Palladium-catalyzed double cross-coupling reaction of vic-diborylalkenes and -arenes with vic-bromo(bromomethyl)arenes

Article abstract of DOI:10.1055/s-0029-1218341

Efficient annulation of vic-diborylalkenes and -arenes with vic-bromo(bromomethyl)arenes has been achieved, using Pd(PPh₃) ₄ as a catalyst in the presence of Cs₂CO₃ and water in THF at 60°C, giving rise to the c

Full text of DOI:10.1055/s-0029-1218341

LETTER
3147
Palladium-Catalyzed Double Cross-Coupling Reaction of vic-Diborylalkenes
and -arenes with vic-Bromo(bromomethyl)arenes
R
eactionof vic
-
Dibory
a
lalkenes an
sd -arenes
w
ith vic-B
r
k
omo(bromom
i
ethyl)arenesShimizu,* Yosuke Tomioka, Ikuhiro Nagao, Tamejiro Hiyama
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto University Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
Fax +81(75)3832445; E-mail: m.shimizu@hs2.ecs.kyoto-u.ac.jp
Received 19 September 2009
Initially, we chose 1-bromo-2-(bromomethyl)benzene
Abstract: Efficient annulation of vic-diborylalkenes and -arenes
with vic-bromo(bromomethyl)arenes has been achieved, using
Pd(PPh3)4 as a catalyst in the presence of Cs2CO3 and water in THF
at 60 °C, giving rise to the corresponding indene and fluorene deriv-
atives in good to high yields.
(2a) as a coupling partner for (Z)-1,2-bis(pinacolatobor-
yl)stilbene (1a).6 After screening the reaction conditions,
the desired product, 2,3-diphenylindene (3aa), was isolat-
ed in 80% yield as a sole product using Pd(PPh3)4 (5
mol%), Cs2CO3 (6 mol equiv), and H2O (50 mol equiv) in
THF at 60 °C for 48 hours (Table 1, entry 1).7 Neither oli-
gomers nor polymeric products were observed. The use of
K2CO3/H2O or 3 M aq K3PO4, which was the optimized
base for annulation with 2,2¢-dibromobiaryls,3b was less
effective. When the amount of Cs2CO3 was reduced to 0.5
mol equivalent, borylstilbene 4a, whose structure was
confirmed by X-ray analysis of its single crystal, was ob-
tained as the sole product (Table 1, entry 2).8 When 4a
was subjected to the optimal reaction conditions, 3aa was
isolated in 74% yield. These results clearly indicate that
4a is the intermediate of the annulation process, and thus
that the initial coupling takes place selectively at the ben-
zylic position of 2a, consistent with results for the Pd-
catalyzed monocoupling of 2a with arylboronic acids, re-
ported by Duchêne.9
Key words: annulations, arenes, boron, bromine, cross-coupling
The transition-metal-catalyzed/mediated cross-coupling
reaction of alkenyl and aryl metals with electrophiles
serves as one of the most useful methods for stereospecif-
ic formation of s-bond between carbons substituted by a
metal and a (pseudo)halogen, respectively.1 Hence, the
double cross-coupling reaction of dimetal reagents (and
their equivalents) with di(pseudo)halides is a straightfor-
ward route to synthesize cyclic p-conjugated compounds,
if the annulation proceeds efficiently in preference to the
possible oligomerization and/or polymerization. Indeed,
copper-mediated and uncatalyzed annulation of zircona-
cyclopentadienes and 2,2¢-biphenylidiylzirconium, re-
spectively, have been reported.2 Palladium-catalyzed
double cross-coupling reactions of 2,2¢-bis(trimethylstan-
nyl)biphenyl, 9-stannafluorenes, vic-diborylalkenes, and
9,10-diboryl-phenanthrenes has also been demonstrated.3
These precedents involve the formation of six-, seven-,
and eight-membered rings, while the annulative synthesis
of a five-membered ring via the double cross-coupling
reaction of dimetal reagents has remained unexplored.
Herein we report the Pd-catalyzed annulation of vic-dibo-
ryl reagents 1 with vic-bromo(bromomethyl)arenes 2,
which provides a new synthetic method for arene-fused
cyclopentadiene frameworks 3 such as indenes and fluo-
renes,4 which are often found as a key structure in biolog-
ically active compounds and functional organic
materials.5
Table 1 Pd-Catalyzed Coupling Reactions of 1a with 2a–fa
X1
X2
2a–f
Ph
Ph
Bpin
Bpin
Ph
Ph
Ph
+
Pd(PPh3)4 (cat.)
Cs2CO3, H2O
THF, 60 °C, 48 h
Bpin
X2
Ph
1a
3aa
4
Entry
2
X1
X2
GC yield (%) Isolated yield
of 3aa
(%) of 4
1
2c
3
4
5
6
7
2a
Br
Br
Br
Br
Br
I
Br
Br
Cl
>99 (80)b
0
2a
2b
2c
2d
2e
2f
0
0
75d (4a)
86 (4b)
R
Pd(PPh3)4
(5 mol%)
R
OTf
65
48
28
0
0
0
0
0
R
R
R
Bpin
Bpin
Br
+
I
Cs2CO3 (6 equiv)
H2O (50 equiv)
THF, 60 °C
R
Br
I
1
2
3
Cl
Cl
Equation 1 Double cross-coupling reaction of vic-diboryl reagents
with vic-bromo(bromomethyl)arenes (Bpin: pinacolatoboryl)
a Conditions: 1a (0.06 mmol), 2 (0.05 mmol), Pd(PPh3)4 (2.5 mmol),
Cs2CO3 (0.3 mmol), H2O (2.5 mmol), THF, 60 °C, 48 h.
b The value in parentheses was the isolated yield.
c Conditions 1a (0.06 mmol), 2 (0.05 mmol), Pd(PPh3)4 (2.5 mmol),
Cs2CO3 (0.025 mmol), H2O (2.5 mmol), THF, 60 °C, 48 h.
d 1H NMR yield.
SYNLETT 2009, No. 19, pp 3147–3150
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.11.2009
DOI: 10.1055/s-0029-1218341; Art ID: U09609ST
© Georg Thieme Verlag Stuttgart · New York

3148
M. Shimizu et al.
LETTER
The effect of the leaving groups in 2 was subsequently ex- When bromo- or iodomethyl-substituted iodobenzene 2d
amined under the optimized conditions. The results are or 2e was used, the yield of 3aa dropped significantly,
summarized in Table 1. Chlorobenzene 2b reacted with presumably because of the instability of 2d and 2e under
1a to give the uncyclized product 4b in 86% isolated yield the conditions (entries 5 and 6). The reaction of chlo-
(Table 1, entry 3), indicating that the chloride on the ben- ro(chloromethyl)benzene 2f resulted in the production of
zene ring was unreactive under the conditions toward the a complex mixture (entry 7). Thus, the combination of
oxidative addition which was essential for the second cou- bromo and bromomethyl functionalities turned out to be
pling step. In the case of 2-(bromomethyl)phenyl triflate the best choice for 2.
(2c), 3aa was isolated in 65% GC yield along with some
oligomeric byproducts (entry 4).
Table 2 Pd-Catalyzed Annulation of Diboryl Reagents 1 with Bromo(bromomethyl)arenes 2a
Entry
Diboryl reagent 1
Bromo(bromomethyl)arene 2 Product 3
Yield (%)b
Br
R
Bpin
Bpin
R
1
2
88
75
Br
2g (R = Cl)
2h (R = CN)
3ag (R = Cl)
3ah (R = CN)
1a
1a
Br
3c
83
75
S
S
Br
2i
3ai
Br
4
1a
N
Br
N
2j
3aj
MeO
MeO
Bpin
Bpin
5
2a
84
MeO
1b
MeO
3ba
Bpin
6d
2a
2a
75
84
Bpin
1c
3ca
3da
Bpin
7e
Bpin
1d
Bpin
Bpin
8
2a
73
3ea
1e
Synlett 2009, No. 19, 3147–3150 © Thieme Stuttgart · New York

LETTER
Reaction of vic-Diborylalkenes and -arenes with vic-Bromo(bromomethyl)arene
3149
Table 2 Pd-Catalyzed Annulation of Diboryl Reagents 1 with Bromo(bromomethyl)arenes 2a (continued)
Entry
Diboryl reagent 1
Bromo(bromomethyl)arene 2 Product 3
Yield (%)b
Br
Br
Br
Bpin
Bpin
9c
70
Br
2k
3ak
3dk
1a
1d
10
2k
39
a Conditions: 1 (1.2 mmol), 2 (1.0 mmol), Pd(PPh3)4 (0.05 mmol), Cs2CO3 (6.0 mmol), H2O (50 mmol), THF, 60 °C, 48 h.
b Isolated yield.
c Conditions: 1 (1.2 mmol), 2 (1.0 mmol), Pd(PPh3)4 (0.05 mmol), 3 M K3PO4 (6.0 mmol), THF, 60 °C, 48 h.
d Conditions: 1 (1.2 mmol), 2 (1.0 mmol), Pd(PPh3)4 (0.05 mmol), K3PO4 (6.0 mmol), H2O (50 mmol), THF, 60 °C, 48 h.
e Conditions: 1 (1.2 mmol), 2 (1.0 mmol), Pd(PPh3)4 (0.05 mmol), 3 M Cs2CO3 (6.0 mmol), THF, 60 °C, 48 h.
The scope of the present annulation is shown in Table 2.10
Bromobenzenes substituted with functional groups such
Acknowledgment
This work was supported by Grants-in-Aid for Creative Scientific
Research, No. 16GS0209, from the Ministry of Education, Culture,
Sports, Science and Technology, Japan and The Asahi Glass Foun-
dation.
as chloro and cyano, that is, 2g and 2h, reacted with 1a to
give 2,3-diphenylindenes 3ag and 3ah in high yields, with
their functional groups intact (entries 1 and 2). The annu-
lation of 1a was applicable to the preparation of hetero-
cycle-fused cyclopentenes 3ai and 3aj by use of the
corresponding dibrominated thiophene (2i) and pyridine
(2j) as the coupling partners, respectively (entries 3 and
4). Bis(4-methoxyphenyl)diborylethene 1b and (Z)-4,5-
diboryloct-4-ene 1c also provided the corresponding an-
nulated products (3ba and 3ca) in 84% and 75% yields,
respectively (entries 5 and 6). In addition to vic-diboryl-
olefins, vic-diborylarenes such as 1d11 and 1e3b also un-
derwent the five-membered ring formation to give the cor-
responding fluorenes (3da and 3ea) in 84% and 73%
yields (entries 7 and 8). Additionally, straightforward syn-
thesis of dihydroindacene 3ak and indeno[2,1-b]fluorene
3dk was achieved by carrying out the double annulation of
1,5-dibromo-2,4-bis(bromomethyl)benzene (2k). How-
ever, further study for attaining higher yields will be nec-
essary (entries 9 and 10).
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In summary, we have demonstrated that the palladium-
catalyzed double cross-coupling reaction of vic-diboryl-
alkenes and -arenes with vic-bromo(bromomethyl)arenes
can serve as an efficient and straightforward route for
(hetero)arene-fused cyclopentadienes. Further optimiza-
tion of the scope of the dibromides and application of the
new annulation protocol to the exploration and develop-
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Synlett 2009, No. 19, 3147–3150 © Thieme Stuttgart · New York

3150
M. Shimizu et al.
LETTER
b = 10.2322(7), c = 13.9705(9) Å, a = 86.0320(10),
b = 69.5850(10), g = 64.4340(10)°, U = 1199.82(14)
Å3, T = 300 K, space group P1, Z = 2, 6571 reflections
collected, unique 4380 (Rint = 0.0142), final R indices [I >
2s(I)] R1 = 0.0558, wR2 = 0.1530. CCDC-737101 contains
the supplementary crystallographic data.
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(7) For details, see Supporting Information.
(8) Crystallographic Data for 4a
C27H28BBrO2, M = 475.21, triclinic, a = 9.9742(7),
Synlett 2009, No. 19, 3147–3150 © Thieme Stuttgart · New York