Intermolecular Friedel-Crafts reaction catalyzed by InCl3

Article abstract of DOI:10.1016/j.tetlet.2007.08.011

Our recent discovery that In(III) salts were able to activate halides catalytically under mild conditions for the intermolecular Friedel-Crafts cyclization prompted us to explore this highly efficient activation in intermolecular Friedel-Crafts reactions. The alkylation of p-xylene with allylic and benzylic halides was demonstrated under catalytic and mild condition to afford in some cases quantitative yields of the monoalkylated products without the need to employ large excesses of reactants.

Full text of DOI:10.1016/j.tetlet.2007.08.011

Tetrahedron Letters 48 (2007) 7085–7087
Intermolecular Friedel–Crafts reaction catalyzed by InCl3
Miho Kaneko, Ryuji Hayashi and Gregory R. Cook*
Department of Chemistry and Molecular Biology, North Dakota State University, Fargo, ND 58105, USA
Received 30 July 2007; accepted 1 August 2007
Available online 8 August 2007
Abstract—Our recent discovery that In(III) salts were able to activate halides catalytically under mild conditions for the intermo-
lecular Friedel–Crafts cyclization prompted us to explore this highly efficient activation in intermolecular Friedel–Crafts reactions.
The alkylation of p-xylene with allylic and benzylic halides was demonstrated under catalytic and mild condition to afford in some
cases quantitative yields of the monoalkylated products without the need to employ large excesses of reactants.
Ó 2007 Elsevier Ltd. All rights reserved.
Since Friedel and Crafts discovered addition of alkyl
halides to aromatic compounds in the presence of
stoichiometric amount of Lewis acids in 1877, electro-
philic aromatic substitutions (FC-reactions1) have been
one of the most important C–C bond formations in
the field of organic synthesis. In general, because nucleo-
philicity of aromatic compounds are relatively low
compared to other typical nucleophiles, severe condi-
tions2 for the intermolecular process with alkyl halides
are classic problems in FC-reactions. These reactions
typically require stoichiometric amounts of Lewis acids,
high temperatures, and large excess of arenes. To over-
come these limitations in the intermolecular FC-reaction
there has been growing interest in methods that are
catalytic, mild, and more environmentally friendly.
tion onto alkynes.11 While there are examples of direct
allylation catalyzed by a Lewis acid such as AlCl3, the
reaction affords a complex mixture of products.2a There
are also arene additions to allylic halides catalyzed by a
few Lewis acids. However, large excess (20–140 equiv) of
arenes were required for successful reaction.14 Addition-
ally, indium metal15 has been known to catalyze inter-
molecular FC-reactions with allyl chlorides, however
this reaction required the use of 10–15 equiv of arene,
80 °C, and strongly basic conditions.
Recently, we discovered Lewis acids such as In(III) and
Bi(III) were capable of selectively activating allylic
halides catalytically.12 We have succeeded in developing
an efficient, mild, and catalytic intramolecular FC-reac-
tion13 to synthesize a variety of benzocycles (Scheme 1).
Herein, we report the development of intermolecular
FC-reactions via catalytic halide activation by In(III)
under mild conditions.
In(III) Lewis acids have distinct advantages3 over other
Lewis acids including their relatively low toxicity,
stability in the air, and recyclability. In(III) Lewis acid
catalysis has been utilized in FC-reactions employing
electrophiles such as carbonyl compounds,4 sulfuryl
chloride,5 electron deficient alkenes,6 alkynes,7 aziri-
dines,8 and epoxides.9 In nearly all these examples the
Lewis acid coordinates to strong Lewis basic functional-
ity including oxygen and nitrogen in order to activate
the electrophile. In order to directly activate organo-
halides stoichiometric quantities of Lewis acid are
required. Examples include exo-2-chloro and 7-chloro-
norbornane activated with various Lewis acids (SnCl4,
AlCl3, BF3, and SbF5).10 Additionally, Zn(II) salts have
been reported to activate allyl chlorides for cycloaddi-
In order to optimize the conditions, we examined
p-xylene (5 equiv) as the nucleophilic arene and benzyl
bromide as the electrophile. Previously we discovered
that In and Bi Lewis acids were optimal for activating
R
R
InCl3 (5-20 mol%), 4Å MS
CH2Cl2 (0.05M), rt, 16 h
Y
Y
X
80% - 100%
X = Br or Cl
18 examples
Y = C(CO2Et)2 or NTs
R = alkyl, alkoxy, F, Cl, Br
*
Corresponding author. Tel.: +1 701 231 7413; fax: +1 701 231
1057; e-mail: Gregory.Cook@ndsu.edu
Scheme 1. Ring-closing FC-reaction via catalytic halide activation.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.011

7086
M. Kaneko et al. / Tetrahedron Letters 48 (2007) 7085–7087
Table 1. Solvent effect and screen of Lewis acids
InCl3 (10 mol%), 4Å MS
CH2Cl2, rt, 16 h
R
+
Br
R
LA (10 mol%), 4Å MS
Solvent, rt, 16 h
Br
+
1
Entry
LA
p-Xylene (equiv)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
InCl3
InCl3
InCl3
InCl3
InCl3
InBr3
In(OTf)3
In(NO3)3
InI
5
5
5
5
5
5
5
5
5
5
5
1.5
CH2Cl2
THF
MeCN
EtOH
i-PrOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
100
0a
82%a, 2
96%, 5
89%a, 3
98%, 4
0a
0a
0a
97
88b
69b
94b
99b
79b
Mixturec
F
Cl
100%, 6
100%, 7
10
11
12
BiCl3
Bi(OTf)3
InCl3
a Starting material recovered.
b NMR yield.
c Mixture of polyalkylated products (ratio could not be determined).
Cl
CF3
99%b, 10
71%a, 8
100%, 9
organohalides catalytically. Thus we screened a variety
of In and Bi salts under a range of conditions (Table
1). 4 A molecular sieves played the role of a neutral
Br
Br
Br
˚
99%, 11
98%, 12
93%, 13
base16 in the reaction. Under InCl3 catalysis in CH2Cl2,
a quantitative yield of desired product 1 was obtained
(entry 1). We screened several solvents that posses donor
atoms (O or N) and found them to be detrimental to the
reaction (entries 2–5). Other Lewis acids such as InBr3,
In(OTf)3, InI, and BiCl3 were suitable catalysts (entries
6, 7, 9, and 10) affording excellent yields of monoalkylat-
ed products. Employing In(NO3)3 and Bi(OTf)3 worked
as well with slightly diminished yields (entries 8 and 11).
Utilizing only 1.5 equiv of p-xylene resulted in an effi-
cient reaction, however, mixtures of polyalkylated prod-
ucts were obtained (entry 12). It should be pointed out
that although the reaction was optimal at 5 equiv of
arene, this is significantly less than catalytic intermolec-
ular FC-reactions previously reported. General optimal
conditions were found to employ 10 mol % of the cata-
lyst, 5 equiv of the arene in non-coordinating CH2Cl2
at room temperature.17
aNMR yield. b10 equiv xylene, 70 °C, neat.
Scheme 2. Electrophile scope and limitations.
InCl3 (10 mol%), 4Å MS
50 ºC, 16 h, 75%
Cl
+
10 eq
Scheme 3. Intermolecular FC-reaction with benzyl chloride.
Intermolecular FC-reaction with benzyl chloride was
also achieved using InCl3 catalysis. Performing the reac-
tion with 10 equiv of p-xylene at 50 °C resulted in 75%
yield of the desired product (Scheme 3).
In conclusion, we have demonstrated a catalytic and effi-
cient intermolecular FC-reaction with allyl and benzyl
halides under mild conditions. As compared to previous
reports, our general protocol required less arene (only
5 equiv) and lower temperatures. Quantitative yields of
monoalkylated products were obtained. We are cur-
rently examining the scope and limitation of this cata-
lytic activation of halides by halophilic Lewis acids
and other metals in order to gain further insight into this
distinctive reactivity.
Next we turned our attention to the scope and limitation
of the electrophile in the intermolecular FC-reaction and
the results are summarized in Scheme 2. In addition to
benzyl bromide, we found a variety of benzylic and
allylic halides reacted with high efficiency. Under InCl3
catalysis, electrophilic aromatic substitution of p-xylene
with allyl or crotyl bromide yielded our desired products
2 and 3 in high yields. Methyl-substituted benzyl
bromides yielded 4 and 5 in excellent yields. Benzylic
bromides possessing electron withdrawing halogen
substituents performed admirably in the reaction to
afford compounds 6, 7, 11, 12, and 13. Only the o-substi-
tuted substrates afforded a yield of was not essentially
quantitative (71%, 8 and 93%, 13). Product 10 was
obtained in excellent yield, however, the p-CF3-substi-
tuted benzyl bromide required higher temperature and
10 equiv of p-xylene for reaction to complete.
Acknowledgments
We are grateful to the National Science Foundation
(NSF-CHM-0616485) for financial support of this pro-
ject. We also thank Pfizer for an undergraduate summer
fellowship for M.K.

M. Kaneko et al. / Tetrahedron Letters 48 (2007) 7085–7087
7087
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17. General experimental procedure: InCl3 (0.05 mmol) and
˚
4 A MS (250 mg) were placed in a small screw-cap
scintillation vial equipped with a magnetic stir bar. p-
Xylene (2.5 mmol), dicholoromethane (1 mL) and halide
(0.5 mmol) were added. The reaction was stirred under
room temperature. Upon completion of the reaction
(ꢀ16 h), the mixture was filtered through a small pad of
silica gel and rinsed with ethyl acetate. After removing
solvent in vacuo, analytically pure alkylated products were
obtained. (For some examples, 1, 2, 3-trimethoxy benzene
was used as an internal standard for NMR yields.) All
products afforded satisfactory spectral data for their
structure identification.