Cascade reactions to 2,4-disubstituted thiazoles via ligand-free palladium(II)-catalyzed C(sp)–C(sp2) coupling

Article abstract of DOI:10.1016/j.tet.2020.130953

A simple construction for various 2,4-disubstituted thiazoles via palladium(II)-catalyzed C(sp)–C(sp²) and C-N cascade coupling reactions was developed. Various substrates can be tolerated with good yields. And its ligand-free condition demonst

Full text of DOI:10.1016/j.tet.2020.130953

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Cascade reactions to 2,4-disubstituted thiazoles via ligand-free palladium(II)-
2
catalyzed C(sp)–C(sp ) coupling
Zi-Juan Wang, Wen-Teng Chen, Chang He, Hao-Fan Luo, Guo-Lin Zhang, Yong-Ping
Yu
PII:
S0040-4020(20)30043-0
https://doi.org/10.1016/j.tet.2020.130953
TET 130953
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 December 2019
Revised Date: 9 January 2020
Accepted Date: 10 January 2020
Please cite this article as: Wang Z-J, Chen W-T, He C, Luo H-F, Zhang G-L, Yu Y-P, Cascade reactions
2
to 2,4-disubstituted thiazoles via ligand-free palladium(II)-catalyzed C(sp)–C(sp ) coupling, Tetrahedron
(2020), doi: https://doi.org/10.1016/j.tet.2020.130953.
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Cascade reactions to 2,4-disubstituted
thiazoles via ligand-free palladium(II)-
catalyzed C(sp)–C(sp2) coupling
Leave this area blank for abstract info.
Zijuan Wang, a Wenteng Chen, a Chang He, a Haofan Luo, a and Guolin Zhang, *, a Yongping Yu *, a
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou 310058, P. R. China

1
Tetrahedron
journal homepage: www.elsevier.com
Cascade reactions to 2,4-disubstituted thiazoles via ligand-free palladium(II)-
catalyzed C(sp)–C(sp2) coupling
Zi-Juan Wanga , Wen-Teng Chena , Chang Hea , Hao-Fan Luoa and Guo-Lin Zhanga, , Yong-Ping Yua,
a
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple construction for various 2,4-disubstituted thiazoles via palladium(II)-catalyzed C(sp)–
C(sp2) and C-N cascade coupling reactions was developed. Various substrates can be tolerated
with good yields. And its ligand-free condition demonstrates the practicability of this method.
2009 Elsevier Ltd. All rights reserved
.
Available online
Keywords:
2,4-disubstituted thiazoles
palladium
ligand-free
cascade reactions
C(sp)–C(sp2) Coupling
1. Introduction
Owing to its diverse pharmaceutical applications,
methodologies for construction of 2,4-disubstituted thiazoles
have been extensively investigated. Nowadays, the most widely
Thiazoles and their derivatives are one of the most important
classes of five-membered heteroaromatic compound exhibiting
wide pharmacological applications. 1-4 Thiazole derivatives have
attracted interest over the past years because of their broad
biological activities such as anticancer,5 anti-tubercular,6
antihypertensive,7 antimicrobial,8-9 analgesic and anti-
inflammatory.10 In particular, 2,4-disubstituted thiazoles have
been well known for their therapeutic applications and frequently
utilized in bioactive compounds and pharmaceuticals, such as
used synthetic method to access thiazoles is the Hantzsch
15-17
thiazole synthesis reaction,
cyclization of α-haloaldehyde or
ketone and thiourea or thioamide under neutral water-free
conditions. 18 This reaction normally gives excellent yields for
19
simple thiazoles but low yields for some substituted thiazoles.
Then, various methods for the synthesis of 2,4-disubstituted
thiazoles have been developed (Scheme 1). Mahesh and co-
workers reported a two-step reaction from styrene, NBS and
thioamides to afford 2,4-disubstituted thiazoles. 20 The research
by Kirchberg and co-workers reported palladium(II)-catalyzed
biaryl coupling of thiazoles and boronic acids. 21 However, in this
preparation method, the starting material already contains
thiazole ring. Cosford and co-workers disclosed the synthesis of
thiazole by using α-thiocyanomethyl ketones and aryl boric acid
as starting material. 22 However, this is a three-step reaction using
acids with lots of industrial wastes and pollution. Therefore, a
more convenient construction for various 2,4-disubstituted
thiazoles is still in demand.
Fatostatin, p38 MAP kinase inhibitor and Fentiazac (Figure 1).11-
14
Figure 1. Selected examples of bioactive molecules based on
2,4-disubstituted thiazoles.
———
Corresponding author. Tel.: (+ 86)-0571-8820-8450; fax: (+ 86)-0571-8820-8450; e-mail: guolinzhang@zju.edu.cn
Corresponding author. Tel.: (+ 86)-0571-8820-8450; fax: (+ 86)-0571-8820-8450; e-mail: yyu@zju.edu.cn

2
Tetrahedron
13 c
14 d
15
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
1:2.0
1:2.0
1:1.5
1:2.5
60
60
60
60
Toluene
Toluene
Toluene
Toluene
51
80
62
78
16
a
Reaction conditions: 1a (1.0 mmol), catalyst (30 mol %),
b
c
solvent (15 mL), 24 h in air. Isolated yield. 20 mol %
Pd(OAc)2 catalyst was used. 40 mol % Pd(OAc)2 catalyst was
d
used.
With the optimized reaction conditions in hand, the scope of
the reaction was then explored. As shown in Table 2 the
optimized reaction conditions can be applied to a variety of
substrates. In terms of electronic e ects, α-thiocyanomethyl
ketones containing either electron-deficient groups (3b–3c) or
electron-rich groups (3d–3e) on the phenyl ring were all
compatible with this reaction (with 67% to 88% yield, Table 2).
The results indicate that the electronic nature of α-
thiocyanomethyl ketones has a little e ect on the reaction yields.
So we next investigated the steric effects of the reaction. A steric
hindrance e ect was observed when the chlorine atom was
substituted at the ortho-position of the phenyl ring. And the
desired product was obtained in a relatively lower yield (3b,3f
and 3g, 67%, 66% and 60%).
Scheme 1. Methods to the synthesis of 2,4-disubstituted
thiazoles.
2. Results and discussion
Inspired by the work of predecessors, we proposed a
palladium(II)-catalyzed tandem reaction for the synthesis of 2,4-
disubstituted thiazoles. We first investigated the reaction of 1a
and 2a in the presence of Pd(OAc)2 (30 mol %) at 40 °C in
toluene and obtained the major product 3a (Table 1, entry 1).
Then we changed the reaction temperature. When the reaction
Based on these promising initial results, we then turned our
attention toward the scope of arylboronic acids in this reaction.
As expected, arylboronic acids with electron-donating group on
the phenyl ring showed more reactivity than those electron-
withdrawing groups (3j, 71% compared to 3m, 81% and 3a,
79%, Table 2). The reaction barely proceeded (3k) when (4-
(trifluoromethyl)phenyl) boronic acid, with a strong electron-
withdrawing group, was used. Changing the position of chlorine
atom on the phenyl ring (3h-3j), the results showed that the steric
effects almost did not influence the progress of the reaction
(3h,3i and 3j, 66%, 68% and 71%). In order to further expand the
compound library, we synthesized a series of compounds with
other groups, such as tert-butyl group and thiophene group with
high yields (3n,68% and 3o,73%). However, methyl boric acid
was not compatible with this process (3r), probably due to its low
activity.
o
o
temperature was raised from 40 C to 60 C, the yield increased
to 79% (Table 1, entries 1–2). While further increasing the
reaction temperature, the yields decreased (Table 1, entries 3–5).
In order to further improve the yields, we tested the reaction
under the catalysis of a set of Pd (Table 1, entries 6–8). None of
them showed more effective than Pd(OAc)2. Additionally, other
solvents, such as DMF, MeCN, EtOH and DMSO were tested
(Table 1, entries 9–12). And toluene stood out as the best choice
of solvent for further reactions with its highest product yield
(Table 1, entry 2). Decreasing catalyst loading or amount of 4-
methylphenylboric acid 2a resulted in the reduced yields (Table
1, entries 13 and 15). And increasing catalyst loading to 40% or
amount of 4-methylphenylboric acid 2a to 2.5 equivalents did not
have a significant effect on the yields (entries14 and 16). On the
basis of the above studies, the most favorable reaction conditions
for the formation of 3a were established (Table 1, entry 2).
Table 2. Synthesis of 2,4-disubstituted thiazoles. a, b
Table 1. Optimization of the reaction conditions for 3a.
Entrya
catalyst
Equiv
1a:2a
T/oC
solvent yield
(%)b
3a, 79%
3c, 88%
3e,81%
3b,67%
3d,85%
3f,66%
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2 1:2.0
Pd(PPh3)4
−
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
1:2.0
1:2.0
1:2.0
1:2.0
40
60
80
Toluene
Toluene
Toluene
Toluene
73
79
60
56
44
24
15
100
1:2.0 Reflux Toluene
60
60
60
60
60
60
60
Toluene
Toluene
1:2.0
1:2.0
1:2.0
1:2.0
1:2.0
1:2.0
Toluene Trace
DMF
MeCN
EtOH
55
25
Trace
28
10
11
12
3g,60%
3h,66%
DMSO

3
MHz and 13C NMR at 125 MHz. For 1H NMR,
tetramethylsilane (TMS) served as internal standard (δ=0) and
data are reported as follows: chemical shift, integration,
multiplicity (s=singlet, d=doublet, t= triplet, q=quartet,
m=multiplet), and coupling constant(s) in Hertz. For 13C NMR,
TMS (δ=0) was used as internal standard and spectra were
obtained with complete proton decoupling. HRMS data was
obtained using Agilent Technologies 6224 TOF LC/MS. The
3i, 68%
3j, 71%
3l,76%
3k,Trace
starting material α-thiocyanomethyl ketones was prepared
24
according to literature methods.
The starting material
arylboronic acids were commercially available.
3m,81%
3o,73%
3n,68%
4.2. General Procedure for the Synthesis of 3
A mixture of α-thiocyanomethyl ketones 1 (1.0 mmol, 1.0
equiv.), arylboronic acids 2 (2.0 mmol, 2.0 equiv.) and Pd(OAc)2
(0.3 mmol, 0.3 equiv.) was stirred in toluene (15.0 mL) at 60 C
for 24h. After the completeness of the reaction, the mixture was
filtrated with diatomite. The solids were rinsed with EtOAc
(2mLx3), and the combined filtrate was concentrated in vacuo
and purified by flash column chromatography using PE and
EtOAc as eluent to yield 3a-3o.
3p,No Reaction
o
a Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), Pd(OAc)2 (30
mol %), toluene (15 mL), 60 oC, 24 h in air. b Isolated yield.
A tentative mechanism for the construction of various 2,4-
disubstituted thiazoles has been proposed (Scheme 2).23 In the
process of producing 2,4-disubstituted thiazoles, the
transmetalation reaction of the Pd(II) catalyst and arylboronic
acids affords intermediate B. Afterwards the coordination of
intermediate B and the N atom of the cyano group forms
compound C. Then the aryl group inserts into the nitrile group to
generate the corresponding ketimine Pd(II) complex D.
Intermediate D exchanges with AcO- to produce ketimine
derivative E, and thus regenerates the Pd(II) catalyst. Finally, the
intramolecular condensation of ketimine derivative E affords the
corresponding product F.
4.3. Characterization Data of 3a-3o
4.3.1. 4-phenyl-2-(p-tolyl) thiazole (3a)
1
Pale yellow solid; mp: 125.7-126.6 oC; H NMR (500 MHz,
CDCl3) δ 7.99 (dd, J = 8.5, 1.5 Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H),
7.48 – 7.40 (m, 3H), 7.37 – 7.30 (m, 1H), 7.25 (d, J = 9.0 Hz,
2H), 2.40 (s, 3H); HRMS (ESI): m/z calcd for C16H13NS [M+H]
+: 252.0841, found: 252.0845.
4.3.2. 4-(4-chlorophenyl)-2-(p-tolyl) thiazole (3b)
o
Yellow solid; mp: 141.4-142.1 C; 1H NMR (500 MHz,
CDCl3) δ 8.31 (d, J = 9.0 Hz, 2H), 8.16 (d, J = 9.0 Hz, 2H), 7.93
(d, J = 8.0 Hz, 2H), 7.66 (s, 1H), 7.29 (d, J = 7.5 Hz, 2H), 2.42 (s,
+
3H); HRMS (ESI): m/z calcd for C16H12N2O2S [M+H]
297.0692, found: 297.0697.
:
4.3.3. 4-(4-nitrophenyl)-2-(p-tolyl) thiazole (3c)
o
Yellow solid; mp: 141.4-142.1 C; 1H NMR (500 MHz,
CDCl3) δ 8.31 (d, J = 9.0 Hz, 2H), 8.16 (d, J = 9.0 Hz, 2H), 7.93
(d, J = 8.0 Hz, 2H), 7.66 (s, 1H), 7.29 (d, J = 7.5 Hz, 2H), 2.42 (s,
+
3H); HRMS (ESI): m/z calcd for C16H12N2O2S [M+H]
297.0692, found: 297.0697.
:
4.3.4. 2,4-di-p-tolylthiazole (3d)
White solid; mp: 139.4-140.0 oC; 1H NMR (500 MHz, CDCl3)
δ 7.93 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 7.39 (s, 1H),
7.27 (d, J = 5.0 Hz,2H), 7.25 (d, J = 6.0 Hz, 2H), 2.41 (s, 3H),
Scheme 2. Proposed Mechanism.
+
2.40 (s, 3H); HRMS (ESI): m/z calcd for C17H15NS [M+H] :
266.0998, found: 266.0998.
3. Conclusions
4.3.5. 4-(4-methoxyphenyl)-2-(p-tolyl) thiazole (3e)
Pale yellow solid; mp: 150.0-150.8 oC; H NMR (500 MHz,
1
In summary, an e cient method to access 2,4-disubstituted
thiazoles through palladium(II)-catalyzed was demonstrated. The
reaction involves C(sp)–C(sp2) coupling followed by
intramolecular C–N bond formation. The plausible mechanism
was also proposed. The reaction can tolerate various substrates
with good yields. Notably, this reaction is a palladium(II)-
catalyzed but without any ligand progress. Because of its ligand-
free condition, this method is particularly attractive.
CDCl3) δ 7.93 (d, J = 9.0 Hz, 4H), 7.31 (s, 1H), 7.26 (d, J = 8.0
Hz, 3H), 6.97 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H), 2.41 (s, 3H).;
HRMS (ESI): m/z calcd for C17H15ONS [M+H] : 282.0947,
found: 282.0951.
+
4.3.6. 4-(3-chlorophenyl)-2-(p-tolyl) thiazole (3f)
o
1
Light pink solid; mp: 85.0-85.7 C; H NMR (500 MHz,
CDCl3) δ 8.02 (t, J = 2.0 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.87 –
7.83 (m, 1H), 7.47 (s, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.33-7.31 (m,
1H), 7.27 (d, J = 7.5 Hz, 2H), 2.41 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 168.38, 154.62, 140.53, 136.31, 134.73, 130.92,
129.97, 129.66, 128.07, 126.63, 126.56, 124.45, 113.11, 21.48;
4. Experimental section
4.1. General experimental information
All solvents were purified according to standard methods prior
to use. Melting points were recorded on a BÜCHI B-540 melting
point apparatus. NMR spectra were recorded for 1H NMR at 500
+
HRMS (ESI): m/z calcd for C16H12ClNS [M+H] : 286.0452,
found: 286.0458.

4
Tetrahedron
4.3.7. 4-(2-chlorophenyl)-2-(p-tolyl) thiazole (3g)
References and notes
o
1
Pale yellow solid; mp: 54.6-55.4 C; H NMR (500 MHz,
1. Venkateswararao, E.; Jalani, H. B.; Manoj, M. Journal of
Heterocyclic Chemistry. 2016, 53, 1449-1456.
2. Mishra, R.; Sharma, P. K.; Verma, P. K. Journal of Heterocyclic
Chemistry. 2017, 54, 2103-2116.
3. Chen, L.; Zhu, H.; Wang, J. Molecules. 2019, 24, 893-905.
4. Wu, G.; Wang, X.; Liu, H. Catalysts. 2016, 6, 126-134.
5. Zheng, S.; Zhong, Q.; Jiang, Q. Medicinal Chemistry Letters.
2013, 4, 191-196.
6. Malipeddi, H.; Karigar, A. A.; Malipeddi, V. R.; Sikarwar, M. S.
Tropical Journal of Pharmaceutical Research. 2012, 11, 611-620.
7. Dash, J.; Melillo, B.; Arseniyadis, S.; Cossy, J. Tetrahedron
Letters. 2011, 52, 2246-2249.
8. Sarojini, B.K.; Krishna, B.G.; Darshanraj, C.G.; Bharath, B.R.;
Manjunatha, H. European Journal of Medicinal Chemistry. 2010,
45, 3490-3496.
9. Singh, I.; Kaur, H.; Kumar, S.; Kumar, A.; Lata, S.; Arun, K.
International Journal of ChemTech Research. 2010, 2, 1745-1752.
10. Karthikeyan, M. S. European Journal of Medicinal Chemistry.
2009, 44, 827-833.
CDCl3) δ 8.08 (dd, J = 8.0, 2.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H),
7.80 (s, 1H), 7.48 (dd, J = 8.0, 1.0 Hz, 1H), 7.37 (td, J = 7.5, 1.0
Hz, 1H), 7.29 (dd, J = 7.5, 1.5 Hz, 1H), 7.27 (d, J = 8.5 Hz, 2H),
2.41 (s, 3H); 13C NMR (125 MHz, CDCl3) 167.03, 152.44,
140.48, 133.38, 132.08, 131.79, 131.01, 130.58, 129.74, 129.09,
127.09, 126.67, 117.65, 21.60; HRMS (ESI): m/z calcd for
C16H12ClNS [M+H] +: 286.0452, found: 286.0450.
4.3.8. 2-(2-chlorophenyl)-4-phenylthiazole (3h)
Yellow solid; mp: 53.9-54,8 oC; 1H NMR (500 MHz, CDCl3) δ
8.40 (dd, J = 7.5, 2.0 Hz, 1H), 8.02 (dd, J = 8.0, 1.0 Hz, 2H), 7.65
(s, 1H), 7.52 (dd, J = 8.0, 2.0 Hz, 1H), 7.47 (m, J = 7.5 Hz, 2H),
7.42 – 7.34 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 163.30,
155.10, 134.51, 132.15, 132.13, 131.18, 130.80, 130.43, 128.90,
128.35, 127.20, 126.61, 114.73; HRMS (ESI): m/z calcd for
C15H10ClNS [M+H] +: 272.0295, found: 272.0297.
11. Tani, S.; Uehara, T. N.; Yamaguchia, J.; Itami, K. Chemical
Science. 2014, 5, 123-135.
4.3.9. 2-(3-chlorophenyl)-4-phenylthiazole (3i)
o
1
Pale brown solid; mp: 59.9-60.8 C; H NMR (500 MHz,
CDCl3) δ 8.08 (s, 1H), 8.00 (d, J = 7.0 Hz, 2H), 7.90 (td, J = 7.0,
1.5 Hz, 1H), 7.51 (s, 1H), 7.46 (t, J = 7.0 Hz, 2H), 7.41 – 7.35
(m, 3H); HRMS (ESI): m/z calcd for C15H10ClNS [M+H] :
272.0295, found: 272.0295.
12. Bellale, E.; Naik, M.; VB, V.; Ambady, A.; Narayan, A.;
Ravishankar, S.; Ramachandran, V.; Kaur, P.; McLaughlin, R.;
Whiteaker, J.; Morayya, S.; Guptha, S.; Sharma, S.; Raichurkar,
A.; Awasthy, D.; Achar, V.; Vachaspati, P.; Bandodkar, B.;
Panda, M.; Chatterji, M. Journal of Medicinal Chemistry. 2014,
57, 6572-6582.
+
13. Gholkar, A. A.; Cheung, K.; Williams, K. J.; Lo, Y.; Hamideh, S.
A.; Nnebe, C.; Khuu, C.; Bensinger, S.J.; Torres, J. Z. The Journal
of Biological Chemistry. 2016, 291, 17001-17008.
14. Miwatashi, S.; Arikawa, Y.; Naruo, K.; Igaki, K.; Watanabe, Y.;
Kimura, H.; Kawamoto, T.; Ohkawa, S. Chemical and
Pharmaceutical Bulletin. 2005, 53, 410-418.
15. Bagley, M. C.; Dale, J. W.; Jenkins, R. L.; Bower, J. Chemical
Communications. 2004, 102-103.
16. Qiao, Q.; So, S. S.; Goodnow, R. A. Organic Letters. 2001, 3,
3655-3658.
4.3.10. 2-(4-chlorophenyl)-4-phenylthiazole (3j)
White solid; mp: 95.0-95.7 oC; 1H NMR (500 MHz, CDCl3) δ
8.02 – 7.93 (m, 4H), 7.50 – 7.41 (m, 5H), 7.37 (t, J = 7.0 Hz,
1H).; HRMS (ESI): m/z calcd for C15H10ClNS [M+H]
272.0295, found: 272.0287.
+
:
4.3.11. 2,4-diphenylthiazole (3l)
1
White solid; mp: 93.7-94.5 oC; H NMR (500 MHz, CDCl3)
δ
8.06 (dd, J = 8.0, 1.5 Hz, 2H), 8.01 (dd, J = 8.5, 1.5 Hz, 2H), 7.50
– 7.44 (m, 6H), 7.37 (t, J = 7.0 Hz, 1H).; HRMS (ESI): m/z calcd
for C15H11NS [M+H] +: 238.0685, found: 238.0692.
17. Katritzky, A. R.; Chen, J.; Yang, Z. J. Journal of Organic
Chemistry. 1995, 60, 5638-5642.
18. Hantzsch, A.; Weber, J. H. Berichte der deutschen chemischen
Gesellschaft. 2006, 20, 3118-3132.
19. Hodgetts, K. J.; Kershaw, M. T. Organic Letters. 2002, 4, 1363-
1365.
20. Shinde, M. H.; Kshirsagar, U. A. Green Chemistry. 2016, 18,
1455-1458.
21. Kirchberg, S.; Tani, S.; Ueda, K.; Yamaguchi, J.; Studer, A. Itami,
K. Angewandte Chemie. 2011, 50, 2387-2391.
22. Cosford, N. D. P.; Dhanya, R. P.; S., Douglas, J. WO2015191630.
23. Yu, H.; Xiao, L.; Yang, X.; Shao, L. Chem. Commun. 2017, 53,
9745–9748.
4.3.12. 2-(4-methoxyphenyl)-4-phenylthiazole (3m)
o
White yellow solid; mp 100.5-101.6 C; 1H NMR (500 MHz,
CDCl3) δ 8.02 – 7.96 (m, 4H), 7.45 (t, J = 7.5 Hz, 2H), 7.41 (s,
1H), 7.35 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 3.87 (s,
3H); HRMS (ESI): m/z calcd for C16H14NOS [M+H] +:268.0791,
found: 268.0791.
4.3.13. 4-(tert-butyl)-2-(p-tolyl) thiazole (3n)
24. Xie, J.; Si, X.; Gu, S.; Wang, M.; Shen, J.; Li, H.; Li, D.; Fang, Y.;
Liu, C.; Zhu, J. Journal of Medicinal Chemistry. 2017, 60, 10205-
10219.
Pale yellow liquid; 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J =
8.5 Hz, 2H), 7.22 (d, J = 7.5 Hz, 2H), 6.84 (s, 1H), 2.39 (s, 3H),
1.39 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 167.66, 167.17,
139.80, 131.76, 129.58, 126.57, 109.84, 35.07, 30.23, 21.55;
HRMS (ESI): m/z calcd for C14H17NS [M+H] +: 232.1154, found:
232.1159.
Supplementary Material
Supplementary
data
(Experimental
procedures,
characterization data, and copies of 1H and 13C NMR spectra for
all products.) associated with this article can be found in online
version at http://dx.doi.org/.
4.3.14. 4-(thiophen-2-yl)-2-(p-tolyl) thiazole (3o)
1
Pale purple solid; mp: 109.6-110.4 oC; H NMR (500 MHz,
CDCl3) δ 7.91 (d, J = 8.0 Hz, 2H), 7.51 (dd, J = 4.0, 1.5 Hz, 1H),
7.34 – 7.28 (m, 2H), 7.26 (d, J = 7.5 Hz, 2H), 7.08 (dd, J = 5.0,
4.0 Hz, 1H), 2.41 (s, 3H).; 13C NMR (125 MHz, CDCl3) δ
168.30, 150.70, 140.59, 138.62, 130.89, 129.73, 127.81, 126.69,
125.37, 124.29, 111.04, 21.62; HRMS (ESI): m/z calcd for
C14H11NS2 [M+H] +: 258.0406, found: 258.0413.
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Acknowledgments
This project was supported from the National Key R&D
Program of China (No.2017YFE0102200), Osteoporosis &
Breast Cancer Research Center, USA to Y. Yu.

ꢀA simple construction for various 2,4-disubstituted thiazoles.
ꢀThe reaction involves C(sp–ꢀC(sp2– coupling followed by intramolecular CꢀN bond
formation.
ꢀVarious substrates can be tolerated with good yields in ligand-free condition.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: