Cross-coupling of alkenyl/aryl carboxylates with grignard reagent via Fe-catalyzed C-O bond activation

Article abstract of DOI:10.1021/ja907281f

(Chemical Equation Presented) Iron-catalyzed cross-coupling of alkenyl/aryl carboxylates with primary alkyl Grignard reagent was described. This reaction brought a new family of electrophiles to iron catalysis. The combination of an inexpensive carboxylat

Full text of DOI:10.1021/ja907281f

Published on Web 09/29/2009
Cross-Coupling of Alkenyl/Aryl Carboxylates with Grignard Reagent via
Fe-Catalyzed C-O Bond Activation
Bi-Jie Li,† Li Xu,†,‡ Zhen-Hua Wu,† Bing-Tao Guan,† Chang-Liang Sun,† Bi-Qin Wang,‡ and
Zhang-Jie Shi*,†,§
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education, College of Chemistry and Green Chemistry Center, Peking
UniVersity, Beijing 100871, Department of Chemistry, Sichuan Normal UniVersity, Chengdu, Sichuan, 610068, and
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received August 28, 2009; E-mail: zshi@pku.edu.cn
Transition metal catalyzed cross-coupling reactions are indispen-
sable tools for forging C-C bonds.1 The search for novel electrophiles
and efficient catalysts continues to capture significant interest.2
Recently, Garg’s and our group independently reported the examples
of Ni-catalyzed Suzuki and Negishi coupling of aryl/alkenyl carboxy-
lates.3 Compared with traditional cross-coupling reactions of aryl
(pseudo)halides, such cross-couplings showed some advantages: (1)
aryl/alkenyl carboxylates are easily available and are less expensive
than the corresponding halides and sulfonates; (2) the use of halides
was avoided, which pollute the environment; (3) aryl/alkenyl carboxy-
lates may exhibit orthogonal reactivity to organohalides. However,
several problems still remain, such as a high catalyst loading and
elevated temperature. Therefore, we set out to search for alternative
coupling partners and novel catalytic systems.
and alkyl (pseudo)halides with Grignard reagents.4-7 Notably, Fu¨rstner’s
report indicated that iron-catalyzed coupling of aryl tosylate and triflate
was even more efficient than the corresponding aryl bromide and iodide.6a
These interesting findings led us to assume that iron favors activating
oxygen-based electrophiles, for example, carboxylates as leaving groups.
To test the feasibility of such a hypothesis, alkenyl pivalate 1a
was chosen as the model substrate to react with n-hexylmagnesium
chloride 2a. To our delight, the desired cross-coupling proceeded
smoothly in the presence of iron catalyst (entry 1, Table 1).
Screening of the ligands revealed that heterocyclic carbene (NHC)
improved the yield, while other mono- or bidentated phosphine and
nitrogen ligands gave either lower yields or no product (entry 2-6).
Obviously, the reaction could not proceed without iron catalyst
(entry 7). Several iron catalyst precursors showed similar efficien-
cies, presumably due to their in situ reduction by the Grignard
reagent to generate the active low-valent catalyst (entry 8-10).8
Finally, we chose FeCl2 as the catalyst since it is air-stable and
easy to handle. Interestingly, the counteranion of the Grignard
reagent was highly important. n-HexylMgCl reacted well, while
n-hexylMgBr completely failed (entry 11). The reason for this result
is still unclear at present. This problem could be solved by the
addition of an excess amount of LiCl (entry 12). Under this modified
condition, no ligand was required.
Grignard reagents emerged as an attractive candidate due to its high
reactivity. For the catalyst selection, iron has drawn our attention since
it is cheap, nontoxic, and environmentally benign. According to the
Table 1. Optimization Studya
Table 2. Substrate Scope of Alkyl Grignard Reagenta
a Reaction condition: 0.5 mmol of 1a, 1.0 mmol of 2, 0.005 mmol of
iron catalyst, 0.01 mmol of ligand. b Isolated yields. c 6 equiv of LiCl
were added.
previous work by Kochi, Cahiez, Fu¨rstner, Nakamura and others, iron
exhibits remarkable reactivity in the cross-coupling of alkenyl, aryl,
a Reaction condition: 0.5 mmol of 1a, 1.0 mmol of Grignard reagent,
0.005 mmol of FeCl2, 3.0 mmol of LiCl. b Isolated yields. c 2 mol % of
NHC ligand instead of LiCl.
† Peking University.
‡ Sichuan Normal University.
§ Chinese Academy of Sciences.
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14656 J. AM. CHEM. SOC. 2009, 131, 14656–14657
10.1021/ja907281f CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
With this efficient catalytic system, we next studied the scope
of Grignard reagents (Table 2). Primary alkyl Grignard reagents
with different chain lengths proceeded efficiently to give the desired
products in high yields (entry 4-13). Functional groups such olefin,
ether, and acetal were well tolerated. It is important to note that
methyl Grignard reagents were unreactive (entry 2), which may be
implied that low valent iron species might be generated through
ꢀ-H elimination as reported.6b,8 Secondary and tertiary Grignard
reagents did not react either (entry 3).
was dramatically inhibited (<5% product) with 80% of 1f recovered.
Therefore, it is very likely that a vinyl radical was generated, since an
aryl substituted vinyl radical possesses a linear structure to some
extent.6f,11,12 Alternatively, the loss of stereochemistry could be
explained by the addition of an alkyl radical, generated from an alkyl
Grignard reagent, to the double bond to produce a benzylic radical.
The subsequent elimination of a pivaloxy radical would afford the
product. However, this mechanism seems less feasible based on the
good reactivity of aryl carboxylate, since the addition of an alkyl radical
to an aryl carboxylate is relatively difficult.
The functional group tolerance was further demonstrated by the
successful reactions of different alkenyl pivalates (Table 3). For
example, substrates 1a-1c with various ring sizes reacted to afford
the corresponding products in high yields. Alkenyl pivalate (1d) derived
from 4-hydroxycoumarin was exclusively cleaved in the presence of
an aryl carboxylate moiety. Furthermore, the conjugated ketone
functionality in the six-membered ring survived in the reaction,
demonstrating the high reactivity of the catalyst toward alkenyl
carboxylate (entry 5). 1,2-Diarylvinyl pivalates were also suitable
substrates (entries 6-8), affording two products with similar ratios
(E/Z ) 2:1). Such stereoisomerization is relatively rare in other related
metal-catalyzed, especially iron-catalyzed, cross-couplings of alkenyl
electrophiles,5,9 which might suggest that a different mechanism is
operating. Acyclic and cyclic stryryl carboxylates also resulted in high
yields (entries 9 and 10). However, attempts to couple inactivated
alkenyl carboxylates such as 1-cyclohexenyl pivalate were unsuccess-
ful. In addition to alkenyl pivalates, the reaction of 2-naphthyl pivalate
gave a moderate yield. However, the yield was dramatically improved
by using a more stable carbamate, which has rarely been reported as
electrophiles (entry 11).10
In conclusion, we reported an efficient iron-catalyzed cross-coupling
reaction of alkenyl/aryl pivalate with a Grignard reagent under mild
conditions. The combination of an inexpensive and stable carboxylate
electrophile and an iron catalyst would generate ample advantages.
Further studies to clearly understand the detailed mechanism as well
as application in natural product synthesis are currently underway.
Acknowledgment. Support of this work by Peking University and
the grant from National Sciences of Foundation of China (Nos. 20672006,
20821062) and the “973” Project from National Basic Research Program
of China (2009CB825300) is gratefully acknowledged.
Supporting Information Available: Experimental section and
characterization of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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To probe the origin of the double bond isomerization process, 30
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