In(III)-mediated chemoselective dehydrogenative interaction of ClMe 2SiH with carboxylic acids: Direct chemo- And regioselective friedel-crafts acylation of aromatic ethers

Article abstract of DOI:10.1021/ol062723e

Chemoselective dehydrogenative interaction of ClMe₂SiH with a carboxylic acid group in the presence of InX₃ is reported. ¹³C NMR investigation revealed the formation of PhCOOSi(Cl)Me ₂as the major transient intermediate. Chemo- and regioselective Friedel-Crafts acylation of aromatic ethers directly from carboxylic acids was established.

Full text of DOI:10.1021/ol062723e

ORGANIC
LETTERS
2007
Vol. 9, No. 3
405-408
In(III)-Mediated Chemoselective
Dehydrogenative Interaction of ClMe2SiH
with Carboxylic Acids: Direct Chemo-
and Regioselective Friedel−Crafts
Acylation of Aromatic Ethers
Srinivasarao Arulananda Babu, Makoto Yasuda, and Akio Baba*
Department of Applied Chemistry, Graduate School of Engineering, Osaka UniVersity,
2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
baba@chem.eng.osaka-u.ac.jp
Received November 7, 2006
ABSTRACT
Chemoselective dehydrogenative interaction of ClMe2SiH with a carboxylic acid group in the presence of InX3 is reported. 13C NMR investigation
revealed the formation of PhCOOSi(Cl)Me2 as the major transient intermediate. Chemo- and regioselective Friedel
ethers directly from carboxylic acids was established.
−Crafts acylation of aromatic
Silicon-based reagents have found extensive synthetic ap-
plications and are intensively studied in organic syntheses.1
Indium-mediated reactions are emerging as effective proto-
cols in modern organic chemistry.2,3 Significantly, the
combination of indium and silicon reagents has been found
to be exciting in recent synthetic applications.4
2-propanol into 1-phenylpropane using a ClPh2SiH/InCl3
system, in which elimination of HCl took place.5a Surpris-
ingly, addition of benzil changed the reaction path to give
(3) For some reports on indium reagents, see: (a) Paquette, L. A.
Synthesis 2003, 765. (b) Babu, S. A.; Yasuda, M.; Okabe, Y.; Shibata, I.;
Baba, A. Org. Lett. 2006, 8, 3029. (c) Min, J.-H.; Jung, S.-Y.; Wu, B.; Oh,
J. T.; Lah, M. S.; Koo, S. Org. Lett. 2006, 8, 1459. (d) Cook, G. R.; Kargbo,
R.; Maity, B. Org. Lett. 2005, 7, 2767. (e) Vilaivan, T.; Winotapan, C.;
Banphavichit, V.; Shinada, T.; Ohfune, Y. J. Org. Chem. 2005, 70, 3464.
(f) Yi, X.-H.; Meng, Y.; Li, C.-J. J. Chem. Soc, Chem. Commun. 1998,
449. (g) Hirashita, T.; Kamei, T.; Satake, M.; Horie, T.; Shimizu, H.; Araki,
S. Org. Biomol. Chem. 2003, 1, 3799. (h) Babu, S. A.; Yasuda, M.; Shibata,
I., Baba, A. Synlett 2004, 1223.(i) Khan, F. A.; Dash, J. Eur. J. Org. Chem.
2004, 2692. (j) Miura, K.; Fujisawa, N.; Hosomi, A. J. Org. Chem. 2004,
69, 2427. (k) Loh, T.-P.; Yin, Z.; Song, H.-S.; Tan, K.-L. Tetrahedron Lett.
2003, 44, 911. (l) Babu, S. A.; Yasuda, M.; Shibata, I.; Baba, A. J. Org.
Chem. 2005, 70, 10408.
(4) For indium-silicon-based organic synthesis, see: (a) Mukaiyama, T.;
Ohno, T.; Nishimura, T.; Han, J. S.; Kobayashi, S. Bull. Chem. Soc. Jpn.
1991, 64, 2524. (b) Mukaiyama, T.; Ohno, T.; Han, J. S.; Kobayashi, S.
Chem. Lett. 1991, 20, 949. (c) Lee, P. H.; Lee, K.; Sung, S.-y.; Chang, S.
J. Org. Chem. 2001, 66, 8646. (d) Sakai, N.; Annaka, K.; Konakahara, T.
Tetrahedron Lett. 2006, 47, 631. (e) Onishi, Y.; Ito, T.; Yasuda, M.; Baba,
A. Tetrahedron 2002, 58, 8227. (f) Onishi, Y.; Ito, T.; Yasuda, M.; Baba,
A. Eur. J. Org. Chem. 2002, 1578. (g) Miyai, T.; Onishi, Y.; Baba, A.
Tetrahedron 1999, 55, 1017. (h) Saito, T.; Nishimoto, Y.; Yasuda, M.; Baba,
A. J. Org. Chem. 2006, 71, 8516. (i) In this stage, it appears to be reasonable
that this distinctive process requires 30 mol % of InX3.
In the course of applications of indium/silicon-mediated
processes, recently we have found the reduction of 1-phenyl-
(1) For some reviews on silicon reagents in organic synthesis, see: (a)
Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. (b) Denmark, S. E.;
Ober, M. H. Aldrichimica Acta 2003, 36, 75. (c) Denmark, S. E.; Sweis, R.
F. Acc. Chem. Res. 2002, 35, 835. (d) Denmark, S. E.; Baird, J. D. Chem.
Eur. J. 2006, 12, 4954. (e) Fleming, I.; Barbero, A.; Walter, D. Chem. ReV.
1997, 97, 2063. (f) Chan, T. H.; Fleming, I. Synthesis 1974, 761. (g) Parnes,
Z. N.; Bolestova, G. I. Synthesis 1984, 991. (h) Procter, G.; Russell, A. T.;
Murphy, P. J.; Tan, T. S.; Mather, A. N. Tetrahedron 1988, 44, 3953. (i)
Dilman, A. D.; Ioffe, S. L. Chem. ReV. 2003, 103, 733.
(2) For some reviews on indium reagents, see: (a) Li, C. J.; Chan, T. H.
Tetrahedron 1999, 55, 1149. (b) Nair, V.; Ros, S.; Jayan, C. N.; Pillai, B.
S. Tetrahedron 2004, 60, 1959. (c) Araki, S.; Hirashita, T. Main Group
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Z. Y. Can. J. Chem. 1994, 72, 1181. (e) Loh, T.-P. Sci. Synth. 2004, 7,
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2002, 531. (i) Cintas, P. Synlett 1995, 1087. (j) Chauhan, K. K.; Frost, C.
G. J. Chem. Soc., Perkin Trans. 1 2000, 3015. (k) Babu, G.; Perumal, P. T.
Aldrichimica Acta 2000, 33, 16.
10.1021/ol062723e CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/12/2007

2-chloro-1-phenylpropane via evolution of H2 gas instead
of 1-phenylpropane (Scheme 1).5b
Scheme 1
Prompted by the mechanistic illustration of these exciting
reactions, we envisioned that evolution of H2 gas by the
interaction of carboxylic acids with ClMe2SiH in the presence
of InX3 would generate transient silyl intermediates that are
applicable in synthetic organic processes. Although prepara-
tions of silyl esters have been reported, nevertheless, there
exist very rare reports that reveal the utility of silyl esters in
organic syntheses.6 Herein we report the chemoselective
interaction of ClMe2SiH with carboxylic acids in the presence
of InX3 and application of the protocol for the direct Friedel-
Crafts acylation of aromatic ethers.7,8
Figure 1. Partial 13C NMR spectra in the investigation of the
interaction of PhCOOH with ClMe2SiH.
gradual evolution of H2 gas was observed,9a which ceased
within 1 h. Surprisingly, no additive (benzil) was required,
unlike in the case of chlorination of an alcohol.5b However,
the expected PhCOCl generation was not observed. Interest-
ingly, the 13C NMR spectrum revealed the formation of a
new peak at 165.9 ppm,9b which plausibly corresponds to
the carbonyl group of the silyl ester PhCOOSi(Cl)Me2,
because a quantitative evolution of H2 gas was observed
(Figure 1, spectra C/D).
Unfortunately, we failed in our attempts to isolate the
transient intermediate PhCOOSi(Cl)Me2. Further, a mixture
of PhCOOH, ClMe2SiH, and InCl3 in ClCH2CH2Cl was
heated at 80 °C for 4 h. The 13C NMR spectrum showed the
formation of two new peaks at 168.3 and 165.4 ppm, which
plausibly correspond to PhCOCl and PhCOOSi(Cl)Me2,
respectively (spectra E). In addition, we set up the distillation
of the solution (spectra E) under reduced pressure (see
Supporting Information for details), which gave PhCOCl in
<20% yield.9c,d These results possibly revealed that PhCOCl
is produced from in situ chlorination of silyl ester (PhCOOSi-
(Cl)Me2) at high temperature; however, the conversion rate
is extremely slow.
Initially, we investigated the interaction of PhCOOH (1a,
1 mmol) and ClMe2SiH (1.2 mmol) in the absence of InCl3.
13C NMR spectra at various intervals showed only the peaks
corresponding to PhCOOH and ClMe2SiH (Figure 1, spectra
B). Apparently, neither elimination of HCl nor an interaction
of PhCOOH with ClMe2SiH was detected.
Next, when InCl3 (10-30 mol %) was added to a solution
of PhCOOH (1a) and ClMe2SiH in 1,2-dichloroethane, a
(5) (a) Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org.
Chem. 2001, 66, 7741. (b) Yasuda, M.; Yamasaki, S.; Onishi, Y.; Baba, A.
J. Am. Chem. Soc. 2004, 126, 7186. (c) Onishi, Y.; Ogawa, D.; Yasuda,
M.; Baba, A. J. Am. Chem. Soc. 2002, 124, 13690.
(6) For some works based on RCOOH-silicon, see: (a) RCOOH with
Et3SiH/ZnCl2 system in DMF at 120 °C afforded the silyl esters via a
dehydrogenative process; Liu, G.-B. Synlett 2006, 1431 and references
therein. (b) Wata, A.; Ohshita, J.; Tang, H.; Kunai, A. J. Org. Chem. 2002,
67, 3927. (c) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron
1993, 49, 2793. (d) Fennell, J. W.; Semo, M. J.; Wirth, D. D.; Vaid, R. K.
Synthesis 2006, 2659. (e) Watanabe, Y.; Shibasaki, Y.; Ando, S.; Ueda,
M. Chem. Mater. 2002, 14, 1762. (f) Chauhan, M.; Chauhan, B. P. S.;
Boudjouk, P. Org. Lett. 2000, 2, 1027. (g) Sini, G.; Bellassoued, M.; Brodie,
N. Tetrahedron 2000, 56, 1207. (h) Hudrlik, P. F.; Roberts, R. R.; Ma, D.;
Hudrlik, M. A. Tetrahedron Lett. 1997, 38, 4029. (i) Castafio, A. M.;
Echavarren, A. M. Tetrahedron 1992, 48, 3377. (j) Chan, T. H.; Wong, L.
T. L. J. Org. Chem. 1971, 36, 850.
(7) (a) Gore, P. H. In Aromatic Ketone Synthesis in Friedel-Crafts and
Related Reactions; Olah, G. A., Ed.; John Wiley & Sons Inc.: London,
1964; Vol. III, Part 1, p 1. (b) Gore, P. H. Chem. ReV. 1955, 55, 229. (c)
Heaney, H. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. II, p 733. (d) Olah, G. A. Friedel-
Crafts Chemistry; Wiley: New York, 1973.
(8) For other methods of the acylation of aromatic ethers from carboxylic
acids, see: (a) Ranu, B. C.; Ghosh, K.; Jana, U. J. Org. Chem. 1996, 61,
9546 and references therein. (b) Smith, K.; El-Hiti, G. A.; Jayne, A. J.;
Butters, M. Org. Biomol. Chem. 2003, 1, 2321. (c) Wang, Q. L.; Ma, Y.;
Ji, X.; Yana, H.; Qiub, Q. J. Chem. Soc., Chem. Commun. 1995, 2307. (d)
Firousabadi, H.; Iranpoor, N.; Nowrouzi, F. Tetrahedron Lett. 2003, 44,
5343 and references therein. (e) Sarvari, M. H.; Sharghi, H. Synthesis 2004,
2165 and references therein. (f) Cui, D.-M.; Zhang, C.; Kawamura, M.;
Shimada, S. Tetrahedron Lett. 2004, 45, 1741 and references therein.
Next, we focused our attention on the direct Friedel-Crafts
reaction process from carboxylic acids. Initially, the con-
(9) (a) In a separate experiment (carried out with equimolar amounts of
reactants), after the addition of InCl3 the evolution of H2 gas was observed,
which was collected into a graduated cylinder (100 mL) inversely kept in
a beaker (300 mL). The observed volume change was quantitative. However,
employing ZnCl2 failed to afford the evolution of H2 gas effectively at room
temperature under our experimental condition. In the case of AlCl3 the
observed volume change was very low (<20%). (b) Based on the kind hint
by a referee, using a platinum catalyst (10 mol % of H2PtCl6‚6H2O), the
formation of a new peak at δ 165.5 (1,2-DCE, C6D6 as an external standard),
for the CdO group of PhCOOSi(Cl)Me2 was noted with the evolution of
H2 gas as in the InCl3 system. However, the reaction was incomplete even
after a prolonged time. (c) Details of the reaction and 13C NMR spectra are
given in Supporting Information. (d) We have not observed the other
possible intermediate (PhCOO)2SiMe2 (7) along with PhCOCl during
distillation under reduced pressure (150-165 °C/0.2-0.3 mm), as it was
(7, CdO, 165.7 ppm, 1,2-DCE, C6D6 as an external standard) prepared
and distilled at a similar temperature under reduced pressure (150-165
°C/0.2-0.3 mm, see Supporting Information). (e) In some of the reactions,
traces of regioisomers could be detected in the crude NMR.
406
Org. Lett., Vol. 9, No. 3, 2007

ventional benzoylation of anisole with PhCOCl (1b) was
performed. InCl3 (5 mol %) gave the product 3a in 89%
yield. In contrast, an equimolar amount of AlCl3 was required
to obtain a high yield of 3a (Scheme 1). This was because
of the strong oxophilicity that disturbed the dissociation of
AlCl3 from produced ketone. The above results strongly
encouraged us to envision the InX3-mediated direct acylation
of aromatic ethers using carboxylic acids.
Table 2. Friedel-Crafts Acylation Using Carboxylic Acidsa
Scheme 2
At first, we selected the reaction of 5-phenylvaleric acid
(1c) with anisole for optimization of the reaction conditions
(Table 1). We screened the reactions using InX3 under
Table 1. Optimization of the Reaction Conditions
a 30 mol %. b Solvent ) EtOAc or MeCN. c Solvent ) toluene. d Solvent
) THF or 1,4-dioxane. e Et3SiH was used instead of HSiMe2Cl. f (EtO)3SiH
was used instead of HSiMe2Cl. g Ph3SiH was used instead of HSiMe2Cl.
h HSi(iPr)2Cl was used instead of HSiMe2Cl.
a Reaction conditions: 2a-j (1.5-2 mmol), acid (1 mmol), HSiMe2Cl
(1.2 mmol), and InCl3 (30 mol %) in ClCH2CH2Cl (2-3 mL) were used;
1 h at rt, then heated at 80 °C for 4 h. b Yields in parentheses correspond
to the reactions in which InBr3 was used instead of InCl3. c No solvent was
used; reaction was carried out in neat condition. d In the case of 1j, 6 mL
of solvent was used.
various conditions to afford the product 3b. Solvents having
strong coordination ability such as THF and 1,4-dioxane gave
no products. MeCN and EtOAc gave poor results. Nonpolar
solvent such as toluene also afforded the product 3b in
moderate yield, and competitive acylation of toluene was
not detected. We successfully optimized the conditions
whereupon InCl3 or InBr3 (30 mol %) in ClCH2CH2Cl serves
as the best system. Under similar conditions, other traditional
and water-tolerant Lewis acids such as AlCl3, BiCl3, and Sc-
(OTf)3 did not afford the product 3b. Using Et3SiH or
(EtO)3SiH instead of HSiMe2Cl did not promote the reaction,
and recovery of the acid was noted even though evolution
of H2 gas was observed. However, HSi(iPr)2Cl gave the
product 3b like HSiMe2Cl. In all runs, the competitive
intramolecular acylation product 3b′ from 1c was not
observed.
and 2-phenylbutyric acid (1e) reacted with various phenyl
ethers to give the corresponding ketones in good yields.
Competitive over-reactions or intramolecular Friedel-Crafts
acylation at the terminal phenyl moieties was not observed
(entries 1-9). Comparatively higher yields were obtained
using InBr3 instead of InCl3. Employing the ω-halo car-
boxylic acids 1f, 1g, and 1h, the chemoselective acylation
of aromatic ethers was observed. However, competitive
Friedel-Crafts alkylation of aromatic ethers was not detected
(entries 10-14), although this process would be readily
promoted by a catalytic amount of Lewis acid. Unfunction-
alized aliphatic/aromatic carboxylic acids (1i-1m and 1a)
were also reacted to furnish the corresponding ketones
(entries 15-22). Interestingly, the reactions were also carried
out without any solvent to afford acylation products (e.g.,
entries 15 and 16).
The generality of this reaction was tested with a variety
of functionalized carboxylic acids and aromatic ethers.
Interestingly, in all cases, the regioselective carbonylation
took place at the para position of aromatic ethers (Table
2).9e 5-Phenylvaleric acid (1c), 3-phenylpropionic acid (1d),
Though rare reports are available on Friedel-Crafts
acylations using acid chlorides having a free hydroxyl
moiety,10 we believed that InX3 would promote the Friedel-
Crafts acylations of aromatic ethers with hydroxyl carboxylic
Org. Lett., Vol. 9, No. 3, 2007
407

acids because of its mildness and moisture tolerance. The
reaction of 4-hydroxybenzoic acid (1n) with 2d gave the
product 4a in 67% yield (Table 3). Other examples of
Scheme 4
Table 3. Friedel-Crafts Reaction of Hydroxyl Carboxylic
Acida
a Conditions: 2a-d,f (1.5 mmol), 1n,o (1 mmol), HSiMe2Cl (2.4 mmol),
and InCl3 (50 mol %) in ClCH2CH2Cl (6 mL) were used; 1.5-2 h at rt,
then heated at 80 °C for 4-5 h. b Yield in the parentheses corresponds to
the reactions in which InBr3 was used instead of InCl3.
PhCOOSiMe2Cl,4h thereby making the silicon center more
electropositive. Apparently, this interaction might be impor-
tant for mediating the dehydrogenative interaction to give
the transient species (PhCOOSiMe2Cl) and the successive
Friedel-Crafts acylation,4i because Et3SiH or (EtO)3SiH were
ineffective in the present case. Further, it could be plausibly
proposed that the major transient silyl ester PhCOOSi(Cl)-
Me2 itself is the predominant acylating agent.11 This proposal
could be supported by an experiment in which the treatment
of silyl ester (PhCOO)2SiMe2 (7,9d 0.8 mmol) with excess
amounts of reagents (anisole (2 mmol) and InCl3 (0.4 mmol))
gave the product 3a, in very low yield (38%). Further, in
this stage, perhaps we cannot ignore PhCOCl as the minor
intermediate in the present system (though its formation from
PhCOOSi(Cl)Me2 is very low at high temperature, Figure
1).
acylation of aromatic ethers using 1n or 3-(4-hydroxyphen-
yl)-propionic acid (1o) were also developed. These results
allowed further expansion of the capability of the Friedel-
Crafts acylation directly from free hydroxyl-substituted
carboxylic acid.
Next, we checked the scope and limitations of this
protocol. At this stage, a limitation of this reaction is the
acylation of toluene was not effective. However, 4-phenyl-
butyric acid (1p) successfully afforded the intramolecular
Friedel-Crafts acylation product 6a (67% Scheme 3) without
In conclusion, we have discovered a chemoselective
dehydrogenative interaction of ClMe2SiH with the carboxylic
acid group in the presence of InX3. In view of exploiting
the process, chemo- and regioselective direct Friedel-Crafts
acylation of aromatic ethers from functionalized carboxylic
acids was established. Further work and applications are
under investigation.
Scheme 3
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan.
Thanks are due to Mr. H. Moriguchi, Faculty of Engineering,
for assistance in obtaining MS spectra.
the assitance of alkoxy moiety (OR). Similarly, 4-(4-
methoxyphenyl)-butyric acid (1q) also afforded the product
6b (52%).
On the basis of 13C NMR studies on the interaction of
PhCOOH with ClMe2SiH and the observed results, the
mechanism of direct Friedel-Crafts acylation could be
proposed via in situ generated transient species (PhCOOSi-
(Cl)Me2, Scheme 4). It might be considered that there is an
interaction of InCl3 with the chlorine atom of HSiMe2Cl/
Supporting Information Available: Experimental pro-
cedures, spectral data of products, 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL062723E
(10) (a) Martin, R.; Massy, F. Monatsh. Chem. 1981, 112, 1155. (b)
Belen’kii, L. I.; Gromova, G. P.; Kolotaev, A. V.; Luiksaar, S. I. ARKIVOC
2001, 9, 49. (c) Jeon, K. O.; Jun, J. H.; Yu, J. S.; Lee, C. K. J. Heterocycl.
Chem. 2003, 40, 763.
(11) We sincerely thank the referees for their kind suggestions to improve
the proposed mechanism.
408
Org. Lett., Vol. 9, No. 3, 2007