Dehydrative C-H alkylation and alkenylation of phenols with alcohols: Expedient synthesis for substituted phenols and benzofurans

Article abstract of DOI:10.1021/ja302710v

A well-defined cationic Ru-H complex catalyzes the dehydrative C-H alkylation reaction of phenols with alcohols to form ortho-substituted phenol products. Benzofuran derivatives are efficiently synthesized from the dehydrative C-H alkenylation and annulation reaction of phenols with 1,2-diols. The catalytic C-H coupling method employs cheaply available phenols and alcohols, exhibits a broad substrate scope, tolerates carbonyl and amine functional groups, and liberates water as the only byproduct.

Full text of DOI:10.1021/ja302710v

Communication
pubs.acs.org/JACS
Dehydrative C−H Alkylation and Alkenylation of Phenols with
Alcohols: Expedient Synthesis for Substituted Phenols and
Benzofurans
Dong-Hwan Lee, Ki-Hyeok Kwon, and Chae S. Yi*
Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53201-1881, United States
S
* Supporting Information
complex [(C6H6)(PCy3)(CO)RuH]+BF4 (1).9 The catalytic
−
ABSTRACT: A well-defined cationic Ru−H complex
catalyzes the dehydrative C−H alkylation reaction of
phenols with alcohols to form ortho-substituted phenol
products. Benzofuran derivatives are efficiently synthesized
from the dehydrative C−H alkenylation and annulation
reaction of phenols with 1,2-diols. The catalytic C−H
coupling method employs cheaply available phenols and
alcohols, exhibits a broad substrate scope, tolerates
carbonyl and amine functional groups, and liberates
water as the only byproduct.
C−H alkylation reaction utilizes cheaply available alcohols as
the alkylating agent and tolerates a variety of oxygen and
nitrogen functional groups in forming elaborated alkene
products. We have also devised a number of catalytic oxidative
C−H coupling reactions of arenes and alkenes by employing
alkenes as both the substrate and the hydrogen acceptor.10
Here we report a highly regioselective catalytic dehydrative C−
H alkylation and alkenylation of phenols with alcohols to form
substituted phenol and benzofuran products. The “green”
features of the catalytic coupling method are that it employs
readily available phenols and alcohols, tolerates a number of
common heteroatom functional groups, uses cheaply available
alkenes as the dehydrogenation agent, and generates water as
the only byproduct in forming these coupling products.
ransition-metal-catalyzed oxidative C−H coupling reac-
T
tions constitute an expedient C−C bond formation
protocol for arenes and related hydrocarbon substrates.1
Recent seminal reports on the carbonyl-directed oxidative C−
H arylation and alkenylation reactions have led to the
development of a powerful synthetic methodology for
producing both bis-arenes and vinylarenes.2 A variety of
nitrogen atom directing groups have also been successfully
used for the oxidative C−C, C−O, and C−Si bond forming
reactions of arenes.3 Very recently, remarkably selective
catalytic oxygenation and silylation reactions on aliphatic sp3-
C−H bonds have been achieved by using the heteroatom
directing strategy.4 The chelate-assisted catalytic oxidative C−H
coupling methods have been utilized for intramolecular
annulation of arene compounds in forming benzofurans5 as
well as for lactone and lactam products,6 and for the synthesis
of biologically active complex organic molecules.7 While the
oxidative C−H coupling methods allow the introduction of
vinyl and aryl groups directly to unreactive hydrocarbon
substrates, a relatively limited substrate scope and the
requirement of stoichiometric metal oxidants and chelate
directing groups still remain as major drawbacks in applying
these methods to large-scale organic synthesis. In this regard,
recent reports on the catalytic C−H oxidative coupling
reactions under aerobic conditions represent a major advance-
ment toward the development of practical catalytic C−C bond
formation methods.8
We initially compared the catalytic activity of 1 with selected
ruthenium and common acid catalysts for the coupling reaction
of 3-methoxyphenol with cyclohexanol (eq 1). Among the
screened catalysts, complex 1 was found to exhibit distinctively
high activity in forming the coupling product 2a along with a
trace amount of the alkenylation product 3a, as analyzed by
both GC and NMR spectroscopic methods (Table S1,
Supporting Information (SI)). Addition of a substoichiometric
amount of simple alkene (10 mol %) was found to promote the
coupling reaction, and cyclopentene was most effective among
several screened olefins. Protected phenols are typically used
for the C−H coupling reactions to avoid side reactions, as
exemplified by a recent report on the C−H insertion of silyl-
protected phenols,11 but in our case, complex 1 effectively
promotes the alkylation reaction without using any protecting
groups on either phenol or alcohol substrates.
The substrate scope of the C−H alkylation reaction was
explored by using catalyst 1 (Table 1). In general, both primary
and secondary alcohols were found to react smoothly with 3-
methoxyphenol to give the alkylation products 2a−2i at a
relatively low catalyst loading (entries 1−9). Only linear C−H
alkylation products were formed with primary alcohols without
giving any branched alkylation products. Phenols with a meta-
Alcohols have been rarely employed as the substrate for the
catalytic C−H coupling reactions because of their tendency for
undergoing energetically more favorable alkoxylation and
oxidation reactions over the respective C−O bond cleavage
reaction. We recently discovered an exceptionally selective
dehydrative C−H alkylation reaction of alkenes with alcohols
that is catalyzed by a well-defined cationic ruthenium hydride
Received: March 20, 2012
Published: April 11, 2012
© 2012 American Chemical Society
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°C yielded the dehydrogenative coupling product 3a−3c
exclusively within 8 h of the reaction time (eq 2). The
Table 1. Dehydrative ortho-C−H Alkylation of Phenols with
a
Alcohols
formation of 3 can be readily rationalized by invoking a chelate-
directed ortho-C−H alkylation followed by the dehydrogen-
ation steps, where cyclopentene is acting as the dehydrogen-
ation agent.12,14 The catalytic method achieves the regiose-
lective C−H alkenylation without using any expensive and
often toxic metal oxidants.
We have been able to extend the synthetic utility of the
dehydrative C−H alkenylation method to form benzofuran
derivatives. Thus, the treatment of phenol with 1,2-diols under
similar conditions as specified in eq 2 cleanly led to the desired
benzofuran products 4 (Table 2). Both substituted phenols and
Table 2. Dehydrative ortho-C−H Alkenylation and
a
Cyclization of Phenols with Diols
a
Reaction conditions: phenol (1.0 mmol), alcohol (1.2 mmol),
cyclopentene (0.1 mmol), toluene (2 mL), 1 (1 mol %), 100 °C.
electron-donating group were found to promote the coupling
reaction, but 3-chlorophenol and phenol also yielded the
coupling products 2j−2l with a slightly longer reaction time
(entries 10−12). An optically pure chiral alcohol (R)-1-
phenylethanol gave the racemic product ( )-2g (entry 7),
while the reaction with (R)-2-phenyl-1-propanol afforded the
coupling product (R)-2m without any racemization (entry 13).
The alkylation of both 1- and 2-naphthols with alcohols led to
the regioselective formation of the coupling products 2n−2q
(entries 14−17). The reaction of both cyclohexenone and α-
tetralone with 1-phenylethanol yielded the arene coupling
product 2k and 2p, apparently resulted from the dehydrogen-
ation of the ketone substrate (entries 18 and 19).12 Both ortho-
and para-substituted phenols smoothly reacted with 1-phenyl-
ethanol to afford the alkylation products 2r−2t (entries 20−
22). In all cases, ortho-selective C−H coupling products are
obtained predictably without giving any 1:2 coupling products
or other byproducts.
a
Reaction conditions: phenol (1.0 mmol), diol (1.2 mmol), cyclo-
pentene (3 mmol), toluene (2 mL), 1 (1 mol %), 100 °C, 8−12 h.
naphthols readily reacted with 1,2-diols to generate benzofuran
products with a relatively low catalyst loading (1 mol %).
Exclusive formation of the α-substituted benzofuran products
resulted from the regioselective addition of the linear 1,2-diols
to the ortho-arene position (4h−4j, 4l, 4o, 4q). 1-Naphthol
with 1,2-diols exclusively formed the corresponding naph-
thylfuran products 4n and 4o, while the analogous reaction
with a 1,3-diol led to the hydropyran product 4p. Both 5-
hydroxyindole and 2-hydroxycarbazole with 1,2-cyclohexane-
diol led to the corresponding furan products 4r and 4s,
respectively, tolerating an amine functional group. The catalytic
method constitutes an effective intermolecular synthetic method
for α-substituted benzofurans, as most catalytic methods rely on
the intramolecular couplings to synthesize substituted benzofur-
an compounds.5,15
The ortho-alkenylated phenols are a valuable class of
synthetic precursor for a number of biologically active core
structures.13 We have been able to directly form the ortho-C−H
alkenylation products 3 from the tandem alkylation and
dehydrogenation protocol. Thus, the treatment of 3-methox-
yphenol (1.0 mmol) with a cycloalkanol (1.2 mmol) and excess
cyclopentene (3 equiv) in the presence of 1 (1 mol %) at 100
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Communication
To further illustrate the synthetic versatility of the catalytic
coupling method, we next surveyed the C−H alkylation and
alkenylation reactions for a number of functionalized phenol
and alcohol substrates of biological importance (Table 3). The
The following kinetic experiments were performed to gain
mechanistic insights into the catalytic C−H alkylation reaction.
To examine the H/D exchange pattern on the phenol substrate,
the reaction of phenol-d6 (1.0 mmol) with 1-phenylethanol (1.2
mmol) in the presence of 1 (3 mol %) and cyclopentene (10
mol %) in toluene at 100 °C was stopped after 1 h (eq 3). The
Table 3. Dehydrative C−H Alkylation and Alkenylation of
a
Biologically Active Phenols with Alcohols and Diols
selective H/D exchange pattern on the ortho-arene positions of
both the coupling product 2k (57% D) and the phenol
substrate (36% D) was observed at 27% product conversion
(Figure S1, SI). Such an extensive H/D exchange pattern on
the phenol substrate is consistent with a rapid and reversible
ortho-C−H bond activation step. In support of this notion, a
negligible isotope effect of kH/kD = 1.1
0.1 was measured
from the reaction of C6H5OH and C6D5OD with 1-phenyl-
ethanol at 100 °C (Figure S2, SI).
To discern the rate-limiting step of the alkylation reaction,
the 12C/13C kinetic isotope effect was measured from the
coupling reaction of 3-methoxyphenol and 1-phenylethanol by
employing Singleton’s NMR technique.17 We observed the
most pronounced carbon isotope effect on the ortho-carbon of
2g when the 13C ratio of the product 2g at 90% conversion was
compared to the ones obtained from three low conversions
[(13C at 90% conversion)/(average of 13C at 10, 16 and 18%
conversion) at C(6) = 1.038] (Table S2, SI). The result is
consistent with the C−C bond formation rate-limiting step for
the alkylation reaction, and is in-line with the carbon isotope
effects observed in other ruthenium-catalyzed C−C bond
formation reactions via C−H activation.18
To probe the electronic influence on the phenol substrate,
we constructed a Hammett plot by comparing the rate of a
series of m-X-C6H4OH with 1-phenylethanol (X = OCH3, CH3,
H, F, Cl). A linear correlation from the relative rate vs
Hammett σp led to a negative ρ value of −1.6 0.2 (Figure S3,
SI). A strong promotional effect by the electron-releasing group
suggests a substantial cationic character on the transition state,
which is promoted by an electrophilic Ru catalyst.
a
General reaction conditions: phenol (1.0 mmol), alcohol (1.2 mmol),
cyclopentene (0.1 mmol for the alkylation; 3.0 mmol for the
alkenylation), solvent (2−3 mL), 1 (1−2 mol %), 100 °C. See SI
for more specific reaction conditions for each product.
alkylation of estrone with 3-methoxybenzyl alcohol led to the
alkylation product 2u in 84% yield. The reaction of 4-
hydroxycoumarin with 4-phenyl-4-hydroxy-2-butanone led to
the warfarin product 2v in a single step. Treatment of 5-
hydroxyindole with (R)-2-phenyl-1-propanol led to the
optically active coupling product (R)-2w, without any
detectable racemization.
Though details are not clear at the present time, we present a
putative mechanism of the C−H alkylation reaction on the
basis of these results (Scheme 1). We propose that the cationic
ortho-metalated Ru species 5 is initially generated from the
ortho-C−H activation of phenol and dehydrogenation steps. As
supporting evidence for the cationic Ru species 5, we have been
able to detect the formation of both cyclopentane and free
benzene molecules from the crude reaction mixture. The
The analogous C−H alkenylation of 2-hydroxycarbazole with
cholesterol led to the clean formation of the oxidative coupling
product 3d, while the C−H alkylation of estrone with
cholesterol formed a 1:1 diastereomeric mixture of the coupling
product 2x. The C−H alkenylation/annulation of 3-methox-
yphenol with an amide-substituted bicyclo[3.2.1]octendiol was
found to occur in a regioselective manner in yielding the
coupling product 4t, while tolerating both amide and carbonyl
functional groups. Highly regioselective formation of the
product 4t is apparently culminated from the alkylation of a
sterically less hindered alcohol to the ortho-phenolic group,
following the same regioselectivity pattern as the linear 1,2-
diols. Cyclic 1,2-diols were predictively attached to estrone,
tyrosine, and hydrophenanthrenol to form the corresponding
benzofuran derivatives, 4u−4w, without affecting any functional
groups. The regioselective addition of 1,2-hexanediol to a
coumarin derivative led to the α-substituted furanocoumarin
compound 4x. Synthetic furanocoumarin derivatives have been
commonly used as photosensitizers for the treatment of
psoriasis.16
Scheme 1. Possible Mechanism for the Dehydrative C−H
Alkylation Reaction of Phenol with an Alcohol
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observed H/D exchange pattern on both the coupling product
and the recovered phenol substrate is consistent with a facile
ortho-C−H activation step. Either an oxidative addition of the
C−O bond followed by the C−C reductive elimination or a σ-
bond metathesis coupling mechanism can explain the formation
of the product 2.19 A few Ru-hydroxo complexes have been
shown to mediate C−H activation reactions,20 and our previous
results from the catalytic C−H alkylation of alkenes with
alcohols are inconsistent with either an SN2 type of displace-
ment or a Friedel−Crafts type electrophilic pathway.9 The
observation of a pronounced carbon isotope effect on the ortho-
arene carbon of the product provides strong support for the C−
C bond formation as the rate-determining step. The subsequent
ortho-C−H activation of phenol and water elimination steps are
envisaged for the regeneration of the ortho-metalated species 5.
The benzofuran formation can similarly be rationalized by
invoking the ortho-alkylation of phenol followed by the
dehydration and dehydrogenation steps.21
In summary, a highly regioselective catalytic C−H alkylation
and alkenylation method of phenols with alcohols has been
developed by using a well-defined ruthenium-hydride catalyst.
The catalytic method employs environmentally benign and
cheaply available phenols and alcohols and exhibits a broad
substrate scope with high chemoselectivity in providing an
expedient synthetic route to a library of substituted phenol and
benzofuran compounds.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and methods, Tables S1 and S2,
Figures S1−S3, and NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
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L.; Saint-Louis, C.; Landry, A.; Vez
Ramaseshan, M.; Beaubien, S.; Benakli, K.; Beauchemin, S.; Dez
́
ina, M.; Ouellet, L.; Wang, Z.;
AUTHOR INFORMATION
Corresponding Author
chae.yi@marquette.edu
■
́
iel, R.;
Peeters, T.; Fraser, G. L. J. Med. Chem. 2006, 49, 7190. (c) Pathak, T.
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Org. Chem. 2005, 70, 10292. (b) Nakamura, I.; Mizushima, Y.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science of Foundation
(CHE-1011891) is gratefully acknowledged. We thank Mr.
Mohamed El Mansy and Dr. William A. Donaldson (Marquette
University) for providing diol substrates.
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