Palladium-catalyzed arylation at C-H and C-C bonds of masked thiazole derivatives

Article abstract of DOI:10.3987/COM-08-S(D)3

The differently substituted 2,5-diarylthiazole derivatives are synthesized via palladium catalyzed sequential C-H arylation at the 5-position and C-C bond activation at the 2-positon with masked thiazole.

Full text of DOI:10.3987/COM-08-S(D)3

HETEROCYCLES, Vol. 79, 2009
303
HETEROCYCLES, Vol. 79, 2009, pp. 303 - 309. © The Japan Institute of Heterocyclic Chemistry
Received, 7th, July 2008, Accepted, 1st August, 2008, Published online, 4th August, 2008.
DOI: 10.3987/COM-08-S(D)3
PALLADIUM-CATALYZED ARYLATION AT C-H AND C-C BONDS OF
MASKED THIAZOLE DERIVATIVES‡
Hirotoshi Furukawa, Suguru Matsumura, Atsushi Sugie, Daiki Monguchi,
and Atsunori Mori*
Department of Chemical Science and Engineering, Kobe University, 1‒1
Rokkodai, Nada, Kobe 657-8501, Japan
E-mail: amori@kobe-u.ac.jp
‡To the memory of Dr. John Daly.
Abstract – The differently substituted 2,5-diarylthiazole derivatives are
synthesized via palladium catalyzed sequential C–H arylation at the 5-position
and C–C bond activation at the 2-positon with masked thiazole.
Since 2,5-diarylated thiazoles show remarkable characteristics in photoluminescence, liquid crystal, and
electrochemical redox, development of synthetic protocols for 2,5-diarylthiazoles is our major concern.1
The cross-coupling methodology with a transition metal catalyst is a tool for the introduction of a
substituent into the thiazole ring.2 In particular, direct coupling of a thiazole derivative at the
carbon–hydrogen bond by the catalysis of palladium is one of the practical way to introduce aryl and
alkenyl groups via the carbon–carbon bond formation.3,4 We have reported that the C–H bond at the 2-
and 5-positions of thiazole is efficiently substituted by various aryl groups with a palladium catalyst.5
Meanwhile, catalytic reactions via the cleavage of a C–C bond, in which a tertiary alcohol serves as a
masked group of the corresponding C–H bond, have attracted much attention as a new class of transition
metal-catalyzed carbon–carbon bond formation, and various catalytic processes involving different modes
to activate the relatively inert bond have been developed.6,7 Our concern has thus focused on the use of
such a reaction to the functionalization of thiazole derivatives. We herein describe that a new synthetic
route to introduce an aryl moiety into thiazole at the 5-position and the 2-position with a thiazole
derivative masked by a tertiary alcohol 1 via the C–H bond arylation and the arylation through C–C bond
activation as shown in Scheme 1.

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HETEROCYCLES, Vol. 79, 2009
CC bond activation
Ph
OH
Ph
N
N
N
Aryl1-I
Ph
OH
Ph
Aryl2-I
Aryl1
Aryl1
Aryl2
S
S
S
1
3
4
CH arylation
Scheme 1.
i
The masked thiazole 1 was prepared by the reaction of 2-bromothiazole with PrMgBr to form the
intermediate Grignard reagent8 and following addition of benzophenone to afford the corresponding
tertiary alcohol 1 in 68% yield. (Scheme 2)
N
N
iPrMgBr
Ph2CO
1 (68%)
Br
MgBr
S
S
Scheme 2.
C–H arylation at the 5-position was first examined with masked thiazole 1 and an aryl iodide in the
presence of a palladium catalyst and silver(I) nitrate/potassium fluoride as an activating agent. It was
found to undergo the reaction affording the 5-arylated product. The reaction proceeded under similar
conditions to those of 2-arylthiazole with an aryl iodide despite the presence of a hydroxy group in the
molecule. Formation of the C–C bond at the 5-position of thiazole was found to occur.5b Accordingly, the
masked thiazole serves as a protective group in the palladium-catalyzed reaction. The reaction with other
aryl iodides was examined as shown in Table 1. Iodobenzene and aryl iodides bearing an
electron-donating substituent at the 4-position afforded 3 in 39-51% yields (entries 1-3). On the other
hand, iodides bearing an electron-withdrawing substituent CF3 (82%, entry 4) or CO2Et (quant, entry 5)
resulted in excellent yields.
Deprotection of the masked group was found to take place by treatment of 3e with Cs2CO3 under reflux in
xylene to afford the corresponding 5-arylated thiazole in a quantitative yield. (Scheme 3) Since few
example on regioselective arylation at the 5-position of unsubstituted thiazole is reported,3b,3k the method
would be a practical surrogate for the direct 5-arylation.5b
N
N
Ph
OH
Ph
Cs2CO3
EtO2C
EtO2C
H
xylene, reflux, 62 h
S
S
3e
5
(quant)
Scheme 3.

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305
Table 1. Reaction with C–H arylation at the 5-position of 1a
N
N
Ph
OH
Ph
Ph
OH
Ph
PdCl2(PPh3)2, AgNO3, KF
DMSO
+ Aryl1-I
Aryl1
S
S
3
1
Entry Aryl1–I
Product
Yield (%)
1
2
3
4
5
C6H5I (2a)
4-MeOC6H4I (2b)
3a
39
40
3b
3c
3d
3e
4-MeC6H4I (2c)
51
4-CF3C6H4I (2d)
4-EtOCOC6H4I (2e)
82
quant
a The reaction was carried out with 1 (0.5 mmol) and 2 (0.6 mmol)
in the presence of 5 mol% of PdCl2(PPh3)2, AgNO3 (0.6 mmol) and
KF (1.0 mmol) in DMSO (3 mL) at 100 ºC for 5 h.
We then carried out the palladium-catalyzed reaction at the 2-position through the C–C bond activation in
the presence of Cs2CO3 to undergo the 2-arylation (Table 2). The reaction of 3e with various aryl halides
2 (Cl, Br, and I) was employed for the reaction to obtain 4a to bring about similar yields (entry 1-3). It
should be pointed out that aryl bromides and chlorides reacted similarly to aryl iodides when a bulky
phosphine was employed as a ligand of palladium catalyst.7f,10 The masked thiazole bearing a
electron-withdrawing substituent was found to undergo the reaction smoothly. Indeed, the reaction of 3e
proceeded with both electron-rich iodides 2a,b and those having an electron-withdrawing substituent 2d-e
to give 4a-d. The reaction of 3b, which possesses electron-enriched aryl group as a substituent at the
5-position, with electron-deficient aryl iodide 2e proceeded in a good yield (entry 7), while the reaction of
electron-enriched 2b resulted in a poor yield (entry 8).
With differently substituted 2,5-diarylthiazole 4b and 4e in hand, we then compared characteristics of
these isomers. Figure 1 shows fluorescence spectra of the obtained 2,5-diarylthiazoles. Both compounds
showed photoluminescence. The quantum yield of 4e was found to be Φ = 0.56, which was ca. twice
higher than that of 4b (Φ = 0.24).

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Table 2. Reaction at the 2-position through the C–C bond activation of 3 with aryl halide 2
Pd(OAc)2,
P(biphenylene-2-yl)(tBu)2,
N
N
Cs2CO3
Ph
OH
Ph
Aryl2-X
Aryl1
+
Aryl1
Aryl2
S
xylene
S
3
4
Entry
3
Aryl2-X
Product
4a
Time (h)
Yield (%)
49a
1
2
3
4
5
6
7
8
3e
3e
3e
3e
3e
3e
3b
3b
C6H5Cl (2f)
C6H5Br (2g)
C6H5I (2a)
33
11
11
22
15
80
60
12
4a
66a
4a
55a
4-MeOC6H4I (2b)
4b
61a
4-CF3C6H4I (2d)
4c
45b
4-EtOCOC6H4I (2e)
4d
48b
2e
4e
54a
2b
4f
15a
a The reaction was carried out with 3 (0.1 mmol) and 2 (0.12 mmol) in the presence of 5
mol% of Pd(OAc)2, 10 mol% of P(biphenylene-2-yl)(tBu)2 and Cs2CO3 in xylene (1.6
mL) at 150 ºC. b CuI (10 mol%) was used as a cocatalyst. PPh3 was employed in place
of P(biphenylene-2-yl)(tBu)2.
140
N
MeO
CO2Et
OMe
120
100
80
60
40
20
0
S
4e
4e
(Φ = 0.56)
N
EtO2C
S
4b
4b (Φ = 0.24)
350
400
450
500
Wavelength [nm]
550
600
650
Figure 1. Fluorescence spectra of 4b and 4e as 1 × 10-5 and 1 × 10-6 M solutions of chloroform,
respectively.
In summary, we showed that palladium-catalyzed arylation reactions of masked thiazole took place at the
C-H bond of the 5-position of thiazole and at the C–C bond of the 2-position. The masked group was
found to serve as a functional group to promote C–C bond formation via C–C bond activation at the
2-position of thiazole, as well as a protective group in the 5-arylation reaction with a palladium catalyst

HETEROCYCLES, Vol. 79, 2009
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and a silver salt. The protocols allow the introduction of the substituent in an opposite order, which reacts
at the 5-position and then at the 2-position, to our conventional 2-arylation and the following 5-arylation
sequence.10
ACKNOWLEDGEMENT
This work was partially supported by a Grant-in-Aid for Scientific Research on Priority Areas,
"Advanced Molecular Transformation of Carbon Resources" by Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
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10. Arylation of 3e at the 2-position through the C–C bond activation with 2e (Table 2, Entry 6) To
a 25 mL Schlenk tube equipped with a magnetic stirring bar were added Cs2CO3 (39.1 mg, 0.12
mmol), Pd(OAc)2 (1.42 mg, 0.005 mmol), P(biphenylene-2-yl)(tBu)2 (2.98 mg, 0.01 mmol), xylene
(1.6 mL), ethyl 4-iodobenzoate 2e (33 mg, 20 µL, 0.12 mmol), and 3e (41.6 mg, 0.1 mmol). The
reaction mixture was stirred at 150 oC under N2 atmosphere for 80 h. After cooling to rt, the mixture
was poured onto saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layer
was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced
pressure to leave a crude solid, which was purified by chromatography on silica gel to afford 18.3 mg
of 4d (48%).5a