Annulative tandem reactions based on Pd0/tBu3P- catalyzed cross-coupling and C(sp3)-H bond activation

Article abstract of DOI:10.1002/anie.200504310

(Chemical Equation Presented) All together now: Pd⁰/tBu ₃P-catalyzed annulative tandem reactions of 1,2-dihalobenzenes were carried out with hindered Grignard reagents. This new type of tandem reaction is believed to occur through cross-coupling followed by cyclization with C(sp ³)-H bond activation as the key step and allows one-step access to potentially useful substituted fluorenes in high yield from readily available 1,2-dibromobenzenes and 1-bromo-2-iodobenzene.

Full text of DOI:10.1002/anie.200504310

Angewandte
Chemie
Synthetic Methods
DOI: 10.1002/anie.200504310
0
Annulative Tandem Reactions Based on Pd /
3
tBu P-Catalyzed Cross-Coupling and C(sp )ꢀH
3
Bond Activation**
Cheng-Guo Dong and Qiao-Sheng Hu*
Over recent decades, transition-metal-catalyzed bond-form-
ing reactions using the cross-coupling strategy have become
extremely powerful tools for the synthesis of an array of small
[
1,2]
organic molecules and macromolecules.
More recently,
transition-metal-catalyzed carbon–carbon bond-forming
3
reactions by C(sp )ꢀH bond activation have emerged as
[
3,4]
new efficient tools for synthetic organic chemistry. Inspired
[
5–7]
by recent elegant examples of tandem/“domino” reactions,
we reasoned that these two types of powerful transition-
metal-catalyzed reactions could be transformed into even
more powerful tools if they could be arranged to occur in a
tandem or “domino” fashion. We were particularly attracted
by the possibility of having ring-forming tandem or “domino”
reactions that combine transition-metal-catalyzed cross-cou-
3
plings and an C(sp )ꢀH bond-activation strategy, as such
reactions could not only concomitantly generate multiple
bonds with a rapid increase in molecular complexity but also
allow us to access ring systems that are difficult to access by
other methods. Herein, we report a new type of such
0
annulative tandem reaction—Pd /tBu P-catalyzed tandem
3
reactions of 1,2-dihalobenzenes with hindered Grignard
reagents—which provides efficient access to substituted
[
8,9]
fluorenes.
Our mechanistic consideration of the Pd-catalyzed
tandem reaction of 1,2-dihalobenzenes is shown in
0
Scheme 1. We envisioned that a Pd -catalyzed reaction of a
1
,2-dihalobenzene with an organometallic reagent would
generate the initial cross-coupling product I and recognized
II
that its subsequent oxidative-addition product, the Pd
complex II, could 1) couple with another equivalent of an
organometallic reagent to yield the direct cross-coupling
3
product and/or 2) undergo intramolecular C(sp )ꢀH bond
activation followed by cyclization (Scheme 1). As the cross-
coupling of aryl halides with organometallic reagents is well
[*] C.-G. Dong, Prof. Dr. Q.-S. Hu
Department of Chemistry
College of Staten Island and
Graduate Center of the City University of New York
Staten Island, NY 10314 (USA)
Fax: (+1)718-982-3910
E-mail: qiaohu@mail.csi.cuny.edu
[
**] We thank the NIH (GM69704) for funding. Partial support from the
PSC-CUNY Research Award Program is gratefully acknowledged. We
thank Ms. Hui-Yu Liu and Ms. Anna P. Yeung for some experimental
work, Prof. Shuiqin Zhou for helpful discussions, and Prof. Alec
Greer for help with the GCMS analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 2289 –2292
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Communications
Table 1: Pd-catalyzed cyclization of 2-bromo-2’-methylbiaryl com-
[
a]
pounds.
Entry
R
ArM
Base
T
Yield [%]
[
b]
Scheme 1. Competition between direct cross-coupling (path A) and cyclization
through C(sp )ꢀH bond activation (path B).
1
2
H
H
K3PO4
RT/reflux
RT
0
3
[
c]
<2
[
d]
3
4
H
RT
RT
19
91
[
1]
established, the challenge to realize a ring-forming tandem
reaction through a CꢀH bond-activation reaction thus lies in
how to achieve cyclization by intramolecular CꢀH bond
[e]
CH3
activation (path B) over the intermolecular direct cross-
coupling process (path A). Based on reports that sterically
hindered substrates/reagents were more reluctant to undergo
[a] Reaction conditions: Aryl bromide (1.0 equiv) and either an arylbor-
onic acid (1.5 equiv) and K PO (3 equiv) or a Grignard reagent
3
4
(2.5 equiv) in THF (2 mL). [b] 1,2-Diarylbenzene was obtained in 37%
[
10]
yield. [c] 1,2-Diarylbenzene was obtained in 68% yield. [d] 1,2-Diaryl-
benzene was obtained in 43% yield based on GCMS. [e] Yield of the
isolated product.
cross-coupling reactions, we surmised that the cyclization
pathway should be more favored with bulkier substrates and/
or reagents. We thus began our
study by examining the cyclization
[
a]
Table 2: Pd-catalyzed tandem reactions of 1,2-dihalobenzenes with hindered Grignard reagents.
behavior of 2-bromo-2’-methylbi-
phenyls under cross-coupling reac-
tion conditions (namely, in the
[
11]
presence of ArM) and expected
the products to be formed via
[b]
Entry
Aryl dihalide
Substituted fluorene
Yield [%]
0
complex II. With Pd /tBu P as the
3
[
12]
catalyst, we found that although
-bromo-2’-methylbiphenyl only
1
2
99
99
2
yielded the direct cross-coupling
product with o-tolylboronic acid
(
Table 1, entry 1), it indeed yielded
3
93
more cyclization product with a
bulkier Grignard reagent, which
served as both a coupling reagent
and base (Table 1, entries 2 and 3).
The use of the bulkier 2-bromo-
[
c]
4
5
6
99 (44/56)
[
d]
95
91
78
99
89
3
2
’,4’,6’-trimethylbiphenyl as the
[
d]
substrate led to clean cyclization
with 2-mesitylmagnesium bromide,
thus suggesting the cyclization
pathway through CꢀH activation
[
d]
7
8
9
could be efficiently controlled over
the direct cross-coupling process
by adjusting the bulkiness of the
substrates/reagents.
[
[
[
e]
e]
e]
[d,f]
10
11
12
(94)
(97)
(96)
With the feasibility of cycliza-
tion through CꢀH bond activation
[d,f]
[d,f]
2
established, we turned our atten-
tion to test the annulative tandem
reaction of 1,2-dibromobenzene
with 2-mesitylmagnesium bromide,
which was expected to proceed via
complex II as the intermediate. We
were pleased to find that the annu-
lative tandem reaction took place
as expected in excellent yield
3
[
a] Reaction conditions (not optimized): aryl dihalide (1.0 equiv), Grignard reagent (2.5 equiv), Pd
catalyst (3 mol%), THF (2 mL), room temperature. [b] Yields of the isolated products. [c] Ratio based on
H NMR spectroscopic analysis. [d] Reaction temperature: 608C. [e] Based on H NMR spectroscopic
analysis. [f] In parenthesis: yields of the isolated product for 2-chlorobiaryl compounds I.
1
1
(
Table 2, entry 1). This result encouraged us to examine a
were observed for 1,2-dibromobenzenes (Table 2, entries 1–7)
and 1-bromo-2-iodobenzene (Table 2, entries 8,9). 1,2-
Dibromo-4,5-dimethylbenzene and 1,2-dibromo-4,5-dime-
number of 1,2-dihalobenzenes for this new type of annulative
tandem reaction (Table 2). We found good-to-excellent yields
2
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Angewandte
Chemie
thoxybenzene, which are more electron rich than 1,2-dibro-
mobenzene, required heating to 608C for the reaction to go to
completion. We also found that 1-chloro-2-halobenzenes only
gave very low yields of fluorenes and excellent yields of 2-
chlorobiphenyls (I, X = Cl) were obtained (Table 2,
Table 3: Pd-catalyzed reactions of 1,2-dihalobenzenes with a limited
amount of 2-mesitylmagnesium bromide.
[
a]
[
13]
entries 10–12).
[
b]
Entry
X
R
Conversion [%]
I [%]
III [%]
We carried out preliminary studies on whether the first
carbon–carbon bonding-forming step indeed proceeded
1
2
3
Br
Br
I
H
CH3
48
45
34
7
12
19.5
93
88
80.5
[
14–16]
through the envisioned cross-coupling strategy.
As the
H
formation of I and the subsequent oxidative addition of I with
0
Pd are involved in such a cross-coupling process, we reasoned
[a] Reaction conditions: aryl dihalide (1.0 equiv), Grignard reagent
0.5 equiv), Pd catalyst (3 mol%), THF (2 mL), room temperature,
0 h. Ratio I/III was based on GCMS data. [b] Based on 1,2-dihaloben-
(
2
that it could be validated by the detection of the existence of
this intermediate. Reactions with 1-chloro-2-halobenzenes as
the substrates were apparently consistent with the formation
of the first carbon–carbon bond through the cross-coupling
strategy, with I (X = Cl) being obtained in excellent yields
zene.
(
Table 2, entries 10–12) because of its reluctance to undergo
0
oxidative addition with Pd /tBu P under the new tandem
3
reaction conditions (Scheme 2). Because I (X = Br) can
Scheme 3. Pd-catalyzed tandem reaction of 1,2,4,5-tetrabromobenzene
with 2,6-dimethyphenylmagnesium bromide.
Scheme 2. Pd-catalyzed reactions of 2-chloro-2’,4’,6’-trimethylbiphenyls
with 2-mesitylmagnesium bromide.
bromo-2-iodobenzene with hindered Grignard reagents based
on a Pd-catalyzed cross-coupling reaction and CꢀH activation
strategy. This new type of tandem reaction allows efficient
access to potentially useful substituted fluorenes. Future work
will focus on expansion of the reaction scope, elucidation of
more detailed reaction mechanisms, and extension of the
cyclization strategy for the preparation of other cyclic
compounds and substituted oligofluorenes/polyfluorenes.
0
readily undergo oxidative addition with Pd /tBu P, the
3
0
detection of the existence of I (X = Br) in Pd /tBu P-catalyzed
3
tandem reactions of 1,2-dibromobenzenes would require the
reactions to be stopped before completion by methods such as
using a limited amount of Grignard reagent. We thus carried
out the reaction of 1,2-dibromobenzene with 0.5 equivalents
of 2-mesitylmagnesium bromide. Our results showed that I
was observed in 7% yield (Table 3, entry 1). As the envi- Experimental Section
sioned cross-coupling strategy also involves the oxidative
addition of I with a regenerated Pd species, substrates such as
General procedure for the palladium-catalyzed tandem reaction of
1,2-dihalobenzenes with hindered Grignard reagents: In a glove box
0
with a N2 atmosphere, [Pd (dba) ] (13.7 mg, 0.015 mmol; dba =
2
3
1
,2-dibromo-4-methylbenzene that yield less reactive I, or
dibenzylideneacetone) and tBu P (12.1 mg, 0.06 mmol) were added
[
15,16]
3
substrates such as 1-bromo-2-iodobenzene
that undergo
to a mixture of dihalobenzenes (1.0 mmol) and THF (2.0 mL) in a
Schlenk flask. After stirring the reaction mixture for 5–10 min, the
Grignard reagent (2.5 mL, 1m in THF, 2.5 mmol) was added. The
oxidative addition faster than I (X = Br), should lead to the
detection of greater amounts of I (X = Br); indeed, our study
on these substrates showed that more of I was found (Table 3,
entries 2,3). In combination with our recent observation of
reaction mixture was allowed to stir in a N atmosphere for 20 h,
2
quenched with water, and extracted with ethyl acetate. The organic
layer was washed with brine, and the solvent was evaporated under
vacuum. Flash chromatography on silica gel (hexane/ethyl acetate,
0
[17]
preferential oxidative addition with Pd /tBu P, the detec-
3
tion of a significant amount of I strongly suggests that the
100:0!90:10) gave the reaction products.
cross-coupling strategy should be a main pathway, if not the
[
18,19]
only one,
for the first carbon–carbon bond-forming step
Received: December 4, 2005
Published online: March 3, 2006
of the reaction of 1,2-dibromobenzenes and 1-bromo-2-
iodobenzene with hindered Grignard reagents.
We also extended the tandem reaction to 1,2,4,5-tetra-
bromobenzene as a substrate and found that the tandem
reaction occurred as expected to give indenofluorenes in good
ꢀ
Keywords: C H activation · cross-coupling · palladium ·
phosphanes · tandem reactions
.
[
20]
yield (Scheme 3).
In summary, we have demonstrated that cyclization
3
0
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3
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achieved by employing hindered substrates/reagents. Further-
more, we have developed a new type of Pd-catalyzed
annulative tandem reaction of 1,2-dibromobenzenes and 1-
Angew. Chem. Int. Ed. 2006, 45, 2289 –2292
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2291

Communications
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3
2
[
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1
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mixing 1-bromo-2-chlorobenzene or 1,2-dibromobenzene with
2-mesitylmagnesium bromide and 2) no Diels–Alder addition
product was observed when the reaction was carried out in the
presence of furan (see the Supporting Information).
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absence of a palladium source was successful for 1-bromo-2-
iodobenzene, it was unsuccessful in the presence of a palladium
source. This observation suggested that either the direct
formation of the benzyne intermediate did not occur or that
the formed benzyne intermediate interacted with the Pd source
rather than having reacted with furan. As the palladium source
was used in a catalytic amount relative to the excess of furan, the
latter case was unlikely. The observation of a significant amount
of I (X = Br) with a limited amount of 2-mestitylmagnesium
bromide (Table 3, entry 3) suggested that the initial oxidative
[
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[
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0
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1111.
[
7] For a report on Pd-catalyzed tandem cross-coupling cyclization
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0
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[
elimination to form palladium-coordinated benzynes; for Pd-
II
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n
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