Communications
DOI: 10.1002/anie.201100293
Nitrogen Heterocycles
À
Combining Gold(I)/Gold(III) Catalysis and C H Functionalization: A
Formal Intramolecular [3+2] Annulation towards Tricyclic Indolines
and Mechanistic Studies**
Guozhu Zhang, Yingdong Luo, Yanzhao Wang, and Liming Zhang*
Homogeneous gold catalysis involving gold(I)/gold(III) cata-
lytic cycles[1] has recently attracted much attention and is
poised to ignite the next round of “gold rush” because of its
mechanistic resemblance to versatile reactions catalyzed by
transition metals such as palladium, nickel, copper, and
rhodium. Before 2009, several notable reports of oxidative
homocoupling[2] using catalytic[3] or stoichiometric amounts[4]
of gold complexes or salts suggested that a gold(I)/gold(III)
catalytic cycle is feasible, albeit with limited mechanistic
proof. The first examples of homogeneous gold-catalyzed
oxidative cross-coupling reactions were reported by us in
coupling reaction.[11] Lately, arylsilanes[12] have been used
instead of arylboronic acids in the three-component reaction.
À
Transition-metal-catalyzed C H activation/functionaliza-
tion[13] and gold catalysis are contemporary research topics of
immense interest. The combination of these two areas[4c,14]
offers an increasing number of exciting opportunities for the
À
development of efficient synthetic methods. Notably, Csp2
H
bonds have so far been coupled with alkynyl[8a,b,d] or alkenyl
gold compounds[15] but not alkyl gold compounds through
oxidative gold catalysis. During our studies of gold(I)/gold-
À
(III) catalysis, we decided to examine whether Csp2 H bonds
[5a]
[5b]
2009,[5] where Csp2 Csp2 and Csp2
bonds were formed.
could replace the aforementioned Csp2 M bonds (M = Si or B)
À
À
O
À
In these studies along with a homocoupling reaction,[6]
in the coupling with alkyl gold compounds (Scheme 1B). This
À
Selectfluor
[1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-
C H functionalization would employ simple and economical
substrates and, moreover, offer a valuable opportunity to
[2.2.2]octane bis(tetrafluoroborate)][7] was found to be a
uniquely versatile oxidant for promoting these oxidative
processes.
À
probe the mechanism of gold-mediated Csp3 Csp2 bond
À
formations in the absence of any potential F M (M = Si or
To expand the bond types[4c,8] that could be formed, we
recently reported an oxidative coupling between alkyl gold
compounds and arylboronic acids, thus resulting in the
efficient functionalization of vinyl groups (Scheme 1A).[9]
B) interaction.[10,12b] Herein we report a convenient synthesis
of tricyclic indolines in a formal intramolecular [3+2] manner
by oxidative gold catalysis. Mechanistic studies suggest that
À
the Csp2 H bond is activated by electrophilic aromatic
auration and the Csp3 Csp2 bond formation proceeds through
an inner-sphere reductive elimination on a gold(III) center.
Although our attempt to use benzene and toluene, as
either the solvent[16] or an excess reagent, to achieve
À
À
Our deuterium-labeling studies established that the Csp3 Csp2
bond formation was highly stereoselective. Toste and co-
workers later reported the use of a different gold catalyst for
this chemistry[10] and extended it to a three-component
À
intermolecular cross-coupling of C H bonds with in situ
generated alkyl gold compounds had failed, we turned to the
intramolecular coupling reaction of N,N-diallyl-N’-phenyl-
urea (1a).[8c] We anticipated that this reaction would proceed
through a selective cyclization by the urea nitrogen atom and
the subsequent desired oxidative coupling of the formed alkyl
À
gold moiety with the ortho C H bond on the tethered phenyl
group (Table 1). Notably, this reaction constitutes a formal
[3+2] annulation[17] between the aniline moiety and the C C
À
À
double bond, and the first formal C H functionalization by
Scheme 1. A) The oxidative coupling of an alkyl gold compound with a
alkyl gold intermediates; moreover, the tricyclic indoline
motif has been studied in the search for inhibitors of 11B-
HSD1.[18]
C B bond[9,10] and B) the oxidative coupling of an alkyl gold compound
À
À
with a C H bond (this work).
Our initial screening of various [LAuX] complexes (X =
halide) included [Ph3PAuCl] (entry 1) and [dppm(AuBr)2][10]
(entry 2), and cationic gold(I) complexes (entries 3 and 4), all
of which led to disappointing results. However, a small
amount of the desired 2a[19] was detected when the solvent
was changed from MeCN to THF and the more reactive [(4-
CF3C6H4)3PAuNTf2] catalyst[20] was used (entry 5). To our
delight, the reaction was significantly improved when H2O
(15 equiv) was added (entry 6); 30 equivalents of H2O was
found to be optimal and the reaction yield was improved to
[*] G. Zhang, Y. Luo, Y. Wang, Prof. Dr. L. Zhang
Department of Chemistry and Biochemistry, University of California
Santa Barbara, CA (USA)
Fax: (+1)805-893-4120
E-mail: zhang@chem.ucsb.edu
[**] We thank the NSF (CHE-0969157), Amgen, and UCSB for generous
financial support. L.Z. is a Sloan Fellow.
Supporting information for this article is available on the WWW
4450
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 4450 –4454