Diversified syntheses of multifunctionalized thiazole derivatives via regioselective and programmed C-H activation

Article abstract of DOI:10.1039/c4cc10419f

The sequential construction of diversified multifunctionalized thiazole derivatives through Pd-catalyzed regioselective C-H alkenylation has been accomplished. This versatile approach provides the diversified thiazole derivatives featuring orthogonal subs

Full text of DOI:10.1039/c4cc10419f

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Diversified Syntheses of Multifunctionalized Thiazole
Derivatives via Regioselective and Programmed C-H
Cite this: DOI: 10.1039/x0xx00000x
Activation
†
XiangꢀWei Liu,a JiangꢀLing Shi,b JiangꢀBo Wei,a Chao Yang,c JiaꢀXuan Yan,a Kun
Peng,d Le Dai,d ChenꢀGuang Li,d BiꢀQin Wang,b and ZhangꢀJie Shi*ae
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Accomplished is a sequential construction of diversified multifunctionalized thiazole derivatives
through Pdꢀcatalyzed regioselective CꢀH alkenylation. This versatile approach provides the
diversified thiazole derivatives featuring orthogonal substitution patterns at Cꢀ2, Cꢀ4 and Cꢀ5
positions from monoꢀsubstituted (2ꢀ or 4ꢀ substituted) thiazole derivatives or even more challenging
simple thiazole
.
pharmaceuticals as a critical step. As an elegant strategy, the
synthesis involving CꢀH activation has emerged owing to the
overwhelming merits of the avoidance of prefunctionalization of
starting materials and the requirements of atomꢀeconomy and stepꢀ
economy, as well as the ubiquity of CꢀH bonds in various organic
Introduction
Thiazoleꢀcontaining molecules represent an important class of
structurally privileged heterocyclic compounds that are frequently
found in naturally occurring compounds, bioactive entities,
pharmaceuticals, as well as functional organic materials.1 5ꢀ
Alkenylated thiazole derivatives and its hydrogenated congeners are
of particular interest. For example, 5ꢀalkyl thiazole B was found to
be a good agonist of peroxisome proliferator activated receptors
chemicals.3 Compared with the well documented directed CꢀH bond
4
activation/transformation,3c,
nonꢀdirected CꢀH bond activation
/transformation is less developed.5 Specifically, the regioselective Cꢀ
H bond activation/transformation with respect to the wellꢀknown
important heterocyclic compounds is much less developed.6, 7i More
importantly, targetꢀoriented development of a method involving the
regioselective CꢀH bond activation of selected molecular scaffolds
could be more efficient and feasible for the rapid establishment of a
compound library, and consequently, facilitate the search for new
drug candidates. 8
(PPARs), which comprise
a large family of ligandꢀactivated
transcription factors that play a key role in lipid homeostasis (Figure
1).2 Noteworthy is that only a limited array of such derivatives were
investigated due to their unavailability. In view of the importance of
such structural motifs, exploration of more active candidates of the
thiazoleꢀcontaining derivatives could be a longstanding goal for the
medicinal scientists. Because of this, we herein report the
As for the direct CꢀH activation/functionalization of thiazole
derivatives, a series of reaction types have been well developed
development of
a
palladiumꢀcatalyzed regioselective and
stereoselective 5ꢀalkenylation of thiazole derivatives, including 2ꢀ
substituted, 4ꢀsubstituted thiazole derivatives, and even more
challenging simple thiazole, and application of this established
method to the diversified syntheses of multifunctionalized thiazole
derivatives.
7
during the past decade.6n, Among these, direct alkenylation of
thiazole derivatives has been sporadically reported.9 It is not
surprising that the direct oxidative crossꢀcoupling of thiazole
derivatives with alkenes is recognized as the most atomꢀeconomical
approach to the syntheses of alkenylated thiazole derivatives.
However, this is a rather challenging transformation since homoꢀ
coupling of thiazole derivatives is strongly preferred under oxidative
conditions.10 Notably, 2ꢀalkenylated products were generally
obtained when 2ꢀunsubstituted thiazole derivatives were utilized as
substrates. 9a Conversely, to achieve the 5ꢀalkenylation of thiazole
derivatives, 2ꢀsubstituted or even 2,4ꢀdisubstituted thiazole
derivatives were employed as substrates accordingly. 9c To date, no
report has brought direct regioselective 5ꢀalkenylation reaction to
practice with the use of 2,5ꢀunsubstituted thiazole derivatives or
even thiazole as substrate.
Figure 1 Representatives of the 5ꢀAlkenylated Thiazole Derivatives
and its Hydrogenated Congeners.
Recently, direct CꢀH bond activation/transformation has emerged
as a powerful synthetic tool, which has been thus applied to the
syntheses of many biologically active natural products as well as
Results and Discussion
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DOI: 10.1039/C4CC10419F
To substantiate the feasibility of direct alkenylation of thiazole yields (55% and 67%, respectively). This method provided a
derivatives in a regioselective manner, 4ꢀmethylthiazole (1a) and nꢀ complementary but straightforward approach to the medicinally
butyl acrylate (2a) were initially tested as the model substrates. We important stilbene analogues.
first embarked on the examination of different solvents by using 10
mol % of Pd(OAc)2 as the catalyst, 2.0 equiv of Cu(OAc)2 as the
o
oxidant and 1.0 equiv of Cs2CO3 as the base at 100 C under N2
atmosphere (see the supporting information, Table S1). To our
t
delight, with the use of AmylOH as the solvent, the reaction
proceeded and afforded the desired product in 18% GC yield with
the desired regioselectivity, whereas other solvents either gave
inferior yields or delivered no product. The structure of desired
product 3ac was further confirmed by comparing to the reported
structures. 9a
Next, we tested a series of ligands, such as phosphine ligand (L1)
and Nꢀcontaining ligands (L2, L3, L4 and L5), and found that the
electronꢀdeficient 5ꢀnitroꢀ1,10ꢀphenantroline (L5) exhibited the best
performance, promoting the reaction to afford the regioselective and
stereoselective alkenylated Eꢀproduct (3aa) in 51% GC yield (Table
S1, entry 9).11 Moreover, several representative Pd(II) species have
been screened. Only cationic palladium species, such as Pd(OTFA)2
and Pd(CH3CN)4(BF4)2 could catalyze the reaction with comparable
efficacy in 47% and 48% GC yields, respectively (Table S1, entries
Scheme 1 Scope for the Alkene Partners and 4ꢀSubstituted Thiazole
a
Derivatives. Note:
Additional inseparable mixture of terminal
11 and 12). Furthermore, we tried to improve the efficiency by
screening various bases and oxidants, but in vain (Table S1, entries
12ꢀ16). Finally, further improvement of the efficiency was achieved
(70% GC yield, Table S1, entry 17) by introducing 6.0 equiv of
DMSO as an additive, of which the coordinative capability might
play a crucial role.12 Moreover, a satisfying isolated yield of 70%
could be achieved by using a semiꢀcontinuous process by feeding
thiazole derivative in five portions (Table S1, entry 18). Thus we
established the optimized reaction parameters as following (see the
Supporting Information, Table S1): thiazole 1a (0.2 mmol, in five
portions), alkene 2a (0.5 mmol), 5ꢀnitroꢀ1,10ꢀphenanthroline (0.02
mmol), Cu(OAc)2 (2.0 equiv), Cs2CO3 (1.0 equiv), DMSO (6.0
equiv), tAmylOH (1.0 mL), 100 oC, 12 h.
With the optimized conditions in hand, we immediately
examined the scope of different alkene partners. As is shown in
Scheme 1, nꢀbutyl and tertꢀbutyl acrylates smoothly reacted with 4ꢀ
methylthiazole, affording the desired regioselective and
stereoselective alkenylated Eꢀproducts in 70% and 71% yields,
respectively. As for the methyl and ethyl acrylates, moderate to good
yields (3ac, 58% and 3ad, 65% yields, respectively) were also
obtained. Moreover, benzyl acrylate could also be utilized as a
qualified partner in this catalytic system to deliver the desired
alkenylated Eꢀproduct 3ae in 49% yield. Noteworthy, phenyl
acrylate (2f) could also be employed as substrate, although,
relatively lower yield of 3af (32%) was obtained. Interestingly,
styrene derivatives could also be well applied to the reaction system
and afforded the 4ꢀmethylꢀ5ꢀstyrylthiazole derivatives (3agꢀ3aj) in
moderate to good yields. It should be noted that when styrene and 4ꢀ
chlorostyrene were employed as reaction partners, not only the
separable Eꢀconfigured internal alkene stereoisomer (3ag and 3ah)
could be obtained, but also an inseparable mixture of Zꢀconfigured
internal alkene stereoisomer and terminal alkene product (3ag' and
3ag'', 3ah' and 3ah'') were formed as minor product. However,
when sterically hindered 2ꢀmethylstyrene and 2,5ꢀdimethylstyrene
were utilized as substrates, terminal alkene products (3ai and 3aj)
were formed as the major products. Besides the 4ꢀmethylthiazole, 4ꢀ
arylthiazole derivatives could also be employed as the substrates,
affording the corresponding regioselective 5ꢀalkenylꢀ4ꢀaryl
disubstituted thiazole derivatives (3ba and 3ca) in moderate to good
alkene product (3ag') and Zꢀconfigured product (3ag'') was formed
in 24% combined yield (the ratio of 3ag'/3ag'' = 10/1). b Additional
inseparable mixture of terminal alkene product (3ah') and Zꢀ
configured product (3ah'') was formed in 22% combined yield (the
ratio of 3ah'/3ah'' = 5/1). The reaction was carried out in one pot
procedure.
c
We then turned our attention to examine more challenging
thiazole in the direct regioselective and stereoselective alkenylation
reaction. As expected, thiazole could also be smoothly coupled with
acrylates to deliver the regioselective 5ꢀalkenylated Eꢀproducts in
synthetically useful yields when the reactions were carried out in 2.0
mL of tAmylOH.
Pd(OAc)2 (10 mol %)
Cu(OAc)2 (2.0 eq.)
Cs2CO3 (1.0 eq.)
5-nitro-1,10-phen (0.1 eq.)
R
H
H
S
N
S
H
H
+
H
R
DMSO (6.0 eq.)
tAmylOH (2.0 mL), N2, 100 ºC, 12 h
N
H
1d
2
3
R = nBu, 3da, 35% yield
tBu, 3db, 30% yield
C6H5, 3dg, 48% yield
Scheme 2 Regioselective and stereoselective Alkenylation of a
Challenging Thiazole.
To expand the substrate scope further, we then examined the 2ꢀ
substituted thiazole derivatives (Scheme 3). Gratifyingly, all 2ꢀ
arylthiazole derivatives, regardless of the electronic nature on the 2ꢀ
phenyl group, could be totally tolerated under the established
conditions, affording the desired Eꢀ5ꢀalkenylated 2ꢀarylthiazole
derivatives in moderate to good yields (22ꢀ88% yields, Scheme 3).
Especially, 2ꢀphenylthiazoles bearing a sterically hindered group,
such as 2'ꢀmethyl and 2'ꢀmethoxy groups, have no obvious effect on
the reactions and such reactions could proceed quite well, which
afforded the desired products in 75% and 77% yields, respectively.
Interestingly, an ester group was also compatible, giving the
transformable product (3qa) in 46% yield. What’s more, the strongly
coordinating cyano (3ra) group, was well tolerated under the optimal
conditions, although, relatively lower yield was obtained (39%).
Most importantly, the regiochemistry of this method has been
unambiguously determined by Xꢀray diffraction (XRD) analysis of
compound 3ea as a representative. (Figure 2)13 Apart from the 2ꢀ
arylthiazole derivatives, the commercially available 2ꢀmethylthiazole
2 | J. Name., 2012, 00, 1-3
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(3ta) and 2ꢀ(methylthio)thiazole (3ua) could also be applied to the
reaction system, which afforded the alkenylated products in
moderate yields (46% and 53%, respectively) and in a highly
regioselective and stereoselective manner.
Experimental procedure for the regioselective
alkenylations
To a flame dried 25 mL Schlenk tube were added Pd(OAc)2 (4.5 mg,
0.02 mmol; Acros), 5ꢀnitroꢀ1,10ꢀphenanthroline (4.5 mg, 0.02 mmol;
TCI), Cu(OAc)2 (72.0 mg, 0.40 mmol; Acros) and Cs2CO3 (65.2 mg,
0.40 mmol; Ourchem), then the tube was capped with rubber stopper
and alternatively extracted under vacuum pump and backfilled with
nitrogen gas for three times. Then tAmylOH (1.0 mL or 2.0 mL, Alfa
Aesar) was added via a syringe followed by sequential addition of
DMSO (85.2 µL, 1.20 mmol, unpurified) and nꢀbutyl acrylate (2a,
0.50 mmol). Finally, a solution of 4ꢀmethylthiazole (1a, 0.20 mmol,
J&K) in tAmylOH (0.5 mL) was introduced intermittently (0.1 mL
every hour) after the tube was placed on the preheated parallel
reactor (100 oC). The reaction mixture was stirred at 100 oC for 12 h.
After completion of the reaction, the reaction mixture was directly
filtered by a short silica pad and further purified by flash column
chromatography to afford (3aa, 31.5 mg, 70% yield) as colorless oil.
Pd(OAc)2 (10 mol %)
Cu(OAc)2 (2.0 eq.)
Cs2CO3 (1.0 eq.)
CO2nBu
H
S
5-nitro-1,10-phen (10 mol %)
S
N
H
CO2nBu
+
R
R
DMSO (6.0 eq.), tAmylOH (1.0 mL)
N2, 100 ºC, 12 h
N
H
1e-u
2a
3ea-3ua
R = C6H5, 3ea, 64% yield
4-MeO-C6H4, 3fa, 66% yield
3-MeO-C6H4, 3ga, 35% yield
2-MeO-C6H4, 3ha, 77% yield
3-Me-C6H4, 3ia, 88% yield
2-Me-C6H4, 3ja, 75% yield
3,5-Me2-C6H3, 3ka, 70% yield
4-i-Pr-C6H4, 3la, 53% yield
4-t-Bu-C6H4, 3ma, 78% yield
R = 4-F-C6H4, 3na, 65% yield
4-Cl-C6H4, 3oa, 54% yield
4-CF3-C6H4, 3pa, 52% yield
2-Me-4-MeO2C-C6H4, 3qa, 46% yield
4-CN-C6H4, 3ra, 39% yield
4-NO2-C6H3, 3sa, 22% yield
Me, 3ta, 46% yield
MeS, 3ua, 53% yield
Scheme 3 Regioselective and Stereoselective Alkenylation of 2ꢀ
Substituted Thiazole Derivatives.
Conclusions
In conclusion, we have developed
a
regioselective and
stereoselective alkenylation of thiazole derivatives and application of
this established method to the divergent and programmed syntheses
of multifunctionalized thiazole derivatives has also been successfully
Figure 2 Xꢀray crystal structure of compound 3ea.
To demonstrate the synthetic utility of this developed demonstrated. This research could provide a feasible solution for the
methodology, we then applied it to the diversified syntheses of fast establishment of thiazoleꢀcontaining small molecule library.
thiazoleꢀcontaining derivatives. At first, the 5ꢀalkenylated thiazole Moreover, toward the fluorescent materials syntheses, especially
derivative 3da was used to carry out the homoꢀcoupling reaction. As those incorporating the thiazole moiety, this research could provide a
expected, this reaction proceeded smoothly in the presence of 10 new approach for their syntheses. Therefore, screening of these
mol % of Pd(OAc)2, 1.0 equiv of CuI and 0.5 equiv of phenyl iodide synthesized thiazole derivatives from biological activity aspect and
with N,Nꢀdimethyl formamide as the reaction media at 100 oC, further application of this method in the syntheses of fluorescent
affording the dimerized product in 68% yield (Scheme 4, eq. a). materials are underway in our laboratory.
Moreover, starting from the commercially available thiazole 1d, 5ꢀ
alkenylꢀ2ꢀarylthiazole 3ea could be facilely obtained via a twoꢀstep
sequence. By analogy, 5ꢀalkenylꢀ2ꢀarylꢀ4ꢀmethylthiazole 6 could be
easily synthesized in good yields starting from 4ꢀmethylthiazole 1a.
Finally, a sequential installation of an alkenyl group has also been
achieved by using 4ꢀmethylthiazole as a feedstock, the 2,5ꢀ
Acknowledgements
We thank Prof. WenꢀXiong Zhang and Dr. NengꢀDong Wang for
their help on the Xꢀray crystallographic analysis. Financial support
by MOST (2015CB856600 and 2013CB228102) and NSFC (Nos.
21332001 and 21431008) China Postdoctoral Science Foundation
(No. 2013M530464) and DSM is gratefully acknowledged.
differently alkenylated 4ꢀmethylthiazole derivative
7
was
synthesized, together with the formation of applicable 2,2'ꢀhomoꢀ
coupling product 8 in synthetically useful yield.
Notes and references
a
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry, Peking University, Beijing
100871.
b
College of Chemistry and Material Chemistry, Sichuan Normal
University, Sichuan 610066, China.
c
Shenzhen Graduate School of Peking University, Shenzhen 518055,
China.
d
DSM nutritional products, DSM nutrition center, DSM (China) limited,
No. 476 Li Bing Road, Zhangjiang Hiꢀtech Park, Pudong new area,
Shanghai, 201203, China.
e
State Key Laboratory of Organometallic Chemistry, Chinese Academy
of Sciences, Shanghai 200032, China.
Scheme
4
Divergent
and
Sequential
Syntheses
of
†
Electronic Supplementary Information (ESI) available: See
Multifunctionalized Thiazole Derivatives.
DOI: 10.1039/c000000x/
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determination of compound 3ea. And the original
crystallographic data (CCDC 1024929) for this compound can
be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
4 | J. Name., 2012, 00, 1-3
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