Gold-catalyzed three-component coupling: Oxidative oxyarylation of alkenes

Article abstract of DOI:10.1021/ja1034123

The three-component coupling of terminal alkenes with arylboronic acids and oxygen nucleophiles is described. The reaction employs a binuclear gold(I) bromide as a catalyst and Selectfluor reagent as the stoichiometric oxidant. Alcohols, carboxylic acids, and water can be employed as oxygen nucleophiles, thus providing an efficient entry into β-aryl ethers, esters, and alcohols from alkenes.

Full text of DOI:10.1021/ja1034123

Published on Web 06/17/2010
Gold-Catalyzed Three-Component Coupling: Oxidative Oxyarylation of
Alkenes
Asa D. Melhado, William E. Brenzovich, Jr., Aaron D. Lackner, and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received April 21, 2010; E-mail: fdtoste@berkeley.edu
The past decade has seen rapid expansion in the area of
homogeneous gold catalysis. The majority of reported methods rely
on the π-acidic nature of cationic gold species to activate π-bonds
toward nucleophilic attack.1 On the other hand, the two electron
oxidation/reduction cycles typical of other late transition metal
catalysts are not commonly encountered in gold catalysis.1e,2
Recently, a few reports of transformations best explained by Au(I)/
(III) redox cycles, including Au-catalyzed oxidative intramolecular
heteroarylation reactions, have appeared.3 Different modes of such
heteroarylation reactions are accessible by combining two or all
three reactant functional groups into a single substrate.4 Notably,
examples of the fully intermolecular, three-component coupling
variant have not previously been reported.5,6 Herein we disclose a
protocol for the three-component gold-catalyzed oxidative oxyaryl-
ation of alkenes; alcohols, carboxylic acids, and even water are
viable nucleophiles in this context.
Substituting carboxylic acids in place of alcohols afforded the
corresponding esters, albeit in slightly lower yield (entries 9-12).
Table 1. Alkoxy- and Acyloxyarylation with Various Nucleophilesa
a 100 µmol of alkene, 0.1 M in 9:1 MeCN:ROH at 50 °C for 14 h; 2
equiv of PhB(OH)2, 2 equiv of Selectfluor reagent (Air Products and
Chemicals Inc.). The catalyst and PhB(OH)2 were added in two portions
at t ) 0 and 2 h. b Yield determined by 1H NMR versus an internal
standard (nitrobenzene). c 10 equiv of ROH used.
The arylboronic acid component of the reaction was also varied
with similar success. The gold-catalyzed coupling of alkene 6,
methanol, and various arylboronic acids gave the expected methyl
ethers in good yields (Table 2). The reaction performed well with
alkyl-, halo-, carboxymethyl-, and formyl-substituted arylboronic
acids. Moreover, ortho- (eq 3), meta- (entries 3 and 6), and para-
substituted (entries 1, 2, 4, and 5) arylboronic acids were tolerated
in the methoxyarylation reaction.
We initially observed this mode of reactivity while studying the
related intramolecular aminoarylation.3b In an attempt to improve
the solubility of the arylboronic acid, methanol was used as a co-
solvent; however, the expected pyrrolidine 3a was not observed.
Instead, the alkoxyarylation product 2a was isolated in 38% yield
(eq 1). The yield of 2a could be improved to 72% by increasing
the temperature and employing 2 equiv of phenylboronic acid.7
While previously reported gold-catalyzed additions of oxygen
nucleophiles to alkenes have required temperatures greater than 85
°C,8 the oxidative alkoxyarylation proceeds efficiently at 50 °C.
Under these conditions, various alkenylamines (1b and 4a,b)
participated in the methoxyarylation reaction to afford the adducts
of a three-component coupling in good yields (eq 2). Moreover,
gold-catalyzed reaction of 4b shows excellent chemoselectivity,
leaving the more electron-deficient allylic amine unreacted.
In order to probe the scope of the reaction, 5-phthalimidopentene
(6) was subjected to the optimized conditions for coupling with
various alcohols and phenylboronic acid (Table 1). The expected
ethers were obtained in high yield when using several primary
alcohols (entries 1, 2, 4, and 6) and secondary alcohols (entries 3,
7, and 8). While neopentyl ether 10 was formed in 91% yield (entry
4), gold-catalyzed reaction with the more sterically encumbered
tert-butyl alcohol gave only 33% of tert-butyl ether 11 (entry 5).9
a
Table 2. Methoxyarylation with Various ArB(OH)2
entry
R
product yield (%)
entry
R
product yield (%)
1
2
3
4-Me
4-Br
3-F
19
20
21
88
90
79
4
5
6
4-MeO2C
4-H(CO)
3,5-bis-CF3
22
23
24
83
82
77
a 100 µmol of alkene, 0.1 M in 9:1 MeCN:MeOH at 50 °C for 14 h;
2 equiv of ArB(OH2), 2 equiv of Selectfluor reagent. The catalyst and
ArB(OH)2 were added in two portions at t ) 0 and 2 h.
The nitrogen-containing functional groups in 1a,b, 4a,b, and 6
are not required for successful oxyarylation. Simple alkenes lacking
these functionalities proved to be suitable substrates for alkoxy-
and acyloxyarylation under our optimized conditions. The expected
ethers were obtained in good yields when alkenes such as 1-octene
and 1-bromo-2-(3-buten-1-yl)benzene were reacted with several
combinations of alcohols and arylboronic acids (Table 3). Acetate
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10.1021/ja1034123  2010 American Chemical Society
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C O M M U N I C A T I O N S
esters were isolated in attenuated but synthetically useful yields
from simple alkenes when using acetic acid as the nucleophile
(entries 2 and 7).
groups, including ether (entry 2), ester (entry 3), amide (entry 1),
cyano (entry 2), nitro (entry 3), and aryl halide (entries 5-7), were
well-tolerated.
The ability to use either alcohols or water as nucleophiles in the
gold-catalyzed three-component coupling provides access to a
greater diversity of products. Moreover, the hydroxyarylation
reaction offers the opportunity to form an additional C-O bond to
the resulting alcohol. For example, methoxyarylation of 6 with
boronic acid 40 furnished methyl ether 41 in 85% yield. Using
water as a nucleophile, 42 was formed in 87% yield from gold-
catalyzed hydroxyarylation, followed by in situ lactone formation
of the resulting alcohol (eq 3).
Table 3. Alkoxy- and Acyloxyarylation of Simple Alkenesa
a 100 µmol of alkene, 0.1 M in 9:1 MeCN:R1OH at 50 °C for 14 h; 2
equiv of ArB(OH2), 2 equiv of Selectfluor reagent. The catalyst and
ArB(OH)2 were added in two portions at t ) 0 and 2 h. b Only 5 equiv
of R1OH used, 0.1 M in MeCN.
At present, we proffer a catalytic cycle for the gold-catalyzed
oxyarylation of alkenes that is analogous to the mechanism proposed
for the related intramolecular aminoarylation reaction.3b Initial
oxidation of the gold(I) bromide is thought to provide a cationic
gold(III) species capable of activating the alkene toward nucleo-
philic attack. Oxyauration of the π-bond is then followed by C-C
bond formation, without prior transmetalation of the aryl group from
boron to gold (Figure 1).
Using water as a nucleophile would allow for the formation of
alcohols directly via hydroxyarylation, circumventing the require-
ment for protective groups for installation of the alcohol functional-
ity.10 We were pleased to find that simply replacing the alcohol in
our protocol with water cleanly effected the formation of the desired
hydroxyarylation products. A variety of terminal alkenes and
arylboronic acids were subjected to these conditions, furnishing the
expected products in good yield (Table 4). Various functional
Table 4. Scope of Hydroxyarylation Reactiona
Figure 1. Proposed catalytic cycle for alkene hydroxyarylation.
Reaction of monodeuterated alkene d1-6 stereospecifically pro-
duced d1-42 with stereochemistry consistent with initial syn-
hydroxyauration followed by invertive C-C bond formation. The
stereochemical course of the hydroxyarylation is consistent with
our earlier observations from the gold-catalyzed intramolecular
aminoarylation (eq 4).3b
a At 0.1 M alkene in MeCN, 10 equiv of H2O, catalyst (2.5 mol %/
addition), and ArB(OH)2 (1 equiv/addition) were added in two portions
each, at t ) 0 and 1 h. b Isolated as a 1.2:1 mixture of diastereomers.
c Three portions of catalyst (2.5 mol %/addition) and ArB(OH)2 (1 equiv/
addition). d Using (4-CF3C6H4)3PAuBr as catalyst, two portions of 5 mol %
each.
In conclusion, we have demonstrated the gold-catalyzed three-
component coupling reaction of alkenes, arylboronic acids, and
several types of oxygen nucleophiles, including alcohols, carboxylic
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C O M M U N I C A T I O N S
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acids, and water. It is notable that the latter effectively participates
as a nucleophile in these reactions, especially given difficulties
associated with transition metal-catalyzed hydration of alkenes.11
This method represents the first fully intermolecular alkene het-
eroarylation reaction and stands as one of the few examples of gold-
catalyzed multicomponent couplings.12
Acknowledgment. We gratefully acknowledge NIHGMS (RO1
GM073932), Amgen, and Novartis for financial support and thank
Johnson Matthey for a gift of AuCl3.
(5) For a Pd-catalyzed intermolecular aminofluorination of styrenes, see: Qui,
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Chem. ReV. 2009, 109, 4439. (b) Domling, A. Chem. ReV. 2006, 106, 17.
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(9) Readily oxidized (benzyl, allyl) alcohols do not participate in the reaction.
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A. S.; Widenhoefer, R. A. Tetrahedron 2009, 65, 1794.
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Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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