Iron-catalyzed benzylation reaction of arenes with benzyl thiocyanates

Article abstract of DOI:10.1055/s-0031-1290343

A novel, regioselective protocol for the synthesis of diphenylmethane derivatives has been developed by using iron-catalyzed Friedel-Crafts reaction of arenes with benzyl thiocyanates. In the presence of FeBr₃, a variety of benzyl thiocyanates underwent the reaction with arenes to selectively afford the corresponding diarylmethane derivatives in moderate to high yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290343

LETTER
627
Iron-Catalyzed Benzylation Reaction of Arenes with Benzyl Thiocyanates
B
enzylation of Are
i
nes ao-Kang Guo,a Dong-Yun Zhao,a Jin-Heng Li,*b Xing-Guo Zhang,a Chen-Liang Deng,a Ri-Yuan Tang*a
a
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, P. R. of China
Fax +86(577)86689615; E-mail: jhli@hnu.edu.cn; E-mail: try@wzu.edu.cn
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, P. R. of China
b
Received 23 November 2011
The reaction between (thiocyanatomethyl)benzene (1a)
and p-xylene (2a) was investigated to optimize the reac-
tion conditions; the results are summarized in Table 1. Ini-
tially, three iron salts, FeCl3, FeBr3 and FeF3, were
Abstract: A novel, regioselective protocol for the synthesis of
diphenylmethane derivatives has been developed by using iron-
catalyzed Friedel–Crafts reaction of arenes with benzyl thiocyan-
ates. In the presence of FeBr3, a variety of benzyl thiocyanates un-
derwent the reaction with arenes to selectively afford the examined (Table 1, entries 1–3). Both FeCl3 and FeBr3
corresponding diarylmethane derivatives in moderate to high
yields.
were suitable catalysts for the reaction, affording the tar-
get product 3 in 25% and 29% yields, respectively
(Table 1, entries 1 and 2). However, FeF3 had no effect on
this reaction (Table 1, entry 3). Further screening revealed
that the amount of FeBr3 did not affect the reaction signif-
icantly (Table 1, entries 4 and 5). Upon studying the effect
Key words: iron, benzylation, Friedel–Crafts reaction, benzyl thio-
cyanate, diarylmethane
The diarylmethane moiety is a valuable structural unit in of reaction temperature, it turned out that the reaction per-
numerous biological compounds.1 For this reason, consid- formed at 80 °C gave the best results (Table 1, entries 2
erable effort has been devoted to the synthesis of diaryl- and 6–8). In light of these results, a number of other sol-
methane derivatives.2–8 Among the developed vents, including N,N-dimethylformamide (DMF), tetrahy-
approaches, the Friedel–Crafts reaction is one of the most drofuran (THF), toluene and MeCN, were tested, but they
efficient methods for the formation of diarylmethane de- were not suitable for this reaction (Table 1, entries 9–12).
rivatives.2 Although the Friedel–Crafts method can pro- We were pleased to find that the amount of p-xylene (2a)
vide efficient access to substituted diarylmethane affected the yield of 3: the yield was enhanced sharply to
derivatives, there are noticeable drawbacks associated 63% when four equivalents p-xylene (2a) was added
with this approach; it usually requires stoichiometric (Table 1, entry 13), and to 75% at 10 equivalents p-xylene
amounts of Lewis acids, high temperatures, and/or a large (2a; Table 1, entry 14). Notably, in the presence of 20
excess of arene for the relatively low nucleophilic aromat- equivalents p-xylene (2a) the target product 3 was ob-
ic compounds.3–5 To overcome these limitations, palladi- tained in 85% yield under solvent-free conditions
um- or ruthenium-catalyzed C–H bond activation (Table 1, entry 15). The results demonstrated that, in the
strategies for direct benzylation of aromatic compounds presence of 2,6-di-tert-butylpyridine or NaHCO3, the re-
were developed recently.6 However, both palladium and action did not take place, and substrate 1a was almost
ruthenium catalysts are highly expensive. Thus, develop- completely recovered (Table 1, entries 16 and 17).
ment of some new protocols using inexpensive and more
With the optimal conditions in hand, the reaction scope
environmentally benign catalysts is interesting. Here, we
was explored (Table 2). In the presence of FeBr3, a variety
wish to report a novel Friedel–Crafts-type reaction for di-
of (thiocyanatomethyl)benzenes 1b–h were first exam-
ined by reacting with p-xylene (2a; Table 2, entries 1–7).
The results demonstrated that several substituents, includ-
rect benzylation of arenes with benzyl thiocyanate cata-
lyzed by inexpensive iron salts (Scheme 1). To the best of
our knowledge, this is the first example of direct benzyla-
ing Me, MeO, F and Br, on the aromatic ring of (thio-
tion of aromatic compounds with benzyl thiocyanate us-
cyanatomethyl)benzenes were well-tolerated (Table 2,
ing a catalytic amount of iron salts.
entries 1–6). Substrate 1c, with an ortho-methyl group, for
instance, was treated with p-xylene (2a) and FeBr3 to af-
ford the desired product 5 in good yield (Table 2, entry 2).
A 23% yield was still isolated from methoxy-substituted
FeBr3
(20 mol%)
Ar
Ar
SCN
+
R
R
1
80 °C, 24 h
substrate 1e (Table 2, entry 4). Interestingly, substrates 1f
and 1g, with a fluorine or bromine group, were compatible
with the optimal conditions (Table 2, entries 5 and 6). For
example, treatment of substrate 1g (with a Br group) with
p-xylene (2a) and FeBr3 furnished the corresponding
product 9 in 67% yield (Table 2, entry 6). Gratifyingly, 3-
(thiocyanatomethyl)thiophene (1h), a heterocyclic com-
pound, was also suitable for the reaction (Table 2, entry
2
Scheme 1 Fe-catalyzed benzylation reaction
SYNLETT 2012, 23, 627–631
x
x
.
x
x
.
2
0
1
1
Advanced online publication: 10.02.2012
DOI: 10.1055/s-0031-1290343; Art ID: W70511ST
© Georg Thieme Verlag Stuttgart · New York

628
X.-K. Guo et al.
LETTER
7). Subsequently, a range of arenes 2 were investigated reaction with 1a, selectively giving the para-substituted
under the optimal conditions (Table 2, entries 8–14). The benzylation product 20 in 55% yield (Table 2, entry 14).
results showed that electron-rich arenes were compatible However, electron-deficient nitrobenzene did not undergo
with the optimal conditions. Notably, several substituents, the reaction (Table 2, entry 15).
such as Me, MeO, Cl or OH, on the aryl ring in substrates
2 were perfectly tolerated. 1-Chloro-4-methoxybenzene
Surprisingly, the reaction of 1,3,5-trimethoxybenzene (2i)
with (thiocyanatomethyl)benzene (1a) and FeBr3 afforded
(2e), for instance, selectively reacted with (thiocyanato-
a thiocyanation product 21 in 85% yield, and not the de-
methyl)benzene (1a) and FeBr3 to give the desired prod-
uct 15 in 89% yield (Table 2, entry 11). It was noted that
substrates 2d, 2f and 2g gave a mixture of para- and
ortho-products in moderate yields (Table 2, entries 10, 12
and 13). Phenol (2h) was also a suitable substrate for the
sired diarylmethane (Scheme 2).9
SCN
OMe
SCN
OMe
1a
FeBr3 (20 mol%)
Table 1 Screening Optimal Conditionsa
+
OMe
DCE, 80 °C, 24 h
MeO
21 (85%)
[Fe]
SCN
+
MeO
OMe
2i
1a
2a
3
Scheme 2 FeBr3-catalyzed reaction of 1,3,5-trimethoxybenzene
(2i) with (thiocyanatomethyl)benzene (1a)
Entry
1
[Fe] (mol%)
FeCl3 (20)
FeBr3 (20)
FeF3 (20)
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMF
THF
Temp (°C) Yield (%)b
120
120
120
120
120
100
80
25
A possible mechanism, outlined in Scheme 3, was pro-
posed.2,3 Initially, the reaction of 1a with FeBr3 affords a
cation intermediate A and an anion intermediate B. Inter-
mediate A subsequently undergoes electrophilic alkyla-
tion with substrate 2a to form intermediate C. Finally,
deprotonation of intermediate C gives the target product
3.
2
29
3
trace
27
4
FeBr3 (50)
FeBr3 (100)
FeBr3 (20)
FeBr3 (20)
FeBr3 (20)
FeBr3 (20)
FeBr3 (20)
FeBr3 (20)
FeBr3 (20)
FeBr3 (20)
FeBr3 (20)
FeBr3 (20)
FeBr3 (20)
FeBr3 (20)
5
34
6
32
Br
–
+
CH2 Br Fe SCN
+
CH SCN
+ FeBr3
7
31
2
Br
B
8
60
15
1a
A
Br
9
80
trace
trace
trace
trace
63
–
+
Br Fe SCN
Br
CH2
10
11
12
13c
14d
15e
16e f
17e g
80
A
H
toluene
MeCN
DCE
DCE
neat
80
Ph
80
+
FeBr3 + HSCN
80
C
3
2a
80
75
Scheme 3 Possible mechanism
80
85
In summary, we have developed a novel protocol for the
synthesis of diarylmethanes using inexpensive and envi-
ronmentally benign iron catalysts.10 This method allows
direct benzylation of aromatic compounds with numerous
thiocyanates with high regioselectivity under neat condi-
tions.
neat
80
0
neat
80
0
a Reagents and conditions: 1a (0.4 mmol), 2a (0.4 mmol), [Fe] and
solvent (3 mL), 24 h.
b Isolated yield.
c 2a (4 equiv).
d 2a (10 equiv).
e 2a (20 equiv).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
f 2,6-di-tert-butylpyridine (2 equiv) was added.
g NaHCO3 (2 equiv) was added.
Synlett 2012, 23, 627–631
© Thieme Stuttgart · New York

LETTER
Benzylation of Arenes
629
Table 2 Synthesis of Diarylmethanes by Fe-Catalyzed Friedel–Crafts-Type Reactiona
FeBr3 (20 mol%)
Ar
R
+
R
Ar
SCN
80 °C, 24 h
1
2
Entry
1
Compound 1
Compound 2
Product
Isolated yield (%)
SCN
71
2a
2a
1b
4
2
73
77
SCN
1c
5
6
7
3
4
SCN
1d
2a
2a
2a
OMe
SCN
23
MeO
1e
F
SCN
5
81
67
F
1f
8
Br
6
7
8
SCN
Br
2a
2a
1g
9
S
35
75
S
SCN
SCN
1h
1a
10
2b
11
12
SCN
9b
95
1a
2c
OMe
OMe
OMe
Ph
SCN
SCN
10b
11b
70
89
+
Ph
13/14 (10:1)c
1a
1a
2d
OMe
OMe
Cl
Cl
2e
15
© Thieme Stuttgart · New York
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630
X.-K. Guo et al.
LETTER
Table 2 Synthesis of Diarylmethanes by Fe-Catalyzed Friedel–Crafts-Type Reactiona (continued)
FeBr3 (20 mol%)
Ar
R
+
R
Ar
SCN
80 °C, 24 h
1
2
Entry
12
Compound 1
Compound 2
Product
Ph
Isolated yield (%)
36
Cl
Cl
Cl
Cl
SCN
+
Ph
16/17 (1.6:1)c
1a
2f
Cl
Cl
SCN
SCN
SCN
13
35
55
0
+
Ph
Ph
18/19 (1.8:1)c
1a
1a
1a
2g
2h
2i
OH
NO2
14b
HO
20
15 b
–
a Reagents and conditions: 1 (0.4 mmol), 2 (20 equiv), FeBr3 (20 mol%), 80 °C, 24 h.
b 1 (0.4 mmol), 2 (10 equiv) in DCE (3 mL) for 24 h.
c The products were determined by 1H NMR analysis.
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Acknowledgment
We thank the National Natural Science Foundation of China (Nos.
20872112 and 21002010), Zhejiang Provincial Natural Science
Foundation of China (Nos. Y407116, Y4080169 and Y4100307).
References and Notes
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Synlett 2012, 23, 627–631
© Thieme Stuttgart · New York

LETTER
Benzylation of Arenes
631
(10) Typical Procedure: A mixture of benzyl thiocyanate (1a;
0.4 mmol), substrate (2a; 20 equiv), and FeBr3 (23.4 mg, 20
mol%) was stirred in a Schlenk tube at 80 °C (oil bath
temperature) until complete consumption of starting
material was observed (reaction monitored by TLC and GC-
MS analyses). The mixture was filtered through a crude
column, washed with ethyl acetate, and evaporated under
vacuum. The residue was purified by flash column chroma-
tography (hexane/ethyl acetate) to afford the product 3.
Benzyl-1,4-dimethylbenzene (3): Yellow oil; 1H NMR
(500 MHz, CDCl3): d = 7.25 (t, J = 7.5 Hz, 2 H), 7.19–7.15
(m, 1 H), 7.11 (d, J = 7.5 Hz, 2 H), 7.04 (d, J = 7.6 Hz, 1 H),
6.95 (d, J = 7.7 Hz, 1 H), 6.92 (s, 1 H), 3.94 (s, 2 H), 2.28 (s,
3 H), 2.18 (s, 3 H); 13C NMR (125 MHz, CDCl3): d = 140.5,
138.7, 135.3, 133.4, 130.8, 130.2, 128.7, 128.3, 127.1,
125.8, 39.4, 21.0, 19.2; MS (EI, 70 eV): m/z (%) = 196 (90)
[M]+, 181 (100), 118 (43).
Typical Procedure: A mixture of benzyl thiocyanate (1a;
0.4 mmol), 1,3,5-trimethoxybenzene (2i; 10 equiv), FeBr3
(23.4 mg, 20 mol%) and DCE (3 mL) was stirred in a
Schlenk tube at 80 °C (oil bath temperature) until complete
consumption of starting material was observed (reaction
monitored by TLC and GC-MS analyses). The mixture was
filtered through a crude column, washed with ethyl acetate,
and evaporated under vacuum. The residue was purified by
flash column chromatography (hexane/ethyl acetate) to
afford the product 21.
1,3,5-Trimethoxy-2-thiocyanatobenzene (21): Yellow
soild; mp 159.3–160.5 °C; 1H NMR (500 MHz, CDCl3): d =
6.15 (s, 2 H), 3.92 (s, 6 H), 3.84 (s, 3 H); 13C NMR (125
MHz, CDCl3): d = 164.2, 161.3, 111.8, 91.3, 89.7, 56.3,
55.6; LRMS (EI, 70 eV): m/z (%) = 225 (100) [M]+, 179
(34).
© Thieme Stuttgart · New York
Synlett 2012, 23, 627–631

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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.