A simple catalyst for the efficient benzylation of arenes by using alcohols, ethers, styrenes, aldehydes, or ketones

Article abstract of DOI:10.1002/chem.200802740

The compound [IrCp* (OTf)₂(I^nBu)] (I ^nBu = 1,3-di-n-butyl-imidazolylidene) is an effective catalyst in the benzylation of arenes with different benzylating agents, such as alcohols, ethers and styrenes, representing an unprecedented highly versatile catalyst for this type of process. The same compound also catalyses a remarkable tandem process that allows the use of aldehydes and ketones as benzylating agents, through the base-free hydrogenation of C=O bonds with iPrOH and further use of the resulting primary or secondary alcohols as benzylating agents.

Full text of DOI:10.1002/chem.200802740

DOI: 10.1002/chem.200802740
A Simple Catalyst for the Efficient Benzylation of Arenes by Using Alcohols,
Ethers, Styrenes, Aldehydes, or Ketones
Amparo Prades, Rosa Corberꢀn, Macarena Poyatos, and Eduardo Peris*[a]
(InBu)] (InBu =1,3-di-n-butyl-imidazolylidene)
Abstract: The compound [IrCp*ACHTUNRGTENNUG(OTf)2ACHTUNGTRENNUGN
is an effective catalyst in the benzylation of arenes with different benzylating
agents, such as alcohols, ethers and styrenes, representing an unprecedented highly
versatile catalyst for this type of process. The same compound also catalyses a re-
markable tandem process that allows the use of aldehydes and ketones as benzy-
lating agents, through the base-free hydrogenation of C=O bonds with iPrOH and
further use of the resulting primary or secondary alcohols as benzylating agents.
Keywords: arenes · benzylation ·
hydroarylation · hydrogen transfer ·
N-heterocyclic carbenes · tandem
reactions
Introduction
cesses.[10–13] The versatility of such catalysts can be exempli-
fied by the fact that the same compound is capable of dehy-
drogenating alcohols, coupling alcohols to form ethers, and
allows all three possible cross-coupling combinations be-
tween amines and alcohols, depending on the reaction con-
ditions used.[13] We now show that the same compound is an
effective catalyst in the benzylation of arenes with alcohols,
ethers and styrenes, and also catalyses a remarkable tandem
process that allows the unprecedented use of aldehydes and
ketones as benzylating agents.
The functionalisation of arenes is an important tool toward
the preparation of highly valuable chemicals of industrial
relevance. The typical procedures for this type of transfor-
mation imply the use of traditional Friedel–Crafts reactions,
in which alkyl halides and Lewis acid catalysts are utilised.[1]
These conditions, however, afford the concomitant produc-
tion of hydrogen halides that often induce side reactions
and many byproducts. As an alternative, recent reports have
proposed the use of alcohols,[2–4] ethers,[5,6] styrenes[7,8] or
benzylic acetates[9] for which milder reaction conditions are
needed and side reactions are avoided.
Results and Discussion
In the search for new catalytic systems capable to afford
the functionalisation of arenes, it is not only desirable to
have a catalyst with high activity and selectivity, but also
that its versatility widens the scope of substrates able to
afford the final products. Simple catalysts that are able to fa-
cilitate multistep processes may also lead to a wider library
of potential useful products. In this sense, most Lewis acid
catalysts used in the traditional Friedel–Crafts processes are
able to catalyse only one or two specific reactions, thus lim-
iting their scope.
In first place, we studied the different activities of several
Ir–Cp* complexes (1–3) in the benzylation of toluene using
We have recently described a series of [IrCp*ACTHNUGRTNEUNG(NHC)]
complexes (NHC=N-heterocyclic carbenes) that have
À
shown excellent activity in a wide set of C H activation pro-
benzyl alcohols (Table 1). We observed that all NHC con-
taining complexes of the type [IrCp*
a higher activity than that shown by [{IrCp*Cl2}2]/AgOTf.
From all, [IrCp*(OTf)2A
(InBu)] (1: InBu =1,3-di-n-butyl-imida-
ACHUTGTNRNE(UNG OTf)2ACHUTNGTREN(NUNG NHC)] showed
[a] A. Prades, Dr. R. Corberꢀn, Dr. M. Poyatos, Prof. E. Peris
Departamento de Quꢁmica Inorgꢀnica y Orgꢀnica
Universitat Jaume I, 12071-Castellꢂn (Spain)
Fax : (+34)964-72-82-15
A
CHTUNGTRENNUNG
zolylidene) was the one to show better catalytic activities.
The direct use of 1 or its in situ preparation from
E-mail: eperis@qio.uji.es
[IrCp*Cl2ACTHNGUTERNNUG
(InBu)] and addition of an excess of AgOTf,[10] did
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FULL PAPER
Table 1. Comparison of the different catalysts towards benzylation of tol-
uene using benzyl alcohol.[a]
the final products (entries 10 and 11). These data compare
well and even improve the results obtained for other recent-
ly used transition-metal catalysts for the benzylation of
arenes with benzyl alcohols, in which higher catalyst load-
ings and longer reaction times were needed.[4,5]
Direct addition of styrenes to arenes (also known as hy-
droarylation of styrenes) has recently appeared as an inter-
esting alternative for the preparation of 1,1-diarylarenes.[7,8]
As shown by the data presented in Table 3, compound 1
Catalyst
[{IrCp*Cl2}2]/AgOTf
1
1
2
3
3
T [8C]
t [h]
Yield [%]
1
2
3
4
5
6
G
110
110
70
110
110
70
7
3
10
7
3
10
53
>95
>95
>95
>95
75
Table 3. Reaction of styrene derivatives with arenes with 1.[a]
[a] Reaction Conditions: benzyl alcohol (3 mmol), toluene (15 mmol),
catalyst (0.003 mmol, 0.1 mol%). Yields determined by 1H NMR
ACHTUNGTRENNUNGspectroscopy.
Styrene
Arene
Cat.
t
Yield
Ratio
o:p
not lead to any significant differences in the catalytic activi-
ties shown.
loading [h] [%]
[%]
We then used 1 in a series of reactions in which different
benzylating agents were used for the functionalisation of
several arenes. Table 2 shows the catalytic results when
1
2
3
4
5
6
styrene
styrene
styrene
4-chloro styrene
1,2-dihydro naphthalene anisole
indene anisole
toluene
anisole
phenol
anisole
1
0.1
1
1
0.1
0.1
6
4
4
4
4
4
30
10:90
>95[b] 10:90
>95
>95
>95
>95
40:60
15:85
10:90
25:75
Table 2. Benzylation of arenes with catalyst 1.[a]
[a] Reaction Conditions: Styrene derivative (1 mmol), arene (5 mmol)
1
and catalyst (1 or 0.1 mol%). Yields determined by H NMR spectrosco-
py. [b] Isolated yield 87%.
AHCTUNGTREGdNNNU isplayed an excellent activity in this type of reaction.
Benzylating
agent
Arene
Cat.
t
Yield
Ratio
o:p
loading [%] [h] [%]
Except for the case of the benzylation of toluene (Table 3,
entry 1), the catalyst showed high activity for all other com-
binations of arenes and styrenes. Remarkably, in the case of
the benzylation of anisole, catalyst loadings as low as
0.1 mol% afforded full conversions in only 4 h under the re-
action conditions used. In most cases the reaction proceeds
with a high selectivity to the para isomers.
We also performed an experiment implying the coupling
of styrene and [D8]anisole, in which we clearly observe that
the deuterium from the anisole selectively moves to the
methyl group of the ethyl bridge in the final product
(Scheme 1), so that the reaction can be regarded as an inser-
1
2
3
4
5
6
7
8
9
benzyl alcohol
benzyl alcohol
benzyl alcohol
benzyl alcohol
benzyl alcohol
1-phenyl ethanol toluene
1-phenyl ethanol anisole
1-phenyl ethanol p-xylene 0.1
toluene
anisole
benzene 0.1
o-xylene 0.1
p-xylene 0.1
0.1
0.1
3
3
6
3
3
4
3
4
4
6
5
>95(89)[b] 35:65
>95
75
>95
>95(89)[b]
32
>95
40
35:65
–
35:65
–
10:90
10:90
10:90
40:60
0.1
0.1
1-phenyl ethanol phenol
0.1
1
1
>95
10 dibenzyl ether
11 dibenzyl ether
toluene
anisole
>95(90)[b] 35:65
>95
35:65
[a] Reaction Conditions: Benzylating agent (1 mmol), arene (5 or
10 mmol) and catalyst (1 or 0.1 mol%). Yields determined by 1H NMR
spectroscopy. [b] Isolated yields.
À
tion of the molecule of styrene in one of the C D bonds in
a Markovnikov fashion. It has been proposed that the mech-
anism for this reaction operates through a metal-mediated
electrophilic aromatic substitution,[8] but a mechanism im-
benzyl alcohol, 1-phenyl ethanol and dibenzyl ether are
used. As can be seen from the results shown, a catalyst load-
ing as low as 0.1 mol%, affords high to excellent conver-
sions at short reaction times (3–4 h) when both alcohols
were used (Table 2, entries 1–9). The benzylation of benzene
required a longer reaction time, and a maximum yield of
75% was achieved. Poor selectivities in the production of
the ortho/para isomers were obtained when benzyl alcohol
was used (entries 1, 2 and 4), although they improved when
the higher steric demanding 1-phenyl ethanol was utilised
(entries 6–8). The reactions carried out with dibenzyl ether
required a higher catalyst loading of 1 mol% and longer re-
action times, although they also afforded full conversions to
À
plying the oxidative addition of a C D bond of the anisole
to the Ir centre and further insertion of the olefin in the
À
Ir D bond cannot be discarded. This result is also interest-
Scheme 1. Reaction of styrene with [D8]anisole.
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E. Peris et al.
ing because we did not detect any further scrambling of deu-
terium about the molecule as a consequence of any other
Conclusion
À
C H associated processes, considering that 1 also proved to
Although a wide variety of Lewis acids and transition-metal
complexes have been used to catalyze the Friedel–Crafts
benzylation, there are always limitations of the structure of
the benzylation reagents. In this work, we proved that com-
plex 1 is an efficient catalyst for a wide set of benzylation
reactions, for which different benzylating agents such as al-
cohols, ethers and styrenes have been used, confirming the
wide applicability of this catalyst. All the reactions consti-
tute valuable processes for the preparation of biologically
active species and industrial chemicals. The fact that 1 is
also an excellent catalyst in hydrogen transfer processes al-
lowed us to carry out an unprecedented tandem reaction,
implying the reduction of aldehydes or ketones to alcohols,
which are further used as benzylating agents of arenes. This
latter process can be carried out with a minimum amount of
iPrOH as reducing agent, thus implying that the overall re-
action is performed under environmentally benign
be a highly efficient catalyst in H/D exchange reactions.[12]
Compound 1 also catalysed the benzylation of anilines
with styrenes, as shown in Table 4, providing results that
compare well with those previously reported which made
use of Brønsted acids[14,15] or metal complexes[16,17] as cata-
lysts.
Table 4. Reaction of styrene with aniline derivatives with catalyst 1.[a]
Aniline
Yield [%]
o:N[b]:p
1
2
3
4
5
6
aniline
50
72
14
75
>95
50
72:26:2
70:14:16
90:10:–
50:50:–
90:10:–
83:17:–
o-methylaniline
p-methylaniline
p-fluoroaniline
p-chloroaniline
p-methoxyaniline
AHCTUNGTRENNGcUN onditions.
Experimental Section
[a] Reaction Conditions: Styrene (1 mmol), aniline derivative (5 mmol)
and catalyst (1 mol%). Yields determined by 1H NMR spectroscopy.
[b] N-alkylation products.
General procedures: [{IrCp*Cl2}2] was prepared according to literature
methods.[18] [IrCp*Cl
2A(NHC)] complexes (NHC=1,3-di-n-butyl-imidazol-
CTHUNGTRENNUNG
2-ylidene,[12] 1,2,3-trimethyl-imidazol-4-ylidene[19] and 1,2-dimethyl-pyra-
zol-3-ylidene[13]) were prepared as previously reported by us. The catalyt-
ic experiments were performed either by the direct use of the isolated
bistriflate complexes[10] or their in situ generation from the dichloro com-
pounds and addition of an excess of AgOTf. All other reagents were
used as received from commercial suppliers and used without further pu-
rification. For the isolation of the products of the catalytic experiments,
the crude was extracted with dichloromethane and filtrated through a
pad of Celite. The solvent was removed under vacuum, and the crude
solid purified by flash chromatography on silica gel using hexanes as
eluent. NMR spectra were recorded on a Varian Innova 300 MHz and
500 MHz, using CDCl3 as solvent.
The fact that 1 is also very active in many other metal-
mediated catalysed reactions, prompted us to carry out a
tandem process for which standard Friedel–Crafts catalysts
would be ineffective. In this sense, we carried out the reac-
tion of benzaldehyde or acetophenone with anisole in the
presence of 1 and iPrOH, as shown in Table 5. It is impor-
tant to point out that only 1.5 equivalents of iPrOH were
needed in order to facilitate the reduction of the carbonyl
group of the aldehyde or ketone. The reaction provided full
conversions to the final benzylated products. Remarkably,
this catalytic tandem process gathers two different reactions
for which 1 has shown excellent activities, namely, the re-
duction of aldehydes and ketones with iPrOH through hy-
drogen transfer,[10] and the benzylation of the arene with the
resulting alcohol.
Catalytic experiments
Benzylation of arenes: A mixture of benzylating agent (1 mmol), arene (5
or 10 mmol), catalyst (0.1 or 1 mol%) and silver triflate (0.3 or 3 mol%)
was heated at 1108C in a thick-walled glass tube fitted with a Teflon cap.
The reaction mixture was analysed by 1H NMR spectroscopy and yields
calculated based on the amount of arene.
Reaction of styrene derivatives with arenes: A mixture of styrene deriva-
tive (1 mmol), arene (5 mmol), catalyst (0.1 or 1 mol%) and silver triflate
(0.3 or 3 mol%) was heated at 1108C in a thick-walled glass tube fitted
with a Teflon cap. The reaction mixture was analysed by 1H NMR spec-
troscopy and yields calculated based on the amount of arene. Products of
the benzylation of arenes were identified according to previously report-
ed spectroscopic data: 2- and 4-(methylphenyl)phenylmethane,[5] 2- and
4-(methoxyphenyl)phenylmethane,[3] diphenylmethane,[3] 2,3- and 3,4-(di-
methylphenyl)phenylmethane,[3] 2,5-(dimethylphenyl)phenylmethane,[3] 1-
methyl-2-(1-phenylethyl)benzene and 1-methyl-4-(1-phenylethyl)ben-
zene,[7] 1-methoxy-2-(1-phenylethyl)benzene and 1-methoxy-4-(1-phenyl-
ethyl)benzene,[7] 1,4-dimethyl-2-(1-phenylethyl)benzene,[7] 2- and 4-(1-
phenylethyl)phenol,[7] 1-chloro-4-(1-(2-methoxyphenyl)ethyl)benzene and
1-chloro-4-(1-(4-methoxyphenyl)ethyl)benzene,[7] 1-(2-methoxyphenyl)-
1,2,3,4-tetrahydronaphthalene and 1-(4-methoxyphenyl)-1,2,3,4-tetrahy-
dronaphthalene,[7] 1-(2-methoxyphenyl)-2,3-dihydro-1H-indene and 1-(4-
methoxyphenyl)-2,3-dihydro-1H-indene.[7]
Table 5. Tandem reaction—reduction of alcohol and benzylation.[a]
Benzylating
agent
Yield
[%]
Ratio o:p
1
2
benzaldehyde
acetophenone
>95(88)[b]
>95
35:65
10:90
[a] Reaction Conditions: Benzylating agent (1 mmol), anisole (10 mmol),
iPrOH (1.5 mmol) and catalyst (1 mol%). Yields determined by
1H NMR spectroscopy. [b] Isolated yield.
Reaction of styrene with aniline derivatives:
A mixture of styrene
(1 mmol), aniline derivative (5 mmol), catalyst (1 mol%) and silver trif-
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Iridium Catalysts
FULL PAPER
A
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troscopy and yields calculated based on the amount of arene. Products
were identified according to previously reported spectroscopic data: 2-(1-
phenylethyl)benzenamine and 4-(1-phenylethyl)benzenamine, N-(1-phe-
nylethyl)aniline,[20] 2-methyl-6-(1-phenylethyl)benzenamine and 2-
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benzenemethanamine,[21] 4-methyl-2-(1-phenylethyl)benzenamine, a-
methyl-N-(4-methylphenyl)benzenemethanamine, 4-fluoro-2-(1-phenyl-
ACHTUNGTRENNUNGethyl)benzanamine and N-(4-fluorophenyl)-a-methylbenzenemethan-
ACHTUNGTRENNUNG
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phenyl)-a-methylbenzenemethanamine,[22] 4-methoxy-2-(1-phenylethyl)-
benzanamine[17] and N-(4-methoxyphenyl)-a-methylbenzenemethana-
mine.[21]
Tandem reaction: A mixture of benzylating agent (1 mmol), anisole
(10 mmol), iPrOH (1.5 mmol), catalyst (1 mol%) and silver triflate (3
mol%) was heated at 1108C in a thick-walled glass tube fitted with a
Teflon cap. The reaction mixture was analysed by 1H NMR spectroscopy
and yields calculated based on the amount of arene.
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Coates, Org. Lett. 2005, 7, 5135.
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We gratefully acknowledge financial support from the Ministerio de
Ciencia e Innovaciꢂn (CTQ2008-04460) and Bancaixa (P1.1B2007-04).
We would also like to thank the Spanish Ministerio de Ciencia e Innova-
ciꢂn for a fellowship (R.C.) and to the Juan de la Cierva program (M.P.).
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Published online: March 12, 2009
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