Direct benzylic alkylation via Ni-catalyzed selective benzylic sp 3 C-O activation

Article abstract of DOI:10.1021/ja710944j

This article demonstrates the first cross coupling of benzyl ether with Grignard reagents via Ni-catalyzed benzylic sp³ C-O activation with high efficiency and excellent chemoselectivity. Benzylic sp³ C-O and aryl sp² C-O were differentiated, controlled by ligands. Copyright

Full text of DOI:10.1021/ja710944j

Published on Web 02/26/2008
Direct Benzylic Alkylation via Ni-Catalyzed Selective Benzylic sp3 C-O
Activation
Bing-Tao Guan,† Shi-Kai Xiang,†,‡ Bi-Qin Wang,†,‡ Zuo-Peng Sun,†,‡ Yang Wang,§
Ke-Qing Zhao,‡ 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, Peking UniVersity, Beijing 100871, China,
College of Chemistry and Material Science, Sichuan Normal UniVersity, Chengdu, Sichuan 410066, China, and
Department of Chemistry, China Agricultural UniVersity, Beijing 100094, China, and State Key Laboratory of
Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received December 8, 2007; E-mail: zshi@pku.edu.cn
Table 1. Methylation of 2-(Methoxymethyl)naphthalene (1a) under
Kumada coupling is a very useful method to construct C-C
Different Conditionsa
bonds by utilizing aryl halides and Grignard reagents via Ni-
catalyzation.1 New developments to apply cheap and easily available
aryl chlorides and tosylates into this reaction made it more practical.2
Recently, Fu and co-workers showed that alkyl halides could be
applied into this coupling to construct sp3 C-C bonds.3 Much
attention has also been paid to the activation of the relatively stable
but commonly encountered C-O bonds. In direct C-O fuction-
alizations, aryl Grignard reagents showed good reactivity to react
with sp2 C-OMe.4 Some recent studies showed that Suzuki
coupling with methoxyl arenes can be achieved as well.5 Our recent
studies showed that direct methylation of anisole and its derivatives
occurred with MeMgBr via Kumada coupling.6 In this article, we
demonstrated the first benzyl alkylation to construct the sp3 C-C
bond through Kumada coupling via Ni-catalyzed highly selective
benzylic sp3 C-O activation.
Compared to the activation of sp2 C-O bonds, sp3 C-O
activation was not well studied. Alkyl C-O with good leaving
groups, such as OTs, showed satisfying activity in different
reactions.7 However, few cases were reported to selectively activate
an sp3 C-O bond in ethers, since, (1) generally, an sp3 C-O bond
has a relatively high bond dissociation energy (BDE); (2) the
discrimination of two different sp3 C-O bonds of the ether is
challenging; and (3) after the cleavage of sp3 C-O bonds, the
transformation with other reagents to construct C-C bonds is hard
to control. Thus, although the cleavage of the relatively active allylic
sp3 C-O bond of allyl ether has been reported via transition-metal
catalyzation,8 the C-C formation directly via etheric sp3 C-O
activation is unknown.
a All the reactions were carried out in the scale of 0.5 mmol of 1a with
the corresponding amount of MeMgBr, catalyst, and solvent under N2. b GC
yields with the use of n-dodecane as an internal standard. c 10 mol % of
the ligand was used. d 2.0 mol % of NiCl2(dppf) and 2.0 mol % of dppf
were used in this reaction.
(entries 13-17). Further studies showed that the strongly coordinat-
ing solvents, such as THF, were not beneficial for this transforma-
tion (entry 18). However, this coupling took place quantitively in
Et2O (entry 19).
We chose first 2-(methoxylmethyl)naphthalene (1a) as the
substrate (Table 1). Although there are two types of sp3 C-O bonds,
they could be differentiated since benzylic C-O is much more
active. However, when previous methods to activate aryl sp2 C-O
bonds were applied, only a very small amount of methylated product
2a was observed (entry 2). With dppe as the ligand, the methylation
was totally shut down (entry 4). Gratifyingly, when dppf was
applied as the ligand, the desired product 2a was isolated in a good
yield (entry 5). Both NiCl2 and hydrated NiCl2 were not very
efficient for this transformation (entries 11 and 12). Ni(acac)2
showed a better catalytic ability in the presence of bidentated ligands
other than dppe in this coupling (entries 9 and 10). It was of great
importance to note that the coupling occurred smoothly even in
the presence of 2.0 mol % catalyst (entry 6). Other than nickel
catalysts, different inorganic salts were investigated but failed
Different protecting groups of benzyl alcohol were detected
(Table 2). Alkyl groups were suitable for this transformation
regardless of their steric hindrances (entries 1-3). The phenyl group
was also checked, and the methylated product was isolated in 75%
yield with no observation of methylation on the phenyl ring (entry
4). As a common hydroxyl protecting group, TMS also showed
good reactivity (entry 5). However, acetate and free alcohol failed
to furnish the desired products, arising from their high reactivity
toward Grignard reagents (entries 6 and 7). The derivatives of
secondary benzylic alcohol were further investigated. The aryl
substituent is helpful for this transformation (entry 8). However,
alkyl substituents decreased the yields with the eliminated alkenes
as byproducts (entries 9 and 10). Different Grignard reagents were
further tested. The results indicated that EtMgBr was good for this
n
i
coupling (entry 11). However, BuMgCl, PrMgBr, and PhMgBr
showed lower reactivities (entries 12-14).
Various aryl methyl ethers were further surveyed (Table 3). We
† Peking University.
‡ Sichuan Normal University.
§ China Agricultural University.
| Chinese Academy of Sciences.
found that (1) both naphthyl and phenyl groups were perfectly fit
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J. AM. CHEM. SOC. 2008, 130, 3268-3269
10.1021/ja710944j CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Direct Functionalization of Benzylic sp3 C-OMe with
Scheme 1. High Chemoselective C-O Activation of Both sp3 and
sp2 C-OMe
Different Grignard Reagentsa
(Scheme 1). Starting from substrate 3, benzylic sp3 C-OMe was
activated and converted into a methyl group with 99% yield. With
Dankwardt’s or our developed method, sp2 C-OMe could be further
transformed into a phenyl or a methyl group with high efficiency.4d,6
Most importantly, these two processes did not crossover each other,
which could be well controlled by ligands. These two processes
were also combined into one-pot to methylate both sp3 C-OMe
and sp2 C-OMe in the presence of two ligands with an excellent
efficiency.
In summary, we demonstrated an unprecedented cross-coupling
of relatively stable benzyl ether via Ni-catalyzed sp3 C-O activa-
tion. This transformation showed high efficiency and excellent
chemoselectivity. With this method, sp2 C-OMe and benzylic sp3
C-OMe in the same molecule could be differentiated by the
methylation tuned by the ligand. It offers new tools for assembling
complex molecules.
a All the reactions were carried out with 1 (0.5 mmol) and R2MgBr (0.75
mmol) in the presence of NiCl2(dppf) (2.0 mol %) and dppf (2.0 mol %) in
toluene (4.0 mL) at rt under nitrogen atmosphere. b Isolated yields unless
otherwise noted. c GC yields with the use of n-dodecane as an internal stand-
ard. d NMR yields with the use of 1,2-dibromoethane as an internal standard.
Table 3. Benzylic Methylation with Different Substractes via
Ni-Catalyzationa
Acknowledgment. This research was supported by Peking
University and the National Natural Science Foundation of China
(20542001, 20521202). We also thank Professor Hisashi Yamamoto
for his constructional suggestions on this project.
Supporting Information Available: Experimental details and other
spectral data for products 2 and 4-6. This material is available free of
charge via the Internet at http://pubs.acs.org.
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With this developed method, different methoxyl groups in one
molecule were transformed into different functionalities stepwise
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