Cu-Catalyzed Suzuki-Miyaura reactions of primary and secondary benzyl halides with arylboronates

Article abstract of DOI:10.1039/c4cc05376a

A copper-catalyzed Suzuki-Miyaura coupling of benzyl halides with arylboronates is described. Varieties of primary benzyl halides as well as more challenging secondary benzyl halides with β hydrogens or steric hindrance could be successfully converted into the corresponding products. Thus it provides access to diarylmethanes, diarylethanes and triarylmethanes. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc05376a

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Cu-Catalyzed Suzuki–Miyaura reactions of
primary and secondary benzyl halides with
arylboronates†
Cite this: Chem. Commun., 2014,
50, 11060
Received 12th July 2014,
Accepted 29th July 2014
Yan-Yan Sun, Jun Yi, Xi Lu, Zhen-Qi Zhang, Bin Xiao and Yao Fu*
DOI: 10.1039/c4cc05376a
www.rsc.org/chemcomm
A copper-catalyzed Suzuki–Miyaura coupling of benzyl halides with
arylboronates is described. Varieties of primary benzyl halides as well as
more challenging secondary benzyl halides with b hydrogens or steric
hindrance could be successfully converted into the corresponding
products. Thus it provides access to diarylmethanes, diarylethanes
and triarylmethanes.
Transition metal catalyzed cross-coupling reactions provide
efficient approaches for the construction of C–C bonds and play
an important role in organic synthesis.1 Apart from Kumada2,3
and Negishi,4 the Suzuki–Miyaura reaction is widely used due to
the superior features of organoboron compounds, such as easy
manipulation, ready availability and low toxicity. Extensive studies
on palladium or nickel catalyzed Suzuki–Miyaura reactions have
Scheme 1 Copper catalyzed reactions of alkyl electrophiles with aryl-
boronates. Neop = (OCH2CMe2CH2O).
been investigated during the past few decades.5,6a–f Recently, more benzylation in a fundamental sense, and simultaneously com-
attention has been paid to the inexpensive and environmentally plements the nickel- and palladium-catalyzed Suzuki–Miyaura
benign copper catalyst.6g For instance, Sawamura7 and Lalic8 reaction. Also, this methodology provides a fruitful and efficient
have reported SN20-selective arylation of allylic electrophiles with synthesis for functionalized diarylmethanes, diarylethanes and
arylboronates using copper as the catalyst (Scheme 1a). In 2011 triarylmethanes,11d–g which have emerged as structural constituents
the copper-catalyzed cross-coupling reaction of alkyl electrophilic in pharmacologically interesting molecules (e.g. Papaverin and
reagents and arylboronates was also reported (Scheme 1b),9 which Piritrexim).11a–c
was recognized as the pioneering work in this area. Notwithstanding
We commenced our study by choosing benzyl chloride (1a)
these advances, the Cu-catalyzed Suzuki–Miyaura reaction of and phenylboronate (2a) as the model substrates (Table 1). First
benzyl electrophiles with arylboronates has surprisingly never we tested the previously reported catalytic system.9 Gratifyingly,
been reported.
the desired product was obtained in 35% GC yield (entry 1). The
Herein, we report the first example of a copper-catalyzed result indicated that the conditions previously reported for the
cross-coupling reaction of benzyl halides with arylboronates coupling of primary alkyl electrophiles were not suitable for
(Scheme 1c). The primary benzyl halides could be converted benzyl halides. Thus, we devoted our efforts to improve the
successfully into the desired products, even more challenging yield by screening various ligands. Bidentate nitrogen ligands
partners – secondary benzyl halides with b hydrogens or extra (e.g. TMEDA) and monodentate phosphine ligands (e.g. PPh3,
steric hindrance – performed well in such a catalytic system.10 This PCy3) were examined first, but gave a lower yield (entries 3–5 vs.
reaction expands the scope of copper-catalyzed cross-coupling entries 1 and 2). To our delight, we observed 65% yields with L4
(entry 6). This finding encouraged us to test the diketone family
ligands (entries 6–8). Surprisingly, the ligand L6 dramatically
increased the yield to 75%. In a further evaluation of various
solvents (entries 9–12), the desired product was obtained in
Anhui Province Key Laboratory of Biomass Clean Energy Department of Chemistry,
University of Science and Technology of China, Hefei 230026, P. R. China.
E-mail: fuyao@ustc.edu.cn
90% yield employing N-methylcaprolactam (NMCPL) as a solvent
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc05376a
(entry 12). Notably, to rule out the probable involvement of
11060 | Chem. Commun., 2014, 50, 11060--11062
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Table 1 Optimization of the reaction conditionsa
Table 2 Scope of primary benzyl chloridesa,b
Entry
Catalyst
Solvent
Ligand
Yielda
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
Pd(OAc)2
NiI2
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMPU
THF
NMCPL
NMCPL
NMCPL
NMCPL
NMCPL
—
—
35b
40
33
28
25
65
70
75
66
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
L6
9
10
11
12
13
14d
15d
16
68
20
90(85c)
50
18
Trace
0
a
Reaction conditions: benzyl chlorides (0.5 mmol), arylboronic esters
b
(1.5 equiv.), LiOtBu (3 equiv.), NMCPL = N-methylcaprolactam. Isolated
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), CuI (20 mol%),
LiOtBu (3 equiv.), ligand (20 mol%) in 0.5 mL solvent at 60 1C for 12 h
under an Ar atmosphere. The yield was determined by GC using
yields.
b
benzophenone as the internal standard (average of two GC runs). CuI
(10 mol%), LiOtBu (2 equiv.) in 0.5 mL solvent at 60 1C for 12 h under an
c
d
Ar atmosphere. Isolated yield. Catalyst loading: 2 mol%. DMF = N,N-
dimethylformamide. NMP = 1-methyl-2-pyrrolidinone. DMPU = 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, THF
furan. NMCPL = N-methylcaprolactam.
= tetrahydro-
Ni or Pd contamination in the reaction, we conducted the reaction
using Pd(OAc)2 or NiI2, and found that only a very low amount of
product was formed (entries 14 and 15). Furthermore, a blank
experiment demonstrated that the copper catalyst is necessary for
the reaction (entry 16).
Under the optimized conditions, we decided to investigate
the scope of this transformation (Table 2). To our delight, a
series of synthetically relevant functional groups including
ether (3a), naphthyl (3b), meta-/para-substituted methyl/phenyl
(3c, 3d, 3e), ester (3f), trifluoromethoxy (3g), trifluoromethyl (3h),
ketal (3i), olefin (3j) can be well tolerated at a yield of 41–87%.
Compounds bearing sulphur atoms, which were another interesting
Fig. 1 Gram-scale synthesis and functionalization of the products. Reaction
conditions: LiOtBu (3 equiv.), neop = (OCH2CMe2CH2O). Isolated yields.
NMCPL = N-methylcaprolactam. For reaction conditions of (i)–(v), see ref. 12.
substrates, can also participate in the reaction (3k, 3l). It is note- cross-coupling reactions at the halogenated sites were also
worthy that aryl–X (X = F, Cl, Br, I) bonds (in products 3m, 3n, 3o, 3p) proceeded to excellent yield, which supplies a general approach
do not interfere with the reaction and could be tolerated with the to an array of useful compounds12 such as styrenes, benzamides,
yield of 54–92%, which may thus give the possibility for further nitrobenzoates, benzonitrile.
functionalizations of C–X. Significantly, we observed selective cross-
Since varieties of primary benzyl halides could be successfully
coupling of an aryl boronate ester over that of alkyl pinacol boronate converted into the corresponding products, we envisioned whether
ester (3q). This feature makes additional transformation possible more challenging secondary benzyl electrophiles with b hydrogens,
at the C–B bond. Finally, the phenylethylene substrate was also could involve in the reaction. Fortunately, after a considerable
successfully employed to prepare the corresponding styrene number of screening experiments, the desired product (4a) through
compounds and derivatives (3r).
the reaction of (1-bromoethyl)benzene and arylboronate (2b) was
A gram-scale reaction was carried out (Fig. 1), furnishing indeed obtained in 83% yield (see ESI†). As illustrated in Table 3,
1.97 g of the desired product with an isolated yield of 85%. No secondary benzyl bromides containing b hydrogens, which tended
detrimental effect on the yield was observed upon increasing the to suffer undesired b-hydride elimination in palladium-catalyzed
reaction scale. Further functionalizations via palladium-catalyzed reactions,10 are suitable substrates (4a–4e). Interestingly, secondary
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Table 3 Scope of secondary benzyl halidesa,b
(20123402110051), FRFCU (WK2060190025), CAS (KJCX2-EW-J02)
and Fok Ying Tung Education Foundation for financial supports.
Notes and references
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Wiley-VCH, Weinheim, 1998.
2 Recent examples for Cu-catalyzed Kumada-type reactions:
(a) C. T. Yang, Z. Q. Zhang, J. Liang, J. H. Liu, X. Y. Lu,
H. H. Chen and L. Liu, J. Am. Chem. Soc., 2012, 134, 11124;
(b) P. Ren, L. A. Stern and X. Hu, Angew. Chem., Int. Ed., 2012,
51, 9110; (c) J. Terao, H. Todo, S. A. Begum, H. Kuniyasu and
N. Kambe, Angew. Chem., Int. Ed., 2007, 46, 2086.
3 Recent examples for Ni-catalyzed or Pd-catalyzed Kumada-type
reactions: (a) S. Lou and G. C. Fu, J. Am. Chem. Soc., 2010,
132, 1264; (b) P. Ren, O. Vechorkin, K. von Allmen, R. Scopelliti
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4 Recent examples for Negishi-type reactions: (a) C. Fischer and
G. C. Fu, J. Am. Chem. Soc., 2005, 127, 4594; (b) H. Gong, R. Sinisi
a
Reaction conditions: benzyl halides (0.5 mmol), arylboronic esters
b
(1.5 equiv.), LiOtBu (3 equiv.), NMCPL = N-methylcaprolactam. Isolated
yields.
´
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Scheme 2 Selectivity in competitive experiments.14
benzyl halides, such as (bromomethylene)dibenzene, could also
perform well in the coupling (4f). In addition, the reaction
could tolerate an array of functional groups, such as ether (4a),
olefin (4b), nitro group (4c), thioether (4d), trifluoromethoxy
(4e) in 55–83% yield, thus offering an easy access to diarylethanes
and triarylmethanes.13
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To better understand the selectivity trend between benzyl
chlorides and alkyl electrophiles, we conducted a few competitive
experiments. As illustrated in Scheme 2, we observed that highly
selective coupling was carried out at the benzyl C–Cl site over that
of alkyl C–X (X = OTs, Br, I) in the present catalytic system.
To demonstrate the mechanism of the reaction, we carried
out the radical scavenger experiment and found that the effect
of TMEPO is not similar for different substrates (for more
details, see ESI†). Further investigations on the possible mechanism
are underway.15,16
In summary, an efficient and practical copper-catalyzed cross-
coupling reaction of benzyl halides with arylboronates has been
developed for the first time. A series of primary benzyl halides as well
as more challenging secondary benzyl halides with b hydrogens or
steric hindrance could be successfully converted into the corres-
ponding products. Additionally, this reaction conceptually broadens
the scope of copper catalyzed cross-coupling, and complements the
palladium- and nickel-catalyzed Suzuki–Miyaura reaction of benzyl
electrophiles. The reaction provides a straightforward, effective
means for the synthesis of diarylmethanes, diarylethanes and triar-
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ylmethanes with various functional groups. Further studies on the 14 Reaction conditions see ESI†.
15 We thank one of our reviewers for helpful suggestions on mechanism
mechanism are ongoing in our laboratory.
We thank the NSFC (21325208, 21302178, 21172209,
21361140372), 973 Program (2013CB228103, 2012CB215306), SRFDP
studies.
16 P. G. Gildner, A. A. S. Gietter, D. Cui and D. A. Watson, J. Am. Chem.
Soc., 2012, 134, 9942.
11062 | Chem. Commun., 2014, 50, 11060--11062
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