Indium(III)-catalyzed reductive monoalkylation of electron-rich benzenes with aliphatic carboxylic acids leading to arylalkane derivatives

Article abstract of DOI:10.1002/ejoc.201500096

Described herein is the reaction of electron-rich aromatic compounds with aliphatic carboxylic acids treated with a catalytic amount (5 mol-%) of InI₃, 1,1,3,3-tetramethyldisiloxane (TMDS), and molecular iodine. The reductive monoalkylation occurs smoothly to produce the corresponding arylalkane derivatives.

Full text of DOI:10.1002/ejoc.201500096

Job/Unit: O50096
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FULL PAPER
DOI: 10.1002/ejoc.201500096
Indium(III)-Catalyzed Reductive Monoalkylation of Electron-Rich Benzenes
with Aliphatic Carboxylic Acids Leading to Arylalkane Derivatives
[a]
[a]
[a]
[a]
Toshimitsu Moriya, Kentaro Takayama, Takeo Konakahara, Yohei Ogiwara, and
Norio Sakai*[
a]
Keywords: Indium / Friedel–Crafts alkylation / Carboxylic acids / Reduction / Hydrosiloxanes
Described herein is the reaction of electron-rich aromatic
compounds with aliphatic carboxylic acids treated with a
catalytic amount (5 mol-%) of InI , 1,1,3,3-tetramethyldisilox-
3
ane (TMDS), and molecular iodine. The reductive monoalk-
ylation occurs smoothly to produce the corresponding aryl
alkane derivatives.
Introduction
pound 1 was obtained with alkyl iodide 1Ј [Equation (3) in
[
10,11]
Scheme 1 and reaction in Scheme 2)].
This result was
The alkylation of aromatic compounds occupies an im-
portant and central position of the C–C bond formation
unique, because it demonstrated direct introduction of the
[
1]
process used in organic and pharmaceutical chemistry. In
particular, the preparation of diphenylmethane derivatives
by Friedel–Crafts (FC) alkylation of benzenes with benzyl
derivatives having a variety of leaving groups has been
thoroughly studied [Equation (1) in Scheme 1]. Most Frie-
del–Crafts benzylations have been achieved by either Lewis
[2]
[3]
[4]
or Brønsted acids such as FeBr , Ca(OTf)2, BF /OEt ,
3
3
2
[
5]
[6]
InCl3, and TfOH. As another approach to the alkyl-
ation of a benzene ring, reductive benzylation of benzenes
with aromatic aldehydes in the presence of a Lewis acid and
an appropriate reducing reagent has been reported [Equa-
tion (2) in Scheme 1]. For example, Palomo’s group investi-
gated an TMSOTf-catalyzed intermolecular FC alkylation
of benzene or toluene with benzaldehyde derivatives in the
presence of polymethylhydrosiloxane (PMHS).[ Baba’s
group also reported an InCl –Me SiClH reducing system
7]
3
2
acting as catalyst for a reductive FC benzylation of benzene
derivatives with benzaldehydes, leading to the preparation
of diphenylmethane derivatives.[ Moreover, Fukuzawa and
8]
co-workers reported a combination of Sc(OTf) and 1,3-
3
propanediol that catalyzed a reductive benzylation of benz-
[
9]
enes. However, these studies did not include a reductive
monoalkylation of benzenes with aliphatic aldehydes. In
this context, we found that when an aromatic compound
was used as a solvent in the reductive iodination of carb-
oxylic acids, unexpected monoalkylated aromatic com-
Scheme 1. Diverse approaches to the monoalkylation of a benzene
ring.
[
a] Department of Pure and Applied Chemistry,
Faculty of Science and Technology,
Tokyo University of Science (RIKADAI),
Noda, Chiba 278-8510, Japan
E-mail: sakachem@rs.noda.tus.ac.jp
http://www.rs.tus.ac.jp/sakaigroup
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500096.
Scheme 2. Preliminary results for the monoalkylation of p-xylene.
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T. Moriya, K. Takayama, T. Konakahara, Y. Ogiwara, N. Sakai
FULL PAPER
alkyl chain onto the benzene ring without isomerization of Table 1. Examination of the reaction conditions.
an alkyl chain.
In general, with the exception of benzylation, a mono-
alkylation by use of aliphatic carbonyl compounds has
not been reported often, because an in situ generated
carbocation in a typical FC reaction is readily rearranged
to a more stable branched carbocation, which leads to the
formation of undesired products.[
12]
Consequently, the
Yield [%][a]
1
Entry
InX
5 mol-%]
3
Hydrosilane
[Si–H: 6 equiv.]
achievement of a direct alkylation of aromatic compounds
without isomerization of an alkyl chain is highly desirable.
Augustine and Chandrasekhar independently found a TFA-
Et SiH reducing system and a B(C F ) -PMHS reducing
[
1Ј
1[b]
InBr
InBr
3
3
TMDS
TMDS
TMDS
TMDS
TMDS
TMDS
TMDS
PhSiH3
67
99
99 (76)
94
90
80
79
33
17
[c]
2
3
4
5
6
7
8
ND
ND
ND
ND
ND
ND
ND
ND
–
InI
InCl
3
3
6 5 3
system, respectively, which promoted a reductive mono-
alkylation of electron-rich benzenes with aliphatic alde-
hydes [Equation (4) in Scheme 1].[ As an interesting ex-
ample, Saigo et al. disclosed that Ga Cl mediated a re-
3
In(OTf)
In(OAc)
3
13]
3
In(OH)
InI3
3
2
4
ductive Friedel–Crafts monoalkylation of anisole with ali- 9 [
phatic aldehydes. To the best of our knowledge, no exam-
InI
InI3
3
MePh
TMDS
2
SiH
70
CM
d]
[e]
[
14]
10
ple of a reductive monoalkylation of benzenes with ali- [a] GC (Isolated) yield. [b] Reaction time = 2 h. [c] ND: not de-
2
tected. [d] Without I . [e] CM: complex mixture.
phatic carboxylic acids has been reported yet [Equation (5)
in Scheme 1]. In this paper, we report our detailed results
on a novel approach to the monoalkylation of benzene de- the number of methyl substituents seemed to cause a ten-
dency toward an upswing in the yields of products 2–4.[
16]
rivatives.
Although it is well known that demethylation of anisole by
[
17]
the in situ generated silyl iodide occurs, the present reac-
tion produced the expected diarylated product 5 without
demethylation in a good yield. Also, when the reaction was
Results and Discussion
Table 1 shows the results of changing the reaction condi- conducted with 1,3-dimethoxybenzene under the same con-
tions. Based on our preliminary results, when 3-phenyl- ditions, the corresponding diarylalkane 6 was produced
[
15]
propanoic acid was treated with InBr (5 mol-%), TMDS without demethylation. For benzene without an activating
3
(
Si-H: 6 equiv.), and I (1 equiv.) in p-xylene at 100 °C for group, the alkylation was able to produce 1,3-diphenylprop-
2
2
h, the desired alkylation product 1 was obtained in 67% ane (7), although a long reaction time was necessary. How-
GC yield with 17% of alkyl iodide 1Ј, which was simply
produced from the carboxylic acid and I (entry 1). When
the reaction time was prolonged to 12 h at the same tem-
Table 2. Scope and limitations of benzene derivatives.[a]
2
perature, the yield of alkylation product 1 improved to
quantitative yield (entry 2). During the screening, InBr and
3
InI showed a slightly better activity in comparison to other
3
indium(III) salts (entries 2–7). When the reactions were
conducted with PhSiH and MePh SiH instead of TMDS,
3
2
the yields of both alkylations decreased (entries 8 and 9).
When the substrate was not treated with iodine, the reaction
led to a complicated mixture (entry 10). This result defi-
nitely showed that this reaction proceeds via the alkyl iod-
ide intermediate, which was formed by the reductive iodin-
ation of a carboxylic acid using this indium–hydrosilane
system. On the other hand, isolation of the alkylated prod-
uct from the crude product including a siloxane and an
alkyl halide was extremely difficult, so that a drastic de-
crease of the product yield was observed after several col-
umn purifications (see entry 3).
With the optimal conditions shown in Table 1, the scope
of this reaction was examined with various aromatic com-
pounds (Table 2). In all cases, when aromatic compounds
with an electron-donating group, such as a methyl or a
methoxy substituent, were used, the reaction proceeded
smoothly, producing the corresponding products 2–6 in
[
a] Isolated yields are given; NMR yields are in parentheses. [b]
PhSiH (Si-H: 9 equiv.) was used instead of TMDS. [c] 80 °C, 48 h.
d] ND: not detected; 3-phenylpropyl iodide was obtained as a
3
[
moderate to excellent yields. Furthermore, an increase in major product.
2
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Indium(III)-Catalyzed Reductive Monoalkylation
ever, the use of benzene derivatives with an electron-with- (phenylthio)acetic acid; however, the yield of the desired
drawing group, such as halogens, did not yield the corre- sulfide 18 was only 10%. For the carboxylic acid, although
sponding alkylation products 8–10; instead, 3-phenylpropyl several examinations with various amounts of the indium
iodide was obtained.
catalyst and the hydrosilane were conducted, the product
Next, the scope and limitations of carboxylic acids with yield was not improved.
InI was examined with p-xylene both as a solvent and a
As extension of a substrate, monoalkylations of p-xylene
3
nucleophile, and the results are summarized in Table 3. with an aliphatic aldehyde and acyl chloride were per-
When 2-phenyl acetic acids with a variety of functional formed, and the results are outlined in Scheme 3. When
groups, such as a methyl group and halogens (Cl, Br, and both an aldehyde and an acyl chloride were treated under
I), were used, the alkylation proceeded smoothly, and the the optimized conditions, the corresponding product 1 was
corresponding products 11–14 were produced in good to obtained in good yield.
excellent yields. Strangely, when the reaction was conducted
with 4-methoxyphenylacetic acid, diarylated alkane deriva-
tive 15Ј, with demethylation of the methoxy group, was ob-
tained in relatively good yield. On the other hand, the use
of a 2-phenylacetic acid with a nitro group did not lead to
alkylation, and the starting material was recovered, proba-
bly because the indium catalyst strongly coordinated to a
nitro group rather than a carbonyl group. Also, the
carboxylic acid having a naphthalene ring gave product 16
in a relatively satisfactory yield. Moreover, when an alkyl-
Scheme 3. Reductive monoalkylation of p-xylene with carboxylic
acid derivatives.
ation of p-xylene with a dicarboxylic acid was tried under
Several control experiments were then conducted. For ex-
the optimized conditions in the hope of intramolecular cy- ample, when 3-phenyl-1-iodopropane (1Ј) was treated either
clization, intermolecular alkylation occurred instead at each with 5 mol-% of InI or without the indium catalyst in p-
3
carboxylic acid moiety, producing diarylated product 17 in xylene at 100 °C for 5 h, only the reaction with the indium
60% NMR yield. This reaction system was applicable to catalyst produced the corresponding alkylation product 1
in a 71% yield [Equation (1) in Scheme 1]. Also, TMDS
was not necessary, the presence of only the indium catalyst
Table 3. Scope and limitations of aliphatic carboxylic acids to p- was enough to bring about this substitution. We do not
[
a]
xylene.
have reasonable and clear proof of whether the monoalkyl-
ation series proceeds with a carbocation rearrangement at
present. However, we anticipate that, because the aromatic
compound, which functions as both a solvent and a nucleo-
phile, exists in excess amounts (9 equiv. to a reaction sub-
strate), the rearrangement of an alkyl chain that occurs in
a typical FC alkylation using a Lewis acid was restrained.
Also, when silyl ether 19 was treated either with only 5 mol-
[
4
a] Isolated yields are given; NMR yields are in parentheses. [b] 2 h;
-methoxyphenylacetic acid was used.
Scheme 4. Control experiments for elucidation of the reaction
mechanism.
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T. Moriya, K. Takayama, T. Konakahara, Y. Ogiwara, N. Sakai
FULL PAPER
%
of InI or with a combination of TMDS and I in p- monitored by thin-layer chromatography (TLC) analysis of reac-
3
2
tion aliquots. TLC was performed on silica gel 60 F254, and the
components were located by observation under UV light. Column
xylene, neither reaction produced the corresponding prod-
uct [Equation (2) in Scheme 4]. These results showed that
1
chromatography was also performed with silica gel. H NMR spec-
InI strongly activates the alkyl iodide to the corresponding
3
tra were measured at 500 or 300 MHz with tetramethylsilane as an
internal standard (δ = 0.00 ppm). C NMR spectra were measured
at 125 or 75 MHz by using the center peak of chloroform (δ =
7.0 ppm) as reference. High-resolution mass spectra (GC) were
measured with NBA (3-nitrobenzylalcohol) as a matrix.
silyl ether and is indispensable for the latter substitution.
We anticipated that a reaction pathway for the monoalk-
ylation of aromatic compounds with carboxylic acids would
proceed almost as well as that of the indium(III)-catalyzed
1
3
7
[
11]
reductive halogenation of carboxylic acids (Scheme 5).
First, a carboxylic acid was transformed into alkyl iodide
General Procedure for Indium(III)-catalyzed Monoalkylation of
Aromatic Compounds: To freshly distilled p-xylene (0.6 mL) in a
[18]
C via both silyl carboxylate A and silyl ether B.
Then,
screw-capped vial under a N
magnetic stirring bar, carboxylic acid (0.6 mmol), indium triiodide
14.9 mg, 0.0300 mmol), 1,1,3,3-tetramethyldisiloxane (318 μL,
2
atmosphere were successively added a
III
alkyl iodide C, which was activated by the In salt, reacted
with the aromatic compound and behaved both as a solvent
(
and as a nucleophile, and the corresponding monoalkylated 1.80 mmol), and iodine (152 mg, 0.600 mmol). The resultant mix-
product was obtained. Due to the existence of excess ture was heated at 100 °C (bath temperature) for 12 h. The reaction
amounts of aromatic compounds, we assumed that only was quenched with H
monoalkylation products could be obtained.
2
O (1 mL). The aqueous layer was extracted
three times with AcOEt (5 mL), and the combined organic phases
were dried with anhydrous Na SO , then filtered and concentrated
2
4
under reduced pressure. The quantity of the product yield in the
residue was determined with 1,1,2,2-tetrachloroethane as an in-
1
ternal standard by H NMR spectroscopy. The crude product was
purified by silica gel chromatography (eluent: hexane) to obtain the
corresponding monoalkylation product. If necessary, further purifi-
cation was performed by either preparative chromatography (elu-
ent: hexane) or gel permeation chromatography (eluent: CHCl
3
).
1
,4-Dimethyl-2-(3-phenylpropyl)benzene (1): 1H NMR (300 MHz,
3
CDCl ): δ = 1.90 (quint, J = 7.8 Hz, 2 H), 2.22 (s, 3 H), 2.29 (s, 3
H), 2.60 (t, J = 7.8 Hz, 2 H), 2.70 (t, J = 7.8 Hz, 2 H), 6.90–7.02
1
3
(
=
1
m, 3 H), 7.19–7.31 (m, 5 H) ppm. C NMR (75 MHz, CDCl
18.8, 21.0, 31.8, 32.8, 35.8, 125.7, 126.4, 128.2, 128.4, 129.5,
30.0, 132.7, 135.1, 140.2, 142.3 ppm. HRMS (EI): calcd. for
20 224.1565; found 224.1564.
3
): δ
17
C H
1
1
,3,5-Trimethyl-2-(3-phenylpropyl)benzene (4): H NMR (500 MHz,
CDCl ): δ = 1.77 (quint, J = 8.0 Hz, 2 H), 2.21 (s, 6 H), 2.23 (s, 3
H), 2.58 (t, J = 8.0 Hz, 2 H), 2.73 (t, J = 8.0 Hz, 2 H), 6.81 (s, 2
3
Scheme 5. Plausible reaction pathway for the reductive monoalkyl-
ation.
13
H), 7.18–7.30 (m, 5 H) ppm. C NMR (125 MHz, CDCl
3
): δ =
1
1
2
9.6, 20.8, 28.9, 30.6, 36.3, 125.7, 128.3, 128.4, 128.8, 134.8, 135.8,
36.1, 142.2 ppm. HRMS (EI): calcd. for C18
38.1705.
H22 238.1722; found
Conclusions
Supporting Information (see footnote on the first page of this arti-
We have demonstrated a one-pot monoalkylation of cle): Detailed experimental procedures and characterization data
1
benzene derivatives with aliphatic carboxylic acids having a for the products obtained by this method and copies of the H and
1
3
variety of substituents with a combination of InI , TMDS,
C NMR spectra of the products.
3
and molecular iodine. This reaction system presents a novel
alternative preparation for various arylated alkane deriva-
tives through the monoalkylation of aromatic compounds.
We have also found that this reducing system could be ap-
plied to other aliphatic carbonyl compounds, such as an
aldehyde and an acyl halide. Further studies on the applica-
Acknowledgments
This work was partially supported by the Ministry of Education,
Culture, Sports, Science and Technology (MEXT) through a
Grant-in-Aid for Scientific Research (C) (No. 25410120). We
tion to other aromatic compounds are ongoing in our labo- deeply thank Shin-Etsu Chemical Co., Ltd., for the gift of hydro-
ratory.
silanes.
[
1] a) C. Friedel, J. M. Crafts, C. R. Hebd. Seances Acad. Sci. 1877,
Experimental Section
8
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Sci. 1877, 84, 1450; c) G. A. Olah, Friedel–Crafts and Related
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G. K. S. Prakash in Comprehensive Organic Synthesis (Eds.:
2
General Method: All reactions were carried out under a N atmo-
sphere, unless otherwise noted. p-Xylene was distilled and dried
with molecular sieves 4A. All indium compounds were commer-
cially available and were used without further purification. Hydro-
silanes were used without further purification. Reactions were
4
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Indium(III)-Catalyzed Reductive Monoalkylation
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15] The aryl group on the carboxylic acid employed is not neces-
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[
[
[
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2
[16] Compared with the use of either InBr
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3 3
or InI , the yield of the
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Received: January 21, 2015
Published Online: ᭿
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T. Moriya, K. Takayama, T. Konakahara, Y. Ogiwara, N. Sakai
FULL PAPER
Reductive Monoalkylation
T. Moriya, K. Takayama, T. Konakahara,
Y. Ogiwara, N. Sakai* ...................... 1–6
Indium(III)-Catalyzed Reductive Mono-
alkylation of Electron-Rich Benzenes with
Aliphatic Carboxylic Acids Leading to Ar-
ylalkane Derivatives
A combination of InI
3
, 1,1,3,3-tetramethyl-
with aliphatic carboxylic acids having a
variety of substituents, leading to the
preparation of arylated alkane derivatives.
disiloxane (TMDS), and molecular iodine
effectively undergoes one-pot monoalkyl-
ation of electron-rich benzene derivatives
Keywords: Indium / Friedel–Crafts alk-
ylation / Carboxylic acids / Reduction /
Hydrosiloxanes
6
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