Tetrahedron Letters
Metal free synthesis of a-keto amides from 2-hydroxy acetophenones
through domino alcohol oxidation–oxidative amidation reaction
⇑
Surya Srinivas Kotha, Govindasamy Sekar
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu 600036, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of
domino alcohol oxidation and oxidative amidation reaction sequence between 2-oxoalcohols and amines
under metal-free conditions is developed. In this protocol, IBX is used as an oxidizing agent to synthesize
a-keto amides using 2-iodoxybenzoic acid (IBX) promoted
Received 7 August 2015
Revised 14 September 2015
Accepted 15 September 2015
Available online xxxx
the
a-keto amides, which makes this methodology highly efficient, practical, and environmentally
benign.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Metal free synthesis
a-Keto amide
2-Hydroxy acetophenone
Oxidative amidation
2-Iodoxybenzoic acid
a
-Keto amides are the important structural units of many syn-
O
O
S
O
thetic reagents, natural products, and drugs.1
a-Keto amides are
F3C
O
N
O
found in various types of natural products and inhibitors such as
FK 506, cyclotheonamide, eurystatin, potent thrombin inhibitor,
and calpain inhibitor (Fig. 1). They also serve as useful intermedi-
ates in many organic transformations.2 Many methods have been
N
N
O
O
Ph
developed for the synthesis of
a-keto amides in the past decades
Caspase-3 inhibitor
Orexin receptor anatgonist
from different starting materials.3–8 Most of these synthetic
methodologies involved the usage of metal catalysts for the syn-
O
F
O
H
H
N
N
O
thesis of a-keto amides. Very recently, a-keto amide was prepared
from 2-oxoaldehydes by using SeO2,9 CuBr,10 and iodine11 at high
temperatures. However, these 2-oxoaldehydes are highly unstable,
air sensitive, and difficult to synthesize. In order to overcome these
difficulties, several methodologies were developed for the synthe-
O
COOH
F3C
O
Ph
Epoxide inhibitor
RARg agonist
a
-keto amides from alkynes,6 ketones, phenyl glyoxal,10
Figure 1. Repersentative examples for biologically active molecules containing
a-
sis of
keto amides.
2-oxo alcohols,13 phenyl acetaldehydes,5b etc.
As part of our ongoing research toward metal free reactions,12
we herein report a new method for the synthesis of a-keto amide
afforded 40% of 3a (Table 1, entry 1). When the same reaction
was carried out at room temperature, the reaction provided 3a in
42% yield. In order to achieve the best reaction condition, the
reaction was screened with various solvents such as DMSO, DMF,
THF, acetonitrile, and dioxane. Acetonitrile was found to be the
best solvent for this domino alcohol oxidation–oxidative amidation
reaction sequence with 95% of the desired product (entry 4). The
efficiency of this reaction was decreased when the equivalents of
IBX and piperidine decreased. This may be due to the solubility
of the IBX in MeCN solvent. This reaction did not provide even
from 2-hydroxy acetophenones and amines by using IBX as an oxi-
dizing agent at room temperature under metal free conditions
through domino alcohol oxidation and oxidative amidation reac-
tion sequence (Scheme 1).
The initial study was carried out by using 2-hydroxyacetophe-
none 1 and piperidine 2 in the presence of IBX (3 equiv) as an oxi-
dizing agent. After 4 h in DMSO at 80 °C, the domino reaction
⇑
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0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.