Palladium-catalyzed direct oxidative alkenylation of azoles

Article abstract of DOI:10.1021/jo101214y

(Figure presented) The direct heteroaromatic sp² C-H alkenylation of 2-substituted azole compounds with alkenes proceeds in the presence of Pd(OAc)₂ and AgOAc as catalyst and oxidant, respectively, to afford the corresponding 5-alken

Full text of DOI:10.1021/jo101214y

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complexity in various arenes and heteroarenes.2 For exam-
Palladium-Catalyzed Direct Oxidative Alkenylation
of Azoles
ple, the reactions of six-membered arenes having a directing
group3 such as benzoic acid, anilide, or benzylamine and
electron-rich heteroarenes4 including indole, thiophene, furan,
and indolizine have been developed. Previously, we also
reported the palladium-catalyzed direct site-selective alke-
nylation of thiophenes and furans as well as heteroarenecar-
boxylic acids with concomitant decarboxylation.5 In addi-
tion, the direct alkenylation of unactivated electron-deficient
arenes like pyridine N-oxide and perfluoroarene has been
achieved.6 However, less attention has so far been focused on
azoles, which are useful heteroaromatic cores in pharma-
ceutical and material chemistry.7 Most direct alkenylations
of azoles still rely on use of the corresponding alkenyl
halides8 due to the problematic homocoupling under the
oxidative conditions.9 Herein, we report a palladium-based
catalyst system for the direct C-H alkenylation of azoles
with a number of alkenes.
Mitsuru Miyasaka, Koji Hirano, Tetsuya Satoh, and
Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan
miura@chem.eng.osaka-u.ac.jp
Received June 22, 2010
As an initial attempt, treatment of isobutylthiazole (1a)
with n-butyl acrylate (2a) in the presence of 10 mol % of
Pd(OAc)2 and 3.0 equiv of AgOAc as an oxidant in mesity-
lene (2.5 mL) at 120 °C for 8 h afforded the corresponding
5-alkenylated product 3aa albeit in 29% yield (Table 1, entry 1).
While an acidic additive, PivOH, was found to accelerate the
direct alkenylation, a small but significant amount of alke-
nylated mesitylene was also detected as byproduct (entry 2).
Thus, nonaromatic solvents were tested. Aprotic polar sol-
vents such as DMAc and DMSO were ineffective (entries 3
and 4). On the other hand, the reaction in PivOH itself gave
3aa in high yield, and no byproduct was formed (entry 5).
EtCOOH further improved the yield of 3aa (entry 6). The
use of Cu(OAc)2 in place of AgOAc or lower temperature
decreased the reaction efficiency (entries 7 and 8). The lower
catalyst loading had no negative influence on the yield (entry 9).
With the effective reaction conditions in hand (Table 1,
entry 9), a variety of alkenes were tested for the direct
alkenylation of 1a (Table 2). Acrylate esters bearing bulky
The direct heteroaromatic sp2 C-H alkenylation of
2-substituted azole compounds with alkenes proceeds in
the presence of Pd(OAc)2 and AgOAc as catalyst and
oxidant, respectively, to afford the corresponding 5-alke-
nylated azoles in good yields.
Transition-metal-catalyzed direct C-C bond-forming
reactions via C-H bond cleavage have attracted much
attention in modern organic synthesis because they require
no prefunctionalization step of the starting materials and
provide a potentially more efficient alternative to the con-
ventional methodologies using organic halides and organo-
metallic reagents.1 In particular, the palladium-catalyzed
oxidative cross-coupling of arenes and alkenes via C-H
bond cleavage of both the substances, the so-called Fujiwara-
Moritani reaction, is quite attractive from the viewpoint of
step economy and enables a rapid increase of molecular
(4) (a) Fujiwara, Y.; Maruyama, O.; Yoshidomi, M.; Taniguchi, H.
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Y. Org. Lett. 1999, 1, 2097. (c) Capito, E.; Brown, J. M.; Ricci, A. Chem.
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Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125. (e) Beck, E. M.;
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(7) There are only two precedents for the direct alkenylation of pyrazole
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A.; Guillaumet, G. Synthesis 2009, 271.
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F.; Grierson, D. S. Org. Lett. 2008, 10, 4029.
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(b) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200. (c) Beccalli, E. M.;
Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318.
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(b) Karimi, B.; Behzadnia, H.; Elhamifar, D.; Akhavan, P. F.; Esfahani,
F. K.; Zamani, A. Synthesis 2010, 1399.
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Chem. 1998, 63, 5211. (b) Boele, M. D. K.; van Strijdonck, G. P. J.; de Vries,
A. M. H.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am.
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DOI: 10.1021/jo101214y
r
Published on Web 07/13/2010
J. Org. Chem. 2010, 75, 5421–5424 5421
2010 American Chemical Society

Miyasaka et al.
JOCNote
TABLE 1. Optimization for Palladium-Catalyzed Reaction of 2-Isobutyl-
TABLE 3. Palladium-Catalyzed Alkenylation of Various Thiazoles 1
thiazole (1a) with n-Butyl Acrylate (2a)a
with n-Butyl Acrylate (2a)a
entry
oxidant
additive
solvent
temp (°C) 3aa, yieldb (%)
1
2
3
4
5
6
7
8
9c
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Cu(OAc)2
AgOAc
AgOAc
mesitylene
120
120
120
120
120
120
120
90
(29)
(88)
(15)
(49)
(88)
(93)
(54)
(30)
(93) 88
PivOH mesitylene
PivOH DMSO
PivOH DMAc
PivOH
EtCOOH
EtCOOH
EtCOOH
EtCOOH
120
aA mixture of 1a (0.2 mol), 2a (0.4 mmol), Pd(OAc)2 (0.02 mmol),
additive (0.2 mmol), and oxidant (0.6 mmol) was stirred in solvent (1 mL)
for 8 h. bGC yield is in parentheses. cPd(OAc)2 (0.01 mmol) was used.
TABLE 2. Palladium-Catalyzed Alkenylation of 2-Isobutylthiazole (1a)
with Various Alkenes 2a
aA mixture of 1 (0.50 mmol), 2a (1.0 mmol), Pd(OAc)2 (0.05 mmol),
and AgOAc (1.5 mmol) was stirred in EtCOOH (2.5 mL) at 120 °C for 8
h. Key: 1b, R = Me, R0 = H; 1c, R = nBu2COH, R0 = H; 1d, R = MeO,
R0 = H; 1e, R = MeS, R0 = H; 1f, R = NnBuAc, R0 = H; 1g, R = Ph,
R0 = H; 1h, R = 2,6-Me2C6H3, R0 = H; 1i, R = Ph, R0 = Me; 1j, R,
R0 = Me.
employed for the oxidative coupling. Not only simple styrene
(2e) but also electron-rich and -deficient styrenes 2f and 2g
reacted with 1a smoothly to furnish 3ae-ag in good yields.
Interestingly, methacrylate ester 2h provided the unconjugated
(to azole) product 3ah as the major product (3ah/3ah0 = 4.2:1).
In contrast, internal or aliphatic alkenes such as methyl cinna-
mate and 1-hexene gave the corresponding coupled products in
low yields (ca. <10% by GC-MS).
The oxidative coupling reaction was further extended to
various thiazoles 1 as shown in Table 3. A smaller methyl-
substituted thiazole 1b also afforded the desired product 3ba
in 80% yield. Thiazole having a free hydroxyl group 1c
reacted with 2a without any difficulties. Moreover, thiazoles
bearing heteroatom substituents at the 2-position 1d-fgave 3da,
3ea, and 3fa in moderate to good yields. On the other hand,
2-phenylthiazole showed less activity toward the reaction. This is
probably because of the catalyst deactivation arising from a
competitive cyclopalladation on benzene ring.10 Therefore, we
tested 2-(2,6-dimethylphenyl)thiazole (1h) as the reactant to
suppress the unfavorable palladation mentioned above. As
aA mixture of 1a (0.50 mmol), 2 (1.0 mmol), Pd(OAc)2 (0.025 mmol),
and AgOAc (1.5 mmol) was stirred in EtCOOH (2.5 mL) at 120 °C for
8 h. Key: 2a, R = COOnBu; 2b, R = COOtBu; 2c, R = COOPh; 2d, R =
CONMe2; 2e, R = Ph; 2f, R = 4-MeOC6H4; 2g, R = 4-FC6H4. bButyl
methacrylate (2h) was used as alkene.
tert-butyl 2b and aromatic phenyl groups 2c resulted in the
formation of 3ab and 3ac in 62% and 81% yields, respectively.
Acrylamide 2d showed a similar reactivity. Styrenes also could be
(10) Hiraki, K.; Fuchita, Y.; Takakura, S. J. Organomet. Chem. 1981,
210, 273.
5422 J. Org. Chem. Vol. 75, No. 15, 2010

Miyasaka et al.
JOCNote
TABLE 4. Palladium-Catalyzed Alkenylation of Oxazoles 4 with
Alkenes 2a
SCHEME 2. Synthesis of 2,5-Dialkenylthiazoles 10
alkenylated thiazole 3bb was first prepared by our palladium-
catalyzed direct alkenylation of 2-methylthiazole (1b). The
deprotonation of 3bb with LDA at -78 °CinTHFandaddition
of the resultant lithium reagent to aromatic aldehydes at room
temperature gave aldol-type products 9a-d. Finally, we ob-
tained the desired 2,5-dialkenylthiazoles 10 by dehydration of 9
upon treatment with mesyl chloride and triethylamine.
aA mixture of 4 (0.50 mmol), 2 (1.0 mmol), Pd(OAc)2 (0.05 mmol),
and AgOAc (1.5 mmol) was stirred in EtCOOH (2.5 mL) at 120 °C for
8 h. Key: 4a, R1 = Ph, R2 = H; 4b, R1, R2 = Me.
SCHEME 1. Palladium-Catalyzed Alkenylation of 4,5-Dimethyl-
thiazole (6) with 2d
expected, 1h could be transformed to 3ha in 71% yield. Notably,
the introduction of a methyl group to the 4-position of thiazole
significantly accelerated the reaction despite the presence of a
phenyl substituent at the 2-position (3ja).11 Furthermore, the
coupling of 2,4-dimethylthiazole (1j) proceeded smoothly under
the standard conditions.
2-Substituted oxazoles instead of thiazoles 1 were also
available for use (Table 4). Interestingly, 2-phenyloxazole
(4a) gave 5-alkenyled product 5aa in 69% yield, which is in
marked contrast to the trend of thiazole (Table 2, 3ga). 2,4-
Dimethyloxazole (4b) also reacted with 2a and 2e smoothly
to afford excellent yields of 5ba and 5be, respectively.
Next, we attempted the direct C2 alkenylation of 4,5-
dimethylthiazole (6) (Scheme 1). Under the standard condi-
tions, we obtained the desired 7 albeit in 35% yield, con-
taminated with the conceivable homocoupling product 8.
π-Extended 2,5-disubstituted thiazoles are known to show
unique optical properties.12 Inspired by the literature, we syn-
thesized some 2,5-dialkenylated thiazoles 10 and investigated
their fluorescence in the solid state (Scheme 2). The mono-
FIGURE 1. Fluorescence spectra of 10a,a 10b,a 10c,b and Alq3c in the
solid state. aExcited at 430 nm. bExcited at 500 nm. c Excited at 380 nm.
Dialkenylthiazoles 10 except for 10d showed solid-state
fluorescence (Figure 1). The emission spectra of styryl-sub-
stituted 10a exhibited the major band with maximum emis-
sion λem at 492 nm. By installation of the strongly electron-
donating dimethylamino group to the benzene ring, this peak
was red-shifted by 78 nm (10c). The methoxy substituent
caused a similar shift, although the effect was considerably
small (10b). These compounds exhibited similar or relatively
strong emissions compared to a typical emitter, tris(8-hydro-
xyquinolinato)aluminum (Alq3).
In summary, we have described an effective palladium
catalyst system for the direct alkenylation of thiazoles and oxa-
zoles with alkenes.13 In addition, with the catalysis as the key
transformation, we succeeded in the synthesis of π-conjugated
2,5-dialkenylated thiazoles with interesting optical properties.
Experimental Section
Typical Procedure for Palladium-Catalyzed Alkenylation of
Azoles 1 or 4 with Alkenes 2. In a 20 mL two-necked flask were
(11) This is probably because the methyl group at 4-position in thiazole
inhibited the unfavorable coordination of nitrogen to the palladium center
necessary for the competitive cyclopalladation.
(12) Selected examples: (a) Shu, C.-F.; Wang, Y.-K. J. Mater. Chem.
€
1998, 8, 833. (b) Eckert, K.; Schroder, A.; Hartmann, H. Eur. J. Org. Chem.
2000, 1327.
(13) The fact that the alkenylation of azoles 1 and 4a occurs selectively at
the relatively electrophile-susceptible 5-position rather than the 4-position is
consistent with the relevant Pd-catalyzed direct arylation chemistry.1a-e
J. Org. Chem. Vol. 75, No. 15, 2010 5423

Miyasaka et al.
JOCNote
added 2-isobutylthiazole (1a, 0.5 mmol, 71 mg), n-butyl acrylate
(2a, 1 mmol, 128 mg), Pd(OAc)2 (0.03 mmol, 5.6 mg), AgOAc
(1.5 mmol, 250 mg), dibenzyl (ca. 50 mg) as internal standard,
and propionic acid (2.5 mL). The resulting mixture was stirred
under nitrogen at 120 °C (bath temperature) for 8 h. After the
suspension was allowed to cool to room temperature, analysis of
the mixture by GC confirmed the formation of the desired com-
pound. The reaction mixture was poured into satd aq NaHCO3
and extracted with Et2O. The organic layer was dried over Na2-
SO4 and concentrated in vacuo. The product 3aa (0.44 mmol,
118 mg, 88%) was also isolated by chromatography on silica gel
using hexane-ethyl acetate (95:5, v/v). 3aa: oil; 1H NMR (400
MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz, 3H), 1.00 (d, J = 6.9 Hz,
6H), 1.39-1.45 (m, 2H), 1.64-1.69 (m, 2H), 2.09-2.16 (m, 1H),
2.87 (d, J = 7.0 Hz, 2H), 4.19 (t, J = 7.0 Hz, 2H), 6.13 (d, J =
15.7 Hz, 1H), 7.74 (d, J = 15.7 Hz, 1H), 7.76 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 13.6, 19.1, 22.2, 29.7, 30.7, 42.7, 64.5,
119.6, 134.0, 134.3, 145.4, 166.3, 172.8; HRMS m/z (Mþ) calcd
for C14H21NO2S 267.1293, found 267.1297.
Acknowledgment. This work was partly supported by
Grants-in-Aid from MEXT and JSPS. M.M. acknowledges
JSPS for financial support.
Supporting Information Available: Detailed experimental
procedures and characterization data of compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
5424 J. Org. Chem. Vol. 75, No. 15, 2010