Metal-free in situ sp3, sp2, and sp C-H functionalization and oxidative cross coupling with benzamidines hydrochloride: A promising approach for the synthesis of α-ketoimides

Article abstract of DOI:10.1039/c4ra07556k

A new metal-free tandem protocol for the synthesis of α-ketoimides via sp³, sp², and sp C-H functionalization followed by oxidative cross coupling with benzamidines hydrochloride using catalytic iodine with TBHP in DMSO has been developed. A wide range of functional group tolerance, an inexpensive catalyst, operational simplicity and good to excellent yields of the products are the striking features of this method.

Full text of DOI:10.1039/c4ra07556k

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PAPER
Metal-free in situ sp3, sp2, and sp C–H
functionalization and oxidative cross coupling with
benzamidines hydrochloride: a promising approach
for the synthesis of a-ketoimides†
Cite this: RSC Adv., 2014, 4, 60316
*
Hanuman P. Kalmode,‡ Kamlesh S. Vadagaonkar‡ and Atul C. Chaskar‡
A new metal-free tandem protocol for the synthesis of a-ketoimides via sp3, sp2, and sp C–H
functionalization followed by oxidative cross coupling with benzamidines hydrochloride using catalytic
iodine with TBHP in DMSO has been developed. A wide range of functional group tolerance, an
inexpensive catalyst, operational simplicity and good to excellent yields of the products are the striking
features of this method.
Received 24th July 2014
Accepted 4th November 2014
DOI: 10.1039/c4ra07556k
www.rsc.org/advances
The Cu-catalyzed synthesis of a-ketoamides through oxida-
tive coupling of phenyl acetylenes, aryl acetaldehydes,
Introduction
a-carbonyl aldehydes and aryl methyl ketones with anilines is
well documented.15 However, the use of toxic metal oxidants
limits the utility of these methods especially in case of synthesis
of drug intermediates owing to possible contamination of these
with trace amount of heavy metals. Iodine or iodine-peroxide
has emerged as an effective reagent for sp3 C–H bond oxida-
tive amidation of methyl ketones.16 Zhang and co-workers had
employed anodic oxidation of aryl methyl ketones.17 Muppar-
apu et al. have used dimethyl sulfoxide for the oxidative ami-
dation of 2-oxoaldehydes.18 The synthesis of polysubstituted
oxazoles was reported through domino oxidative cyclization by
using I2/TBHP.19a Wang et al. synthesized 2,5-disubstituted
oxazoles by using 2-amino-1-phenylethanone and aromatic
aldehydes,19b 2-phenylquinazolines from 2-amino benzophe-
nones and benzylic amines,19c quinazolines from a-amino acids
and 2-aminobenzoketones,19d ketones from benzylic methyl-
enes and nitriles from primary amines by using I2/TBHP.19e
Jurczak and co-workers20 reported the diastereoselective addi-
tion of Grignard reagents to chiral a-ketoimides derived from
Oppolzer's sultam.
Considering the advantages of domino reaction and limita-
tions of aforementioned methods, herein we present a novel
metal-free synthetic protocol for the synthesis of a-ketoimide
from diverse substrates. We have centered our attention on
multiple C–H bond functionalization of ethyl arenes (1),
ethylene arenes (4), and ethyne arenes (5) followed by oxidative
coupling with benzamidines hydrochloride (2) to give a-ketoi-
mides (3) (Scheme 1).
The model reaction between ethylbenzene (1a) and benza-
midine hydrochloride (2a) in presence of I2/TBHP in DMSO was
run to test our speculations thus for the same we optimized the
reaction conditions. Optimization of reaction conditions was
Amides, imides, a-ketoamides and a-ketoimides are versatile
synthetic building blocks owing to easy further functional group
manipulation resulting in ready access to diverse biologically
active heterocyclic ring systems.1 Additionally they are crucial
segments in numerous natural products, drugs and proteins.2
Imides are key constituents of variotin, aniracetam, and
many heterocycles.2 Similarly, a suitably substituted a-ketoa-
mide is a precursor of bioactive FK506, rapamycin, FKBP12, Na-
channel blocker GW 356194, 5-HT6 binding ligands, a-diones
and b-lactams etc.3 Hence, several methodologies have been
developed for synthesizing this group of building blocks.
Conventionally, a carboxylic acid or its derivative is coupled
with an amine to give an amide4 while acyl halides are used in
the preparation of imides.5 a-Ketoamides are synthesized by
amidation of a-ketoacids,6 a-ketoaryl halides,7 cyanoketones,8
oxidation or photochemical reaction of amides,9 double car-
boxylative amidation of aryl halides,10 oxidation of acyl cyano-
phosphoranes followed by the amidation of a,b-diketone
nitrile11 and reaction of isocyanides with aromatic acyl chlo-
rides.12 Yoo and Li13 used copper while Liu et al.14 used n-Bu4NI,
together with TBHP for the synthesis of amides from aldehydes.
Recent years have seen efforts devoted towards the synthesis of
a-ketoamides and a-ketoimides via C–H activation. This
strategy has emerged as an impressive novel tool for its diverse
applications.
Department of Dyestuff Technology, Institute of Chemical Technology, Mumbai
400019, India. E-mail: achaskar25@gmail.com; Fax: +91 22 3361 1020; Tel: +91 22
3361 1111 ext. 2706
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra07556k
‡ These authors contributed equally to this work.
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Scheme 1 The tandem oxidative cross coupling of ethyl arenes, ethylene arenes, and ethyne arenes with benzamidines hydrochloride.
carried out through reacting ethylbenzene (1a) in presence of the yield, and 120 ꢀC was found to be the optimum condition for
ꢀ
1.0 eq. of I2 and 2.0 eq. TBHP as an oxidant at 80 C for 1 h. the oxidative coupling reaction.
Benzamidine hydrochloride (2a) in DMSO was added to this
Tꢀhen, the amount of I2 was varied from 0.5 to 0.1 eq. at
reaction mixture and heating continued for 2 h to obtain a- 120 C by using 3.0 eq. TBHP in DMSO (Table 1, entries 7–10).
ketoimide (3aa) in 26% yield. A slight increase in yield (33%, Use of 0.2 eq. of I2 in presence of 3.0 eq. of TBHP in DMSO as
Table 1, entry 2) was obtained when the same reaction was run solvent gave the best yield (87%). We carried out the neat
by using 3.0 eq. of TBHP. Next, the reactions at varying reaction by adding all components at the same time but could
temperatures (Table 1, entries 3–6) were carried out to improve isolate only a trace amount of the product (Table 1, entry 11).
Table 1 Optimization studies for the oxidative imidation of ethylbenzene
Entry
Catalyst (eq.)
Oxidante (eq.)
Solvent
Temp. (ꢀC)
Yieldd (%)
1a
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (1.0)
I2 (0.5)
I2 (0.3)
I2 (0.2)
I2 (0.1)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
—
TBHP (2.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
DTBP (3.0)
IBX (3.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
80
80
26
33
58
64
56
43
72
84
87
81
Trace
0
35
Trace
Trace
Trace
Trace
Trace
0
—
22
14
18
28
—
—
—
2a
3a
100
120
130
140
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
4a
5a
6a
7a
8a
9a
10a
11b
12a
13a
14a
15a
16a
17a
18a
19a
20c
21a
22a
23a
24a
25a
26a
27a
28a
DMP (3.0)
DIB (3.0)
HTIB (3.0)
DDQ (3.0)
K2S2O8 (3.0)
O2 (1.0 atm)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
TBHP (3.0)
NIS (0.2)
KI (0.2)
CuI (0.2)
TBAI (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
I2 (0.2)
1,4-Dioxane
THF
Toluene
—
a
Reaction conditions: 1a (1.0 mmol), catalyst, and oxidant was heated in sealed tube for 1.0 h, 2a (1.0 mmol) in solvent (3.0 mL) was then added and
heating continued for 2 h. b Reaction condition: 1a (1.0 mmol), I2 (0.2 mmol), TBHP (3.0 mmol) and 2a (1.0 mmol) in DMSO was heated in sealed
tube at 120 ꢀC for 3 h. c Reaction condition: 1a (1.0 mmol), TBHP (3.0 mmol) was heated in sealed tube at 120 ꢀC for 1.0 h, 2a (1.0 mmol) in DMSO
was then added and heating continued for 2 h. d Isolated yield. e TBHP ¼ tert-butyl hydroperoxide, DTBP ¼ di-tert-butyl peroxide, IBX ¼ o-iodoxy-
benzoic acid, DMP ¼ 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)one, DIB ¼ (diacetoxyiodo)benzene, HTIB ¼ [hydro(tosyloxy)iodo]benzene,
DDQ ¼ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, K2S2O8 ¼ potassium persulfate.
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This clearly indicates the importance of stepwise addition. We entries 12–19). The reaction did not proceed in absence of iodine
screened different oxidants namely DTBP, IBX, DMP, DIB, thereby highlighting its importance as a catalyst for this reaction
HTIB, DDQ, K2S2O8, and molecular oxygen with 0.2 eq. of (Table 1, entry 20). Then to further investigate the scope of
molecular I2. A 35% yield was observed in the case of IBX catalyst, we used different catalysts for this reaction such as NIS,
whereas with other oxidants either no reaction occurred or KI, CuI, and TBAI. Low yields (14–28%) were obtained (Table 1,
formation of product in trace amounts was observed (Table 1, entries 21–24) by using above mentioned catalysts.
Table 2 I2/TBHP catalyzed synthesis of a-ketoimides from ethyl arenes and benzamidines hydrochlorideab
a
Reaction conditions: 1 (1.0 mmol), I2 (0.2 mmol), and TBHP (3.0 mmol) was heated in sealed tube at 120 ꢀC for 1.0 h, 2 (1.0 mmol) in DMSO (3.0
b
mL) was added and heating continued for 2 h. Isolated yield.
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No product was formed when DMF, 1,4-dioxane, THF, and yield. 4-Chloro- and 4-bromo-ethylbenzene underwent a smooth
toluene were used as a solvents thereby indicating the dual role reaction to give the corresponding a-ketoimide 3da and 3ea
of DMSO as a solvent as well as co-oxidant in this reaction in 85 and 86% respectively. 4-Nitro- and 2-nitro-ethylbenzene
(Table 1, entries 25–28). Similar results were obtained when reacted satisfactorily with benzamidine hydrochloride (2a)
ethylbenzene (1a) was replaced by styrene (4a) and phenyl- providing the corresponding products 3ba and 3ca in 87
acetylene (5a).
and 81% respectively. Likewise, 1-ethylnaphthalene and
In order to study the wider applicability of this protocol, 2-ethylnaphthalene also offered the corresponding a-ketoimides
we investigated a range of substituted ethyl arenes (1). It was (3ja, 3ka) in 88 and 86% respectively. Notably, heteroaryl
found that various functional groups were compatible with ethanes such as 3-ethyl-2H-benzopyran-2-one and
the reaction conditions furnishing the desired products 3aa– 2-ethylfuran reacted well with selectivity and furnished the
3ad (Table 2) in good to excellent yields. Methyl, methoxy, corresponding a-ketoimides 3la, and 3ma in 88 and 84%
nitro and halogen substituents remained unaffected during yields respectively.
the course of the reaction and their position in the benzene
The scope of the study was further extended to substituted
ring did not show any signicant impact on the rate of reac- benzamidines hydrochloride. The electron neutral (4-CH3),
tion as well as yield of products. 2-Methyl-, 3-methyl-, electron-decient (4-NO2), and electron-rich (4-OMe) groups on
4-methyl- and 4-methoxy-ethylbenzene reacted with benza- the phenyl rings of benzamidines hydrochloride reacted
midine hydrochloride (2a) and formed the corresponding smoothly to afford the corresponding products 3ab–3ad in
a-ketoimides 3fa, 3ga, 3ha and 3ia respectively in 82–88% 83–85% yields (Table 2).
Table 3 I2/TBHP catalyzed synthesis of a-ketoimides from ethylene arenes and benzamidines hydrochlorideab
a
Reaction conditions: 1 (1.0 mmol), I2 (0.2 mmol), and TBHP (3.0 mmol) was heated in sealed tube at 120 ꢀC for 1.0 h, 2 (1.0 mmol) in DMSO (3.0
b
mL) was added and heating continued for 2 h. Isolated yield.
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Delighted with these inspiring results we next focused our hydrochloride reacted smoothly to form the corresponding
attention on C–H functionalization of ethylene arenes (4) and oxidative coupling products (3ab–3ad, Table 3) in good yields
their subsequent oxidative coupling with benzamidines hydro- (82–85%). The above results indicate that the steric and elec-
chloride (2). With the optimal conditions in hand, the scope of tronic nature of the ethylene arenes have little inuence on the
the imidation was investigated. The reaction of styrene (4a) with reaction efficiency.
benzamidine hydrochloride (2a), catalyzed with I2/TBHP gave
With all these results of ethyl arenes (1) and ethylene arenes
the corresponding a-ketoimide (3aa, 90%) in excellent yield. To (4) in hand, we intended to observe the outcome of the reaction
our pleasure, various substituents on the aryl ring such as (4-F, of ethynyl arenes (5) with benzamidines hydrochloride (2).
3-Cl, 2,4-Cl, 2-Br, 4-Br) were compatible with reaction condi- Thus, phenylacetylene (5a) was treated with benzamidine
tions and desired products (Table 3, 3na, 3oa, 3pa, 3qa, and 3ea) hydrochloride (2a) to give the N-(2-oxo-2-phenylacetyl)
were acquired in good to excellent yields (81–88%). Further 2- benzamide 3aa in excellent yield (Table 4, 92%). We then
ethylenenaphthalene and 3-ethylene-2H-benzopyran-2-one also studied the effect of various functional groups onto the oxida-
offered the desired products (3ka, 3la, Table 3) in 89 and 87% tive imidation reaction. We found that methyl, methoxy, and
yield respectively. Then the range of various substituted ben- halogen groups were compatible with the reaction conditions
zamidines hydrochloride was screened. It was found that the 4- and afforded the corresponding imides (Table 4, 3ga, 3ra, 3oa,
CH3, 4-NO2 and 4-OMe substituted benzamidines and 3qa) in good to excellent yields (82–90%). The reaction of
Table 4 I2/TBHP catalyzed synthesis of a-ketoimides from ethyne arenes and benzamidines hydrochlorideab
a
Reaction conditions: 1 (1.0 mmol), I2 (0.2 mmol), and TBHP (3.0 mmol) was heated in sealed tube at 120 ꢀC for 1.0 h, 2 (1.0 mmol) in DMSO (3.0
b
mL) was added and heating continued for 2 h. Isolated yield.
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1-ethynylnaphthalene with benzamidine hydrochloride (2a) iodide (B) was observed and then treatment with DMSO gives
gave the corresponding product in excellent yield (3ja, Table 4, phenyl glyoxal (C). Thus proving the requirement of TBHP as an
90%). Intriguingly, 4-ethynyl furan reacted smoothly to give oxidant, and DMSO as an co-oxidant (Scheme 2b). Phenacyl
N-(2-(furan-2-yl)-2-oxoacetyl)benzamide (3ma, Table 4) in 86% iodide (B) reacted with benzamidine hydrochloride (2a) in
yield. Interestingly, the reaction of 4-ethylphenylacetylene DMSO forming a-ketoimide (3aa) exclusively (Scheme 2c). In
selectively gave the N-(2-(4-acetylphenyl)-2-oxoacetyl)benzamide the presence of additional iodine, phenylglyoxal (C) was
(3sa, Table 4, 85%) under optimal condition as the reactivity of reacted with 2a and afford the oxidative coupling product
acetylene is higher than that of ethyl. Benzamidines hydro- 3aa in 87% yield (Scheme 2d). These results clearly
chloride bearing 4-CH3, 4-NO2 and 4-OMe groups reacted conrmed that the phenacyl iodide (B) and phenylglyoxal (C)
smoothly to form the corresponding products (3ab–3ad, Table was the intermediate in this transformation. However, this
4) in 83–87% yield.
reaction cannot be performed smoothly in the absence of I2
A few control experiments (Scheme 2) were performed in (Scheme 2d and e). This clearly highlights the signicant
order to affirm our proposed mechanism. To prove the role of I2 in C–H functionalization. a-Ketoimide (3aa) was
involvement of TBHP in the formation of phenacyl iodide (B), a not formed when the substrates (1a, 4a, and 5a) were
key intermediate, we treated ethylbenzene (1a), or styrene (4a), reacted with benzamide (2b) under optimum condition
or phenylacetylene (5a) with I2 and DMSO. The reaction failed to (Scheme 2f). The results showed that benzamidine hydro-
produce phenacyl iodide (B) thereby implying the crucial role chloride (2a) may be reacted with phenyl glyoxal (B) gener-
played by TBHP in its formation, through radical intermediates ated in situ from the diverse substrates (1a, 4a, and 5a)
(Scheme 2a). When substrates (1a, 4a, and 5a) was treated with rst and then underwent hydrolysis to obtain the target
I2/TBHP successive formation of acetophenone, phenacyl product 3aa.
Scheme 2 Control experiment.
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Scheme 3 Plausible reaction mechanism.
In context of control experiment the plausible mechanism
for multiple C–H activation followed by oxidative cross-coupling
is depicted in Scheme 3. In the beginning reaction presumably
proceeded via formation of benzylic radical of ethylbenzene and
then 1-phenyl ethanol using I2/TBHP, which eventually were
oxidized to acetophenone (A). This was conrmed by using TLC,
GC-MS and H-NMR. Acetophenone (A) on iodination offered
a-iodo acetophenone (B), a key intermediate, which was also
obtained from styrene (4a) and phenylacetylene (5a) using
General methods
Chemical reagents were obtained from commercial suppliers and
used without further purication. All reactions were performed
in sealed tube and monitored by TLC performed on aluminum
plates (0.25 mm, E. Merck) precoated with silica gel Merck 60 F-
254. Reactions were conducted under atmospheric condition in
anhydrous solvents such as DMSO, DMF, 1,4-dioxane, THF and
toluene. Developed TLC plates were visualized under a short-
1
I2/TBHP. This a-iodo acetophenone (B) was further transformed wavelength UV lamp. Yields refer to spectroscopically (1H, 13C
to aryl glyoxal (C) through Kornblum oxidation which on reac- NMR) homogeneous material obtained aer column chroma-
tion with benzamidine hydrochloride (2a) followed by sequen- tography. Column chromatography was performed on silica gel
tial oxidation and hydrolysis furnished the a-ketoimide (3aa).
(100 : 200 mesh size) supplied by S. D. Fine Chemicals Limited,
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India. IR spectra were recorded on a JASCO-FT/IR-4100 LE with (m, 2H), 7.48–7.54 (distorted dd, J ¼ 7.8, 6.9 Hz, 2H); 13C NMR
1
attenuated total reection (ATR) method. H NMR spectra were (CDCl3, 125 MHz, ppm): d ¼ 184.43, 170.52, 165.57, 148.61,
¨
recorded in CDCl3 or DMSO-d6 solution with a Bruker 300, 400 136.21, 134.66, 132.82, 131.67, 131.26, 128.79, 128.59, 124.89,
and Agilent/Bruker 500 MHz spectrometers. Chemical shis (d) 123.61; HRMS (ESI): calc. for [(C15H10N2O5)H] [M + H]+
¨
are reported relative to SiMe4 (d ¼ 0.0) as an internal standard. 299.0668, found 299.0673.
The number of protons (n) for a given resonance is indicated by
N-(2-(4-Chlorophenyl)-2-oxoacetyl)benzamide (3da). Yellow
nH. Peak multiplicities are designated by the following abbrevi- solid; mp 72–74 C; IR (ATR) ṽ (cmꢂ1): 3447, 1695, 1590, 1421,
ations: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, 1214, 1091, 693; 1H NMR (CDCl3, 300 MHz, ppm): d ¼ 10.03
doublet of doublet; ddd, doublet of doublet of doublet; tt, triplet (bs, 1H), 8.07 (d, J ¼ 8.1 Hz, 2H), 7.92 (d, J ¼ 7.5 Hz, 2H),
of triplet; br, broad; J, coupling constant in Hz. 13C NMR spectra 7.46–7.66 (m, 5H); 13C NMR (CDCl3, 75 MHz, ppm): d ¼ 185.39,
ꢀ
¨
were recorded in CDCl3 or DMSO-d6 solution with a Bruker 75, 169.31, 165.41, 141.47, 134.12, 131.50, 131.01, 130.90, 129.39,
100 and Agilent/Bruker 125 MHz spectrometers and resonances 129.17, 128.19; HRMS (ESI): calc. for [(C15H10ClNO3)H] [M + H]+
¨
are given in ppm. High-resolution mass spectra were obtained by 288.0427, found 288.0422.
using positive electrospray ionization (ESI) by Time of Flight
(TOF) method.
N-(2-(4-Bromophenyl)-2-oxoacetyl)benzamide (3ea). Yellow
solid; mp 74–76 C; IR (ATR) ṽ (cmꢂ1): 3444, 1695, 1585, 1219,
ꢀ
1071, 978, 695; 1H NMR (CDCl3, 500 MHz, ppm): d ¼ 9.67
(bs, 1H), 8.03 (d, J ¼ 7.0 Hz, 2H), 7.89 (d, J ¼ 7.5 Hz, 2H), 7.65–
7.69 (distorted dd, J ¼ 8.0, 5.5 Hz, 3H), 7.53 (t, J ¼ 5.5 Hz, 2H);
13C NMR (DMSO-d6, 75 MHz, ppm): d ¼ 186.55, 170.64, 167.39,
134.03, 132.34, 131.66, 131.44, 131.25, 130.70, 130.21, 128.78;
HRMS (ESI): calc. for [(C15H10BrNO3)H] [M + H]+ 331.9922,
found 331.9926.
General experimental procedure for the synthesis of a-
ketoimides
A sealed tube equipped with a magnetic stirring bar was
charged with ethyl arenes (1) or ethylene arenes (4) or ethyne
arenes (5) (1.0 mmol), I2 (0.20 mmol), tert-butyl hydroperoxide
(TBHP, 3.0 mmol, 70% aq. solution). The reaction vessel was
carried out at 120 ꢀC for 1 h. Aer disappearance of the reactant
monitored by TLC, benzamidines hydrochloride (2) in DMSO (3
mL) was added to the above reaction mixture at R. T. and heated
for 2 h. Aer completion, the reaction mass was quenched with
10% aq. Na2S2O3 solution (20 mL) and extracted with EtOAc (3
ꢁ 30 mL). The above organic layer was washed with brine
solution (1 ꢁ 50 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was puried
by column chromatography on silica gel with n-hexane : ethyl
acetate (75 : 25) as eluent to afford desired products 3.
N-(2-oxo-2-(o-Tolyl)acetyl)benzamide (3fa). White solid; mp
152–154 ꢀC; IR (ATR) ṽ (cmꢂ1): 3445, 3290, 1712, 1692, 1675,
1
1602, 1341, 1242, 1218, 742; H NMR (CDCl3, 500 MHz, ppm):
d ¼ 9.74 (bs, 1H), 7.81 (d, J ¼ 6.0 Hz, 4H), 7.54 (distorted t, J ¼
7.0, 6.0 Hz, 1H), 7.46 (distorted t, J ¼ 7.0, 6.0 Hz, 4H), 2.42 (s,
3H); 13C NMR (CDCl3, 100 MHz, ppm): d ¼ 186.82, 168.89,
165.91, 141.61, 134.66, 134.60, 134.01, 132.76, 130.79, 129.05,
128.18, 127.69, 123.21, 21.41; HRMS (ESI): calc. for
[(C16H13NO3)H] [M + H]+ 268.0973, found 268.0976.
N-(2-oxo-2-(m-Tolyl)acetyl)benzamide (3ga). White solid; mp
164–166 ꢀC; IR (ATR) ṽ (cmꢂ1): 3447, 3287, 1715, 1697, 1680,
1
1608, 1344, 1247, 1222, 751; H NMR (CDCl3, 500 MHz, ppm):
Characterization data of compounds 3aa–3sa and 3ab–3ad
d ¼ 9.57(bs, 1H), 8.09 (s, 1H), 8.00 (d, J ¼ 7.5 Hz, 1H), 7.87
N-(2-oxo-2-Phenylacetyl)benzamide (3aa). Light yellow solid; (d, J ¼ 7.0 Hz, 2H), 7.61–7.66 (distorted dd, J ¼ 8.0 Hz, 2H), 7.52
mp 138–140 ꢀC; IR (ATR) ṽ (cmꢂ1): 3445, 3288, 1723, 1684, 1596, (distorted t, J ¼ 7.0 Hz, 2H), 7.46 (distorted t, J ¼ 7.5, 7.0 Hz, 1H),
1346, 1210, 761, 714; 1H NMR (CDCl3, 400 MHz, ppm): d ¼ 9.86 2.33 (s, 3H); 13C NMR (CDCl3, 125 MHz, ppm): d ¼ 186.03,
(bs, 1H), 8.13 (d, J ¼ 7.2 Hz, 2H), 7.92 (d, J ¼ 7.6 Hz, 2H), 7.62– 170.92, 166.31, 148.89, 135.80, 134.13, 132.65, 131.31, 129.30,
7.69 (q, J ¼ 7.6 Hz, 2H), 7.50–7.55 (m, 4H); 13C NMR (CDCl3, 75 128.94, 128.36, 128.28, 127.74, 21.44; HRMS (ESI): calc. for
MHz, ppm): d ¼ 186.62, 165.31, 134.71, 134.00, 132.40, 131.06, [(C16H13NO3)H] [M + H]+ 268.0973, found 268.0978.
130.17, 129.14, 128.95, 128.13; HRMS (ESI): calc. for
[(C15H11NO3)H] [M + H]+ 254.0817, found 254.0822.
N-(2-oxo-2-(p-Tolyl)acetyl)benzamide (3ha). White solid; mp
156–158 ꢀC; IR (ATR) ṽ (cmꢂ1): 3450, 3292, 1720, 1685, 1675,
1
N-(2-(4-Nitropꢀhenyl)-2-oxoacetyl)benzamide (3ba). Yellow 1612, 1352, 1254, 1226, 749; H NMR (CDCl3, 500 MHz, ppm):
solid; mp 80–82 C; IR (ATR) ṽ (cmꢂ1): 3256, 1718, 1693, 1675, d ¼ 9.70 (bs, 1H), 8.09 (d, J ¼ 8.0 Hz, 2H), 7.90 (d, J ¼ 7.5 Hz, 2H),
1530, 1342, 1205, 765, 718; 1H NMR (DMSO-d6, 300 MHz, ppm): 7.64 (t, J ¼ 7.5, 7.0 Hz, 1H), 7.52 (t, J ¼ 8.0, 7.5 Hz, 2H), 7.33
d ¼ 12.10 (bs, 1H), 8.40 (d, J ¼ 8.7 Hz, 2H), 8.20 (d, J ¼ 8.7 Hz, (d, J ¼ 8.0 Hz, 2H), 2.45 (s, 3H); 13C NMR (DMSO-d6, 75 MHz,
2H), 7.86 (t, J ¼ 6.9, 1.5 Hz, 2H), 7.43–7.55 (m, 3H); 13C NMR ppm): d ¼ 187.25, 171.07, 167.09, 145.00, 133.90, 130.44, 129.97,
(CDCl3, 125 MHz, ppm): d ¼ 185.21, 170.09, 168.21, 150.56, 129.68, 128.97, 128.75, 21.29; HRMS (ESI): calc. for
136.04, 133.51, 131.42, 130.08, 128.40, 127.16, 123.15; HRMS [(C16H13NO3)H] [M + H]+ 268.0973, found 268.0969.
(ESI): calc. for [(C15H10N2O5)H] [M + H]+ 299.0668, found
299.0673.
N-(2-(4-Methoxyphenyl)-2-oxoacetyl)benzamide (3ia). Off
white solid; mp 158–160 ꢀC; IR (ATR) ṽ (cmꢂ1): 3448, 3295, 1718,
1
N-(2-(2-Nitropꢀhenyl)-2-oxoacetyl)benzamide (3ca). Yellow 1691, 1675, 1604, 1269, 1152, 738; H NMR (CDCl3, 400 MHz,
solid; mp 76–78 C; IR (ATR) ṽ (cmꢂ1): 3251, 1719, 1692, 1671, ppm): d ¼ 10.13 (bs, 1H), 8.23 (d, J ¼ 4.4 Hz, 2H), 8.07 (d, J ¼ 5.6
1526, 1349, 1208, 746; 1H NMR (DMSO-d6, 300 MHz, ppm): Hz, 1H), 7.93 (s, 2H), 7.64 (s, 1H), 7.52 (s, 1H), 6.99 (distorted t, J
d ¼ 12.17 (bs, 1H), 8.38–8.41 (dd, J ¼ 8.1, 1.0 Hz, 1H), 8.10–8.17 ¼ 7.6, 6.4 Hz, 2H), 3.90 (s, 3H); 13C NMR (CDCl3, 100 MHz,
(ddd, J ¼ 8.1, 7.8, 1.5, 1.0 Hz, 2H), 7.96–8.00 (m, 2H), 7.85–7.90 ppm): d ¼ 184.58, 165.11, 164.04, 133.79, 133.22, 132.35, 129.10,
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128.07, 125.34, 114.36, 113.77, 55.66; HRMS (ESI): calc. for 127.44, 125.50; HRMS (ESI): calc. for [(C15H10ClNO3)H] [M + H]+
[(C16H13NO4)H] [M + H]+ 284.0923, found 284.0919.
288.0427 found 288.0423.
N-(2-(Naphthalen-1-yl)-2-oxoacetyl)benzamide (3ja). Light
N-(2-(2,4-Dichlorophenyl)-2-oxoacetyl)benzamide
(3pa).
yellow solid; mp 74–76 ꢀC; IR (ATR) ṽ (cmꢂ1): 3442, 3281, 1715, Yellow solid; mp 78–80 ꢀC; IR (ATR) ṽ (cmꢂ1): 3451, 3279, 1717,
1681, 1645, 1397, 1318, 1219, 768, 695; 1H NMR (CDCl3, 400 1687, 1673, 1509, 1244, 759; 1H NMR (DMSO-d6, 300 MHz,
MHz, ppm): d ¼ 9.79 (s, 1H), 9.12 (d, J ¼ 8.4 Hz, 1H), 8.12 (d, J ¼ ppm): d ¼ 12.55 (s, 1H), 8.07 (t, J ¼ 9.0, 8.4 Hz, 2H), 7.95 (d, J ¼
8.0 Hz, 2H), 7.93 (distorted t, J ¼ 7.2 Hz, 3H), 7.72 (t, J ¼ 7.6 Hz, 7.2 Hz, 1H), 7.86 (s, 1H), 7.66–7.75 (distorted q, J ¼ 9.6, 8.7, 6.9
1H), 7.48–7.65 (m, 5H); 13C NMR (CDCl3, 100 MHz, ppm): d ¼ Hz, 2H), 7.60 (distorted t, J ¼ 6.9 Hz, 2H); 13C NMR (DMSO-d6,
188.69, 172.43, 165.23, 135.54, 134.11, 133.96, 133.60, 131.29, 75 MHz, ppm): d ¼ 183.93, 170.40, 167.75, 139.68, 134.92,
131.08, 129.18, 129.14, 128.72, 128.10, 127.98, 126.99, 125.86, 134.16, 133.40, 130.82, 130.16, 129.35, 128.92, 128.80, 128.36;
124.31; HRMS (ESI): calc. for [(C19H13NO3)H] [M + H]+ 304.0973, HRMS (ESI): calc. for [(C15H9Cl2NO3)H] [M + H]+ 322.0037,
found 304.0967.
found 322.0035.
N-(2-(Naphthalen-2-yl)-2-oxoacetyl)benzamide (3ka). Light
N-(2-(2-Bromophenyl)-2-oxoacetyl)benzamide (3qa). Yellow
yellow solid; mp 184–186 ꢀC; IR (ATR) ṽ (cmꢂ1): 3448, 1715, solid; mp 70–72 C; IR (ATR) ṽ (cmꢂ1): 3456, 3274, 1719, 1688,
ꢀ
1
1684, 1627, 1465, 1251, 710; H NMR (CDCl3, 400 MHz, ppm): 1587, 1211, 747; 1H NMR (CDCl3, 400 MHz, ppm): d ¼ 10.13 (s,
d ¼ 9.84 (s, 1H), 8.82 (s, 1H), 8.15 (d, J ¼ 8.4 Hz, 1H), 7.89–8.00 1H), 7.91–8.02 (distorted ddd, J ¼ 7.6, 6.8 Hz, 2H), 7.68 (d, J ¼
(m, 5H), 7.51–7.65 (m, 5H); 13C NMR (CDCl3, 100 MHz, ppm): d 7.2 Hz, 1H), 7.58–7.64 (distorted q, J ¼ 7.2 Hz, 1H), 7.43–7.52 (m,
¼ 186.46, 165.25, 136.53, 134.09, 134.03, 132.59, 131.50, 130.31, 5H); 13C NMR (CDCl3, 100 MHz, ppm): d ¼ 186.50, 168.73,
129.82, 129.69, 129.31, 129.15, 128.20, 128.06, 127.26, 124.50; 165.71, 137.10, 134.56, 134.32, 134.05, 132.82, 130.87, 129.10,
HRMS (ESI): calc. for [(C19H13NO3)H] [M + H]+ 304.0973, found 128.25, 127.62, 123.12; HRMS (ESI): calc. for [(C15H10BrNO3)H]
304.0969.
N-(2-oxo-2-(2-oxo-2H-Chromen-3-yl)acetyl)benzamide (3la).
[M + H]+ 331.9922 found 331.9929.
N-(2-(2,6-Dimethoxyphenyl)-2-oxoacetyl)benzamide
(3ra).
Yellow solid; mp 216–218 ꢀC; IR (ATR) ṽ (cmꢂ1): 3262, 1725, Light yellow solid; mp 124–126 ꢀC; IR (ATR) ṽ (cmꢂ1): 3448,
1708, 1671, 1602, 1563, 1252, 956, 760; 1H NMR (DMSO-d6, 400 3287, 1708, 1677, 1655, 1602, 1252, 1160, 742; 1H NMR (CDCl3,
MHz, ppm): d ¼ 12.39 (s, 1H), 9.07 (s, 1H), 8.03–8.10 (dd, J ¼ 8.0, 400 MHz, ppm): d ¼ 10.05 (s, 1H), 7.96 (d, J ¼ 6.8 Hz, 2H), 7.59 (t,
7.6 Hz, 3H), 7.84 (t, J ¼ 7.6 Hz, 1H), 7.72 (t, J ¼ 7.6, 7.2 Hz, 1H) J ¼ 8.4, 6.8 Hz, 2H), 7.46 (d, J ¼ 6.8 Hz, 2H), 7.17 (d, J ¼ 7.2 Hz,
7.49–7.59 (m, 4H); 13C NMR (DMSO-d6, 100 MHz, ppm): d ¼ 1H), 6.93 (d, J ¼ 8.4 Hz, 1H), 3.84 (s, 3H), 3.74 (s, 3H); 13C NMR
182.73, 170.16, 167.93, 158.83, 154.80, 148.65, 135.56, 134.00, (CDCl3, 100 MHz, ppm): d ¼ 185.14, 170.92, 165.96, 154.92,
131.46, 130.10, 128.84, 128.64, 125.44, 119.93, 118.11, 116.54; 154.33, 133.84, 130.58, 129.04, 128.21, 124.11, 122.65, 114.40,
HRMS (ESI): calc. for [(C18H11NO5)Na] [M + Na]+ 344.0534, 112.22, 56.75, 55.89; HRMS (ESI): calc. for [(C17H15NO5)H] [M +
found 344.0537.
H]+ 314.1028, found 314.1031.
N-(2-(Furan-2-yl)-2-oxoacetyl)benzamide (3ma). Off white
N-(2-(4-Acetylphenyl)-2-oxoacetyl)benzamide (3sa). Off white
solid; mp 154–156 ꢀC; IR (ATR) ṽ (cmꢂ1): 3241, 1723, 1652, 1465, solid; mp 191–192 ꢀC; IR (ATR) ṽ (cmꢂ1): 3452, 3275, 1718, 1680,
1411, 1351, 1273, 773; 1H NMR (CDCl3, 400 MHz, ppm): d ¼ 1668, 1560, 1248, 1162, 784; 1H NMR (CDCl3, 500 MHz, ppm): d
10.01 (s, 1H), 8.55 (t, J ¼ 3.6, 3.2 Hz, 1H), 8.24 (d, J ¼ 3.2 Hz, 1H), ¼ 9.80 (bs, 1H), 8.16 (d, J ¼ 7.5 Hz, 2H), 8.02 (d, J ¼ 7.5 Hz, 2H),
8.20 (s, 1H), 7.82 (s, 1H), 7.67 (s, 1H), 7.54 (distorted t, J ¼ 3.2, 7.78–7.82 (distorted dd, J ¼ 7.0, 5.0 Hz, 3H), 7.66 (distorted t, J ¼
2.0 Hz, 2H), 7.48 (d, J ¼ 3.2 Hz, 1H); 13C NMR (CDCl3, 100 MHz, 5.0 Hz, 1H), 2.67 (s, 3H); 13C NMR (CDCl3, 125 MHz, ppm): d ¼
ppm): d ¼ 178.30, 164.39, 160.90, 157.59, 148.51, 137.24, 131.16, 197.24, 186.91, 167.10, 165.33, 145.33, 134.85, 132.61, 130.30,
128.71, 124.77, 113.27, 110.94; HRMS (ESI): calc. for 130.03, 129.12, 128.36, 27.28; HRMS (ESI): calc. for
[(C13H9NO4)Na] [M + Na]+ 266.0429, found 266.0430.
[(C17H13NO4)H] [M + H]+ 296.0923, found 296.0927.
N-(2-(4-Fluorophenyl)-2-oxoacetyl)benzamide (3na). Off
4-Methyl-N-(2-oxo-2-phenylacetyl)benzamide (3ab). White
white solid; mp 158–160 ꢀC; IR (ATR) ṽ (cmꢂ1): 3438, 1694, 1589, solid; mp 148–150 ꢀC; IR (ATR) ṽ (cmꢂ1): 3352, 3288, 1719, 1681,
1423, 1214, 1085, 698; 1H NMR (DMSO-d6, 300 MHz, ppm): d ¼ 1674, 1518, 1256, 1228, 751; 1H NMR (CDCl3, 500 MHz, ppm): d
12.48 (s, 1H), 7.98–8.05 (m, 4H), 7.70 (t, J ¼ 7.2 Hz, 1H), 7.55 (t, J ¼ 9.76 (bs, 1H), 8.12 (d, J ¼ 7.5 Hz, 2H), 7.80–7.81 (distorted dd,
¼ 7.8, 7.5 Hz, 2H), 7.44 (t, J ¼ 8.7 Hz, 2H); 13C NMR (DMSO-d6, J ¼ 8.0, 1.5 Hz, 2H), 7.66 (distorted tt, J ¼ 7.5, 1.5 Hz, 1H), 7.53
75 MHz, ppm): d ¼ 186.16, 170.84, 167.34, 165.55 (d, JF ¼ 252.3 (distorted tt, J ¼ 7.5, 1.5 Hz, 2H), 7.30 (d, J ¼ 7.5 Hz, 2H), 2.43 (s,
Hz), 134.00, 132.00 (d, JF ¼ 9.75 Hz), 130.36, 129.20 (d, JF ¼ 2.8 3H); 13C NMR (CDCl3, 125 MHz, ppm): d ¼ 186.85, 165.27,
Hz), 128.83, 128.80, 116.45 (d, JF ¼ 22.3 Hz); HRMS (ESI): calc. 145.27, 134.79, 132.55, 130.24, 129.97, 129.06, 128.30, 21.85;
for [(C15H10FNO3)H] [M + H]+ 272.0723, found 272.0729.
HRMS (ESI): calc. for [(C16H13NO3)H] [M + H]+ 268.0973, found
N-(2-(3-Chlorophenyl)-2-oxoacetyl)benzamide (3oa). Light 268.0970.
white solid; mp 74–76 C; IR (ATR) ṽ (cmꢂ1): 3445, 3275, 1713,
4-Methoxy-N-(2-oxo-2-phenylacetyl)benzamide (3ac). White
ꢀ
1694, 1678, 1513, 1238, 768; 1H NMR (CDCl3, 500 MHz, ppm): d solid; mp 162–164 ꢀC; IR (ATR) ṽ (cmꢂ1): 3260, 1721, 1685, 1675,
¼ 9.59 (bs, 1H), 8.11 (s, 1H), 8.02 (d, J ¼ 8.0 Hz, 1H), 7.89 (d, J ¼ 1585, 1254, 1226, 749; 1H NMR (CDCl3, 500 MHz, ppm): d ¼ 9.83
7.5 Hz, 2H), 7.63–7.68 (distorted dd, J ¼ 8.5 Hz, 2H), 7.54 (dis- (bs, 1H), 8.09 (d, J ¼ 7.5 Hz, 2H), 7.89 (d, J ¼ 9.0 Hz, 2H), 7.65 (t, J
torted t, J ¼ 7.0, 6.5 Hz, 2H), 7.48 (distorted t, J ¼ 7.5 Hz, 1H); 13
C
¼ 7.5 Hz, 1H), 7.52 (t, J ¼ 8.0 Hz, 2H), 6.97 (d, J ¼ 9.0 Hz, 2H),
NMR (CDCl3, 100 MHz, ppm): d ¼ 185.08, 170.85, 169.35, 3.87 (s, 3H); 13C NMR (CDCl3, 125 MHz, ppm): d ¼ 186.99,
134.62, 133.38, 132.80, 132.45, 130.16, 129.75, 128.75, 128.18, 164.80, 164.42, 134.70, 132.63, 130.58, 130.11, 129.06, 123.05,
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114.55, 55.76; HRMS (ESI): calc. for [(C16H13NO4)H] [M + H]+
284.0923, found 284.0925.
H. Khanwalkar, P. Germain, G. Lemaire, F. Rodrıguez-
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4-Nitro-N-(2-oxo-2-phenylacetyl)benzamide (3ad). Light
yellow solid; mp 188–190 ꢀC; IR (ATR) ṽ (cmꢂ1): 3336, 3250,
1
1736, 1680, 1515, 1356, 1208, 1168, 768, 720; H NMR (CDCl3,
500 MHz, ppm): d ¼ 9.54 (bs, 1H), 8.38 (d, J ¼ 9.0 Hz, 2H), 8.28
(d, J ¼ 8.5 Hz, 2H), 7.89 (d, J ¼ 7.0 Hz, 2H), 7.68 (t, J ¼ 7.5 Hz,
1H), 7.55 (t, J ¼ 8.0, 7.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz,
ppm): d ¼ 186.27, 170.20, 165.57, 151.62, 137.10, 136.20, 134.57,
131.14, 129.46, 128.22, 124.21; HRMS (ESI): calc. for
[(C15H10N2O5)H] [M + H]+ 299.0668, found 299.0671.
Conclusion
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In summary, an iodine catalyzed operationally simple synthetic
protocol for formation of a-ketoimide from diverse substrates
in presence of TBHP has been developed. We strongly believe
that this functional group tolerant metal-free tandem synthetic
approach would be useful for the synthesis of complex mole-
cules in the eld of pharmaceuticals and materials.
Acknowledgements
This work was supported by Council of Scientic and Industrial
Research, New Delhi (sanction no. 01(2427)/10/EMR-II dated 28/
12/2010 and pool scheme no. 8644 A). H.P.K. and K.S.V. thank
Council of Scientic and Industrial Research, New Delhi and
University Grants Commission-Special Assistance Programme,
respectively for award of Senior Research Fellowships. The
authors thank Prof. Prakash M. Bhate for his generous support.
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