An efficient synthesis of unsymmetrical diarylmethanes from the dehydration of arenes with benzyl alcohols using InCl3·4H2O/acetylacetone catalyst system

Article abstract of DOI:10.1016/j.tet.2007.07.093

An efficient and practical synthesis of unsymmetrical diarylmethanes has been achieved from the dehydration of arenes with benzyl alcohols in the presence of catalytic amount of InCl₃·4H₂O/acetylacetone.

Full text of DOI:10.1016/j.tet.2007.07.093

Tetrahedron 63 (2007) 10185–10188
An efficient synthesis of unsymmetrical diarylmethanes from
the dehydration of arenes with benzyl alcohols using
InCl3$4H2O/acetylacetone catalyst system
*
Hong-Bin Sun, Biao Li, Songjie Chen, Jie Li and Ruimao Hua
Department of Chemistry, Tsinghua University, Innovative Catalysis Program, Key Laboratory of Organic Optoelectronics &
Molecular Engineering of Ministry of Education, Beijing 100084, China
Received 13 June 2007; revised 25 July 2007; accepted 26 July 2007
Available online 31 July 2007
Abstract—An efficient and practical synthesis of unsymmetrical diarylmethanes has been achieved from the dehydration of arenes with ben-
zyl alcohols in the presence of catalytic amount of InCl3$4H2O/acetylacetone.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
catalyst for the dehydration of electron-rich arenes with tri-
oxane affording symmetrical diarylmethane derivatives.7 As
a continuation of our research, here we wish to report the re-
sults of InCl3$4H2O/acetylacetone-catalyzed benzylation of
arenes with a variety of benzyl alcohols to produce unsym-
metrical diarylmethane derivatives in good to excellent
yields (Eq. 1).
Benzylation of arenes is an important reaction in the synthe-
sis of diarylmethane derivatives, which are important and
useful intermediates in organic and polymer synthesis.1 Fur-
thermore, some of diarylmethane derivatives have interesting
biological and physiological properties.2 The common syn-
thetic method for diphenylmethane derivatives has been the
Friedel–Crafts type alkylation of arenes with benzyl
halides historically. But the use of benzyl halides as benzylat-
ing agent is undesirable from an environmental point of view,
since this procedure not only requires to use the acid cata-
lysts, which are corrosive (e.g., H2SO4, AlCl3, BF3, etc.),
but also generates a large amount of waste materials during
isolation of the products.3 Therefore, recently the benzyla-
tion of arenes with benzyl alcohols as benzylating reagent un-
der various catalytic conditions has been investigated
extensively4 and become an attractive method for the synthe-
sis of diarylmethane derivatives, because (1) it generates only
H2O as byproduct; (2) benzyl alcohols are more readily avail-
able than the corresponding halides in most cases.
.
HO
InCl3 4H2O/Hacac
+
ð1Þ
120 °C, 6 h
R
R'
R
R'
2. Results and discussion
We initiated our studies to examine the dehydration reaction
of mesitylene (1a) with a variety of benzyl alcohols and the
results are listed in Table 1. When a mixture of 20.0 mmol of
1a, 2.0 mmol of benzyl alcohol (2a), and 0.1 mmol of
InCl3$4H2O was heated with stirring at 120 ꢀC for 24 h,
GC and GC–MS analyzes of the reaction mixture indicated
that phenyl-(2,4,6-trimethylphenyl)methane (3a) was
formed in 32% GC yield (entry 1).8 The yield of 3a was dras-
tically affected by the reaction temperature, if the reaction
was carried out at 150 ꢀC for 24 h, 3a could be obtained in
86% isolated yield (92% of GC yield, entry 2). In order to de-
velop an efficient and practical catalytic system for the pres-
ent benzylation reaction, we have checked the reaction by
addition of some additives, and found that the addition of cat-
alytic amount of acetylacetone (Hacac) could accelerate the
dehydration reaction significantly. Thus, repeating the reac-
tion by addition of Hacac (15 mol %) at 120 ꢀC for 6 h re-
sulted in the formation of 3a in 93% of GC yield (entry 3).
These encouraging results led us to examine the benzylation
On the other hand, developing the catalytic organic reactions
using air-stable and water-tolerant inorganic salts as Lewis
acid catalysts is one of the promising and challenging sub-
jects in modern synthetic chemistry. Recently, InX3
(X¼Cl, Br, I, OTf) have been attracting considerable atten-
tion because of its broad applications as catalysts in organic
synthesis.5 In particular, InX3 have been the efficient cata-
lysts for the carbon–carbon bond formation.6 In our previous
work, we have demonstrated that InCl3$4H2O is an efficient
* Corresponding author. Fax: +86 10 62792596; e-mail: ruimao@mail.
tsinghua.edu.cn
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.093

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H.-B. Sun et al. / Tetrahedron 63 (2007) 10185–10188
Table 1. InCl3$4H2O-catalyzed dehydration of mesitylene with benzyl
Table 2. InCl3$4H2O-catalyzed dehydration of arene with benzyl alcohola
alcoholsa
.
InCl3 4H2O (5 mol%)
Hacac (15 mol%)
120 °C, 6 h
OH
.
InCl3 4H2O (5 mol%)
+
R
R
Hacac (15 mol%)
120 °C, 6 h
OH
+
R'
R'
1
2a
3
1a
2
3
Entry
Arene
Product 3
Yieldb
(%)
Entry
Benzyl alcohol
Product 3
Yieldb (%)
OH
1c
(32)
3g
1
2
92
90
1b
3a
2a
2d
3
2a
2a
3a
3a
86 (92)
86 (93)
Ph
Ph
1c
(29:71)c
3h
3h'
OH
4
5
6
7
82
87
87
67
3b
2
2b
2
Ph
Ph
3
62
OH
1d
(18:81)c
3c
3i
3i'
Cl
2c
Cl
OH
4
5
3j
87
93
3d
1e
2d
OH
2e
Mes
Mes
3e
3k
1f
OH
OMe
OH
Mes
Ph
Ph
2f
8
39
3f
1g
6
MeO
81
MeO
3l
3l'
OH
Mes
(52:48)d
a
Reactions were carried out at 120 ꢀC for 6 h using 20 mmol of 1a, 2 mmol
of 2, 0.1 mmol of catalyst, and 0.3 mmol of Hacac.
Isolated yield based on the amount of 2 used. Numbers in parentheses are
GC yields.
b
Ph
c
Without Hacac, at 120 ꢀC for 24 h.
Ph
d
Without Hacac, at 150 ꢀC for 24 h.
7
8
1h
77
75
41
3m
(81:19)d
3m'
of 1a with a variety of benzyl alcohols in the presence
of InCl3$4H2O/Hacac. As shown in Table 1, diphenylmetha-
nol, para-chloro, para-methyl-substituted benzyl alcohols
underwent the benzylation smoothly to give the correspond-
ing dehydrated products in high isolated yields (entries 4–6).
In addition, under the same reaction conditions, the reaction
of 1a with 1,2- or 1,3-benzenedimethanol afforded the
expected products 3e and 3f in fair to good isolated yields
(entries 7 and 8).
1i
3n
Br
Ph
Ph
1j
9
Br
Br
(56:44)d
3o
3o'
a
Reactions were carried out at 120 ꢀC for 6 h using 20 mmol of 1, 2 mmol
of 2a, 0.1 mmol of catalyst, and 0.2 mmol of Hacac.
Isolated yield based on the amount of 2 used.
Determined by 1H NMR.
The results of the InCl3$4H2O/Hacac-catalyzed benzylation
of several arenes with 2a are summarized in Table 2. The di-,
penta- and tetramethyl substituted arenes showed high reac-
tivity to produce the corresponding benzylated products in
high yields (entries 1–5). In the cases of o-xylene (1c) and
m-xylene (1d), the reactions gave a mixture of two benzyl-
ated products, which were not separable. In the benzylation
of anisole (1g) and cumene (1h), the benzylated products
were obtained in 81 and 77% isolated yields, respectively
(entries 6 and 7). In both cases, two regioisomers were
b
c
d
Determined by GC.
formed, only regioisomers 3l and 3l0 could be further sepa-
rated by careful preparative TLC (silica gel) isolation.
InCl3$4H2O/Hacac catalyst system could also be applied
to the reactions of neutral and electron-deficient arenes,

H.-B. Sun et al. / Tetrahedron 63 (2007) 10185–10188
10187
although the desired benzylated products were obtained in
3. Conclusion
somewhat low yields. In the case of benzene (1i), the mono-
benzylated product 3n was isolated in 75% yield (entry 8).
The reaction of bromobenzene (1j) with 2a afforded an
isomeric mixture in moderate yield (entry 9). In this case, un-
fortunately, the separation of two isomers was not successful
either.
In summary, we have developed an efficient and practical
catalyst system of InCl3$4H2O/Hacac for the dehydration
of arenes with benzyl alcohols to afford unsymmetrical
diarylmethane derivatives in good to high yields. The pres-
ent catalytic procedure provides a valuable alternative for
benzylation of arenes with benzyl alcohols. Further study
to apply InCl3$4H2O/Hacac as catalyst to another carbon–
carbon bond formation is now in progress.
Attempts to develop the multi-benzylation of arene in
one-pot by using the excess amount of benzyl alcohols
(5.0 equiv) were not successful, since the use of the excess
amount of benzyl alcohols not only resulted in the great de-
crease of catalytic activity of catalyst system for the forma-
tion of 3, but also produced a complicated mixture of the
benzylated products.8 In addition, in these cases the forma-
tion of dibenzyl ether became the main reaction.
4. Experimental section
4.1. General method
All organic starting materials are analytically pure and used
without further purification. 1H and 13C NMR spectra were
recorded on a Joel JNM-ECA300 spectrometer at 300 and
75 MHz, respectively. 1H chemical shifts (d) were referenced
to TMS, and 13C NMR chemical shifts (d) were referenced to
internal solvent resonance. GC analyzes of organic com-
pounds were performed on an Agilent Technologies 1790
GC (with a TC-WAX capillary 25 m column) instrument.
Mass spectra were obtained on a Hewlett 5890 Packard
SERIES II GC/MS spectrometer with a PEG-25M column.
High-resolution mass spectra were obtained with a ZAB-
HS mass spectrometer in the Department of Chemistry of
Peking University. Element analyzes were obtained with a
Flash EA 1112 element analyzer in the Institute of Chemis-
try, Chinese Academy of Sciences.
We have also examined briefly the reactions of 3c and 3k with
the electron-deficient benzyl alcohol (2c) (3c/2c¼1:2; 3k/
2c¼1:1), the desired dibenzylated products 4a and 4b were
obtained in low yields after a prolonged reaction time
(Schemes 1 and 2). Compounds 3c and 3k could be recovered
in 76 and 53%, respectively. In both cases, the formation of
bis(4-chlorobenzyl)ether was also observed. Furthermore,
when 3k was employed, there were three more isomers
with the same molecular weight (MS) as 4b, indicating that
the benzylation also took place in the aromatic ring of benzyl
group in 3k. It resulted in the difficult isolation of 4b.
.
InCl3 4H2O (5 mol%)
Hacac (15 mol%)
3c
+
2c
120 °C, 24 h
- H2O
4.2. A typical procedure for the benzylation of
mesitylene (1a) with benzyl alcohol (2a): formation
of 3a (Table 1, entry 3)
Cl
Cl
1 : 2
4a
Isolated yield: 21%
Scheme 1.
A mixture of mesitylene (1a) (2.4 g, 20.0 mmol), benzyl
alcohol (2a) (216.0 mg, 2.0 mmol), InCl3$4H2O (29.5 mg,
0.1 mmol), and Hacac (ca. 30 mL, 0.3 mmol) was stirred at
120 ꢀC for 6 h. To this resulting reaction mixture, hexane
(15.0 mL) as diluent and n-docosane (124.7 mg) as an inter-
nal standard for GC analysis were added. After GC and
GC–MS analyzes, the insoluble materials were removed
by filtration. The solvent was then removed by rotary evap-
oration and mesitylene was then distilled out under reduced
pressure (ca. 100 Torr). The resulting residue was dissolved
in toluene (ca. 2 mL) and subjected to column chromato-
graphic purification (silica gel, eluted with hexane, then a
mixture of hexane and CH2Cl2 (20:1)) to afford 3a as a
colorless oil (362.0 mg, 1.72 mmol, 86%). The GC yield
of 3a in the reaction mixture was 93%.
.
InCl3 4H2O (5 mol%)
Hacac (15 mol%)
3k
+
2a
120 °C, 24 h
- H2O
1 : 1
4b
Isolated yield: 38%
Purity: 92% (GC)
Scheme 2.
It is clear that InCl3$4H2O as a Lewis acid catalyzes the
benzylation of arenes with benzyl alcohols, and the addition
of Hacac can greatly increase its catalytic activity. In order to
get insight into the role of Hacac, we assumed that In(acac)3
might be formed in situ. Therefore, we prepared and exam-
ined the catalytic activity of In(acac)3.9 But unfortunately,
In(acac)3 could not catalyze the present dehydration at all
under the similar reaction conditions, both starting materials
were completely recovered. Attempts to prepare InCl(acac)2
or InCl2(acac) failed, since we usually got a mixture of
indium complexes. Therefore, the catalytic species (or its
precursor) is not clear at the present stage.
The selected spectroscopic data for the new compounds
3c, 3f, and 4a are shown below. The characterization
data for known products and the copies of 1H and 13C
NMR for all the products are provided in Supplementary
data.
4.3. Characterization data of 3c, 3f, and 4a
4.3.1. (4-Chlorophenyl)-(2,4,6-trimethylphenyl)methane
3c. Viscous colorless oil; 1H NMR (300 MHz, CDCl3)
d 7.17 (d, 2H, J¼8.2 Hz), 6.92 (d, 2H, J¼8.2 Hz), 6.88 (s,

10188
H.-B. Sun et al. / Tetrahedron 63 (2007) 10185–10188
2H), 3.96 (s, 2H), 2.28 (s, 3H), 2.17 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 138.6, 136.9, 135.9, 133.2, 131.4,
129.2, 129.0, 128.4, 34.1, 20.9, 20.1 GC–MS m/z (% rel in-
ten.) 244 (M+, 77), 229 (100), 194 (42), 179 (46), 132 (55),
91 (35); Anal. Calcd for C16H17Cl: C, 78.51; H, 7.00. Found:
C, 78.18; H, 6.99.
1952; (e) Prat, L.; Mojovic, L.; Levacher, V.; Dupas, G.;
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Brandsma, L.; Kramer, H.; Seinen, W. Tetrahedron 1998, 54,
2953–2966; (g) Rische, T.; Eilbracht, P. Tetrahedron 1999, 55,
1915–1920; (h) Elz, S.; Kramer, K.; Leschke, C.; Schunack,
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4.3.2. 1,3-Bis[(2,4,6-trimethylphenyl)methyl]benzene 3f.
Needle crystal (from ethanol); 1H NMR (300 MHz,
CDCl3) d 7.04 (m, 1H), 6.85 (s, 4H), 6.74–6.72 (m, 3H),
3.93 (s, 4H), 2.28 (s, 6H), 2.16 (s, 12H); 13C NMR
(75 MHz, CDCl3) d 140.0, 136.9, 135.5, 133.9, 128.8,
128.3, 127.9, 125.0, 34.6, 20.9, 20.1; GC–MS m/z (% rel in-
ten.) 342 (M+, 67), 327 (15), 222 (41), 207 (100), 192 (30),
133 (76), 91 (31); Anal. Calcd for C26H30: C, 91.17; H, 8.83.
Found: C, 90.86; H, 9.01. HRMS calcd for C26H30:
342.2348, found: 342.2349.
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4.3.3. 2,6-Bis(4-chlorobenzyl)-1,3,5-trimethylbenzene 4a.
Needle crystal (from a mixture of cyclohexane and dichloro-
methane); 1H NMR (300 MHz, CDCl3) d 7.18 (d, 4H,
J¼8.3 Hz), 6.96 (s, 1H), 6.92 (d, 4H, J¼8.3 Hz), 4.01 (s,
4H), 2.22 (s, 6H), 2.02 (s, 3H); 13C NMR (75 MHz,
CDCl3) d 138.6, 136.1, 135.3, 134.4, 131.4, 130.2, 129.1,
128.5, 34.8, 20.2, 16.1; GC–MS m/z (% rel inten.): 368
(M+, 100), 256 (82), 192 (33), 165 (9), 152 (4), 139 (4),
125 (35), 115 (6), 91 (5), 77 (4).
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Acknowledgements
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This project was supported by National Natural Science
Foundation of China (20573061) and Specialized Research
Fund for the Doctoral Program of Higher Education
(20060003079). The authors thank Dr. Asish K. Sharma
for his kind English proofreading.
Supplementary data
Characterization data for the known products and copies of
1H and 13C NMR charts of 3 and 4. Supplementary data as-
sociated with this article can be found in the online version,
at doi:10.1016/j.tet.2007.07.093.
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further benzylation of 3 and benzylation of benzyl alcohol itself,
it is important to use an excess amount of arene. Arene can be re-
covered in a range of 80–85% (on the basis of the total amount of
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