One-step synthesis of diphenylmethanes

Article abstract of DOI:10.1081/SCC-200050959

The coupling reaction of substituted toluenes themselves and the cross-coupling reaction of substituted toluene and aromatic in the presence of bromine in anhydrous CC14 under irradiation lead to diphenylmethanes with moderate to good yields. The methylen

Full text of DOI:10.1081/SCC-200050959

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One‐Step Synthesis of Diphenylmethanes
Qiyan Wei a , Yinggang Luo a , Min Zhou a , Feiyan Tao a & Guoling Zhang a
a Chengdu Institute of Biology, Chinese Academy of Sciences , Chengdu,
China
Published online: 20 Aug 2006.
To cite this article: Qiyan Wei , Yinggang Luo , Min Zhou , Feiyan Tao & Guoling Zhang (2005) One‐Step
Synthesis of Diphenylmethanes, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 35:6, 835-843, DOI: 10.1081/SCC-200050959
To link to this article: http://dx.doi.org/10.1081/SCC-200050959
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Synthetic Communicationsw, 35: 835–843, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050959
One-Step Synthesis of Diphenylmethanes
Qiyan Wei, Yinggang Luo, Min Zhou, Feiyan Tao,
and Guoling Zhang
Chengdu Institute of Biology, Chinese Academy of Sciences,
Chengdu, China
Abstract: The coupling reaction of substituted toluenes themselves and the cross-
coupling reaction of substituted toluene and aromatic in the presence of bromine in
anhydrous CCl4 under irradiation lead to diphenylmethanes with moderate to good
yields. The methylene moiety in diphenylmethanes comes from the toluene with
fewer electron-donating groups, and regioselectivity was observed.
Keywords: Diphenylmethane, coupling reaction
INTRODUCTION
Many diphenylmethane derivatives possess interesting biological properties.
Also, a large number of bioactive molecules contain a diphenylmethane
moiety.[1–3] Diphenylmethanes are frequently used as monomers in supramo-
lecules such as macrocycles, catenanes, and rotaxanes.[4,5] As a starting
material in the perfumery, film, and drug industries, benzophenone can be
synthesized from the oxidation of diphenylmethanes.[6]
Friedel–Crafts alkylation and Friedel–Crafts acylation followed by
reduction are the common methods for the synthesis of diphenylmethane.[7–10]
However, the total yield of diphenylmethane was limited. In some cases,
the preparation of the starting material (benzyl halide and benzoyl halide) is
tedious. At the same time, problems may occur when the substrates are
unstable to the reaction condition, such as Lewis acids. Another efficient
Received in Japan October 15, 2004
Address correspondence to Guoling Zhang, Chengdu Institute of Biology, Chinese
Academy of Sciences, Chengdu 610041, China. E-mail: zhanggl@cib.ac.cn

836
Q. Wei et al.
method for preparing diphenylmethanes was the cross-coupling between aryl
nucleophiles and benzyl halides or between aryl halides and benzyl nucleo-
philes, catalyzed by transition metal.[11–13] In such processes the synthesis
of starting compounds may not be very easy. Herein, we wish to report a
one-step synthesis of diphenylmethanes.
RESULTS AND DISCUSSION
In an attempt to prepare 3,4-dimethoxybenzyl bromide from 3,4-dimethoxy
toluene (1a) and bromine in anhydrous CCl4 under irradiation with heating,
an unexpected product, (4,5-dimethoxy-2-methylphenyl)-(3,4-dimethoxyphe-
nyl)-methane (3a) was obtained with a yield of 53%. Therefore, the formation
of diphenylmethanes following this procedure was investigated in detail with
respect to the regioselectivity and requirement for substrates.
The coupling reaction of substituted toluenes themselves was carried out
as illustrated in Scheme 1 and Table 1. Only 3a was obtained from the
coupling reaction of 3,4-dimethoxytoluene (1a). No diphenylmethanes were
detected in the case of toluene (1b) or 3,4,5-trimethoxytoluene (1c). A com-
plicated mixture was obtained in the case of toluene (1b), whereas only
3,4,5-trimethoxybenzyl bromide was detected in the reaction of 3,4,5-tri-
methoxytoluene (1c).
We want to investigate the cross-coupling reaction of substituted toluenes
(Scheme 2). The diphenylmethanes from the cross-coupling were obtained
with moderate to good yields (Table 2). The self-coupling reaction of 1a
was also observed in the reaction between 1a and 1b (entry 1, Table 2), and
between 1a and 1c (entry 3, Table 2) but no self-coupling diphenylmethanes
Scheme 1.

One-Step Synthesis of Diphenylmethanes
837
Table 1. Coupling reaction of substituted toluenes themselves
Substituents
Yield
(%)b
Entry
Substrates
R5
R6
R7
R8
Productsa
1
2
3
1a
1b
1c
H
H
OCH3
H
OCH3
OCH3
H
OCH3
H
H
3a
3b
3c
53
0c
0d
OCH3
OCH3
aThe products were characterized by EIMS and NMR spectral data.
bIsolated yield.
cComplicated mixture was obtained.
dOnly 3,4,5-trimethoxybenzyl bromide was obtained with high yield (.80%).
from 1b or 1c were obtained (entry 4, Table 2). Interestingly, when a substrate
with more electron-donating groups was added dropwise to the mixture of the
other substrate and Br2, more diphenylmethane was obtained (entry 2,
Table 2). Only the cross-coupling diphenylmethane was obtained in the
cross-coupling reaction between 3,4-dimethoxytoluene and toluene (entry 4,
Table 2).
The coupling reaction between substituted toluene and other aromatics
was also investigated (Scheme 3). The diphenylmethanes were obtained
with moderate yield (Table 3), but in the case of 3,4,5-trimethoxytoluene,
only 3,4,5-trimethoxybenzyl bromide was detected with high yield (.80%,
entry 3, Table 3). The results of the self-coupling reaction of the substituted
toluenes (1a–1c) were similar to those mentioned above (Table 1).
The coupling reaction of 1a with 4-nitrotoluene, 2,4-dinitrotoluene,
indole, and thiophene was carried out in the same reaction condition. No
Scheme 2.

Table 2. Coupling reaction between substituted toluenes
Substituents
R6
Ratio of
productsc
Entry
Substrates
R5
R7
R8
Productsa
Yield (%)b
1
2
3
4
1a þ 1b
1a þ 1b
1a þ 1c
1b þ 1c
H
H
OCH3
OCH3
OCH3
OCH3
H
H
H
H
H
H
3a and 3d
3a and 3d
3a and 3e
3f
66
75d
62
54
2:3 (3d:3a)
6:1 (3d:3a)
4:1 (3e:3a)
OCH3
OCH3
OCH3
H
aAll products were characterized by EIMS and NMR spectral data.
bIsolated yield.
cThe ratio was determined by compounds isolated.
d1a was added dropwise to the reaction mixture of 1b and Br2.

One-Step Synthesis of Diphenylmethanes
839
Scheme 3.
coupling product between 1a and 4-nitrotoluene, between 1a and 2, 4-dinitro-
toluene, between 1a and indole, and between 1a and thiophene was detected in
the reaction mixture, whereas only the self-coupling product 3a was obtained.
It was found that the electronic nature of the substituents on the aromatics
played a significant role in the coupling reaction. Diphenylmethanes were
obtained with reasonable yields when substrates bearing sufficient electron-
donating groups (Tables 1, 2, and 3), except the self-coupling of 4-methylanisole
(1b) (entry 2, Table 1), the self-coupling of 3,4,5-trimethoxytoluene (1c) (entry
3, Table 1), and the cross-coupling between 1c and anisole (2a) (entry 3,
Table 3).
The methylene moiety in diphenylmethanes came from the toluenes with
fewer electron-donating groups (Table 2). As described in Scheme 2, the
methylene moiety was located on the ortho-position of the methyl group of
the toluene with more electron-donating groups when two different toluenes
reacted (Table 2). When substituted toluenes reacted with anisole (2a) or
1,2,3-trimethoxybenzene (2b), the methylene moiety was located at C-4 of
2a or 2b (Table 3).
The substituted benzyl bromide was obtained when the reaction was
carried out without irradiation. Thus, we believe that the irradiation plays
an important role in the formation of diphenylmethanes. Additionally, the
detailed reaction mechanism may be deserve to be discussed and investigated,
considering the differences of the reaction products with irradiation and
without irradiation.
EXPERIMENTAL
A 500-W mercury—tungsten blended lamp was purchased from OSRAM
Company, China. Melting points were determined on an XRC-1 micromelting

Table 3. Coupling reaction of substituted toluenes with aromatics
Substituents
Ratio of
productsc
Entry
Substrates
R5
R6
R7
R8
Productsa
Yield (%)b
1
2
3
4
5
6
1a þ 2a
1b þ 2a
1c þ 2a
1a þ 2b
1b þ 2b
1c þ 2b
H
H
H
H
H
H
OCH3
H
H
H
3a and 4a
4b
42
54
0d
2:5 (4a:3a)
5:1 (4d:3a)
OCH3
OCH3
H
OCH3
H
4c
3a and 4d
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
44
45
40
H
OCH3
4e
4f
OCH3
aAll products were characterized by EIMS and NMR spectral data.
bIsolated yield.
cThe ratio was determined by compounds isolated.
dOnly 3,4,5-trimethoxybenzyl bromide was obtained.

One-Step Synthesis of Diphenylmethanes
841
point apparatus and are uncorrected. NMR spectral data were recorded in
CDCl3 with a Bruker Avance 600 spectrometer (600 MHz for 1H and
150 MHz for 13C), using TMS as internal standard. The chemical shifts (d)
are given in ppm and the coupling constants (J) in Hertz. Silica gel (200–
300 mesh) for column chromatography (CC) and silica gel G (10–40 mm)
for thin-layer chromatography (TLC) were purchased from Qingdao Ocean
Chemical Engineering Company, China.
General Procedure
To a solution of 0.4 mmol of each substrate in 10 mL absolute anhydrous CCl4
was dropwise added 0.4 mmol of Br2 diluted in 8 mL of absolute anhydrous
CCl4 with stirring, heating, and irradiating. The resulting mixture was cooled
to 258C and washed with cold water and cold saturated NaHCO3 (aq.). The
organic layer was combined and the solvent was removed under reduced
pressure to give a residue that was separated by column chromatography
eluted with petroleum ether (bp 60–908C) and ethyl acetate (40:1) to give
the corresponding diphenylmethanes.
3a: white powder; mp 74–758C (lit.[14] mp 75–768C); 1H NMR: d 6.78
(1H, d, J ¼ 8.1 Hz), 6.71 (1H, s), 6.66 (1H, s), 6.64 (1H, s), 6.62 (1H, d,
J ¼ 8.1 Hz), 3.88 (2H, s), 3.88 (3H, s), 3.86 (3H, s), 3.82 (3H, s), 3.81 (3H,
s), 2.20 (3H, s). 13C NMR: d 149.1, 147.4, 147.4, 147.1, 133.5, 131.1,
128.7, 120.6, 113.9, 113.7, 112.1, 111.3, 56.2, 56.1, 56.1, 56.0, 38.7, 19.4;
EIMS (m/z%): 302 (100), 287 (19), 271 (19), 164 (23).
3d: yellow powder; mp 58–598C; 1H NMR: d 7.03 (2H, d, J ¼ 8.3 Hz),
6.82 (2H, d, J ¼ 8.3 Hz), 6.70 (1H, s), 6.64 (1H, s), 3.87 (2H, s), 3.81 (3H, s),
3.79 (3H, s), 3.79 (3H, s), 2.19 (3H, s). 13C NMR: d 157.8, 147.2, 147.0, 132.8,
131.2, 129.4, 128.5, 113.8, 113.7, 56.0, 56.0, 55.2, 38.1, 19.1; EIMS (m/z%):
272 (100), 257 (63), 241 (47), 164 (32), 121 (46).
1
3e: white powder; mp 82–838C; H NMR: d 6.76 (1H, d, J ¼ 8.2 Hz),
6.73 (1H, d, J ¼ 1.6 Hz), 6.61 (1H, dd, J ¼ 8.2, 1.6 Hz), 6.55 (1H, s), 3.95
(2H, s), 3.89 (3H, s), 3.88 (3H, s), 3.85 (3H, s), 3.84 (3H, s), 3.78 (3H, s),
2.22 (3H, s). 13C NMR: d 152.2, 151.5, 148.8, 147.0, 140.3, 133.8, 132.5,
125.1, 119.8, 111.7, 111.2, 109.5, 61.0, 60.8, 55.9, 55.9, 55.8, 31.6, 19.9;
EIMS (m/z%): 332 (100), 151 (37).
3f: yellow oil; 1H NMR: d 7.03 (2H, d, J ¼ 8.5 Hz), 6.80 (2H, d,
J ¼ 8.5 Hz), 6.53 (1H, s), 3.93 (2H, s), 3.88 (3H, s), 3.86 (3H, s), 3.77 (3H,
s), 3.74 (3H, s), 2.19 (3H, s). 13C NMR: d 157.6, 152.2, 151.5, 140.4,
133.2, 132.4, 128.9, 125.3, 113.7, 109.5, 61.0, 60.8, 55.9, 55.2, 31.2, 19.9;
EIMS (m/z%): 302 (100), 287 (20), 121 (39).
1
4a: white powder; mp 36–388C; H NMR: d 7.10 (2H, d, J ¼ 8.3 Hz),
6.84 (2H, d, J ¼ 8.3 Hz), 6.80 (1H, d, J ¼ 8.1 Hz), 6.72 (1H, d, J ¼ 8.1 Hz),
6.70 (1H, s), 3.88 (2H, s), 3.86 (3H, s), 3.83 (3H, s), 3.80 (3H, s),

842
Q. Wei et al.
13C NMR: d 158.0, 149.0, 147.4, 134.2, 133.5, 129.7, 120.8, 113.9, 112.2,
111.3, 55.9, 55.8, 55.3, 40.6; EI-MS (m/z%): 258 (100), 227 (41), 57 (47).
1
4b: white powder; mp 46–488C; H NMR: d 7.10 (4H, d, J ¼ 8.5 Hz),
6.83 (4H, d, J ¼ 8.5 Hz), 3.88 (2H, s), 3.79 (6 H, s). 13C NMR: d 157.9,
133.7, 129.7, 113.8, 55.3, 40.1; EI-MS (m/z%): 228 (100), 197 (64), 121 (27).
1
4d: white powder; mp 54–558C; H NMR: d 6.79 (1H, d, J ¼ 8.3 Hz),
6.78 (1H, d, J ¼ 8.2 Hz), 6.75 (1H, s), 6.72 (1H, d, J ¼ 8.2 Hz), 6.61 (1H,
d, J ¼ 8.3 Hz), 3.88 (3H, s), 3.87 (2H, s), 3.85 (3H, s), 3.84 (3H, s), 3.84
(3H, s), 3.77 (3H, s). 13C NMR: d 152.3, 151.8, 148.8, 147.2, 142.4, 134.0,
127.5, 124.3, 120.7, 112.3, 111.2, 107.2, 60.8, 60.7, 56.0, 55.9, 55.8, 35.3;
EI-MS (m/z%): 318(100), 303 (40), 287 (41), 151 (55), 121 (35).
4e: yellow oil; 1H NMR: d 7.12 (2H, d, J ¼ 8.6 Hz), 6.83 (2H, d,
J ¼ 8.6 Hz), 6.89 (1H, d, J ¼ 8.5 Hz), 6.78 (1H, d, J ¼ 8.5 Hz), 3.88 (3H,
s), 3.87 (2H, s), 3.84 (3H, s), 3.79 (3H, s), 3.75 (3H, s); 13C NMR: d 157.8,
152.3, 151.8, 142.4, 133.5, 129.7, 127.8, 124.4, 113.7, 107.2, 60.7, 56.0,
55.2, 34.8; EIMS (m/z%): 288 (100), 273 (31), 257 (20), 121 (43).
4f: yellow oil; 1H NMR: d 6.72 (1H, d, J ¼ 8.5 Hz), 6.54 (1H, d,
J ¼ 8.5 Hz), 6.35 (2H, s), 3.81 (3H, s), 3.80 (2H, s), 3.78 (3H, s), 3.74 (3H,
s), 3.74 (6H, s), 3.72 (3H, s). 13C NMR: d 153.1, 152.4, 151.8, 142.4,
137.1, 127.0, 124.3, 107.2, 105.9, 60.8, 60.8, 60.7, 56.1, 56.0, 36.0; EIMS
(m/z%): 348 (100), 258 (14), 181 (19).
NOEs between CH3 at d 2.20 (3H, s) and CH2 at d 3.88 (2H, s) and
between CH3 at d 2.20 (3H, s) and CH at d 6.71 (1H, s) were observed in
the NOE difference experiments of compound 3a. The structure of
compound 3d was confirmed by the key NOESY correlations between d
2.19 (3H, s, CH3) and 3.87 (2H, s, CH2) and between d 2.19 (3H, s, CH3)
and 6.70 (1H, s).
CONCLUSION
In summary, diphenylmethanes were synthesized by an one-step process from
the coupling of substituted toluenes themselves and from the cross-coupling
between substituted toluene and aromatic with reasonable yields. The
methylene moiety in diphenylmethanes comes from the toluene with fewer
electron-donating groups, and regioselectivity was observed.
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