Nickel-Catalyzed Cyanation of Phenol Derivatives with Zn(CN)2 Involving C-O Bond Cleavage

Article abstract of DOI:10.1021/acs.joc.8b02498

An efficient nickel-catalyzed cyanation of aryl sulfonates, fluorosulfonates, and sulfamates with Zn(CN)₂ was developed, which provides a facile access to the nitrile products in generally good to excellent yields. The reaction is accomplished by using Ni^II complex as the precatalyst and DMAP as the additive. The method also displays wide functional group compatibility; for example, keto, methoxy, N,N-dimethylamino, cyano, ester, and pyridyl groups are well-tolerated during the reaction process.

Full text of DOI:10.1021/acs.joc.8b02498

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Article
Nickel-Catalyzed Cyanation of Phenol Derivatives
with Zn(CN)2 Involving C-O Bond Cleavage
Yi Gan, Gaonan Wang, Xin Xie, and Yuanhong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02498 • Publication Date (Web): 11 Oct 2018
Downloaded from http://pubs.acs.org on October 13, 2018
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Nickel-Catalyzed Cyanation of Phenol Derivatives with Zn(CN) Involving C-O Bond
2
Cleavage
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Yi Gan, Gaonan Wang, Xin Xie and Yuanhong Liu*
State Key Laboratory of Organometallic Chemistry,
Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese
Academy of Sciences, 345 Lingling Lu, Shanghai 200032, People’s Republic of China
Fax: (+86) 21-64166128, E-mail: yhliu@sioc.ac.cn
Zn(CN)2
cat. [Ni], DMAP
OR
CN
R1 Ar
R1 Ar
o
CH CN, 50-100 C
3
R = Ms, SO F, Tf, Ts, SO NMe
2
41 examples, up to 94% yield
2
2
less toxic cyanide source
Ni complex as the precatalyst
high efficiency, mild reaction conditions
extendable to vinyl sulfonates
II
Abstract: An efficient nickel-catalyzed cyanation of aryl sulfonates, fluorosulfonates
or sulfamates with Zn(CN) has been developed, which provides a facile access to the
2
nitrile products in generally good to excellent yields. The reaction is accomplished by
II
using Ni complex as the precatalyst and DMAP as the additive. The method also
displays wide functional group compatibility, for example, keto, methoxy,
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N,N-dimethylamino, cyano, ester or pyridyl groups are well tolerated during the
reaction process.
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INTRODUCTION
Aromatic nitriles are highly important intermediates, which not only serve as
1
efficient building blocks for a variety of synthetic transformations, but also are present
in a large number of pharmaceuticals, agrochemicals, bioactive natural products and
functional materials.2 Traditionally, aryl nitriles were prepared through the
3
4
Rosenmund-von Braun reaction or the Sandmeyer reaction . However, these reactions
have some limitations such as the use of aryl diazonium salts, high temperature and
5
6
limited substrate scope. Transition metals such as Pd - or Ni -catalyzed cross-coupling
reactions of aryl halides with cyanide sources have become one of the most promising
approaches to access aryl nitriles. Despite much progress in this area, the development
of efficient and practical methods for the synthesis of aryl nitriles utilizing low-cost,
more available and green reagents in transformations are still highly desired. Compared
with aryl halides, phenol-derived electrophiles are more attractive for cross-coupling
reactions since these compounds are naturally abundant or can be readily prepared from
7
easily-available aromatic substrates. In addition, no hazardous halogen-containing
waste is generated by using these electrophiles. However, due to the higher C-O bond
strength relative to C-Cl, C-Br, and C-I bond, the use of phenol derivatives as
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electrophilic coupling partners in the cross-coupling reactions is highly challengeable.
Although several practical methods for the synthesis of aryl nitriles from phenol
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derivatives have been developed using palladium catalyst, the earth-abundant nickel
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catalyzed cyanation of C-O electrophiles have less been developed. It was not until
1989 that the first metal-catalyzed cyanation of aryl triflates with KCN was reported by
0
Widdowson et al. catalyzed by Ni (PPh ) formed in situ by reduction of (PPh ) NiBr
3
4
3 2
2
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a
with Zn under highly concentrated conditions ( ≥ 2 M). Soon after, Takagi et al.
reported a similar catalyst system for nickel-catalyzed cyanation of aryl triflates.9b
Since then, only very limited examples utilizing phenol derivatives as electrophiles
have been reported. In 1995, Percec et al. reported that cyanation of less reactive aryl
mesylates could be achieved by nickel-catalyzed reaction with KCN. In one example,
they observed that a moderate yield (46% GC yield) of benzonitrile could be obtained
9
c
using Zn(CN) as the cyanide source and NaBr as an additive. In 2016, Itami and
2
Yamaguchi reported that aryl pivalates or carbamates could be cyanated by
aminoacetonitrile catalyzed by nickel complex bearing an unique diphosphine ligand
9
d
o
such as dcype or dcypt. However, high reaction temperature of 150 C was required
in these reactions. Recently, we reported an efficient nickel-catalyzed cyanation of
1
0
hetero(aryl) chlorides with less toxic Zn(CN) using DMAP as the additive. Inspired
2
by this work, in this paper, we report Ni-catalyzed cyanation of phenol derivatives with
Zn(CN) for the synthesis of aryl nitriles by C-O bond cleavage. These reactions were
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carried out at temperatures ranging from 50 to 100 C, allowing the cyanation of aryl
sulfonates, fluorosulfonates or sulfamates to the corresponding nitriles (Scheme 1). Under
these conditions, vinyl sulfonates could also be cyanated by Zn(CN) . During our work
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going on, Morandi reported a nickel-catalyzed cyanation of aryl triflates or aryl
chlorides using butyronitrile as the cyanating reagent in the presence of Lewis acid.11
More recently, Heravi and Panahi reported that phenols activated by
1
2
2,4,6-trichloro-1,3,5-triazine (TCT) could be cyanated by Zn(CN) . However, these
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reactions utilized highly unstable Ni(COD) as the catalyst.
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Scheme 1. Nickel-catalyzed Cyanation of Phenol Derivatives
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Widdowson et al. and Takagi et al. (1989), Percec et al. (1995)
cat. Ni(II)/PPh /Zn
3
Ar OR + KCN
R = Tf, Ms
Ar CN
2016, Itami and Yamaguchi et al.
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CN cat. [Ni]/base
Ar OR +
Ar CN
O
N
o
toluene, 150 C
R = Piv, C(O)NMe , Ts, Ms, Tf, OSO NMe , OP(O)(OEt)
2
2
2
3
2017, our previous work:
cat. [Ni]/DMAP
Ar Cl + Zn(CN)2
Ar CN
o
CH CN, 50-80 C
3
This work:
cat. [Ni]/DMAP
Ar OR + Zn(CN)2
Ar CN
o
CH CN, 50-100 C
3
R = Ms,SO F, Tf, Ts, SO NMe
2
2
2
2017, Morandi et al.
cat. Ni(COD) /Xantphos
2
AlCl , Et N
3
3
CN
Ar OTf
+
Ar CN
Ar CN
o
toluene, 50 C
2018, Heravi and Panahi et al.
OAr
cat. Ni(COD) /dcype
2
+
Zn(CN)2
N
N
o
dioxane, 110 C
ArO
N
OAr
RESULTS AND DISCUSSION
We first investigated the nickel-catalyzed cyanation of 4-acetylphenyl
methanesulfonate 1a bearing an electron-withdrawing group with Zn(CN) under our
2
previous conditions for cyanation of aryl halides.10 To our delight, the desired
4-acetylbenzonitrile 2a was obtained in a high yield of 81% (Table 1, entry 1).
However, when we applied this reaction condition for the cyanation of less reactive
4
-methoxyphenyl methanesulfonate 1b bearing an electron-donating group, only 19%
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of the corresponding product 2b was obtained, possibly due to its lower reactivity
towards oxidative addition in the catalytic cycle (entry 2). In order to find out more
general reaction conditions that could be compatible with a wide range of the functional
groups, we continued to explore the reaction conditions using 1a as the reaction
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partner. We first investigated the effects of ligands using NiBr (DME) as a catalyst in
2
the presence of 1.5 equiv of DMAP. Monodentate ligands such as PMe Ph or PMePh
2
2
provided 2a in good to high yields of 76-90% (entries 3-4), while PPh , which has been
3
shown to be an active ligand in Ni-catalyzed cyanation of aryl triflates with KCN,9a-b
afforded the product in only 26% yield (entry 5). The use of PCy resulted in only trace
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amount of the desired product (entry 6). Further optimizations revealed that bidentate
ligands such as dppf and DPEphos were also highly effective for this reaction (entries
7-8), while Xantphos with a large bite angle (β = 111°) resulted in erosion in yield
(entry 9). The best result was obtained using dppb as the ligand (entry 10). Reducing
the amount of DMAP to 1.0 equiv or
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Table 1. Optimization of the Reaction Conditions
5
mol % catalyst
ligand
0 mol % Zn
DMAP
2
R1
R1
OMs + Zn(CN)2
.8 equiv
CN
o
1
1
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CH CN, 80 C, 12 h
3
0
1a or 1b
2
a or 2b
1
1
R = COMe (1a); R = OMe (1b)
entry substrate
catalyst
ligand (mol %) DMAP (equiv) yield (%)a
1
2
3
4
1a
1b
1a
1a
NiCl •6H O
dppf (6)
1
81
19
76
90
2
2
NiCl •6H O
dppf (6)
1
2
2
NiBr (DME)
PMe2Ph (12)
PMePh2 (12)
1.5
1.5
2
NiBr (DME)
2
5
6
7
1a
1a
1a
1a
NiBr (DME)
PPh (12)
1.5
1.5
1.5
26
5
2
3
NiBr (DME)
PCy3 (12)
dppf (6)
2
NiBr (DME)
87
2
8
9
1
1
NiBr (DME)
DPEphos (6)
Xantphos (6)
dppb (6)
1.5
1.5
1.5
1
87
2
1a
1a
1a
NiBr (DME)
35
2
0
1
NiBr (DME)
94
2
NiBr (DME)
dppb (6)
87
2
1a
NiBr2(DME)
dppb (6)
1
2b
1.5
1.5
1.5
1.5
86
13
1a
1a
1a
1a
1a
1a
NiCl (DME)
dppb (6)
dppb (6)
dppb (6)
93
2
14
NiCl •6H O
89
2
2
15
Ni(acac)2
(-97)
16
17
18
NiBr (DME)
dppb (6)
dppb (6)
0
19 (-73)
(-98)
2
-
1.5
NiBr (DME)
-
1.5
1.5
(-97)
(-98)
2
1
2
2
9c
0
1
a
NiBr2(DME)
dppb (6)
1b
NiBr (DME)
dppb (6)
dppb (12)
dppb (6)
1.5
1.5
1.5
61
2
1d
1
b
a
NiBr2(DME)
NiBr2(DME)
80
22e
1
0 (-66)
a
b
o
c
The yields of the recovered 1a are shown in the parentheses. 60 C. In the
d
absence of Zn. 10 mol % NiBr (DME), 12 mol % dppb, 40 mol % Zn and 1.5
2
e
equiv DMAP were used. 1.2 equiv TMSCN was used instead of 0.8 equiv
Zn(CN)2.
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lowering the reaction temperature to 60 °C led to a slightly drop in the yield of 2a
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(
entries 11-12). NiCl (DME) or NiCl ·6H O also catalyzed the desired transformation
2 2 2
efficiently (entries 13-14). However, Ni(acac) failed to give the desired nitrile (entry
2
1
5). In the absence of DMAP, 2a was formed in 19% yield (entry 16). The results
indictaed that DMAP played a crucial role. And DMAP may have the effect on the
activation of Zn(CN) by forming of a DMAP-Zn(CN) complex, which facilitates the
2
2
10
transmetalation, or acts as a co-ligand. Control experiments indicated that the reaction
could not proceed in the absence of the nickel catalyst, a ligand or zinc (entries 17-19).
Under the conditions shown in entry 10, the use of less reactive substrate 1b gave 2b in
61% yield (entry 20). To our delight, the yield of 2b could be improved to 80% by
doubling the amounts of NiBr (DME), dppb and Zn (entry 21). It was noted that no
2
desired nitrile was observed using other cyanide source such as TMSCN under the
conditions shown in entry 10.
Next, we concentrated on the examination of the substrate scope of this
Ni-catalyzed cyanation reaction under the conditions shown in Table 1, entry 10. In
some cases, higher catalyst loading was employed in order to improve the product
yields. To our delight, a wide range of electron-donating and electron-withdrawing
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groups could be accommodated in this reaction (Scheme 2). We first investigated the
electronic effect of the substituents on the aryl moiety of the aryl mesylates. For
1
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Scheme 2. Scope of the Ni-Catalyzed Cyanation of Aryl Mesylates with Zn(CN)2
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mol % NiBr (DME)
2
mol % dppb
0 mol % Zn
.5 equiv DMAP
R
R
OMs + Zn(CN)2
.8 equiv
CN
o
CH CN, 80 C, 12 h
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For aryl or heteroaryl mesylates
CN CN
CN
CN
O
MeO
Me
2c, 77% (85%)
nBu
2b, 80%a
a
a,b
2d, 76%a
2a, 94%
10 mmol scale, 92%
CN
CN
CN
CN
O
tBu
O
Me
OMe HOH C
2
2
e, 64%a,c
2f, 64%a
2g, 73%
2h, 94%
2l, 88%
MeO
CN
CN
Me N
CN
CN
2
O
NC
OMe
Ph
63% (84%)d
2
i, 87%
2j, 86%
2k
,
CN
CN
CN
EtO C
CN
2
N
O
N
OMe
2p, 73%a
2m, 95%
2n, 93%
2o, 48%
O
NC
H
N
H
H
H
NC
CN
2
q, 66%a
2r, 79%
For naphthyl or biaryl mesylates
CN
Ph
CN
2
s, 94%e
2t, 89%e
2u, 93%
2z, 86%
MeO
R
CN
S
CN
CN
R = Me, 2v, 85%
R = F, 2w, 77%
R = CN, 2x, 86%
2y, 91%
1
0
a
10 mol % NiBr (DME), 12 mol % dppb, 40 mol % Zn and 1.5 equiv DMAP were
2
b
c
o
d
e
o
used. NMR yield. 100 C. 12 mol % PMePh was used instead of dppb. 50 C.
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example, para-methyl substituted aryl mesylate transformed to the nitriles 2c in 85%
NMR yield (due to the low boiling point of this product, a NMR yield of 2c was
n
provided). When the para-substituent was a larger Bu group, a similar yield of 2d was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
t
obtained (76%). The presence of a bulky Bu group at the para-position was cyanated
smoothly, although higher catalyst loading and temperature were needed (2e). Other
functional groups such as 2-methoxy-4-methyl, p-CH OH or methylenedioxy groups
2
could also be well tolerated, and the corresponding products 2f-2h were obtained in
moderate to high yields. Aryl mesylate bearing an N,N-dimethylamino group was
compatible to provide 2i in 87% yield. Substrate with two m-methoxy groups showed a
high reactivity for this reaction (2j). The presence of a benzoyl group on the aryl ring
resulted in moderate yield (63%) of the desired nitrile 2k under the standard conditions.
Remarkably, using a monodentate phosphine ligand PMePh instead of dppb improved
2
the yield of 2k to 84%. Other electron-withdrawing groups such as cyano and ester
groups were well tolerated (2l-2n). Heterocyclic substrates such as pyridyl or
quinolyl-substituted mesylates were also suitable (2o and 2p). Unprotected indole
substrate was also compatible in the reaction (2q). Estrone derivative underwent the
cyanation smoothly to give the corresponding nitrile 2r in 79% yield. Naphthyl
sulfonates, which were proved to be more efficient electrophiles than phenyl sulfonates
in Ni-catalyzed cross-coupling via C-O bond activation,13 coupled with Zn(CN)2
o
cleanly at 50 C to afford 2s and 2t in high yields. The reaction could be applied to
1
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biaryl systems. A wide variety of functional groups such as methyl (2v), fluoride (2w),
cyano (2x), methoxy (2y), and 3-thienyl (2z) on the aryl rings were well tolerated. To
demonstrate the practicality of this method, a gram-scale synthesis of 2a was conducted
under the standard reaction conditions, and it was found that 2a was obtained in an
excellent yield of 92%.
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α,β-Unsaturated nitriles serve as important building blocks and also are present in
natural products and pharmaceutical agents.2a,14 The above results encouraged us to
investigate the cyanation of enol derivatives with Zn(CN) (Scheme 3). To our delight,
2
the expected cross-coupling took place smoothly. For example, enol substrates
prepared from α- or β-tetralone derivatives were converted to nitriles 4a and 4b in 86%
and 92% yields, respectively. Vinyl tosylate bearing a cyclohexene ring converted
efficiently to 4c. Linear vinyl tosylate 3d coupled with Zn(CN) well
2
Scheme 3. Ni-Catalyzed Cyanation of Enol Derivatives with Zn(CN)2
1
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mol % NiBr (DME)
2
6 mol % dppb
20 mol % Zn
R1
R1
1.5 equiv DMAP
OR + Zn(CN)2
.8 equiv
CN
o
CH CN, 80 C, 12 h
3
0
3
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
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3
4
4
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4
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0
1
2
3
4
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9
0
1
2
3
4
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0
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2
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2
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9
0
CN
CN
CN
Ph
R = Ts, 4a, 86%
R = Ms, 4b, 92%
R = Ts, 4c, 87%
CN
Ph
Ph
CN
CN
b
R = Ts , 4f, 90%
a
R = Ts, 4d, 81%
R = Ts , 4e, 60%
(
Z/E = 14:1)
a
b
Z-3e was used. Z-3f was used.
to afford 4d in 81% yield. Moreover, when stereodefined (Z)-3e was used as the
substrate, the corresponding product (Z)-4e was formed as the major product. In the
case of (Z)-3f, the product 4f was obtained as a mixture of Z/E isomers in a ratio of
1
4:1, indicating a slight double bond isomerization occurred during the process.
The reactivity of other electrophiles with different protection groups was also
investigated (Scheme 4). Aryl fluorosulfonates, which can be easily prepared from
1
5
phenol and sulfuryl fluoride in the presence of a base, have been utilized as an
Scheme 4. Scope of the Ni-Catalyzed Cyanation of Phenol Derivatives with Zn(CN)2
1
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2
2
2
2
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5
5
5
5
5
5
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5
6
2
1
mol % NiBr (DME)
2
mol % dppb
0 mol % Zn
.5 equiv DMAP
R1
R1
OR + Zn(CN)2
.8 equiv
CN
o
CH CN, 80 C, 12 h
3
0
0
1
2
3
4
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9
0
1
2
3
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0
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0
1
2
3
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9
0
5
, 6
2
For aryl fluorosulfonates (R = SO F)
2
MeOC
CN
CN
MeO
O
CN
CN
Me
2c
CN
a, 88%a
60% (68%)b
2
2b, 68%
,
CN
N
tBu
N
H
2p, 92%a
2
e, 61%
2za, 65%
For other phenol derivatives
from R = Tf (6a), 86%
CN
from R = Ts (6b), 94%
from R = SO NMe (6c), 68%
c
MeOC
2
2
2a
from R = H (6d), 0%
a5 mol % NiBr (DME), 6 mol % dppb, 20 mol % Zn in DMF. NMR yield.
c10 mol % NiBr (DME), 12 mol % dppb, 40 mol % Zn and 1.5 equiv
b
2
2
o
DMAP in CH CN at 100 C.
3
1
6
inexpensive alternative to aryl halides in the cross-coupling reactions. Until now,
examples
of
cyanation
reactions
of
aryl
fluorosulfonates
under
transition-metal-catalyzed conditions are scarce.8g Here we found that aryl
fluorosulfonates 5 could be successfully converted into the nitriles in moderate to
excellent yields under mild reaction conditions. When the 4-acetylphenyl
sulfurofluoridate was used, the desired product 2a was obtained in 88% yield in the
absence of DMAP. Aryl fluorosulfonates bearing electron-donating group such as
t
methoxy, methyl, Bu and amide substituents underwent cyanation smoothly (2b-2c, 2e,
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2
za). Heterocyclic substrate such as quinolyl-substituted fluorosulfonate was also
compatible (2p). Excellent product yields were also achieved using 4-acetylphenyl
triflate 6a and tosylate 6b as the substrates. Aryl sulfamate 6c was also a suitable
coupling partner. Unfortunately, unprotected phenol 6d was not suitable for this
reaction.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
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3
3
3
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0
1
2
3
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5
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7
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9
0
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3
4
5
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9
0
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2
3
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5
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9
0
1
2
3
4
5
6
7
8
9
0
Finally, the catalytic systems without using the reducing agent of Zn were
Scheme 5. Ni-Catalyzed Cyanation without Using Reducing Agent
5
mol % Ni(cod)2
6 mol % dppf
1.5 equiv DMAP
OMs
CN
+
Zn(CN)2
.8 equiv
(1)
(2)
o
CH CN, 80 C, 12 h
3
MeOC
MeOC
2a, 96%
0
1
a
Ph
P
2
5
1
mol % Ni(II) complex 7
.5 equiv DMAP
Cl
Fe
Ni
1a + Zn(CN)2
2a, 85%
o
CH CN, 80 C, 12 h
P
3
0
.8 equiv
Ph
2
7
examined. It was found that Ni(COD) could catalyze the cyanation reaction of 1a with
2
a high yield (Scheme 5, eq 1). When pre-prepared air-stable Ni(II) complex
[(dppf)Ni(II)(Cl)(o-MeC H )] 7 was used as the catalyst, 2a could also be formed in
6
4
8
5% yield (Scheme 5, eq 2). These results indicated the involvement of a catalytically
active Ni(0) species in the reaction.
1
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5
6
We propose the following reaction mechanism for this reaction, which is similar to
that of metal-catalyzed cyanation reactions of aryl halides with metal cyanides (Scheme
6
). The first step involves the formation of Ni(0) species by reduction of Ni(II) complex
0
1
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4
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7
8
9
0
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2
3
4
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7
8
9
0
with Zn. This is followd by oxidative addition of aryl mesylate to Ni(0) to give an
arylnickel(II) intermediate 8. Transmetalation of 8 with Zn(CN) in the presence of
2
DMAP as a promotor occurs to give complex 10. This process is possibly accelerated
through the formation of “ate” complex 9 with enhanced
Scheme 6. Possible Reaction Mechanism
NiBr (DME)
2
Zn, L
ZnCl2
Ar OMs
LnNi(0)
1
Ar CN
Ar
LnNi(II)
OMs
DMAP
Ar
8
Ar DMAP
LnNi
LnNi
CN
CN
Zn(CN)2
1
0
11
N
DMAP
Zn(CN)2
9
NMe2
solubility and reactivity. Reductive elimination of 10 delivers the target nitriles. It is
possible that DMAP may ligate with Ni in complex 11 to facilitate the reductive
elimination by forcing the aryl and cyanide groups into closer proximity. The
1
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analogous bimolecular attack leading to a five-coordinate intermediate involved in
reductive elimination of benzonitrile from (cyano)phenylnickel(II) complex has been
reported.17
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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1
2
3
4
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8
9
0
CONCLUSION
In summary, we have developed an efficient methodology for the conversion of
phenol derivatives to aryl nitriles by using NiBr (DME)/dppb/Zn/DMAP as the catalyst
2
system and Zn(CN) as the cyanating reagent. Aryl mesylates, fluorosulfonates,
2
triflates, tosylates, sulfamates as well as vinyl sulfonates all coupled well with
Zn(CN) . The reaction also displays wide functional group compitability, for example,
2
keto, methoxy, N,N-dimethylamino, cyano, ester or pyridyl groups were well tolerated
during the reaction. This method is also highly useful to pharmaceutical chemists for
the drug discovery and development. Further extensions of the electrophiles to other
phenol derivatives for cyanation reactions are in progress.
EXPERIMENTAL SECTION
General Methods. Unless noted, all reactions were carried out using standard Schlenk
technique under an argon atmosphere or a dry box technique under a nitrogen atmosphere.
Tetrahydrofuran was distilled from sodium and benzophenone. MeCN was dried using
Innovative Technology Solvent Purifier. N,N-Dimethylformamide was distilled from calcium
1
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2
2
2
2
2
2
2
2
2
3
3
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3
3
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5
6
hydride. o-Tolylmagnesium chloride (1.0 M solution in THF) was purchased from J&K
Chemical Company. Zn(CN) was purchased from Alfa Aesar. Zinc powder (99.9% metals
2
basis, -100 mesh) was purchased from Alfa Aesar. Before using, zinc flake was stirred with 1
M HCl aqueous solution, filtered and washed thoroughly with water, acetone and diethyl ether
and dried under vacuum. NiBr (DME) and NiCl (DME) were purchased from Sigma-Aldrich.
0
1
2
3
4
5
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8
9
0
1
2
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0
1
2
3
4
5
6
7
8
9
0
2
2
NiCl ·6H O was purchased from Alfa Aesar. Ni(COD) and Ni(acac) was purchased from
2
2
2
2
Strem Chemicals Inc. [(dppf)Ni(II)(Cl)(o-MeC H )] 7 was synthesized according to published
6
4
1
0
methods. Unless otherwise noted, all other reagents and starting materials were purchased
1
13
from commercial sources. H and C NMR spectra were recorded at room temperature in
CDCl or d -DMSO (containing 0.03% TMS) solutions on Varian or Agilent XL-400 MHz
3
6
1
spectrometer. H NMR spectra was recorded with tetramethylsilane (0.00 ppm) or solvent
1
3
residual peak (CDCl : 7.26 ppm; d -DMSO: 2.50 ppm) as internal reference; C NMR spectra
3
6
was recorded with CDCl (77.00 ppm) or d -DMSO (39.52 ppm) as internal reference.
3
6
High-resolution mass spectra were obtained by using Waters Micromass GCT Premier,
Agilent Technologies 6224 TOF LC/MS, or Thermo Fisher Scientific LTQ FT Ultra mass
spectrometers. The IR spectra were measured on a ThermoFisher Nicolet FT-IR spectrometer.
Elemental analyses were performed on an Italian Carlo-Erba 1106 analyzer.
18
Aryl mesylates 1a-1f, 1h-1u were synthesized according to the published methods. For the
characterization of new aryl mesylate substrates, see following:
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4
-Butylphenyl methanesulfonate (1d). Ten mmol scale. Column chromatography on silica
gel (eluent: petroleum ether/ethyl acetate = 4/1) afforded the title product in 98% yield (2.24
1
g) as a light yellow liquid. H NMR (400 MHz, CDCl ): δ 0.93 (t, J = 7.2 Hz, 3H), 1.32-1.38
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
4
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4
4
5
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5
5
5
5
5
5
5
6
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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3
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13
1
(m, 2H), 1.55-1.63 (m, 2H), 2.61 (t, J = 7.6 Hz, 2H), 3.11 (s, 3H), 7.17-7.26 (m, 4H). C{ H}
NMR (100 MHz, CDCl ): δ 13.8, 22.2, 33.4, 34.9, 37.1, 121.6, 129.8, 142.3, 147.2. IR (neat):
3
3
029, 2957, 2932, 2860, 1503, 1365, 1330, 1197, 1173, 1147, 1113, 1018, 968, 865, 841, 814,
-1
+
776, 740, 681cm . HRMS (ESI): m/z [M+NH ] calcd for C H NO S, 246.1158; found
4
11 20
3
2
46.1157.
2-Methoxy-4-methylphenyl methanesulfonate (1f). Five mmol scale. Column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane = 4/1/1)
1
afforded the title product in 94% yield (1.013 g) as a white solid. H NMR (400 MHz, CDCl ):
3
δ 2.35 (s, 3H), 3.14 (s, 3H), 3.86 (s, 3H), 6.74-6.77 (m, 1H), 6.81 (d, J = 1.6 Hz, 1H), 7.16 (d,
13
1
J = 8.4 Hz, 1H). C{ H} NMR (100 MHz, CDCl ): δ 21.3, 37.9, 55.8, 113.6, 121.4, 123.9,
3
136.0, 138.5, 150.8. IR (neat): 3037, 3013, 2933, 2843, 1602, 1505, 1473, 1415, 1356, 1290,
-1
+
1
196, 1174, 1145, 1110, 1035, 966, 850, 812, 786, 684 cm . HRMS (ESI): m/z [M+NH ]
4
calcd for C H NO S, 234.0795; found 234.0792.
9
16
4
Synthesis of 4-(hydroxymethyl)phenyl methanesulfonate (1g): To a solution of
4-hydroxybenzaldehyde (1.22 g, 10 mmol) in ethyl acetate (30.0 mL) at 0 °C was added
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triethylamine (2.8 mL, 20 mmol) followed by MsCl (1.0 mL, 13 mol). After addition of MsCl,
the ice-water bath was removed and the resulting thick slurry was vigorously stirred for 1 h.
To the slurry was then added water. The two-phase mixture was separated and extracted with
ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous
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MgSO . The mixture was filtered and the solvent was evaporated under the reduced pressure.
4
The residue was dissolved in MeOH (20.0 mL) and DCM (20.0 mL), then NaBH (491.8 mg,
4
13.0 mmol) was added to the solution. The reaction mixture was then stirred at room
temperature overnight before adding a saturated NH Cl solution. Then the mixture was
4
extracted with dichloromethane, washed with water and brine, dried over Na SO , and
2
4
concentrated in vacuo. The residue was purified by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate/dichloromethane = 1/1/1) to afford the title product in
1
94% yield (1.899 g) as a colorless oil. H NMR (400 MHz, CDCl ): δ 2.56 (brs, 1H), 3.11 (s,
3
1
3
1
3
H), 4.65 (s, 2H), 7.24 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H). C{ H} NMR (100 MHz,
CDCl ): δ 37.2, 64.0, 121.9, 128.3, 140.3, 148.2. IR (neat): 3561, 3383, 3024, 2938, 2871,
3
-1
1603, 1504, 1412, 1358, 1196, 1170, 1144, 1015, 969, 865, 838, 812, 773, 678 cm . HRMS
+
(
ESI): m/z [M+NH ] calcd for C H NO S, 220.0638; found 220.0637.
4
8
14
4
Synthesis of aryl mesylates 1v-1z
Typical procedure for the synthesis of 1v:
A mixture of 4-iodophenol (1.76 g, 8 mmol), p-tolylboronic acid (1.31 g, 9.6 mmol), 1.5
2
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mol% Pd/CaCO (5% Pd/CaCO , 255 mg, 0.12 mmol), K CO (2.21 g, 16 mmol), ethanol (16
3
3
2
3
mL) and distilled water (16 mL) were stirred at 50 °C in air for 7 h. The mixture was cooled
down to room temperature and filtered over a celite pad. The mixture was added to brine and
extracted with ethyl acetate. The combined organic layers were washed with water and brine,
1
1
1
1
1
1
1
1
1
1
2
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9
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dried over anhydrous MgSO and filtered. The organic solvent was removed under vacuum,
4
and the product was isolated by column chromatography on silica gel (eluent: petroleum
ether/ethyl acetate = 10/1) followed by recrystallization from dichloromethane/hexane
afforded 4'-Methyl-[1,1'-biphenyl]-4-ol in 71% yield (1.04 g) as a white solid.
To a solution of 4'-Methyl-[1,1'-biphenyl]-4-ol (921.2 mg, 5 mmol) in ethyl acetate (15.0
mL) at 0 °C was added Et N (1.4 mL, 10 mmol) followed by MsCl (0.5 mL, 6.5 mmol). After
3
addition of MsCl, the ice-water bath was removed and the resulting thick slurry was
vigorously stirred for 1 h. To the slurry was then added water. The two-phase mixture was
separated and extracted with ethyl acetate. The organic layer was washed with water, brine
and dried over anhydrous MgSO . The mixture was filtered through a silica gel and the solvent
4
was evaporated under the reduced pressure, and the residue was recrystallized from
dichloromethane/hexane afforded the product 1v in 89% yield (1.1649 g) as a white solid.
1
4
'-Methyl-[1,1'-biphenyl]-4-yl methanesulfonate (1v). M.p.: 148.6-149.7 ℃. H NMR (400
MHz, CDCl ): δ 2.39 (s, 3H), 3.15 (s, 3H), 7.24 (d, J = 7.6 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H),
3
1
3
1
7.44 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 7.6 Hz, 2H). C{ H} NMR (100 MHz, CDCl ): 21.0,
3
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3
7.3, 122.2, 126.9, 128.4, 129.6, 136.8, 137.6, 140.5, 148.3. IR (neat): 3039, 3026, 2944,
-1
1611, 1491, 1360, 1334, 1173, 1151, 973, 964, 867, 852, 811, 788, 720, 655 cm . HRMS
+
(ESI): m/z [M+NH ] calcd for C H NO S, 280.1002; found 280.0998.
4
14 18
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4'-Fluoro-[1,1'-biphenyl]-4-yl methanesulfonate (1w). 4'-fluoro-[1,1'-biphenyl]-4-ol was
synthesized according to the general procedure from 4-iodophenol and
(4-fluorophenyl)boronic acid. Compound 1w was synthesized according to the general
procedure from 4'-fluoro-[1,1'-biphenyl]-4-ol (941.0 mg, 5 mmol), ethyl acetate (15 mL), Et N
3
(1.4 mL, 10 mmol), MsCl (0.5 mL, 6.5 mmol). The mixture was stirred at room temperature
for 1 h. Recrystallization from dichloromethane/hexane afforded the title product in 95% yield
1
(1.27 g) as a white solid. M.p.: 120.8-122.2 ℃. H NMR (400 MHz, DMSO-d ): δ 3.43 (s,
6
1
3
1
3H), 7.27-7.31 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.69-7.75 (m, 4H). C{ H} NMR (100
MHz, DMSO-d ): δ 37.4, 115.8 ( J = 21.3 Hz), 122.7, 128.3, 128.8 (3JC-F = 7.5 Hz), 135.4
2
6
C-F
(4
JC-F = 3.8 Hz), 138.3, 148.6, 162.1 (1JC-F = 242.9 Hz). IR (neat): 3062, 3029, 2944, 1735,
1599, 1491, 1370, 1336, 1254, 1210, 1182, 1157, 1115, 1016, 1006, 968, 945, 864, 825, 789,
-1
+
7
39, 719, 653 cm . HRMS (ESI): m/z [M+NH ] calcd for C H FNO S, 284.0751; found
4 13 15 3
284.0750.
4
'-Cyano-[1,1'-biphenyl]-4-yl methanesulfonate (1x). 4'-hydroxy-[1,1'-biphenyl]-4-carb-
onitrile was synthesized according to the general procedure from 4-iodophenol and
2
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(
4-cyanophenyl)boronic acid. Compound 1x was synthesized according to the general
procedure from 4'-hydroxy-[1,1'-biphenyl]-4-carbonitrile (976.1 mg, 5 mmol), ethyl acetate
20 mL), Et N (1.4 mL, 10 mmol), MsCl (0.5 mL, 6.5 mmol). The mixture was stirred at room
(
3
1
1
1
1
1
1
1
1
1
1
2
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9
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temperature for 1 h. Recrystallization from dichloromethane/hexane afforded the title product
1
in 90% yield (1.23 g) as a white solid. H NMR (400 MHz, DMSO-d ): δ 3.44 (s, 3H), 7.49 (d,
6
1
3
1
J = 7.6 Hz, 2H), 7.85-7.89 (m, 4H), 7.93 (d, J = 7.6 Hz, 2H). C{ H} NMR (100 MHz,
DMSO-d ): 37.5, 110.4, 118.8, 123.0, 127.7, 128.9, 132.9, 137.4, 143.3, 149.5. The
6
spectroscopic data are in agreement with that previously reported.19
3'-Methoxy-[1,1'-biphenyl]-4-yl methanesulfonate (1y). 3'-methoxy-[1,1'-biphenyl]-4-ol
was synthesized according to the general procedure from 4-iodophenol and
(3-methoxyphenyl)boronic acid. Compound 1y was synthesized according to the general
procedure from 3'-methoxy-[1,1'-biphenyl]-4-ol (1.00 g, 5 mmol), ethyl acetate (15 mL), Et N
3
(1.4 mL, 10 mmol), MsCl (0.5 mL, 6.5 mmol). The mixture was stirred at room temperature
for 1 h. Recrystallization from dichloromethane/hexane afforded the title product in 95% yield
1
(1.32 g) as a white solid. H NMR (400 MHz, CDCl ): δ 3.16 (s, 3H), 3.86 (s, 3H), 6.91 (d, J =
3
8.4 Hz, 1H), 7.07 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.33-7.38 (m, 3H), 7.59-7.61 (m, 2H).
1
3
1
C{ H} NMR (100 MHz, CDCl ): 37.3, 55,2, 112.9, 113.0, 119.5, 122.2, 128.7, 129.9, 140.4,
3
1
41.1, 148.6, 159.9. IR (neat): 2962, 2938, 2838, 1608, 1576, 1482, 1356, 1333, 1299, 1215,
-1
+
1171, 1147, 1056, 972, 963, 862, 838, 793, 735, 721, 696 cm . HRMS (ESI): m/z [M+NH ]
4
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calcd for C H NO S, 296.0951; found 296.0948.
1
4
18
4
4
-(Thiophen-3-yl)phenyl methanesulfonate (1z). 4-(thiophen-3-yl)phenol was synthesized
0
1
2
3
4
5
6
7
8
9
0
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2
3
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8
9
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8
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according to the general procedure from 4-iodophenol and thiophen-3-ylboronic acid.
Compound 1z was synthesized according to the general procedure from
4
-(thiophen-3-yl)phenol (881.2 mg, 5 mmol), ethyl acetate (15 mL), Et N (1.4 mL, 10 mmol),
3
MsCl (0.5 mL, 6.5 mmol). The mixture was stirred at room temperature for 1 h.
Recrystallization from dichloromethane/hexane afforded the title product in 84% yield (1.07
1
g) as a white solid. M.p.: 160.8-162.2 ℃. H NMR (400 MHz, DMSO-d ): δ 3.41 (s, 3H), 7.40
6
(d, J = 8.0 Hz, 2H), 7.57 (d, J = 3.6 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 2H),
1
3
1
7
.91 (s, 1H). C{ H} NMR (100 MHz, DMSO-d ): 37.4, 121.7, 122.7, 126.2, 127.4, 127.6,
6
134.3, 140.1, 148.1. IR (neat): 3096, 3037, 3024, 2941, 1600, 1530, 1495, 1372, 1327, 1203,
-
1
1
182, 1155, 1107, 1012, 970, 863, 850, 819, 792, 781, 729, 705 cm . HRMS (ESI): m/z
+
[
M+NH ] calcd for C H NO S , 272.0410; found 272.0410.
4
11 14
3 2
Nickel-catalyzed cyanation of aryl mesylates 1 with Zn(CN)2:
Typical procedure for the synthesis of 2a:
The reaction was conducted in an oven-dried screw-cap vial (volume: 12 mL) equipped
with a magnetic stir bar. In a nitrogen-filled glove box, NiBr (DME) (7.7 mg, 0.025 mmol),
2
dppb (12.8 mg, 0.03 mmol), Zinc (6.5 mg, 0.1 mmol), Zn(CN) (47.0 mg, 0.4 mmol), DMAP
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(
91.6 mg, 0.75 mmol), 4-acetylphenyl methanesulfonate 1a (107.1 mg, 0.5 mmol), CH CN (5
3
mL) were added sequentially to a screw-cap vial. The vial cap was then securely fitted and
o
taken outside the glove box. The vial was immersed into an oil bath preheated at 80 C. After
1
1
1
1
1
1
1
1
1
1
2
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stirring for 12 h, the mixture was cooled down to room temperature. Then the reaction mixture
was filtered through a short pad of silica gel and washed with ethyl acetate. The solvent was
evaporated under the reduced pressure and the residue was purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 6/1) to afford 2a in 94%
yield (67.9 mg) as a white solid.
1
4-Acetylbenzonitrile (2a). H NMR (400 MHz, CDCl ): δ 2.67 (s, 3H), 7.80 (d, J = 8.8 Hz,
3
1
3
1
2
H), 8.07 (d, J = 8.4 Hz, 2H). C{ H} NMR (100 MHz, CDCl ): δ 26.6, 116.1, 117.8, 128.5,
3
132.3, 139.7, 196.4. The spectroscopic data are in agreement with that previously reported.10
4
-Methoxybenzonitrile (2b). NiBr (DME) (15.4 mg, 0.05 mmol), dppb (25.6 mg, 0.06
2
mmol), Zn (13.1 mg, 0.2 mmol), Zn(CN) (47.0 mg, 0.4 mmol), DMAP (91.6 mg, 0.75 mmol),
2
4
-methoxyphenyl methanesulfonate (101.1 mg, 0.5 mmol) and CH CN (5 mL) were stirred at
3
o
80 C for 12 h. Purification of the crude product by column chromatography on silica gel
(eluent: petroleum ether/ethyl acetate = 12/1) afforded the title product in 80% yield (53.2 mg)
1
as a white solid. H NMR (400 MHz, CDCl ): δ 3.86 (s, 3H), 6.95 (d, J = 8.8 Hz, 2H), 7.58 (d,
3
1
3
1
J = 8.8 Hz, 2H). C{ H} NMR (100 MHz, CDCl ): δ 55.4, 103.7, 114.6, 119.1, 133.8, 162.7.
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The spectroscopic data are in agreement with that previously reported.20
4
-Methylbenzonitrile (2c). NiBr (DME) (15.4 mg, 0.05 mmol), dppb (25.6 mg, 0.06 mmol),
2
0
1
2
3
4
5
6
7
8
9
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1
2
3
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Zn (13.1 mg, 0.2 mmol), Zn(CN) (47.0 mg, 0.4 mmol), DMAP (91.6 mg, 0.75 mmol), p-tolyl
2
o
methanesulfonate (93.1 mg, 0.5 mmol) and CH CN (5 mL) were stirred at 80 C for 12 h.
3
Purification of the crude product by preparative TLC on silica gel (eluent: petroleum
ether/ethyl acetate/dichloromethane = 30/1/1) afforded the title product in 77% yield (45.2
mg) as a colorless oil. Due to the lower boiling point of this product, the NMR yield of 2c
1
(
85%) was also determined. H NMR (400 MHz, CDCl ): δ 2.42 (s, 3H), 7.27 (d, J = 8.0 Hz,
3
1
3
1
2H), 7.53 (d, J = 8.0 Hz, 2H). C{ H} NMR (100 MHz, CDCl ): δ 21.7, 109.1, 119.0, 129.7,
3
1
31.9, 143.6. The spectroscopic data are in agreement with that previously reported.21
4
-Butylbenzonitrile (2d). NiBr (DME) (15.4 mg, 0.05 mmol), dppb (25.6 mg, 0.06 mmol),
2
Zn (13.1 mg, 0.2 mmol), Zn(CN) (47.0 mg, 0.4 mmol), DMAP (91.6 mg, 0.75 mmol),
2
4-butylphenyl methanesulfonate (114.2 mg, 0.5 mmol) and CH CN (5 mL) were stirred at 80
3
oC for 12 h. Purification of the crude product by preparative TLC on silica gel (eluent:
petroleum ether/ethyl acetate/dichloromethane = 90/3/1) afforded the title product in 76%
1
yield (60.4 mg) as a colorless oil. H NMR (400 MHz, CDCl ): δ 0.93 (t, J = 7.4 Hz, 3H),
3
1
.30-1.39 (m, 2H), 1.56-1.64 (m, 2H), 2.66 (t, J = 7.8 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.55
1
3
1
(d, J = 8.0 Hz, 2H). C{ H} NMR (100 MHz, CDCl ): δ 13.7, 22.1, 32.9, 35.7, 109.3, 119.1,
3
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29.1, 131.9, 148.5. The spectroscopic data are in agreement with that previously reported.10
4
-(tert-Butyl)benzonitrile (2e). NiBr (DME) (15.4 mg, 0.05 mmol), dppb (25.6 mg, 0.06
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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3
3
3
3
3
3
3
3
3
3
4
4
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4
4
4
4
4
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8
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0
mmol), Zn (13.1 mg, 0.2 mmol), Zn(CN) (47.0 mg, 0.4 mmol), DMAP (91.6 mg, 0.75 mmol),
2
4-(tert-butyl)phenyl methanesulfonate (114.2 mg, 0.5 mmol) and CH CN (5 mL) were stirred
3
o
at 100 C for 12 h. Purification of the crude product by preparative TLC on silica gel (eluent:
petroleum ether/ethyl acetate = 30/1) afforded the title product in 64% yield (50.6 mg) as a
1
light yellow oil. H NMR (400 MHz, CDCl ): δ 1.33 (s, 9H), 7.49 (d, J = 8.0 Hz, 2H), 7.59 (d,
3
13
1
J = 8.4 Hz, 2H). C{ H} NMR (100 MHz, CDCl ): δ 30.8, 35.2, 109.2, 119.1, 126.1, 131.9,
3
156.6. The spectroscopic data are in agreement with that previously reported.10
2-Methoxy-4-methylbenzonitrile (2f). NiBr (DME) (15.4 mg, 0.05 mmol), dppb (25.6 mg,
2
0
.06 mmol), Zn (13.1 mg, 0.2 mmol), Zn(CN) (47.0 mg, 0.4 mmol), DMAP (91.6 mg, 0.75
2
mmol), 2-methoxy-4-methylphenyl methanesulfonate (108.1 mg, 0.5 mmol) and CH CN (5
3
o
mL) were stirred at 80 C for 12 h. Purification of the crude product by preparative TLC on
silica gel (eluent: petroleum ether/ethyl acetate/dichloromethane = 15/1/1) afforded the title
1
product in 64% yield (47.3 mg) as a white solid. H NMR (400 MHz, CDCl ): δ 2.41 (s, 3H),
3
1
3
1
3
.91 (s, 3H), 6.78 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H). C{ H} NMR
(100 MHz, CDCl ): δ 22.2, 55.8, 98.6, 112.0, 116.8, 121.5, 133.2, 145.7, 161.1. IR (neat):
3
3074, 3019, 2951, 2921, 2849, 2217, 1608, 1572, 1503, 1466, 1409, 1380, 1302, 1286, 1272,
2
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+
1
200, 1164, 1123, 1033, 929, 864, 813, 741, 728 cm . HRMS (ESI): m/z [M] calcd for
C H NO, 147.0684; found 147.0690.
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-(Hydroxymethyl)benzonitrile (2g). NiBr (DME) (7.7 mg, 0.025 mmol), dppb (12.8 mg,
2
0.03 mmol), Zinc (6.5 mg, 0.1 mmol), Zn(CN) (47.0 mg, 0.4 mmol), DMAP (91.6 mg, 0.75
2
mmol) ， 4-(hydroxymethyl)phenyl methanesulfonate (101.1 mg, 0.5 mmol) and CH CN (5
3
o
mL) were stirred at 80 C for 12 h. Purification of the crude product by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 3/1) afforded the title
1
product in 73% yield (48.8 mg) as a white solid. H NMR (400 MHz, CDCl ): δ 2.91 (brs,
3
1
3
1
1H), 4.74 (s, 2H), 7.46 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H). C{ H} NMR (100 MHz,
CDCl ): δ 63.8, 110.6, 118.8, 126.9, 132.1, 146.4. The spectroscopic data are in agreement
3
with that previously reported.5d
Benzo[d][1,3]dioxole-5-carbonitrile (2h). NiBr (DME) (7.7 mg, 0.025 mmol), dppb (12.8
2
mg, 0.03 mmol), Zinc (6.5 mg, 0.1 mmol), Zn(CN) (47.0 mg, 0.4 mmol), DMAP (91.6 mg,
2
0
.75 mmol), benzo[d][1,3]dioxol-5-yl methanesulfonate (108.1 mg, 0.5 mmol) and CH CN (5
3
o
mL) were stirred at 80 C for 12 h. Purification of the crude product by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 12/1) afforded the title
1
product in 94% yield (69.5 mg) as a white solid. H NMR (400 MHz, CDCl ): δ 6.08 (s, 2H),
3
1
3
1
6.87 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H). C{ H} NMR (100 MHz,
2
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Page 29 of 65
The Journal of Organic Chemistry
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CDCl ): δ 102.1, 104.7, 109.0, 111.2, 118.7, 128.0, 147.9, 151.4. The spectroscopic data are in
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agreement with that previously reported.22
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-(Dimethylamino)benzonitrile (2i). NiBr (DME) (7.7 mg, 0.025 mmol), dppb (12.8 mg,
2
0.03 mmol), Zinc (6.5 mg, 0.1 mmol), Zn(CN) (47.0 mg, 0.4 mmol), DMAP (91.6 mg, 0.75
2
mmol), 3-(dimethylamino)phenyl methanesulfonate (107.6 mg, 0.5 mmol) and CH CN (5 mL)
3
o
were stirred at 80 C for 12 h. Purification of the crude product by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 15/1) afforded the title product in 87% yield
1
(
63.8 mg) as a colorless oil. H NMR (400 MHz, CDCl ): δ 2.96 (s, 6H), 6.86-6.88 (m, 2H),
3
1
3
1
6.92 (d, J = 7.2 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H). C{ H} NMR (100 MHz, CDCl ): δ 39.9,
3
1
12.5, 114.5, 116.1, 119.1, 119.7, 129.6, 150.0. The spectroscopic data are in agreement with
that previously reported.9d
3
,5-Dimethoxybenzonitrile (2j). NiBr (DME) (7.7 mg, 0.025 mmol), dppb (12.8 mg, 0.03
2
mmol), Zinc (6.5 mg, 0.1 mmol), Zn(CN) (47.0 mg, 0.4 mmol), DMAP (91.6 mg, 0.75
2
mmol), 3,5-dimethoxyphenyl methanesulfonate (116.1 mg, 0.5 mmol) and CH CN (5 mL)
3
o
were stirred at 80 C for 12 h. Purification of the crude product by column chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 10/1) afforded the title product in 86% yield
1
(
69.8 mg) as a white solid. H NMR (400 MHz, CDCl ): δ 3.81 (s, 6H), 6.65 (s, 1H), 6.75 (d, J
3
1
3
1
= 0.8 Hz, 2H). C{ H} NMR (100 MHz, CDCl ): δ 55.5, 105.4, 109.7, 113.2, 118.6, 160.8.
3
2
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