Programmed synthesis of arylthiazoles through sequential C-H couplings

Article abstract of DOI:10.1039/c3sc52199k

A programmed synthesis of privileged arylthiazoles via sequential C-H couplings catalyzed by palladium or nickel catalysts has been accomplished. This versatile protocol can supply all possible arylthiazole substitution patterns (2-aryl, 4-aryl, 5-aryl, 2

Full text of DOI:10.1039/c3sc52199k

View Article Online
View Journal
Chemical Science
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Tani, T. N. Uehara, J. Yamaguchi and
K. Itami, Chem. Sci., 2013, DOI: 10.1039/C3SC52199K.
This is an Accepted Manuscript, which has been through the RSC Publishing peer
review process and has been accepted for publication.
Chemical Science
Accepted Manuscripts are published online shortly after acceptance, which is prior
www.rsc.org/chemicalscience
Volume 1 | Number 4 | 1 October 2010 | Pages 417–528
to technical editing, formatting and proof reading. This free service from RSC
Publishing allows authors to make their results available to the community, in
citable form, before publication of the edited article. This Accepted Manuscript will
be replaced by the edited and formatted Advance Article as soon as this is available.
To cite this manuscript please use its permanent Digital Object Identifier (DOI®),
which is identical for all formats of publication.
More information about Accepted Manuscripts can be found in the
Information for Authors.
ISSN 2041-6520
PERSPECTIVE
Barry M. Trost et al.
Catalytic asymmetric allylic alkylation
Andrew J. deMello, Joshua B. Edel et al. employing heteroatom nucleophiles:
Please note that technical editing may introduce minor changes to the text and/or
graphics contained in the manuscript submitted by the author(s) which may alter
content, and that the standard Terms & Conditions and the ethical guidelines
that apply to the journal are still applicable. In no event shall the RSC be held
responsible for any errors or omissions in these Accepted Manuscript manuscripts or
any consequences arising from the use of any information contained in them.
EDGE ARTICLE
Rapid cell extraction in aqueous two-
phase microdroplet systems
a powerful method for C–X bond
formation
2041-6520(2010)1:4;1-
X
www.rsc.org/chemicalscience
Registered Charity Number 207890

Chemical Science
Page 1 ofC13hemical Science
Dynamic Article Links ►
View Article Online
Cite this: DOI: 10.1039/c0xx00000x
EDGE DAOI:R10.1T03I9/CC3SCL521E99K
www.rsc.org/xxxxxx
Programmed Synthesis of Arylthiazoles through Sequential C–H
Couplings
Satoshi Tani,a Takahiro N. Uehara,a Junichiro Yamaguchi,a and Kenichiro Itami*,a,b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
A programmed synthesis of privileged arylthiazoles via sequential C–H couplings catalyzed by palladium or nickel catalysts has been
accomplished. This versatile protocol can supply all possible arylthiazole substitution patterns (2-aryl, 4-aryl, 5-aryl, 2,4-diaryl, 2,5-
diaryl, 4,5-diaryl, and 2,4,5-triaryl) from an unfunctionalized thiazole platform by 11 distinct synthetic routes. We have generated over
150 arylthiazoles by using this methodology. We have applied this method to the rapid synthesis of fatostatin (SREBP inhibitor), and the
10 gram-scale synthesis of triarylthiazoles has been demonstrated.
50 strategically utilize them in orthogonal functionalization
(programmability).
Introduction
Thiazoles attached with aryl or heteroaryl groups
(arylthiazoles) represent privileged structural motifs that are
frequently utilized in functional organic materials including
15 organic electroluminescent devices, as well as in bioactive
compounds and pharmaceuticals (Figure 1).1 Thus, an efficient
synthetic methodology that allows cost- and step-efficient
production of arylthiazoles is in high demand. Moreover, in a
situation where the structure-property relationships are not
20 predictable, a uniform and programmable design that allows the
synthesis of all possible arylthiazoles (2-aryl, 4-aryl, 5-aryl, 2,4-
diaryl, 2,5-diaryl, 4,5-diaryl, and 2,4,5-triaryl) would help
accelerate identifying and optimizing the “functional”
arylthiazole structures. Therefore, both step economy and
25 programmability need to be implemented in the next-generation
synthesis of privileged arylthiazoles.
Me
Me
H
O
N
N
N
S
S
N
N
Me
Me
TAK-715
p38 MAP kinase inhibitor
fatostatin
SREBP inhibitor
F
OMe
MeO
MeO
N
S
N
NH2
N
S
SO2Me
EtO
tubulin polymerization inhibitor
p38 MAP kinase inhibitor
To date, the majority of arylthiazoles are synthesized by the
classical Hantzsch thiazole synthesis, connecting α-haloketones
and thioamides in a convergent manner.2 The advantage of this
30 method is that it is possible to synthesize large amounts of
arylthiazoles from inexpensive starting materials. However, the
syntheses of both α-haloketones and thioamides typically require
several steps from commercially available compounds, rendering
the rapid construction of arylthiazole libraries difficult. To
35 address this drawback, various cyclization methods for the
synthesis of arylthiazoles have been developed.3 As an alternative
and newer method, palladium-catalyzed cross-coupling reactions
allow the divergent synthesis of arylthiazoles.4,5 However,
superfluous steps are required prior to the cross-coupling; the
40 parent thiazole must be pre-functionalized with a halogen or a
metal group at the position where aryl groups are to be installed.
Me
N
NH2
S
N
N
O
N
SH
HN
N
S
H
N
O
NCH-31
HDAC inhibitor
CYC116
aurora kinase inhibitor
N
O
MeO
MeO
MeO
N
N
Me
N
N
O
N
N
NH2·HCl
Me
S
H
N
S
H
Me
CKD-516
tubulin polymerization inhibitor
hMAO-B inhibitor
Me
N
In pursuit of developing a step-economical and programmable
arylthiazole synthesis, we have been attracted by the potential of
catalytic C–H arylation reactions of thiazoles.6–9 Unlike the cross-
45 coupling method, aryl groups can be installed onto the thiazole
core directly in C–H arylation (step economy). Moreover, as the
three C–H bonds on thiazole (C2, C4, C5) are chemically
nonequivalent, it is in principle possible to acquire bond
selectivity (regioselectivity) in aryl-installing reactions and to
CN
O
N
F3C
HO
S
S
S
O
CF3
N
Me
Me
febuxostat
xanthine oxidase inhibitor
n-Type OFET
Fig 1. Selected examples of functional arylthiazoles.
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Chemical Science
Page 2 of 13
i) Stepwise C2–C5–C4 direct arylation of thiazole N-oxide [Fagnou, 2008]
Herein, we report a general and programmable synthetic
scheme that can synthesize all possible arylthiazole substitution
patterns (2-aryl, 4-aryl, 5-aryl, 2,4-diaryl, 2,5-diaryl, 4,5-diaryl,
and 2,4,5-triaryl) from an unfunctionalized thiazole platform
(Figure 2).10 In this article, an application to the rapid synthesis of
fatostatin (SREBP inhibitor), a re-optimization of C4-selective
arylation of 2-substituted thiazoles, and a gram-scale synthesis of
triarylthiazole are also described. Noteworthy features of the
present methodology are that (i) all aryl groups assembled stem
H
O
H
5
H
O
4
[Ox]
C2
C5
View Article Online
N
N
N
2
H
Ar1
H
H
H
H
DOI: 10.1039/C3SC52199K
S
S
S
thiazole N-oxide
thiazole
5
Ar3
Ar2
H
O
Ar3
Ar2
O
C4
[Red]
N
N
N
Ar2
Ar1
Ar1
Ar1
S
S
S
Triarylthiazoles
10 from readily available aryl halides or arylboronic acids, (ii) the
aryl-group-installation at the desired position can be achieved by
the choice of catalytic systems, and (iii) due to the regiodivergent
nature of established catalytic conditions, 11 distinct pathways for
7 arylthiazoles has been established.
ii) Sequential C5–C2–C4 direct arylation of thiazole [Murai and Shibahara, 2011]
Ar3
H
H
5
H
4
C4
C2
C5
N
N
N
N
2
Ar2
Ar2
Ar1
H
Ar2
Ar1
H
H
S
S
S
S
Triarylthiazoles
15
1 synthetic route, 3 substitution patterns
H
H
C2
N
N
Fig 3. Selective synthesis of multiply arylated thiazoles by Fagnou and
50 Murai/Shibahara.
Ar2
C5
C2
C4
C5
Ar2
Ar3
Ar1
Ar1
H
H
Ar1
H
S
S
C5
C4
Ar3
Ar2
Triarylthiazoles
H
H
5
4
N
N
N
N
2
Ar1
H
H
H
H
S
S
S
S
C2
C5
Ar3
Ar3
These seminal works clearly show the limitation of relying
solely on substrate control (reactivity difference of C–H bonds of
thiazole). Catalyst-controlled regioselectivity (regiodivergency)
55 and selective C–H arylation at the least reactive C4 position have
to be established to realize the programmed synthesis of
arylthiazoles. The latter issue is evident from the previous reports
by Fagnou and Murai/Shibahara as they both conducted the C4
arylation in the last step.
C4
N
N
C2
Ar2
H
S
S
11 synthetic routes, 7 substitution patterns
Fig 2. Programmed synthesis of arylthiazoles.
In order to achieve fully programmed synthesis of
20 arylthiazoles as shown in Figure 2, it is essential to acquire
regiodivergency in thiazole C–H arylation by catalyst control. 11
This is conceptually different from the previously reported
procedures for the selective synthesis of multiply arylated
thiazoles, which are mainly based on the inherent reactivity
25 difference of three thiazole C–H bonds (substrate control).12 In
2008, Fagnou and coworkers reported a pioneering work on the
regioselective synthesis of arylthiazoles via Pd-catalyzed C–H
couplings to install three different aryl groups (Figure 3; i).11a
Their method, wherein a thiazole was first oxidized to a thiazole
30 N-oxide, involved C–H arylations of thiazole N-oxides with aryl
halides in the order of C2, C5 then C4; these reactions all
proceeded regioselectively to give the desired triarylthiazole N-
oxides. Finally, reduction of the N-oxides was conducted to afford
the target triarylthiazoles. In 2011, Murai, Shibahara, and
35 coworkers reported a sequential C–H arylation of thiazoles using
their own Pd catalyst (Figure 3; ii).11b Thiazoles were coupled
with aryl halides in the order of C5, C2, then C4 to afford
triarylthiazoles. Although these two protocols successfully
provide arylthiazoles in a regioselective manner, only one
40 pathway en route to triarylthiazoles has been developed.
Moreover, these protocols allow access to only 3 arylthiazole
substitution patterns and the pathways leading to 4 remaining
substitution patterns have not been developed (4-aryl, 5-aryl, 2,4-
diaryl, and 4,5-diaryl for the Fagnou method, and 2-aryl, 4-aryl,
45 2,4-diaryl, and 4,5-diaryl for the Murai-Shibahara method).
Similar limitation was also observed in our previous work on the
regioselective synthesis of multiply arylated thiophenes.13a
60
Although the catalyst-controlled C4-selective thiazole
arylation is critically needed, it has been well documented that C2
and/or C5 positions are preferentially arylated over the C4
position under transition-metal-catalyzed C–H arylation
conditions (Figure 4).7 Under forcing conditions, diarylation
65 occurs at the C2 and C5 positions under the influence of
palladium catalysts.7b,8 The reactivity of three positions of
thiazole in C–H arylation (C2, C5 >> C4) is in line with the
typical reactivity profile of the thiazole ring (Figure 4). For
example, the deprotonation of thiazoles occurs preferentially at
70 the C2 position. Thus, under the C–H arylation conditions using a
strong base, C2 arylation tends to take place preferentially. On the
other hand, thiazoles react with electrophiles preferentially at the
C5 position. Thus, under the C–H arylation conditions where the
nucleophilicity of thiazole plays a key role, C5 arylation tends to
75 predominate. Radical reactions of thiazoles are also known, but
the C4 position is least reactive. Only one example of reactivity
preference for the C4 position of thiazoles is known, but the C2
position has to be substituted and some C5 substitution is also
observed.14 Thus, the introduction of an aryl group at the C4
80 position of a thiazole derivative required a number of synthetic
steps.15
C4-Selective Arylation
Not reported
Ar
X
C2(-Selective) Arylation
>20 Reactions [ref. 7]
C5(-Selective) Arylation
>20 Reactions [ref. 7]
H
5
4
N
2
X
X
Ar
H
H
S
Ar
General reactivity of thiazole
+ With Base (C–H Acidity):
C2 > C5 > C4
+ With Electrophiles:
+ With Radical:
C5 > C4 (C2 Elusive)
C2 > C5 > C4
2 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 13
Chemical Science
Fig 4. Paucity of C4-selective thiazole C–H arylation and the general
reactivity of thiazole.
the
corresponding
coupling
product
with
complete
regioselectivity at the C2 position.
View Article Online
Recently, we discovered the first C4-selective C–H arylation
of 2-phenylthiazole with arylboronic acids, catalyzed by a
50
DOI: 10.1039/C3SC52199K
Table
1
Synthesis of 2-arylthiazoles by C2-selective arylation of
5
Pd(OAc)2/phen
(1,10-phenanthroline)/TEMPO
(2,2,6,6-
thiazole.a
tetramethylpiperidine 1-oxyl) system (Scheme 1).9 This
previously inaccessible regiochemical outcome and the hitherto
unrecognized regiocontrolling elements that have been uncovered
in this study should provide a deeper understanding of the
[Method A] Pd(OAc)2 (5 mol%)
CuI (2.0 equiv), DMF, 140 ºC
[Method B] Ni(OAc)2 (10 mol%)
bipy (10 mol%), LiOt-Bu (2.0 equiv)
1,4-dioxane, 120 ºC
N
N
10 reactivity of thiazoles. Although a full understanding of the
mechanism is still ongoing, our preliminary experiments and
theoretical calculations of related reactions indicated that our C4-
selective arylation occurs by a mechanism involving Heck-like
concerted arylpalladation across the C=C bond of thiazoles.16
15 Although we did not fully explore the scope of this reaction in
our previous communication (only three reactions of 2-
phenylthiazole were examined), this breakthrough finding finally
opened the door for the programmed synthesis of arylthiazoles,
providing access to 7 arylthiazole substitution patterns by 11
20 different synthetic routes.
X
Ar
H
Ar
S
S
[Method C] Pd[P(t-Bu)3]2 (2 mol%)
LiOt-Bu (1.5 equiv)
1,4-dioxane, 100 ºC
1
2
(X = I, Br)
3
Products
N
N
N
S
N
Me
S
S
S
t-Bu
Me
Me
3e: 80% [Method A]
3a: 93% [Method A]
61% [Method B]
3b: 84% [Method A]
3c: 71% [Method A]
Me
N
N
S
N
N
OMe
O
S
S
S
O
OMe
OMe
OMe
3f: 76% [Method B]
3g: 77% [Method A]b
3h: 77% [Method A]
3i: 70% [Method C]
Scheme 2 C4-Selective C–H arylation of 2-phenylthiazole.
N
N
N
N
Pd(OAc)2 (10 mol%)
Ar
phen (10 mol%)
TEMPO (4.0 equiv)
S
S
S
S
4
Cl
CF3
CO2Me
COMe
N
N
(HO)2B
Ar
5
S
S
DMAc, air
100 ˚C, 48 h
3j: 88% [Method A]
3k: 71% [Method A]
3n: 82% [Method A]
3o: 75% [Method A]
59–74% yield
85–96% C4 selectivity
3 examples
N
S
N
S
N
N
S
S
SO2Me
NO2
S
N
Me
deprotonation
X–
3p: 41% [Method C]
3q: 78% [Method A]
3r: 50% [Method C]
3t: 49% [Method B]
X–
a
Heck-like concerted
arylpalladation
Reaction conditions. Method A: 1 (0.8 mmol), 2 (X = I, 0.4 mmol),
N
N
N
N
55 Pd(OAc)2 (0.02 mmol), CuI (0.8 mmol), DMF (1.0 mL), 140 °C, 40 h.
Method B: 1 (0.6 mmol), 2 (X = I, 0.4 mmol), Ni(OAc)2 (0.04 mmol),
bipy (0.04 mmol), LiOt-Bu (0.8 mmol), 1,4-dioxane (1.0 mL), 120 °C, 36
h. Method C: 1 (0.6 mmol), 2 (X = Br, 0.4 mmol), Pd[P(t-Bu)3]2 (0.008
Pd
Pd
Ar
S
S
Ar
N
N
H
b
mmol), LiOt-Bu (0.6 mmol), 1,4-dioxane (1.2 mL), 100 °C, 12 h. The
60 reaction was performed for 16 h.
25 Results and Discussion
The synthesis of 5-arylthiazoles 4 via C–H arylation of
thiazoles has already been reported under various reaction
conditions.7 However, these conditions had not been optimized
65 for unfunctionalized thiazole (1). Therefore, we began by
optimizing the conditions for C5-selective C–H arylation of 1,
based on our protocol [PdCl2, bipy in DMF at 120 °C]7q and
Fagnou’s protocol [Pd(OAc)2, PMe(t-Bu)2·HBF4, Cs2CO3 in t-
AmylOH].7m As a result, optimal conditions for the coupling of
70 thiazole (1) and aryl halides 2 have been determined.17 Treatment
of iodobenzene (2; X =I) with thiazole (1: 1.5 equiv) in the
presence of Pd(OAc)2 (5 mol%), PMe(t-Bu)2·HBF4 (10 mol%),
and Cs2CO3 (1.5 equiv) in t-AmylOH at 80 °C for 36 h afforded
the desired C5-phenylated product 4a in 80% yield with virtually
75 complete regioselectivity (Method D). Under these conditions,
we examined the substrate scope of C5-selective C–H arylation
of thiazole with aryl halides as shown in Table 2. Aryl iodides
bearing an alkyl group at the para, meta and even ortho position
underwent C5-selective arylation to give the corresponding
80 products (4b–4f) in good yields. Aryl iodides bearing electron-
rich substituents (resulting in products 4g–4i) and electron-
deficient substituents (resulting in products 4j–4q) as well as
heteroaryl iodides (resulting in products 4s–4u) gave the desired
products. However, when 2-iodo-5-ethylthiophene (2i) was used
Transition-metal-catalyzed C–H arylation of thiazoles at the
C2 position has already been reported by several groups
including our own.7 After extensive screening of various reaction
30 conditions for the preparation of 2-arylthiazoles,17 we came to the
conclusion that Rossi’s Pd/Cu-based protocol (Method A),7g our
Ni-based protocol (Method B),7k,7r and Mori’s Pd-based protocol
(Method C)7n can effectively convert thiazole (1) to 2-
arylthiazoles 3 using aryl halides 2 as an aryl source (Table 1). It
35 should be noted, however, that there is no single, universal
catalytic system; all three systems have pros and cons.
It was found that Rossi’s palladium catalyst system [Method
A: Pd(OAc)2 and CuI in DMF at 140 °C] was generally preferred
for the synthesis of 2-arylthiazole 3 from 1. When a sterically
40 hindered aryl iodide such as 2-methyl-1-iodobenzene (2f) and an
electron-deficient heteroaryl iodide such as 3-iodopyridine (2t)
were used, our nickel catalytic system [Method B: Ni(OAc)2,
bipy (2,2’-bipyridyl) and LiOt-Bu in 1,4-dioxane at 85 °C] was
most effective and gave higher yields than Method A (76% for 3f
45 and 49% for 3t). In the synthesis of 2-arylthiazoles 3j, 3p and 3r,
Mori’s palladium catalyst system [Method C: Pd[P(t-Bu)3]2,
LiOt-Bu and 1,4-dioxane at 100 °C] was most effective, affording
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Chemical Science
Page 4 of 13
35 Scheme 2 Protection-arylation-deprotection sequence for the synthesis of
4-Arylthiazoles 8.
as the coupling partner, the yield of product 4i was low (26%)
due to the occurrence of homocoupling of 2i as a side reaction. In
some cases, aryl bromides were also applicable to give the
corresponding coupling products (4i, 4o, 4t and 4u) in good to
excellent yields. Since 4’-bromoacetophenone (2o), bromo-4-
(methylsulfonyl)benzene (2p), and bromopyridines (2t and 2u)
were less reactive under Method D, we changed the reaction
conditions to those reported by Doucet and coworkers [Method
E: Pd(OAc)2, KOAc in DMAc, 130 °C].7l As a result, these
View Article Online
N
Protection
N
+
DOI: 10.1039/C3SC52199K
Ar
(HO)2B
PG
H
S
S
5
1
6
5
Ar
Ar
Deprotection
N
N
PG
S
C4-selective
Arylation
S
10 coupling reactions performed well to give the desired products
(4o, 4p, 4t, and 4u).
8
7
Among many possible protecting groups at the C2-position of
Table
2
Synthesis of 5-arylthiazoles by C5-Selective Arylation of
40 thiazole, we decided to apply Mori’s procedure using
a
Thiazole.a
diphenylmethanol group.18 The protected thiazole 5 was readily
prepared by the treatment of 1 with n-BuLi, followed by the
reaction with benzophenone in 86% yield (Scheme 3).
[Method D]
Pd(OAc)2 (5 mol%)
PMe(t-Bu)2•HBF4 (10 mol%)
N
N
Cs2CO3 (1.5 equiv)
Ar
X
Ar
H
S
S
t-AmylOH (0.4 M)
80 ˚C, 36 h
45 Scheme 3 “Protection” of thiazole at C2-position.
1
2
4
(X = I, Br)
n-BuLi
O
N
N
Ph
Ph
OH
+
Products
H
S
Ph
Ph
S
Et2O
N
N
N
N
Me
[86%]
1
5
S
S
S
S
Me
t-Bu
Me
4a: 80%
4b: 78%
4c: 71%
4e: 57%
Me
The protected thiazole 5 was then reacted with arylboronic
acid under the influence of Pd(OAc)2/phen/TEMPO. During these
50 studies, we re-optimized our C4-selective arylation conditions,
employing less amounts of TEMPO but using LiBF4 as an
additive (Method F). Details of these conditions are discussed
later in the manuscript (Table 7). Thus, the treatment of 5 (1.0
equiv) and phenylboronic acid (6a: 4.0 equiv) in the presence of
55 Pd(OAc)2 (10 mol%), phen (10 mol%), TEMPO (50 mol%), and
LiBF4 (1.5 equiv) in DMAc under air at 100 °C afforded the C4-
phenylated thiazole 7a in 71% yield with complete
regioselectivity (Table 3). Deprotection of the diphenylmethanol
group of 7a was accomplished by treatment with Cs2CO3 at
60 150 °C18 to afford 4-phenylthiazole (8a) in 95% yield. The scope
of C4-selective C–H arylation of thiazole 5 with respect to
various arylboronic acids 6 (followed by diphenylmethanol group
removal) is summarized in Table 3. A variety of arylboronic acids
reacted smoothly to furnish the coupling products (7b–7n), and
65 the desired 4-arylthiazoles (8b–8n) were obtained in good yields
after deprotection.
N
N
N
N
MeO
O
S
S
S
S
O
MeO
MeO
MeO
4i: 58%b
4g: 81%
4k: 75%
4f: 76%
4j: 63%
4h: 77%
4m: 72%
N
N
N
N
N
S
S
S
S
S
Cl
F3C
F3CO
MeO2C
4n: 61%
N
N
S
N
S
S
MeOC
4o: 82%c
MeO2S
4p: 66%c
O2N
S
Et
4q: 41%
4s: 26%
N
N
S
S
N
N
4t : 65%c
4u: 62%c
a
15 Reaction conditions. Method D: 1 (0.6 mmol), 2 (X = I, 0.4 mmol),
Pd(OAc)2 (0.02 mmol), PMe(t-Bu)2·HBF4 (0.04 mmol), Cs2CO3 (0.6
mmol), t-AmylOH (1.0 mL), 80 °C, 36 h. Bromobenzene (0.4 mmol)
b
was used instead of iodobenzene, and the reaction was performed at
c
100 °C for 18 h. Method E: 1 (0.8 mmol), 2 (X = Br, 0.4 mmol),
Table 3 Synthesis of 4-arylthiazoles by C–H arylation.a
20 Pd(OAc)2 (0.004 mmol), KOAc (0.8 mmol), DMAc (1.0 mL), 130 °C, 20
h.
As already described, we have developed a palladium-
catalyzed C4-selective C–H arylation of 2-arylthiazoles with
arylboronic acids under Pd(OAc)2/phen/TEMPO system (Scheme
25 1).9 However, when we applied this first-generation protocol to
the C–H arylation of an unfunctionalized thiazole (1) with
phenylboronic acid (6a), the yield of the desired coupling product
8a was abysmal (<10% yield). We envisioned that some form of
protecting group at the C2 position was necessary. Namely, it was
30 thought that the C4-arylation product 8 could be synthesized by a
sequence of (i) protection of 1, (ii) C4-arylation of 2-substituted
thiazole 5 with an arylboronic acid 6, and (iii) removal of the C2
substituent from the resulting C4-arylated thiazole 7 (Scheme 2).
4 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 5 of 13
Chemical Science
partner to obtain diarylthiazoles. We first performed the C5-
(HO)2B
Ar
selective arylation of 2-arylthiazoles 3 with aryl iodides 2 under
our developed conditions [PdCl2(bipy), Ag2CO3 in V1i,e4w-dAiroticxleanOenliante
15 120 °C].7q After a slight modification DoOfI:r1e0a.c1t0i3o9n/Cc3oSnCd5i2ti1o9n9sK
(Method G), we turned our attention to defining the scope and
functional group tolerance of the aryl iodide coupling partner in
the synthesis of 2,5-diarylthiazoles 9 from 2-arylthiazoles 3
(Table 4). Numerous aryl iodides and 2-arylthiazoles were
20 coupled with each other to give 2,5-diarylthiazole products 9 in
excellent yields. When coupling reactions between 4-
iodopyridine (2u) and 2-(4-methoxyphenyl)thiazole (3g) as well
as chloropyridine (2j) and methyl 4-(2-thiazolyl)benzoate (3n)
were conducted, the yields of the resulting diarylthiazoles (9gu
25 and 9nj) were low under our standard conditions (Method G).
After increasing the reaction temperature and time, these yields
were rendered moderate (48% and 52% yield, respectively).
6
[Method F]
Pd(OAc)2/phen (10 mol%)
TEMPO (0.5 equiv)
Ar
Ar
H
Cs2CO3
N
N
Ph
Ph
OH
N
Ph
Ph
OH
m-xylene
150 ˚C
S
LiBF4 (1.5 equiv)
DMAc, air
100 ˚C, 48 h
S
S
8
5
7
Products
Me
Me
Me
Me
N
N
N
N
S
S
S
S
8a
8b
8d
8e
71%
95%
75%
78%
77%
84%
62%
66%
Yield of 7
Yield of 8
MeO
Cl
MeOOC
F
Starting from 5-arylthiazoles 4, we found that C2-selective
30 arylation was possible using two different methods, namely the
protocols originally developed by Murai/Shibahara8d and
Greaney.7h For example, when Murai’s protocol [Method H:
Pd(phen)2(PF6)2, Cs2CO3, DMAc, 150 °C] was used for the
coupling of 2-phenylthiazole (3a) with iodobenzene, 2,5-
35 diphenylthiazole (9aa) was obtained in 83% yield, whereas
Greaney’s protocol [Method I: PdCl2(dppf)·CH2Cl2, Ph3P,
Ag2CO3, water, 60 °C] gave a 96% yield. Employing these
conditions, the C2-selective arylation of 4 was conducted with
various aryl iodides (Table 5). Although most of the coupling
40 reactions proceeded by Method H to give the corresponding
products in good yields, the yields of 9an, 9hg, 9qa, and 9vb
were low due to competing hydrolysis of the substituents or
functional group intolerance. After changing the reaction
conditions to Method I, these products were generated in
45 moderate yields. In the case of 9bg, 9ga, 9gb and 9jb, the yields
were better at lower temperatures (130 °C) to prevent
decomposition of the product.
N
N
N
N
S
S
S
S
8g
8j
8l
8n
53%b,c
74%
66%
87%
56%
80%
63%b
88%
Yield of 7
Yield of 8
a Reaction conditions. Method F: 5 (0.25 mmol), 6 (1.0 mmol), Pd(OAc)2
(0.025 mmol), phen (0.025 mmol), TEMPO (0.125 mmol), LiBF4 (0.38
mmol), DMAc (0.5 mL), air, 100 °C, 48 h; then 7 (0.1–0.2 mmol),
b
5 Cs2CO3 (1.0 mmol), m-xylene (0.8 mL), 150 °C, 40 h. TEMPO (0.25
mmol) was used. c The yield was determined by 1H-NMR.
We have established methods for the first arylation of thiazole
(1) to obtain mono-arylated thiazoles of three different
substitution patterns (3, 4, and 8) with complete regioselectivity.
10 Thus, we then carried out the second arylation, in which the
mono-arylated thiazoles were coupled with another aryl coupling
Table 4 Synthesis of 2,5-diarylthiazoles by C5-selective arylation of 2-arylthiazoles.a
[Method G]
PdCl2(bipy) (5 mol%)
Ag2CO3 (1.0 equiv)
N
N
I
Ar
H
S
Ar
S
1,4-dioxane
120 ˚C, 22 h
3
2
9
Products
N
N
N
N
N
S
Me
S
S
S
S
MeO
Me
OMe
COMe
Me
Me
9aa: 89%
9ab: 85%
9gb: 75%
9oe: 69%
9ag: 81%
N
S
N
S
N
S
N
S
N
S
Cl
Me
Cl
Me
OMe
O
O
CO2Me
O
O
O
O
9nj: 48%b
9ah: quant
9bh: 89%
9gh: 82%
9bj: 73%
N
S
N
S
N
S
N
S
N
S
N
OMe
F3C
MeO2C
CF3
MeOC
Me
Me
O2N
OMe
9gu: 52%c
9gk: 89%
9kn: 79%
9bo: 68%
9bq: 64%
a
Reaction conditions. Method G: 3 (0.375 mmol), 2 (0.25 mmol), PdCl2(bipy) (0.0125 mmol), Ag2CO3 (0.25 mmol), 1,4-dioxane (1.0 mL) at
120 °C, 22 h. b The reaction was performed over 36 h. c The reaction was performed at 150 °C.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

Chemical Science
Page 6 of 13
Table 5 Synthesis of 2,5-diarylthiazole by C2-selective arylation of 5-arylthiazoles.a
[Method H]
[Pd(phen)2](PF6)2 (5 mol%)
Cs2CO3 (1.1 equiv)
DMAc, 150 ˚C, 18 h
View Article Online
DOI: 10.1039/C3SC52199K
N
N
H
Ar
I
S
Ar
Ar
Ar
S
[Method I]
PdCl2(dppf)·CH2Cl2 (5 mol%)
PPh3 (10 mol%)
2
4
9
Ag2CO3 (2.0 equiv)
water, 60 ˚C, 24 h
Products
N
N
N
N
S
N
S
S
S
S
MeO2C
Me
MeO
F3C
9aa: 96% [Method I]
9ab: 92% [Method H]
9ag: 70% [Method H]
9ak: 93% [Method H]
9an: 58% [Method I]
N
S
N
S
N
S
N
S
N
S
Me
N
MeO
MeO
Me
OMe
Me
Me
9bg: 82% [Method H]b
9ga: 86% [Method H]b
9ba: 87% [Method H]
9ua: 65% [Method H]
9eg: 71% [Method H]
N
S
N
S
N
S
N
S
N
S
MeO
Cl
Me
Me
OMe
CF3
Cl
O
O
9gb: 59% [Method H]b
9jb: 63% [Method H]b
9hg: 87% [Method I]
9ja: 67% [Method H]
9ka: 85% [Method H]
N
S
N
S
N
S
N
Me
MeO
CF3
NO2
N
9kg: 72% [Method H]
9qa: 60% [Method I]
9vb: 33% [Method I]
a
Reaction conditions. Method H: 4 (0.2 mmol), 2 (0.22 mmol), Pd(phen)2(PF6)2 (0.01 mmol), Cs2CO3 (0.22 mmol), DMAc (0.8 mL), 150 °C, 18 h.
Method I: 4 (0.2 mmol), 2 (0.24 mmol), PdCl2(dppf)·CH2Cl2 (0.01 mmol), Ph3P (0.02 mmol), Ag2CO3 (0.4 mmol), water (1.0 mL), 60 °C, 24 h. b The
reaction was performed at 130 °C.
The C2-selective C–H arylation of 4-arylthiazoles 8 has not
been reported thus far. Thus, without literature precedent, we
attempted the coupling under several reaction conditions.17 When
the coupling reaction between 4-phenylthiazole (8a) and
iodobenzene was conducted with our Ni catalyst7k,7r or under Pd
catalysis reported by Rossi7g and Hoarau7j, the coupling product
10aa was obtained in low yield (22% and 6% yield, respectively).
We then found that Mori’s protocol [Method C: Pd[P(t-Bu)3]2 and
5
10 LiOt-Bu in 1,4-dioxane]7n was superior to others for the C–H
arylation; 2,4-diphenylthiazole (10aa) was obtained in 55% yield
from 8a and bromobenzene, and the yield was increased to 77%
after the slight modification of conditions (Method C’: reaction
temperature was lowered to 80 °C).17 Using these optimal
15 conditions, we further investigated the coupling of various 4-
arylthiazoles and bromoarenes as shown in Table 6. Gratifyingly,
we found that a relatively broad range of 4-arylthiazoles and
bromoarenes can couple with complete C2 selectivity and in good
yields.
20
We subsequently applied this protocol to the synthesis of
fatostatin, which was reported as a sterol regulatory element-
binding protein (SREBP) by Uesugi and coworkers.19 4-(p-
Tolyl)thiazole (8b) was reacted with 4-bromo-2-propylpyridine
(11)20 under the influence of Pd[P(t-Bu)3]2/LiOt-Bu (Method C)
25 to give fatostatin in 53% yield (Scheme 4). Although this
synthesis is not shorter than that of the original report,19 it could
easily bring structural diversity to the aryl substituent at the C2
position of the thiazole core.
Table 6. Synthesis of 2,4-Diarylthiazoles by C2-Selective Arylation of 4-
30 Arylthiazoles.a
6 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 13
Chemical Science
under an atmosphere of air. Surprisingly, the coupling reaction
Ar
[Method C']
Pd[P(t-Bu)3]2 (2 mol%)
LiOt-Bu (1.5 equiv)
Ar
proceeded well without TEMPO to give the corresponding
N
N
View Article Online
+
Ar
Br
25 coupling product 10aa in 71% isolated yield (entry 4). We
Ar
S
H
1,4-dioxane
80 ˚C, 48 h
S
DOI: 10.1039/C3SC52199K
hypothesized that the oxidation of Pd(0) to Pd(II) might not
8
2
10
always require any co-oxidants, and also worked under air
(molecular oxygen) as a terminal oxidant in the case of 2-
phenylthiazole (3a). However, we continued to use 0.5 equiv of
30 TEMPO, since it was often effective for the C–H arylation of 2-
arylthiazoles 3 (see Table 8). It should be noted that C4-selective
C–H arylation of thiophenes necessitates the use of TEMPO as a
co-oxidant under air; otherwise the products were produced in
low yield.9 Next, after screening additives, LiBF4 (1.5 equiv) was
35 identified as the optimal additive; both the reaction yield (77%)
and regioselectivity (90%) were slightly improved (entry 5).
Although the role of LiBF4 remains unclear, we assume that the
lithium cation coordinates with the nitrogen atom of 2-
arylthiazole to prevent over-arylation as well as to increase
40 regioselectivity. In contrast, the use of lithium base additives such
as LiOAc (entry 6) and LiOH (entry 7) decreased the yield and
regioselectivity.
Products
MeO
MeO
N
N
N
S
S
S
Me
10aa: 77%
10ag: 46%
10bg: 65%
MeO
MeO
Cl
N
S
N
S
N
S
OMe
OMe
OMe
O
O
OMe
10gj: 67%
10hg: 74%
10ig: 57%
Me
Me
N
N
S
N
S
S
Me
S
Table 7 Optimization of C4-selective C–H arylation of 2-phenylthiazole.a
CF3
N
10kb: 63%
10tb: 82%b
10ra: 62%
Me
Pd(OAc)2 (10 mol%)
phen (10 mol%)
TEMPO (X equiv)
H
N
N
additive (1.5 equiv)
(HO)2B
N
N
Me
S
S
DMAc, air
100 ˚C, 24 h
S
S
Cl
10aa
3a
6
45
Me
entry
TEMPO/equiv
additive
C4/C5
86:14
86:14
88:12
88:12
90:10
58:42
9:91
yield (%)b
85 (74)
85 (74)
77
10ea: 72%c
10jb: 70%
1
2
3
4
5
6
7
4.0
0.5
0.2
–
–
–
N
N
S
S
OMe
O
–
O
10ha: 78%
10wa: 68%c
–
83 (71)
93 (83)
40
0.5
0.5
0.5
LiBF4
LiOAc
LiOH
a
Reaction conditions. Method C’: 8 (0.2 mmol), 2 (0.24 mmol), Pd[P(t-
Bu)3]2 (0.004 mmol), LiOt-Bu (0.3 mmol), 1,4-dioxane (0.6 mL), 80 °C,
48 h. 8 (0.3 mmol), 2 (0.2 mmol), LiOt-Bu (0.4 mmol), 100 °C. The
5 reaction was performed at 100 ºC.
b
c
68
a Reaction conditions: 3a (0.25 mmol), 6 (1.0 mmol), Pd(OAc)2 (0.025
mmol), phen (0.025 mmol), TEMPO (none to 1.0 mmol), additive (0.38
b
mmol), DMAc (0.5 mL), air, 100 °C, 24 h. The combined yield of
regioisomers is given. Isolated yield of 10aa is given in parenthesis.
Scheme 4 Synthesis of Fatostatin by C–H Arylation.
Me
Me
50
Pd[P(t-Bu)3]2 (2 mol%)
LiOt-Bu (1.5 equiv)
N
N
With these optimal conditions in hand (Method F), a range of
2,4-diarylthiazoles 10 were synthesized from 2-arylthiazoles 3
(Table 8). 2-Arylthiazoles bearing electron-donating groups (such
as 4-methyl, 4-tert-butyl, 3,5-dimethyl, and 4-methoxy groups)
N
Br
+
H
1,4-dioxane
100 ˚C, 48 h
[53% yield]
S
S
N
8b
11
fatostatin
SREBP inhibitor
55 on the aryl substituent were coupled with various arylboronic
acids 6 to give the corresponding products 10aa–10ag in good
yields. 2-Arylthiazoles with electron-deficient groups (such as 4-
methylester and 4-chloro groups) on the aryl substituent also gave
products 10ah–10aj in moderate to good yields after slight
60 modification of our standard conditions. Additionally, a broad
range of arylboronic acids 6 was also successfully employed in
the C4-selective arylation. Although some reactions displayed
incomplete regioselectivity, it is noteworthy that 2,4-
diarylthiazoles 10 can be readily separated from the minor
10
Next, a C4-selective C–H arylation of 2-arylthiazoles 3 was
investigated. Following our previously reported conditions for the
C4-selective arylation of 2-arylthiazoles,9 2-phenylthiazole (3a)
was treated with 4.0 equiv of phenylboronic acid (2a) in the
presence of Pd(OAc)2/phen catalyst and TEMPO (4.0 equiv) to
15 give diphenylthiazole in 85% combined yield (10aa and its
regioisomer) with 86% regioselectivity at the C4 position of 3a
(74% isolated yield; Table 7, entry 1). Although 10aa could be
synthesized, the reaction requires an excess amount of TEMPO
(4.0 equiv to thiazole substrate), and the regioselectivity was not
20 perfect. Therefore, a re-optimization of the coupling reaction was
conducted (Table 7). The amount of TEMPO was eventually
reduced to 0.5 equiv (entry 2) as well as to 0.2 equiv (entry 3)
65 regioisomer
(2,5-diarylthiazoles)
by
flash
column
chromatography.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7

Chemical Science
Page 8 of 13
Table 8 Synthesis of 2,4-diarylthiazoles by C4-selective arylation of 2-
Scheme 5 Two possible routes for the synthesis of 2,5-diarylthiazoles.
arylthiazoles.a
[Route A]
Ar1
[Route B]
Ar2
View Article Online
Ar2
Ar1
H
Ar2
X
X
[Method F]
Pd(OAc)2 (10 mol%)
phen (10 mol%)
TEMPO (0.5 equiv)
LiBF4 (1.5 equiv)
DOI: 10.1039/C3SC52199K
N
N
N
Ar1
S
H
Ar
S
S
C5-Selective
Arylation
H
N
12
8
4
N
(HO)2B
Ar
S
S
DMAc, air
100 ˚C, 24 h
Deprotection
Protection
10
3
6
Ar2
Ar1
H
N
X
Ar2
N
Products
Ar1
P
P
S
S
Me
t-Bu
C4-Selective
Arylation
N
S
N
N
S
S
25
Thus, we investigated coupling reaction conditions for the
10aa: 83% (90%)
Me
10ab: 84% (89%)
10ac: 88% (90%)b
MeO2C
synthesis of 2,5-diarylthiazoles via route A. As described in Table
2, we had already optimized the reaction conditions (Method D)
for the C5-selective C–H arylation of thiazole (1). Using those
conditions with slight modifications,17 the coupling reaction of 4-
MeO
Me
N
N
N
S
S
S
30 phenylthiazole (8a) with iodobenzene (2) in the presence of
Pd(OAc)2 (10 mol%), PMe(t-Bu)2·HBF4 (10 mol%) and Cs2CO3
(1.5 equiv) in t-AmylOH at 80 °C for 36 h afforded 4,5-
diphenylthiazole (12aa) in 77% yield. Under these conditions, an
over-arylation product (triphenylthiazole) was obtained in 14%
35 yield. The substrate scope for the C5-selective C–H arylation of
4-arylthiazoles was further investigated as shown in Table 9.
Although each reaction produced triarylthiazoles in less than 10%
yield, the desired 2,5-diarylthiazoles 12 were only obtained in
moderate yields, since the reactivity was similar to the C5-
40 selective C–H arylation of unfunctionalized thiazole (see Table
2). To obtain 12ah, 12ai, and 12gi in better yields, higher
temperatures were required, and in the case of an electron-rich
aryl coupling partner such as 3,4,5-trimethoxyphenyl halide, the
use of the aryl bromide instead of the aryl iodide provided a
45 better result to give 12gi in 55% yield.
10ag: 71% (88%)b
10ah: 63% (>99%)b
10ae: 78% (92%)
Cl
Cl
N
S
N
S
N
S
Me
Me
10bj: 59% (78%)b
10aj: 59% (75%)c
10ba: 84% (95%)
Me
Me
N
S
N
S
N
S
OMe
O
OMe
O
10ga: 99% (>96%)
10gb: 58% (96%)
10hb: 82% (97%)
MeO2C
N
S
N
S
N
S
Table 9 Synthesis of 4,5-diarylthiazoles by C5-selective arylation of 4-
arylthiazoles.a
CF3
Cl
Cl
10ja: 64% (82%)b
10jn: 45% (>99%)b,d
10ka: 69% (77%)
N
N
S
S
COMe
COOMe
10oa: 71% (77%)
10na: 65% (82%)
a Reaction conditions. Method F: 3 (0.25 mmol), 6 (1.0 mmol), Pd(OAc)2
5 (0.025 mmol), phen (0.025 mmol), TEMPO (0.125 mmol), LiBF4 (0.38
mmol), DMAc (0.5 mL), air, 100 °C, 24 h. Yield of the isolated product
b
and regioselectivity (in parenthesis) are given.
The reaction was
c
performed for 48 h. 4-MeO-TEMPO (0.125 mmol) was used instead of
TEMPO. d TEMPO (0.25 mmol) was used.
10
The synthesis of 4,5-diarylthiazoles 12 by direct arylation has
also not been reported thus far. For the synthesis of this motif
using C–H coupling methodology, it is possible to select two
synthetic routes: (i) C5-selective C–H arylation of 4-arylthiazoles
15 8 (route A, Scheme 5) and (ii) C4-selective C–H arylation of 5-
arylthiazoles 4 (route B; Scheme 5). However, we only attempted
route A since route B has synthetic problems in that 5-substituted
thiazoles show a low reactivity at the C4 position due to steric
reasons. Since the C2-arylation of 5-arylthiazoles is preferred, the
20 substrate might need to be protected at C2, reacted at C4, and
subsequently deprotected (see Table 3).
8 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 9 of 13
Chemical Science
[Method D]
Pd(OAc)2 (5 mol%)
PMe(t-Bu)2•HBF4 (10 mol%)
Cs2CO3 (1.5 equiv)
10 uses Pd(phen)2(PF6)2 as a catalyst, and Cs2CO3 as a base in
Ar
Ar
DMAc.8d These reaction conditions were modified with respect to
temperature, time, and equivalents of aryl iodideV, ieawndArttihclee Obnelisnte
results were obtained at 130 °C for 40 hDuOsiIn: 1g01.1.053e9q/Cu3ivSCo5f21a9ry9lK
iodide (68% isolated yield of 13aaa). Under the optimized
15 conditions (Method H’), we carried out a direct C4-arylation
using various 2,5-diarylthiazoles 9 and aryl iodides 2 (Table 10).
Not only were triarylthiazoles generated using iodobenzene (2; to
give 13aaa and 13gak), but also substituted iodobenzenes
(methyl, dimethyl, methoxy, trifluoromethyl substituents) and
20 even heteroaromatics led to the corresponding triarylthiazoles
13aba, 13gek, 13aga, 13aka, and 13bea.
N
N
X
Ar
H
S
Ar
Cl
S
t-AmylOH
80 ˚C, 36 h
8
2
(X = I, Br)
12
Products
Me
MeO
N
N
N
N
S
S
S
S
12aa: 77%
12ba: 77%
12ga: 81%
12ja: 80%
MeO
Table 10 Synthesis of triarylthiazoles by C4-arylation of 2,5-
diarylthiazoles.a
N
N
N
S
S
S
Me
Me
MeO
12ab: 69%
12gb: 78%
12ag: 75%
[Method H']
[Pd(phen)2](PF6)2 (5 mol%)
Cs2CO3 (1.2 equiv)
Ar
H
Me
N
N
Ar
I
Ar
Ar
Ar
Ar
DMAc
130 ˚C, 40 h
S
S
N
N
N
S
MeO
MeO
9
2
13
S
S
MeO
MeO2C
Products
Me
MeO
12ai: 60%b,c
12bg: 66%
12ah: 49%b
N
N
N
MeO
Cl
S
S
S
F3C
OMe
N
N
N
MeO
MeO
13gak: 54%b
13aba: 64%
O
13aaa: 68%
S
S
S
O
Cl
Me
MeO
N
MeO
Me
12gi: 55%c,d
Me
12jh: 35%
12aj: 66%
N
N
N
S
Me
S
S
F3C
Me
OMe
N
13bta: 28%b
13gek: 42%
13aga: 42%b
N
N
S
F3C
F3C
MeO
MeO
S
S
Cl
F3C
12bj: 58%
12ak: 59%
12bk: 40%
N
S
N
S
N
S
a
Me
Me
Reaction conditions. Method D: 8 (0.2 mmol), 2 (X = I, 0.2 mmol),
13aka: 54%b
13bga: 37%
13agb: 43%
Pd(OAc)2 (0.01 mmol), PMe(t-Bu)2·HBF4 (0.02 mmol), Cs2CO3 (0.3
mmol), t-AmylOH (0.5 mL), 80 °C, 36 h. b The reaction was performed at
25
c
d
5 100 °C for 18 h. 2 (X = Br, 0.2 mmol) was used. The reaction was
performed at 100 °C for 36 h.
a
Reaction conditions. Method H’: 9 (0.2 mmol), 2 (0.22 mmol),
Pd(phen)2(PF6)2 (0.01 mmol), Cs2CO3 (0.24 mmol), DMAc (0.8 mL), 130
b
ºC, 40 h.
The reaction was performed at 150 ºC, 18 h using
Pd(phen)2(PF6)2 (0.02 mmol) and Cs2CO3 (0.30 mmol).
C–H arylation of 2,5-diarylthiazoles at the C4 position has
only been reported by Shibahara, Murai and co-workers, which
30
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 9

Chemical Science
Page 10 of 13
Table 11 Synthesis of triarylthiazoles by C5-arylation of 2,4-diarylthiazoles.
View Article Online
DOI: 10.1039/C3SC52199K
[Method G]
PdCl2(bipy) (5 mol%)
Ag2CO3 (1.0 equiv)
Ar
Ar
N
N
I
Ar
H
Ar
Ar
S
Ar
S
1,4-dioxane
120 ˚C, 12 h
10
13
2
Me
Me
Products
N
N
N
N
S
S
S
S
Me
MeO
OMe
13aaa: 90%
13gba: 86%
13aab: 90%
13abg: 91%
Cl
Cl
N
S
N
N
S
N
O
O
S
S
MeO
MeO
Me
Me
MeO
13aag: 90%
13bag: 89%
13bjg: 64%
13ajh: 87%
Me
N
S
N
S
N
S
N
S
F3C
Cl
F3C
MeO2C
Me
OMe
13aaj: 74%b
13bak: 63%
13gbk: 88%
13aan: 71%c
Cl
N
S
N
S
N
S
N
S
N
MeO2C
O2N
MeOC
Me
Me
13bjn: 51%
13aao: 51%c
13baq: 61%
13aau: 69%c
a Reaction conditions. Method G: 2 (0.375 mmol), 10 (0.25 mmol), PdCl2(bipy) (0.0125 mmol), Ag2CO3 (0.25 mmol), 1,4-dioxane (1.0 mL), 120 °C, 12 h. b
The reaction was performed for 22 h. c The reaction was performed at 140 ºC for 22 h.
The somewhat lower yields of the coupling reaction were
aryl iodides 2 can be coupled to give triarylthiazoles 13 under
analyzed by GC analysis, and it was found that the arylation at 20 those conditions (Table 11). Both electron-poor and electron-rich
the aryl groups on the thiazole cores took place in these particular
reactions (Scheme 6). Thus, the possible side reactions are (i)
overarylation of triarylthiazole 13 at the ortho position of the C2-
or C4-aryl substituents after/before C4-arylation of 9 and (ii)
aryl iodides can be used in the C–H coupling reaction, but the
reactions using more electron-poor aryl iodides (those containing
chloro, ester and acetyl groups) as well as iodopyridine required
longer reaction times and higher temperatures. When electron-
5
further C–H arylation from 2,5-diarylthiazoles at the C4 or C2 25 deficient 2,4-diarylthiazoles were used, the corresponding
position to give multi-arylated products.
triarylthiazoles were formed in relatively low yields (13bjg and
13njn). To improve the yields of 13aaj, 13aan, 13aao and
13aau, the reactions were conducted over longer time periods (12
h to 22 h) and/or at elevated temperatures (120 °C to 140 °C).
10 Scheme
6 Potential side reactions in the C4-arylation of 2,5-
diarylthiazoles.
30
To demonstrate the utility of the C5-arylation of 2,4-
diarylthiazoles, a gram-scale synthesis of triarylthiazole 13abh
was undertaken (Scheme 7). Thiazole (1) was coupled with
iodobenzene under Pd(OAc)2/CuI catalysis (Method A) to give 2-
phenylthiazole (3a) in 72% yield (1.38 g). Afterwards, palladium-
H
N
Ar
C–H Arylation
(ortho position)
H
N
H
H
Ar–X
Ar
S
Ar
Ar
S
Ar
C4-Arylation
9
13
35 catalyzed C4-selective C–H arylation of 3a with p-tolylboronic
acid was conducted under the influence of
C–H Arylation
C–H Arylation
(Ortho Position)
Ar–X
Ar–X
Multi-arylated
Products
(Ortho Position)
Pd(OAc)2/phen/TEMPO/LiBF4 (Method F) to furnish the
corresponding 2,4-diarylthiazole 10ab in 75% yield with >95%
regioselectivity (1.51 g). Finally, the C–H arylation of 10ab at the
40 C5-position with aryl iodide in the presence of
PdCl2(bipy)/Ag2CO3 catalyst (Method G) gave triarylthiazole
13abh in 92% yield (1.50 g).
H
Ar
Ar
Ar
H
N
N
Ar–X
Ar
Ar
S
Ar
S
Ar
C–H Arylation
(Ortho Position)
C4-Arylation
Scheme 7 Gram-scale synthesis of triarylthiazole by sequential C–H
45 arylations.
When the reaction conditions of C5-selective C–H arylation of
15 2-arylthiazoles were optimized (see Table 4), the best results were
obtained using our previous conditions for palladium catalysis,
PdCl2(bipy)/Ag2CO3 in 1,4-dioxane (Method G).7q We were
pleased to find that a wide range of 2,4-diarylthiazoles 10 and
10 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 11 of 13
Chemical Science
20 Conclusions
Me
B(OH)2
(3.0 equiv)
[Method F]
Pd(OAc)2 (10 mol%)
phen (10 mol%)
TEMPO (0.5 equiv)
LiBF4 (1.5 equiv)
In summary, we have developed a programmeVdieswyAnrtthicelesiOsnloinfe
DOI: 10.1039/C3SC52199K
all substitution patterns of arylthiazoles (2-aryl, 4-aryl, 5-aryl,
I
(1.0 equiv)
2,4-diaryl, 2,5-diaryl, 4,5-diaryl, and 2,4,5-triaryl) via sequential
C–H coupling. Representative reaction conditions are
25 summarized in Scheme 8. Noteworthy features of our method are:
(i) the synthetic expediency in introducing aryl groups by step-
economical, direct C–H arylation, (ii) all aryl groups assembled
stem from readily available aryl halides or arylboronic acids, (iii)
the aryl-group-installation at the desired position can be achieved
30 by the choice of catalytic systems, and (iv) the possibility of
synthesizing all substitution patterns of arylthiazoles by 11
distinct pathways. Using this protocol, we have accomplished the
synthesis of over 150 different arylthiazoles, among which exists
fatostatin, known as a SREBP inhibitor. This method can be
35 applied to a gram-scale synthesis of triarylthiazoles. Testing the
biological activity of the generated library of arylthiazoles for
agrochemical and pharmaceutical research is now the focus of
our ongoing efforts.
[Method A]
Pd(OAc)2 (5 mol%)
CuI (2.0 equiv)
H
N
N
H
S
DMF
DMAc, air
100 ˚C, 48 h
[75% yield]
gram scale: 1.51g
C4-Selective
S
140 ˚C, 40 h
[72% yield]
gram scale:1.38 g
C2-Selective
1 (1.5 equiv)
3a
O
O
I
Me
Me
(1.5 equiv)
[Method G]
PdCl2·bipy (5 mol%)
Ag2CO3 (1.0 equiv)
N
N
O
O
H
1,4-dioxane
120 ˚C, 22 h
[92% yield]
gram scale: 1.50g
C5-Selective
S
S
13abh
10ab
We first selected two representative catalyst systems [our own
conditions (Method G)7q and Murai’s conditions (Method H)8d]
for the C–H arylation of 4,5-diarylthiazoles to provide
triarylthiazoles 13 (Table 12). The coupling of 4,5-
diphenylthiazole (12aa) with iodobenzene (2) under these two
conditions gave an identical yield (66% yield) of the desired
triphenylthiazole (13aaa). However, the starting material 12aa
Supporting Information Available
5
40 Detailed experimental procedures and spectral data for all
compounds, including scanned image of 1H and 13C NMR
spectra. This material is available free of charge via the Internet at
http://www.rsc.org.
10 still remained under Murai’s conditions, whereas 12aa was
consumed using our protocol. After some modification of Murai’s
conditions with respect to the equivalents of base and
iodobenzene (Method H’’), the yield of 13aaa was increased to
85% (isolated yield). When the same reaction was performed
15 under Greaney’s conditions (Method I),7h 13aaa was obtained in
95% yield. These two different conditions for the C–H arylation
of 12aa led to an extension of the reaction scope with respect to
the 4,5-diarylthiazoles and aryl halide substrates (Table 12).
Acknowledgment
45 This work was supported by the Funding Program for Next
Generation World-Leading Researchers from JSPS (220GR049 to
K.I.), and Grants-in-Aid for Scientific Research on Innovative
Areas “Molecular Activation Directed toward Straightforward
Synthesis” (25105720 to J.Y.) and KAKENHI (25708005 to J.Y.)
50 from MEXT. ITbM is supported by the World Premier
International Research Center (WPI) Initiative, Japan.
Table 12 Synthesis of triarylthiazoles by C2-arylation of 4,5-diarylthiazoles.
[Method I]
PdCl2(dppf)·CH2Cl2 (5 mol%)
[Method H'']
[Pd(phen)2](PF6)2 (5 mol%)
Cs2CO3 (1.0 equiv)
PPh3 (10 mol%)
Ag2CO3 (2.0 equiv)
Ar
Ar
Ar
N
N
N
Ar
Ar
I
I
Ar
Ar
Ar
H
H
water
100 ˚C, 24 h
S
Ar
DMAc
140 ˚C, 40 h
S
S
13
12
2
12
2
Cl
Products
N
N
N
N
N
S
S
S
S
S
Me
OMe
Me
OMe
OMe
13aaa: 95% [Method H"]
13baa: 76% [Method H"]
13gaa: 68% [Method H"]
13gja: 90% [Method I]
MeO
13gab: 79% [Method H"]
MeO
N
N
S
N
S
N
S
N
S
O
S
Me
Me
O
CF3
CF3
Cl
Cl
13haa: 63% [Method I]
13jaa: 58% [Method H"]
13jgb: 46% [Method I]
13kgb: 80% [Method H"]
13kaa: 80% [Method H"]
Cl
Me
N
N
N
S
N
S
N
S
N
S
S
N
MeO
Me
CO2Me
CO2Me
COMe
N
13naa: 45% [Method I]
13nbg: 87% [Method I]
13oab: 82% [Method I]
13uaa: 53% [Method H"]
13vja: 86% [Method I]
a
Reaction conditions. Method H’’: 12 (0.2 mmol), 2 (0.3 mmol), Pd(phen)2(PF6)2 (0.01 mmol), Cs2CO3 (0.20 mmol), DMAc (0.8 mL), 140 °C, 40 h.
Method I: 12 (0.125–0.15 mmol), 2 (0.15–0.18 mmol), PdCl2(dppf)·CH2Cl2 (5 mol%), Ph3P (10 mol%), Ag2CO3 (0.25–0.3 mmol), water (1.0 mL),
100 °C, 24 h.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 11

Chemical Science
Page 12 of 13
Scheme 8 Programmed synthesis of all substitution patterns of thiazoles.
View Article Online
DOI: 10.1039/C3SC52199K
2
(a) A. Hantzsch, Justus Liebigs Ann. Chem., 1889, 250, 257; (b)
H. Erlenmeyer, Helv. Chim. Acta., 1945, 28, 924.
3
For selected recent examples, see: (a) R. Marbet, H. Scheukel, P.
W. Sheldrake, M. Matteucci and E. McDonald, Synlett, 2006,
460; (b) Y. Ishiwata and H. Togo, Synlett, 2008, 2637; (c) J. F.
Sanz-Cervera, R. Blasco, J. Piera, M. Cynamon, I. Ibáñez, M.
Murguía and S. Fustero, J. Org. Chem., 2009, 74, 8988; (d) G.
S. Lingaraju, T. R. Swaroop, A.C. Vinayaka, K. S. S. Kumar, M.
P. Sadashiva, and K. S. Rangappa, Synthesis, 2012, 1373.
Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; A. de
Meijere and F. Diederich, Eds.; Wiley-VCH: Weinheim, 2004;
(b) Topics in Current Chemistry, Vol. 219, Cross-Coupling
Reactions: A Practical Guide; N. Miyaura, Ed.; Springer:
Berlin, 2002; (c) K. C. Nicolaou, P. G. Bulger and D. Sarlah,
Angew. Chem., Int. Ed., 2005, 44, 4442.
For selected examples, see: (a) D. Guianvarc’h, J.-L. Fourrey, R.
Maurisse, J.-S. Sun and R. Benhida, Org. Lett., 2002, 4, 4209;
(b) G. A. Molander and B. Biolatto, J. Org. Chem., 2003, 68,
4302; (c) E. L. Stangeland and T. Sammakia, J. Org. Chem.,
2004, 69, 2381; (d) B. H. Lipshutz, B. Frieman and H.
Birkedal, Org. Lett., 2004, 6, 2305; (e) P. Vachal and L. M. Toth,
Tetrahedron Lett., 2004, 45, 7157; (f) P. Stanetty, M. Schnürch
and M. D. Mihovilovic, J. Org. Chem., 2006, 71, 3754.
Recent reviews on catalytic C–H arylation, see: (a) D. Alberico,
M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174; (b) F.
Kakiuchi and T. Kochi, Synthesis, 2008, 3013; (c) L.
Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem., Int.
Ed., 2009, 48, 9792; (d) X. Chen, K. M. Engle, D.-H. Wang and
J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (e) T. Satoh
and M. Miura, Synthesis, 2010, 3395; (g) J. Bouffard and K.
Itami, Top. Curr. Chem., 2010, 292, 231; (h) J. Yamaguchi, A.
D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51,
Notes and References
a
35
40
45
50
55
60
Department of Chemistry, Graduate School of Science, Nagoya
University, Chikusa, Nagoya 464-8602, Japan. Fax: (+81)52-788-6098
5 E-mail: itami.kenichiro@a.mbox.nagoya-u.ac.jp
b
Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya
University, Chikusa, Nagoya 464-8602, Japan
4
† Electronic Supplementary Information (ESI) available: experimental
10 procedures, characterization of data for all new compounds, details of
modification of reaction conditions.
1 (a) S. Miwatashi, Y. Arikawa, E. Kotani, M. Miyamoto, K. Naruo,
H. Kimura, T. Tanaka, S. Asahi and S. Ohkawa, J. Med. Chem.,
5
15
20
25
30
2005, 48, 5966; (b) Y. Choi, Y. Kawazoe, K. Murakami, H.
Misawa and M. Uesugi, J. Biol. Chem., 2003, 278, 7320; (c) J.
Lee, S. J. Kim, H. Choi, Y. H. Kim, I. T. Lim, H. Yang, C. S.
Lee, H. R. Kang, S. K. Ahn, S. K. Moon, D.-H. Kim, S. Lee, N.
S. Choi and K. J. Lee, J. Med. Chem., 2010, 53, 6337; (d) T.
Suzuki, S. Hisakawa, Y. Itoh, N. Suzuki, K. Takahashi, M.
Kawahata, K. Yamaguchi, H. Nakagawa and N. Miyata, Bioorg,
Med. Chem. Lett., 2007, 17, 4208; (e) M.S. Alam, L. Liu, Y.-E.
Lee and D.-U. Lee, Chem. Pharm. Bull., 2011, 59, 568; (f) D.
Zwilling, S.-Y. Huang, K. V. Sathyasaikumar, F. M.
Notarangelo, P. Guidetti, H.-Q. Wu, J. Lee, J. Truong, Y.
Andrews-Zwilling, E. W. Hsieh, J. Y. Louie, T. Wu, K. Scearce-
Levie, C. Patrick, A. Adame, F. Giorgini, S. Moussaoui, G.
Laue, A. Rassoulpour, G. Flik, Y. Huang, J. M. Muchowski, E.
Masliah, R. Schwarcz and P. J. Muchowski, Cell, 2011, 145,
863.
6
12 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 13 of 13
Chemical Science
8960; (i) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5,
S. I. Gorelsky and K. Fagnou, J. Org. Chem., 2010, 75, 1047.
369.
16 M. Steinmetz, K. Ueda, S. Grimme, J. Yamaguchi, S. Kirchberg,
7
For selected examples of C2 or C5 selective arylation of
thiazoles, see: (a) Y. Aoyagi, A. Inoue, I. Koizumi, R. 75 17 See the Supporting Information for the details and further
K. Itami and A. Studer, Chem. Asian J., 2012, 7, 1256.
View Article Online
DOI: 10.1039/C3SC52199K
5
Hashimoto, K. Tokunaga, K. Gohma. J. Komatsu, K. Sekine, A.
Miyafuji, J. Kunoh, R. Honma, Y. Akita and A. Ohta,
Heterocycles, 1992, 33, 257; (b) S. Pivsa-Art, T. Satoh, Y.
Kawamura, M. Miura and M. Nomura, Bull. Chem. Soc. Jpn.,
1998, 71, 467; (c) Y. Kondo, T. Komine and T. Sakamoto, Org.
Lett., 2000, 2, 3111; (d) A. Mori, A. Sekiguchi, K. Masui, T.
Shimada, M. Horie, K. Osakada, M. Kawamoto and T. Ikeda, J.
Am. Chem. Soc., 2003, 125, 1700; (e) K. Masui, A. Mori, K.
Okano, K. Takamura, M. Kinoshita and T. Ikeda, Org. Lett.,
2004, 6, 2011; (f) M. Parisien, D. Valette and K. Fagnou, J. Org.
Chem., 2005, 70, 7578; (g) F. Bellina, S. Cauteruccio and R.
Rossi, Eur. J. Org. Chem., 2006, 1379; (h) G. L. Turner, J. A.
Morris and M. F. Greaney, Angew. Chem., Int. Ed., 2007, 46,
7996; (i) H. A. Chiong and O. Daugulis, Org. Lett., 2007, 9,
1449; (j) T. Martin, C. Verrier, C. Hoarau and F. Marsais, Org.
Lett., 2008, 10, 2909; (k) J. Canivet, J. Yamaguchi, I. Ban and
K. Itami, Org. Lett., 2009, 11, 1733; (l) J. Roger, F. Požgan and
H. Doucet J. Org. Chem., 2009, 74, 1179; (m) B. Liégault, D.
Lapointe, L. Caron, A. Vlassova and K. Fagnou, J. Org. Chem.,
2009, 74, 1826; (n) S. Tamba, Y. Okubo, S. Tanaka, D.
Monguchi and A. Mori, J. Org. Chem., 2010, 75, 6998; (o) H.
Hachiya, K. Hirano, T. Satoh and M. Miura, Angew. Chem., Int.
Ed., 2010, 49, 2202; (p) D. Lapointe, T. Markiewicz, C. J.
Whipp, A. Toderian and K. Fagnou, J. Org. Chem., 2011, 76,
749; (q) S. Yanagisawa and K. Itami, Tetrahedron, 2011, 67,
4425; (r) T. Yamamoto, K. Muto, M. Komiyama, J. Canivet, J.
Yamaguchi and K. Itami, Chem.–Eur. J., 2011, 17, 10113; (s) K.
Muto, J. Yamaguchi and K. Itami, J. Am. Chem. Soc., 2012, 134,
169; (t) K. Amaike, K. Muto, J. Yamaguchi and K. Itami, J. Am.
Chem. Soc., 2012, 134, 13573.
screening of conditions.
18 H. Furukawa, S. Matsumura, A. Sugie, D. Monguchi and A.
Mori, Heterocycles, 2009, 79, 303.
19 S. Kamisuki, Q. Mao, L. Abu-Elheiga, Z. Gu, A. Kugimiya, Y.
Kwon, T. Shinohara, Y. Kawazoe, S. Sato, K. Asakura, H.-Y. P.
Choo, J. Sakai, S. J. Wakil and M. Uesugi, Chem. Biol., 2009,
16, 882.
80
10
15
20
25
30
20 D. L. Comins and N. B. Mantlo, J. Org. Chem., 1985, 50, 4410.
35
40
45
50
55
8
C–H diarylation of thiazole on C2 and C5 positions, (a) Ref. 7b.
(b) A. Yokooji, T. Okazawa, T. Satoh, M. Miura and M.
Nomura, Tetrahedron, 2003, 59, 5685; (c) H.-Q. Do, R. M. K.
Khan and O. Daugulis, J. Am. Chem. Soc., 2008, 130, 15185;
(d) F. Shibahara, E. Yamaguchi and T. Murai, J. Org. Chem.,
2011, 76, 2680; (e) F. Shibahara, T. Yamauchi, E. Yamaguchi
and T. Murai, J. Org. Chem., 2012, 77, 8815.
9
S. Kirchberg, S. Tani, K. Ueda, J. Yamaguchi, A. Studer and K.
Itami, Angew. Chem., Int. Ed., 2011, 50, 2387..
10 For a review on platform synthesis, see: (a) K. Itami and J.
Yoshida, Chem.–Eur. J., 2006, 12, 3966; Multisubstituted
olefins: (b) K. Itami, T. Nokami, Y. Ishimura, K. Mitsudo, T.
Kamei and J. Yoshida, J. Am. Chem. Soc., 2001, 123, 11577; (c)
K. Itami, T. Kamei and J. Yoshida, J. Am. Chem. Soc., 2003,
125, 14670; (d) K. Itami, M. Mineno, N. Muraoka and J.
Yoshida, J. Am. Chem. Soc., 2004, 126, 11778; (e) K. Itami, Y.
Ohashi and J. Yoshida, J. Org. Chem., 2005, 70, 2778; (f) K.
Tonogaki, K. Itami and J. Yoshida, J. Am. Chem. Soc., 2006,
128, 1464; Multisubstituted heteroarenes: (g) K. Itami, D.
Yamazaki and J. Yoshida, J. Am. Chem. Soc., 2004, 126, 15396;
(h) S. Yanagisawa, K. Ueda, H. Sekizawa and K. Itami, J. Am.
Chem. Soc., 2009, 131, 14622.
11 (a) L.-C. Campeau, M. Bertrand-Laperle, J.-P. Leclerc, E.
Villemure, S. Gorelsky and K. Fagnou, J. Am. Chem. Soc.,
2008, 130, 3276; (b) See ref 8d.
60 12 T. Okazawa, T. Satoh, M. Miura and M. Nomura, J. Am. Chem.
Soc., 2002, 124, 5286.
13 Multiple C–H arylation of heteroarenes to install all different
aryl group, see; (a) Ref 10h. (b) L.-C. Campeau, D. R. Stuart, J.-
P. Leclerc, M. Bertrand-Laperle, E. Villemure, H.-Y. Sun, S.
65
Lasserre, N. Guimond, M. Lecavallier and K. Fagnou, J. Am.
Chem. Soc., 2009, 131, 3291; (c) R. Goikhman, T. L. Jacques
and D. Sames, J. Am. Chem. Soc., 2009, 131, 3042.
14 N. Chatani, T. Fukuyama, H. Tatamidani, F. Kakiuchi and S.
Murai, J. Org. Chem., 2000, 65, 4039.
70 15 (a) J. Hämmerle, M. Spina, M. Schnürch, M. D. Mihovilovic
and P. Stanetty, Synthesis, 2008, 3099; (b) B. Liégault, I. Petrov,
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 13