Synthesis of diarylmethanes via metal-free reductive cross-coupling of diarylborinic acids with tosyl hydrazones

Article abstract of DOI:10.1021/jo302207b

This paper describes a practical and efficient procedure that takes advantage of diarylborinic acids as a cost-effective alternative to arylboronic acids for synthesis of diarylmethanes through metal-free reductive cross-coupling with N-tosylhydrazones of aromatic aldehydes and ketones. The procedure tolerates hydroxyl, halide, amine, and allyl functionality, complementary to the transition-metal catalyzed cross-coupling techniques.

Full text of DOI:10.1021/jo302207b

Note
pubs.acs.org/joc
Synthesis of Diarylmethanes via Metal-Free Reductive Cross-
Coupling of Diarylborinic Acids with Tosyl Hydrazones
Xijing Li, Yuanyuan Feng, Lin Lin, and Gang Zou*
Department of Fine Chemicals, East China University of Science & Technology, 130 Meilong Road, Shanghai, China
S
* Supporting Information
ABSTRACT: This paper describes a practical and efficient
procedure that takes advantage of diarylborinic acids as a cost-
effective alternative to arylboronic acids for synthesis of
diarylmethanes through metal-free reductive cross-coupling
with N-tosylhydrazones of aromatic aldehydes and ketones.
The procedure tolerates hydroxyl, halide, amine, and allyl
functionality, complementary to the transition-metal catalyzed cross-coupling techniques.
proven highly effective in the synthesis of symmetrical and
iarylmethanes have attracted intensive attention because
Dof the presence of their structural motif in supramolecular unsymmetrical diarylmethanes, metal-free cross-coupling pro-
architectures,1 pharmaceuticals, and biologically active com-
cedures are still advantageous considering the possible toxicity,
pounds,2 such as piritrexim, papaverine, beclobrate, and
cost, and metal residual in final products of transition-metal
catalysts. Generally, only highly reactive substrates, such as aryl
iodides5 and allyl bromides,6 could be used in metal-free Suzuki
coupling unless unconventional conditions were applied.7
dimetindene (Figure 1).
́
However, Barluenga and Valdes reported a novel metal-free
reductive carbon−carbon cross-coupling between N-tosylhy-
drazones and organoboronic acids under mild conditions in
2009,8 inspiring great interest in exploring N-tosylhydrazones
in metal-free cross-coupling reactions.9
Compared with arylboronic acids, high-order arylborons, e.g.,
diarylborinic acids (Ar2B(OH)), triarylboranes (Ar3B), and
tetraarylborates ([Ar4B]−), have higher atom economy as aryl
reagents and could be more economically prepared from aryl
halides, boronates, and magnesium under noncryogenic
conditions.10 However, high-order arylborons have been rarely
applied as aryl sources in cross-coupling.11 We have recently
found that diarylborinic acids, which have properties closest to
arylboronic acids among the high-order arylborons, could take
part in Suzuki coupling as efficient as arylboronic acids under
proper conditions.10c As part of our ongoing efforts to use
diarylborinic acids as a cost-effective alternative to arylboronic
acids, we report herein a general and practical synthesis of
symmetrical and unsymmetrical diarylmethanes through a
metal-free reductive cross-coupling of tosylhydrazones with
diarylborinic acids or anhydrides.
It has been well established from the elegant work by
Aggarwal et al. that the key to using N-tosylhydrazones as a safe
and effective source of active diazo compounds lies in their
controllable decomposition.12 Therefore, reaction of N-
tosylhydrazone (1a) of acetophenone with bis(4-methoxy-
phenyl)borinic acid (2a) was chosen as model reaction to
screen conditions for the metal-free reductive cross-coupling
Figure 1. Selected biologically active diarylmethanes.
The direct method for synthesis of diarylmethanes is
Friedel−Crafts benzylation. Although there have been many
modifications to the traditional Friedel−Crafts benzylation
using new catalysts and benzyl sources,2a,3 the intrinsic
problems of regioselectivity and oversubstitution, except for
the presence of strong directing effects, often decrease the
effectiveness of Friedel−Crafts benzylation in the synthesis of
diarylmethanes. To overcome the drawbacks of Friedel−Crafts
benzylation, transition-metal-catalyzed cross-coupling reactions
have been extensively explored for synthesis of diarylmethanes4
using organoboronic acids (Suzuki coupling),4b−d organo-
magnesium reagents (Kumada coupling), and zinc reagents
(Negishi coupling),4e−j among which Suzuki coupling is
particularly attractive due to the friendly properties of
organoboronic acids, e.g., nontoxicity, air/moisture stability,
and tolerance of a variety of functional groups. Although the
transition-metal-catalyzed cross-coupling approaches have
Received: October 8, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo302207b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
considering both of the substrates could be readily monitored
by TLC (Table 1).
Therefore, we tested the model reaction in PEG-400 under
otherwise identical conditions, but the coupling product 3aa
was isolated in only 43% yield. The poor performance of THF
and CH3CN in the model reaction could, at least partly, be
attributed to their low boiling points considering a slow
reaction observed at low temperature (80 °C) in dioxane
(Table 1, entries 8, 16, and 17).
Table 1. Reductive Coupling of N-Tosylhydrazone 1a with
a
Diarylborinic Acid 2a
Generality of the synthesis of diarylmethanes via the metal-
free reductive cross-coupling of N-tosylhydrazones with
diarylborinic acids was investigated (Table 2). Because of the
Table 2. Scope of Cross-Coupling of N-Tosylhydrazones
a
with Diarylborinic Acids
b
entry
base
solvent
T (°C) time (h) yield (%)
1
2
3
4
5
6
K3PO4·3H2O
K2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
pyridine
DMF
reflux
reflux
reflux
reflux
reflux
reflux
reflux
80
3
3
65
92
Na2CO3
NaOAc
Ba(OH)2·8H2O
KOH
3
26
12
3
trace
trace
trace
53
b
3
entry
R1/R2 (1)
R3 (2)
H (2b)
3
time (h) yield (%)
c
7
K2CO3
6
1
2
H/Me (1a)
3ab
3bb
3cb
3db
3eb
3fb
3gb
3hb
3ib
3jb
3kb
3lb
3ca
3ea
3ha
3ia
2
78
82
93
85
35
72
92
94
93
79
75
86
89
14
83
92
75
93
88
37
91
84
80
80
79
70
90
71
d
h
8
K2CO3
12
3
38
H/Et (1b)
H (2b)
2.5
2
e
9
K2CO3
reflux
reflux
reflux
reflux
110
92
3
4-Br/Me (1c)
4-OH/Me (1d)
4-NO2/Me (1e)
4-NH2/Me (1f)
4-MeO/H (1g)
4-CN/H (1h)
4-OH/H (1i)
2-OH/H (1j)
2-OAllyl/H (1k)
2,4-(Cl)2/H (1l)
4-Br/Me (1c)
4-NO2/Me (1e)
4-CN/H (1h)
4-OH/H (1i)
H/Me (1a)
H (2b)
f
10
g
K2CO3
6
81
4
H (2b)
2.5
2.5
2.5
1
11
K2CO3
3
94
5
H (2b)
12
13
14
15
16
17
K2CO3
12
6
50
6
H (2b)
K2CO3
24
7
H (2b)
K2CO3
n-BuOH
PEG-400
CH3CN
THF
reflux
110
6
59
8
H (2b)
1
K2CO3
6
43
9
H (2b)
1
K2CO3
reflux
reflux
12
12
15
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
H (2b)
1
K2CO3
20
H (2b)
1.5
1
a
Reaction conditions: 1a, 1.0 mmol; 2a, 0.6 mmol (1.2 equiv); solvent,
5 mL. Isolated yield. In air. 32% of 1a was recovered. 2.0 equiv of
K2CO3 was used. 1.0 equiv of 2a was used. 1.5 equiv of 2a (0.75
mmol) was used. 1,2-Bis(1-phenylethylidene)hydrazine was isolated
H (2b)
b
c
d
e
4-OMe (2a)
4-OMe (2a)
4-OMe (2a)
4-OMe (2a)
4-F (2c)
4-F(2c)
3
f
g
2
h
1
as the major byproduct.
1.5
2
3ac
3bc
3cc
3ec
3gc
3hc
3lc
The model reaction proceeded smoothly to offer the desired
product 3aa in 65%, 92%, and 26% yields with a slight excess of
borinic acid 2a (1.2 equiv) after refluxing for 3 h under nitrogen
in dioxane in the presence of 1.0 equiv of K3PO4, K2CO3, and
Na2CO3, respectively, while either weaker or stronger bases,
e.g., NaOAc, Ba(OH)2, and KOH, failed (Table 1, entries 1−
6). When the reaction was run in air, the yield of 3aa decreased
to 53% (Table 1, entry 7). Increasing the stoichiometry of
bis(4-methoxyphenyl)borinic acid (2a) or K2CO3 showed no
remarkable influence on the reaction while a significant
decrease of 3aa yields from 92% to 81% was observed with a
loading of 1.0 equiv of 2a, possibly due to the common side
reaction of organoborons, proton deboronation (Table 1,
entries 9−11).
H/Et (1b)
3
4-Br/Me (1c)
4-NO2/Me (1e)
4-MeO/H (1g)
4-CN/H (1h)
2,4-(Cl)2/H (1l)
2-OH/H (1j)
H/Me (1a)
4-F (2c)
4-F (2c)
4-F(2c)
2.5
3
1
4-F (2c)
4-F (2c)
4-F (2c)
2-Me (2e)
2-Me (2e)
4-Me (2d)
2-Me (2e)
1
1
3jc
1.5
2.5
2.5
2.5
2.5
3ae
3be
3cd
3ce
H/Et (1b)
4-Br/Me (1c)
4-Br/Me (1c)
a
Reaction run on 1.0 mmol scale of 1 with 0.6 mmol of 2a, 2c−e or
0.3 mmol of 2b in anhydride form in 5 mL of dioxane. Isolated yield.
b
The reaction appeared to strongly depend on solvents (Table
1, entries 12−17). Product 3aa was isolated in low yields, and
byproducts acetophenone from hydrolysis of N-tosylhydrazone
(1a) and 1,2-bis(1-phenylethylidene)hydrazine from trapping
the corresponding carbene by phenyldiazoethane were also
isolated when the model reaction was conducted in DMF and
pyridine, respectively. When the reaction was run in n-butanol
3aa was isolated in 59% yield due to the formation of some 1-
methylbenzyl butyl ether.13 A metal-free cross-coupling of aryl
iodides with arylboronic acids was reported to occur to afford
biaryls in PEG preferably over conventional organic solvents.5a
ready dehydration, diphenylborinic acid was used in anhydride
form for convenient stoichiometry. A variety of symmetrical
and unsymmetrical diarylmethanes with a wide range of
functional groups, such as CN, OH, NH2, halide, and allyl
groups, could be readily obtained in good to excellent yields,
while the presence of a NO2 group in N-tosylhydrazones
appeared to be deleterious, leading to complicated reactions
and low yields (14−37%) of the desired coupling products
(Table 2, entries 5, 14, and 20). The tolerance of halide and
allyl groups make the metal-free method complementary to
B
dx.doi.org/10.1021/jo302207b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
transition-metal-catalyzed techniques, which generally destroy
C−X (X ≠ F) and allyl groups. Generally, N-tosylhydrazones of
aryl alkyl ketones required longer reaction time to give
comparable results than aryl aldehydes. No reaction was
observed for N-tosylhydrazone of diphenylketone. A small
steric effect was observed in the reaction with respect to both
N-tosylhydrazones and diarylborinic acids. For example,
although N-tosylhydrazones of propiophenone and acetophe-
none reacted similarly to provide the desired diarylmethanes
3ab and 3bb in comparable yields (78% and 82%), reaction of
N-tosylhydrazones of 2-hydroxybenzaldehyde and 2-allylox-
ybenzaldehyde with diphenylborinic anhydride 2b gave
products 3jb and 3kb in lower yields (75 and 79%) than that
of 4-hydroxybenzaldehyde (93%) (Table 2, entries 9−11).
Similarly, yields of diarylmethanes from ortho-substituted
diarylborinic acids, such as di(2-methylphenyl)borinic acid,
were lower than those from para- or nonsubstituted ones
(Table 2, entries 1, 2, and 25−28).
other features of this procedure include elimination of possible
toxicity, cost, and metal residual of transition-metal catalysts,
and tolerance of hydroxyl, halide, amine, and allyl functionality,
thus complementary to the transition-metal catalyzed cross-
coupling techniques.
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under a
nitrogen atmosphere unless otherwise stated. Commercially available
chemicals were used as received. N-Tosylhydrazones14 and diary-
lborinic acids10c were prepared according to previously reported
1
procedures. H and 13C NMR spectra were recorded in CDCl3 at
ambient temperature. Chemical shifts in NMR were reported in ppm
(δ), relative to the internal standard of tetramethylsilane (TMS). The
signals observed were described as s (singlet), d (doublet), t (triplet),
dd(double doublet), m (multiplets), br (board). The number of
protons (n) for a given resonance was indicated as nH. Coupling
constants were reported as J in hertz. The high-resolution mass spectra
(HRMS) were performed on an electron ionization mass spectrometer
with a quadrupole analyzer.
Electronic effects of substituents at aryl moieties of both N-
tosylhydrazones and diarylborinic acids appeared to be
negligible except for NO2-containing N-tosylhydrazones that
seemed to competitively decompose under the reaction
conditions. For example, reaction of diphenylborinic anhydride
(2b) with N-tosylhydrazones bearing both electron-donating
(OH, OMe and NH2) and -withdrawing (CN and Cl) groups
at the para-position of the benzene ring proceeded similarly
with respect to rate and yields (Table 2, entries 4, 6, 7, 8, and
12). p-Methoxy- (2a) and p-fluoro-substituted (2c) diary-
lborinic acids also showed little difference from diphenylborinic
anhydride (2b) in the reaction. It is worth pointing out that, in
all of the cases investigated, hydroxyl and amino groups on
aromatic rings of N-tosylhydrazones survived, and no aryl ether
or amine product was detected in our experiments although
that oxygen and sulfur ethers could be synthesized from
reaction of N-tosylhydrazones with phenols and arylthiols,
respectively, under similar conditions.13 Reaction of N-
tosylhydrazones of heterocyclic carbonyls, such as 2-fufural
(1m) and 4-acetylpyridine (1n), with 2a also afforded the
desired products 3ma and 3na in 56% and 70% yields,
respectively (Scheme 1).
General Procedure for Reductive Coupling Reaction. Under a
N2 atmosphere, to a 10 mL flask were added N-tosylhydrazone (1.0
mmol), diarylborinic acid (0.6 mmol) or anhydride (0.3 mmol),
K2CO3 (1.0 mmol), and dioxane (5 mL). The mixture was stirred at
110 °C and monitored by TLC until N-tosylhydrazone was completely
consumed. The reaction mixture was diluted with CH2Cl2 (20 mL),
followed by washing twice with H2O (2 × 20 mL). The organic layer
was dried over Na2SO4, filtered, and evaporated under reduced
pressure to give crude product diarylmethane, which was purified by
column chromatography on silica gel with EtOAc/petroleum ether.
1-Methoxy-4-(1-phenylethyl)benzene (3aa):15 colorless liquid
(0.195 g, 92%); 1H NMR (CDCl3, 400 MHz) δ 7.27−7.12 (m,
7H), 6.82 (d, J = 8.4 Hz, 2H), 4.10 (q, J = 7.2 Hz, 1H), 3.76 (s, 3H),
1.61 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 156.8, 145.7,
137.5, 127.4, 127.3, 126.5, 124.9, 112.7, 54.1, 42.9, 21.0.
Ethane-1,1-diyldibenzene (3ab):3a colorless liquid (0.142 g, 78%);
1H NMR (CDCl3, 400 MHz) δ 7.29−7.15 (m, 10H), 4.14 (q, J = 7.2
Hz, 1H), 1.63 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
146.5, 128.5, 127.7, 126.1, 44.9, 22.0.
Propane-1,1-diyldibenzene (3bb):16 colorless liquid (0.161 g,
1
82%); H NMR (CDCl3, 400 MHz) δ 7.27−7.21 (m, 8H), 7.16−
7.12 (m, 2H), 3.77 (t, J = 8.0 Hz, 1H), 2.10−2.02 (m, 2H), 0.88 (t, J =
7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 145.3, 128.5, 128.1,
126.2, 53.4, 28.7, 12.9.
1-Bromo-4-(1-phenylethyl)benzene (3cb):3a light yellow liquid
1
Scheme 1. Synthesis of Pyridyl/Furylarylmethanes
(0.243 g, 93%); H NMR (CDCl3, 400 MHz) δ 7.39 (d, J = 8.4 Hz,
2H), 7.30−7.26 (m, 2H), 7.20−7.17 (m, 3H), 7.08 (d, J = 8.4 Hz,
2H), 4.10 (q, J = 7.2 Hz, 1H), 1.61 (d, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 145.8, 145.5, 131.5, 129.5, 128.6, 127.6, 126.4,
119.9, 44.3, 21.9.
4-(1-Phenylethyl)phenol (3db):17 light yellow liquid (0.168 g,
85%); 1H NMR (CDCl3, 400 MHz) δ 7.26 (t, J = 7.2 Hz, 2H), 7.19−
7.14 (m, 3H), 7.05 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 7.6 Hz, 2H), 5.37
(br. s, 1H), 4.06 (q, J = 7.2 Hz, 1H), 1.58 (d, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 153.7, 147.0, 138.9, 128.9, 128.6, 127.7,
126.2, 115.5, 44.1, 22.2.
1-Nitro-4-(1-phenylethyl)benzene (3eb):18 yellow liquid (0.079 g,
1
35%); H NMR (CDCl3, 400 MHz) δ 8.05 (dd, J = 2.0, 6.8 Hz, 2H),
7.30−7.21 (m, 4H), 7.17−7.10 (m, 3H), 4.17 (q, J = 7.2 Hz, 1H), 1.59
(d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 154.1, 146.4,
144.6, 128.7, 128.5, 127.6, 126.7, 123.7, 44.8, 21.5.
4-(1-Phenylethyl)aniline (3fb):19 yellow liquid (0.142 g, 72%); H
1
In conclusion, metal-free reductive cross-coupling of N-
tosylhydrazones of aromatic aldehydes and aryl alkyl ketones
with diarylborinic acids or anhydrides was shown to be a
practical and efficient protocol for synthesis of diarylmethanes
under mild conditions in good yields. The higher process and
atom economies of diarylborinic acids over arylboronic acids
promise a more cost-effective synthesis of diarylmethanes. The
NMR (CDCl3, 400 MHz) δ 7.26−7.15 (m, 5H), 7.00 (d, J = 8.4 Hz,
2H), 6.59 (d, J = 8.4 Hz, 2H), 4.04 (q, J = 7.2 Hz, 1H), 3.51 (br. s,
2H), 1.58 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 147.3,
144.6, 136.6, 128.5, 128.4, 127.7, 126.0, 115.3, 44.0, 22.2.
1-Benzyl-4-methoxybenzene (3gb):20 light yellow liquid (0.182 g,
92%); 1H NMR (CDCl3, 400 MHz) δ 7.29−7.25 (m, 2H), 7.22−7.15
(m, 3H), 7.10 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 3.92 (s,
C
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Note
2H), 3.77 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 156.9, 140.5,
Hz), 131.6, 129.4, 129.0 (d, J = 7.6 Hz), 120.0, 115.3 (d, J = 21.1 Hz),
43.6, 22.0.
132.2, 128.8, 127.7, 127.4, 124.9, 112.8, 54.1, 40.0.
4-Benzylbenzonitrile (3hb):15 colorless liquid (0.182 g, 94%); H
1
1-Fluoro-4-(1-(4-nitrophenyl)ethyl)benzene (3ec): yellow liquid
1
NMR (CDCl3, 400 MHz) δ 7.55 (d, J = 8.0 Hz, 2H), 7.36−7.21 (m,
5H), 7.15 (d, J = 7.2 Hz, 2H), 4.02 (s, 2H); 13C NMR (CDCl3, 100
MHz) δ 146.8, 139.4, 132.3, 129.7, 129.0, 128.8, 126.7, 119.1, 110.0,
42.0.
(0.091 g, 37%); H NMR (CDCl3, 400 MHz) δ 8.04 (d, J = 8.8 Hz,
2H), 7.26 (d, J = 8.8 Hz, 2H), 7.08−7.05 (m, 2H), 6.92−6.88 (m,
2H), 4.15 (q, J = 7.2 Hz, 1H), 1.57 (d, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 160.5 (d, J = 243.7 Hz), 152.8, 145.4, 139.2 (d, J
= 3.1 Hz), 128.0 (d, J = 7.8 Hz), 127.3, 122.7, 114.4 (d, J = 21.1 Hz),
43.0, 20.6; HRMS (EI) m/z (M+) calcd for C14H12FNO2 245.0852,
found 245.0855.
4-Benzylphenol (3ib):15 white solid (0.171 g, 93%); mp 83−84 °C;
1H NMR (CDCl3, 400 MHz) δ 7.18−7.15 (m, 2H), 7.10−7.05 (m,
3H), 6.93−6.91 (m, 2H), 6.64−6.61 (m, 2H), 5.35 (br. s, 1H), 3.79 (s,
2H); 13C NMR (CDCl3, 100 MHz) δ 153.7, 141.6, 133.6, 130.2,
128.9, 128.6, 126.1, 115.5, 41.1.
1-Fluoro-4-(4-methoxybenzyl)benzene (3gc):24 colorless liquid
(0.197 g, 91%); 1H NMR (CDCl3, 400 MHz) δ 7.05−6.98 (m,
4H), 6.89−6.84 (m, 2H), 6.75 (d, J = 8.8 Hz, 2H), 3.80 (s, 2H), 3.69
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 160.3 (d, J = 242.2 Hz),
157.0, 136.2 (d, J = 3.1 Hz), 132.0, 129.1 (d, J = 7.7 Hz), 128.7, 114.1
(d, J = 21.1 Hz), 112.9, 54.1, 39.1.
2-Benzylphenol (3jb):21 yellow liquid (0.145 g, 79%); H NMR
1
(CDCl3, 400 MHz) δ 7.30−7.27 (m, 2H), 7.23−7.18 (m, 3H), 7.14−
7.10 (m, 2H), 6.88 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 4.78
(br. s, 1H), 3.99 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 153.8, 140.1,
131.1, 128.8, 128.7, 127.9, 127.2, 126.4, 121.0, 115.8, 36.4.
1-(Allyloxy)-2-benzylbenzene (3kb):22 colorless liquid (0.168 g,
75%); 1H NMR (CDCl3, 400 MHz) δ 7.27−7.07 (m, 7H), 6.89−6.82
(m, 2H), 6.05−5.95 (m, 1H), 5.36 (dd, J = 1.6, 17.2 Hz, 1H), 5.23
(dd, J = 1.6, 10.4 Hz, 1H), 4.51 (d, J = 4.8 Hz, 2H), 4.00 (s, 2H); 13C
NMR (CDCl3, 100 MHz) δ 156.4, 141.2, 133.6, 130.6, 130.2, 129.1,
128.3, 127.5, 125.9, 120.8, 117.1, 111.8, 68.8, 36.2.
4-(4-Fluorobenzyl)benzonitrile (3hc):25 light yellow liquid (0.177
g, 84%); 1H NMR (CDCl3, 400 MHz) δ 7.45 (d, J = 8.0 Hz, 2H), 7.15
(d, J = 8.0 Hz, 2H), 7.01 (dd, J = 5.6, 12.4 Hz, 2H), 7.00−6.86 (m,
2H), 4.00 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 160.6 (d, J = 243.5
Hz), 145.5, 134.1 (d, J = 3.3 Hz), 131.3, 129.4 (d, J = 7.9 Hz), 128.5,
117.9, 114.5 (d, J = 21.1 Hz), 109.1, 40.0.
2,4-Dichloro-1-(4-fluorobenzyl)benzene (3lc): light yellow liquid
1-Benzyl-2,4-dichlorobenzene (3lb):23 light yellow liquid (0.204 g,
86%); 1H NMR (CDCl3, 400 MHz) δ 7.39 (d, J = 2.4 Hz, 1H), 7.31−
7.14 (m, 6H), 7.05 (d, J = 8.4 Hz, 1H), 4.06 (s, 2H); 13C NMR
(CDCl3, 100 MHz) δ 139.0, 137.4, 134.9, 132.7, 131.8, 129.4, 129.0,
128.7, 127.2, 126.6, 38.7.
1
(0.204 g, 80%); H NMR (CDCl3, 400 MHz) δ 7.39 (s, 1H), 7.18−
6.95 (m, 6H), 4.02 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 161.6 (d,
J = 243.3 Hz), 137.2, 134.8, 134.6 (d, J = 3.2 Hz), 132.9, 131.7, 130.3
(d, J = 7.9 Hz), 129.4, 127.2, 115.4 (d, J = 21.2 Hz), 37.9. HRMS (EI)
m/z (M+) calcd for C13H9Cl2F 254.0065, found 254.0061.
1-Bromo-4-(1-(4-methoxyphenyl)ethyl)benzene (3ca):17 colorless
liquid (0.259 g, 89%); 1H NMR (CDCl3, 400 MHz) δ 7.30 (d, J = 8.4
Hz, 2H), 7.03−6.98 (m, 4H), 6.75 (d, J = 8.8 Hz, 2H), 3.98 (q, J = 7.2
Hz, 1H), 3.70 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 156.9, 144.7, 136.7, 130.3, 128.3, 127.4, 118.6, 112.8,
54.1, 42.3, 20.9.
2-(4-Fluorobenzyl)phenol (3jc):2d Light yellow liquid (0.162 g,
80%), 1H NMR (CDCl3, 400 MHz) δ 7.21−7.06 (m, 4H), 6.96−6.86
(m, 3H), 6.73 (d, J = 7.6 Hz, 1H), 4.93 (br. s, 1H), 3.93 (s, 2H); 13C
NMR (CDCl3, 100 MHz) δ 161.5 (d, J = 242.3 Hz), 153.6, 135.8,
130.9, 130.2 (d, J = 7.8 Hz), 127.9, 127.1, 121.1, 115.7, 115.3 (d, J =
21.1 Hz), 35.4.
1-Methoxy-4-(1-(4-nitrophenyl)ethyl)benzene (3ea):18 yellow
1-Methyl-2-(1-phenylethyl)benzene (3ae):3c colorless liquid
(0.155 g, 79%); 1H NMR (CDCl3, 400 MHz) δ 7.28−7.11 (m,
9H), 4.31 (q, J = 7.2 Hz, 1H), 2.22 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H);
13C NMR (CDCl3, 100 MHz) δ 146.4, 144.0, 136.2, 130.5, 128.4,
127.8, 126.8, 126.2, 126.1, 125.9, 41.1, 22.3, 19.9.
1
liquid (0.036 g, 14%); H NMR (CDCl3, 400 MHz) δ 8.04 (d, J =
8.8 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.77
(d, J = 8.4 Hz, 2H), 4.12 (q, J = 7.2 Hz, 1H), 3.70 (s, 3H), 1.56 (d, J =
7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 158.3, 154.5, 146.3,
136.7, 128.5, 128.4, 123.7, 114.1, 55.3, 44.0, 21.7.
1-Methyl-2-(1-phenylpropyl)benzene (3be):26 colorless liquid
(0.147 g, 70%); 1H NMR (CDCl3, 400 MHz) δ 7.33−7.09 (m,
9H), 3.97 (t, J = 7.6 Hz, 1H), 2.25 (s, 3H), 2.05 (m, 2H), 0.91 (t, J =
7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 144.9, 143.0, 136.5,
130.6, 128.4, 128.3, 126.7, 126.1, 126.0, 125.9, 48.9, 29.2, 20.1, 13.0.
1-Bromo-4-(1-p-tolylethyl)benzene (3cd): light yellow liquid
(0.248 g, 90%); 1H NMR (CDCl3, 400 MHz) δ 7.39−7.36 (m,
2H), 7.10−7.06 (m, 6H), 4.06 (q, J = 7.2 Hz, 1H), 2.30 (s, 3H), 1.59
(d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 145.8, 142.9,
135.9, 131.5, 129.5, 129.3, 127.5, 119.9, 44.0, 22.0, 21.2; HRMS (EI)
m/z (M+) calcd for C15H15Br 274.0357, found 274.0359.
4-(4-Methoxybenzyl)benzonitrile (3ha):8 white solid (0.185 g,
83%); mp 48−49 °C; 1H NMR (CDCl3, 400 MHz) δ 7.55 (d, J = 8.0
Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.85 (d, J
= 8.8 Hz, 2H), 3.96 (s, 2H), 3.78 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 158.4, 147.3, 132.3, 131.5, 130.0, 129.6, 119.1, 114.2, 109.9,
55.3, 41.1.
4-(4-Methoxybenzyl)phenol (3ia):15 light yellow solid (0.197 g,
92%); mp 81−82 °C; 1H NMR (CDCl3, 400 MHz) δ 7.06 (d, J = 8.0
Hz, 2H), 6.99 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 6.71 (d, J
= 8.4 Hz, 2H), 5.75 (br. s, 1H), 3.82 (s, 2H), 3.75 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 157.8, 153.9, 134.0, 133.8, 130.0, 129.9, 115.4,
114.0, 55.4, 40.2.
1-(1-(4-Bromophenyl)ethyl)-2-methylbenzene (3ce): light yellow
liquid (0.195 g, 71%); 1H NMR (CDCl3, 400 MHz) δ 7.36 (d, J = 8.4
Hz, 2H), 7.24−7.11 (m, 4H), 7.01 (d, J = 8.4 Hz, 2H), 4.26 (q, J = 7.2
Hz, 1H), 2.20 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 145.4, 143.3, 136.1, 131.5, 130.6, 129.6, 126.7, 126.5,
126.3, 119.7, 40.6, 22.1, 19.8; HRMS (EI) m/z (M+) calcd for
C15H15Br 274.0357, found 274.0359.
1-Fluoro-4-(1-phenylethyl)benzene (3ac):3a light yellow liquid
1
(0.150 g, 75%); H NMR (CDCl3, 400 MHz) δ 7.30−7.26 (m, 2H),
7.20−7.14 (m, 5H), 6.98−6.93 (m, 2H), 4.13 (q, J = 7.2 Hz, 1H), 1.61
(d, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 161.4 (d, J =
242.4 Hz), 146.3, 142.1 (d, J = 3.1 Hz), 129.1 (d, J = 7.7 Hz), 128.5,
127.6, 126.3, 115.2 (d, J = 20.9 Hz), 44.1, 22.1.
2-(4-Methoxybenzyl)furan (3ma):27 colorless liquid (0.105 g,
1-Fluoro-4-(1-phenylpropyl)benzene (3bc): light yellow liquid
(0.199 g, 93%); 1H NMR (CDCl3, 400 MHz) δ 7.29−7.16 (m,
7H), 6.95 (t, J = 8.8 Hz, 2H), 3.77 (t, J = 8.0 Hz, 1H), 2.08−2.00 (m,
2H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 161.3
(d, J = 242.3 Hz), 145.0, 140.9 (d, J = 3.0 Hz), 129.3 (d, J = 7.7 Hz),
128.5, 127.9, 126.2, 115.1 (d, J = 21.0 Hz), 52.5, 28.8, 12.8; HRMS
(EI) m/z (M+) calcd for C15H15F 214.1158, found 214.1163.
1-Bromo-4-(1-(4-fluorophenyl)ethyl)benzene (3cc):3a light yellow
liquid (0.245 g, 88%); 1H NMR (CDCl3, 400 MHz) δ 7.39 (d, J = 8.4
Hz, 2H), 7.15−7.11 (m, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.98−6.94 (m,
2H), 4.08 (q, J = 7.2 Hz, 1H), 1.59 (d, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 161.4 (d, J = 242.9 Hz), 145.3, 141.5 (d, J = 3.1
1
56%); H NMR (CDCl3, 400 MHz) δ 7.22 (d, J = 1.2 Hz, 1H),
7.06 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 6.19 (dd, J = 2.8, 1.6
Hz, 1H), 5.88 (d, J = 2.8 Hz, 1H), 3.81 (s, 2H), 3.68 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 158.3, 155.1, 141.4, 130.2, 129.7, 113.9,
110.3, 106.0, 55.3, 33.6.
4-(1-(4-Methoxyphenyl)ethyl)pyridine (3na):8 light yellow liquid
1
(0.149 g, 70%); H NMR (CDCl3, 400 MHz) δ 8.50 (br s, 2H), 7.15
(d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H),
4.07 (q, J = 7.8 Hz, 1H), 3.78 (s, 3H), 1.61 (d, J = 8.0 Hz, 3H). 13C
NMR (CDCl3, 100 MHz) δ 158.3, 156.3, 136.3, 128.6, 123.2, 114.0,
55.3, 43.5, 21.2.
D
dx.doi.org/10.1021/jo302207b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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(13) (a) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C.
ASSOCIATED CONTENT
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Angew. Chem., Int. Ed. 2010, 49, 4993. (b) Ding, Q.; Cao, B.; Yuan, J.;
Liu, X.; Peng, Y. Org. Biomol. Chem. 2011, 9, 748.
(14) Zhou, L.; Ye, F.; Ma, J.; Zhang, Y.; Wang, J. Angew. Chem., Int.
Ed. 2011, 50, 3510.
S
* Supporting Information
1H and 13C NMR spectra for all compounds and HRMS for
new compounds reported. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zougang@ecust.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We are grateful for financial support provided by the National
Science Foundation of China (No. 20972049).
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dx.doi.org/10.1021/jo302207b | J. Org. Chem. XXXX, XXX, XXX−XXX