Molecular iodine-catalyzed benzylation of arenes with benzyl alcohols

Article abstract of DOI:10.1016/j.tetlet.2008.05.146

A novel molecular iodine-catalyzed benzylation of arenes with benzyl alcohols has been developed. The reaction can be carried out under mild conditions to afford a series of diarymethane derivatives in high yields and good regioselectivities.

Full text of DOI:10.1016/j.tetlet.2008.05.146

Tetrahedron Letters 49 (2008) 4929–4932
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Tetrahedron Letters
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Molecular iodine-catalyzed benzylation of arenes with benzyl alcohols
*
Gaojun Sun, Zhiyong Wang
Hefei National Laboratory for Physical Science at Microscale, Joint Laboratory of Green Synthetic Chemistry and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel molecular iodine-catalyzed benzylation of arenes with benzyl alcohols has been developed. The
reaction can be carried out under mild conditions to afford a series of diarymethane derivatives in high
yields and good regioselectivities.
Received 14 January 2008
Revised 20 May 2008
Accepted 30 May 2008
Available online 4 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Benzylation
Molecular iodine
Synthesis
Solvent-free
Recently benzylation with benzyl alcohols has become an
attractive method in organic synthesis.1 Benzyl alcohols used as
benzylating agents are preferable to benzylic halide because the
formation of hydrogen halides is avoided.2 Benzyl alcohols are also
superior to benzyl carboxylates in benzylation because no modi-
fied substrates are involved.3 In comparison with the styrene
derivatives,4 benzyl alcohols are more easily available. However,
heavy metals are often involved in the benzylation, which results
in the residue of heavy metals in the products such as pharmaceu-
ticals. In order to avoid the metal catalysts in the benzylation, we
attempted to explore non-metal catalysts to synthesize 1,1-diaryl-
alkane and 1-aryl-1-heteroalkane, which are important moieties in
various valuable biologically active compounds and pharmaceuti-
cals.5 To the best of our knowledge, iodine is favorable to pharma-
ceutical synthesis owing to its inexpensive, non-toxic, and
environmental friendly characteristics. Besides, iodine can be eas-
ily removed from the reaction system. Moreover, molecular iodine
is not sensitive to air or moisture. Recently iodine was employed in
some nucleophilic substitution reactions.6 And we have used
iodine in two kinds of iodocyclization.7 Herein we report a new
benzylation method catalyzed by iodine without any metal
catalyst.
the reaction system so as to promote the reaction. Subsequently,
the optimal reaction conditions, such as catalyst loading and reac-
tion temperature, were screened. The experimental results are
listed in Table 1.10 The best result was obtained with 10 mol % of
molecular iodine and 10 mg of ground 4 Å molecular sieve at 60 °C.
Following the optimization of the reaction conditions, we
examined the benzylation of different arenes with primary benzyl
alcohol (Table 2). As shown in Table 2, electron-rich arenes such as
anisole, toluene, o-xylene, m-xylene, p-xylene, 1,2,3,4-tetrahydro-
naphthalene and arenes bearing phenolic hydroxyl and mercapto
groups were tested, and all of them reacted smoothly with benzyl
alcohol to give the corresponding benzylation products in good
yields after short reaction time (4 h). The para-substituted product
Table 1
Reaction of anisole and benzyl alcohol in the presence of 4 Å molecular sievea
OMe
I2
HO
+
OMe
1
2
Entry
Cat. (mol %)
Temperature (°C)
Time (h)
Yieldb (%)
Initially, the reaction of anisole 1 with benzyl alcohol 2 was
employed as a model reaction. The reaction afforded the desired
product in a low yield and with a slow rate. Considering the release
of stoichiometric water as a side-product, ground 4 Å molecular
sieve was added into the reaction mixture to remove water from
1
2
3
4
5
6
20
20
20
10
10
5
100
80
60
60
25
60
4
4
4
4
8
8
89
88
88
87
45
66
a
Reactions were carried out with 1 (1.1 mmol) and 2 (1 mmol) in the presence of
ground 4 Å molecular sieve (10 mg).
* Corresponding author. Tel.: +86 551 3603185; fax: +86 551 3601592.
E-mail address: zwang3@ustc.edu.cn (Z. Wang).
b
Isolated yield based on the amount of 2.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.146

4930
G. Sun, Z. Wang / Tetrahedron Letters 49 (2008) 4929–4932
Table 2
was obtained as the major product (Table 2, entries 1, 2, 3, 4 and 6).
Reaction of arenes with benzyl alcohola
As for the reaction of m-xylene (Table 2, entry 4), 2-benzyl-1,3-
dimethylbenzene, another isomer of the main product, was also
obtained in spite of the strong steric hindrance from two methyl
groups. However, when p-cresol and 4-methylbenzenethiol were
used as reaction substrates, 2-benzyl-4-methylphenol and 2-benz-
yl-4-methylbenzenethiol were provided as the main products,
respectively. This is the first example of benzylation of mercapto
group-containing substrate to give corresponding arylation
product.
I2
OH
Ar
Arene
1
+
60 ºC, M.S.
2
Entry
1
Arene
MeO
Major product
Yieldb (%)
88
Selectivityc
62:38
OMe
In Table 3, different primary benzyl alcohols are employed in
the benzylation of anisole. Both electron-rich (Table 3, entries 1–
3) and electron-poor primary benzyl alcohols (Table 3, entries 5–
8) could react with anisole smoothly to afford the corresponding
diarylmethanes in high yields. In all cases, the corresponding prod-
ucts were obtained with excellent selectivities (99:1). As for sec-
ondary benzyl alcohols, so far, there were only a few successful
reports about the employment of the secondary benzyl alcohols
bearing b-H atom as the benzylation substrates.1f,4e,8 Under our
conditions, the secondary benzyl alcohols can undergo the benzy-
lation to afford the desired benzylation products (Table 4). For in-
stance, the reaction of 1-phenylethanol with anisole catalyzed by
molecular iodine gave the corresponding product in 90% yield,
and the ratio of p-:o-product was 87:13 (Table 4, entry 1). Other
secondary benzyl alcohols produced the corresponding benzylated
products in good yields and with excellent selectivity of p- versus
o-product (99:1). However, when 1-phenylethanol was employed
as an alkylating agent in the benzylation under Brønsted or Lewis
acid-catalyzed conditions, styrene was detected as the major prod-
uct.4a,9 This indicated that the molecular iodine-catalyzed benzyla-
tion was an efficient benzylation involving secondary benzyl
alcohols as reaction substrates.
2
3
4
70
76
72
59:41
74:36
85:15d
5
6
65
60
—
68:32
OH
SH
HO
HS
7
75
68
67:33e
Based on the above experimental results, we proposed a
possible reaction mechanism for this molecular iodine-catalyzed
benzylation, as shown in Scheme 1. A benzyl carbocation 2 might
be formed from benzyl alcohol 1 in the presence of molecular
iodine, and then 2 could be attacked by arenes to afford the
corresponding product 3.
f
8
—
In summary, we have developed an efficient iodine-catalyzed
benzylation of arenes with benzyl alcohols in the presence of 4 Å
molecular sieve. Compared to previous benzylation reactions, me-
tal catalysts were avoided in this new method. The reaction can
tolerate water and air. Advantages such as mild reaction condi-
tions, short reaction time, broad substrate scope, and simple work-
up render this transformation a practical route to the valuable 1,1-
diarylalkanes.
a
Reactions were carried out with iodine (10 mol %), 1 (1.1 mmol) and 2 (1 mmol)
in the presence of ground 4 Å molecular sieve (10 mg) at 60 °C for 4 h.
b
Isolated yield based on the amount of benzyl alcohol.
c
Regioselectivity was determined by 1H NMR or 13C NMR spectroscopic data,
ratio = p-:o-product.
d
Ratio = 1-(2,4-dimethylbenzyl) benzene: 2-benzyl-1,3-dimethylbenzene.
Ratio = 2-benzyl-4-methylphenol:3-benzyl-4-methylphenol.
Almost only 2-benzyl-4-methylbenzenethiol.
e
f
Table 3
Reaction of primary benzyl alcohols with anisolea
OMe
I2
60 ºC, M.S.
Ar
+
Benzyl Alcohol
OMe
1
2
Entry
1
Benzyl alcohol
Major product
Yieldb (%)
81
Selectivityc
99:1
OH
OMe
OH
2
80
99:1
MeO
MeO
OMe

G. Sun, Z. Wang / Tetrahedron Letters 49 (2008) 4929–4932
4931
Table 3 (continued)
Entry
Benzyl alcohol
Major product
Yieldb (%)
78
Selectivityc
99:1
OMe
OMe
3
OH
OH
OMe
MeO
4
75
99:1
OH
5
6
7
85
88
87
99:1
99:1
99:1
F
F
OMe
OMe
OMe
OH
Cl
Cl
OH
Br
Br
Cl
Cl
8
80
99:1
OH
OMe
a
Reactions were carried out with iodine (10 mol %), 1 (1.1 mmol) and 2 (1 mmol) in the presence of ground 4 Å molecular sieve (10 mg) at 60 °C for 4 h.
Isolated yield based on the amount of benzyl alcohol.
b
c
Regioselectivity was determined by 1H NMR or 13C NMR spectroscopic data, ratio = p-:o-product.
Table 4
Reaction of secondary benzyl alcohols with anisolea
R
OMe
I2
Ar
+
Benzyl Alcohol
80 ºC, M.S.
OMe
1
2
Entry
1
Benzyl alcohol
Major product
Yieldb (%)
90
Selectivityc
87:13
OH
OMe
OMe
OH
OH
2
65
99:1
3
4
60
91
99:1
OMe
OH
99:1
Cl
OMe
Cl
(continued on next page)

4932
G. Sun, Z. Wang / Tetrahedron Letters 49 (2008) 4929–4932
Table 4 (continued)
Entry
Benzyl alcohol
Major product
Yieldb (%)
72
Selectivityc
99:1
OH
5
NC
Cl
OMe
NC
Cl
OH
6
88
99:1
OMe
a
Reactions were carried out with iodine (10 mol %), 1 (1.1 mmol) and 2 (1 mmol) in the presence of ground 4 Å molecular sieve (10 mg) at 80 °C for 6 h.
Isolated yield based on the amount of benzyl alcohol.
b
c
Regioselectivity was determined by 1H NMR or 13C NMR spectroscopy and comparison with literature data, ratio = p-:o-product.
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R2
R2
10 mol% I2
Heating
OH
R1
R1
1
2
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R2
Arene
Ar
R1
3
Scheme 1.
Acknowledgments
The authors are grateful to National Nature Science Foundation
of China (Nos. 20472078 and 30572234).
Supplementary data
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10 mg of ground 4 Å molecular sieve. The mixture was heated at 60 °C for 4 h,
cooled down, and treated with aqueous NaS2O3, then extracted three times
with ethyl acetate. The combined organic extracts were dried with anhydrous
Na2SO4 and evaporated under reduced pressure; the resulting crude mixture
was purified by column chromatography on silica gel to afford the product.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.146.
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