Synthesis of indoles via domino reaction of N-Aryl amides and ethyl diazoacetate

Article abstract of DOI:10.1021/ja805706r

A general and concise synthesis of functionalized indoles via domino reaction of N-aryl amides and ethyl diazoacetate has been developed. The methodology offers a great potential for the synthesis of biologically active and naturally occurring indole derivatives. Copyright

Full text of DOI:10.1021/ja805706r

Published on Web 09/18/2008
Synthesis of Indoles via Domino Reaction of N-Aryl Amides and Ethyl
Diazoacetate
Sun-Liang Cui, Jing Wang, and Yan-Guang Wang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, P. R. China
Received July 22, 2008; E-mail: orgwyg@zju.edu.cn
Table 1. Indole Synthesis via Domino Reaction of N-Arylamides
Indoles are probably the most ubiquitous heterocycles in nature
and have been referred to as “privileged structures” in drug
discovery because of their capacity of binding to many receptors
with high affinity.1 Accordingly, many powerful methodologies for
the synthesis of these heterocycles have been developed,2 the
majority of which involve Fischer-type indole synthesis,3 heteroan-
nulations and cyclization of 2-alkynylanilines,4 reductive cycliza-
tion,5 and metal-catalyzed coupling/condensation cascades.6 Still,
general and efficient methods for the synthesis of indoles from
simple and readily available precursors are of great value. We herein
report a single-step approach to indoles via a domino reaction of
N-aryl amides and ethyl diazoacetate (EDA).
and EDAa
Recently, Charette and Movassaghi reported pioneering works
on the electrophilic activation of amides with trifluoromethane-
sulfonic anhydride (Tf2O) in the presence of pyridine or 2-chlo-
ropyridine (2-ClPy) and a suitable nucleophile, which led to the
synthesis of carboxylic acid derivatives,7a chiral piperidines,7b
amines,7c pyridines,7d,e and pyrimidines.7f Inspired by these works
and our recent findings around domino reactions,8 we assumed that
the addition of EDA to the highly activated amides would lead to
the formation of indoles since diazo carbon bears a partial negative
charge and thus has considerable nucleophilicity.9
The reaction of benzamide 1a (1 equiv), EDA (1.5 equiv), and
Tf2O (1.2 equiv) were used to screen the reaction conditions
(Supporting Information, SI-Table 1). The combination of 2-ClPy
(1.2 equiv) and 2,6-dichloropyridine (2,6-Cl2Py, 0.2 equiv) proved
to be the most effective base additives, which allow a direct
conversion of 1a to indole 3aa (SI-Table 1, entry 8). It is noteworthy
that 2,6-Cl2Py (0.2 equiv) is crucial to the domino process. Thus
upon optimal conditions, the reaction of EDA with the activated
amide 1a at -30 °C for 20 min afforded 3aa in 52% yield.
We next examined the scope of the reaction with a variety of
differently substituted N-aryl amides. As shown in Table 1, all
N-aryl amides proceeded to furnish the corresponding substituted
indoles in moderate to good yields (46-82%). Importantly,
benzamides gave the corresponding 2-phenylindoles (entries 1-4,
10, 14, and 15), which are important structures owing to their
biological activity and commonly prepared by multistep synthesis
or by metal-catalyzed 2-arylation of indoles.10 Moreover, N-m-
tolylacetamide 1h gave the less hindered 2,6-dimethyl-1H-indole
3ha as major product and its isomer 2,4-dimethyl-1H-indole 3hb
as minor product while N-(naphthalen-1-yl)benzamide 1i afforded
1H-benzo[de]quinoline 4 in 71% yield and no 1H-benzo[g]indole
was observed (Scheme 1), so the reaction exhibited high regiose-
lectivity. The structure of compound 3db was unambiguously
confirmed by X-ray analysis (see Supporting Information).
A demonstration of the intensive synthetic utility was shown in
Scheme 2. Indole 3bd was converted to pyrrolo[1,2-a]indole 5 in
high yield when treated with NaH in THF. This two-step strategy
for access to pyrrolo[1,2-a]indole from N-aryl amides is concise
and highly efficient compared with the published methods.11
a All reactions were performed on 1 mmol of amide. b Isolated yield
refers to amide.
The mechanism of the domino reaction is depicted in Scheme
3. The activation of amide 1 and addition of 2-ClPy is envisioned
to give a highly electrophilic 2-chloropyridinium adduct A,7 which
then converts to a more active electrophile B by a reversible
exchange of 2-chloropyridinium with 2,6-Cl2Py. B is then attacked
by diazo anion to form a diazonium intermediate C followed by
9
13526 J. AM. CHEM. SOC. 2008, 130, 13526–13527
10.1021/ja805706r CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20672093).
Supporting Information Available: Detailed experimental proce-
dures, characterizaton data, copies of 1H and 13C NMR spectra for all
products, and crystallographic information files for compounds 3db.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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Scheme 2
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expulsion of 2,6-Cl2Py·TfOH. C undergoes an intramolecular
electrophilic substitution accompanied by expulsion of N2 and TfOH
to provide E, which subsequently isomerizes to indole 3. In the
presence of stoichiometric 2-ClPy, the resulting 2,6-Cl2Py·TfOH
is transformed to 2,6-Cl2Py and enters to catalysis cycle.
In summary, we have developed a general, concise, and single-
step synthesis of functionalized indoles from readily available
N-arylamides and ethyl diazoacetate. The domino approach may
prove to be the most useful for the synthesis of biologically active
and naturally occurring indole derivatives. Efforts are actually
directed toward the extension of this methodology to natural
products and drug synthesis.
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