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. Author manuscript; available in PMC: 2009 Mar 28.
Published in final edited form as: Org Lett. 2008 Aug 28;10(19):4275–4278. doi: 10.1021/ol801711p

A Sequential Metal-Catalyzed C-N Bond Formation in the Synthesis of 2-Amido-Indoles

Pei-Yuan Yao †, Yu Zhang ‡, Richard P Hsung ‡, Kang Zhao †
PMCID: PMC2662137  NIHMSID: NIHMS104361  PMID: 18754591

Abstract

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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 formation8 with the first involving the sp-hybridized carbon9-13 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 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 synthesis of 2-amido-indoles via a sequential metal-catalyzed C-N bond formation.

Scheme 1.

Scheme 1

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A selective amidative cross-coupling of ortho-haloaryl acetylenic bromides 120 could be readily established as shown in Scheme 2. By employing 10 mol% CuSO4-5H2O and 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.

Scheme 2.

Scheme 2

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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.

Figure 1. N-Alkynylation Products.a.

Figure 1

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a. Reaction conditions are the same as those in Scheme 2. All are isolated yields.

Having established this selective amidation, we recognized that we have an excellent protocol to access o-haloaryl-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.

Figure 2. Synthetic Potential of o-Haloaryl Ynamides.

Figure 2

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To illustrate such synthetic potential, we chose to pursue aminative cross-coupling of aryl halides8,14 to access 2-acetylenic 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 employing 2.5 mol% Pd2(dba)3 and p-Tol-NH2, 2-amido-indole 24 was obtained in good yields when using either 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 corresponding indole [not shown], thereby suggesting that aryl chlorides and bromides are better suited in this operation than aryl iodides.

Scheme 3.

Scheme 3

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The generality of this tandem amination-5-endo-dig cyclization is shown in Table 1, featuring a range of different amines and o-chloroaryl- or o-bromoaryl-substituted ynamides 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 activities against human peptidyl prolyl cis/trans isomerase [PPI] Pin-1,25 which catalyzes the isomerization of prolyl peptides from cis to trans26,27 and accommodates such orthogonality at its active site. We are currently investigating such potential biological activity.

Table 1. N-Alkenylation in the 2-Amido-Indole Synthesis.

entry ynamidesa,b 2-amido-indoles yield [%]c
1 graphic file with name nihms-104361-t0008.jpg 6-Br graphic file with name nihms-104361-t0009.jpg 25: R = p-Tol 91
2 6-Br 26: R = o-Tol 82
3 graphic file with name nihms-104361-t0010.jpg 7-Cl graphic file with name nihms-104361-t0011.jpg 27d 91
4 graphic file with name nihms-104361-t0012.jpg 8 graphic file with name nihms-104361-t0013.jpg 28 65
5 graphic file with name nihms-104361-t0014.jpg 12 graphic file with name nihms-104361-t0015.jpg 29 60
6 graphic file with name nihms-104361-t0016.jpg 14 graphic file with name nihms-104361-t0017.jpg 30 72
7 graphic file with name nihms-104361-t0018.jpg 15 graphic file with name nihms-104361-t0019.jpg 31 64
8 graphic file with name nihms-104361-t0020.jpg 16 graphic file with name nihms-104361-t0021.jpg 32 80
9 graphic file with name nihms-104361-t0022.jpg 18-Br graphic file with name nihms-104361-t0023.jpg 33 71
10 graphic file with name nihms-104361-t0024.jpg 19 graphic file with name nihms-104361-t0025.jpg 34: R1 = H 82
11 20 35: R1 = CO2Me 75
12 graphic file with name nihms-104361-t0026.jpg 21 graphic file with name nihms-104361-t0027.jpg 36 88
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a

Reaction conditions: 2.5 mol % Pd2(bda)3, 5.0 mol % X-phos, 3.3 equiv Cs2CO3, 1.3 equiv 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.

Figure 3. X-Ray Structure of 2-Amido-Indole 28.

Figure 3

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We have described here a sequential metal-catalyzed C-N bond formation employing ortho-haloaryl acetylenic bromides. The initial amidation is highly selective for 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 structural manifold.

Supplementary Material

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Acknowledgement

We thank UW-Madison and Cancer Center for funding. PYY and KZ 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.

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