Metal-free oxidative amidation of 2-oxoaldehydes: A facile access to α-ketoamides

Article abstract of DOI:10.1021/ol5000204

A novel and efficient method for the synthesis of α-ketoamides, employing a dimethyl sulfoxide (DMSO)-promoted oxidative amidation reaction between 2-oxoaldehydes and amines under metal-free conditions is presented. Furthermore, mechanistic studies supported an iminium ion-based intermediate as a central feature of reaction wherein C₁-oxygen atom of α-ketoamides is finally derived from DMSO.

Full text of DOI:10.1021/ol5000204

Letter
pubs.acs.org/OrgLett
Metal-Free Oxidative Amidation of 2‑Oxoaldehydes: A Facile Access
to α‑Ketoamides
Nagaraju Mupparapu,†,‡ Shahnawaz Khan,†,‡ Satyanarayana Battula,†,‡ Manoj Kushwaha,§
Ajai Prakash Gupta,§ Qazi Naveed Ahmed,*,†,‡ and Ram A. Vishwakarma*,†,‡
‡
§
†Medicinal Chemistry Division, Academy of Scientific and Innovative Research (AcSIR), Quality Control and Quality Assurance
(QC & QA), Indian Institute of Integrative Medicine (IIIM), Jammu, Jammu and Kashmir 180016, India
S
* Supporting Information
ABSTRACT: A novel and efficient method for the synthesis
of α-ketoamides, employing a dimethyl sulfoxide (DMSO)-
promoted oxidative amidation reaction between 2-oxoalde-
hydes and amines under metal-free conditions is presented.
Furthermore, mechanistic studies supported an iminium ion-
based intermediate as a central feature of reaction wherein C1-oxygen atom of α-ketoamides is finally derived from DMSO.
α-Ketoamides, a well-known structural element of many natural
products, pharmaceuticals and synthetic agents, have attracted
considerable attention for their synthesis using different starting
materials.1−8 Not only have these compounds been optimized
for their remarkable biological and pharmacological activities,
but also they are known with wide application in a wide variety
of functional group transformations as well.9,10 Consequently, a
number of synthetic methods for construction of this important
unit have been established in the past decades. Nevertheless,
most of these methods described synthesis under (1) harsh
conditions (use strong oxidizing conditions) or (2) metal salt
catalytic conditions. Recently chemistry around 2-oxoaldehyde
(OA) has been explored by two different groups for the
construction of α-ketoamides (Scheme 1).7 It is a well familar
The present method employing a dimethyl sulfoxide
(DMSO) promoted oxidative amidation reaction between OA
and amine under metal-free conditions has clearly demon-
strated the unusual behavior of OA toward amine in a DMSO
environment.
Interestingly, it was observed that reaction of phenylglyoxal
1a with pyrrolidine 2a in DMSO at 60 °C for 12 h afforded the
desired product 3j in 10% yield (entry 1, Table 1). Same
reaction when kept for 24 h could not increase the yields to that
extent (12%, entry 2). To improve upon the yields of α-
ketoamides, a preliminary set of reaction between 1a and
pyrrolidine 2a under different condition has been carried out
(entry 3−22). The effects of reaction temperature on the yields
of 3j at different time intervals (pyrrolidine taken at 0.75
mmol) were subsequently examined. A higher conversion rate
was obtained when the reaction was performed at 80 °C for 1.5
h (80%, entry 4). No further increase in yield was observed
when the reaction temperature was >80 °C and time more than
1.5 h. The same reaction when tried at 45 °C for 48 h failed to
produce desired product (entry 8 and 9). Next, various
concentrations of amine were screened at 80 °C (entry 10−16).
0.97 mmol of pyrrolidine 2a was subsequently determined as
the best concentration for the reaction. Finally as observed, the
optimal reaction conditions for the reaction turned out to be
phenylglyoxal 1a (0.75 mmol) with pyrrolidine 2a (0.97 mmol)
at 80 °C in DMSO (95%, entry 11). Since the reaction was
carried out in air atmosphere, it was necessary to perform
reaction in different solvent conditions so as to ascertain the
role of DMSO (entry 17−22). Reaction of 2a with 1a in
different solvents under reflux conditions failed to produce
desired product. Furthermore test reaction between 1a and 2a
failed to produce α-ketoamides in DMSO/THF solution
(DMSO taken in 10 equiv) as well. These results clearly
Scheme 1. 2-Oxoaldehyde-Based Methods for Synthesis of α-
Ketoamides
fact that OA possessing adjacent aldehyde and ketone
functional groups with different reactivity shows interesting
chemical properties. The higher reactivity of aldehyde of OA in
comparison to normal aldehyde is attributed to existence of an
electron-withdrawing ketone group and has been well explored
to produce different important structures.11 Because of the
importance of α-ketoamides and broad synthetic applications of
OA, we developed a unique, alternative, convenient, and
efficient method to access α-ketoamides using a metal-free
oxidative amidation approach (Scheme 1).
Received: January 3, 2014
© XXXX American Chemical Society
A
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Letter
Table 1. Optimization Studies for Synthesis of α-
Ketoamides
Scheme 2. DMSO-Promoted Oxidative Amidation of 2-
a
a
Oxoaldehyde (1) and Amine (2)
amine
temp
time
(h)
yield
b
entry
solvent
DMSO
(mmol)
(°C)
(%)
1
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.97
0.97
0.97
0.97
1.125
1.5
60
60
12
24
1
10
12
76
80
80
80
82
0
2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
ACN
3
80
4
80
1.5
12
24
1
5
80
6
80
7
120
45
8
1
9
45
48
1
0
10
11
12
13
14
15
16
17
18
19
20
21
22
80
90
95
95
95
94
95
93
trace
0
80
1.5
2
80
120
80
1.5
1
80
1
3.75
0.97
0.97
0.97
0.97
0.97
0.97
80
1
80
12
12
12
12
12
12
MeOH
H2O
65
100
120
66
0
DMF
trace
0
THF
c
DMSO in THF
80
0
a
Reaction conditions: 1a (0.75 mmol), 2a (0.97 mmol), and DMSO
b
c
(3 mL) were heated for 1.5 h. Yields of the isolated product. DMSO
taken at 10 equiv in THF.
revealed the unusual role of DMSO as oxidant in these
conditions.
Following these optimized procedure, different sets of
experiments were carried out to investigate the scope and
limitations of this reaction. In one set of experiments reaction
was performed between different 2-oxoaldehyde 1 and
pyrrolidine 2a (entry 3a−3j, Scheme 2). It was observed that
both electron rich and electron-deficient OA could be smoothly
transformed into α-ketoamides. Furthermore, substituents at
different positions of the arene group and their electronic
nature do not affect the efficiency of the reaction. Both
electron-donating and electron-withdrawing groups attached to
the phenyl rings of substrates could afford the corresponding
product in moderate to good yields (65−92%).
Another set of experiments was performed between different
amines 2 and phenylglyoxal (entry 3j−3r) for the preparation
of different α-ketoamides. Yields were generally good for all
secondary amines tested (entry 3j−3o). However primary
amines including anilines (entry 3p−3r) when tested failed to
produce desired product even if tried for days under refluxed
conditions. According to the above experimental results it is
quite clear that this method is applicable with secondary amines
only as supported by stark enamine reaction, wherein iminium
ion intermediate is being produced by the reaction of secondary
amine with carbonyl substrate.12 After having established the
scope and limitation of the reaction, a small library of different
α-ketoamides was also generated by assembling the building
blocks shown in Scheme 2 (entry 3s−3ad). In addition, for
a
Reaction conditions: 1a (0.75 mmol), 2 (0.97 mmol), and DMSO (3
mL) were heated for 1.5−4 h. Yields given for isolated products after
chromatography. NO: Not observed.
certain moderate yielding reactions (entry 3g, 3i, and 3ab), we
also observed minor quantity of hydroxy compound 4.
In order to have mechanistic insight into the unusual
functioning of DMSO as oxidant, experiments 17−22 (Table 1)
and few additional reactions were keenly observed.
In reaction 1, a reaction was tried between pyrrolidine 2a and
phenylglyoxal 1a at rt (room temperature). Absence of product
in the reaction revealed that this reaction is feasible only at
higher temperature. Experiments 17−22 (Table 1) demon-
strated that the reaction of substrates in different solvent
B
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Organic Letters
Letter
conditions failed to produce desired product. These facts clearly
pointed toward the importance of DMSO environment for
bringing some transition state in to existence. In further
investigation, reaction of substrates in argon atmosphere
produced desired product in good yield, thereby ruling out
the probability of aerobic oxidation (reaction 2). To exclude the
role of compound 4 as an intermediate, a reaction was tried
between 4 and pyrrolidine 2a under optimized conditions
Figure 2. (a) DMSO O-labeled experiment. (b) LC-ESI-MS analysis
of reaction mixture (entry 3l) at 80 min to investigate reaction
mechanism. *Iminium ion peak (both syn and anti). **Product ion
peak.
1
(reaction 3). No product was observed in H NMR, which
achieved by analyzing three different sets of LC-ESI-MS
analysis experiments performed between 1 and 2 at different
time intervals (for detail, see Supporting Information page 3).
On the basis of these observations, we speculated that reaction
is only feasible through iminium ion facilitated by carbonyl
group of OA and promoted by DMSO environment at heating
conditions.
Further application of our method was extended in
developing a one-pot method for synthesis of α-ketoamides
employing acetophenones as source of 2-oxoaldehyde. For this
a reaction was carried out between acetophenones and iodine
in DMSO at 80 °C for initial generation of OA13 followed by
addition of respective amine to produce desired product in
comparable yields (Scheme 3).
clearly revealed nonparticipation of 4. Further reaction between
benzaldehyde 5 and pyrrolidine 2a failed to produce desired
amide (reaction 4). This observation clearly pointed toward
role of electron-withdrawing ketone in OA to α-ketoamides
synthesis. In addition, absence of product formation in case of
reaction between phenylglyoxal 1a and n-propylamine 2b
(reaction 5) supported the role of some intermediate toward
product formation.
On the basis of the above results, the only plausible route for
synthesis of α-ketoamides can be visualized by the presence of
iminium ion as an intermediate (Figure 1). Monohydrate form
Scheme 3. One-Pot Synthesis of α-Ketoamides Employing
Acetophenones (6)
Figure 1. Proposed mechanism for direct transformation.
of OA on heating undergoes dehydration to produce 2-
oxoaldehyde 1.11 Reaction of OA 1 with amine 2 at 80 °C in
DMSO environment facilitated formation of iminium ion as a
reactive intermediate. Generation of iminium ion is expected
through DMSO solvated complex promoted by the carbonyl
group of OA, which on reaction with DMSO at electrophilic
carbon, through elimination of water and dimethyl sulfide
(DMS), produced the desired product in good yields. This
proposed mechanism perhaps shows unusual behavior of two
reactants in DMSO environment at heating condition wherein
the C1-oxygen atom of 3 is derived from DMSO.
In order to support our mechanism, an O-labeled DMSO
experiment was performed between phenylglyoxal 1a and
morpholine 2c under optimized conditions (Figure 2). Mass
analysis (Supporting Information, page 9) of desired product
18O3l clearly indicated that DMSO served as the oxidant in this
transformation. Further confirmation of mechanism was
In conclusion we have successfully demonstrated a unique
DMSO-promoted oxidative amidation approach for synthesis of
α-ketoamides. This method is perhaps an efficient approach
wherein DMSO plays a dual role both as solvent and as oxidant.
This protocol has additional uniqueness, as it is also applicable
for synthesis of aliphatic α-ketoamides. Furthermore, mecha-
nism studies revealed that the carbonyl group of OA plays a
vital role as a directing/stabilizing group in the DMSO
environment at heating conditions (temperature ≥ 80 °C) to
facilitate iminium ion formation, which on DMSO-mediated
oxidation results in synthesis of α-ketoamides having a C1-
oxygen atom derived from DMSO. In addition, we successfully
C
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experiment details and spectral data for all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: naqazi@iiim.ac.in.
*E-mail: ram@iiim.ac.in.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge CSIR/DST for the award of Senior
Research Fellowship and AcSIR for Ph.D. registration. This
work was generously supported by network project through
Grant No. BSC0108. IIIM/1593/2014.
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