A general metal free approach to α-ketoamides via oxidative amidation-diketonization of terminal alkynes

Article abstract of DOI:10.1039/c4cc03783a

A novel catalytic system TMSOTf/I₂/DMSO for the oxidative coupling of terminal alkynes with virtually any primary/secondary amine leading to α-ketoamides has been developed. The reaction possibly proceeds via iminium ion formation, wherein DMSO acts as a solvent as well as an oxidizing agent. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03783a

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A general metal free approach to a-ketoamides
via oxidative amidation–diketonization of
terminal alkynes†
Cite this: Chem. Commun., 2014,
50, 9533
Received 19th May 2014,
Accepted 11th June 2014
Ramesh Deshidi, Manjeet Kumar, Shekaraiah Devari and Bhahwal Ali Shah*
DOI: 10.1039/c4cc03783a
www.rsc.org/chemcomm
A novel catalytic system TMSOTf/I2/DMSO for the oxidative coupling stable Schiff base. We reasoned that developing a strategy for
of terminal alkynes with virtually any primary/secondary amine iminium ion formation through C–H activation of terminal
leading to a-ketoamides has been developed. The reaction possibly alkynes might be a solution to this problem. Specifically, it was
proceeds via iminium ion formation, wherein DMSO acts as a solvent envisaged that employing a Lewis acid in combination with
as well as an oxidizing agent.
DMSO and I2 could be a starting point.
To test our hypothesis, a test reaction between phenyl
a-Ketoamide, a privileged motif, is a characteristic underlying acetylene (1) and pyrrolidine (2) was run in the presence of
element of many bio-active molecules such as FK506, rapamycin TMSOTf (1 equiv.) and a catalytic amount of iodine in DMSO at
and FKBP12.1 Furthermore, it is an attractive candidate to synthetic room temperature. As anticipated, our proposition worked and
chemists due to its ability to access a wide range of functional group the reaction gave the desired product (3aa), but in low yields
transformations.2,3 Its varied and significant biological activities (35%) (Table 1, entry 1). The reaction possibly involves in situ
have been the impetus to the recent development of manifold C–H activation of terminal alkynes which proceeds via iminium
synthetic methods, with each allowing for a greater scope in ion formation to give a-ketoamides. Intriguingly, the method
terms of coupling partners and milder approaches.4,5 However, circumvents the need for any metal catalysts or oxidizing agent
most of these methods involve metal catalysts in combination and requires stoichiometric quantities of the reactants. How-
with co-oxidants and harsh reaction conditions. Remarkably, there ever, the results warranted optimization of the reaction condi-
is still no single route which can work without discriminating tions. To monitor the effect of temperature, we carried out the
the basic reactivity of aromatic–aliphatic or primary–secondary reaction at 60 and 80 1C to afford 3aa in 49 and 57% yields
coupling partners. Therefore, developing a general method for respectively (Table 1, entries 2 and 3). Further increasing the
the synthesis of a-ketoamides is highly desirable.
temperature to 120 1C had no significant effect on the overall
In this context, we thought of exploiting terminal alkynes for yields (Table 1, entry 4). To establish the role of TMSOTf, we
the synthesis of a-ketoamides via C–H activation. To the best of performed the reaction with other metal triflates such as
our knowledge, the only example of terminal alkynes described Yb(OTf)3, Sc(OTf)3, and In(OTf)3, but none afforded the product
by Zhang and Jiao,6 for the synthesis of a-ketoamides, was
applicable to only primary amines and employed a cocktail of
reagents i.e., metal catalyst, oxidizing agents, excessive base and
alkyne (5–10 equiv.) (Fig. 1). Recently, Ahmed and co-workers7
developed a new route involving highly reactive iminium ions
as an intermediate to facilitate a-ketoamides synthesis using
DMSO as the oxidant. However, the reaction suffered with
limited substrate scope in terms of primary amines, as they
failed to generate iminium ions due to the formation of a more
Academy of Scientific and Innovative Research (AcSIR), Natural Product Microbes,
CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, 180001,
India. E-mail: bashah@iiim.res.in
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra.
Fig. 1 Synthesis of a-ketoamides.
See DOI: 10.1039/c4cc03783a
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Table 1 Optimization studies for the oxidative amidation of phenylacetylenea
Entry Solvent Lewis acid Equiv. Temp. (1C) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN TMSOTf
DMF
THF
Toluene TMSOTf
DCM TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
Yb(OTf)3
Sc(OTf)3
In(OTf)3
TMSOTf
TMSOTf
TMSOTf
TMSOTf
1
1
1
1
1
1
1
0.5
1.5
2
2.5
2
2
2
rt
60
12
10
10
10
10
8
8
8
6
6
35
49
57
54
—
—
—
46
70
72
83
—
—
—
—
—
80
120
80
80
80
80
80
80
80
80
80
80
80
40
Scheme 1 Generality of the reaction in terms of alkynes for constructing
various a-ketoamides.
9
10
11
12
13
14
15
16
6
16
22
12
12
4
TMSOTf
TMSOTf
2
2
a
b
Reactants: 1 (1 mmol), 2 (1.5 mmol). Isolated yields.
(Table 1, entries 5–7). The identification of the optimum loading was
another important aspect of the reaction strategy. Decreasing the
amount of TMSOTf to 0.5 equiv. resulted in a considerable yield loss
(Table 1, entry 8). However, an increase in loading to 1.5 equiv.
resulted in the corresponding product in 70% yield, which increased
to 72 and 83% when the amount was increased to 2 and 2.5 equiv.
respectively (Table 1, entries 9–11). A further increase in TMSOTf
loading didn’t cause any significant change in the overall yield.
Thus, TMSOTf loading of 2.5 equiv. at 80 1C were found to be the
conditions of choice. We also examined the feasibility of the reaction
in other solvents such as acetonitrile, DMF, THF and DCM, but
found no product formation (Table 1, entries 12–16).
Having optimized the conditions, we explored the utility of this
approach for the oxidative coupling of various substituted alkynes
with pyrrolidine. The reaction with both electron-rich and electron-
deficient aryl acetylenes afforded the desired products in quantita-
Scheme 2 Generality of the reaction in terms of amines for constructing
various a-ketoamides.
tive yields. The reaction also tolerated 4-bromo phenyl acetylene and formation of acetophenone (I), and (b) by the use of TMSOTf
cyclohexenyl acetylene well to afford the desired products 3ag and in catalytic amounts (20 mol%) resulting in the dimerization of
3ah in 72% and 47% yields respectively (Scheme 1).
phenyl acetylene (II). The trifluoromethylated alkyne reacts
Encouraged by these results, we decided to test the generality of with iodine to produce a-iodoacetophenone (III), which then
our method with a range of substituted amines and phenyl acetylene undergoes Kornblum oxidation resulting in the formation of
(1) (Scheme 2). The reaction with secondary amines like pyrrolidine, arylglyoxal (IV) with the release of HI.8 HI in the presence of
piperidine, morpholine, N-methyl piperazine, N-Boc piperazine and DMSO regenerates iodine, which activates the aldehyde group
N,N-diethyl amine gave the corresponding products in excellent of arylglyoxal followed by the subsequent attack of amine to
yields. Moreover, aromatic primary amines which have both generate an iminium ion (V), which is the active intermediate
electron-releasing and electron-withdrawing groups were found to required for further progress of the reaction. As we know,
be good substrates for producing the corresponding a-ketoamides DMSO can act as an oxygen donor,7 therefore, the more
in good yields. In general, aromatic amines bearing electron- electrophilic carbon centre of the iminium ion creates a sub-
donating substituents gave comparatively higher yields than strate available for nucleophilic attack from the DMSO, which
electron-withdrawing substituents. These results demonstrate on elimination of water and dimethyl sulfide (DMS) results in
the versatility of the present methodology.
the formation of the product. The reaction between primary
The reaction possibly proceeds via trifluoromethylation of amines/anilines with phenylglyoxals, which is promoted by
the terminal alkyne which was corroborated; (a) by the reaction molecular iodine, generates a Schiff base that is eventually
without amine and iodine in DCM, which resulted in the protonated resulting in an iminium ion (V), leading to the
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Fig. 2 Plausible mechanism of formation.
synthesis of a-ketoamides in a similar way as discussed already.
Furthermore, to rule out the possibility of aerial oxidation, the
reaction was carried out under inert conditions resulting in the
product without any significant drop in yield (Fig. 2).
In conclusion, we demonstrated the first metal free catalytic
system employing TMSOTf/I2 in DMSO for the oxidative amidation–
diketonization of terminal alkynes to produce a wide variety of
a-ketoamides. The reaction circumvents the need for molecular
oxygen and additional oxidizing agents. Furthermore, this may
serve as an excellent method for studying the scope of C–H
activation of terminal alkynes in other reactions.
We thank DST, New Delhi for financial assistance. R.D., S.D.
and M.K. thank UGC and CSIR, New Delhi for the award of
Research Fellowship. We thank Dr Qazi Naveed Ahmed for
helpful discussions and Dr Deepika Singh for analytical support.
IIIM Communication No. IIIM/1682/2104.
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This journal is ©The Royal Society of Chemistry 2014
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