Gold-catalyzed benzylation of arenes and heteroarenes

Article abstract of DOI:10.1002/adsc.200505433

Friedel-Crafts type benzylation of arenes and heteroarenes with benzylic acetates, alcohols, and carbonates is effectively promoted under mild reaction conditions using catalytic amounts of gold salts. The resulting 1,1-diarylalkanes and 1-aryl-1-heteroarylalkanes are obtained in high yields and with high selectivity. The utility of the method is demonstrated by a short synthesis of beclobrate {ethyl 2-[4-(4-chlorobenzyl)-phenoxy]-2-methylbutyrate (3)}, a fibric acid derivative.

Full text of DOI:10.1002/adsc.200505433

COMMUNICATIONS
DOI: 10.1002/adsc.200505433
Gold-Catalyzed Benzylation of Arenes and Heteroarenes
Kristin Mertins, Irina Iovel, Jette Kischel, Alexander Zapf, Matthias Beller*
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Fax: (þ49)-381-1281-5000, e-mail: matthias.beller@ifok-rostock.de
Received: November 2, 2005; Accepted: February20, 2006
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Friedel–Crafts type benzylation of arenes
and heteroarenes with benzylic acetates, alcohols,
and carbonates is effectivelypromoted under mild
reaction conditions using catalytic amounts of gold
salts. The resulting 1,1-diarylalkanes and 1-aryl-1-
heteroarylalkanes are obtained in high yields and
with high selectivity. The utility of the method is
demonstrated bya short snythesis of beclobrate
{ethyl 2-[4-(4-chlorobenzyl)-phenoxy]-2-methylbuty-
rate (3)}, a fibric acid derivative.
The direct benzylation of simple (and in general non-
functionalized) arenes has been described mainlywith
benzyl halides (benzyl chloride, benzyl bromide) as sub-
strates.[17] However, these reactions have drawbacks
such as the necessityof drastic conditions (high temper-
ature and strong acidic conditions). In addition, signifi-
cant amounts of salt by-products (resulting from the
neutralization of the by-products HCl or HBr) are
formed.
Previous to our work onlyfew transition metal cata-
lysts based on palladium and ruthenium have been de-
scribed for the benzylation of arenes.[18] Whilepalladium
complexes have been used onlyon a stoichiometric ba-
sis,[19] ruthenium complexes work onlyat higher temper-
ature (2008C) and gave the corresponding 1,1-diarylme-
thanes in low to mediocre yield (22–77%).[20] Veryre-
cently, we demonstrated that salts of precious metals,
Keywords: arene functionalization; arylation; benzy-
lation; Friedel–Crafts reaction; homogeneous cataly-
sis; gold
The application of gold salts and complexes is an emerg- such as IrCl3, RhCl3, H2PtCl6, and even FeCl3 are able
ing area in organometallic chemistryand organic syn-
to catalyze the addition of benzylic acetates to arenes
and heteroarenes with high yield and selectivity under
thesis.[1] In addition to industriallyimportant oxidation
processes, which proceed in the presence of heterogene- ambient conditions.
ous gold catalysts,[2] more and more organic reactions
In order to improve these reactions further on, we are
are discovered to be catalyzed by homogeneous gold interested in alternative catalyst systems, which can be
complexes. So far, mainlyhydrogenations, [3] isomeriza- applied in the synthesis of all kinds of 1,1-diarylme-
tions,[4] aldol reactions,[5] reactions of alkynes with nucle- thanes. Here, we describe the arylation reaction of ben-
ophiles,[6] reactions of propargyl or allenyl ketones,[7] ad- zyl alcohols and benzyl acetates leading to functional-
ditions of electron-rich arenes to methyl vinyl ketones,[8] ized 1,1-diarylalkanes in the presence of gold salts. Ap-
and domino processes with isobenzopyrylium cation in- plying this novel catalyst benzylation of activated and
termediates[9] have been discovered. Recentlypublished
non-activated arenes and heteroarenes proceeds with
articles include the synthesis of oxazoles,[10] domino hy- high yield and selectivity often under mild conditions.
droarylation and cycloisomerization reactions,[11] trans-
Looking for new catalysts, the reaction of o-xylene
formations of alkynyl epoxides to furans[12] and the ben- and 1-phenylethyl acetate was studied as a model reac-
efits of N and N,O ligands in gold-catalyzed reactions.[13] tion (see Scheme 1 and Table 1). Here, different gold
Based on our interest in the benzylation of arenes and salts, catalyst concentrations and solvents were tested
heteroarenes,[14,15] we initiated a program to search for at room temperature to 808C. Table 1 shows a summary
gold catalysts for Friedel–Crafts-like reactions. Obvi- of the obtained results.
ously, such direct CH-functionalization reactions of are-
nes avoid the necessityof introducing activating groups
or protection and deprotection steps. Thus, in general
ꢀ
C C bonds can be formed more efficientlycompared
to other methods, e.g., palladium-catalyzed coupling re-
actions of aryl halides and benzylmagnesium re-
agents.[16]
Scheme 1. Reaction of o-xylene and 1-phenylethyl acetate.
Adv. Synth. Catal. 2006, 348, 691 – 695
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
691

Kristin Mertins et al.
Conversion [%][b]
COMMUNICATIONS
Table 1. Screening of the model reaction.
Entry
Catalyst
mol % Catalyst
Solvent
T [8C]
Yield [%][a]
1
2
3
4
5
6
7
8
9
HAuCl4
HAuCl4
AuCl3
AuPPh3Cl
AuPPh3Cl/AgOTf (1: 1)
HAuBr4
HAuCl4
HAuCl4
AuCl3
10
10
10
10
10
10
5
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
CH3NO2
ethyl acetate
CH2Cl2
RT
80
RT
80
80
80
RT
RT
80
80
80
99
99
95
5
42
97
75
11
99
99
20
90
100
100
100
39
100
100
100
26
1
10
10
10
10
100
100
76
10
11
12
AuCl3
AuCl3
AuCl3
CH3CN
80
100
Reaction conditions: 10 mL o-xylene or 10 mmol o-xylene in 8.8 mL solvent, 0.5 mmol 1-phenylethyl acetate, 1–10 mol % cat-
alyst, room temperature to 808C, 20 h.
[a]
GC yield.
[b]
GC conversion based on 1-phenylethyl acetate.
At room temperature excellent results are obtained in
the presence of 10 mol % HAuCl4 (99% of 1c) and
AuCl3 (95% of 1c) (Table 1, entries 1 and 3). In addition,
also AuPPh3Cl gave a significant yield of the desired
product (42%), but onlywith added silver triflate (Ta-
ble 1, compare entries 4 and 5). The use of 5 mol %
(1 mol %) HAuCl4 at room temperature afforded 75%
(11%) yield of 1c (Table 1, entries 7 and 8).[21] Notewor-
Scheme 2. Benzylation of o-xylene with different benzylating
reagents.
thy, the benzylation ofo-xylene can be carried out in ex-
cellent yield in polar solvents like CH3NO2, ethyl ace-
tate, and CH3CN (Table 1, entries 9, 10, and 12).
Having reliable catalysts for the benzylation of o-xy- ble 3). As shown in Table 3 in addition to 1-phenylethyl
lene in hand, we were interested in the benzylation of acetate also sec-phenylethanol, benzyl alcohol, benzyl
other arenes and heteroarenes (Table 2) and in the use acetate, benzyl methyl carbonate, 4-methoxybenzyl ace-
of different benzylating agents (Table 3).
tate, 4-methoxybenzyl alcohol, 4-methoxybenzyl meth-
Due to its easier handling most of the reactions were yl carbonate, and 4-chlorobenzyl alcohol react with o-
performed byapplying HAuCl 4 as catalyst. As expected xylene in the presence of HAuCl4 or AuCl3 at 808C to
a varietyof electron-rich arenes such as o-xylene (99%, give the corresponding benzylated products.
Table 2, entry3), anisole (99%, Table 2, entry4), 1,4-di-
There is no general trend observed for the different
methoxybenzene (99%, Table 2, entry 5), 4-chloroani- benzylating reagents. While benzyl alcohol gave the
sole (99%, Table 2, entry6), 2-chloroanisole (99%, Ta-
ble 2, entry7), and 2-iodoanisole (90%, Table 2, en-
try8) gave the corresponding products in good to excel-
best result (60%) among the simple benzyl derivatives
(Table 3, entries 2–4), 1-phenylethyl acetate (99%)
and 4-methoxybenzyl methyl carbonate (59%) proved
lent yields. The reaction of 2-anisaldehyde (63%, Ta- to be superior in case of the substituted benzylation re-
ble 2, entry9) illustrates that activation occurs
chemoselectivelyat the benzyl position and not at the
formyl group.
agents (Table 2, entry3, Table 3, entries 1, 5–7).
Since manybiologicallyactive substances and current
pharmaceuticals such as piritrexim, trimethoprim, av-
In addition, heteroarenes such as 3-methylthiophene rainvilleol, papaverine, beclobrate or letrozole contain
(82%, Table 2, entry10), 2,5-dimethylfuran (87%, Ta-
ble 2, entry11) and 2-acetylfuran (82%, Table 2, en-
try12) react well.
a 1,1-diarylmethane motif, we attempted to apply our
benzylation method to the synthesis of an actual drug.
Indeed, the reaction of ethyl 2-methyl-2-phenoxybuty-
rate[22] with commerciallyavailable 4-chlorobenzyl ace-
In general, the regioselectivityof the reaction is good
to excellent (86 to>99%). However, in the case of 3- tate in the presence of HAuCl4 gave compound 3 in 90%
methylthiophene three isomers (2-/4-/5-positions) yield (see Scheme 3). This product is known as beclo-
were obtained in a ratio of 62/7/3 (Table 2, entry10).
Next, we set out to studythe scope and limitations of
brate, a fibric acid derivative with potent hypolipidemic
activity. Noteworthy, it is not necessary to apply a large
the benzylating agent in more detail (Scheme 2; Ta- excess of the arene in this reaction.
692
asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 691 – 695

Gold-Catalyzed Benzylation of Arenes and Heteroarenes
COMMUNICATIONS
Table 2. Benzylation of arenes and heteroarenes.
[a]
EntryEduct
1
Product
Yield [%]
52
Conversion [%][b]
100
Regioselectivity( o/p)
1a
1b
1c
1d
14/86
2
3
4
47
99
99
96
100
100
–
<1/99
13/87
5[d]
6
1e
1f
99
99
99
90
63
100
100
100
100
100
–
<1/99
<1/99
<1/99
<1/99
7
1g
1h
1i
8[d]
9
10
1j
82
100
62/7/31[c]
11
1k
1l
87
82
100
100
–
12[d]
>1/99
Reaction conditions: 10 mL educt, 0.5 mmol 1-phenylethyl acetate, 10 mol % HAuCl4, 808C, 20 h.
[a]
GC yield.
[b]
GC conversion based on 1-phenylethyl acetate.
2-/4-/5-isomer.
10 mmol educt in 8 mL MeNO2.
[c]
[d]
arylmethanes and 1-aryl-1-heteroarylmethanes is possi-
ble. Typically reactions proceed under mild conditions
(room temperature to 808C; no strong acid or base).
The practical utilityof this benzlyation protocol is
shown bythe synthesis of the fibric acid derivative be-
clobrate.
Experimental Section
General Remarks
Scheme 3. Synthesis of beclobrate.
All reactions were carried out without anyspecial precautions
1
in air. H and 13C NMR spectra were recorded on a Bruker
ARX 400 spectrometer. Chemical shifts (d) are given in ppm
and refer as internal standard to the residual solvent (CDCl3:
7.26 ppm) or TMS: 0.00 ppm. Gas chromatographywas per-
formed on a Hewlett Packard HP 6890 chromatograph with
In conclusion, we have developed the first gold-cata-
lyzed arylation of benzyl alcohols and carboxylates. Us-
ing Au catalysts an easy and general synthesis of 1,1-di- an HP5 column. Mass spectra were recorded on a AMD 402/
Adv. Synth. Catal. 2006, 348, 691 – 695
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
693

Kristin Mertins et al.
COMMUNICATIONS
Table 3. Variation of the benzylating agent.
3
EntryProduct
R
Yield [%][a]
83
Conversion [%][b]
100
Regioselectivity( o/p)
1
1c
2a
H
1/99
Ac
H
30
60
39
100
1/99
1/99
2
3
4
CO2Me
38
68
1/99
5[c]
6
7
Ac
H
CO2Me
58
52
59
100
100
100
1/99
1/99
1/99
2b
8
2c
H
H
41
99
77
36/64
38/62
9[d]
2d
100
Reaction conditions: 10 mL educt, 0.5 mmol benzylating agent, 10 mol % HAuCl4, 808C, 20 h.
[a]
GC yield.
[b]
GC conversion based on benzylating agent.
AuCl3 as catalyst.
10 mmol phenol in 8 mL MeNO2.
[c]
[d]
3 mass spectrometer. Chemicals and solvents were purchased
from Fluka and Aldrich and used as received.
References and Notes
[1] a) R. J. Robert, Science 2003, 301, 926–927; b) G. J.
Hutchings, Gold Bull. 2004, 37, 3–11; c) A. Arcadi, S.
Di Giuseppe, Curr. Org. Chem. 2004, 8, 795–812;
d) G. J. Hutchings, Catal. Today 2005, 100, 55–61;
e) D. T. Thompson, Appl. Catal. A 2003, 243, 201–205;
f) G. J. Hutchings, M. Haruta, Masatake. Appl. Catal. A
2005, 291, 2–5.
[2] a) C. T. Campbell, Science 2004, 306, 234–235; b) M. Co-
motti, C. Della Pina, R. Matarrese, M. Rossi, Angew.
Chem. 2004, 116, 5936–5939; Angew. Chem. Int. Ed.
2004, 43, 5812–5815; c) S. Demirel-Guelen, M. Lucas,
P. Claus, Catal. Today 2005, 102, 166–172; d) P. Claus,
Appl. Catal. A 2005, 291, 222–229.
General Procedure for the Benzylation of o-Xylene
In a pressure tube, 1-phenylethyl acetate (0.5 mmol) and cata-
lyst (10 mol %, 0.05 mmol) were dissolved in o-xylene (5 mL).
Then decane (50 mL) was added as internal GC standard. After
stirring for 20 h aliquots were taken from the reaction mixture
and subjected to GC analysis for determination of yield and
conversion. For isolation of the products the reaction was
quenched with water. The water phase was extracted with di-
chloromethane. The combined organic layers were dried over
MgSO4 and the solvents were distilled off. The product was pu-
rified bycolumn chromatographyon silica gel (70–230 mesh),
eluent: n-heptane/ethyl acetate (50:1).
[3] G. C. Bond, P. A. Sermon, G. Webb, D. A. Buchanan,
P. B. Wel ls, J. Chem. Soc. Chem. Commun. 1973, 444–
445.
Characterization data for 1a–l, 2a–d, and 3 are listed in the
Supporting Information.
[4] a) L.-U. Meyer, A. de Meijere, Tetrahedron Lett. 1976,
497–500; b) P. G. Gassman, G. R. Meyer, F. J. Williams,
J. Am. Chem. Soc. 1972, 94, 7741–7748.
[5] Y. Ito, M. Sawamura, T. Hayashi, J. Am. Chem. Soc.
1986, 108, 6405–6406.
[6] a) Y. Fukuda, K. Utimoto, J. Org. Chem. 1991, 56, 3729–
3731; b) Y. Fukuda, K. Utimoto, Bull. Chem. Soc. Jpn.
1991, 64, 2013–2015; c) Y. Fukuda, K. Utimoto, H. Noza-
ki, Heterocycles 1987, 25, 297–300; d) Y. Fukuda, K. Uti-
moto, Synthesis 1991, 875–978; e) J. H. Teles, S. Brode,
M. Chabanas, Angew. Chem. 1998, 110, 1475–1478; An-
gew. Chem. Int. Ed. 1998, 37, 1415–1418; f) E. Mizushi-
ma, K. Sato, T. Hayashi, M. Tanaka, Angew. Chem.
2002, 114, 4745–4747; Angew. Chem. Int. Ed. 2002, 41,
4563–4565.
Acknowledgements
The authors thank Prof. Dr. M. Michalik, Dr. D. Michalik, Dr.
W. Baumann, Dr. C. Fischer, Mrs. S. Buchholz, and Ms. K.
Reincke (all Leibniz-Institut für Katalyse e.V.) for analytical
support. Generous support from the state Mecklenburg-Vor-
pommern, the BMBF (“Bundesministerium für Bildung und
Forschung”), and the “Fonds der Chemischen Industrie” are
gratefully acknowledged.
694
asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 691 – 695

Gold-Catalyzed Benzylation of Arenes and Heteroarenes
COMMUNICATIONS
[7] a) A. S. K. Hashmi, T. L. Ruppert, T. Knçfel, J. W. Bats,
J. Org. Chem. 1997, 62, 7295–7304; b) A. S. K. Hashmi,
L. Schwarz, J.-H. Choi, T. M. Frost, Angew. Chem.
2000, 112, 2382–2385; Angew. Chem. Int. Ed. 2000, 39,
2285–2288; c) A. S. K. Hashmi, L. Schwarz, J. W. Bats,
J. Prakt. Chem. 2000, 342, 40–51; d) A. S. K. Hashmi,
T. M. Frost, J. W. Bats, J. Am. Chem. Soc. 2000, 122,
11553–11554; e) A. S. K. Hashmi, T. M. Frost, J. W.
Bats, Catal. Today 2002, 72, 19–27; f) A. S. K. Hashmi,
Gold Bull. 2003, 36, 3–9.
[17] For example, Fe catalysts have been used for reactions of
benzyl chloride with non-functionalized arenes. Here,
stoichiometric amounts of unwanted hydrogen chloride
are formed; recent examples: a) S. G. Pai, A. R. Bajpai,
A. B. Deshpande, S. D. Samant, J. Mol. Catal. A: Chem.
2000, 156, 233–243; b) V. R. Choudhary, S. K. Jana,
A. S. Mamman, Microporous and Mesoporous Materials
2002, 56, 65–71; c) V. R. Choudhary, S. K. Jana, Appl.
Catal. 2002, 224, 51–62; d) V. R. Choudhary, S. K. Jana,
J. Mol. Catal. A: Chem. 2002, 180, 267–276.
[8] G. Dyker, D. Hildebrandt, J. H. Liu, K. Merz, Angew.
Chem. 2003, 115, 4536–4538; Angew. Chem. Int. Ed.
2003, 42, 4439–4402.
[9] G. Dyker, E. Muth, Adv. Synth. Catal. 2003, 345, 1247–
1252.
[10] A. S. K. Hashmi, J. P. Weyrauch, W. Frey, J. W. Bats, Org.
Lett. 2004, 6, 4391–4394.
[11] a) A. S. K. Hashmi, L. Grundl, Tetrahedron 2005, 61,
6231–6236; b) N. Morita, N. Krause, Org. Lett. 2004, 6,
4121–4123.
[18] A special exception is the cyclization of substituted ben-
zyl alcohols with pyrrole see: a) G. Dyker, D. Hilde-
brandt, J. Liu, K. Merz, Angew. Chem. 2003, 115,
4536–4538; Angew. Chem. Int. Ed. 2003, 42, 4399–
4402; see also: b) Y. Nishibayashi, M. Yoshikawa, Y. Ina-
da, M. D. Milton, M. Hidai, S. Uemura, Angew. Chem.
2003, 115, 2663–2666; Angew. Chem. Int. Ed. 2003, 42,
2681–2684; c) Y. Nishibayashi, Y. Inada, M. Yoshikawa,
M. Hidai, S. Uemura, Angew. Chem. 2003, 115, 1533–
1536; Angew. Chem. Int. Ed. 2003, 42, 1495–1498.
[19] E. Mincione, P. Bovicelli, Gazz. Chim. Ital. 1982, 112,
437–440.
[12] A. S. K. Hashmi, P. Sinha, Adv. Synth. Catal. 2004, 346,
432–438.
[13] A. S. K. Hashmi, J. P. Weyrauch, M. Rudolph, E. Kurpe-
jovic, Angew. Chem. 2004, 116, 6707–6709; Angew.
Chem. Int. Ed. 2004, 43, 6545–6547.
[14] a) K. Mertins, I. Jovel, J. Kischel, A. Zapf, M. Beller, An-
gew. Chem. 2005, 117, 242–246; Angew. Chem. Int. Ed.
2005, 44, 238–242; b) I. Jovel, K. Mertins, J. Kischel, A.
Zapf, M. Beller, Angew. Chem. 2005, 117, 3981–3985;
Angew. Chem. Int. Ed. 2005, 44, 3913–3917.
[15] For other examples using transition metal complexes see:
a) G. Dyker, D. Hildebrandt, J. Liu, K. Merz, Angew.
Chem. 2003, 115, 4536–4538; Angew. Chem. Int. Ed.
2003, 42, 4399–4402; b) Y. Nishibayashi, M. Yoshikawa,
Y. Inada, M. D. Milton, M. Hidai, S. Uemura, Angew.
Chem. 2003, 115, 2663–2666; Angew. Chem. Int. Ed.
2003, 42, 2681–2684; c) Y. Nishibayashi, Y. Inada, M.
Yoshikawa, M. Hidai, S. Uemura, Angew. Chem. 2003,
115, 1533–1536; Angew. Chem. Int. Ed. 2003, 42, 1495–
1498.
[20] a) T. Kondo, S. Kajiya, S. Tantayanon, Y. Watanabe, J.
Organomet. Chem. 1995, 489, 83–91; b) T. Kondo, S.
Tantayanon, Y. Tsuji, Y. Watanabe, Tetrahedron Lett.
1989, 30, 4137–4140.
[21] For comparison: 1 mol % (10 mol % HBF4 at room tem-
perature leads to 3% (99%) of 1c. The use of HBF4 in po-
lar solvents leads to lower yields compared to gold cata-
lysts. For example the reaction of o-xylene with 1-phe-
nylethyl acetate in the presence of 10 mol % HBF4 in
ethyl acetate (80 8C, 20 h) gives 23% yield of 1c (with
AuCl3: 99% yield of 1c, see Table 1, entry10). In addition
the reaction of phenol with 4-chlorobenzyl alcohol in the
presence of 10 mol % HBF4 in MeNO2 (80 8C, 20 h) re-
sults in 38% yield of 2d (with HAuCl4: 99% yield of
2d, see Table 3, entry9).
[22] Synthesis of ethyl 2-[4-(4-chlorobenzyl)phenoxy]-2-
ꢀ
methylbutanoate via Hell–Volhard Zelinskybromina-
tion of 2-methylbutanoic acid: H. E. Zimmerman, J. D.
Robbins, R. D. McKelvey, C. J. Samuel, L. R. Sousa, J.
Am. Chem. Soc. 1974, 96, 4630–4643; and subsequent
Williamson ether synthesis: M. Julia, Bull. Soc. Chim.
Fr. 1956, 776–783.
[16] a) R. van Asselt, J. C. Elsevier, Tetrahedron 1994, 50,
323–334; b) R. van Asselt, J. C. Elsevier, Organometal-
lics 1992, 11, 1999–2001.
Adv. Synth. Catal. 2006, 348, 691 – 695
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
695