e195 ꢀC; 1H
128.9, 128.7, 128.6, 116.3, 116.0, 39.1, 31.7, 20.2, 13.8; IR (KBr) 3334,
2958, 2931, 2872, 1654, 1517, 1467, 1232, 1157, 999, 840, 693,
633 cmꢁ1; HRMS (ESI) calcd for [C28H28F2N4O2S2þH]þ 555.1700,
found 555.1694.
NMR (300 MHz, CDCl3)
d
8.33 (d, 4H, J¼8.0 Hz), 7.80 (d, 4H,
J¼8.0 Hz), 3.95 (s, 6H); 13C NMR (75 MHz, CDCl3)
d 161.2, 160.8,
141.4, 134.6, 133.7, 133.3, 128.8, 127.6, 126.1, 126.0, 125.4, 121.8, 52.8;
IR (KBr) 2962, 1737, 1629, 1567, 1503, 1415, 1327, 1276, 1221, 1126,
1087, 1065, 1010, 932, 850, 808, 707 cmꢁ1; HRMS (ESI) calcd for
[C24H14F6N2O6þNa]þ 563.0654, found 563.0664.
4.2.21. N,N0-Di-n-butyl
4,40-diformamide (3u). Yield: 84%; Off-white powder; mp:
183e185 ꢀC; 1H NMR (300 MHz, CDCl3)
7.98 (s, 2H), 7.79 (d, 2H,
2,20-di-(3-chlorophenyl)-bis-5,50-thiazole-
d

Z. Li et al. / Tetrahedron 67 (2011) 5550e5555
5555
4.2.29. Dimethyl 2,20-diphenylethyl-bis-5,50-oxazole-4,40-dicarbox-
ylate (5g). Yield: 69%; White powder; mp: 67.5e68.5 ꢀC; 1H NMR
(300 MHz, CDCl3) 7.21e7.32 (m, 10H), 3.86 (s, 6H), 3.10e3.25 (m,
8H); 13C NMR (75 MHz, CDCl3)
165.3, 161.0, 141.2, 139.6, 128.7,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.123.
d
d
128.3, 126.6, 52.4, 32.9, 30.1; IR (KBr) 2948, 2850, 1730, 1572, 1440,
1302, 1214, 1084, 1035, 935, 739, 699 cmꢁ1; HRMS (ESI) calcd for
[C26H24N2O6þH]þ 461.1713, found 461.1697.
References and notes
1. (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508; (b) Heck, R. F. In Com-
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Ed. 1998, 37, 2180; (d) Bergman, R. G. Nature 2007, 446, 391; (e) Brookhart, M.;
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J. Q. Angew. Chem., Int. Ed. 2009, 49, 5094.
4.2.30. N,N0-Di-n-butyl 2,20-diphenyl-bis-5,50-oxazole-4,40-diforma-
mide (5h). Yield: 76%; White oil; 1H NMR (300 MHz, CDCl3)
d
8.11e8.14 (m, 4H), 7.46e7.54 (m, 6H), 7.40 (s, 1H), 3.43 (q, 4H,
J¼7.3 Hz), 1.62 (p, 4H, J¼7.3 Hz), 1.33e1.48 (m, 4H), 0.96 (t, 6H,
J¼7.3 Hz); 13C NMR (75 MHz, CDCl3)
d 167.0 160.1, 141.8, 138.0 131.4,
128.9, 127.1, 126.3, 39.1, 31.6, 20.2, 13.8; IR (KBr) 3293, 2956, 2924,
2853, 1737, 1648, 1449, 1378, 1275, 1261, 1152, 1089, 1009, 764,
750 cmꢁ1; HRMS (ESI) calcd for [C28H30N4O4þH]þ 487.2345, found
487.2330.
4.2.31. N,N0-Di-n-butyl 2,20-di-(4-trifluorophenyl)-bis-5,50-oxazole-
4,40-diformamide (5i). Yield: 74%; White powder; mp: 207e208 ꢀC;
1H NMR (300 MHz, CDCl3)
d
8.26 (d, 4H, J¼8.0 Hz), 7.77 (d, 4H,
3. Rice, R. L.; Rusnak, J. M.; Yokokawa, F.; Yokokawa, S.; Messner, D.; Boynton, A. L.;
Wipf, P.; Lazo, J. S. Biochemistry 1997, 36, 15965.
J¼8.0 Hz), 7.32 (s, 2H), 3.44 (q, 4H, J¼7.3 Hz), 1.60e1.68 (m, 4H),
1.39e1.47 (m, 4H), 0.97 (t, 6H, J¼7.3 Hz); 13C NMR (75 MHz, CDCl3)
4. Huang, Y.; Ni, L.; Gan, H.; He, Y.; Xu, J.; Wu, X.; Yao, H. Tetrahedron 2011, 67, 2066.
5. (a) Kim, D. H.; Lee, B. L.; Moon, H.; Kang, H. M.; Jeong, E. J.; Park, J. I.; Han, K. M.;
Lee, S.; Yoo, B. W.; Koo, B. W.; Kim, J. Y.; Lee, W. H.; Cho, K.; Becerril, H. A.; Bao, Z.
J. Am. Chem. Soc. 2009, 131, 6124; (b) Wakamiya, A.; Taniguchi, T.; Yamaguchi, S.
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Cravatt, B. F.; Boger, D. L. J. Med. Chem. 2007, 50, 1058.
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(b) Hammerle, J.; Spina, M.; Schnurch, M.; Mihovilovic, M. D.; Stanetty, P. Syn-
thesis 2008, 3099; (c) Hammerle, J.; Schnurch, M.; Stanetty, P. Synlett 2007, 2975;
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d
160.2, 159.6, 139.1, 137.4, 133.3, 132.9, 130.9, 129.3, 128.8, 127.4,
126.0, 39.2, 31.6, 20.2, 13.8; IR (KBr) 3294, 2959, 2933, 2873, 1656,
1556, 1322, 1167, 1126, 1064, 1018, 851, 750, 702, 594 cmꢁ1; HRMS
(ESI) calcd for [C30H28F6N4O4þH]þ 623.2093, found 623.2087.
Acknowledgements
Financial support from the National Natural Science Foundation
(No. 20902111), Program for New Century Excellent Talents in
University (NCET 2008) by the Ministry of Education of China, and
Fundamental Research Funds for the Central Universities
(JKZ2009002 for H.Y. and JKY2009013 for Y.H.) is highlyappreciated.
8. Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc. 2004, 126, 5074.
9. (a) Xia, J. B.; Wang, X. Q.; You, S. L. J. Org. Chem. 2009, 74, 456; (b) Liang, Z.; Zhao,
J.; Zhang, Y. J. Org. Chem. 2010, 75, 170; (c) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.;
Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc. 2010, 132, 1822; (d) Han, W.; Mayer, P.;
Ofial, A. R. Angew. Chem., Int. Ed. 2011, 50, 2178.