Angewandte
Chemie
Heterocycles
À
Zinc-Catalyzed Alkyne Oxidation/C H Functionalization: Highly Site-
Selective Synthesis of Versatile Isoquinolones and b-Carbolines**
Long Li, Bo Zhou, Yong-Heng Wang, Chao Shu, Yi-Fei Pan, Xin Lu,* and Long-Wu Ye*
À
Abstract: An efficient zinc(II)-catalyzed alkyne oxidation/C
H functionalization sequence was developed, thus leading to
highly site-selective synthesis of a variety of isoquinolones and
b-carbolines. Importantly, in contrast to the well-established
gold-catalyzed intermolecular alkyne oxidation, over-oxida-
tion can be completely suppressed in this system and the
reaction most likely proceeds by a Friedel–Crafts-type path-
way. Mechanistic studies and theoretical calculations are
described.
Scheme 1. Initial design.
D
uring the past decade, transition-metal-catalyzed direct
functionalization of C H bonds has proven to be an
extremely powerful and highly versatile synthetic tool for
the construction of natural products and pharmaceuticals.[1]
alkyne oxidation.[5] Despite these findings,[6] synthetic appli-
cation of N-oxide-mediated oxidation of alkynes faces two
major technical hurdles: 1) The carbene intermediate, partic-
ularly when generated from an internal alkyne such as
ynamide,[7] can undergo over-oxidation which generates
unwanted byproducts.[8,4c] 2) A noble transition-metal catalyst
usually is required for optimal reaction efficiency, and may
severely limit the practical application of this approach
À
À
Because of the presence of different types of C H bonds in
complex molecules, it still presents particular challenges in
achieving highly site-selective C H functionalization with
practical interest. For example, the insertion of metal
À
À
carbenes into saturated C H bonds invariably favors the
2
À
À
related C(sp ) H insertion for transition-metal-catalyzed C
-H insertion of a-diazo compounds (Scheme 1).[2] Reversing
this site selectivity not only represents an attractive method to
build six-membered heterocycles, but also complements the
conventional metal carbene insertion reaction. Therefore, it is
because of the high cost and toxicity of the catalyst. Herein,
2
À
we report the first zinc-catalyzed alkyne oxidation/C(sp ) H
functionalization sequence,[9,8b] thus providing practical
access to synthetically useful isoquinolones and b-carbolines.
In particular, the undesired over-oxidation could be dramat-
ically suppressed in such an oxidative zinc catalysis.[10] Most
importantly, mechanistic studies and theoretical calculations
revealed that the reaction presumably proceeds by a Friedel–
Crafts-type pathway, which is distinctively different from the
related gold-catalyzed oxidative cyclization.
À
highly desirable to develop a direct C H functionalization
method that specifically targets such a C(sp ) H bond.
2
À
In recent years, gold-catalyzed intermolecular alkyne
oxidation by an N-oxide oxidant, a process which presumably
involves an a-oxo gold carbenoid intermediate, has attracted
significant research attention because it avoids the use of
hazardous a-diazo ketones as starting materials for carbene
generation.[3,4] Recently, the groups of Tang and Li reported
that rhodium could also catalyze such an intermolecular
Our initial investigation[11] focused on the reaction of the
ynamide substrate 1a with 2-bromopyridine N-oxide (3a) in
DCE at 808C in the presence of a gold catalyst (5 mol%;
Table 1). However, in most cases, only the diketone 2aa was
obtained through the gold-catalyzed over-oxidation of 1a.[12]
We then sought to use other metal catalysts, hoping to
circumvent the competing over-oxidation process. Surpris-
ingly, other metal catalysts, especially the non-noble metals,
also promoted such an oxidative cyclization (entries 1–3).
Importantly, no diketone formation was observed in the
presence of either Fe(OTf)2 or Zn(OTf)2 (entries 2 and 3),
and the reaction could afford the oxidatively cyclized product
2a in 47% yield by using 10 mol% of Zn(OTf)2 as the
catalyst, albeit along with the hydration product 2ab in 25%
yield (entry 3). Of note, HOTf could also catalyze this
reaction in 16% yield.[12,13] In addition, the use of PhCl as
the solvent at 1008C gave a slightly improved yield (entry 4).
The yield of product 2a was further increased to 61% by using
2,6-dibromopyridine N-oxide (3b) as the oxidant (entry 5).
Pleasingly, the use of 4 molecular sieve minimized the
formation of the hydration byproduct and 86% yield of 2a
[*] L. Li,[+] B. Zhou,[+] C. Shu, Y.-F. Pan, Prof. Dr. L.-W. Ye
State Key Laboratory for Physical Chemistry of Solid Surfaces &
The Key Laboratory for Chemical Biology of Fujian Province
Department of Chemistry, Xiamen University
Xiamen 361005 (China)
E-mail: longwuye@xmu.edu.cn
Y.-H. Wang, Prof. Dr. X. Lu
State Key Laboratory of Physical Chemistry of Solid Surfaces &
Center for Theoretical Chemistry
Department of Chemistry, Xiamen University
Xiamen 361005 (China)
E-mail: xinlu@xmu.edu.cn
[+] These authors contributed equally to this work.
[**] We are grateful for financial support from NNSFC (No. 21272191
and 21273177), NFFTBS (No. J1310024), and PCSIRT.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 8245 –8249
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8245