A sequential metal-catalyzed C-N bond formation in the synthesis of 2-amido-indoles

Article abstract of DOI:10.1021/ol801711p

(Chemical Equation Presented) A sequential metal-catalyzed C-N bond formation employing ortho-haloaryl acetylenic bromides is described. The initial amidation is highly selective for C⁸P-N bond formation, leading to o-haloaryl-substiluted ynami

Full text of DOI:10.1021/ol801711p

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4275-4278
A Sequential Metal-Catalyzed C-N Bond
Formation in the Synthesis of
2-Amido-indoles
Pei-Yuan Yao,† Yu Zhang,‡ Richard P. Hsung,*,‡ and Kang Zhao*,†
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705, and College of Pharmaceuticals and
Biotechnology, Tianjin UniVersity, Tianjin 300072, People’s Republic of China
rhsung@wisc.edu; kz2@columbia.edu
Received July 25, 2008
ABSTRACT
A sequential metal-catalyzed C-N bond formation employing ortho-haloaryl acetylenic bromides is described. The initial amidation is highly
selective for Csp-N bond formation, leading to o-haloaryl-substituted ynamides that can be useful building blocks, while the overall sequence
provides a facile construction of 2-amido-indoles.
Given the importance of heterocyclic manifolds,1 we have
been developing synthetic methods that feature ynamides2,3
en route to various heterocycles.4 These efforts led us to
examine a possible entry for constructing amide-substituted
indoles.5-7 Specifically, as shown in Scheme 1, this pathway
would commence with ortho-haloaryl acetylenic bromides
1 and adopt a consecutive metal-catalyzed C-N bond
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† Tianjin University.
‡ University of WisconsinsMadison.
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10.1021/ol801711p CCC: $40.75
Published on Web 08/28/2008
2008 American Chemical Society

2-amido-indoles17,18 5 from ortho-haloaryl acetylenes 1,
which can be readily derived from aromatic aldehydes in
two steps.19 We report here the synthesis of 2-amido-indoles
via a sequential metal-catalyzed C-N bond formation.
A selective amidative cross-coupling of ortho-haloaryl
acetylenic bromides 120 could be readily established as shown
in Scheme 2. By employing 10 mol % of CuSO4·5H2O and
Scheme 1
Scheme 2
formation8 with the first involving the sp-hybridized car-
bon9-13 in an N-alkynylation manner and the second one
pertaining to an sp2-hybridized carbon in a N-arylation
manner.8,14 The second C-N bond formation can also occur
in a tandem manner with the ensuing indole formation
promoted by the metal15,16 in a 5-endo-dig cyclization mode
via 3. While copper can be employed to catalyze the Csp-N
formation,9-13 we intend to utilize palladium for the Csp2-N
formation.15 If this sequential C-N bond formation is
selective, it would constitute a facile entry to de novo
20 mol % of 1,10-phenanthroline,13 ynamide 6-Cl was
attained in 87% yield from 1-Cl. The amidation remained
selective when using 1-Br and even 1-I, leading to 6-Br and
6-I in 84% and 86% yield, respectively. Under the same
conditions, ynamides 7-Cl and 7-Br were obtained also via
a highly selective Csp-N formation.
A diverse array of ortho-haloaryl acetylenic bromides
could be subjected to this selective amidation to give
ynamides 8-16 (Figure 1). Moreover, a range of cyclic and
acyclic amides including sulfonamides could be employed
for the N-alkynylation to afford ynamides 17-23 in good
yields.
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Org. Lett., Vol. 10, No. 19, 2008

Scheme 3
5.0 mol % of van Leeuwen’s xantphos22 or Buchwald’s
X-phos as ligands.23 Intriguingly, the use of X-phos appears
to shorten the reaction time relative to xantphos, while
BINAP was not useful. On the other hand, amination of 7-Cl
led to 24 in 78% yield only when using X-phos. It is
noteworthy that amination of 6-I gave only 26% yield of
the corresponding indole (not shown), thereby suggesting
that aryl chlorides and bromides are better suited in this
operation than aryl iodides.
Figure 1. N-Alkynylation products. Reaction conditions are the
same as those in Scheme 2. All are isolated yields.
The generality of this tandem amination-5-endo-dig cy-
clization is shown in Table 1, featuring a range of different
amines and o-chloroaryl- or o-bromoaryl-substituted yna-
mides in excellent yields for their respective reactions. X-ray
crystallographic analysis of 2-amido-indole 28 reveals unique
orthogonality of three planes: 2-oxazolidone, the indole ring,
and the para-tolyl ring (Figure 3). Structures with related
orthogonality have been shown24 to possess inhibitory
substituted ynamides 6-23, which represent a new class of
functionally rich building blocks that could be utilized in a
number of transformations involving either the o-haloaryl
or ynamido motif (Figure 2), leading to rapid assembly of
structural complexity.
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Figure 2. Synthetic potential of o-haloaryl ynamides.
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To illustrate such synthetic potential, we chose to pursue
aminative cross-coupling of aryl halides8,14 to access 2-acety-
lenic anilines en route to 2-amido-indoles via metal-promoted
5-endo-dig cyclization.15-19,21 As shown in Scheme 3, when
ynamide 7-Br was subjected to amination conditions em-
ploying 2.5 mol % of Pd2(dba)3 and p-Tol-NH2, 2-amido-
indole 24 was obtained in good yields when using either
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Org. Lett., Vol. 10, No. 19, 2008
4277

Table 1. N-Alkenylation in the 2-Amido-indole Synthesis
Figure 3. X-Ray structure of 2-amido-indole 28.
peptides from cis to trans26,27 and accommodates such
orthogonality at its active site. We are currently investigating
such potential biological activity.
We have described here a sequential metal-catalyzed C-N
bond formation employing ortho-haloaryl acetylenic bro-
mides. The initial amidation is highly selective for the Csp-N
bond, leading to o-haloaryl-substituted ynamides that can be
useful building blocks. The overall sequence provides a facile
construction of 2-amido-indoles possessing a unique struc-
tural manifold.
Acknowledgment. We thank NIH[GM066055] for fund-
ing. P.Y.Y. and K.Z. thank the Cheung Kong Scholar
Program for funding. We thank Dr. Haibing Song [Nankai
University] for solving single-crystal X-ray structure. We
also thank Dr. Yunfei Du [Tianjin University] for valuable
suggestions.
Supporting Information Available: Experimental pro-
cedures as well as NMR spectra, characterizations, and X-ray
crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Reaction conditions: 2.5 mol % of Pd2(bda)3, 5.0 mol % of X-phos,
3.3 equiv of Cs2CO3, 1.3 equiv of R-NH2, 110 °C, 8-24 h. b Toluene was
used as solvent in entries 4, 5, 7, and 9, and dioxane was used in entries
1-3, 6, 8, and 10-12. c Isolated yields. d PMP ) para-methoxy-phenyl.
OL801711P
activities against human peptidyl prolyl cis/trans isomerase
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[PPI] Pin-1,25 which catalyzes the isomerization of prolyl
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