Br?nsted acid-catalyzed synthesis of diarylmethanes under non-genotoxic conditions

Article abstract of DOI:10.1016/j.tetlet.2011.01.033

Triflic acid and triflimide were found to efficiently catalyze the formation of a wide diversity of diarylmethanes from the non-genotoxic benzylic acetates and electron-rich arenes or heteroarenes. The reaction worked best with acetates capable of generating a stabilized benzylic cationic species. In most cases, the reactions were conveniently run in the absence of solvent under mild conditions.

Full text of DOI:10.1016/j.tetlet.2011.01.033

Tetrahedron Letters 52 (2011) 2235–2239
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Tetrahedron Letters
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Brönsted acid-catalyzed synthesis of diarylmethanes under
non-genotoxic conditions
⇑
Oscar Mendoza, Guy Rossey, Léon Ghosez
Institut Européen de Chimie et Biologie, Université de Bordeaux-CNRS UMR 5248, 2 rue Robert Escarpit, 33607 Pessac, France
Sanofi-Aventis Research & Development, 371 rue du Professeur Joseph Blayac, 34184 Montpellier, Cedex 04, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 14 January 2011
Triflic acid and triflimide were found to efficiently catalyze the formation of a wide diversity of diarylme-
thanes from the non-genotoxic benzylic acetates and electron-rich arenes or heteroarenes. The reaction
worked best with acetates capable of generating a stabilized benzylic cationic species. In most cases, the
reactions were conveniently run in the absence of solvent under mild conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor Harry Wasserman on
the occasion of his 90th birthday
Keywords:
Brönstedt acid catalysis
Diarylmethanes
Friedel–Crafts benzylation
Triflic acid
Triflimide
The benzylation of arenes is an important reaction for the con-
struction of diarylmethanes, which are found in a substantial num-
ber of biologically active compounds and are useful synthetic
intermediates. Many groups have reported useful and reliable me-
tal-catalyzed Friedel–Crafts alkylation of aromatic compounds for
the construction of diarylmethane derivatives. Syntheses of diary-
lmethanes based on organozinc1 or organoboron2 derivatives cata-
lyzed by Pd have also been reported. The traditional Friedel–Crafts
reaction of arenes has many drawbacks, such as the requirement of
fairly drastic conditions incompatible with many functional groups,
the generation of large amounts of undesirable by-products or the
use of genotoxic benzylating agents (e.g., benzyl chlorides or bro-
mides).3 The increasing concern about health and environmental
protection has stimulated the search of new procedures for the syn-
thesis of diarylmethanes. In this context benzylations of arenes
using the cheap, non-genotoxic but less electrophilic benzyl alco-
hols or esters have attracted the attention of several research
groups. Several heavy metal-derived catalysts4 and in particular
rare earth triflates5 have been successfully used but these methods
often require more complex work-up procedures to remove resi-
dues of heavy metals. Recently, Beller and co-workers6 showed that
iron catalysts efficiently catalyze the arylation of benzyl alcohols
and benzyl carboxylates under mild conditions. An important fea-
Table 1
Benzylation and p-methoxybenzylation of anisole
OAc
OMe
5 mol% Cat
+
RT
OMe
MeO
OMe
1a
OAc
OMe
MeO
5 mol%
+
(3:2)
°
100
C
1b
OMe
Entry
Electrophile
Cat. (5 mol %)
Yielda (%)
1
2
H3PO4
CF3COOH
HCl
HOTf
HNTf2
H2SO4
CH3SO3H
0
0
OAc
3
4
5
6
7
6–9
100
100
100
25
MeO
8
9
10
HOTf
HNTf2
H2SO4
100
100
5
OAc
⇑
Corresponding author. Tel.: +33 5 4000 2223/2217; fax: +33 5 4000 2215.
E-mail addresses: l.ghosez@iecb.u-bordeaux.fr, leon.ghosez@uclouvain.be (L.
Yields determined by 1H NMR.
a
Ghosez).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.033

2236
O. Mendoza et al. / Tetrahedron Letters 52 (2011) 2235–2239
+OH
OOCMe
HX
O
catalysts. These silylating agents are stronger Lewis acids than
+
CH2
X-
the corresponding triflates and catalyze a variety of reactions
involving Lewis acid activated carbonyl derivatives.12 More re-
cently, Martin and co-workers reported an elegant approach to
an array of substituted b-heteroaryl propionates by coupling silyl
kd
Me
X-
MeCOOH
+
+
Y
Y
Y
2
ketene acetals and other p-nucleophiles with alcohols and acetates
1a: Y = OMe
1b: Y = H
3
derived from electron-rich heterocycles in the presence of trimeth-
ylsilyl trifluoromethanesulfonate.13 However, with less activated
benzyl acetates, trialkylsilyl triflimides were again found to be lar-
gely superior to the corresponding triflates.12 In their seminal re-
port, Mikami and co-workers10 had claimed that TMS-ethers
derived from benzyl alcohols could alkylate anisole in the presence
of catalytic amounts of TMSNTf2. However, in these reactions,
1 equiv of HNTf2 is produced as a result of the aromatization of
the tetrahedral intermediate. It was, therefore, not excluded that
HNTf2 could take part in the catalytic process.11 This was debatable
in as much as Beller and co-workers6 had reported that HCl, HOAc
and p-toluenesulfonic acid did not catalyze the reaction of o-xylene
with 1-phenylethylacetate while Lachter and co-workers14 and
more recently Sarca and Laali15 reported the successful benzylation
of arenes promoted by amberlyst 15, niobic acid, or triflic acid in
ionic solvents.
H
anisole
+
Y
OMe
Y
OMe
Scheme 1.
ture of this process was the tolerance of a wide variety of functional
groups.
In this context, the observation by Sun and Wang7 that molec-
ular iodine efficiently catalyzed the benzylation of arenes with
benzyl alcohols is also of particular interest. A last approach which
will probably appeal to industrial chemists involves the use of solid
heterogeneous Brönstedt and Lewis acid catalysts.8
In 1997 we,9 and Mikami’s group10 independently introduced
trialkylsilyl triflimides as a new class of non-metallic Lewis acid
Table 2
Reaction of arenes with benzyl acetates 1a–d
Entry
1
Electrophile
Nucleophile
Main product
T (°C)
t
Cat.
Solvent
No
Yielda,b (%)
OH
OAc
rt
20 min
HOTf
95
OH
MeO
MeO
1a
OMe
OMe
2
rt
20 min
HOTf
No
98
OMe
OMe
OMe
MeO
OMe
3
4
5
rt
1 h
HOTf
HOTf
HOTf
No
No
No
90
0
MeO
Me
decomposition
rt
20 min
1 h
Me
OH
OAc
100
99
1b
OH
(3:2)
OMe
OMe
6
100
1 h
HOTf
No
91
OMe
OMe
(3:2)
(3:1)
OMe
7
8
9
100
100
100
1 h
1 h
1 h
HOTf
HOTf
HOTf
No
No
No
86
89
71
OMe
Me
Me
Me
Me
OMe
OAc
OMe
F
F
(3:2)
1c
MeO
OMe
MeO
MeO
OAc
10
rt
20 min
HOTf
No
81
OMe
MeO
1d
a
Only the major isomer is shown. When two isomers are formed, ratios are indicated in brackets.
Yields were determined by GLC.
b

O. Mendoza et al. / Tetrahedron Letters 52 (2011) 2235–2239
2237
We, therefore, decided to test representative Brönsted acids as
catalysts of the reaction of anisole with anisyl and benzyl acetates
1 and 2 (Table 1). No solvent was used except with HNTf2, which
was introduced in the reaction mixture as a 0.5 M solution in
dichloromethane and HCl as a 4 M solution in dioxane. Reactions
were monitored by 1H NMR.
for 1b (entries 5–7) and 1c (entry 9). Benzylacetate 1b also gave
an excellent yield of the substitution product with p-xylene (entry
8) in contrast with anisylacetate 1a, which only yielded decompo-
sition products (entry 4). This should probably be assigned to a
competitive reaction of the cationic species 3 with the more nucle-
ophilic aromatic ring of 1a (Scheme 1).
Phosphoric acid and trifluoroacetic acid did not catalyze the p-
methoxybenzylation of anisole (entries 1 and 2). HCl gave a poor
yield of substitution product at room temperature or at 100 °C
for 1 hr. Both triflic acid and triflimide proved to be excellent cat-
alysts in both test reactions (entries 4, 5, 8, and 9). Sulfuric acid
efficiently catalyzed the p-methoxybenzylation reaction (entry 6)
but was inefficient with the less reactive benzylacetate. Methane-
sulfonic acid exhibited a moderate catalytic activity as compared
to triflic acid and triflimide. The reactions with p-methoxybenzyl
acetate only gave the para isomer. Benzylacetate gave a mixture
of para and ortho substitution products with both HOTf and HNTF2.
The higher reactivity of p-methoxybenzyl acetate probably re-
sulted from a faster dissociation of the protonated ester 2 into a
cationic species 3 and acetic acid (Scheme 1).
We then examined the scope and limitations of these reactions
by varying both the substituent of the acetate and the aromatic
nucleophile (Table 2 and 3). HOTf was selected as the standard cat-
alyst (5 mol %).17 Reactions were run either at room temperature or
at 100 °C in a fivefold excess of arene and in most cases, in the ab-
sence of solvent.
Not surprisingly electron-rich aromatics, such as furan (Table 3,
entries 1 and 2), N-phenylsulfonyl pyrrole (entry 3), indole (entry
4) and N-phenylsulfonyl indole (entry 5) also reacted with anisy-
lacetate at room temperature in the presence of 5 mol % HOTf cat-
alyst The reaction with furan required dilution with
dichloromethane to avoid the decomposition of furan in these very
acidic conditions.
Indole could not be used with the less reactive benzyl acetate: it
consumed the acid catalyst and led to some decomposition product
and unreacted indole as shown by 1H NMR (entry 9). The less
nucleophilic N-phenylsulfonyl indole yielded only the 3-substitu-
tion products (entries 5 and 10). Furan also reacted regioselectively
to exclusively yield the 2-substitution product. However, phenyl-
sulfonyl pyrrole gave a mixture of 2- and 3-substituted products
with 1b (entry 8) probably as a result of a higher reaction temper-
ature and the steric protection of the 2-position by the large sub-
stituent on nitrogen.
The flexibility and versatility of this synthesis of diarylmethanes
were further illustrated by the reaction of arenes and heteroarenes
with acetates 1e–g (Table 4). Disappointingly our attempts to react
the thiophene-derived acetate 1e with anisole in the presence of
triflic acid only led to untractable mixtures (entry 1). We felt that
this probably resulted from the unstability of 1e in these strongly
Electron-rich aromatics, such as phenols or the corresponding
ethers gave high yields of benzylation products at room tempera-
ture for 1a (Table 2, entries 1–3) and 1d (entry 10) and 100 °C
Table 3
Reactions of electron-rich heteroarenes with benzyl- and anisyl acetates
Entry
Electrophile
Nucleophile
Product
T (°)C
t
Cat.
Solvent
Yield (%)
O
1
2
No
CH2Cl2
0
72
O
OAc
rt
10 min
HOTf
MeO
MeO
1a
SO2Ph
N
SO2Ph
N
3
4
rt
5 min
1 h
HOTf
HOTf
No
No
98
60
MeO
O
O
100
N
H
N
H
5
rt
rt
10 min
20 min
HOTf
No
95
N
N
SO2Ph
SO2Ph
6
7
HOTf
HNTf2
CH2Cl2
CH2Cl2
0
0
O
OAc
Decomposition
1b
SO2Ph
SO2Ph
N
N
8
100
1 h
HOTf
No
79
(3:2)
SO2Ph
N
9
No reaction
100
100
1 h
1 h
HOTf
HOTf
No
No
0
N
H
10
88
N
N
SO2Ph
SO2Ph

2238
O. Mendoza et al. / Tetrahedron Letters 52 (2011) 2235–2239
Table 4
and economical, (f) yields are high, (g) the scope is fairly broad and
(h) it is environmentally friendly.
Reactions of arenes and heteroarenes with heteroaryl methylacetates
Electrophile
Arene
OMe
Product
Cat.a
Yieldb (%)
Acknowledgment
1
2
HOTf
HNTf2
0
98
S
S
OAc
The authors are grateful to Sanofi-Aventis and IECB for generous
support of this work.
1e
OMe
References and notes
S
O
3
4
HNTf2
HNTf2
98
70
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O
OMe
O
OAc
1f
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OMe
OMe
OMe
SO2Ph
N
SO2Ph
N
5
6
OAc
HNTf2
HNTf2
88
81
1g
O
SO2Ph
N
O
a
All reactions were run in dichloromethane at room temperature.
Yields determined by after 20 min.
b
acidic conditions and that a weaker acid should be used. Rewar-
dingly the substitution product was obtained in 98% yield in the
presence of 5 mol % of HNTf2 (entry 2).16,18 These conditions
allowed also to couple 1e to the highly acid-sensitive furan. Both
reactions were regioselective. Triflimide was also an efficient cata-
lyst of the reaction of anisole or furan with furan and pyrrole-
derived acetates 1f and 1g.
All these reactions are believed to involve the formation of a
cationic species resulting from the dissociation of the protonated
acetate (Scheme 1). The nature of this cationic intermediate (pla-
nar cation or pyramidal ion pair) should influence the stereochem-
ical course of a reaction involving one enantiomer of an acetate
reagent derived from a secondary benzyl alcohol. We, therefore,
decided to study the stereochemical course of the reaction of ani-
sole with (s)-benzylmethyl acetate 1h in the presence of 5 mol %
HOTf (Scheme 2). After 30 min. at 100 °C, a 3:2 mixture of racemic
(HPLC) para- and ortho-benzylation products were obtained. This
confirmed the formation of a planar cationic intermediate.
We believe that this synthetic procedure should appeal to the
synthetic chemists: (a) it involves stable, easily handled and non-
genotoxic benzylating agents, (b) it avoids the use of metal cata-
lysts, (c) in most cases a solvent is not necessary, (d) it does not re-
quire protection from air or moisture, (e) it is operationally simple
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MeO
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(3:2)
no solvent
30min 100 °C
1h
OMe
17. General procedure for the alkylation reaction of anisole with anisyl acetate in the
presence of triflic acid: 430 lL of anisyl acetate (2.5 mmol, 1 equiv) and 2.2 mL
Scheme 2.

O. Mendoza et al. / Tetrahedron Letters 52 (2011) 2235–2239
2239
of anisole (12.25 mmol, 5 equiv) were placed into a 10 mL round-bottom flask
equipped with magnetic stir-bar. Then 11 5% of pure triflic acid
(0.125 mmol) was added and the solution was stirred for 20 min. The crude
was analyzed by 1H NMR and GC–MS. Purification by column chromatography
gave 484 mg (85% yield) of bis(4-methoxyphenyl)methane, which was
identical to an authentic sample.
addition of 250 lL of a 0.5 M solution of HNTf2 in CH2Cl2, the solution was
a
lL
stirred for 20 min at room temperature. The crude mixture was analyzed by
NMR and GC–MS. Purification by column chromatography gave 408 mg (80%
yield) of 2-(4-methoxybenzyl)thiophene, which was identified by 1H, 13C, and
HRMS. 1H NMR (300 MHz, CDCl3): d = 7.20 (d, J = 8.9 Hz, 2H), 7.17 (dd, J = 1.3,
5.1 Hz, 1H), 6.95 (dd, J = 3.4, 5.3 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.82 (dd, J = 1.1,
3.4 Hz, 1H), 4.14 (s, 2H), 3.83 (s, 3H); 13C NMR (300 MHz, CDCl3): d = 158.3,
144.8, 132.6, 129.6, 126.8, 124.9, 123.8, 113.9, 55.3, 35.2. HRMS calcd for
18. General procedure for the alkylation reaction of anisole with thiophenyl methyl
acetate in the presence of triflimide: 330 lL of (thiophen-2-yl)methyl acetate
(2.5 mmol, 1 equiv) and 2.2 mL of anisole (12.25 mmol, 5 equiv) were placed
into a 10 mL round-bottomed flask equipped with a magnetic stir-bar. After
C
12H12OSAg: 310.9654 (M+Ag+), found: 310.9655.