Ruthenium-Catalyzed Ortho C-H Arylation of Aromatic Nitriles with Arylboronates and Observation of Partial Para Arylation

Article abstract of DOI:10.1021/acs.joc.6b02623

Ruthenium-catalyzed C-H arylation of aromatic nitriles with arylboronates is described. The use of RuH₂(CO){P(4-MeC₆H₄)₃}₃ as a catalyst provided higher yields of the ortho arylation products than the

Full text of DOI:10.1021/acs.joc.6b02623

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pubs.acs.org/joc
Ruthenium-Catalyzed Ortho C−H Arylation of Aromatic Nitriles with
Arylboronates and Observation of Partial Para Arylation
Yuta Koseki, Kentaroh Kitazawa, Masashi Miyake, Takuya Kochi, and Fumitoshi Kakiuchi*
†
†
†
†
,†,‡
†Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa
223-8522, Japan
‡
JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan
S Supporting Information
*
ABSTRACT: Ruthenium-catalyzed C−H arylation of aro-
matic nitriles with arylboronates is described. The use of
RuH (CO){P(4-MeC H ) } as a catalyst provided higher
2
6
4 3 3
yields of the ortho arylation products than the conventional
RuH (CO)(PPh ) catalyst. The arylation takes place mostly
2
3 3
at the ortho positions, but unprecedented para arylation was
also partially observed to give ortho,para diarylation products. In addition to C−H bond cleavage, the cyano group was also
found to function as a directing group for cleavage of C−O bonds in aryl ethers.
INTRODUCTION
directed C−H functionalization to catalytic regioselective
6b 6c
■
introduction of oxygen and halogen atoms on aromatic
rings. Recently, the Jeganmohan group also reported a
ruthenium(II)-catalyzed ortho C−H alkenylation of aromatic
Catalytic C−C bond formation via C−H bond cleavage by
transition-metal catalysts has been studied extensively in the
past decade and become a useful method in organic synthesis.
Control of the regioselectivity of the C−H functionalization is
one of the most important issues in development of useful
transformations. There are two major strategies to achieve high
regioselectivity in C−H functionalizations; one is to employ
heteroarenes as substrates to differentiate and potentially
1
6d
nitriles with alkenes.
Here, we report ruthenium-catalyzed C−H arylation of
aromatic nitriles with arylboronates. The optimized catalyst
for this arylation was RuH (CO){P(4-MeC H ) } , which was
2
6
4 3 3
recently developed in our group and is clearly more efficient for
this reaction than the conventional RuH (CO) (PPh catalyst.
2
2
)
3 3
activate the C−H bonds, and the other is the use of arenes
bearing directing groups. Direct functionalization of the latter
3
The arylation mostly took place at the ortho positions, but
unprecedented para C−H arylation was also observed.
substrates is usually controlled at the ortho positions because
pre-coordination of the directing group to a metal center occurs
and C−H bond cleavage is assisted by chelate formation.
A variety of directing groups have been used for regioselective
C−H functionalization, but most of the examples have employed
directing groups containing sp - and sp -hybridized nitrogen,
oxygen, phosphorus, and sulfur atoms as coordinating atoms to
facilitate the chelate formation.
RESULTS AND DISCUSSION
■
Our group has developed ortho C−H arylation of aromatic
ketones and esters with arylboronates using RuH (CO) (PPh )
2
3 3
2
3
(
1a) as catalyst, pinacolone as solvent and H−B(OR)
2
9
acceptor. Considering the previous observation that com-
plex 1a can cleave the ortho C−H bonds of benzonitriles,
we decided to examine the ruthenium-catalyzed arylation
of benzonitriles with arylboronates. When a reaction of
In contrast, the use of π-electrons in multiple bonds such
4
5−8
as those in alkynes and nitriles
to direct the C−H
10
2
-(trifluoromethyl)benzonitrile (2a) with 2 equiv of phenyl-
boronic acid neopentylglycol ester (3a) was carried out using
a as a catalyst under pinacolone refluxing conditions for 24 h,
ortho phenylation product 4aa was obtained in 10% GC yield
Table 1, entry 1). Other ruthenium complexes, such as
RuH (PPh ) , Ru(CO) (PPh ) , and Ru (CO) , showed lower
functionalization sites has been less explored. Benzonitriles
usually coordinate to metals using the lone pair on the nitrogen
atom, but it is difficult to consider that the coordination mode
facilitates the chelation-assisted C−H bond cleavage. Instead,
the π-coordination of the cyano group may bring the metal
closer to the ortho C−H bond to facilitate the bond cleavage.
In 1999, Murai, Kakiuchi, and co-workers reported the
RuH (CO)(PPh ) -catalyzed alkylation of aryl nitriles with
1
(
2
3 4
2
3 3
3
12
or no catalytic activity for this reaction (entries 2−4). Recently,
we established a synthetic method to access RuH (CO) (PAr ) -
2
3 3
2
3 3
1
1,12
type complexes using various triarylphosphines
and the use of
alkenes via oxidative addition of C−H bonds to a low-valent
5
these complexes for arylation of sterically congested C−H bonds
ruthenium complex. In 2011, Sun and co-workers found
11
of aromatic ketones. Therefore, several ruthenium complexes
the palladium(II)-catalyzed cyano group directed arylation of
aromatic nitriles with aryl iodides where the C−H bond
cleavage was proposed to take place via electrophilic palla-
Received: October 30, 2016
6
a
dation. Subsequently, they have expanded this cyano group
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b02623
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
a
Table 1. Ruthenium-Catalyzed C−H Arylation of 2a with 3a
used for entry 21 were considered optimal and used for further
investigations.
14
Various arylboronates can be used for the C−H aryla-
tion of benzonitrile 2a (Table 2). The reactions with
Table 2. Ruthenium-Catalyzed C−H Arylation of 2a with
a
Various Arylboronates 3
GC yield of 4aa (5aa)
entry
catalyst
base
none
(%)
1
2
3
4
5
RuH (CO)(PPh ) (1a)
10
6
2
3
3
RuH (PPh )
3 4
none
none
none
none
2
c
Ru(CO) (PPh )
nd
2
3
3
c
Ru (CO)
nd
3
12
RuH (CO)(P(4-FC H ) )
25 (trace)
32 (trace)
47 (1)
2
6
4
3
3
yield (%)
(
1b)
6
7
8
9
RuH (CO)(P(4-
none
none
none
entry
3
Ar
4
5
2
MeOC H ) ) (1c)
b
6
4 3 3
1
3b
3c
3d
3e
3f
4-F CC H
4
4ab: 87
4ac: 77
4ad: 88
4ae: 82
4af: 89
4ag: 80
4ah: 84
4ai: 74
4aj: 24
4ak: 49
4al: 87
5ab: nd
3
6
RuH (CO)(P(3-MeC H ) )
c
2
6
4
3
3
3
2
4-FC H4
5ac: −
5ad: 5
6
(
1d)
3
4-MeC H
6
4
RuH (CO)(P(4-MeC H ) )
47 (1)
2
6
4 3
n
b
b
(
1e)
4
4- HexC
H
6
4
5ae: nd
b
1d
KHCO3
KHCO3
NaHCO3
CsHCO3
KF
78 (1)
81 (1)
5
4-MeOC
4-Me NC
6
H
4
5af: nd
5ag: nd
5ah: 2
10
11
12
13
14
15
16
17
18
19
20
21
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
1e
6
3g
3h
3i
2
6
H
4
66 (2)
7
3-MeC
3,5-Me
2-MeC
6
2
6
H
4
c
53 (trace)
30 (trace)
33 (trace)
21 (trace)
80 (2)
8
C
6
H
3
5ai: −
b
9
3j
H
5aj: nd
4
b
NaF
10
11
3k
3l
1-naphthyl
2-naphthyl
5ak: nd
b
CsF
5al: nd
a
K CO
Reaction conditions: 2a (0.2 mmol), 3 (4 equiv), 1e (10 mol %),
2
3
b
Na CO
2
65 (1)
KHCO (1 equiv), pinacolone (0.2 mL), 120 °C, 24 h. Not detected.
3
3
c
Cs CO
24 (1)
Formation of a small amount of 5 was suggested by GCMS and
2
3
1
t
KO Bu
48 (2)
H NMR analyses, but the corresponding fractions could not be
t
completely purified.
NaO Bu
KHCO3
14 (trace)
82 (2)
b
a
Reaction conditions: 2a (0.2 mmol), 3a (2 equiv), catalyst (10 mol %),
4
-(trifluoromethyl)phenylboronate 3b and 4-(fluorophenyl)-
boronate 3c afforded coupling products 4ab and 4ac in 87 and
7% yields, respectively (entries 1 and 2). The arylation with
b
base (1 equiv, if any), pinacolone (0.2 mL), 120 °C, 24 h. 4 equiv of 3a
was used. Not detected.
c
7
arylboronates bearing electron-donating para substituents
such as methyl, n-hexyl, methoxy, and dimethylamino groups
(3d−g) gave 4ad−ag in 80−89% yields (entries 3−6). These
results suggest that the electronic nature of the substituents has
no significant effect on the reactivity. The arylations with meta-
substituted arylboronates 3h and 3i also provided the
corresponding monoarylation products 4ah and 4ai in high
yields (entries 7 and 8). The reactions with bulky 2-tolyl- and
1-naphthylboronates 3j,k resulted in lower yields (entries 9 and
10). In contrast, less sterically congested 2-naphthylboronate 3l
smoothly reacted to give 4al in 87% yield (entry 11). The
reaction was also examined with the corresponding 2-methyl-1-
propenylboronate but did not provide the desired alkenylation
product.
1
b−e containing triarylphosphines other than PPh3 were
investigated for this reaction (entries 5−8). The product
yields were generally improved using these para- or meta-
substituted triarylphosphines, and in particular, RuH (CO)
2
{
P(3-MeC H ) } (1d) and RuH (CO){P(4-MeC H ) } (1e)
6 4 3 3 2 6 4 3 3
provided ortho phenylation product 4aa in 47% yields (entries
7
2
and 8). The ortho,para diphenylation product, 4,6-diphenyl-
-(trifluoromethyl)benzonitrile (5aa), was also obtained, albeit
in very low yield. Although catalytic C−H functionalization at a
position para to the directing group is not unprecedented,
13
this is the first observation of para C−H functionalization
of benzonitriles. This process should be regarded as non-
chelation-assisted arylation and may be facilitated by the
strongly electron-withdrawing cyano group at the para position
of the electron-deficient aromatic ring possessing a trifluor-
Our group has developed several carbonyl-directed C−H
9
arylations, but no para C−H arylation product has been
1
3b
omethyl group.
observed. Therefore, improvement of the yields of the para
C−H arylation products was examined by conducting the
reaction using higher catalyst loading (Table 3). When the reac-
tion was carried out with 20 mol % of catalyst 1e for 24 h, 4aa
and 5aa were obtained in 85 and 5% yields, respectively
(entry 1). The reaction using 20 mol % of 1a instead of 1e as a
catalyst led to significant improvement of the yield of 5aa to
17% (entry 2). The arylation with arylboronates 3b−j also gave
the corresponding ortho,para diarylation products 5ab−aj,
albeit in lower yields than 5aa (entries 3−6). The reaction with
Addition of the base was then examined using complexes 1d
and 1e as catalysts. The use of KHCO dramatically improved
the catalytic activity of 1d and 1e, and ortho arylation product
3
4aa was obtained in 78 and 81% yields, respectively (entries 9
and 10). Other alkali metal bicarbonates (entries 11 and 12),
fluorides (entries 13−15), carbonates (entries 16−18), and
alkoxides (entries 19 and 20) were less effective compared
to KHCO . Increasing the amount of 3a to 4 equiv slightly
improved the yield (entry 21). From these results, the conditions
3
B
DOI: 10.1021/acs.joc.6b02623
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The Journal of Organic Chemistry
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Table 3. Formation of Ortho,Para Diarylation Products 5
a
Using High Catalyst Loading
yield (%)
entry
3
Ar
catalyst 1
4
5
b
1
3a
3a
3b
3d
3f
Ph
Ph
1e
1a
1a
1a
1a
1a
1a
4aa: 85
4aa: 66
4ab: 66
4ad: 67
4af: 43
4ah: 75
4aj: 60
5aa: 5
5aa: 17
5ab: 5
5ad: 8
5af: 2
2
3
4
5
6
4-F CC H
4
3
6
4-MeC H
6
4
4-MeOC H
6
4
3h
3j
3-MeC H
5ah: 6
6
4
c
d
7
2-MeC H
5aj: nd
6
4
a
Reaction conditions: 2a (0.5 mmol), 3 (4 equiv), 1a (20 mol %),
b
KHCO (1 equiv), pinacolone (0.5 mL), 120 °C, 15 h. Reaction
3
conditions: 2a (0.2 mmol), 3a (4 equiv), 1e (20 mol %), KHCO3
c
(
1 equiv), pinacolone (0.2 mL), 120 °C, 24 h. 2 equiv of 3j was used.
d
Not detected.
2
-methylphenylboronate 3j did not give the diarylation product
even in the presence of 20 mol % of 1a (entry 7).
The structures of the diarylation products were determined
by NMR analyses, but synthesis of the same diarylation product
via a different route was also investigated (eq 1). Diarylation
6
a
monoarylation product exclusively, and our C−H arylation
can be regarded complementary to Sun’s cyano-directed C−H
arylation. The phenylation of 2-methoxybenzonitrile 2e with 3a
provided 6da in 65% yield predominantly (eq 4). This result
suggests that the cyano group can be used as a directing group
not only for C−H bond cleavage but also for cleavage of C−O
1
5
bonds in aryl ethers, similarly to acyl groups. The C−H
phenylation was also investigated using 2,6-bis(trifluoromethyl)-
benzonitrile 7, which has no C−H bond at the ortho positions of
the cyano group, and para phenylation product 8 was obtained in
14% yield (eq 5). The formation of 8 from 7 shows that the para
C−H arylation does not require preceding ortho C−H arylation.
Other nitriles such as acrylonitrile, cinnamonitrile, and phenyl-
acetonitrile were also tested as substrates for the reaction with 3a
but failed to give more than a trace amount of the desired
phenylation product. The reaction of an electron-deficient arene,
1,3-bis(trifluoromethyl)benzene, did not proceed either, indicat-
ing that the presence of a cyano group on the benzene ring is
necessary for this reaction.
product 5ab was chosen as a target here because it seems to be
a crystalline material that may be used to form a single crystal
for X-ray analysis. The C−H arylation of p-(trifluoromethyl)-
phenyl benzonitrile 2b with 3b gave 32% yield of o,p-diaryl-
benzonitrile 5ab, which shows the NMR spectra identical to
those of 5ab prepared in entry 3 of Table 3. As expected, the
structure of 5ab was further confirmed by X-ray diffraction
analysis of a single crystal prepared by recrystallization of the
material synthesized here.
Other benzonitriles were also examined for the C−H
arylation. The reaction of 2-methylbenzonirile 2c with 3a
using catalyst 1e provided ortho arylation product 4ca in 29%
yield (eq 2). Elongation of the reaction time to 45 h only
slightly increased the yield to 31%. Screening of the reaction
conditions for this substrate showed that the use of catalyst 1a
In order to gain insight into the mechanism, the reaction of a
1:1 mixture of benzonitrile (2d) and benzonitrile-d (2d-d )
5
5
was performed using only 1 equiv of phenylboronate 3a (eq 6).
As a result, the corresponding diphenylation product was
isolated in 11% yield as a ca. 2:1 mixture of 6da and 6da-d3.
This result suggests that the reaction of 2d-d , which proceed
5
t
with NaO Bu as a base also gave a similar yield within 24 h, but
via C−D bond cleavage, is much slower than that of 2d, and the
C−H(or D) bond cleavage is the turnover-limiting step in the
catalytic cycle. The detailed mechanism for the ruthenium-
catalyzed C−H arylation of aromatic nitriles is unclear, but the
C−H bond cleavage step may proceed via oxidative addition as
was considered for the C−H/olefin coupling of aromatic
nitriles catalyzed by complex 1a. The catalytic cycle of this
reaction may be similar to that of ortho C−H arylation of
aromatic ketones with arylboronates catalyzed by 1a. The C−H
extension of the reaction time to 45 h improved the yield in this
case to 44% without any significant decomposition of cyano
groups. In the case of benzonitrile 2d, complex 1a was found to
be the most effective catalyst, and the reaction with 4 equiv
of 3a provided ortho,ortho′ diarylation product 6da in 44%
yield with no formation of monoarylation product 4da detected
(
eq 3). Interestingly, Sun and co-workers reported that the
Pd-catalyzed coupling of benzonitrile with aryl iodides yielded
C
DOI: 10.1021/acs.joc.6b02623
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The spectroscopic data of 3c are in good agreement with those
1
8c
reported in the literature.
-Methylphenylboronic Acid Neopentylglycol Ester (3d). The
general procedure was followed with 4-(methylphenyl)boronic acid
5.44 g, 40 mmol), neopentylglycol (4.17 g, 40 mmol), and Et O as
4
(
2
solvent. Purification by silica gel column chromatography (19:1
hexane/EtOAc) afforded 3d as a white solid (7.98 g, 98% yield). The
spectroscopic data of 3d are in good agreement with those reported in
1
8d
the literature.
-n-Hexylphenylboronic Acid Neopentylglycol Ester (3e). The
general procedure was followed with 4-n-hexylphenylboronic acid
5.15 g, 25 mmol), neopentylglycol (3.12 g, 30 mmol), and Et O as
4
(
2
solvent. Purification by silica gel column chromatography (20:1
hexane/EtOAc) afforded 3e as a white solid (6.12 g, 89% yield): mp
1
4
6
2
9−50 °C; H NMR (399.7 MHz, CDCl ) δ 0.87 (br t, 3H), 1.02 (s,
3
H), 1.22−1.37 (br m, 6H), 1.59−1.61 (m, 2H), 2.61 (t, J = 7.8 Hz,
H), 3.76 (s, 4H), 7.17 (d, J = 7.6 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H);
C{ H} NMR (98.5 MHz, CDCl ) δ 14.1, 21.9, 22.6, 29.0, 31.3, 31.7,
1
3
1
3
3
1.9, 36.1, 72.3, 127.8, 133.8, 145.7 (one signal for arylcarbon is too
bond cleavage step became slow and turnover-limiting because
it could not be effectively assisted by chelate formation.
16
broad to be seen due to the quadrupole effect of the adjacent boron
atom); IR (KBr) 2961 s, 2930 s, 2855 s, 1611 m, 1481 m, 1419 m,
−1
1
380 m, 1306 s, 1248 m, 1130 m cm ; HRMS (DART-TOF) calcd
CONCLUSION
We developed the ruthenium-catalyzed C−H arylation of
aromatic nitriles with arylboronates. The use of RuH (CO)
+
■
for [M + H] (C H BO ) m/z 275.2182, found 275.2185.
17 28 2
4-Methoxyphenylboronic Acid Neopentylglycol Ester (3f). The
general procedure was followed with 4-methoxyphenylboronic acid
2
(1.52 g, 10 mmol), neopentylglycol (1.15 g, 11 mmol), and Et O as
(
PAr ) catalysts containing triarylphosphines other than PPh
2
3
3
3
solvent. Purification by silica gel column chromatography (15:1
hexane/EtOAc) afforded 3f as a white solid (2.11 g, 96% yield). The
spectroscopic data of 3f are in good agreement with those reported in
was important in obtaining high yields of the ortho arylation
products. The reaction was mostly ortho selective, but unpre-
cedented para arylation was also partially observed to give
o,p-diarylation products. A cyano group was found to function
as a directing group not only for C−H bond cleavage but also
for cleavage of C−O bonds in aryl ethers.
18c
the literature.
4
-(N,N-Dimethylamino)phenylboronic Acid Neopentylglycol
Ester (3g). The general procedure was followed with 4-(N,N-
dimethylamino)phenylboronic acid (3.30 g, 5 mmol), neopentylglycol
(2.29 g, 22 mmol), and THF as solvent. Purification by silica gel
EXPERIMENTAL SECTION
General Information. Aromatic nitriles 2 except for 2b were
purchased from commercial suppliers, dried from CaH , and distilled
under nitrogen prior to use. Pinacolone was dried from CaSO and
column chromatography (30:1 hexane/EtOAc) afforded 3g as a white
■
solid (3.64 g, 78% yield). The spectroscopic data of 3g are in good
1
8e
agreement with those reported in the literature.
-Methylphenylboronic Acid Neopentylglycol Ester (3h). The
general procedure was followed with 3-methylphenylboronic acid
6.12 g, 45 mmol), neopentylglycol (5.21 g, 50 mmol), and THF
2
3
4
distilled under nitrogen. Bases were purchased from commercial
1
7a
(
suppliers and used as received. RuH (CO) (PPh ) - (1a),
2
3 3
17b
17c
as solvent. Purification by silica gel column chromatography (20:1
hexane/EtOA) afforded 3h as a white solid (9.15 g, >99% yield).
The spectroscopic data of 3h are in good agreement with those
RuH (PPh ) -, Ru(CO) (PPh ) -, and RuH (CO) (PAr ) -type
2
3
3
2
3
3
2
3 3
11
complexes using various triarylphosphines (1b−e) were prepared
according to the literature procedure. Ru (CO) were recrystallized
from dry hexane under nitrogen prior to use.
General Procedures for Syntheses of Arylboronates 3. A
2
12
1
8f
reported in the literature.
,5-Dimethylphenylboronic Acid Neopentylglycol Ester (3i). The
general procedure was followed with 3,5-dimethylphenylboronic acid
12.0 g, 80 mmol), neopentylglycol (9.17 g, 88 mmol), and THF as
3
round-bottom flask was charged with arylboronic acid, neopentylgly-
(
col, and solvent (Et O or THF). The mixture was stirred for 0.5−2 h
2
solvent. Purification by silica gel column chromatography (30:1
hexane/EtOAc) afforded 3i as a white solid (16.4 g, 94% yield). The
spectroscopic data of 3i are in good agreement with those reported in
at room temperature under air. After the reaction, an excess amount
(
ca. 5−10 equiv) of CaCl was added to the mixture, which was then
2
stirred for at least 0.5 h, filtered through Celite, and concentrated.
1
8b
the literature.
-Methylphenylboronic Acid Neopentylglycol Ester (3j). The
general procedure was followed with 2-methylphenylboronic acid
1.36 g, 10 mmol), neopentylglycol (1.04 g, 10 mmol), and THF as
Purification of the crude material by silica gel column chromatography
hexane/EtOAc) afforded the arylboronate.
Phenylboronic Acid Neopentylglycol Ester (3a). The general
procedure was followed with phenylboronic acid (2.19 g, 18 mmol),
neopentylglycol (2.08 g, 20 mmol), and Et O as solvent. Purification
by silica gel column chromatography (30:1 hexane/EtOAc) afforded
a as a white solid (3.34 g, 98% yield). The spectroscopic data of 3a
are in good agreement with those reported in the literature.
2
(
(
solvent. Purification by silica gel column chromatography (20:1
hexane/EtOAc) afforded 3j as a colorless oil (1.90 g, 93% yield). The
spectroscopic data of 3j are in good agreement with those reported in
2
3
18a
18b
the literature.
4
-(Trifluoromethyl)phenylboronic Acid Neopentylglycol Ester
3b). The general procedure was followed with 4-(trifluoromethyl)-
phenylboronic acid (5.13 g, 27 mmol), neopentylglycol (3.02 g,
9 mmol), and Et O as solvent. Purification by silica gel column
1-Naphthylboronic Acid Neopentylglycol Ester (3k). The general
procedure was followed with 1-naphthylboronic acid (1.72 g, 10
mmol), neopentylglycol (1.25 g, 12 mmol), and THF as solvent.
Purification by silica gel column chromatography (30:1 hexane/
EtOAc) afforded 3k as a white solid (2.21 g, 92% yield). The
pectroscopic data of 3k are in good agreement with those reported in
(
2
2
chromatography (2:1 hexane/EtOAc) afforded 3b as a white solid
6.59 g, 95% yield). The spectroscopic data of 3b are in good
agreement with those reported in the literature.
(
18b
18g
the literature.
4
-Fluorophenylboronic Acid Neopentylglycol Ester (3c). The
general procedure was followed with 4-(fluorophenyl)boronic acid
699.6 mg, 5 mmol), neopentylglycol (572.8 mg, 5.5 mmol), and Et O
2-Naphthylboronic Acid Neopentylglycol Ester (3l). The general
procedure was followed with 2-naphthylboronic acid (8.60 g, 50 mmol),
neopentylglycol (5.21 g, 50 mmol) and THF as solvent. Purifi-
cation by silica gel column chromatography (30:1 hexane/EtOAc)
afforded 3l as a white solid (9.14 g, 76% yield). The spectroscopic
(
2
as solvent. Purification by silica gel column chromatography (5:1
hexane/EtOAc) afforded 3c as a white solid (994.7 mg, 98% yield).
D
DOI: 10.1021/acs.joc.6b02623
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
data of 3l are in good agreement with those reported in the liter-
ature.
Procedures for Syntheses of Aromatic Nitriles 2b. The
126.1 (q JC−F = 4.6 Hz), 129.6, 131.6 (q, JC−F = 32.8 Hz), 132.9, 133.5,
134.3 (q, JC−F = 31.9 Hz), 140.6, 146.8; IR (KBr) 3366 w, 2357 m,
2339 w, 2231 s, 1621 m, 1465 s, 1451 s, 1403 s, 1324 vs, 1295 vs,
1203 vs, 1176 vs, 1136 vs, 1108 vs, 1070 vs, 1040 vs, 1016 s, 936 m,
832 s, 813 vs, 792 s, 758 vs, 715 vs, 669 vs, 667 vs, 659 s, 637 s,
18b
Suzuki−Miyaura cross coupling was performed using a procedure
19
similar to the one reported by Camp and co-workers. To a solution
of 4-(trifluoromethyl)phenylboronic acid (1.22 g, 6.4 mmol) and
K CO (1.66 g, 12 mmol) in 22 mL of DME/H O (10:1) degassed
−1
+
603 s cm ; HRMS (ESI-TOF) calcd for [M + Na] (C H F NNa)
1
5
7 6
m/z 338.0380, found 338.0377.
2
3
2
with nitrogen were added 4-iodo-2-(trifluoromethyl)benzonitrile
1.18 g, 4.0 mmol) and Pd(PPh3)4 (300 mg, 0.26 mmol). The
6-(4-Fluorophenyl)-2-(trifluoromethyl)benzonitrile (4ac). General
procedure A was followed with 34.4 mg of 2a and 166.2 mg of 3c.
(
mixture was stirred for 16 h at 80 °C under nitrogen. After the reac-
tion, the solution evaporated under reduced pressure and then purified
by silica gel column chromatography (20:1 hexane/EtOAc) to afford
PTLC (4:1 hexane/EtOAc) afforded 4ac as a white solid (41.1 mg,
1
77% yield): mp 124−125 °C; H NMR (CDCl , 391.8 MHz) δ 7.21
3
(t, J = 8.6 Hz, 2 H), 7.51−7.54 (m, 2 H), 7.69 (d, J = 7.4 Hz, 1 H),
13
1
4
-[4-(trifluoromethyl)phenyl]-2trifluoromethylbenzonitrile (2b) as a
7.75−7.82 (m, 2 H); C{ H} NMR (CDCl , 98.5 MHz) δ 108.9 (q,
3
1
white solid (212.8 mg, 17% yield): mp 115−115.5 °C; H NMR
JC−F = 2.1 Hz), 114.7, 116.0 (d, JC−F = 21.9 Hz), 122.4 (q, JC−F = 274.2
(
CDCl , 399.7 MHz) δ 7.75−7.81 (m, 4 H), 7.93−7.99 (m, 2 H),
Hz), 125.3 (q, JC−F = 4.9 Hz), 130.9 (d, JC−F = 8.5 Hz), 132.6, 133.1
(d, JC−F = 3.5 Hz), 133.4, 134.0 (q, JC−F = 32.1 Hz), 147.2, 163.4 (d,
JC−F = 250.0 Hz); IR (KBr) 2232 m, 1609 m, 1579 w, 1515 s, 1466 w,
3
13
1
8
1
1
.03 (s, 1 H); C{ H} NMR (CDCl , 98.5 MHz) δ 109.4 (q, J
=
3
C−F
.9 Hz), 115.2, 122.2 (q, JC−F = 273.9 Hz), 123.8 (q, JC−F = 272.4 Hz),
25.5 (q, JC−F = 4.4 Hz), 126.3 (q, JC−F = 3.7 Hz), 127.7, 130.7, 131.4
1445 m, 1405 w, 1331 s, 1292 m, 1227 s, 1204 s, 1192 m, 1175 s,
1164 m, 1133 s, 1122 s, 1075 w, 1040 m, 844 m, 816 s, 776 w, 757 m,
(
q, JC−F = 32.6 Hz), 133.6 (q, JC−F = 32.6 Hz), 135.4, 141.2, 144.6; IR
−1
(
KBr) 3106 w, 3068 w, 2234 m, 1935 w, 1814 w, 1616 m, 1586 w,
722 m, 706 w, 669 w, 584 m, 560 w, 520 m cm ; HRMS (APCI-TOF)
+
1
1
8
5
528 w, 1498 w, 1436 m, 1399 m, 1324 s, 1299 m, 1265 s, 1183 s,
167 s, 1141 s, 1116 s, 1071 s, 1055 s, 1033 s, 1011 m, 963 w, 911 m,
63 w, 850 m, 837 s, 775 w, 746 w, 702 m, 675 m, 671 w, 620 w,
calcd for [M + H] (C14H F N) m/z 266.0593, found 266.0582.
8 4
6-(4-Methylphenyl)-2-(trifluoromethyl)benzonitrile (4ad). General
procedure A was followed with 34.2 mg of 2a and 164.5 mg of 3d.
−1
+
99 w, 563 w, 517 w cm ; HRMS (DART-TOF) calcd for [M + H]
C H F N) m/z 316.0561, found 316.0561.
PTLC (10:1 hexane/EtOAc) afforded 4ad as a white solid (45.9 mg,
1
(
88% yield): mp 85.5−86.5 °C; H NMR (CDCl
3
, 399.7 MHz) δ 2.43
15
8 6
General Procedures for Ruthenium-Catalyzed C−H Aryla-
(s, 3 H), 7.32 (d, J = 7.6 Hz, 2 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.69 (dd,
J = 7.6 Hz, 1 H), 7.73 (dd, J = 8.0 Hz, 1 H), 7.77 (dd, J = 7.6 Hz, 1 H);
C{ H} NMR (CDCl , 98.5 MHz) δ 21.2, 108.8, 115.0, 122.5
tion of Aromatic Nitriles. General procedure A: In a glove-
13
1
box, arylboronate (3) (0.8 mmol), 20.9 mg of RuH (CO){P(4-
2
3
MeC H ) } (1e) (0.02 mmol), and 20.0 mg of KHCO (0.2 mmol)
(q, JC−F = 273.3 Hz), 124.9 (q, JC−F = 4.7 Hz), 128.8, 129.5, 132.3,
133.4, 133.9 (q, JC−F = 31.9 Hz), 134.2, 139.4, 148.3; IR (KBr) 3094
w, 2931 w, 2365 w, 2362 w, 2360 m, 2357 w, 2339 w, 2323 w, 2231 s,
1994 w, 1924 w, 1612 s, 1595 m, 1517 m, 1465 s, 1442 s, 1407 w, 1333
vs, 1315 s, 1293 vs, 1213 vs, 1199 vs, 1187 vs, 1173 vs, 1141 vs, 1126
vs, 1098 s, 1075 s, 1042 vs, 999 m, 935 m, 847 s, 832 s, 809 vs, 768 s,
6
4
3
3
3
were placed in a 6 mL screw cap tube, and then 2-(trifluoromethyl)-
benzonitrile (2a) (0.2 mmol) and pinacolone (0.2 mL) were added in
that order. The mixture was heated at 120 °C for 24 h. The resulting
mixture analyzed by GC and GCMS. After removal of the volatile
materials by rotary evaporation, the crude material was passed through
a basic aluminum oxide column to remove the remaining arylboronate.
The arylation product 4 and 5 was isolated by silica gel column
chromatography or preparative thin-layer chromatography (PTLC),
followed by gel permeation chromatography (GPC) in some cases.
General procedure B: In a glovebox, arylboronate (3) (2.0 mmol),
−1
+
756 s, 723 s, 703 vs cm ; HRMS (ESI-TOF) calcd for [M + Na]
(C H F NNa) m/z 284.0663, found 284.0663.
15
10 3
6-(4-n-Hexylphenyl)-2-(trifluoromethy)lbenzonitrile (4ae). Gener-
al procedure A was followed with 35.0 mg of 2a and 219.7 mg of 3e.
PTLC (5:1 hexane/EtOAc) afforded 4ae as a yellow oil (55.7 mg, 82%
1
4
5.9 mg of RuH (CO) (PPh ) (1a) (0.05 mmol), and 50.1 mg of
yield): H NMR (CDCl , 391.8 MHz) δ 0.90 (t, J = 7.1 Hz, 3 H),
2
3
3
3
KHCO (0.5 mmol) were placed in a 20 mL J. Young tube, and then
1.30−1.41 (m, 6 H), 1.62−1.70 (m, 2 H), 2.68 (t, J = 7.4 Hz, 2 H),
7.32 (d, J = 7.8 Hz, 2 H), 7.46 (d, J = 7.8 Hz, 2 H), 7.69 (dd, J =
7.4 Hz, 2.0 Hz, 1 H), 7.73 (t, J = 7.4 Hz, 1 H), 7.77 (dd, J = 7.4 Hz,
3
2
(
1
-(trifluoromethyl)benzonitrile (2a) (0.5 mmol) and pinacolone
0.5 mL) were added in that order. The mixture was heated at
20 °C for 15 h. The resulting mixture was analyzed by GC and
2.0 Hz, 1 H); 13C{ H} NMR (CDCl , 98.5 MHz) δ 14.1, 22.6, 29.1,
1
3
GCMS. After removal of the volatile materials by rotary evaporation,
the crude material was passed through a basic aluminum oxide column
to remove the remaining arylboronate. The arylation product 4 and 5
was isolated by silica gel column chromatography or preparative thin-
layer chromatography (PTLC), followed by gel permeation chromato-
graphy (GPC) in some cases.
31.3, 31.7, 35.8, 108.7 (q, JC−F = 1.9 Hz), 115.0, 122.6 (q, JC−F =
274.4 Hz), 124.9 (q, JC−F = 4.9 H), 128.86, 128.89, 132.4, 133.5, 134.0
(q, JC−F = 31.9 Hz), 134.4, 144.5, 148.4; IR (NaCl) 3029 w, 2929 s,
2857 s, 2231 m, 1612 m, 1516 w, 1467 s, 1448 s, 1408 m, 1333 s, 1293
s, 1201 s, 1174 s, 1140 s, 1076 m, 1042 s, 810 s, 753 w, 723 w, 706 m,
−1
+
699 m, 667 w, 618 w cm ; HRMS (ESI-TOF) calcd for [M + Na]
6
-Phenyl-2-(trifluoromethyl)benzonitrile (4aa). General procedure
(C H F NNa) m/z 354.1446, found 354.1441.
20
20 3
A was followed with 34.0 mg of 2a and 153.8 mg of 3a. PTLC (10:1
6-(4-Methoxylphenyl)-2-(trifluoromethyl)benzonitrile (4af). Gen-
eral procedure A was followed with 33.5 mg of 2a and 175.4 mg of 3f.
hexane/EtOAc) afforded 4aa as a white solid (40.6 mg, 82% yield):
1
mp 63−64 °C; H NMR (CDCl , 391.8 MHz) δ 7.42−7.55 (m, 5 H),
PTLC (10:1 hexane/EtOAc) afforded 4af as a white solid (48.5 mg,
3
1
7
.71 (dd, J = 7.8 Hz, 1.5 Hz, 1 H), 7.76 (t, J = 7.8 Hz, 1 H), 7.80
89% yield): mp 83−84 °C; H NMR (CDCl , 391.8 MHz) δ 3.88
3
(
dd, J = 7.6 Hz, 1.5 Hz, 1 H); 13C{ H} NMR (CDCl , 100.5 MHz) δ
1
(s, 3 H), 7.04 (d, J = 8.6 Hz, 2 H), 7.49 (d, J = 8.6 Hz, 2 H), 7.67−7.76
3
(m, 3 H); 13C{ H} NMR (CDCl , 98.5 MHz) δ 55.5, 108.8 (q, J
1
=
=
108.9 (q, JC−F = 1.8 Hz), 114.8, 122.5 (q, JC−F = 274.0 Hz), 125.2 (q,
JC−F = 4.9 Hz), 128.8, 128.9, 129.3, 132.4, 133.5 (q, JC−F = 1.1 Hz),
3
C−F
1.9 Hz), 114.5, 115.3, 122.7 (q, JC−F = 274.1 Hz), 124.9 (q, JC−F
1
2
1
33.9 (q, JC−F = 32.0 Hz), 137.1, 148.3; IR (KBr) 3054 w, 2926 w,
4.8 Hz), 129.5, 130.5, 132.5, 133.5, 133.6, 134.1 (q, JC−F = 32.0 Hz),
148.2; IR (KBr) 3010 w, 2972 w, 2944 w, 2842 w, 2227 w, 1614 m,
1574 w, 1520 m, 1468 m, 1448 m, 1334 s, 1312 m, 1295 m, 1259 m,
1208 m, 1176 m, 1140 m, 1112 s, 1074 w, 1046 m, 1022 w, 831 m,
753 m, 705 w, 634 w, 594 m, 558 w, 543 w, 522 w, 467 w, 448 w,
233 m, 1721 w, 1589 w, 1457 m, 1431 m, 1335 s, 1295 s, 1168 s,
−1
133 s, 1117 s, 1050 m, 821 s, 763 s, 700 s cm ; HRMS (ESI-TOF)
+
calcd for [M + K] (C H F NK) m/z 286.0246. Found 286.0245.
14
8 3
2
-(Trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]benzonitrile
4ab). General procedure A was followed with 33.4 mg of 2a and
07.2 mg of 3b. PTLC (10:1 hexane/EtOAc) afforded 4ab as a white
−1
+
(
2
438 w, 424 w, 412 w cm ; HRMS (ESI-TOF) calcd for [M + Na]
(C H F NONa) m/z 300.0612, found 300.0612.
15
10 3
1
solid (53.6 mg, 87% yield): mp 101−102 °C; H NMR (CDCl ,
3
6-[4-(N,N-Dimethylamino)phenyl]-2-(trifluoromethyl)benzonitrile
(4ag). General procedure A was followed with 34.2 mg of 2a and
3
99.7 MHz) δ 7.67 (d, J = 7.6 Hz, 2 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.80
(
d, J = 8.4 Hz, 2 H), 7.82 (dd, J = 7.2 Hz, 8.0 Hz, 1 H), 7.87 (d, J = 6.8
186.2 mg of 3g. PTLC (4:1 hexane/EtOAc) afforded 4ag as a yellow
13
1
1
Hz, 1 H); C{ H} NMR (CDCl , 98.5 MHz) δ 109.2, 114.6, 122.5 (q,
JC−F = 274.3 Hz), 123.9 (q, JC−F = 272.3 Hz), 126.1 (q JC−F = 3.8 Hz),
solid (46.7 mg, 80% yield): mp 164−165 °C; H NMR (CDCl ,
3
3
391.8 MHz) δ 3.03 (s, 6 H), 6.80 (d, J = 8.6 Hz), 7.46 (d, J = 8.6 Hz),
E
DOI: 10.1021/acs.joc.6b02623
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
.67 (s, 3 H); 13C{ H} NMR (CDCl , 98.5 MHz) δ 40.2, 107.8
1
(ESI-TOF) calcd for [M + Na] (C H F NNa) m/z 320.0663, found
18 10 3
+
7
3
(
(
q, JC−F = 2.2 Hz), 112.0, 115.6, 122.7 (q, JC−F = 274.0 Hz), 123.9
q, JC−F = 4.9 Hz), 124.3, 129.9, 132.1, 133.2, 133.9 (q, JC−F = 32.0),
320.0661.
6-(2-Naphthyl)-2-(trifluoromethyl)benzonitrile (4al). General pro-
1
1
1
1
8
48.6, 150.9; IR (KBr) 3098 w, 2919 m, 2864 m, 2822 m, 2227 m,
987 w, 1901 w, 1609 s, 1530 s, 1484 m, 1465 m, 1444 s, 1424 w,
411 m, 1368 s, 1335 s, 1295 s, 1267 w, 1231 m, 1209 s, 1197 s,
170 s, 1121 s, 1086 m, 1063 m, 1043 s, 998 m, 960 w, 946 m, 928 w,
cedure A was followed with 32.5 mg of 2a and 191.7 mg of 3l. PTLC
(10:1 hexane/EtOAc) afforded 4al as a white solid (49.1 mg, 87%
1
yield): mp 115.5−116 °C; H NMR (CDCl
, 391.8 MHz) δ 7.55−
3
7.60 (m, 2 H), 7.64 (dd, J = 8.6 Hz, 2.0 Hz, 1 H), 7.77−7.85 (m, 3 H),
7.93 (dd, J = 9.0 Hz, 5.5 Hz, 2 H), 7.99 (d, J = 9.0 Hz, 1 H), 8.03
(s, 1 H); C{ H} NMR (CDCl , 98.5 MHz) δ 109.1 (q, JC−F =
−
1
30 m, 808 s, 792 m, 753 m, 696 s cm ; HRMS (ESI-TOF) calcd for
+
13
1
[
M + H] (C H F N ) m/z 291.1109, found 291.1131.
3
16
14
3
2
6
-(3-Methylphenyl)-2-(trifluoromethyl)benzonitrile (4ah). General
1.9 Hz), 114.9, 122.5 (q, JC−F = 274.4 Hz), 125.2 (q, JC−F = 4.7 Hz),
126.1, 126.9, 127.2, 127.8, 128.4, 128.7, 128.7, 132.5, 133.0, 133.3,
133.8, 134.0 (q, JC−F = 31.9 Hz), 134.4, 148.3; IR (KBr) 3044 m,
procedure A was followed with 34.3 mg of 2a and 163.2 mg of 3h.
PTLC (10:1 hexane/EtOAc) afforded 4ah as a white solid (43.9 mg,
1
2
1
1
9
365 w, 2229 s, 1700 w, 1684 w, 1652 w, 1597 w, 1557 w, 1539 w,
506 w, 1478 m, 1446 m, 1347 s, 1329 s, 1292 s, 1270 w, 1235 w,
206 s, 1177 s, 1163 s, 1134 s, 1126 s, 1076 s, 1045 s, 1014 w, 1001 w,
47 w, 910 w, 884 w, 860 w, 822 s, 810 s, 769 m, 755 s, 737 s,703 s,
8
4% yield): mp 77−78 °C; H NMR (CDCl , 399.7 MHz) δ 1.54
3
(
(
(
s, 3 H), 7.29−7.42 (m, 4 H), 7.69 (dd, J = 7.9 Hz, 1.5 Hz, 1 H), 7.74
t, J = 7.9 Hz, 1 H), 7.79 (dd, J = 7.9 Hz, 1.5 Hz, 1 H); 13C{ H} NMR
1
CDCl , 98.5 MHz) δ 21.3, 108.8 (q, J
JC−F = 274.4 Hz), 125.0 (q, JC−F = 5.6 Hz), 126.0, 126.7, 128.7, 129.6,
30.0, 132.4, 133.8 (q, JC−F = 31.9 Hz), 137.0, 138.5, 148.4; IR (KBr)
049 w, 2917 w, 2851 w, 2231 m, 1610 w, 1585 w, 1464 w, 1336 s,
297 s, 1215 m, 1192 m, 1163 m, 1124 s, 1055 m, 1000 w, 940 w,
= 1.9 Hz), 114.9, 122.5 (q,
C−F
3
−1
+
6
67 s cm ; HRMS (ESI-TOF) calcd for [M + Na] (C H F NNa)
18 10 3
m/z 320.0663, found 320.0661.
1
3
1
9
4
,6-Diphenyl-2-(trifluoromethyl)benzonitrile (5aa). General pro-
cedure B was followed with 83.1 mg of 2a and 379.9 mg of 3a. PTLC
−1
(5:1 hexane/EtOAc) afforded 5aa as a white solid (26.2 mg, 17%
11 w, 895 w, 821 m, 784 m, 755 m, 712 m, 702 m, 640 w cm ;
HRMS (ESI-TOF) calcd for [M + Na] (C H F NNa) m/z 284.0663,
1
+
yield): mp 98.5−99.5 °C; H NMR (CDCl , 391.8 MHz) δ 7.48−7.56
3
15
10 3
(
m, 6 H), 7.59−7.61 (m, 2 H), 7.64−7.66 (m, 2 H), 7.89 (d, J =
found 284.0665.
-(3,5-Dimethylphenyl)-2-(trifluoromethyl)benzonitrile (4ai).
1
9
4
.6 Hz, 1 H), 7.99 (d, J = 1.6 Hz, 1 H); 13C{ H} NMR (CDCl ,
1
6
3
8.5 MHz) δ 107.2, 115.0, 122.6 (q, JC−F = 274.4 Hz), 123.9 (q, JC−F
.9 Hz), 124.0, 127.4, 128.9, 129.0, 129.4, 129.5, 131.7, 134.5 (q,
=
General procedure A was followed with 34.4 mg of 2a and 174.1
mg of 3i. PTLC (4:1 hexane/EtOAc) afforded 4ai as a white solid
1
JC−F = 31.7 Hz), 137.3, 137.8, 145.6, 148.8; IR (KBr) 3063 w, 2923 w,
349 w, 2228 m, 1605 m, 1578 w, 1496 w, 1458 m, 1437 m, 1405 w,
1360 s, 1289 s, 1264 w, 1249 w, 1190 s, 1164 s, 1153 s, 1118 s, 1078 w,
(
40.8 mg, 74% yield): mp 114−115 °C; H NMR (CDCl3,
2
3
91.8 MHz) δ 2.39 (s, 6 H), 7.13 (s, 3 H), 7.67−7.77 (m, 3 H);
1
3
1
C{ H} NMR (CDCl , 98.5 MHz) δ 21.3, 108.8 (q, J
= 1.9 Hz),
3
C−F
1
6
063 w, 1049 m, 1000 w, 917 w, 897 m, 832 w, 764 s, 721 w, 696 s,
1
1
3
2
1
1
14.9, 122.5 (q, JC−F = 274.1 Hz), 124.9 (q, JC−F = 4.9 Hz), 126.7,
30.9, 132.3, 133.4, 133.5 (q, JC−F = 1.2 Hz), 133.8 (q, JC−F
2.1 Hz), 137.1, 138.4, 148.6; IR (KBr) 3091 w, 3029 w, 2922 m,
865 w, 2234 m, 1606 m, 1596 m, 1453 m, 1343 s, 1309 s, 1289 m,
230 m, 1197 m, 1185 s, 1169 s, 1137 s, 1122 s, 1089 s, 1072 s,
−1
30 w, 616 w, 583 w, 541 w, 516 w, 477 w, 449 w, 427 w cm ; HRMS
=
+
(ESI-TOF) calcd for [M + Na] (C H F NNa) m/z 346.0820, found
20
12 3
3
46.0821.
-(Trifluoromethyl)-4,6-bis[4-(trifluoromethyl)phenyl]benzonitrile
5ab). General procedure B was followed with 86.3 mg of 2a and
15.1 mg of 3b. PTLC (10:1 hexane/EtOAc) afforded 5ab as a white
2
(
−1
039 w, 908 w, 900 w, 858 s, 816 s, 757 m, 708 s, 675 m, 634 w cm ;
HRMS (ESI-TOF) calcd for [M + Na] (C H F NNa) m/z 298.0820,
5
+
1
16
12 3
solid (11.5 mg, 5% yield): mp 162−163 °C; H NMR (CDCl3,
found 298.0818.
-(2-Methylphenyl)-2-(trifluoromethyl)benzonitrile (4aj). General
3
99.7 MHz) δ 7.72−7.84 (m, 8 H), 7.89 (s, 1 H), 8.05 (s, 1 H);
6
13
1
C{ H} NMR (CDCl , 98.5 MHz) δ 108.2 (q, J
= 1.5 Hz),
3
C−F
procedure A was followed with 33.9 mg of 2a and 180.0 mg of 3j.
PTLC (10:1 hexane/EtOAc) afforded 4aj as a white solid (12.3 mg,
1
14.3, 122.3 (q, JC−F = 274.4 Hz), 123.8 (q, JC−F = 272.4 Hz), 123.8
(
q, JC−F = 272.4 Hz), 124.7 (q, JC−F = 4.9 Hz), 125.9 (q, JC−F
=
=
1
2
3
(
(
1
(
3
1
1
4% yield): mp 82.5−83 °C; H NMR (CDCl , 399.7 MHz) δ 2.18 (s,
3
3
3
1
.6 Hz), 126.4 (q, JC−F = 3.8 Hz), 127.8, 129.5, 131.6 (q, JC−F
2.8 Hz), 131.6 (q, JC−F = 32.8 Hz), 131.8, 134.9 (q, JC−F = 32.4 Hz),
40.4 (q, JC−F = 1.1 Hz), 140.9 (q, JC−F = 1.1 Hz), 144.5, 147.4; IR
H), 7.21 (dd, J = 7.4 Hz, 1.2 Hz, 1 H), 7.30−7.39 (m, 3 H), 7.59
dd, J = 7.4 Hz, 1.2 Hz, 1 H), 7.77 (td, J = 7.4 Hz, 1.2 Hz, 1 H), 7.81
dd, J = 7.4 Hz, 1.2 Hz, 1 H); 13C{ H} NMR (CDCl , 98.5 MHz) δ
1
3
(
KBr) 3023 w, 2922 w, 2864 w, 2224 s, 1905 w, 1790 w, 1729 w,
9.8, 110.3 (q, JC−F = 1.9 Hz), 114.3, 122.5 (q, JC−F = 274.4 Hz), 125.2
1652 w, 1605 s, 1514 m, 1460 m, 1357 s, 1325 m, 1290 s, 1220 w,
1208 w, 1181 s, 1123 s, 1039 s, 1019 w, 895 s, 860 w, 842 w, 812 s,
q, JC−F = 4.6 Hz), 126.1, 129.3, 129.3, 130.6, 132.2, 133.4 (q, JC−F
=
1.9 Hz), 133.7, 135.6, 136.9, 148.5; IR (KBr) 3050 w, 2925 w, 2233 s,
995 w, 1602 w, 1581 w, 1495 w, 1463 w, 1456 s, 1430 m, 1334 s,
298 s, 1210 s, 1199 s, 1179 s, 1162 s, 1131 s, 1111 s, 1074 s,1053 m,
031 m, 999 w, 953 w, 933 w, 836 w, 819 s, 800 w, 774 w, 760 s, 755 s,
7
5
4
24 w, 719 w, 709 m, 683 w, 667 m, 665 w, 647 w, 642 w, 619 w,
40 w, 531 w, 525 w, 515 s, 507 w, 504 w, 501 w, 496 w, 493 w,
−1
+
88 w cm ; HRMS (ESI-TOF) calcd for [M + Na] (C H F NNa)
22 10 9
1
7
m/z 482.0567, found 482.0544.
4,6-Bis(4-methylphenyl)-2-(trifluoromethyl)benzonitrile (5ad).
General procedure B was followed with 88.6 mg of 2a and 407.9 mg
−1
+
51 s cm ; HRMS (ESI-TOF) calcd for [M + Na] (C H F NNa)
m/z 284.0663, found 284.0661.
6
procedure A was followed with 33.7 mg of 2a and 192.0 mg of 3k.
PTLC (10:1 hexane/EtOAc) afforded 4ak as a white solid (28.7 mg,
9% yield): mp 87.5−89 °C; H NMR (CDCl , 391.8 MHz) δ 7.42−
.50 (m, 3 H), 7.55 (td, J = 6.7 Hz, 1.6 Hz, 1 H), 7.60 (t, J = 7.1 Hz, 1
H), 7.75 (d, J = 7.8 Hz, 1 H), 7.82 (t, J = 7.8 Hz, 1 H), 7.90 (d, J =
.8 Hz, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 8.00 (d, J = 8.2 Hz, 1 H);
C{ H} NMR (CDCl , 98.5 MHz) δ 111.0 (q, J
22.5 (q, JC−F = 274.4 Hz), 124.7, 125.2, 125.6 (q, JC−F = 5.3 Hz),
15 10 3
-(1-Naphthyl)-2-(trifluoromethyl)benzonitrile (4ak). General
of 3d. PTLC (10:1 hexane/EtOAc) afforded 5ad as a white solid
1
(
14.6 mg, 8% yield): mp 97−98 °C; H NMR (CDCl , 399.7 MHz)
3
δ 2.43 (s, 3 H), 2.46 (s, 3 H), 7.33 (t, J = 8.0 Hz, 4 H), 7.49 (d, J =
8.4 Hz, 2 H), 7.55 (d, J = 8.0 Hz, 2 H), 7.85 (s, 1 H), 7.95 (s, 1 H);
C{ H} NMR (CDCl , 98.5 MHz) δ 21.2, 21.3, 106.6, 115.3, 122.6
1
4
7
3
13
1
3
(
1
q, JC−F = 274.4 Hz), 123.3 (q, JC−F = 5.6 Hz), 127.1, 127.1, 128.8,
29.5, 130.0, 131.3, 134.3 (q, JC−F = 31.0 Hz), 134.9, 139.4, 139.7,
7
1
3
1
= 1.6 Hz), 114.3,
3
C−F
145.4, 148.8; IR (KBr) 3093 w, 2938 w, 2642 w, 2360 w, 2357 w,
2226 s, 2003 w, 1943 w, 1934 w, 1807 w, 1700 w, 1695 w, 1652 w,
1619 s, 1607 s, 1588 w, 1577 w, 1523 w, 1461 m, 1438 m, 1406 s,
1393 s, 1363 s, 1325 s, 1296 s, 1271 m, 1255 m, 1191 s, 1123 s, 1069 s,
1062 s, 1035 s, 1014 s, 975 m, 961 m, 915 w, 904 s, 846 s, 832 s,
1
1
3
2
1
1
1
1
7
26.4, 127.0, 127.7, 128.7, 129.8, 131.2, 132.0, 133.7, 133.7 (q, JC−F
=
2.3 Hz), 134.6, 134.8, 147.2; IR (KBr) 3092 w, 3064 w, 3011 w,
368 w, 2324 w, 2230 m, 1843 w, 1733 w, 1718 w, 1700 w, 1695 w,
684 w, 1653 w, 1634 w, 1616 w, 1592 w, 1559 w, 1539 w, 1520 w,
507 m, 1473 w, 1456 w, 1447 m, 1435 w, 1398 m, 1334 s, 1292 s,
252 w, 1214 w, 1178 s, 1173 s, 1149 s, 1132 s, 1106 s, 1072 m,
058 w, 1020 w, 995 w, 981 w, 959 w, 924 w, 855 w, 807 s, 800 s,
−1
766 w, 742 w, 722 w, 698 w, 654 s, 590 m, 503 w cm ; HRMS
+
(ESI-TOF) calcd for [M + Na] (C H F NNa) m/z 374.1133, found
22
16 3
374.1141.
4,6-Bis(4-methoxylphenyl)-2-(trifluoromethyl)benzonitrile (5af).
General procedure B was followed with 86.9 mg of 2a and 441.5 mg
−1
92 m, 781 s, 761 m, 749 m, 741 m, 737 m, 703 m cm ; HRMS
F
DOI: 10.1021/acs.joc.6b02623
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
of 3f. PTLC (10:1 hexane/EtOAc) afforded 5af as a white solid
X-ray crystallographic data for 5ab and NMR spectra for
all new compounds (PDF)
X-ray crystallographic data for 5ab (CIF)
1
(
4.1 mg, 2% yield): mp 146.5−148.5 °C; H NMR (CDCl , 399.7 MHz)
3
δ 3.88 (s, 3 H), 3.89 (s, 3 H), 7.04 (t, J = 8.8 Hz, 4 H), 7.54 (d, J =
8
.8 Hz, 2 H), 7.60 (d, J = 8.8 Hz, 2 H), 7.81 (s, 1 H), 7.90 (s, 1 H);
1
3
1
C{ H} NMR (CDCl , 98.5 MHz) δ 55.4, 55.5, 106.1, 114.3, 114.8,
3
AUTHOR INFORMATION
Corresponding Author
E-mail: kakiuchi@chem.keio.ac.jp.
1
1
1
2
1
1
1
8
6
5
15.5, 122.6 (q, JC−F = 274.3 Hz), 122.8 (q, JC−F = 5.1 Hz), 128.5,
29.7, 130.1, 130.3, 130.8, 134.4 (q, JC−F = 31.6 Hz), 145.0, 148.4,
60.5, 160.8; IR (KBr) 3063 m, 3037 m, 3012 m, 2972 m, 2945 m,
918 m, 2849 m, 2225 m, 2035 w, 1876 w, 1844 w, 1604 s, 1576 w,
515 s, 1461 m, 1436 m, 1419 w, 1413 w, 1362 s, 1333 w, 1318 m,
307 m, 1290 s, 1257 s, 1245 s, 1207 s, 1179 s, 1174 s, 1164 s, 1118 s,
060 m, 1044 m, 1024 s, 1014 m, 917 w, 903 m, 960 w, 847 w, 826 s,
20 s, 799 w, 791 w, 777 w, 763 w, 731 w, 725 w, 710 w, 682 w, 667 s,
56 w, 638 w, 620 w, 594 w, 581 w, 568 w, 559 w, 544 w, 536 m,
■
*
ORCID
Fumitoshi Kakiuchi: 0000-0003-2605-4675
Notes
The authors declare no competing financial interest.
−
1
+
25 m, 521 m cm ; HRMS (ESI-TOF) calcd for [M + Na]
ACKNOWLEDGMENTS
■
(C H F NO Na) m/z 406.1031, found 406.1031.
22
16
3
2
4
,6-Bis(3-methylphenyl)-2-(trifluoromethyl)benzonitrile (5ah).
This work was supported in part by JSPS KAKENHI Grant No.
JP15H05839 in Middle Molecular Strategy, the MEXT-
Supported Program for the Strategic Research Foundation at
Private University, 2009−2013, and CREST and ACT-C from
the Japan Science and Technology Agency (JST), Japan.
General procedure B was followed with 88.1 mg of 2a and 406.4 mg
of 3h. PTLC (10:1 hexane/EtOAc) afforded 5ah as a white solid
1
(
10.5 mg, 6% yield): mp 165 °C dec; H NMR (CDCl , 400.1 MHz) δ
3
2
6
2
4
1
(
.45 (s, 3 H), 2.46 (s, 3 H), 7.30 (t, J = 8.0 Hz, 2 H), 7.38−7.45 (m,
H), 7.86 (s, 1 H), 7.96 (s, 1 H); 13C{ H} NMR (CDCl , 98.5 MHz) δ
1
3
1.5, 21.5, 107.0, 115.1, 122.6 (q, JC−F = 274.4 Hz), 123.7 (q, JC−F
.6 Hz), 124.5, 126.1, 128.0, 128.8, 129.3, 129.6, 130.1, 130.2, 131.7,
34.3 (q, JC−F = 32.9 Hz), 137.3, 137.8, 138.6, 139.2, 145.7, 148.9; IR
KBr) 3651 w, 3028 w, 2963 w, 2925 w, 2864 w, 2352 w, 2229 w, 1947 w,
=
REFERENCES
■
(
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734 m, 1695 m, 1607 m, 1456 m, 1419 m, 1394 m, 1362 s, 1289 s,
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1135 s, 957 s, 894 m, 785 s, 705 w, 671 w cm ; HRMS (ESI-TOF)
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22
16 3
2
0a
Spectroscopic data of 2-methyl-6-phenylbenzonitrile (4ca) and
20b
(
2
2
,6-diphenylbenzonitrile (6da) are in good agreement with those
reported in literature.
Para C−H Arylation of Aromatic Nitrile 7. In a glovebox,
2
phenylboronate (3a) (152 mg, 0.8 mmol), RuH (CO) (PPh ) (1a)
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3 3
Sci. Technol. 2016, 6, 2005.
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(
36.7 mg, 0.04 mmol), 2,6-bis(trifluoromethyl)benzonitrile (7)
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3
in a 6 mL screw cap tube, and then pinacolone (0.2 mL) was added to
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(
15:1:5 hexane/EtOAc/toluene) to afford 2,6-bis(trifluoromethyl)-4-
(5) Kakiuchi, F.; Sonoda, M.; Tsujimoto, T.; Chatani, N.; Murai, S.
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phenylbenzonitrile (8) as a white solid (8.7 mg, 14% yield): mp 111−
1
1
7
1
1
3
2
1
1
6
3
12 °C; H NMR (CDCl , 391.8 MHz) δ 7.55−7.59 (m, 3 H), 7.64−
3
13
1
.66 (m, 2 H), 8.19 (s, 2 H); C{ H} NMR (CDCl , 98.5 MHz) δ
3
06.3 (sep, JC−F = 2.1 Hz), 111.8, 121.8 (q, JC−F = 274.9 Hz), 127.4,
27.9 (qq, JC−F = 4.6 Hz, 0.9 Hz), 129.7, 130.3, 135.9 (q, JC−F
=
2.9 Hz), 136.5, 146.7; IR (KBr) 3098 w, 3069 w, 3042 w, 2921 w,
851 w, 2236 w, 1614 m, 1590 w, 1469 w, 1460 w, 1374 s, 1340 w,
325 w, 1302 s, 1291 s, 1217 s, 1193 s, 1177 s, 1136 s, 1074 m,
058 m, 1000 w, 971 w, 927 w, 908 m, 848 w, 762 m, 693 m, 675 w,
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−1
−
71 w cm ; HRMS (DART-TOF) calcd for [M] (C H F N) m/z
15
7 6
15.0483, found 315.0493.
Procedures for Syntheses of Benzonitrile-d5 (2d-d5).
Benzonitrile-d was prepared using a procedure similar to the one
for synthesis of various aromatic nitriles reported by Friedman and
5
21
Shechter. A three-neck flask was charged with bromobenzene-d5
4.86 g, 30 mmol), CuCN (3.13 g, 35 mmol), and 4.5 mL of DMF.
(
The mixture was heated to reflux for 22 h under nitrogen. The reaction
mixture was quenched by addition of NH aq and extracted with Et O.
The organic layer was washed with 6 M HCl and water, dried over
MgSO , and concentrated. Purification of the crude material by
distillation and then by silica gel column chromatography (20:1
3
2
4
hexane/EtOAc) afforded 2d-d as a colorless oil (1.50 g, 46% yield).
5
1
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ASSOCIATED CONTENT
■
(
*
S
Supporting Information
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ACS Publications website at DOI: 10.1021/acs.joc.6b02623.
G
DOI: 10.1021/acs.joc.6b02623
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
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(
2
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DOI: 10.1021/acs.joc.6b02623
J. Org. Chem. XXXX, XXX, XXX−XXX