Rhenium-catalyzed regioselective alkylation of phenols

Article abstract of DOI:10.1021/ja904360k

(Chemical Equation Presented) Treatment of phenol derivatives with terminal alkenes in the presence of a catalytic amount of a rhenium complex, Re ₂(CO)₁₀, gave monoalkylated phenol derivatives in good to excellent yields. This reaction proceeds at the ortho- or para-position of phenols regioselectively.

Full text of DOI:10.1021/ja904360k

Published on Web 07/01/2009
Rhenium-Catalyzed Regioselective Alkylation of Phenols
Yoichiro Kuninobu,* Takashi Matsuki, and Kazuhiko Takai*
DiVision of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama UniVersity,
Tsushima, Kita-ku, Okayama 700-8530, Japan
Received May 29, 2009; E-mail: kuninobu@cc.okayama-u.ac.jp; ktakai@cc.okayama-u.ac.jp
Table 1. Reactions between Phenols 1 and 1-Octene (2a)a
Selective introduction of substituent(s) into aromatic rings offers a
direct and efficient method to synthesize substituted-aromatic com-
pounds. Well known examples of such a transformation are the
Friedel-Crafts reaction1 and the hydroarylation of olefins.2 However,
in both cases, it is usually difficult to introduce only one alkyl group
into the aromatic rings regioselectively.
Phenols are one of the most important aromatic compounds.
Although several examples of ortho-alkylation of phenols and related
compounds have been reported,3 a number of problems remain: (1) a
mixture of mono- and multialkylated products is formed;4 (2) in some
cases, a stoichiometric amount of a metal salt is necessary to promote
the reaction;5 and (3) there are limitations in the types of substrates
that can be used.4,6 During an investigation of the catalytic activities
of rhenium complexes,7,8 we found that monoalkylation of phenols
proceeded only at the ortho- or para-position of the hydroxyl group
selectively using Re2(CO)10 as a catalyst.
By heating 4-methoxyphenol (1a) in a 1-octene (2a) solvent in the
presence of a catalytic amount of a rhenium complex, Re2(CO)10, the
ortho-alkylated phenol derivative 3a was obtained in 97% yield (eq
1). In this reaction, only the monoalkylated product 3a was yielded as
a single product despite using an excess amount of 1-octene (2a). This
result is interesting because a mixture of mono- and multialkylated
products is usually formed by the Friedel-Crafts reaction.
a 2a (1.5 equiv), 1 (2.0 M). b Isolated yield. c 1 (4.0 M). d The ratio
between 3g and 3g′ is given in square brackets. e The ratio between 3h
and 3h′ is given in square brackets. f 2a (1.0 equiv). g The ratio between
3i and 3i′ is given in square brackets. h 2a (4.5 equiv).
The reaction also proceeded quantitatively in toluene using 1.5 equiv
of 1-octene (2a).9 Although the rhenium complex ReBr(CO)5 also
showed catalytic activities, the yield of the alkylated phenol 3a was
only 23%. Rhenium complexes, [ReBr(CO)3(thf)]2 and ReCl3, gave a
mixture of polyalkylated products.10
yield (entry 1). Olefins bearing a functional group could also be
employed as substrates (entries 2-4). Ether and ester groups did not
inhibit the reaction, and phenols 3k and 3l were obtained in 87% and
83% yields, respectively (entries 2 and 3).14 By using an olefin with
an olefin moiety at the internal position, 2e, the reaction proceeded
only at the terminal olefin position, and ortho-alkylated phenol 3m
was produced in 70% yield (entry 4). In this reaction, the internal olefin
moiety remained unchanged during the reaction. The internal alkenes,
cis-cyclooctene (2f) and norbornene (2g), also reacted with phenol 1a
and generated ortho-alkylated phenol 3n and a mixture of ortho-
alkylated phenols 3o and 3o′ in 93% and 91% yields, respectively
(entries 5 and 6). By using styrene, a mixture of mono- and di-, and
ortho- and meta-alkylated phenols (4 isomers) was produced in
quantitative yield.15,16
In contrast to the terminal alkenes, the regioselectivity of the
substitution changed markedly when gem-disubstituted alkenes were
employed. When gem-disubstituted olefins 2h and 2i were used, no
ortho-monoalkylated phenols were formed, and instead, para-alkylated
phenols 3p and 3q, and ortho- and para-disubstituted phenols 3p′ and
3q′ were obtained in 89% and 86%, and 4% and 8% yields,
respectively (eq 2).
Next, we investigated the scope and limitations of phenol derivatives
(Table 1). Treatment of 4-methylphenol (1b) with 1-octene (2a) in
toluene at 135 °C gave ortho-alkylated phenol 3b in 59% yield;
however, the yield of 3b increased at 150 °C, and 3b was obtained in
82% yield (entry 1). Phenol (1c) produced ortho-alkylated phenol 3c
in 76% yield (entry 2).11,12 ortho-Alkylated phenols 3d, 3e, and 3f
were obtained using 4-fluoro-, 4-chloro-, and 4-bromo-phenols (1d,
1e, and 1f) without losing the halogen atom (entries 3-5). When
3-methoxyphenol (1g) was employed, the alkylation reaction did not
afford a single product, and a mixture of 3g and 3g′ was formed (entry
6). Mono- and dialkylated catechols 3h and 3h′ were yielded using
catechol (1h) (entry 7). By using hydroquinone (1i) a mixture of mono-
and dialkylated products 3i and 3i′ was produced in 54% yield (entry
8).13 The selectivity of 3i′ was improved dramatically by increasing
the amount of olefin 2a (entry 9).
Next, we investigated several alkenes (Table 2). Secondary alkyl-
substituted olefin 2b afforded an ortho-alkylated phenol 3j in 97%
9
9914 J. AM. CHEM. SOC. 2009, 131, 9914–9915
10.1021/ja904360k CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reactions between Phenol 1a and Several Olefins 2a
We hope that this reaction will become a useful method to synthesize
substituted phenols.
Acknowledgment. This work was partially supported by the
Ministry of Education, Culture, Sports, Science, and Technology
of Japan.
Supporting Information Available: General experimental procedure
and characterization data for phenol derivatives. This material is
available free of charge via the Internet at http://pubs.acs.org.
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a 2 (1.5 equiv). b Isolated yield. c The ratio between 3o and 3o′.
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(7) We have recently reported on rhenium-catalyzed transformations. See: (a)
Kuninobu, Y.; Kawata, A.; Takai, K. J. Am. Chem. Soc. 2005, 127, 13498.
(b) Kuninobu, Y.; Kawata, A.; Takai, K. Org. Lett. 2005, 7, 4823. (c)
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(d) Kuninobu, Y.; Nishina, Y.; Nakagawa, C.; Takai, K. J. Am. Chem.
Soc. 2006, 128, 12376. (e) Kuninobu, Y.; Inoue, Y.; Takai, K. Chem. Lett.
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(h) Kuninobu, Y.; Ueda, H.; Takai, K. Chem. Lett. 2008, 37, 878. (i)
Kuninobu, Y.; Nishina, Y.; Matsuki, T.; Takai, K. J. Am. Chem. Soc. 2008,
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(8) Other groups have also reported on rhenium-catalyzed reactions. See: (a)
Ku¨hn, F. E.; Scherbaum, A.; Herrmann, W. A. J. Organomet. Chem. 2004,
689, 4149. (b) Luzung, M. R.; Toste, F. D. J. Am. Chem. Soc. 2003, 125,
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By treatment of phenol (1c) with diene having a methyl group at
the ꢀ-position of the diene moiety, 4a, the reaction occurred at the
δ-position of diene 4a, and 5 was obtained in 87% yield (eq 3).
(9) When this reaction was carried out using 1.0 equiv of 1-octene (2a) and
octane as a solvent, 3a was formed in 85% yield. Friedel-Crafts reactions
are usually performed in halogenated solvents. From this viewpoint, the
reaction here is environmentally friendly.
(10) The product 3a was not formed by a manganese complex, Mn2(CO)10. Other
transition metal carbonyl complexes, such as Cr(CO)6, W(CO)6, Fe2(CO)9,
Fe3(CO)12, Ru3(CO)12, and Ir4(CO)12, did not give alkylated phenol 3a.
Iron(III) chloride, FeCl3, aluminum chloride, AlCl3, and trifluoroborane,
BF3 · OEt2, which are usually used in Friedel-Crafts reactions, were
employed as catalysts; however, FeCl3 did not produce alkylated products,
and AlCl3 and BF3 · OEt2 afforded a mixture of 3a (AlCl3 44%; BF3 · OEt2
11%) and polyalkylated isomers.
(11) Anisol, 1,2-dimethoxybenzene, and 1,2,3-trimethoxybenzene did not provide
an alkylated product. This result shows that a hydroxyl group of phenols
is indispensable to promote the reaction.
(12) Investigation of several rhenium complexes: ReBr(CO)5 32%; [ReBr-
(CO)3(thf)]2 31%; ReCl3 32%; ReCl5 12%; ReCl3(PPh3)2(NCMe) 0%;
ReCl3O(PPh3)2 0%; ReIO2(PPh3)2 3%. In each cases, polyalkylation of
phenol (1c) also occurred.
On the other hand, by the reaction of phenol (1c) with diene 4b in
the presence of a rhenium catalyst, Re2(CO)10, an annulation reaction
proceeded and indane 6 was obtained in 58% yield (eq 4). This
reactivity is quite different from the previous reports in which
dihydrobenzofuran and/or dihydrobenzopyran derivatives are pro-
duced.17
(13) 2,6-Dimethylphenol, 2-methylphenol, 4-methoxyaniline, 2-hydroxypyridine,
3-hydroxypyridine, and 4-hydroxypyridine did not promote the reaction.
4-Trifluoromethylphenol and 4-methoxythiophenol produced complex
mixtures.
(14) Investigation of several acid catalysts in the reaction between phenol 1a
and olefin bearing an ester moiety, 2d: AlCl3 0%; Al(OPh)3 0%; BF3 ·OEt2
10%; para-toluenesulfonic acid 10%. In the case of AlCl3, the reaction
was inhibited by the ester group. See: ref 10.
(15) The reaction did not proceed using 3,3-dimethyl-1-butene, 4-phenyl-1-buten-
3-yne, trans-5-decene, and 2-ethylhexyl acrylate.
In summary, we have succeeded in regioselective alkylation of
phenols in good to excellent yields. In this reaction, monoalkylated
phenols are obtained selectively, offering advantages over the standard
Friedel-Crafts alkylation, in which a complex mixture of ortho- and
para-substituted, and mono- and multisubstituted phenols is usually
formed. The details of the reaction mechanism is under investigation.
(16) There are several reports on ortho-selective alkylation of phenols with
styrene. See: (a) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. AdV.
Synth. Catal. 2006, 348, 1033. (b) Chu, C.-M.; Huang, W.-J.; Liu, J.-T.;
Yao, C.-F. Tetrahedron Lett. 2007, 48, 6881.
(17) (a) Nguyen, R.-V.; Yao, X.; Li, C.-J. Org. Lett. 2006, 8, 2397. (b) Youn,
S. W.; Eom, J. I. J. Org. Chem. 2006, 71, 6705.
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