An efficient synthesis of 2-aryl-3-methoxy-2-cycloalkenones via Suzuki-Miyaura reaction under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2005.07.027

The Suzuki-Miyaura coupling reaction of α-bromocycloalkenones with arylboronic acids has been developed by using microwave heating. This method provides a simple and rapid construction of small molecule libraries of α-arylcycloalkenones with high efficiency.

Full text of DOI:10.1016/j.tetlet.2005.07.027

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5987–5990
An efficient synthesis of 2-aryl-3-methoxy-2-cycloalkenones via
Suzuki–Miyaura reaction under microwave irradiation
Young Seob Song, Bum Tae Kim and Jung-Nyoung Heo*
Bioorganic Science Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea
Received 14 June 2005; revised 4 July 2005; accepted 8 July 2005
Abstract—The Suzuki–Miyaura coupling reaction of a-bromocycloalkenones with arylboronic acids has been developed by using
microwave heating. This method provides a simple and rapid construction of small molecule libraries of a-arylcycloalkenones with
high efficiency.
Ó 2005 Elsevier Ltd. All rights reserved.
The Suzuki–Miyaura coupling reaction provides a con-
venient access to the carbon–carbon bond formation
with high efficiency. Recently, the use of microwave
OMe
O
OMe
Br
i) Br , CH Cl
2
2
2
1
ii) Et N
n
3
n
heating for the coupling reaction is of great interest
to synthetic chemists due to the high-speed construction
O
1 n = 1
3 n = 1 (75%)
2
,3
2 n = 2
4 n = 2 (70%)
of versatile chemical entities. Although, a plethora of
methods has been established on the development of
the Suzuki–Miyaura reaction of aryl (including
heteroaryl) halides or triflates under microwave irradia-
tion, cross-coupling reaction of vinyl halides, in partic-
Scheme 1.
4
The required 2-bromo-3-methoxy-2-cyclopentenone (3)
and its 6-membered analog (4) were prepared via
sequential bromination and base-mediated elimination
reactions of the corresponding cycloalkenones (Scheme
ularof a-halocycloalkenones, remains an attractive
area for investigation using a microwave-promoted
approach. A number of a-arylcycloalkenones served
as key synthetic intermediates for the development of
7
5
1). Subsequently, we examined the Suzuki–Miyaura
biologically active pharmaceuticals and agrochemi-
6
reaction of a-bromocyclopentenone 3 with phenyl-
boronic acid in the presence of a suitable palladium
catalyst. As illustrated in Table 1, ourinitial attempt
was focused on the use of Pd(PPh3)4 (4 mol%) in
combination with K PO (3.0 equiv) in 1,4-dioxane
while microwave heating at 150 °C for5 min (entyr
). This reaction provided 2-phenyl-2-cyclopentenone
a in 58% yield. Based on a GC analysis, the starting
cals. In the event, a-halocycloalkenones have been
coupled with 4-fluorophenylboronic acid using
5
b
Suzuki–Miyaura conditions previously, but not under
microwave irradiation. Therefore, we envisioned a sys-
tematic study of this type of reaction with various aryl-
boronic acids. In this paper, we described the rapid and
efficient synthesis of 2-aryl-3-methoxy-2-cycloalkenones
via Suzuki–Miyaura reaction under microwave
irradiation.
3
4
1
5
a-bromocyclopentenone 3 remained (10%) and biphen-
yl was obtained as a by-product (7% GC yield). As a
next step, we screened a range of solvents such as
THF, CH CN, and DMF to figure out the solvent
3
effects (entries 2–4). The results obtained from reac-
tions using solvents otherthan dioxane tu nr ed out to
be inferior. Changing a base from K PO to Na CO ,
3
4
2
3
Keywords: Suzuki reaction; Palladium; Boronic acid; Microwave;
only trace amount of product 5a was detected by GC
Cycloalkenone.
*
Corresponding author. Tel.: +82 42 860 7085; fax: +82 42 861
307; e-mail: heojn@krict.re.kr
(entry 5). In contrast, the use of Cs CO significantly
improved the reaction yield up to 72% (entry 6).
2
3
0
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.027

5988
Y. S. Song et al. / Tetrahedron Letters 46(2005) 5987–5990
a
Table 1. Suzuki–Miyaura coupling of a-bromocyclopentenone 3 with phenylboronic acid
OMe
Br
PhB(OH)2
Pd
OMe
base
µwave
O
3
O
5a
b
Entry
Pd source
Base
Solvent
Temp (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
3
3
3
3
3
3
)
)
)
)
)
)
)
)
)
4
4
4
4
4
4
4
4
2
K
K
K
K
Na
Cs
K
K
K
K
K
K
3
3
3
3
PO
PO
PO
PO
4
4
4
Dioxane
THF
CH CN
3
DMF
Dioxane
Dioxane
Dioxane/H
Dioxane/H
Dioxane/H
Dioxane/H
Dioxane/H
Dioxane/H
Dioxane/H
Dioxane/H
150
150
150
150
150
150
150
130
150
150
150
150
150
59
35
42
22
4
f
2
CO
3
3
d
2
CO
3
72
77
61
27
4
23
80
89
3
PO
PO
PO
PO
PO
4
4
4
4
4
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
3
3
3
3
2
Cl
2
1
1
1
1
1
0
1
2
3
4
PdCl
Pd(OAc)
2
2
c
c
c
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
)
)
)
4
4
4
CO
3
d
d
Na
Na
2
CO
3
e
g
2
CO
3
150
58
a
Reaction conditions: cyclopentenone 3 (1.0 mmol), PhB(OH)
under microwave irradiation for 5 min.
Isolated yield.
2
(1.3 mmol), Pd (4 mol%), base (3.0 mmol), and solvent (4 mL) using a sealed tube
b
c
d
e
f
1.2 mmol of PhB(OH)
2
was used.
2.4 mmol of base was used.
Conventional oil bath heating was applied.
GC yield.
Biphenyl was detected by GC–MS (20% GC yield).
g
Based on a number of reports regarding the Suzuki–
Miyaura reaction in aqueous media, we decided to
tion, the reaction with ortho-substituted one also pro-
ceeded smoothly to afford coupling product 5f in
excellent yield (entry 6). In case of 2-thienylboronic
acid, however, the reaction was slightly sluggish to give
5k in a moderate yield. Whereas yields of the coupling
reaction obtained herein are compatible to those
described in the previous report under conven-
8
use H O as a co-solvent. In the event, we were pleased
2
to observe that the reaction using dioxane/H O (4:1)
2
provided the coupling product 5a in 77% yield (entry
7
1
). However, decreasing reaction temperature to
30 °C resulted in lower yield due to incompletion of
5
b
reaction (entry 8). Next, we carried out reactions using
palladium(II) precursor catalysts such as Pd(PPh ) Cl ,
tional heating, reaction time could be remarkably
shortened.
3
2
2
PdCl , and Pd(OAc) , but the reactions provided 5a in
2
2
poor yield (entries 9–11). With the result of entry 7,
we attempted to find an optimum condition by changing
bases. With K CO , the reaction furnished 5a in 80%
For further exploration of the Suzuki–Miyaura
coupling reaction, we applied this method to a-
bromocyclohexenone
4
fora synthesis of the
2
3
yield (entry 12). Employing a weaker base, Na CO ,
corresponding a-arylcyclohexenone 6. As highlighted
in Table 3, the reactions under microwave irradiation
proceeded smoothly to afford coupling products
6a–j in good yields irrespective of electronic and
steric properties of the arylboronic acids. It was
found that the reaction conditions were mild enough
for the coupling of arylboronic acid in the pres-
ence of a base-sensitive esterfunctional g or up (ent yr
8).
2
3
the coupling yield increased up to 89% (entry 13).
Therefore, we selected this protocol as the optimum
condition. Finally, we examined thermal effects of
microwave heating compared to conventional heating.
The identical reaction using preheated conventional oil
bath at 150 °C provided the coupling product 5a in
loweryield due to the significant p ro duction of biphenyl
(
entry 14).
Using the optimized reaction conditions (Table 1, entry
3), we performed the microwave-promoted Suzuki–
In summary, we have demonstrated that an efficient
and rapid synthesis of a-arylcycloalkenones can be
achieved via the Suzuki–Miyaura coupling reaction
using microwave irradiation. Such a rapid construction
of small molecule libraries may prompt for the devel-
opment of biologically active molecules. Currently,
our laboratory is on due course for a further applica-
tion of this reaction.
1
Miyaura reaction of a-bromocyclopentenone 3 with a
variety of arylboronic acids. As illustrated in Table 2,
we obtained the coupling products 5a–k in good
9
to excellent yields. It is noteworthy that the cou-
pling reaction tolerates both electron-withdrawing
and -donating substituents of arylboric acids. In addi-

Y. S. Song et al. / Tetrahedron Letters 46(2005) 5987–5990
5989
Table 2. Suzuki–Miyaura coupling of a-bromocyclopentenone 3 with
arylboronic acids
Table 3. Suzuki–Miyaura coupling of a-bromocyclohexenone 4 with
arylboronic acids
a
a
OMe
Br
ArB(OH)2
Pd(PPh3)4
OMe
Ar
OMe
Br
ArB(OH)2
Pd(PPh3)4
OMe
Ar
Na CO
2
3
2
Na CO
3
dioxane/H O
2
O
3
o
O
5
dioxane/H O
µwave, 150 C, 5 min
2
O
o
O
µwave, 150 C, 5 min
b
4
6
Entry Ar
Product
Yield (%)
OMe
b
Entry Ar
Product
Yield (%)
1
Ph
8
9
OMe
1
Ph
79
O
5a
OMe
O
6
a
2
3
4-MeO–C
6
H
4
OMe
83
82
OMe
O
5b
2
3
4-MeO–C
6
H
4
OMe
76
78
OMe
O
6
b
6 4
4-BnO–C H
OBn
OMe
O
5c
4-Cl–C H
6 4
Cl
OMe
O
6
c
4
5
4-Cl–C
6
H
4
Cl
72
77
OMe
O
5
d
e
OMe
4
5
6
7
8
4-CF
3
–C
6
H
4
CF3
O
68
73
72
64
70
4-CF
3
–C
6
H
4
CF3
O
6d
6e
O
OMe
5
O
OMe
O
O
6
7
8
6 3
2-Me–4-F–C H
F
84
83
78
O
O Me
OMe
OMe
5f
6 4
3-F–C H
O
O
O
F
6f
O
O
OMe
O
5
g
OMe
6 4
3-CN–C H
O
CN 6g
6 4
3-F–C H
O
F
OMe
5h
OMe
2 6 4
3-CO Me–C H
O
CO2Me
9
1
1
3-CN–C
6
H
4
75
83
52
6h
O
CN
OMe
5
i
OMe
9
1
2-Naphthyl
2-Thienyl
72
0
1
2-Naphthyl
2-Thienyl
O
6i
O
5j
OMe
OMe
0
60
S
S
O
6
j
O
5
k
a
a
Reaction conditions: a-bromocyclopentenone
ArB(OH) (1.2 mmol), Pd(PPh (4 mol%), Na
dioxane/H O, microwave 150 °C, 5 min.
Isolated yields.
3
(1.0 mmol),
(2.4 mmol),
Reaction conditions: a-bromocyclohexenone
ArB(OH) (1.2 mmol), Pd(PPh (4 mol%), Na
dioxane/H O, microwave 150 °C, 5 min.
Isolated yields.
4
(1.0 mmol),
3
)
4
2
3
CO (2.4 mmol),
2
3
)
4
2
CO
3
2
2
2
b
b

5990
Y. S. Song et al. / Tetrahedron Letters 46(2005) 5987–5990
Z.; Xu, L.; Prasit, P. J. Med. Chem. 1999, 42, 1274; (b)
Acknowledgments
Kuethe, J. T.; Wong, A.; Wu, J.; Davies, I. W.; Dormer, P.
G.; Welch, C. J.; Hillier, M. C.; Hughes, D. L.; Reider, P. J.
J. Org. Chem. 2002, 67, 5993; (c) Lin, Y.-L.; Wu, C.-S.; Lin,
S.-W.; Huang, J.-L.; Sun, Y.-S.; Yang, D.-Y. Bioorg. Med.
Chem. 2002, 10, 685.
We thank the Ministry of Science and Technology and
the Ministry of Commerce, Industry, and Energy (M1-
0
310-08-0000) for the financial support of this work.
The authors are grateful to Professor Sukbok Chang
Korea Advanced Institute of Science and Technology)
6
7
. Wheeler, T. N. U.S. Patent 4422870, 1987.
. Kowalski, C. J.; Weber, A. E.; Fields, K. W. J. Org. Chem.
(
and Dr. Hyuk Lee for their valuable discussions.
1
982, 47, 5088.
8
. For reports of microwave-promoted Suzuki reactions in
water, see: (a) Leadbeater, N. E. Chem. Commun. 2005,
2881; (b) Han, J. W.; Castro, J. C.; Burgess, K. Tetrahedron
Lett. 2003, 44, 9359; (c) Appukkuttan, P.; Orts, A.;
Chandran, R. P.; Goeman, J. L.; Van der Eycken, J.;
Dehaen, W.; Van derEycken, E. Eur. J. Org. Chem. 2004,
3277; (d) Gong, Y.; He, W. Org. Lett. 2002, 4, 3803; (e)
Zhang, W.; Chen, C. H.-T.; Lu, Y.; Nagashima, T. Org.
Lett. 2004, 6, 1473; (f) Solodenko, W.; Sch o¨ n, U.;
Messinger, J.; Glinschert, A.; Kirschning, A. Synlett 2004,
1699; (g) Arvela, R. K.; Leadbeater, N. E. Org. Lett. 2005,
7, 2101.
References and notes
1
. For reviews, see: (a) Bellina, F.; Carpita, A.; Rossi, R.
Synthesis 2004, 2419; (b) Pershichini, P. J. Curr. Org. Chem.
2
003, 7, 1725; (c) Hassan, J.; S e´ vignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359; (d)
Kotha, S.; Lahiri, S.; Kashinath, D. Tetrahedron 2002, 58,
9633; (e) Suzuki, A. J. Organomet. Chem. 1999, 576, 147; (f)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
2
. For recent reviews on microwave heating technology, see:
(
a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250; (b)
9. General procedure: all reactions were conducted by using
TM
Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH:
Weinheim, 2002; (c) Lidstr o¨ m, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225.
Biotage InitiatorEXP microwave reactor. To a thick-wall
borosilicate glass vial (5 mL) was added a-bromocyclo-
pentenone 3 or-cyclohexenone 4 (1 mmol), Pd(PPh )
3
4
3
. For representative examples of the Suzuki reactions using
microwave irradiation, see: (a) Miao, G.; Ye, P.; Yu, L.;
Baldino, C. M. J. Org. Chem. 2005, 70, 2332; (b)
Leadbeater, N. E.; Marco, M. J. Org. Chem. 2003, 68,
2
(4 mol%), arylboronic acid (1.2 mmol), and Na CO
3
(2.4 mmol) sequentially. The mixture was dissolved in
dioxane/H O (4 mL/1 mL) and degassed with argon over
2
5 min. Then, the reaction vial was sealed and placed in the
microwave reactor and irradiated at 150 °C for5 min. After
cooling to rt, the mixture was diluted with EtOAc,
8
2
88; (c) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4,
973; (d) Blettner, C. G.; K o¨ nig, W. A.; Stenzel, W.;
Schotten, T. J. Org. Chem. 1999, 64, 3885; (e) Wang, H.-J.;
Keilman, J.; Pabba, C.; Chen, Z.-J.; Gregg, B. T. Tetra-
hedron Lett. 2005, 46, 2631; (f) N a´ jera, C.; Gil-Molt o´ , J.;
Karlstr o¨ m, S. Adv. Synth. Catal. 2004, 346, 1798.
. (a) Furness, M. S.; Robinson, T. P.; Goldsmith, D. J.;
Bowen, J. P. Tetrahedron Lett. 1999, 40, 459; (b) Scott, T.
L.; Soderberg, B. C. G. Tetrahedron 2003, 59, 6323; (c)
Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C.
B. W. Tetrahedron Lett. 1992, 33, 919.
dried over MgSO , and filtered through a short Celite
pad. The solution was concentrated in vacuo and the
residue was purified by silica gel flash column chromato-
4
graphy with EtOAc/hexanes as eluents. Spectral data
1
4
5
for 5b: H NMR (500 MHz, CDCl
) d 7.68 (d, 2H, J =
3
8.9 Hz), 6.91 (d, 2H, J = 8.9 Hz), 4.01 (s, 3H), 3.81 (s, 3H),
1
3
2.81–2.79 (m, 2H), 2.60–2.58 (m, 2H); C NMR (125 MHz,
CDCl ) d 203.3, 184.0, 158.4, 129.4, 123.3, 118.2, 113.5,
3
56.8, 55.2, 33.8, 24.5; IR (neat) m 3001, 2954, 1670, 1595,
. (a) Black, W. C.; Brideau, C.; Chan, C.-C.; Charleson, S.;
Chauret, N.; Claveau, D.; Ethier, D.; Gordon, R.; Greig,
G.; Guay, J.; Hughes, G.; Jolicoeur, P.; Leblanc, Y.; Nicoll-
Griffith, D.; Ouimet, N.; Riendeau, D.; Visco, D.; Wang,
1508, 1452, 1356, 1290, 1248, 1171, 1053, 1028, 937, 843
cm ; MS (EI) m/z [M + H] forC 13H O calcd: 219.10.
15 3
Found: 219.1 (55), 218.4 (69), 217.6 (87), 203.0 (90), 174.9
(21), 160.5 (87), 146.8 (53), 132.9 (100), 118.9 (53).
À1
+