Nickel-Catalyzed Reductive Cross-Coupling of Benzyl Halides with Aryl Halides

Article abstract of DOI:10.1055/s-0035-1562442

Systematic studies of the coupling of benzylic with aryl halides are presented. The optimized reaction conditions for electron-deficient aryl halides cannot be applied to the electron-rich or neutral counterparts, and vice versa. The excellent functional group tolerance and broad substrate scope may enable the current work to be useful for the construction of diaryl methane products.

Full text of DOI:10.1055/s-0035-1562442

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
A
special topic
Q. Zhang et al.
Special Topic
Synthesis
Nickel-Catalyzed Reductive Cross-Coupling of Benzyl Halides with
Aryl Halides
Qingchen Zhanga
Xuan Wanga
Qun Qian*a
R
NiI2 (10 mol%)
ligand (10 mol%)
Cl
R
R1
R2
Br
R1
Zn (200 mol%)
additvies
DMA
R2
Hegui Gong*a,b
R2 = EDG, additive: KF
R
2 = EWG, additives: MgCl2, Py
a Center for Supramolecular Materials and Catalysis
and Department of Chemistry, Shanghai University,
99 Shang-Da Road, Shanghai 200444, P. R. of China
b Shanghai Key Lab of Chemical Assessment and
Sustainability, Tongji University, 1239 Siping Road,
Shanghai 200092, P. R. of China
1 equiv
1.5 equiv
hegui_gong@shu.edu.cn
Qianqun@shu.edu.cn
Received: 26.04.2016
Accepted after revision: 06.06.2016
Published online: 07.07.2016
lides. In addition to the coupling of benzylic electrophiles
with CO2,9 reductive arylation of activated alkyl halides has
also been studied. Molander and Weix independently uti-
lized a chiral Box ligand in photoredox/Ni and Co/Ni dual
catalytic systems for the arylation of benzyl substrates with
aryl halides, respectively. The highest enantiomeric excess
was 65%.10,11 Doyle illustrated that benzyl acetals can be
used for reductive coupling with aryl halides under NiCl2-
catalyzed conditions.12 In this context, however, systematic
studies of the reductive coupling of benzyl chloride with
aryl halides has not been disclosed. Herein, we present our
studies on the reductive coupling of benzylic electrophiles
with aryl halides by using Zn powder as the sole reductant.
The reactions generally display moderate to excellent cou-
pling efficiency and functional group compatibility.
We set out to investigate the reaction of (1-chloroeth-
yl)benzene with methyl 4-bromobenzoate to identify the
optimal reaction parameters. After considerable efforts, a
combination of NiI2 with bipyridine 1b (Figure 1) in the
presence of MgCl2 (1 equiv) and pyridine delivered 3a in
91% yield at ambient temperature, wherein DMA was used
as the solvent and Zn was used as the reductant (Table 1,
entry 1). A range of bipyridine and phenanthroline ligands
1a,c,d and 2a,b were less effective (entries 2-7). Both MgCl2
and pyridine appeared to be important; without either of
them, the yield decreased, particularly for MgCl2 (entries 8
and 9). Under similar conditions, the coupling was not sat-
isfactory without both MgCl2 and pyridine (entry 10). By
using 1c as the ligand in the presence of pyridine, a number
DOI: 10.1055/s-0035-1562442; Art ID: ss-2016-c0285-st
Abstract Systematic studies of the coupling of benzylic with aryl ha-
lides are presented. The optimized reaction conditions for electron-
deficient aryl halides cannot be applied to the electron-rich or neutral
counterparts, and vice versa. The excellent functional group tolerance
and broad substrate scope may enable the current work to be useful for
the construction of diaryl methane products.
Key words nickel, cross-coupling, arylation, alkyl halide, catalysis
The nickel-catalyzed reductive coupling of alkyl halides
with a variety of other electrophiles has emerged as an im-
portant research field.1 Considerable progress has been
achieved, allowing efficient construction of C(sp3)–C(sp2)
and C(sp3)–C(sp3) bonds.1–7 Good to excellent chemoselec-
tivities between two electrophiles are generally observed
even for two C(sp3) partners.2–4 Whereas the formation of
aryl–alkyl and acyl–alkyl C–C bonds has been extensively
studied, the reaction conditions were initially based on un-
activated alkyl halides decorating with a wide set of func-
tional groups.5,6 Extension of such protocols to activated al-
kyl halides such as benzylic, α-carbonyl and α-cyano alkyl
halides proved to be effective under modified conditions.
More importantly, asymmetric control of the coupling out-
comes by using chiral ligands is now viable, although radi-
cal intermediates were believed to be involved for alkyl
groups. Reisman disclosed that Ni/chiral Box [bis(oxazo-
line)]8 ligands are highly effective for reductive acylation of
benzylic chlorides, leading to enantioenriched acyclic α,α-
disubstituted ketones.8b The same group also succeeded in
the asymmetric vinylation of benzyl chlorides under similar
Ni-catalyzed reductive coupling conditions.8a It appears
that well-matched reactivities between the two electro-
philes is key for successful coupling of activated alkyl ha-
1a, R = H
R
R
1b, R = Me
1c, R = t-Bu
1d, R = Ph
1e, R = OMe
2a, R = H
2b, R = Me
N
N
N
N
R
R
Figure 1 Structures of ligands
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
Q. Zhang et al.
Special Topic
Synthesis
of nickel sources were examined; however, these conditions
proved to be less effective than those with NiI2 (entries 11–
18).
groups on the aryl bromide were also examined. The cyano
group was tolerated (entries 8 and 9), even when a neigh-
boring methyl group was also present. In addition, a mod-
erate yield was observed for 5-bromoisobenzofuran-1(3H)-
one (entry 10). However, no product was detected for 3-
bromopyridine (entry 11). The incorporation of a para-me-
thoxy group into bromo- or iodobenzene did not generate
the product in a detectable amount (entry 12).
Table 1 Optimization of the Reaction Conditions (Method A) with
Methyl 4-Bromobenzoate
method A
Br
NiI2 (10 mol%)
1b (10 mol%)
Cl
+
Table 2 Scope of the Reaction with Aryl Halides for the Coupling with
1-Bromoethylbenzene Using Method A
MgCl2 (100 mol%)
CO2Me
Py (100 mol%)
Zn (200 mol%)
CO2Me
3a
(2 equiv)
(0.3 mmol, 1 equiv)
DMA, 25 °C, 12 h
Entrya
1
Ar-Br
Product
Yield (%)b
75
Entry Deviation from the standard conditionsa
Yield (%)b
CO2Me
3b
1
2
none
91
80
34
55
70
63
31
77
21
11
56
40
trace
ND
25
30
44
42
Br
2a instead of 1b
MeO2C
Br
3
2b instead of 1b
2
3c
62
4
1a instead of 1b
5
1c instead of 1b
O
6
1d instead of 1b
3
4
3d
3e
40
83
Br
H
O
7
1e instead of 1b
8
w/o pyridine
Br
9
w/o MgCl2
10
11
12
13
14
15
16
17
18
1c instead of 1b, w/o MgCl2 and Py
1c instead of 1b, w/o Py
O
5
3f
45
1c instead of 1b, w/o Py, NiBr2·glyme instead of NiI2
1c instead of 1b, w/o Py, NiBr2·diglyme instead of NiI2
1c instead of 1b, w/o Py, NiSO3CF3 instead of NiI2
1c instead of 1b, w/o Py, NiBr2 instead of NiI2
1c instead of 1b, w/o Py, Ni(PPh3)2Cl2 instead of NiI2
1c instead of 1b, w/o Py, NiCl2·glyme instead of NiI2
1c instead of 1b, w/o Py, Ni(COD)2 instead of NiI2
Br
Cl
I
6
7
8
3g
3h
3i
trace
35
CO2Me
CO2Me
CN
Br
66
a See Figure 1 for structures of 1a–e, 2a and 2b. Reaction conditions: See
the Supporting Information for details.
b Yield based on NMR spectroscopic analysis using 2,5-dimethylfuran as in-
ternal standard.
9
3j
80
Br
CN
O
O
With the optimized reaction conditions in hand, we ex-
amined the scope and limitations of the reaction with re-
spect to aryl halides for the coupling with 1-bromoethyl-
benzene, as depicted in Table 2. The meta- and ortho-meth-
oxycarbonyl substituted bromobenzenes were less effective
than the para-analogue, as evident by the reaction with 3a
and 3b (entries 1 and 2). Both 4-bromobenzaldehyde and 1-
(4-bromophenyl)ethan-1-one were compatible with the re-
action conditions, although the former only delivered 3d in
40% yield (entries 3 and 4). By comparison, 1-(3-bromophe-
nyl)ethan-1-one was much less competent than the 4-bro-
mo analogue (entries 4 and 5). Replacing the bromides with
either iodide or chloride in methyl 4-bromobenzoate re-
sulted in poor yield or trace amounts of 3a, respectively
(entries 6 and 7). The use of other electron-withdrawing
10
3k
57
Br
Br
N
11
12
3l
ND
trace
(X = Br or I)
3m
X
OMe
a Method A was used as described in Table 1, entry 1.
b Isolated yield.
The unsuitability of method A for electron-rich aryl ha-
lides prompted us to develop the optimal reaction parame-
ters further based on the coupling of 4-methoxybenzyl bro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
Q. Zhang et al.
Special Topic
Synthesis
mide with (1-chloroethyl)benzene. Pleasingly, a combina-
tion of NiI2/1b/Zn/KF in DMA provided the product 3m in
88% yield (method B, Scheme 1). This approach proved to be
ineffective for generating 3a, suggesting that electron-defi-
cient aryl bromides are not suitable for these reaction con-
ditions. A control experiment without Zn, in either the ab-
sence or presence of NiI2 did not generate the benzylic fluo-
ride.
2,6-Dimethyl benzyl chloride proved to be ineffective; the
coupling with methyl 4-bormobenzoate only delivered 5 in
24% yield. The coupling of 1-(1-bromoethyl)-3-methylben-
zene with a set of bromobenzenes substituted with elec-
tron-withdrawing groups was generally efficient, generat-
ing the products 6a–d in moderate to excellent yields. Low
yield was observed for 7, which contains a 4-chloro substit-
uent on the benzyl moiety. The more hindered 1-(1-bromo-
propyl)-4-methylbenzene was also competent, which re-
sulted in the formation of 8 in 54% yield. 1-Chloro-2,3-dihy-
dro-1H-indene was compatible with the reaction
conditions, which delivered the products 9a and 9b in mod-
erate to excellent yields. Finally, the coupling of 2-(1-bro-
moethyl)naphthalene with methyl 4-bromobenzoate was
not satisfactory; compound 10 was obtained in only 20%
yield.
The scope of the reaction with respect to electron-dense
aryl bromides was investigated for the coupling with (1-
chloroethyl)benzene. A variety of substituted bromoben-
zenes were competent, providing 11–13 in good yields.
Coupling with unsubstituted bromobenzene generated the
product 14 in 92% yield.
In conclusion, we have systematically studied the cou-
pling of functionalized benzylic chlorides with a wide range
of aryl halides under Ni-catalyzed reductive conditions. In
general, the reaction displays moderate to excellent effi-
ciency for electron-deficient aryl bromides, but it is not ef-
method B
Br
Me
Me
NiI2 (10 mol%)
1b (10 mol%)
Cl
+
KF (100 mol%)
Zn (200 mol%)
DMA, 25 °C, 12 h
OMe
OMe
3m, 88% yield
(2 equiv)
(1 equiv)
Scheme 1 The optimized reaction conditions for 1-bromo-4-methoxy-
benzene (method B)
We then investigated the suitability of substituted ben-
zyl chlorides under the reaction conditions. We first stud-
ied the coupling of methyl 4-bormobenzoate with 1-(bro-
momethyl)benzene derivatives decorated with different
substituents on the benzyl rings by using method A. The 2-,
3-, or 4-methyl groups in 4a–c were tolerated, wherein the
substrate bearing an ortho-methyl group gave the lowest
yield of 44% (Figure 2). The benzyl chloride bearing a strong
electron-withdrawing cyano group, gave 4d in 64% yield.
R
CO2Me
NC
CO2Me
CO2Me
4a, R = 2-Me: 44%a
4b, R = 3-Me: 91%a
4c, R = 4-Me: 62%a
4d: 64%a
5, 24%a
7: 45%a
10, 20%a
CO2Me
Cl
CN
R
Me
6a, R = CO2Me: 81%a
6b, R = Ac: 78%a
6d: 48%a
6c, R = CHO: 51%a
Et
R1
CO2Me
R2
CO2Me
9a, R1 = CO2Me, R2 = H: 82%a
9b, R2 = CN, R2 = Me: 57%a
8: 54%a
O
OMe
OMe
N
R
O
OMe
13, R = t-Bu: 53%b
14, R = H: 92%b
11: 69%b
12: 75%b
Figure 2 Examples of diaryl alkyl methane synthesis based on methods Aa and Bb
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
Q. Zhang et al.
Special Topic
Synthesis
fective for electron-rich aryl counterparts. The electron
properties on the benzene rings of the benzylic chlorides
did not appear to have significant impact on the coupling
yields. The methyl and ethyl substituents on the benzylic
positions were also effective. This work should provide
complementary studies for the concurrent examinations on
arylation of benzyl electrophiles using reductive coupling
strategies.
1H NMR (500 MHz, CDCl3): δ = 7.99–7.97 (m, 2 H), 7.32–7.29 (m, 4 H),
7.23–7.22 (m, 3 H), 4.21 (q, J = 7.21 Hz, 1 H), 3.90 (s, 3 H), 1.67 (d, J =
7.22 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 167.08, 151.76, 145.47, 129.80,
128.55, 127.71, 126.37, 52.02, 44.85, 21.63.
The spectroscopic properties of this compound were consistent with
the data available in the literature.13
4-(1-Phenylethyl)benzonitrile (3i)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
All reactions were conducted under N2 atmosphere. NiI2 and MgCl2
were purchased from Alfa Aesar. All other nickel salts were purchased
from Strem or Alfa Aesar. 1-Chloroethylbenzene was purchased from
TCI (>98%). Methyl 4-bromobenzoate was purchased from Alfa Aesar.
All other aryl bromides were purchased from Damas-Beat (China). Zn
powder was activated by using HCl before use. 4,4′-Dimethyl-2,2′-bi-
pyridine was purchased from Nine-Ding Chemical Co. (China). All
other ligands were purchased from Aldrich unless otherwise noted.
The following solvents were purchased and used as received: DMA
(99.8%, super dry, with molecular sieves, Aldrich), pyridine (99.5%,
safe dry, with molecular sieves, Aldrich), CH3OH (AR Aladdin), CHCl3
(AR Aladdin).
Yield: 66% (40.8 mg, 0.198 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.57–7.56 (m, 2 H), 7.33–7.30 (m, 4 H),
7.24–7.18 (m, 3 H), 4.20 (q, J = 7.26 Hz, 1 H), 1.65 (d, J = 7.25 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 151.94, 144.70, 132.28, 128.69,
128.46, 127.59, 126.65, 119.06, 109.93, 44.91, 21.46.
The spectroscopic properties of this compound were consistent with
the data available in the literature.14
1-[4-(1-Phenylethyl)phenyl]ethan-1-one (3e)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Column chromatography was performed using silica gel 300-400
mesh (purchased from Qingdao-Haiyang Co., China) as the solid sup-
port. All NMR spectra were recorded with a Bruker Avance 500 MHz
spectrometer at STP unless otherwise indicated. 1H and 13C NMR
chemical shifts are reported in δ units, parts per million (ppm) rela-
tive to the chemical shift of residual solvent. Reference peaks for chlo-
roform in 1H and 13C NMR spectra were set at δ = 7.26 ppm and δ =
77.16 ppm, respectively. High-resolution mass spectra (HRMS) were
obtained with a Bruker APEXIII 7.0 and IonSpec 4.7 TESLA FTMS.
Melting points were recorded with a micro melting point apparatus
(X-4, YUHUA Co., Ltd, Gongyi, P. R. of China).
Yield: 83% (55.9 mg, 0.249 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.90–7.89 (m, 2 H), 7.33–7.29 (m, 4 H),
7.23–7.21 (m, 3 H), 4.22 (q, J = 7.20 Hz, 1 H), 2.57 (s, 3 H), 1.67 (d, J =
7.25 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 197.81, 152.05, 145.35, 135.21,
128.62, 128.57, 127.87, 127.61, 126.41, 44.84, 26.61, 21.58.
The spectroscopic properties of this compound were consistent with
the data available in the literature.15
4-(1-Phenylethyl)benzaldehyde (3d)
Method A; General Procedure
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
To a flame-dried Schlenk tube equipped with a stir bar was loaded
aryl bromide (0.3 mmol, 100 mol%) and benzyl chloride (0.6 mmol,
200 mol%), followed by addition of ligand 1b (0.03 mmol, 10 mol%),
zinc powder (39 mg, 0.6 mmol, 300 mol%), and MgCl2 (28.6 mg, 0.3
mmol, 100 mol%). The tube was moved into an anhydrous glove box,
then NiI2 (9.4 mg, 0.03 mmol, 10 mol%) was added. The tube was
capped with a rubber septum and moved out of the glove box. N,N-
Dimethyl acetamide (1 mL) and pyridine (24 μL, 0.3 mmol, 100 mol%)
were added by using a syringe. The mixture was stirred for 16 h un-
der N2 atmosphere at 25 °C, then directly loaded onto a silica column
without work-up. The residue in the reaction vessel was rinsed with
small amount of petroleum ether. Flash column chromatography pro-
vided the product as a solid or oil.
Yield: 40% (25.2 mg, 0.12 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 9.96 (s, 1 H), 7.80 (d, J = 8.22 Hz, 2 H),
7.38 (d, J = 8.11 Hz, 2 H), 7.32–7.29 (m, 2 H), 7.22–7.20 (m, 3 H), 4.23
(q, J = 7.20 Hz, 1 H), 1.67 (d, J = 7.19 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 191.97, 153.64, 145.07, 134.63,
130.00, 128.60, 128.33, 127.61, 126.49, 45.03, 21.53.
HRMS (ESI): m/z [M + H]+ calcd for C15H14O: 211.1117; found:
211.1114.
2-Methyl-4-(1-phenylethyl)benzonitrile (3j)
Synthesized according to method A and purified by column chroma-
tography (SiO2: EtOAc–petroleum ether, 2%).
Method B; General Procedure
Yield: 80% (53.1 mg, 0.24 mmol); colorless oil.
Similar to method A except KF (17.4 mg, 0.3 mmol, 100 mol%) was
used to replace MgCl2 and pyridine.
1H NMR (500 MHz, CDCl3): δ = 7.51 (d, J = 7.99 Hz, 1 H), 7.33–7.30 (m,
2 H), 7.24–7.17 (m, 4 H), 7.13 (d, J = 7.99 Hz, 1 H), 4.16 (q, J = 7.14 Hz,
1 H), 2.50 (s, 3 H), 1.64 (d, J = 7.27 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 151.73, 144.87, 142.03, 132.63,
129.57, 128.65, 127.57, 126.57, 125.64, 118.38, 110.37, 44.87, 21.46,
20.59.
Methyl 4-(1-Phenylethyl)benzoate (3a)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Yield: 95% (68.4 mg, 0.285 mmol); colorless oil.
HRMS (ESI): m/z [M + Na]+ calcd for C16H15N: 244.1097; found:
244.1093.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
Q. Zhang et al.
Special Topic
Synthesis
1-[3-(1-Phenylethyl)phenyl]ethan-1-one (3f)
13C NMR (125 MHz, CDCl3): δ = 167.11, 145.98, 138.00, 136.65,
130.45, 130.02, 129.76, 128.73, 127.99, 126.80, 126.15, 52.02, 39.56,
19.67.
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
The spectroscopic properties of this compound were consistent with
the data available in the literature.17
Yield: 45% (30.2 mg, 0.135 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.87 (s, 1 H), 7.78–7.77 (m, 1 H), 7.42–
7.36 (m, 2 H), 7.31–7.28 (m, 2 H), 7.23–7.18 (m, 3 H), 4.22 (q, J =
7.21 Hz, 1 H), 2.58 (s, 3 H), 1.67 (d, J = 7.26 Hz, 3 H).
Methyl 4-(3-Methylbenzyl)benzoate (4b)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
13C NMR (125 MHz, CDCl3): δ = 198.37, 147.00, 145.66, 137.29,
132.56, 128.65, 128.54, 127.57, 127.24, 126.39, 126.31, 44.73, 26.74,
21.79.
Yield: 91% (65.6 mg, 0.273 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 8.27 Hz, 2 H), 7.27 (d, J =
8.27 Hz, 2 H), 7.21 (t, J = 7.72 Hz, 1 H), 7.05 (d, J = 7.72 Hz, 1 H), 7.01–
6.99 (m, 2 H), 4.00 (s, 2 H), 3.91 (s, 3 H), 2.33 (s, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C16H16O: 247.1093; found:
247.1091.
Methyl 3-(1-Phenylethyl)benzoate (3b)
13C NMR (125 MHz, CDCl3): δ = 167.11, 146.71, 140.09, 138.26,
129.85, 129.76, 128.98, 128.53, 128.08, 127.17, 126.03, 52.03, 41.90,
21.43.
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Yield: 75% (53.8 mg, 0.225 mmol); colorless oil.
Methyl 4-(4-Methylbenzyl)benzoate (4c)
1H NMR (500 MHz, CDCl3): δ = 7.87 (s, 1 H), 7.78–7.77 (m, 1 H), 7.42–
7.36 (m, 2 H), 7.31–7.28 (m, 2 H), 7.23–7.18 (m, 3 H), 4.22 (q, J =
7.21 Hz, 1 H), 2.58 (s, 3 H), 1.67 (d, J = 7.26 Hz, 3 H).
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Yield: 62% (44.6 mg, 0.186 mmol), colorless oil.
13C NMR (125 MHz, CDCl3): δ = 198.37, 147.00, 145.66, 137.29,
132.56, 128.65, 127.57, 127.24, 126.39, 126.31, 44.73, 26.74, 21.79.
1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J = 8.26 Hz, 2 H), 7.25 (d, J =
8.30 Hz, 2 H), 7.12–7.06 (m, 4 H), 3.99 (s, 2 H), 3.90 (s, 3 H), 2.33 (s,
3 H).
The spectroscopic properties of this compound were consistent with
the data available in the literature.16
13C NMR (125 MHz, CDCl3): δ = 167.12, 146.88, 137.10, 135.93,
129.83, 129.32, 128.91, 128.85, 128.02, 52.02, 41.53, 21.04.
5-(1-Phenylethyl)isobenzofuran-1(3H)-one (3k)
The spectroscopic properties of this compound were consistent with
the data available in the literature.18
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 10%).
Yield: 57% (40.7 mg, 0.171 mmol); colorless oil.
Methyl 4-(2,6-Dimethylbenzyl)benzoate (5)
1H NMR (500 MHz, CDCl3): δ = 7.82 (d, J = 8.20 Hz, 1 H), 7.40 (d, J =
8.00 Hz, 1 H), 7.33–7.30 (m, 3 H), 7.24–7.20 (m, 3 H), 5.25 (s, 2 H),
4.28 (q, J = 7.24 Hz, 1 H), 1.68 (d, J = 7.27 Hz, 3 H).
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Yield: 24% (18.3 mg, 0.072 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.91–7.89 (m, 2 H), 7.13–7.06 (m, 5 H),
13C (125 MHz, CDCl3): 171.05, 153.72, 147.16, 144.80, 129.02, 128.70,
127.60, 126.65, 125.72, 123.75, 121.00, 69.57, 45.14, 21.70.
4.10 (s, 2 H), 3.88 (s, 3 H), 2.22 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 167.14, 145.52, 137.13, 136.01,
HRMS (ESI): m/z [M + Na]+ calcd for C16H14O2: 261.0886; found:
261.0883.
129.76, 129.65, 128.25, 127.87, 126.65, 52.00, 35.19, 20.22.
Methyl 2-(1-Phenylethyl)benzoate (3c)
The spectroscopic properties of this compound were consistent with
the data available in the literature.19
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Methyl 4-(4-Cyanobenzyl)benzoate (4d)
Yield: 62% (44.6 mg, 0.186 mmol); colorless oil.
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
1H NMR (500 MHz, CDCl3): δ = 7.79 (dd, J = 1.27, 7.82 Hz, 1 H), 7.43
(td, J = 1.27, 7.86 Hz, 1 H), 7.31–7.18 (m, 7 H), 5.14 (q, J = 6.98 Hz,
1 H), 3.86 (s, 3 H), 1.66 (d, J = 7.09 Hz, 3 H).
Yield: 64% (48.2 mg, 0.192 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.91 (d, J = 8.40 Hz, 2 H), 7.59–7.54 (m,
4 H), 7.27 (d, J = 8.40 Hz, 2 H), 3.92 (s, 3 H), 2.43 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 168.69, 147.41, 146.07, 131.77,
130.18, 128.52, 128.25, 127.90, 125.95, 125.84, 52.07, 39.87, 22.03.
13C NMR (125 MHz, CDCl3): δ = 166.37, 143.70, 132.06, 131.72,
HRMS (ESI): m/z [M + Na]+ calcd for C16H14O2: 263.1043; found:
131.13, 129.84, 129.04, 128.05, 119.18, 109.32, 52.31, 21.86.
263.1038.
The spectroscopic properties of this compound were consistent with
the data available in the literature.20
Methyl 4-(2-Methylbenzyl)benzoate (4a)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Methyl 4-[1-(m-Tolyl)ethyl]benzoate (6a)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Yield: 44% (31.7 mg, 0.132 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.95–7.94 (m, 2 H), 7.20–7.16 (m, 5 H),
Yield: 81% (61.8 mg, 0.243 mmol); colorless oil.
7.10–7.09 (m, 1 H), 4.04 (s, 2 H), 3.90 (s, 3 H), 2.22 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
Q. Zhang et al.
Special Topic
Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.98 (d, J = 8.20 Hz, 2 H), 7.31 (d, J =
8.30 Hz, 2 H), 7.20 (t, J = 7.42 Hz, 1 H), 7.04–7.03 (m, 3 H), 4.18 (q, J =
7.10 Hz, 1 H), 3.91 (s, 3 H), 2.33 (s, 3 H), 1.66 (d, J = 7.10 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 167.12, 151.88, 145.43, 138.10,
129.78, 128.43, 127.99, 127.70, 124.63, 52.02, 44.81, 21.64, 21.52.
Methyl 4-[1-(p-Tolyl)propyl]benzoate (8)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Yield: 54% (43.4 mg, 0.162 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.95 (d, J = 8.38 Hz, 2 H), 7.30 (d, J =
8.38 Hz, 2 H), 7.11 (m, 4 H), 3.89 (s, 3 H), 3.82 (t, J = 7.75 Hz, 1 H), 2.31
(s, 3 H), 2.10–2.05 (m, 2 H), 0.90 (t, J = 7.27 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C17H18O2: 277.1199; found:
277.1198.
13C NMR (125 MHz, CDCl3): δ = 167.11, 150.88, 141.25, 135.86,
129.77, 129.22, 127.94, 127.92, 52.86, 51.98, 28.42, 21.00, 12.71.
1-{4-[1-(m-Tolyl)ethyl]phenyl}ethan-1-one (6b)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
HRMS (ESI): m/z [M + Na]+ calcd for C18H20O2: 291.1356; found:
291.1355.
Yield: 78% (55.7 mg, 0.234 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.89 (d, J = 8.26 Hz, 2 H), 7.32 (d, J =
8.26 Hz, 2 H), 7.20 (m, 1 H), 7.02 (m, 3 H), 4.17 (q, J = 7.12 Hz, 1 H),
2.58 (s, 3 H), 2.32 (s, 3 H), 1.65 (d, J = 7.12 Hz, 3 H).
Methyl 4-(2,3-Dihydro-1H-inden-1-yl)benzoate (9a)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
13C NMR (125 MHz, CDCl3): δ = 197.85, 152.16, 145.30, 138.13,
135.16, 128.59, 128.44, 128.40, 127.84, 127.16, 124.59, 44.79, 26.60,
21.58, 21.51.
HRMS (ESI): m/z [M + Na]+ calcd for C17H18O: 261.1250; found:
261.1248.
Yield: 82% (62.1 mg, 0.246 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 8.00 (d, J = 8.32 Hz, 2 H), 7.32 (d, J =
7.37 Hz, 1 H), 7.27 (d, J = 8.16 Hz, 2 H), 7.22 (t, J = 7.37 Hz, 1 H), 7.15
(t, J = 7.37 Hz, 1 H), 6.94 (d, J = 7.47 Hz, 1 H), 4.41 (t, J = 8.36 Hz, 1 H),
3.92 (s, 3 H), 3.11–2.96 (m, 2 H), 2.65–2.59 (m, 1 H), 2.11–2.03 (m,
1 H).
4-[1-(m-Tolyl)ethyl]benzaldehyde (6c)
13C NMR (125 MHz, CDCl3): δ = 167.12, 150.99, 146.08, 144.36,
129.90, 128.32, 128.18, 126.88, 126.55, 124.88, 124.53, 52.06, 51.65,
36.43, 31.89.
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
HRMS (ESI): m/z [M + Na]+ calcd for C17H16O2: 275.1043; found:
Yield: 51% (34.3 mg, 0.153 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 9.97 (s, 1 H), 7.81 (d, J = 8.16 Hz, 2 H),
7.39 (d, J = 8.14 Hz, 2 H), 7.20 (t, J = 7.89 Hz, 1 H), 7.03 (m, 3 H), 4.19
(q, J = 7.22 Hz, 1 H), 2.32 (s, 3 H), 1.66 (d, J = 7.21 Hz, 3 H).
275.1041.
4-(2,3-Dihydro-1H-inden-1-yl)-2-methylbenzonitrile (9b)
13C NMR (125 MHz, CDCl3): δ = 192.02, 153.78, 145.04, 138.20,
134.58, 130.00, 128.49, 128.41, 128.31, 127.25, 124.60, 44.98, 21.54,
21.50.
HRMS (ESI): m/z [M + H]+ calcd for C16H16O: 225.1274; found:
225.1272.
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Yield: 57% (39.4 mg, 0.171 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.53 (d, J = 7.93 Hz, 1 H), 7.32 (d, J =
7.41 Hz, 1 H), 7.22 (t, J = 7.41 Hz, 1 H), 7.15 (m, 2 H), 7.08 (d, J =
7.81 Hz, 1 H), 6.91 (d, J = 7.51 Hz, 1 H), 4.35 (t, J = 8.24 Hz, 1 H), 3.10–
3.04 (m, 1 H), 3.01–2.95 (m, 1 H), 2.63–2.56 (m, 1 H), 2.51 (s, 3 H),
2.06–1.98 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 151.00, 145.51, 144.34, 142.15,
132.73, 129.95, 127.04, 126.63, 126.13, 124.60, 118.40, 110.60, 51.64,
36.32, 31.83, 20.53.
2-Methyl-4-[1-(m-tolyl)ethyl]benzonitrile (6d)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Yield: 48% (33.8 mg, 0.144 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.51 (d, J = 7.99 Hz, 1 H), 7.17 (m, 3 H),
7.02 (m, 3 H), 4.11 (q, J = 4.11 Hz, 1 H), 2.51 (s, 3 H), 2.33 (s, 3 H), 1.62
(d, J = 4.11 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C17H15N: 256.1097; found:
256.1095.
Methyl 4-[1-(Naphthalen-2-yl)ethyl]benzoate (10)
Methyl 4-[1-(4-Chlorophenyl)ethyl]benzoate (7)
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Synthesized according to method A and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 2%).
Yield: 20% (17.4 mg, 0.06 mmol); colorless oil.
Yield: 45% (34.5 mg, 0.135 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J = 8.23 Hz, 2 H), 7.79 (d, J =
7.91 Hz, 2 H), 7.75 (d, J = 8.39 Hz, 1 H), 7.68 (s, 1 H), 7.48–7.42 (m,
2 H), 7.32 (d, J = 8.15 Hz, 2 H), 7.28 (s, 1 H), 4.36 (q, J = 7.14 Hz, 1 H),
3.89 (s, 3 H), 1.74 (d, J = 7.15 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 167.08, 151.58, 142.84, 133.49,
132.49, 132.18, 129.80, 128.17, 128.09, 127.83, 127.74, 127.61,
126.62, 126.12, 125.59, 125.50, 52.04, 44.91, 21.54.
1H NMR (500 MHz, CDCl3): δ = 7.95 (d, J = 8.35 Hz, 2 H), 7.26–7.24 (m,
4 H), 7.12 (d, J = 8.40 Hz, 2 H), 4.16 (q, J = 7.19 Hz, 1 H), 3.89 (s, 3 H),
1.62 (d, J = 7.12 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 166.98, 151.11, 143.93, 132.11,
129.86, 128.97, 128.63, 128.24, 127.60, 52.06, 44.22, 21.56.
HRMS (ESI): m/z [M + Na]+ calcd for C16H15ClO2: 297.0653; found:
297.0651.
The spectroscopic properties of this compound were consistent with
the data available in the literature.21
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
Q. Zhang et al.
Special Topic
Synthesis
1,2,3-Trimethoxy-5-(1-phenylethyl)benzene (11)
(3) For selected examples of allylation of alkyl halides, see: (a) Dai,
Y.; Wu, F.; Zang, Z.; You, H.; Gong, H. Chem. Eur. J. 2012, 18, 808.
(b) Anka-Lufford, L. L.; Prinsell, M. R.; Weix, D. J. J. Org. Chem.
2012, 77, 9989. (c) Qian, X.; Auffrant, A.; Felouat, A.; Gosmini, C.
Angew. Chem. Int. Ed. 2011, 50, 10402.
(4) For dimerization of two alkyl electrophiles, see: (a) Peng, Y.;
Luo, L.; Yan, C.-S.; Zhang, J.-J.; Wang, Y.-W. J. Org. Chem. 2013,
78, 10960. (b) Prinsell, M. R.; Everson, D. A.; Weix, D. J. Chem.
Commun. 2010, 5743. (c) Goldup, S. M.; Leigh, D. A.; McBurney,
R. T.; McGonigal, P. R.; Plant, A. Chem. Sci. 2010, 1, 383.
(5) For selected examples for alkyl–aryl bond formation, see:
(a) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010,
132, 920. (b) Everson, D. A.; Jones, B. A.; Weix, D. J. J. Am. Chem.
Soc. 2012, 134, 6146. (c) Yan, C.-S.; Peng, Y.; Xu, X.-B.; Wang, Y.-
W. Chem. Eur. J. 2012, 18, 6039. (d) Molander, G. A.; Traister, K.
M.; O’Neill, B. T. J. Org. Chem. 2015, 80, 2907. (e) Wang, S.; Qian,
Q.; Gong, H. Org. Lett. 2012, 14, 3352.
Synthesized according to method B and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 10%).
Yield: 69% (56.4 mg, 0.207 mmol); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.30 (m, 2 H), 7.22 (m, 3 H), 6.44 (s,
2 H), 4.09 (q, J = 7.17 Hz, 1 H), 3.82 (s, 3 H), 3.81 (s, 6 H), 1.63 (d, J =
7.17 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 153.07, 146.17, 142.07, 128.40,
127.48, 126.14, 105.22, 104.72, 60.84, 56.07, 45.04, 22.01.
HRMS (ESI): m/z [M + Na]+ calcd for C17H16O2: 295.1305; found:
295.1304.
2-[3-(1-Phenylethyl)phenyl]isoindoline-1,3-dione (12)
Synthesized according to method B and purified by column chroma-
tography (SiO2; EtOAc–petroleum ether, 10%).
(6) For selected examples for alkyl-acyl bond formation, see:
(a) Wu, F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Org. Lett. 2012, 14,
3044. (b) Yin, H.; Zhao, C.; You, H.; Lin, Q.; Gong, H. Chem.
Commun. 2012, 48, 7034. (c) Zhao, C.; Jia, X.; Wang, X.; Gong, H.
J. Am. Chem. Soc. 2014, 136, 17645. (d) Wotal, A. C.; Weix, D. J.
Org. Lett. 2012, 14, 1476. (e) Jia, X.; Zhang, X.; Qian, Q.; Gong, H.
Chem. Commun. 2015, 51, 10302.
(7) For coupling involving generation of organometallic reagents in
situ, see: (a) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am.
Chem. Soc. 2009, 131, 15592. (b) Czaplik, W. M.; Mayer, M.; von
Wangelin, A. J. Angew. Chem. Int. Ed. 2009, 48, 607. (c) Liu, J.-H.;
Yang, C.-T.; Lu, X.-Y.; Zhang, Z.-Q.; Xu, L.; Cui, M.; Lu, X.; Xiao, B.;
Fu, Y.; Liu, L. Chem. Eur. J. 2014, 20, 15334.
(8) (a) Cherney, A. H.; Reisman, S. E. J. Am. Chem. Soc. 2014, 136,
14365. (b) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. J. Am.
Chem. Soc. 2013, 135, 7442. (c) Kadunce, N. T.; Reisman, S. E.
J. Am. Chem. Soc. 2015, 137, 10480.
(9) (a) Moragas, T.; Gaydou, M.; Martin, R. Angew. Chem. Int. Ed.
2016, 55, 5053. (b) Leon, T.; Correa, A.; Martin, R. J. Am. Chem.
Soc. 2013, 135, 1221.
Yield: 75% (73.6 mg, 0.225 mmol); white solid.
1H NMR (500 MHz, CDCl3): δ = 7.94 (dd, J = 3.08, 2.34 Hz, 2 H), 7.77
(dd, J = 3.04, 2.34 Hz, 2 H), 7.42 (m, 1 H), 7.29 (m, 7 H), 7.19 (m, 1 H),
4.23 (q, J = 7.18 Hz, 1 H), 1.69 (d, J = 7.18 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 167.34, 147.48, 145.76, 134.39,
131.79, 131.66, 129.05, 128.49, 127.72, 127.53, 126.25, 125.89,
124.23, 124.71, 44.64, 21.84.
HRMS (ESI): m/z [M + Na]+ calcd for C22H17NO2: 350.1151; found:
350.1147.
Acknowledgment
Financial support was provided by the Chinese NSF (Nos. 21172140,
21372151 and 21572127), Shanghai Municipal Education Commis-
sion for the Programs for Professor of Special Appointment (Dongfang
Scholarship) and Peak Discipline Construction (N.13-A302-15-L02),
and Shanghai Science and Technology Commission (14DZ2261100).
(10) (a) Acker, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J.
Chem. Sci. 2015, 6, 1115. (b) Durandetti, M.; Gosmini, C.;
Perichon, J. Tetrahedron 2007, 63, 1146.
(11) (a) Tellis, J. C.; Primer, D. N.; Monlander, G. A. Science 2014, 345,
433. (b) Ryu, D.; Primer, D. N.; Tellis, J. C.; Molander, G. A. Chem.
Eur. J. 2016, 22, 120. (c) Gutierrez, O.; Tellis, J. C.; Primer, D. N.;
Monlander, G. A.; Kozlowski, M. C. J. Am. Chem. Soc. 2015, 137,
4896.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562442.
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

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Special Topic
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H