Catalytic selective bis-arylation of imines with anisole, phenol, thioanisole and analogues

Article abstract of DOI:10.1039/b800066b

The first highly efficient double Friedel-Crafts reaction of N-tosyl imines with anisole, phenol, thioanisole and analogues has been developed to produce the corresponding symmetric diarylmethanes and triarylmethanes with high regioselectivity in the presence of a catalytic amount of Bi₂(SO ₄)₃-TMSCl at room temperature. The Royal Society of Chemistry.

Full text of DOI:10.1039/b800066b

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Catalytic selective bis-arylation of imines with anisole, phenol,
thioanisole and analoguesw
Cong-Rong Liu, Man-Bo Li, Cui-Feng Yang and Shi-Kai Tian*
Received (in Cambridge, UK) 7th January 2008, Accepted 29th January 2008
First published as an Advance Article on the web 8th February 2008
DOI: 10.1039/b800066b
The first highly efficient double Friedel–Crafts reaction of
N-tosyl imines with anisole, phenol, thioanisole and analogues
has been developed to produce the corresponding symmetric
diarylmethanes and triarylmethanes with high regioselectivity
in the presence of a catalytic amount of Bi2(SO4)3–TMSCl at
room temperature.
methane 3aa selectively in good to excellent yields, though
neither a single Lewis acid nor TMSCl was effective in doing
so.7 The best yield (90%) and regioselectivity (20 : 1)8 were
obtained with bismuth sulfate [Bi2(SO4)3], an environmentally
benign catalyst (entry 8, Table 1).9 Further efforts to decrease
the loading of Bi2(SO4)3 and/or TMSCl resulted in lower
yields. Notably, during the reaction of N-tosyl imine 1a with
anisole (2a) we observed no intermediate resulting from mono
The reaction of imines with aromatic compounds is an im-
portant carbon–carbon bond-forming reaction. In the pre-
sence of acidic catalysts, the addition of electron-rich aromatic
compounds to imines can generate benzylic amines, which are
intrinsically unstable under acidic reaction conditions and can
further undergo the substitution of amino groups with the
remaining electron-rich aromatic compounds to produce sym-
metric diarylmethanes (R = alkyl) and triarylmethanes (R =
aryl) (Scheme 1) that have found widespread applications in
synthetic, medicinal and industrial chemistry.1 To our knowl-
edge, only indoles,2 pyrroles3 and amino-substituted arenes4
have recently been explored as reactive aromatic compounds
for this type of double Friedel–Crafts reaction, and most of
the reported methods are restricted by the formation of a
multitude of products, high catalyst loading and at times
drastic reaction conditions. Herein we report, for the first
time, a highly efficient catalytic bis-arylation of N-tosyl imines
with much less activated aromatic compounds such as anisole,
phenol, thioanisole and analogues at room temperature.
Inspired by our recent discovery that a number of Lewis
acids in combination with chlorotrimethylsilane (TMSCl) are
powerful in promoting the addition of nucleophilic species to
N-alkoxycarbonyl imines formed in situ at room tempera-
ture,5,6 we decided to utilize these catalyst systems to promote
the double Friedel–Crafts reaction of imines with aromatic
compounds such as anisole, phenol and thioanisole, which are
much less activated than indoles, pyrroles and amino-substi-
tuted arenes. The bis-arylation of N-tosyl imine 1a with anisole
(2a) was selected as a model reaction to evaluate the catalytic
activity of Lewis acid in combination with TMSCl at room
temperature. As summarized in Table 1, a number of Lewis
acids (2 mol%) in combination with TMSCl (0.20 equiv.) were
found to catalyze this reaction to give symmetric triaryl-
1
Friedel–Crafts reaction by H NMR analysis of the reaction
mixture.
The replacement of the tosyl group in imine 1a with another
group was further examined. In the presence of 2 mol% of
Bi2(SO4)3 and 0.20 equiv. of TMSCl, the double
Friedel–Crafts reaction of PhCHQNSOPh with anisole (2a)
proceeded smoothly to give product 3aa in a slightly lower
yield (86%) in 6 h. In contrast, no desired product was
obtained at all when PhCHQNAc, PhCHQNCOPh,
PhCHQNPh, PhCHQNBn or PhCHQNOH were treated
with anisole (2a) under the same reaction conditions. Thus,
the tosyl group was chosen to activate the CQN double bond
in the bis-arylation of imines.
Using Bi2(SO4)3–TMSCl as the catalyst system, a wide
variety of alkoxy-, hydroxy-, or methylmercapto-substituted
Scheme 1 Acid-catalyzed double Friedel–Crafts reaction of imines
with aromatic compounds.
Table 1 Survey of catalystsa
Entry
Catalyst
Time/h
Yield (%)b
1
2
3
4
5
6
7
8
a
None
CF3SO3H
FeCl3
48
4
1.5
3
1.5
1
1.5
1.5
NDc
55
60
64
72
58
67
90
Fe2(SO4)3ꢀ5H2O
ZnCl2
AlCl3
BiCl3
Bi2(SO4)3
Joint Laboratory of Green Synthetic Chemistry, Department of
Chemistry, University of Science and Technology of China, Hefei,
Anhui, 230026, China. E-mail: tiansk@ustc.edu.cn; Fax: +86-551-
3601592; Tel: +86-551-3600871
w Electronic supplementary information (ESI) available: General in-
formation, experimental procedures and characterization data for the
products. See DOI: 10.1039/b800066b
Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), catalyst
(2 mol%), TMSCl (0.20 mmol), CH2Cl2 (0.2 mL), rt. PMP =
b
c
4-methoxyphenyl. Isolated yield. No desired product was detected
by TLC analysis.
ꢁc
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Table 2 Bismuth-catalyzed bis-arylation of N-tosyl imine 1a with anisole, phenol, thioanisole and analoguesa
Entry
2
Ar
Product
Time/h
Yield (%)b
1
2a
2b
2c
2d
2e
X = OMe
3aa
3ab
3ac
3ad
3ae
1.5
15
48
1
90
60
80
76
81
2c
3d
4
X = OCH2CH2OAc
X = OCH2OCH2OH
X = OH
5e
X = SMe
32
6
7
8
2f
2g
2h
2i
X = OMe, Y = Me
X = OMe, Y = OMe
X = OH, Y = Me
X = OH, Y = i-Pr
X = OH, Y = Cl
3af
3ag
3ah
3ai
3aj
3
5
2
1
48
93
86
85
83
86
9
10e
2j
11
12
2k
2l
X = OMe
X = OH
3ak
3al
26
1
74
84
13
14
a
2m
2n
4-Methoxynaphthyl
2,4,6-Trimethoxyphenyl
3am
3an
2
0.3
95
99
c
b
Reaction conditions: 1a (1.0 mmol), 2 (3.0 mmol), Bi2(SO4)3 (2 mol%), TMSCl (0.20 mmol), CH2Cl2 (0.20 mL), rt. Isolated yield. 5 mol% of
d
Bi2(SO4)3 was used. 5 mol% of Bi2(SO4)3 and 1.0 equiv. of TMSCl were used. 10 mol% of Bi2(SO4)3 and 1.0 equiv. of TMSCl were used.
e
arenes were found to react well with N-tosyl imine 1a at room
temperature to give the corresponding symmetric triaryl-
methanes selectively in good to excellent yields (Table 2).10
Due to their electron-donating nature, alkoxy, hydroxy, and
methylmercapto groups not only activate arenes toward
the double Friedel–Crafts reaction of N-tosyl imine 1a, but
also dominate the regioselectivity thereof. In the presence of
2 mol% of Bi2(SO4)3 and 0.20 equiv. of TMSCl, the reaction
of N-tosyl imine 1a with most of the alkoxy- or hydroxy-
substituted arenes proceeded completely within hours. In
contrast, the reaction with 2-phenoxyethanol (2c), thioanisole
(2e) or 4-chlorophenol (2j), proceeded much slower, and 5–10
mol% of Bi2(SO4)3 and 1.0 equiv. of TMSCl were required to
accelerate the rate of the reaction (entries 3, 5 and 10, Table 2).
As to the regioselectivity, the para-position of the aromatic
ring in the nucleophile, if available, was alkylated predomi-
nantly by N-tosyl imine 1a. Alternatively, the ortho-position
was the choice if the para-position was occupied by another
group.
Next, a range of N-tosyl imines were found to undergo
double Friedel–Crafts reaction with anisole (2a), phenol (2d)
or thioanisole (2e) at room temperature (Table 3). In the
Table 3 Bismuth-catalyzed bis-arylation of various N-tosyl imines with anisole, phenol and thioanisolea
Entry
1
R
2
Product
Time/h
Yield (%)b
1
2
1b
1c
1c
1c
1d
1e
1f
1g
1h
1i
4-MeC6H4
4-ClC6H4
4-ClC6H4
2a
2a
2d
2e
2a
2a
2d
2a
2a
2a
2a
2d
2e
2a
2a
2a
3ba
3ca
3cd
3ce
3da
3ea
3fd
3ga
3ha
3ia
48
1
1
36
6
1.5
12
3
3
12
6
0.5
30
5
85
94
82
70
84
96
80
70
94
63
79
77
60
62
77
80
3
4c
5
4-ClC6H4
4-O2NC6H4
4-MeO2CC6H4
4-HOC6H4
3-MeOC6H4
3-O2NC6H4
2-MeOC6H4
2-O2NC6H4
2,4-Cl2C6H3
2,4-Cl2C6H3
Et
6
7
8
9
10d
11
12
13c
14
15
16
a
1j
3ja
1k
1k
1l
1m
1n
3kd
3ke
3la
3ma
3na
Me2CH
Cyclohexyl
6
6
b
c
Reaction conditions: 1 (1.0 mmol), 2 (3.0 mmol), Bi2(SO4)3 (2 mol%), TMSCl (0.20 mmol), CH2Cl2 (0.20 mL), rt. Isolated yield. 5 mol% of
d
Bi2(SO4)3 and 1.0 equiv. of TMSCl were used. 5 mol% of Bi2(SO4)3 was used.
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presence of 2–5 mol% of Bi2(SO4)3 and 0.20 equiv. of TMSCl,
anisole (2a) or phenol (2d) could react with a number of N-
tosyl aromatic imines bearing either electron-withdrawing
groups (Cl, NO2 and COOMe) or electron-donating groups
(Me, OH and OMe) on the ortho-, meta- or para-positions of
aromatic rings, and gave the corresponding symmetric triar-
ylmethanes with high regioselectivity and in good to excellent
yields (entries 1–3, 5–12, Table 3). Due to the low reactivity of
thioanisole (2e), 1.0 equiv. of TMSCl was required to promote
its reaction with N-tosyl imines (entries 4 and 13, Table 3).
Furthermore, N-tosyl aliphatic imines were found to be sui-
table substrates to synthesize diarylmethanes (entries 14–16,
Table 3).
Tetrahedron Lett., 2004, 45, 4567; (d) J. Hao, S. Taktak,
K. Aikawa, Y. Yusa, M. Hatano and K. Mikami, Synlett, 2001,
1443. For recent examples on the double Friedel–Crafts reaction of
imines with indoles as a side reaction, see: (e) Y.-Q. Wang, J. Song,
R. Hong, H. Li and L. Deng, J. Am. Chem. Soc., 2006, 128, 8156.
3 (f) Q. Kang, Z.-A. Zhao and S.-L. You, J. Am. Chem. Soc., 2007,
129, 1484.
4 (g) Y.-X. Jia, J.-H. Xie, H.-F. Duan, L.-X. Wang and Q.-L. Zhou,
Org. Lett., 2006, 8, 1621..
5 (a) B. Temelli and C. Unaleroglu, Tetrahedron, 2006, 62, 10130; (b)
B. Temelli and C. Unaleroglu, Tetrahedron Lett., 2005, 46, 7941.
6 (a) M. Soueidan, J. Collin and R. Gil, Tetrahedron Lett., 2006, 47,
5467; (b) Y. L. Floc’H, J. M. Morvan and A. Brault, Bull. Soc.
Chim. Fr., 1980, 2, 157.
7 TMSCl is generated in situ as a by-product in an iron-catalyzed
four-component reaction. See: (a) Q.-Y. Song, B.-L. Yang and
S.-K. Tian, J. Org. Chem., 2007, 72, 5407; (b) B.-L. Yang and
S.-K. Tian, Eur. J. Org. Chem., 2007, 4646.
8 For the activation of imines with Yb(OTf)3–Me3SiCl, see: (a) M.
Yamanaka, A. Nishida and M. Nakagawa, J. Org. Chem., 2003,
68, 3112; (b) M. Yamanaka, A. Nishida and M. Nakagawa, Org.
Lett., 2000, 2, 159.
9 For a study on the enhancement of the catalytic activity of Lewis
acids with TMSCl, see: (a) Y. Onishi, T. Ito, M. Yasuda and A.
Baba, Tetrahedron, 2002, 58, 8227; (b) T. Saito, Y. Nishimoto, M.
Yasuda and A. Baba, J. Org. Chem., 2006, 71, 8516.
10 A small portion (about 5 mL) of the reaction mixture was
directly dissolved in CDCl3 and subject to 1H NMR analysis.
Based on the 1H NMR analysis of the reaction mixture, only
one minor isomer of 3aa was detected and identified as (2-methoxy
phenyl)(4-methoxyphenyl)phenylmethane (3aa0) by comparing the
1H NMR spectrum with that of an authentic sample prepared from
(2-methoxyphenyl)phenylmethanol and anisole (2a) in the presence
of Bi2(SO4)3 at room temperature. The regioselectivity was deter-
mined to be 20 : 1 by integration of the signals at d 5.44 ppm (CH
of 3aa) and d 5.86 ppm (CH of 3aa0).
In summary, we have developed, for the first time, a highly
efficient catalytic bis-arylation of N-tosyl imines with anisole,
phenol, thioanisole and analogues at room temperature. In the
presence of 2–10 mol% of Bi2(SO4)3 and 0.20–1.0 equiv. of
TMSCl, the double Friedel–Crafts reaction of a wide variety of
N-tosyl aromatic and aliphatic imines with anisole, phenol,
thioanisole and analogues proceeded smoothly to give the
corresponding symmetric triarylmethanes and diarylmethanes
with high regioselectivity and in good to excellent yields. The
attractive features of this protocol include high selectivity and
yields, broad substrate scope, the use of an inexpensive and
environmentally benign catalyst, mild reaction conditions and
experimental simplicity.
We are grateful for financial support from the National
Natural Science Foundation of China (20672105), Chinese
Academy of Sciences, and the University of Science and
Technology of China.
11 For a review on catalysis with bismuth(III) salts, see: N. M.
Leonard, L. C. Wieland and R. S. Mohan, Tetrahedron, 2002,
58, 8373.
12 Mercapto-substituted arenes were also found to react with N-
tosyl imine 1a, but the reaction gave the corresponding thioacetals
instead of triarylmethanes. For example, the reaction of N-
tosyl imine 1a with 2-methylthiophenol in the presence of 2
mol% of Bi2(SO4)3 and 0.20 equiv. of TMSCl proceeded smoothly
to give benzaldehyde bis(2-methylphenyl)dithioacetalin 93%
yield. And under the same reaction conditions, the reaction of
N-tosyl imine 1a with 4-chlorothiophenol gave benzaldehyde
bis(4-chlorophenyl)dithioacetal in 92% yield. For details,
see the ESIw.
Notes and references
1 For reviews, see: (a) V. Nair, S. Thomas, S. C. Mathew and K. G.
Abhilash, Tetrahedron, 2006, 62, 6731; (b) M. S. Shchepinov and
V. A. Korshun, Chem. Soc. Rev., 2003, 32, 170; (c) D. F. Duxbury,
Chem. Rev., 1993, 93, 381.
2 (a) J. Esquivias, R. G. Arrayas and J. C. Carretero, Angew.
Chem., Int. Ed., 2006, 45, 629; (b) B. Ke, Y. Qin, Q. He, Z. Huang
and F. Wang, Tetrahedron Lett., 2005, 46, 1751, and references
cited therein; (c) X.-L. Mi, S.-Z. Luo, J.-Q. He and J.-P. Cheng,
ꢁc
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Chem. Commun., 2008, 1249–1251 | 1251