An effective bismuth-catalyzed benzylation of arenes and heteroarenes

Article abstract of DOI:10.1002/adsc.200606068

A highly efficient Bi(OTf)₃-catalyzed benzylation of arenes and heteroarenes has been developed. The mild reaction conditions, high yields, operational simplicity and practicability, broad scope, and remarkably low catalyst loading render this environment friendly process an attractive approach to diarylmethane derivatives. The extension to an intramolecular variant of this procedure provides a valuable route to substituted fluorenes.

Full text of DOI:10.1002/adsc.200606068

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DOI: 10.1002/adsc.200606068
An Effective Bismuth-Catalyzed Benzylation of Arenes and
Heteroarenes
Magnus Rueping,a,* Boris J. Nachtsheim,a and Winai Ieawsuwana
a
Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University Frankfurt,
Marie-Curie Strasse 11, 60439 Frankfurt am Main, Germany
Fax : (+49)-69-798-29248; e-mail: M.Rueping@chemie.uni-frankfurt.de
Received: February 22, 2006; Accepted: May 8, 2006
Abstract: A highly efficient Bi
A
found in biologically active compounds. In addition to
reports on lanthanide triflate catalysts,[13–16] Beller
and co-workers demonstrated that late transition
metal salts such as RhCl3, IrCl3, H2PdCl4, H2PtCl6
and HAuCl4 effectively catalyze the addition of
benzyl acetates and benzyl alcohols to arenes.[17,18]
Due to the high catalyst loading (5–10 mol%) and ex-
penses of the late transition metals employed, this
group recently disclosed an excellent iron-catalyzed
benzylation of arenes.[19] Using 10 mol% of inexpen-
sive FeCl3, the addition of benzyl alcohols and benzyl
acetates to various arenes and heteroarenes could be
well performed. We herein report the application of
yet another highly efficient catalyst, a bismuth salt,
for this important carbon-carbon bond formation.
Attracted by the direct addition of benzyl alcohol
to arenes, and the fact that certain bismuth salts are
benzylation of arenes and heteroarenes has been
developed. The mild reaction conditions, high
yields, operational simplicity and practicability,
broad scope, and remarkably low catalyst loading
render this environment friendly process an attrac-
tiv approach to diarylmethane derivatives. The ex-
tension to an intramolecular variant of this proce-
dure provides a valuable route to substituted fluo-
renes.
Keywords: arylation; benzylation; bismuth; cataly-
sis; diarylmethanes; Friedel–Crafts alkylation
The functionalization of arenes and heteroarenes is of compatible with air and moisture, we wondered
great synthetic importance in the preparation of phar- whether Bi(OTf)3 could be a catalyst for this process.
maceuticals, agrochemicals, and fine chemicals. Con- Hence, initial explorations of the Bi(OTf)3-catalyzed
AHCTREUNG
AHCTREUNG
sequently, various procedures for the acylation and al- reaction of phenylethyl alcohol 1 with arenes 2
kylation of aromatic compounds have been report- (Scheme 1) concentrated on varying the reaction pa-
ed.[1–8] In a classical manner, Friedel–Crafts reactions rameters, such as catalyst loading, temperature, con-
are based on the reaction of arenes with acyl or alkyl centration, and solvent.
chlorides in combination with stoichiometric amounts
From these experiments the best results with re-
of Lewis acid catalysts, such as aluminum(III) chlo- spect to yield and selectivity were obtained when the
AHCTREUNG
ride. Generally, drastic reaction conditions with reaction was performed with 0.5 mol% of bismuth
regard to temperature and acidity are applied along catalyst at elevated temperatures. Further investiga-
with the production of large amounts of salt by-prod- tions concentrated on the reactivity of various arenes
ucts. Additionally, the electrophiles have to be pre- and heteroarenes (Table 1). As anticipated several
formed and co-production of hydrogen halides often electron-rich arenes, such as toluene, 1,2- and 1,4-
induces side reactions. Thus, due to the increasing xylene, 1-methylnaphthalene, phenol, and anisole
demand for efficient, economic and environmentally gave the corresponding diarylmethane products 3 in
friendly processes, the development of direct catalytic good to excellent isolated yields. Additionally, hetero-
carbon-carbon bond forming reactions of arenes in
which products are obtained from the reaction of
prior unmodified substrates is an exciting task. Re-
cently, interesting examples of such catalytic function-
alizations of arenes have been reported.[8–12] Consid-
erable progress has been made in the metal-catalyzed
Friedel–Crafts alkylation of arenes to generate prod-
ucts containing a diarylmethane moiety commonly lyzed by 0.5 mol% of Bi
Scheme 1. Reaction of arenes with phenylethyl alcohol cata-
(OTf)3.
AHCTREUNG
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Table 1. Reaction of 1-phenylethanol with several arenes.[a]
Entry
Arene 2
Major Product 3
Solvent
T [8C]
t [h]
Yield [%][b]
Selectivity[c]
5:1:3[d]
1
-
100
4
72
71
79
2
3
-
-
100
100
3
1
10:1[d]
9:1.3:1[d]
4
MeNO2
100
1
89
99:1
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
55
55
55
55
1
1
8
4
95
71
58
82
4:1
4:1
10:1
5:1
9
MeNO2
100
8
44
99:1
10
CH2Cl2
CH2Cl2
55
55
1
1
65
89
3:1
11
14.7:2.6:1
[a]
Reactions were carried out with 1-phenylethyl alcohol (1.0 mmol), arene (3.0 mmol), solvent (3 mL), and 0.5 mol%
Bi(OTf)3. Reactions were stopped after complete conversion of 1-phenylethyl alcohol.
[b] Isolated yields after silica gel chromatography.
[c]
1
Regioselectivity was determined by H NMR or 13C NMR spectroscopy and comparison with literature data.
[d] But-1-ene-1,3-diyldibenzene.
arenes such as thiophene or 2-methylthiophene react- nylethyl alcohol we decided to test the scope of the
ed well, and even the products of nitrogen-containing benzylation reagent. The reaction of enantiomerically
arenes, such as 3-methylindole were obtained. This is pure (S)-1-phenylethanol with para-xylene led to the
important to note since, so far, only few examples of racemic product, which indicates the formation of a
metal-catalyzed benzylations of nitrogen-containing carbocation as intermediate.
heterocycles have been reported.[20]
Benzyl chloride and benzyl bromide, as well as ben-
Following the successful bismuth-catalyzed benzyla- zylamine did not show any reactivity in the Bi(OTf)3-
tion of arenes and heteroarenes by employing 1-phe- catalyzed alkylation of anisole. However, benzyl alco-
ACHTREUNG
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Bismuth-Catalyzed Benzylation of Arenes and Heteroarenes
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Table 2. Reaction of anisole with different benzylating re-
Having established an efficient bismuth-catalyzed
intermolecular benzylation of arenes we decided to
extend this procedure to an intramolecular version as
it would lead to fluorenes, which have shown to be
valuable scaffolds for blue light emitting polymers.
However, so far only few synthetic approaches to flu-
orenes have been reported, and intramolecular aryla-
tions have only been achieved using harsh reaction
conditions, such as refluxing in sulfuric acid.[21–22] To
agents.[a]
Entry
1
Benzylating reagent
Yield [%][b]
–
2
3
4
5
–
prevent the given limitations we applied Bi
catalyst for the intramolecular arylation. Using 1
mol% of Bi(OTf)3, the biphenyl derivatives 6 and 7
(OTf)3 as
–
AHCTREUNG
were reacted to afford the substituted fluorenes 8 and
9 and subsequent isolation provided the products in
excellent yields (Scheme 3). Given the low catalyst
loading and mild reaction conditions, as well as gener-
ally good functional group tolerance, the bismuth-cat-
alyzed intramolecular arylation is a good alternative
route to substituted fluorene derivatives.
To show that this method is not restricted to the ar-
ylation of benzyl alcohol and derivatives, we won-
dered if it would be possible to use other nucleophiles
instead of arenes. Hence, we analyzed the alkylation
reaction of 1-phenylethanol 1 with acetylacetone 10
as the nucleophile (Scheme 4). The desired product
11 could be isolated after 8 h in moderate yield. In
the case of diethyl malonate as a nucleophile no alky-
91
92
6
59
[a]
Reactions were carried out with anisole (3.0 mmol), ben-
zylating reagent (1.0 mmol) and 0.5–5 mol% Bi
A
[b] Isolated yields after silica gel chromatography.
hol, benzyl acetate and 3-hydroxy-3-phenylpropa- lated product could be observed. While previous alky-
noate gave the desired products in good isolated lations could only be performed with benzyl bromide
yields (Table 2).
as electrophile in the presence of cobalt salts or stoi-
Hence, we tested the benzylation of several arenes chiometric amounts of a Lewis acid such as BF3, this
and heteroarenes by employing benzyl alcohol and is the first example of a Lewis-acid catalyzed alkyla-
benzyl acetate 4 as the electrophile (Scheme 2). tion of acetylacetone with 1-phenylethanol.
Again, we observed complete conversion of the ben-
zylating reagents after short reaction times and under Bi
mild reaction conditions.
In summary, we have developed an efficient
(OTf)3-catalyzed Friedel–Crafts-type benzylation of
several arenes and heteroarenes. Compared to previ-
AHCTREUNG
Isolated yields of the products 5 after chromatogra- ous alkylations with benzyl alcohol and derivatives
phy were a slightly lower for the benzyl alcohol as this method requires remarkably small amounts of
compared to the benzyl acetate which, at first, glance highly reactive, inexpensive and non-toxic Bi(OTf)3
G
can be explained by the better acetate leaving group catalyst. The mild reaction conditions, short reaction
(Table 3). However, when compared to the benzyl times, operational simplicity and practicability render
acetate the reaction of 1-phenylethyl alcohol this transformation an attractive approach to diaryl-
(Table 1) gave similar results, although in the latter methane derivatives, which could be isolated in good
case stoichiometric amounts of water are produced to excellent yields. Additionally, an extension of this
which were expected to deactivate the catalyst. procedure to an intramolecular variant provided a
Hence, in contrast to many metal triflates, Bi
A
a mild and water-tolerable catalyst and even perform- of this bismuth-catalyzed benzylation using other nu-
ing the reaction in aqueous media might be feasible.
cleophiles, such as acetylacetone provided the alkylat-
ed products and showed the principal feasibility of
this method. Further investigations are directed
toward the use of further nucleophiles and the exten-
sion to a possible asymmetric variant of this transfor-
mation.
Scheme 2. Bi(OTf)3-catalyzed reaction of arenes with benzyl
H
alcohol and benzyl acetate.
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Magnus Rueping et al.
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Table 3. Reaction of benzyl alcohol (R=H) and benzyl acetate (R=OAc) with arenes.[a]
Entry
1
Arene
Major Product
R
Solvent
t [h]
Yield [%][b]
Selectivity[c]
-
-
H
Ac
-
-
2
5
59
79
H
Ac
-
-
2
5
69
90
1.4:1
1.3:1
2
3
4
-
-
H
Ac
-
-
2
5
76
92
H
Ac
-
-
2
5
73
95
1.9:1
1.9:1
H
Ac
MeNO2
MeNO2
2
5
66
68
-
-
5
H
Ac
MeNO2
MeNO2
2
5
91
92
1.4:1
1.4:1
6
7
H
Ac
MeNO2
MeNO2
2
5
66
58
2.7:1:1.7
3:1:1.7
H
Ac
MeNO2
MeNO2
2
5
67
63
1.4:1
1.2:1
8
H
Ac
MeNO2
MeNO2
2
5
57
67
-
-
9
H
Ac
MeNO2
MeNO2
3
5
35
58
1.3:1
2:1
10
H
Ac
MeNO2
MeNO2
3
5
58
61
1:1
1:1
11
[a]
Reactions were carried out with benzyl alcohol or benzyl acetate (1.0 mmol), arene (3.0 mmol), solvent (3 mL), and 1
mol% Bi(OTf)3. Reactions were stopped after complete conversion of benzyl alcohol or benzyl acetate.
ACHTREUNG
[b] Isolated yields after silica gel chromatography or distillation.
[c]
1
Regioselectivity was determined by H NMR or 13C NMR and comparison with the literature data.
Experimental Section
General Remarks
Unless otherwise noted, all commercially available com-
pounds were used as supplied without further purification.
Solvents for chromatography were technical grade and dis-
tilled prior to use. Analytical thin-layer chromatography
(TLC) was performed on Merck silica gel-aluminum plates
with F-254 indicator, visualized by irradiation with UV light.
Column chromatography was performed using silica gel
Merck 60 (particle size 0.040–0.063 mm). 1H NMR and
13C NMR spectra were recorded on a Bruker AM 250 spec-
trometer in CDCl3. Data are reported in the following
order: chemical shift (d) in ppm; multiplicities are indicated
[bs (broad singlet), s (singlet), d (doublet), t (triplet), m
(multiplet)]; coupling constants (J) are in Hertz (Hz). Mass
spectra (ESI-MS) were conducted on a VG-Platform II
Scheme 3. Intramolecular Bi(OTf)3-catalyzed arylation.
N
Scheme 4. Bi(OTf)3-catalyzed alkylation of acetylacetone.
G
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Bismuth-Catalyzed Benzylation of Arenes and Heteroarenes
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(Fisons Instruments). IR spectra were recorded on a Jasco
FT/IR-420 spectrometer and are reported in terms of fre-
quency of absorption (cmÀ1). All data of known compounds
are in agreement with literature data, while the new com-
pounds were fully characterized.
726, 699, 632, 590 cmÀ1; mp 197–2008C; ESI-MS: m/z=349
(MH+); anal. calcd. for C26H20O: C 89.62, H 5.79; found: C
89.48, H 6.00.
Acknowledgements
General Synthetic Procedure
We thankfully acknowledge Degussa AG for generous fund-
ing.
Bi(OTf)3·4 H2O (0.005 mmol), benzylating reagent (3 mmol)
A
and arene (1 mmol) were added to a 10 mL flask and sol-
vent (3 mL of nitromethane or dichloromethane) was added
if appropriate. The reaction mixture was heated until com- References
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The reaction mixture was allowed to cool to room tempera-
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product was purified by silica gel column chromatography
or distillation.
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Adv. Synth. Catal. 2006, 348, 1033 – 1037
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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