The oxidative cross-coupling of benzonitriles with multiform substrates: A domino strategy inspired easy access to α-keto-imides

Article abstract of DOI:10.1055/s-0034-1379955

An iodine-promoted highly efficient convergent synthesis of α-ketoimides from multiform substrates and benzonitriles through oxidative imidation reaction is described. This domino oxidative imidation process involves cleavage of C-H bond and construction of C-O and C-N bonds. This method could be a powerful compliment to the existing methods owing to its use of abundantly available starting materials and reagents.

Full text of DOI:10.1055/s-0034-1379955

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 429–438
paper
429
H. P. Kalmode et al.
Paper
Synthesis
The Oxidative Cross-Coupling of Benzonitriles with Multiform
Substrates: A Domino Strategy Inspired Easy Access to α-Keto-
imides
Hanuman P. Kalmodea
Kamlesh S. Vadagaonkara
Atul C. Chaskar*a,b
R
O
N
H
OH
N
I2, DMSO
or
or
+
Ar
Ar
Ar
Ar
110 °C, 12 h
O
O
R
a Department of Dyestuff Technology, Institute of Chemical
Technology, Mumbai 400019, India
b National Centre for Nanosciences and Nanotechnology, Uni-
versity of Mumbai, Mumbai 400098, India
achaskar25@gmail.com
metal-free!
acid-/base-free!
This work is dedicated to our mentor Prof. P. M. Bhate on the
occasion of his 61st birthday.
Received: 18.10.2014
Accepted after revision: 06.12.2014
Published online: 14.01.2015
Conventionally, amides are prepared by coupling a car-
boxylic acid or its derivatives with amines4 while acyl ha-
lides are used for the preparation of imides.5 The literature
reported methods for the synthesis of α-ketoamides are
amidation of α-keto acids,6 α-ketoaryl halides,7 cyano ke-
tones,8 oxidation or photochemical reaction of amides,9
double carboxylative amidation of aryl halides,10 oxidation
of acyl cyanophosphoranes followed by the amidation of
α,β-diketone nitrile,11 and reaction of isocyanides with aro-
matic acyl chlorides.12 Li13 and Liu et al.14 synthesized am-
ides from aldehydes using copper and n-Bu4NI, respectively,
together with TBHP. In recent years, I2 in combination with
DMSO has proved to be an environment-friendly, metal-
free effective system for the series of organic reactions par-
ticularly in C–H functionalization. This approach has
emerged as an attractive tool in organic synthesis due to its
diverse applications.
α-Ketoamides are synthesized via copper-catalyzed oxi-
dative coupling of aryl acetylenes, aryl acetaldehydes, α-
carbonyl aldehydes, and aryl methyl ketones with ani-
lines.15 However, the use of toxic metal oxidants restrict the
utility of these methods, especially in the case of the syn-
thesis of drug intermediates owing to possible contamina-
tion of these with trace amount of heavy metals. Iodine or
iodine-peroxide has emerged as an effective reagent for sp3
C–H bond oxidative amidation of methyl ketones.16 Wu et
al. extensively demonstrated the promising applications of
DOI: 10.1055/s-0034-1379955; Art ID: ss-2014-n0634-op
Abstract An iodine-promoted highly efficient convergent synthesis of
α-ketoimides from multiform substrates and benzonitriles through oxi-
dative imidation reaction is described. This domino oxidative imidation
process involves cleavage of C–H bond and construction of C–O and C–
N bonds. This method could be a powerful compliment to the existing
methods owing to its use of abundantly available starting materials and
reagents.
Key words iodine, metal-free synthesis, Kornblum oxidation, α-keto-
imides, multiform substrates
Amides, imides, α-ketoamides, and α-ketoimides are
crucial structural units in numerous natural products,
drugs, and proteins.1 All these molecules are very import-
ant due to their ability to easily undergo functional group
manipulation during synthesis of various biologically active
heterocyclic ring systems.2 Imides are present in biological-
ly active molecules and have been targets of interest for the
synthesis of pharmaceuticals.1 α-Ketoamides are potent in-
hibitors of the hepatitis C virus NS3 serine protease,
cathepsin K, calpain inhibitor such as SNJ-1945 and p38
MAP kinase, etc.3 Hence, numerous methodologies have
been developed for synthesizing this group of building
blocks.
R
O
H
N
OH
N
I2, DMSO
or
Ar
or
Ar
+
Ar
Ar
110 °C, 12 h
O
O
R
1
4
5
2
3
Scheme 1 The oxidative imidation of ethylenearenes, ethynearenes, and 1-arylethanols with benzonitriles
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 429–438

430
H. P. Kalmode et al.
Paper
Synthesis
multi-pathway coupled domino (MPCD) strategies17 while
Zhang and co-workers had employed anodic oxidation of
aryl methyl ketones.18 The oxidative amidation of 2-oxoal-
dehyde was achieved using dimethyl sulfoxide19 whereas
polysubstituted oxazoles were obtained through domino
oxidative cyclization by using I2/TBHP.20a Wang et al. report-
ed the synthesis of 2,5-disubstituted oxazoles by using 2-
amino-1-phenylethanone and aromatic aldehydes,20b 2-
phenylquinazolines from 2-amino benzophenones and
benzylic amines,20c quinazolines from α-amino acids and 2-
aminobenzoketones,20d ketones from benzylic methylenes,
and nitriles from primary amines by using I2/TBHP.20e Chiral
α-ketoimides have been derived from Oppolzer’s sultam by
the diastereoselective addition of Grignard reagents, as re-
ported by Jurczak and co-workers.21
Moreover, to the best of our knowledge, no reports have
been demonstrated by using multiform substrates and ben-
zonitriles to construct α-ketoimide skeleton. In the context
of the advantages of domino reaction and limitations of
aforementioned methods, herein we present the I2-promot-
ed sequential cleavage of C–H bond and formation of C–O,
C–N bonds of multiform substrates with benzonitriles,
which is highly desirable. We have centered our attention
on oxidative imidation of ethylenearenes 1, ethynearenes 4,
and 1-arylethanols 5 (Scheme 1).
To initiate our study, the reaction of styrene (1a) with
benzonitrile (2a) in the presence of different additives, oxi-
dants, and acids or bases in DMSO was chosen as a model
reaction. The reaction of styrene (1a) (1.0 mmol) and ben-
zonitrile (2a) (3.0 mmol) with 0.5 equivalent of I2 at 100 °C
for 12 hours could only afford the expected product in 12%
yield (Table 1, entry 1).
Varying concentrations of I2 were scanned to improve
the yield and 1.5 equivalents of I2 was found to be the opti-
mal amount for the oxidative coupling reaction (Table 1, en-
tries 2–4). Increase in the concentration of benzonitrile (2a)
from 3 to 5 equivalents with 1.5 equivalents of I2 provided
3a in 52% yield (entry 5). Further increase in the concentra-
tion of benzonitrile from 5 to 15 equivalents afforded the
desired product 3a from 66–77% yield (entries 6, 7). Next,
the reactions at varying temperatures (entries 8, 9) were
carried out to increase the yield, and 110 °C was found to be
the optimum temperature for the oxidative imidation reac-
tion. The reaction could not occur in the absence of I2 (entry
10), which suggests that the I2 played a crucial role in the
reaction.
Table 1 Optimization Studies for the Oxidative Imidation of Styrene
with Benzonitrilea
O
H
1a
N
additive, oxidant
+
acid/base, DMSO
temperature, 12 h
O
O
N
3a
2a
Additive
Entry
Oxidant Acid
(equiv)
Base
Temp
(°C)
Yield
(%)b
(equiv)
1a
2a
3a
4a
5c
6d
7e
8e
I2 (0.5)
I2 (1.0)
I2 (1.5)
I2 (2.0)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
100
100
100
100
100
100
100
110
120
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
12
28
41
37
52
66
77
86
84
0
–
–
–
–
–
–
–
–
–
–
–
–
–
–
9e
–
–
10e
11e
12e
13e
14e
15e
16e
17e
18e
19e
20e
21e
22e
23e
24e
25e
26e
27e
28e
–
–
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
I2 (1.5)
NIS (1.5)
KI (1.5)
CuI (1.5)
TBAI (1.5)
–
PTSA
54
49
43
38
16
14
–
AcOH
–
TFA
–
H2SO4
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
DIPEA
–
DBU
–
Et3N
trace
–
NaHCO3
0
47
33
44
40
37
34
29
26
23
56
TBHP
DTBP
IBX
DMP
DIB
HTIB
–
–
–
–
–
–
–
–
–
–
–
–
–
–
a Reaction conditions: 1a (1.0 mmol), 2a (3.0 mmol), additive (0.5–2.0
mmol), oxidant (1.0 mmol), and acid or base (1.0 mmol) in DMSO (2.0 mL)
were heated in a sealed tube for 12 h. TBHP: tert-butyl hydroperoxide; DTBP:
di-tert-butyl peroxide; IBX: o-iodoxybenzoic acid; DMP: 1,1,1-triacetoxy-1,1-
dihydro-1,2-benziodoxol-3(1H)-one; DIB: (diacetoxyiodo)benzene; HTIB:
[hydro(tosyloxy)iodo]benzene.
b Isolated yields.
Generally in situ hydration of the nitrile group is per-
formed in the presence of acid or base. To optimize the oxi-
dative imidation reaction a variety of acids and bases were
used. It was found that acids or bases could not promote the
reaction effectively (Table 1, entries 11–18). The range of
different oxidizing agents (TBHP, DTBP, IBX, DMP, DIB, and
HTIB) for the oxidative imidation reaction was also investi-
gated. A 47% yield was observed in the case of TBHP where-
as other oxidants gave relatively lower yields (entries 19–
c Amount of 2a: 5.0 mmol.
d Amount of 2a: 10.0 mmol.
e Amount of 2a: 15.0 mmol.
24). Then, to further investigate the scope of additive, dif-
ferent additives such as NIS, KI, CuI, and TBAI were used for
this reaction. Low to moderate yields (23–56%) were ob-
tained (entries 25–28) by using above mentioned additives.
Thus, the optimized conditions for the oxidative coupling
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 429–438

431
H. P. Kalmode et al.
Paper
Synthesis
reaction involved the use of 1.5 equivalents of I2 and 15
equivalents of benzonitrile with styrene in DMSO (2 mL) at
110 °C. Very similar results were obtained when styrene
(1a) was replaced by phenylacetylene (4a) and 1-phenyl-
ethanol (5a).
To extend the scope of this reaction, benzonitriles with
neutral (4-Me), electron-deficient (4-NO2), and electron-
rich (4-OMe) groups on the phenyl ring were reacted with
styrene (1a) to furnish the corresponding products 3q–s in
82−89% yields (Scheme 2). These results indicate that there
is a small influence on reaction efficiency due to steric and
electronic nature of the ethylenearenes 1 and benzonitriles
2.
Delighted with these encouraging results, our attention
was next turned to the oxidative imidation of ethynylarenes
4 with benzonitriles 2. With the optimal conditions in
hand, the scope of the imidation was investigated. The reac-
tion of phenylacetylene (4a) with benzonitrile (2a) using I2
in DMSO gave the corresponding α-ketoimide 3a in 88%
yield. Various substituents on the phenyl ring such as 4-F,
3-Cl, 2,4-Cl2, 2-Br, and 4-Br were compatible with reaction
conditions and the desired products 3l–o, and 3d were ob-
tained in good to excellent yields (84–90%) (Scheme 3). Fur-
ther, 2-ethynylnaphthalene and 3-ethynyl-2H-chromen-2-
one also gave the desired products 3j and 3k in 87 and 88%
In order to study the scope of this protocol, various eth-
ylenearenes 1 were reacted with benzonitriles 2 (Scheme
2). Various functional groups were found to be compatible
under the optimized reaction conditions. Ethylenearenes
with methyl, methoxy, nitro, and halogen substituents on
the phenyl ring underwent oxidative cross coupling reac-
tion with benzonitrile (2a) smoothly to form the corre-
sponding α-ketoimides 3b–g in 83–89% yields. 1-Eth-
ylenenaphthalene and 2-ethylenenaphthalene afforded the
corresponding α-ketoimides 3i and 3j in 86 and 88% yield,
respectively. Notably, heteroaryl ethylenes such as 2-vinyl-
furan and 3-vinyl-2H-chromen-2-one reacted well with se-
lectivity to afford the corresponding α-ketoimides 3h and
3k in 87 and 85% yield, respectively.
R
O
N
H
I2, DMSO
N
Ar
O
Ar
+
110 °C, 12 h
O
O
R
1
2
3
O
O
O
H
H
N
H
H
N
N
N
O
O
O
O
O
O
O
O
O2N
Cl
Br
3c (87%)
3b (89%)
3d (88%)
3a (86%)
O
O
O
O
O
H
N
H
N
H
N
N
O
O
H
O
O
O
O
O
O
O
MeO
3g (84%)
3e (83%)
3f (85%)
3h (87%)
O
O
O
H
H
H
H
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
3j (88%)
3k (85%)
3q (84%)
3i (86%)
NO2
OMe
O
H
N
H
N
O
O
O
O
3r (89%)
3s (82%)
Scheme 2 I2-promoted synthesis of α-ketoimides from ethylenearenes and benzonitriles. Reaction conditions: 1 (1.0 mmol), 2 (15.0 mmol), and I2 (1.5
mmol) were heated in a sealed tube at 110 °C for 12.0 h in DMSO (2.0 mL).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 429–438

432
H. P. Kalmode et al.
Paper
Synthesis
yield, respectively (Scheme 3). Then, the range of various
substituted benzonitriles were screened. It was found that
the 4-Me-, 4-NO2-, and 4-OMe-substituted benzonitriles
reacted smoothly to form the corresponding oxidative cou-
pling products 3q–s in good yields (83–90%) (Scheme 3).
With all these results of ethylenearenes 1 and ethynyl-
arenes 4 in hand, we focused on the outcome of the reac-
tion between various 1-arylethanols (5) and benzonitriles
(2). 1-Phenylethanol (5a) was first treated with benzoni-
trile (2a) to give the N-(2-oxo-2-phenylacetyl)benzamide
(3a) in 84% yield. Next, the effect of various functional
groups onto the oxidative imidation reaction was studied
(Scheme 4). We found that methoxy and halogen groups
were compatible with the reaction conditions and gave the
corresponding imides 3m, 3o, and 3p in good yields (80–
86%). The reaction of 1-(naphthalen-1-yl)ethanol with ben-
zonitrile (2a) gave the corresponding product 3i in 87%
yield. 1-(Furan-2-yl)ethanol reacted smoothly to give N-[2-
(furan-2-yl)-2-oxoacetyl]benzamide (3h) in 85% yield
(Scheme 4). Benzonitriles bearing 4-Me, 4-NO2 and 4-OMe
substituents on the phenyl ring reacted smoothly to offer
the corresponding products 3q–s in 81–87% yields (Scheme
4).
anol (5a) was treated with I2 in DMSO, the successive for-
mation of acetophenone (A), phenacyl iodide (B), and phe-
nyl glyoxal (C) was observed (Scheme 5a). Phenacyl iodide
(B) reacted with benzonitrile (2a) under optimum condi-
tions forming α-ketoimide 3a exclusively in 78% yield
(Scheme 5, b). In the presence of I2, phenylglyoxal (C) was
reacted with 2a to afford the oxidative coupling product 3a
in 89% yield (Scheme 5, c2). These results effectively con-
firmed that the phenacyl iodide (B) and phenylglyoxal (C)
were the key intermediates in this transformation. Howev-
er, this reaction cannot be performed smoothly in the ab-
sence of I2 (Scheme 5, c1 and d). This result clearly high-
lights the significant role of I2 in oxidative imidation reac-
tion. When the substrate 1a or 4a or 5a was reacted with
benzonitrile (2a) in the presence of I2 in DMF under stan-
dard conditions, formation of α-ketoimide 3a was not ob-
served (Scheme 5, e), thus proving the dual role played by
DMSO as a solvent and an oxidant in this transformation. α-
Ketoimide 3a was formed in 81% yield when the substrate
1a or 4a or 5a was reacted with benzamide (6a) under opti-
mum conditions (Scheme 5, f). Furthermore, it was found
that when benzonitrile (2a; 1.0 equiv) was treated with 1.5
equivalents of I2 in DMSO, the benzamide (6a) was formed
in 96% yield (Scheme 5, g). These results showed that ben-
zonitrile (2a) is converted in situ into benzamide (6a) and
A series of control experiments (Scheme 5) were per-
formed in order to confirm our proposed mechanism.
When styrene (1a) or phenylacetylene (4a) or 1-phenyleth-
R
O
H
I2, DMSO
N
N
Ar
Ar
110 °C, 12 h
O
O
R
4
2
3
O
O
O
O
H
H
H
H
N
N
N
N
O
O
O
O
O
O
O
O
F
Cl
Cl
3a (88%)
3l (90%)
3m (87%)
Cl
3n (89%)
O
O
O
O
H
N
H
N
H
N
H
N
O
O
O
O
O
O
O
O
O
Br
Br
O
3o (84%)
3d (86%)
3j (87%)
3k (88%)
NO2
OMe
O
O
O
H
H
H
N
N
N
O
O
O
O
O
O
3q (85%)
3r (90%)
3s (83%)
Scheme 3 I2-promoted synthesis of α-ketoimides from ethynylarenes and benzonitriles. Reaction conditions: 4 (1.0 mmol), 2 (15.0 mmol), and I2 (1.5
mmol) were heated in a sealed tube at 110 °C for 12.0 h in DMSO (2.0 mL).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 429–438

433
H. P. Kalmode et al.
Paper
Synthesis
R
O
H
N
N
OH
I2, DMSO
Ar
+
110 °C, 12 h
Ar
O
O
R
5
2
3
MeO
O
O
H
O
H
N
H
O
N
N
H
N
O
O
O
O
OMe
O
O
Br
O
O
Cl
O
3a (84%)
3m (86%)
3o (82%)
3p (80%)
OMe
O
O
O
O
O
H
N
H
N
H
N
N
H
O
O
O
O
O
O
O
3r (87%)
3q (84%)
3h (85%)
3i (87%)
NO2
O
H
N
O
O
3s (81%)
Scheme 4 I2-promoted synthesis of α-ketoimides from 1-arylethanols and benzonitriles. Reaction conditions: 5 (1.0 mmol), 2 (15.0 mmol), and I2 (1.5
mmol) were heated in sealed tube at 110 °C for 12.0 h in DMSO (2.0 mL).
then reacts with phenylglyoxal (B), generated in situ from
the diverse substrate 1a or 4a or 5a, to afford the target
product 3a.
Chemical reagents were obtained from commercial suppliers and
used without further purification. 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. Devel-
oped TLC plates were visualized under a short-wavelength UV lamp.
Reactions were conducted under atmospheric conditions in anhy-
drous solvents such as DMSO and DMF. Yields refer to spectroscopi-
cally (1H, 13C NMR) homogeneous material obtained after column
chromatography. Column chromatography was performed on silica
gel (100–200 mesh size) supplied by S. D. Fine Chemicals Limited, In-
dia. IR spectra were recorded on a JASCO FT/IR-4100 LE with attenuat-
ed total reflection (ATR) method. NMR spectra were recorded in CDCl3
or DMSO-d6 solution on Agilent/Bruker 300, 400, and 500 MHz spec-
trometers. Chemical shifts (δ) for 1H NMR spectra are reported rela-
tive to TMS (δ = 0.0 ppm) as an internal standard. Standard abbrevia-
tions were used to denote peak multiplicities. Coupling constant J is
given in Hz. High-resolution mass spectra were obtained by using
positive electrospray ionization (ESI) by time-of-flight (TOF) method.
Based on our control experiments, a possible mecha-
nism (Scheme 6) is proposed for the I2 promoted oxidative
imidation reaction of styrene (1a), or phenylacetylene (4a),
or 1-phenylethanol (5a) with benzonitrile (2a) in DMSO at
110 °C. 1-Phenylethanol (5a) under optimal conditions
forms acetophenone (A), which eventually gets converted
into α-iodoacetophenone (B). This was confirmed by using
TLC, GC-MS, and 1H NMR analysis. A key intermediate α-io-
doacetophenone (B) was also obtained from the substrate
1a or 4a. The α-iodoacetophenone (B) is further trans-
formed to phenylglyoxal (C) through Kornblum oxidation,
which on reaction with benzamide (6a) generated in situ
from benzonitrile (2a), furnishes the α-ketoimide 3a exclu-
sively.
In conclusion, an iodine-promoted domino strategy for
the synthesis of α-ketoimides from multiform substrates
has been developed. The striking features of this protocol
are the utilization of a simple and cheap additive, readily
available starting materials and environmentally benign
conditions. We strongly believe that this various functional
group compatible and metal-free tandem synthetic ap-
proach would be useful for the synthesis of complex mole-
cules in the field of medicine and materials.
α-Ketoimides 3; General Procedure
A sealed tube equipped with a magnetic stirring bar was charged
with ethylenearene 1 or ethynylarene 4, or 1-arylethanol 5 (1.0
mmol), benzonitrile 2 (15.0 mmol), I2 (1.5 mmol), and DMSO (2.0 mL).
The reaction vessel was heated at 110 °C for 12 h. After disappearance
of the reactant as monitored by TLC, the reaction mass was quenched
with 10% aq Na2S2O3 (10 mL) and extracted with EtOAc (2 × 10 mL).
The combined organic layers were washed with brine (20 mL), dried
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 429–438

434
H. P. Kalmode et al.
Paper
Synthesis
OH
O
O
H
I
I2, DMSO
DMSO
(a)
or
or
110 °C, 0.5 h
O
110 °C, 0.5 h
B (95%)
1a
5a
4a
C (quant.)
O
O
N
H
I
N
I2, DMSO
(b)
(c)
+
110 °C, 11.5 h
O
O
2a
B
3a (78%)
O
O
N
H
N
H
DMSO
+
110 °C, 11.0 h
O
O
O
2a
C
3a (without I2: 0%; with I2: 89%)
O
OH
H
N
(d)
N
DMSO
or
or
+
110 °C, 12.0 h
O
O
3a (0%)
2b
1a
5a
4a
O
OH
H
N
N
(e)
I2, DMF
or
or
+
110 °C, 12 h
O
O
3a (0%)
2b
1a
5a
4a
O
OH
O
H
N
(f)
I2, DMSO
H2N
or
or
+
110 °C, 10 h
O
O
3a (81%)
6a
1a
5a
4a
O
N
I2, DMSO
H2N
(g)
110 °C, 8 h
6a (96%)
2a
Scheme 5 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 429–438

435
H. P. Kalmode et al.
Paper
Synthesis
DMSO
DMS
I2
1a
4a
HI
O
O
DMS
HI
OH
O
DMSO
DMS
DMSO
I2
O
I
I2
H
A
B
C
5a
I2
HI
2 HI + DMSO = I2 + DMS + H2O
O
N
NH2
H2O
6a
2a
O
OH
Ph
I2
O
H
N
HN
O
O
O
3a
D
Scheme 6 Plausible reaction mechanism
(Na2SO4), and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel with n-hexane–
EtOAc (75:25) as eluent to afford the corresponding α-ketoimide 3.
N-[2-(4-Chlorophenyl)-2-oxoacetyl]benzamide (3c)
Yield: 1.07 g (87%); yellow solid; mp 72–74 °C.
IR (ATR): 3447, 1695, 1590, 1421, 1214, 1091, 693 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 10.03 (br s, 1 H), 8.07 (d, J = 8.1 Hz, 2
H), 7.92 (d, J = 7.5 Hz, 2 H), 7.46–7.66 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 185.39, 169.31, 165.41, 141.47, 134.12,
131.50, 131.01, 130.90, 129.39, 129.17, 128.19.
HRMS (ESI): m/z calcd for [(C15H10ClNO3)H] [M + H]+: 288.0427;
N-(2-Oxo-2-phenylacetyl)benzamide (3a)
Yield: 1.31 g (88%); light yellow solid; mp 138–140 °C.
IR (ATR): 3445, 3288, 1723, 1684, 1596, 1346, 1210, 761, 714 cm–1
1H NMR (400 MHz, CDCl3): δ = 9.86 (br s, 1 H), 8.13 (d, J = 7.2 Hz, 2 H),
7.92 (d, J = 7.6 Hz, 2 H), 7.62–7.69 (q, J = 7.6 Hz, 2 H), 7.50–7.55 (m, 4
.
found: 288.0422.
H).
13C NMR (75 MHz, CDCl3): δ = 186.75, 165.44 (2 C=O), 134.85, 134.13,
132.53, 131.19, 130.30, 129.28, 129.08, 128.26.
HRMS (ESI): m/z calcd for [(C15H11NO3)H] [M + H]+: 254.0817; found:
254.0822.
N-[2-(4-Bromophenyl)-2-oxoacetyl]benzamide (3d)
Yield: 958 mg (88%); yellow solid; mp 74–76 °C.
IR (ATR): 3444, 1695, 1585, 1219, 1071, 978, 695 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.67 (br s, 1 H), 8.03 (d, J = 7.0 Hz, 2 H),
7.89 (d, J = 7.5 Hz, 2 H), 7.65–7.69 (distorted dd, J = 8.0, 5.5 Hz, 3 H),
7.53 (t, J = 5.5 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 186.55, 170.64, 167.39, 134.03,
132.34, 131.66, 131.44, 131.25, 130.70, 130.21, 128.78.
N-[2-(4-Nitrophenyl)-2-oxoacetyl]benzamide (3b)
Yield: 1.08 g (89%); yellow solid; mp 80–82 °C.
IR (ATR): 3256, 1718, 1693, 1675, 1530, 1342, 1205, 765, 718 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 12.10 (br s, 1 H), 8.40 (d, J = 8.7 Hz,
2 H), 8.20 (d, J = 8.7 Hz, 2 H), 7.86 (t, J = 6.9, 1.5 Hz, 2 H), 7.43–7.55 (m,
3 H).
HRMS (ESI): m/z calcd for [(C15H10BrNO3)H] [M + H]+: 331.9922;
found: 331.9926.
13C NMR (125 MHz, CDCl3): δ = 185.21, 170.09, 168.21, 150.56,
136.04, 133.51, 131.42, 130.08, 128.40, 127.16, 123.15.
HRMS (ESI): m/z calcd for [(C15H10N2O5)H] [M + H]+: 299.0668; found:
299.0673.
N-[2-Oxo-2-(o-tolyl)acetyl]benzamide (3e)
Yield: 1.13 g (83%); white solid; mp 152–154 °C.
IR (ATR): 3445, 3290, 1712, 1692, 1675, 1602, 1341, 1242, 1218, 742
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 429–438

436
H. P. Kalmode et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3): δ = 9.74 (br s, 1 H), 7.81 (d, J = 6.0 Hz, 4 H),
7.54 (distorted t, J = 7.0, 6.0 Hz, 1 H), 7.46 (distorted t, J = 7.0, 6.0 Hz, 4
H), 2.42 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 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.
N-[2-(Naphthalen-2-yl)-2-oxoacetyl]benzamide (3j)
Yield: 1.04 g (88%); light yellow solid; mp 184–186 °C.
IR (ATR): 3448, 1715, 1684, 1627, 1465, 1251, 710 cm–1
1H NMR (400 MHz, CDCl3): δ = 9.84 (s, 1 H), 8.82 (s, 1 H), 8.15 (d, J =
8.4 Hz, 1 H), 7.89–8.00 (m, 5 H), 7.51–7.65 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 186.50, 165.29 (2 C=O), 136.57,
134.13, 134.07, 132.63, 131.54, 130.35, 129.86, 129.73, 129.35,
129.19, 128.24, 128.10, 127.30, 124.54.
.
HRMS (ESI): m/z calcd for [(C16H13NO3)H] [M + H]+: 268.0973; found:
268.0976.
HRMS (ESI): m/z calcd for [(C19H13NO3)H] [M + H]+: 304.0973; found:
304.0969.
N-[2-Oxo-2-(p-tolyl)acetyl]benzamide (3f)
Yield: 1.16 g (85%); white solid; mp 156–158 °C.
IR (ATR): 3450, 3292, 1720, 1685, 1675, 1612, 1352, 1254, 1226, 749
N-[2-Oxo-2-(2-oxo-2H-chromen-3-yl)acetyl]benzamide (3k)
cm–1
.
Yield: 994 mg (88%); yellow solid; mp 216–218 °C.
IR (ATR): 3262, 1725, 1708, 1671, 1602, 1563, 1252, 956, 760 cm–1
1H NMR (500 MHz, CDCl3): δ = 9.70 (br s, 1 H), 8.09 (d, J = 8.0 Hz, 2 H),
7.90 (d, J = 7.5 Hz, 2 H), 7.64 (t, J = 7.5, 7.0 Hz, 1 H), 7.52 (t, J = 8.0, 7.5
Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 2.45 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 187.25, 171.07, 167.09, 145.00,
133.90, 130.44, 129.97, 129.68, 128.97, 128.75, 21.29.
.
1H NMR (400 MHz, DMSO-d6): δ = 12.39 (s, 1 H), 9.07 (s, 1 H), 8.03–
8.10 (dd, J = 8.0, 7.6 Hz, 3 H), 7.84 (t, J = 7.6 Hz, 1 H), 7.72 (t, J = 7.6, 7.2
Hz, 1 H), 7.49–7.59 (m, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 182.73, 170.16, 167.93, 158.83,
154.80, 148.65, 135.56, 134.00, 131.46, 130.10, 128.84, 128.64,
125.44, 119.93, 118.11, 116.54.
HRMS (ESI): m/z calcd for [(C16H13NO3)H] [M + H]+: 268.0973; found:
268.0969.
HRMS (ESI): m/z calcd for [(C18H11NO5)Na] [M + Na]+: 344.0534;
found: 344.0537.
N-[2-(4-Methoxyphenyl)-2-oxoacetyl]benzamide (3g)
Yield: 1.06 g (84%); off-white solid; mp 158–160 °C.
IR (ATR): 3448, 3295, 1718, 1691, 1675, 1604, 1269, 1152, 738 cm–1
.
N-[2-(4-Fluorophenyl)-2-oxoacetyl]benzamide (3l)
1H NMR (400 MHz, CDCl3): δ = 10.13 (br s, 1 H), 8.23 (d, J = 4.4 Hz, 2
H), 8.07 (d, J = 5.6 Hz, 1 H), 7.93 (s, 2 H), 7.64 (s, 1 H), 7.52 (s, 1 H), 6.99
(distorted t, J = 7.6, 6.4 Hz, 2 H), 3.90 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 184.58, 165.11, 164.04, 133.79,
133.22, 132.35, 129.10, 128.07, 125.34, 114.36, 113.77, 55.66.
Yield: 1.22 g (90%); off-white solid; mp 158–160 °C.
IR (ATR): 3438, 1694, 1589, 1423, 1214, 1085, 698 cm–1
1H NMR (300 MHz, DMSO-d6): δ = 12.48 (s, 1 H), 7.98–8.05 (m, 4 H),
7.70 (t, J = 7.2 Hz, 1 H), 7.55 (t, J = 7.8, 7.5 Hz, 2 H), 7.44 (t, J = 8.7 Hz, 2
.
H).
HRMS (ESI): m/z calcd for [(C16H13NO4)H] [M + H]+: 284.0923; found:
284.0919.
13C NMR (75 MHz, DMSO-d6): δ = 186.16, 170.84, 167.34, 165.55 (d,
JF = 252.3 Hz), 134.00, 132.00 (d, JF = 9.75 Hz), 130.36, 129.20 (d, JF =
2.8 Hz), 128.83, 128.80, 116.45 (d, JF = 22.3 Hz).
HRMS (ESI): m/z calcd for [(C15H10FNO3)H] [M + H]+: 272.0723; found:
272.0729.
N-[2-(Furan-2-yl)-2-oxoacetyl]benzamide (3h)
Yield: 1.35 g (87%); off-white solid; mp 154–156 °C.
IR (ATR): 3241, 1723, 1652, 1465, 1411, 1351, 1273, 773 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.01 (s, 1 H), 8.55 (t, J = 3.6, 3.2 Hz, 1
H), 8.24 (d, J = 3.2 Hz, 1 H), 8.20 (s, 1 H), 7.82 (s, 1 H), 7.67 (s, 1 H), 7.54
(distorted t, J = 3.2, 2.0 Hz, 2 H), 7.48 (d, J = 3.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 178.30, 164.39, 160.90, 157.59,
148.51, 137.24, 131.16, 128.71, 124.77, 113.27, 110.94.
N-[2-(3-Chlorophenyl)-2-oxoacetyl]benzamide (3m)
Yield: 1.10 g (87%); light white solid; mp 74–76 °C.
IR (ATR): 3445, 3275, 1713, 1694, 1678, 1513, 1238, 768 cm–1
1H NMR (500 MHz, CDCl3): δ = 9.59 (br s, 1 H), 8.11 (s, 1 H), 8.02 (d, J =
8.0 Hz, 1 H), 7.89 (d, J = 7.5 Hz, 2 H), 7.63–7.68 (distorted dd, J = 8.5
Hz, 2 H), 7.54 (distorted t, J = 7.0, 6.5 Hz, 2 H), 7.48 (distorted t, J = 7.5
Hz, 1 H).
.
HRMS (ESI): m/z calcd for [(C13H9NO4)Na] [M + Na]+: 266.0429; found:
266. 0430.
13C NMR (100 MHz, CDCl3): δ = 185.08, 170.85, 169.35, 134.62,
133.38, 132.80, 132.45, 130.16, 129.75, 128.75, 128.18, 127.44,
125.50.
N-[2-(Naphthalen-1-yl)-2-oxoacetyl]benzamide (3i)
Yield: 920 mg (87%); light yellow solid; mp 74–76 °C.
HRMS (ESI): m/z calcd for [(C15H10ClNO3)H] [M + H]+: 288.0427 found
288.0423.
IR (ATR): 3442, 3281, 1715, 1681, 1645, 1397, 1318, 1219, 768, 695
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.79 (s, 1 H), 9.12 (d, J = 8.4 Hz, 1 H),
8.12 (d, J = 8.0 Hz, 2 H), 7.93 (distorted t, J = 7.2 Hz, 3 H), 7.72 (t, J = 7.6
Hz, 1 H), 7.48–7.65 (m, 5 H).
N-[2-(2,4-Dichlorophenyl)-2-oxoacetyl]benzamide (3n)
Yield: 1.01 g (89%); yellow solid; mp 78–80 °C.
13C NMR (100 MHz, CDCl3): δ = 188.69, 172.43, 165.23, 135.54,
134.11, 133.96, 133.60, 131.29, 131.08, 129.18, 129.14, 128.72,
128.10, 127.98, 126.99, 125.86, 124.31.
HRMS (ESI): m/z calcd for [(C19H13NO3)H] [M + H]+: 304.0973; found:
304.0967.
IR (ATR): 3451, 3279, 1717, 1687, 1673, 1509, 1244, 759 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 12.55 (s, 1 H), 8.07 (t, J = 9.0, 8.4 Hz,
2 H), 7.95 (d, J = 7.2 Hz, 1 H), 7.86 (s, 1 H), 7.66–7.75 (distorted q, J =
9.6, 8.7, 6.9 Hz, 2 H), 7.60 (distorted t, J = 6.9 Hz, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 429–438

437
H. P. Kalmode et al.
Paper
Synthesis
13C NMR (75 MHz, DMSO-d6): δ = 183.93, 170.40, 167.75, 139.68,
134.92, 134.16, 133.40, 130.82, 130.16, 129.35, 128.92, 128.80,
128.36.
HRMS (ESI): m/z calcd for [(C15H9Cl2NO3)H] [M + H]+: 322.0037;
found: 322.0035.
IR (ATR): 3336, 3250, 1736, 1680, 1515, 1356, 1208, 1168, 768, 720
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.54 (br s, 1 H), 8.38 (d, J = 9.0 Hz, 2 H),
8.28 (d, J = 8.5 Hz, 2 H), 7.89 (d, J = 7.0 Hz, 2 H), 7.68 (t, J = 7.5 Hz, 1 H),
7.55 (t, J = 8.0, 7.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 186.27, 170.20, 165.57, 151.62,
137.10, 136.20, 134.57, 131.14, 129.46, 128.22, 124.21.
N-[2-(2-Bromophenyl)-2-oxoacetyl]benzamide (3o)
HRMS (ESI): m/z calcd for [(C15H10N2O5)H] [M+ H]+: 299.0668; found:
299.0671.
Yield: 925 mg (84%); yellow solid; mp 70–72 °C.
IR (ATR): 3456, 3274, 1719, 1688, 1587, 1211, 747 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.13 (s, 1 H), 7.91–8.02 (distorted
ddd, J = 7.6, 6.8 Hz, 2 H), 7.68 (d, J = 7.2 Hz, 1 H), 7.58–7.64 (distorted
q, J = 7.2 Hz, 1 H), 7.43–7.52 (m, 5 H).
Acknowledgment
13C NMR (100 MHz, CDCl3): δ = 186.50, 168.73, 165.71, 137.10 134.56,
134.32, 134.05, 132.82, 130.87, 129.10, 128.25, 127.62, 123.12.
HRMS (ESI): m/z calcd for [(C15H10BrNO3)H] [M + H]+: 331.9922;
found: 331.9929.
Financial support from the Council of Scientific and Industrial Re-
search, New Delhi [sanction no. 01(2427)/10/EMR-II dated
28/12/2010 and pool scheme no. 8644-A], India, to carry out this
work is gratefully acknowledged. H.P.K. and K.S.V. thank Council of
Scientific and Industrial Research and University Grants Commission-
Special Assistance Programme, New Delhi, respectively, for the award
of Senior Research Fellowships. The authors thank Prof. Prakash M.
Bhate for his generous support.
N-[2-(2,6-Dimethoxyphenyl)-2-oxoacetyl]benzamide (3p)
Yield: 826 mg (80%); light yellow solid; mp 124–126 °C.
IR (ATR): 3448, 3287, 1708, 1677, 1655, 1602, 1252, 1160, 742 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.05 (s, 1 H), 7.96 (d, J = 6.8 Hz, 2 H),
7.59 (t, J = 8.4, 6.8 Hz, 2 H), 7.46 (d, J = 6.8 Hz, 2 H), 7.17 (d, J = 7.2 Hz,
1 H), 6.93 (d, J = 8.4 Hz, 1 H), 3.84 (s, 3 H), 3.74 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 185.14, 170.92, 165.96, 154.92,
154.33, 133.84, 130.58, 129.04, 128.21, 124.11, 122.65, 114.40,
112.22, 56.75, 55.89.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379955.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
HRMS (ESI): m/z calcd for [(C17H15NO5)H] [M + H]+: 314.1028; found:
314.1031.
References
(1) (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T.
Org. Biomol. Chem. 2006, 4, 2337. (c) Allen, C. L.; Williams, J. M.
J. Chem. Soc. Rev. 2011, 40, 3405. (d) Ozawa, F.; Soyama, H.;
Yamamoto, T.; Yamamoto, A. Tetrahedron Lett. 1982, 23, 3383.
(e) Couve-Bonnaire, S.; Carpentier, J.-F.; Castanet, Y.; Mortreux,
A. Tetrahedron Lett. 1999, 40, 3717. (f) Mehdi, S. Bioorg. Chem.
1993, 21, 249. (g) Patel, D. V.; Gless, R. D. J.; Webb, H. H. K.;
Anandan, S. K.; Aavula, B. R. Patent WO 2008073623, 2008.
(h) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.;
Goto, T.; Hashimoto, M.; Taga, T. J. Am. Chem. Soc. 1987, 109,
5031. (i) Hagihara, M.; Schreiber, S. L.
4-Methyl-N-(2-oxo-2-phenylacetyl)benzamide (3q)
Yield: 1.33 g (85%); white solid; mp 148–150 °C.
IR (ATR): 3352, 3288, 1719, 1681, 1674, 1518, 1256, 1228, 751 cm–1
1H NMR (500 MHz, CDCl3): δ = 9.76 (br s, 1 H), 8.12 (d, J = 7.5 Hz, 2 H),
7.80–7.81 (distorted dd, J = 8.0, 1.5 Hz, 2 H), 7.66 (distorted tt, J = 7.5,
1.5 Hz, 1 H), 7.53 (distorted tt, J = 7.5, 1.5 Hz, 2 H), 7.30 (d, J = 7.5 Hz, 2
H), 2.43 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 186.85, 165.27 (2 C=O), 145.27,
134.79, 132.55, 130.24, 129.97, 129.06, 128.30, 21.85.
HRMS (ESI): m/z calcd for [(C16H13NO3)H] [M + H]+: 268.0973; found:
268.0970.
.
J. Am. Chem. Soc. 1992, 114, 6570. (j) Qian, J.; Cuerrier, D.;
Davies, P. L.; Li, Z.; Powers, J. C.; Campbell, R. L. J. Med. Chem.
2008, 51, 5264. (k) Ovat, A.; Li, Z. Z.; Hampton, C. Y.; Asress, S.
A.; Fernández, F. M.; Glass, J. D.; Powers, J. C. J. Med. Chem. 2010,
53, 6326. (l) Li, Z.; Ortega-Vilain, A. C.; Patil, G. S.; Chu, D. L.;
Foreman, J. E.; Eveleth, D. D.; Powers, J. C. J. Med. Chem. 1996, 39,
4089.
4-Methoxy-N-(2-oxo-2-phenylacetyl)benzamide (3r)
Yield: 1.50 g (90%); white solid; mp 162–164 °C.
IR (ATR): 3260, 1721, 1685, 1675, 1585, 1254, 1226, 749 cm–1
1H NMR (500 MHz, CDCl3): δ = 9.83 (br s, 1 H), 8.09 (d, J = 7.5 Hz, 2 H),
7.89 (d, J = 9.0 Hz, 2 H), 7.65 (t, J = 7.5 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 2 H),
6.97 (d, J = 9.0 Hz, 2 H), 3.87 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 186.99, 164.80, 164.42, 134.70,
132.63, 130.58, 130.11, 129.06, 123.05, 114.55, 55.76.
HRMS (ESI): m/z calcd for [(C16H13NO4)H] [M + H]+: 284.0923; found:
284.0925.
.
(2) (a) Wang, J.; Liu, C.; Yuan, J.; Lei, A. Chem. Commun. 2014, 50,
4736. (b) Hirai, K.; Shikakura, K.; Yano, T.; Ishikawa, C.; Ugai, S.;
Yamada, O. Patent WO 199622285, 1996. (c) Rao, K. V.; Rock, C.
P. J. Heterocycl. Chem. 1996, 33, 447. (d) Yang, L.; Wang, D.-X.;
Huang, Z.-T.; Wang, M.-X. J. Am. Chem. Soc. 2009, 131, 10390.
(e) Reddy, Y. D.; Kumar, P. P.; Devi, B. R.; Dubey, P. K.; Kumari, Y.
B. Lett. Drug Des. Discovery 2014, 10, 226. (f) Ram, S. R.; Devi, A.
R.; Iyengar, D. S. Chem. Lett. 2002, 31, 718. (g) Eveleth, D. D.;
Powers, J. C. J. Med. Chem. 1996, 39, 4089. (h) Chatterjee, S.;
Dunn, D.; Tao, M.; Wells, G.; Gu, Z.; Bihovsky, R.; Ator, M. A.;
Siman, R.; Mallamo, J. P. Bioorg. Med. Chem. Lett. 1999, 9, 2371.
(i) Dubowchik, G. M.; Ditta, J. L.; Herbst, J. J.; Bollini, S.; Vinitsky,
4-Nitro-N-(2-oxo-2-phenylacetyl)benzamide (3s)
Yield: 1.45 g (83%); light yellow solid; mp 188–190 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 429–438

438
H. P. Kalmode et al.
Paper
Synthesis
A. Bioorg. Med. Chem. Lett. 2000, 10, 559. (j) Chen, Y.; Zhang, Y.;
Zhang, H.; Liu, D.; Gu, M.; Li, J.; Wu, F.; Zhu, X.; Li, J.; Nan, F.
J. Med. Chem. 2006, 49, 1613. (k) Sheha, M. M.; Mahfouz, N. M.;
Hassan, H. Y.; Youssef, A. F. Eur. J. Med. Chem. 2000, 35, 887.
(l) Crowley, C. A.; Delaet, N. G. J.; Ernst, J.; Grove, C. G.; Hepburn,
B.; King, B.; Larson, C. J.; Miller, S.; Pryor, K.; Shuster, L. J. Patent
WO 2007146712, 2007. (m) Knust, H.; Nettekoven, M.; Pinard,
E.; Roche, O. Patent WO 2009016087, 2009. (n) Alvarez, S.;
Alvarez, R.; Khanwalkar, H.; Germain, P.; Lemaire, G.;
Rodríguez-Barrios, F.; Gronemeyer, H.; de Lera, A. R. Bioorg.
Med. Chem. 2009, 17, 4345. (o) Natarajan, A.; Wang, K.;
Ramamurthy, V.; Scheffer, J. R.; Patrick, B. Org. Lett. 2002, 4,
1443. (p) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 14066.
(q) Sai, K. K. S.; Esteves, P. M.; da Penha, E. T.; Klumpp, D. A.
J. Org. Chem. 2008, 73, 6506. (r) Tomita, D.; Yamatsugu, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 6946.
(s) Coffinier, D.; El Kaim, L.; Grimaud, L. Org. Lett. 2009, 11,
1825. (t) Zhang, Z.; Zhang, Q.; Ni, Z.; Liu, Q. Chem. Commun.
2010, 46, 1269. (u) Jesuraj, J. L.; Sivaguru, J. Chem. Commun.
2010, 46, 4791.
3987. (b) Chiou, A.; Markidis, T.; Constantinou-Kokotou, V.;
Verger, R.; Kokotos, G. Org. Lett. 2000, 2, 347. (c) Singh, R. P.;
Shreeve, J. M. J. Org. Chem. 2003, 68, 6063.
(8) Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T. Org.
Lett. 2002, 4, 1103.
(9) (a) Buu-Hoï, N. P.; Saint-Ruf, G.; Bourgeade, J. C. J. Heterocycl.
Chem. 1968, 5, 545. (b) Chen, Y.-H.; Zhang, Y.-H.; Zhang, H.-J.;
Liu, D.-Z.; Gu, M.; Li, J.-Y.; Wu, F.; Zhu, X.-Z.; Li, J.; Nan, F.-J.
J. Med. Chem. 2006, 49, 1613. (c) Zaleska, B.; Lis, S. Synth.
Commun. 2001, 31, 189. (d) Yoshifuji, S.; Arakawa, Y. Chem.
Pharm. Bull. 1989, 37, 3380. (e) Wasserman, H. H.; Ives, J. L.
J. Org. Chem. 1985, 50, 3573. (f) Ke-Qing, L.; Gang, J.; Hu, C.; Jian-
Hua, X. Tetrahedron Lett. 1998, 39, 2381. (g) Ling, K.-Q.; Ye, J.-H.;
Chen, X.-Y.; Ma, D.-J.; Xu, J.-H. Tetrahedron 1999, 55, 9185.
(10) (a) Liu, J.; Zhang, R.; Wang, S.; Sun, W.; Xia, C. Org. Lett. 2009, 11,
1321. (b) Ozawa, F.; Soyama, H.; Yanagihara, H.; Aoyama, I.;
Takino, H.; Izawa, K.; Yamamoto, T.; Yamamoto, A. J. Am. Chem.
Soc. 1985, 107, 3235. (c) Hermange, P.; Lindhardt, A. T.; Taaning,
R. H.; Bjerglund, K.; Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc.
2011, 133, 6061. (d) Friis, S. D.; Taaning, R. H.; Lindhardt, A. T.;
Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 18114. (e) Uozumi,
Y.; Arii, T.; Watanabe, T. J. Org. Chem. 2001, 66, 5272. (f) Iizuka,
M.; Kondo, Y. Chem. Commun. 2006, 1739. (g) Murphy, E. R.;
Martinelli, J. R.; Zaborenko, N.; Buchwald, S. L.; Jensen, K. F.
Angew. Chem. Int. Ed. 2007, 46, 1734.
(11) (a) Wasserman, H. H.; Petersen, A. K.; Xia, M. Tetrahedron 2003,
59, 6771. (b) Wasserman, H. H.; Ho, W.-B. J. Org. Chem. 1994, 59,
4364.
(12) (a) Semple, J. E.; Owens, T. D.; Nguyen, K.; Levy, O. E. Org. Lett.
2000, 2, 2769. (b) Bouma, M.; Masson, G.; Zhu, J. J. Org. Chem.
2010, 75, 2748. (c) Grassot, J.-M. Masson G.. Zhu J. Angew. Chem.
Int. Ed. 2008, 47, 947.
(13) Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 13064.
(14) Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew. Chem.
Int. Ed. 2012, 51, 3231.
(15) (a) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 28. (b) Zhang,
C.; Xu, Z.; Zhang, L.; Jiao, N. Angew. Chem. Int. Ed. 2011, 50,
11088. (c) Zhang, C.; Zong, X.; Zhang, L.; Jiao, N. Org. Lett. 2012,
14, 3280. (d) Du, F.-T.; Ji, J.-X. Chem. Sci. 2012, 3, 460.
(16) (a) Lamani, M.; Prabhu, K. R. Chem. Eur. J. 2012, 18, 14638.
(b) Wei, W.; Shao, Y.; Hu, H.; Zhang, F.; Zhang, C.; Xu, Y.; Wan, X.
J. Org. Chem. 2012, 77, 7157. (c) Zhang, X.; Wang, L. Green Chem.
2012, 14, 2141.
(17) (a) Wu, X.; Gao, Q.; Liu, S.; Wu, A. Org. Lett. 2014, 16, 2888.
(b) Xue, W.-J.; Zhang, W.; Zheng, K.-L.; Dai, Y.; Guo, Y.-Q.; Li, H.-
Z.; Gao, F.-F.; Wu, A. Asian J. Org. Chem. 2013, 2, 638. (c) Zhu, Y.;
Jia, F.; Liu, M.; Wu, A. Org. Lett. 2012, 14, 4414. (d) Xue, W.-J.; Li,
Q.; Zhu, Y.-P.; Wang, J.-G.; Wu, A. Chem. Commun. 2012, 48,
3485. (e) Gao, M.; Yang, Y.; Wu, Y.; Deng, C.; Cao, L.; Meng, X.;
Wu, A. Org. Lett. 2010, 12, 1856.
(3) (a) Yang, Y.; Wang, G.; Cao, X.; Yan, X.; Chen, L. J. Chem. Res.
2011, 35, 657. (b) Sperry, J. Synthesis 2011, 3569. (c) Bogen, S. L.;
Arasappan, A.; Velazquez, F.; Blackman, M.; Huelgas, R.; Pan, W.;
Siegel, E.; Nair, L. G.; Venkatraman, S.; Guo, Z.; Doll, R.; Shih, N.-
Y.; Njoroge, F. G. Bioorg. Med. Chem. 2010, 18, 1854. (d) Xu, G.
G.; Etzkorn, F. A. Org. Lett. 2010, 12, 696. (e) Montalban, A. G.;
Boman, E.; Chang, C.-D.; Ceide, S. C.; Dahl, R.; Dalesandro, D.;
Delaet, N. G. J.; Erb, E.; Gibbs, A.; Kahl, J.; Kessler, L.; Lundström,
J.; Miller, S.; Nakanishi, H.; Roberts, E.; Saiah, E.; Sullivan, R.;
Wang, Z.; Larson, C. J. Bioorg. Med. Chem. Lett. 2008, 18, 5456.
(f) Jones, I. L.; Schofield, D. J.; Strevens, R. R.; Horton, P. N.;
Hursthouse, M. B.; Tomkinson, N. C. O. Tetrahedron Lett. 2007,
48, 521. (g) Cuerrier, D.; Moldoveanu, T.; Inoue, J.; Davies, P. L.;
Campbell, R. L. Biochemistry 2006, 45, 7446. (h) Holenz, J.;
Mercè, R.; Díaz, J. L.; Guitart, X.; Codony, X.; Dordal, A.; Romero,
G.; Torrens, A.; Mas, J.; Andaluz, B.; Hernández, S.; Monroy, X.;
Sánchez, E.; Hernández, E.; Pérez, R.; Cubí, R.; Sanfeliu, O.;
Buschmann, H. J. Med. Chem. 2005, 48, 1781. (i) Barrett, D. G.;
Catalano, J. G.; Deaton, D. N.; Long, S. T.; McFadyen, R. B.; Miller,
A. B.; Miller, L. R.; Wells-Knecht, K. J.; Wright, L. L. Bioorg. Med.
Chem. Lett. 2005, 15, 2209. (j) Natarajan, A.; Wang, K.;
Ramamurthy, V.; Scheffer, J. R.; Patrick, B. Org. Lett. 2002, 4,
1443. (k) Mueller-Westerhoff, U. T.; Zhou, M. Tetrahedron Lett.
1993, 34, 571. (l) Inoue, Y. Chem. Rev. 1992, 92, 741.
(4) (a) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606. (b) Al-
Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem. Int. Ed. 2008,
47, 2876. (c) Srinivas, K. V. N. S.; Das, B. J. Org. Chem. 2003, 68,
1165. (d) Dunetz, J. R.; Xiang, Y.; Baldwin, A.; Ringling, J. Org.
Lett. 2011, 13, 5048. (e) Allen, C. L.; Chhatwal, A. R.; Williams, J.
M. J. Chem. Commun. 2012, 48, 666. (f) Li, J.; Subramaniam, K.;
Smith, D.; Qiao, J. X.; Li, J. J.; Qian-Cutrone, J.; Kadow, J. F.; Vite,
G. D.; Chen, B.-C. Org. Lett. 2012, 14, 214.
(18) Zhang, Z.; Su, J.; Zha, Z.; Wang, Z. Chem. Commun. 2013, 49,
8982.
(5) Simas, A. B. C.; de Sales, D. L.; Pais, K. C. Tetrahedron Lett. 2009,
50, 6977.
(19) Mupparapu, N.; Khan, S.; Battula, S.; Kushwaha, M.; Gupta, A. P.;
Ahmed, Q. N.; Vishwakarma, R. A. Org. Lett. 2014, 16, 1152.
(20) (a) Jiang, H.; Huang, H.; Cao, H.; Qi, C. Org. Lett. 2010, 12, 5561.
(b) Wan, C.; Gao, L.; Wang, Q.; Zhang, J.; Wang, Z. Org. Lett. 2010,
12, 3902. (c) Zhang, J.; Zhu, D.; Yu, C.; Wan, C.; Wang, Z. Org.
Lett. 2010, 12, 2841. (d) Yan, Y.; Wang, Z. Chem. Commun. 2011,
47, 9513. (e) Zhang, J.; Wang, Z.; Wang, Y.; Wan, C.; Zheng, X.;
Wang, Z. Green Chem. 2009, 11, 1973.
(6) (a) Ocain, T. D.; Rich, D. H. J. Med. Chem. 1992, 35, 451.
(b) Nakamura, M.; Inoue, J.; Yamada, T. Bioorg. Med. Chem. Lett.
2000, 10, 2807. (c) Papanikos, A.; Rademann, J.; Meldal, M. J. Am.
Chem. Soc. 2001, 123, 2176. (d) Hua, R.; Takeda, H.; Abe, Y.;
Tanaka, M. J. Org. Chem. 2004, 69, 974.
(7) (a) Dubowchik, G. M.; Vrudhula, V. M.; Dasgupta, B.; Ditta, J.;
Chen, T.; Sheriff, S.; Sipman, K.; Witmer, M.; Tredup, J.; Vyas, D.
M.; Verdoorn, T. A.; Bollini, S.; Vinitsky, A. Org. Lett. 2001, 3,
(21) Raszplewicz, K.; Sikorska, L.; Kiegiel, K.; Balakier, T.; Jurczak, J.
Polish J. Chem. 2005, 79, 1901.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 429–438