I2-Catalyzed Oxidative Amidation of Benzylamines and Benzyl Cyanides under Mild Conditions

Article abstract of DOI:10.1021/acs.joc.7b02211

We report a novel and efficient method for the oxidation of benzylic carbons (amines and cyanides) into corresponding benzamides using a catalytic amount of I₂ and TBHP as the green oxidant via the C-H bond cleavage of the benzylic carbon under mild reaction conditions. According to the literature survey, this is the first report for the oxidative amidation of benzylamines and decyanation of benzyl cyanides in one pot under metal-free conditions.

Full text of DOI:10.1021/acs.joc.7b02211

Note
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
I2‑Catalyzed Oxidative Amidation of Benzylamines and Benzyl
Cyanides under Mild Conditions
Sadu Nageswara Rao, N. Naresh Kumar Reddy, Supravat Samanta, and Subbarayappa Adimurthy*
Academy of Scientific & Innovative Research, CSIR−Central Salt & Marine Chemicals Research Institute, G.B. Marg,
Bhavnagar 364 002, Gujarat, India
S
* Supporting Information
ABSTRACT: We report a novel and efficient method for the oxidation of benzylic carbons (amines and cyanides) into
corresponding benzamides using a catalytic amount of I2 and TBHP as the green oxidant via the C−H bond cleavage of
the benzylic carbon under mild reaction conditions. According to the literature survey, this is the first report for the oxidative
amidation of benzylamines and decyanation of benzyl cyanides in one pot under metal-free conditions.
mide linkages are not only key chemical connections of
proteins and peptides1 but also versatile intermediates
I2−TBHP. The present transformation proceeds via the C−H
bond cleavage of benzylic carbon under mild reaction conditions.
To the best of our knowledge, this isthe first convenient procedure
for oxidative amidation of benzylamines and decyanation11 of
arylacetonitriles under metal-free conditions (Scheme 1).
A
used in the preparation of pharmaceuticals, agrochemicals, and
polymers.2 Furthermore, the favorable properties of amides, such
as high polarity, stability, and conformational diversity, make it
one of the most popular and reliable functional groups in all
branches of organic chemistry. Given the prevalence of amides in
both natural and unnatural materials, several synthetic routes
have been developed.3 Traditionally, amides have been prepared
by the reaction of amines with carbonyl derivatives,4 hydro-
amination of alkynes,5 and hydration of nitriles.6 Despite these
advancements,3−6 current trends on amide syntheses are being
focused on the direct oxidation of benzylamines to benzamides.7
Recently, Beller8 and Mountford9 independently reported an
efficient oxidation of benzylamines to benzamides. More recently,
Chen10 and Song11 demonstrated the oxidative decyanation of
arylacetonitriles to primary benzamides using copper and iron
catalysis. Although the reported methods are efficient, they require
the use of transition-metal catalysts to promote the transforma-
tion efficiently.8−11To replace the transition-metal catalysts, the
development of metal-free and sustainable processes for amide
synthesis is desirable and deserves investigation.
Initially, we focused on the optimization of conditions for the
oxidative amidation of N-methylbenzylamine using iodine
catalyst. To test our initial hypothesis, first we examined the
oxidation of N-methylbenzylamine 1a to N-methylbenzamide 2a
with 20 mol % of iodine and 4.0 equiv of TBHP (aq) in aceto-
nitrile at 70 °C in a closed tube; under these reaction conditions,
the desired amide 2a was isolated in 42% yield (Table 1, entry 1).
On the basis of the above observation, we increased the
amount of the oxidant (TBHP) from 4.0 to 8.0 equiv; the desired
amide 2a was increased to 56% yield (Table 1, entry 2). After
a further increase of the oxidant to 10.0 equiv, significant
improvement in the yield of the product 2a was observed
(entry 3). Use of 10.0 equiv of aq TBHP, lowering the reaction
temperature to 60 °C, and performing the reaction at room
temperature also decreased the yield (Table 1, entries 4 and 5).
When the catalyst loading was decreased to 10 mol %, the yield of
2a was declined to 66% (Table 1, entry 6). However, the yield
was suddenly dropped to 40% when the reaction temperature
increased to 100 °C (Table 1, entry 7). At higher temperature,
Due to our continuous efforts on the developments of sus-
tainable methods for amide synthesis,12 and based on previous
reports on the replacement of transition-metal catalysts by iodine
in organic transformations,13 we disclose herein an efficient and
practical approach for the oxidative amidation of benzylamines
and benzyl cyanides into the corresponding benzamides using
Received: September 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b02211
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Oxidative Amidation of Benzylic Carbons Adjacent to the “Amine” and “Cyanide” Group
a
under these conditions a side product formation was observed.14
We then screened the other iodine sources like NIS, TBAI
(tetrabutylammonium iodide), and KI for the present trans-
formation; in these cases, moderate yield (40−43%) of the
desired amide 2a was isolated (Table 1, entries 8−10). In the
absence of the catalyst no product formation was identified
(Table 1, entry 11). The effect of other catalysts like TBAB,
TBAC, AIBN, and NHPI (N-hydroxyphthalimide), were also
checked for the present reaction; no product formation was
observed (Table 1, entries 12−15). In contrast, the reaction
failed to yield the desired product with other oxidants like H2O2
and DTBP ((di-tert-butyl peroxide) (Table 1, entries 16 and 17).
The reaction with TBHP in decane instead of aqueous TBHP
and also under inert atmosphere showed no improvement in
yield (Table 1, entries 18 and 19). Having identified the effective
conditions for oxidative amidation of N-methylbenzylamine 1a
to N-methylbenzamide 2a (Table 1, entry 3), we studied the
scope of substituted N-methylbenzylamines; the results are
illustrated in Table 2. There is no apparent effect of substituent
groups in this system. The presence of both electron-donating
groups (methyl, methoxy, and tert-butyl) and electron-with-
drawing groups (bromo, chloro, fluoro, nitro, cyano, and phenyl)
at the para position of 1a could react smoothly and afford the
corresponding benzamides 2b−j in good yields (51−77%).
The oxidative amidation of 1-(3-fluorophenyl)-N-methylme-
thanamine and N-methyl-1-(naphthalen-1-yl)methanamine also
gave the corresponding amides 2k and 2l in 65% and 44% yield,
respectively. In the case of N,N-dimethyl-1-phenylmethanamine and
N-benzylethanamine, the corresponding amides 2m (traces) and 2n
were isolated in 63% yield. With N-benzyl-2-methylpropan-2-amine,
Table 1. Optimization of Reaction Conditions
entry
additive (mol %)
oxidant (equiv)
temp (°C)
yield(%)
1
I2 (20)
TBHP (4)
70
70
70
60
rt
42
56
2
I2 (20)
TBHP (8)
3
I2 (20)
I2 (20)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
TBHP (10)
H2O2 (10)
DTBP (10)
TBHP (10)
TBHP (10)
82
74
4
5
I2 (20)
40
6
I2 (10)
70
100
70
70
70
70
70
70
70
70
70
70
70
70
66
7
I2 (10)
40
8
NIS (20)
TBAI (20)
KI (20)
41
9
43
10
11
12
13
14
15
16
17
40
nd
nd
nd
trace
nd
nd
nd
44
TBAB(20)
TBAC(20)
AIBN (20)
NHPI (20)
I2 (20)
I2 (20)
b
18
I2 (20)
c
19
I2 (20)
46
a
Conditions: 1a (1.0 mmol), additive, oxidant, solvent in an oil bath,
sealed tube, 18 h, isolated yield. TBHP in decane. TBHP under
argon atmosphere.
b
c
B
DOI: 10.1021/acs.joc.7b02211
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The Journal of Organic Chemistry
Note
a
Table 2. Substrate Scope of Various Benzylamines
a
Conditions: 1 (1.0 mmol), iodine (20 mol %), TBHP (10 equiv), CH3CN (2 mL) in an oil bath in a sealed tube, 70 °C, 18 h, isolated yield.
no reaction was observed (2o). However, the oxidation of
N-benzylaniline gave the desired N-phenylbenzamide 2p in 48%
yield. The oxidation methodology has been extended to a variety
of primary benzylamines.
Benzylamine and other benzylamine substituents with electron-
rich (methyl and methoxy) and electron-deficient(FandCl)groups
at the para/meta position reacted smoothly under these conditions
and gave good yields (54−88%) of the desired primary benzamides
2q−v. However, hetero primary amines like 3-pyridylmethylamine,
furfurylamine, and 2-thiophene methyl amines provided the corre-
sponding heteroamides 2w−y in low yields (40−30%). While the
yields of these products are lower, they exemplify the ability to
expand the method toward different heteroamides.
conversion of benzyl cyanide 3 to primary benzamide 5 which
was obtained in 75% isolated yield with aqueous ammonia
(Table 3, 5a). Under the same conditions, benzyl cyanides
having electron-donating (methyl, tert-butyl) groups at ortho/
para/meta position gave the corresponding products 5b−e in
52−70% yields. 3,4-Dimethoxybenzyl cyanide also gave 53%
yield of the desired amide 5f. Interestingly, the halo (Br, Cl, and
F)-substituted benzyl cyanides afford good product yields
(5b−i). Further, the strong electron-withdrawing 4-nitrobenzyl
cyanide provided the best yield (84%) of desired amide 5j
under the optimized conditions.
For heteroaromatics such as 3-pyridyl and 2-pyridyl aceto-
nitriles, lower yields of 49% and 33% of products 5k and 5l
were obtained, respectively. Furthermore, we extended scope
of the present system to secondary and tertiary amines under
the same conditions. The reaction of benzyl cyanide with
benzylamine and 2-(4-bromophenyl)ethan-1-amine produced
We then evaluated the amidation of benzyl cyanides through
decyanation under the above optimized conditions using aqueous
ammonia and other amines (Table 3). However, the optimization
of reaction time (36 h) was evaluated to achieve the complete
C
DOI: 10.1021/acs.joc.7b02211
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The Journal of Organic Chemistry
Note
a
Table 3. Broad Scope of Different Benzyl Cyanides with Amines
a
Conditions: 3 (0.5 mmol), 4 (aq NH3, 1.5 mL, or other amine, 1.5 mmol), iodine (20 mol %), aq TBHP (8.0 equiv), CH3CN (1.5 mL) in an oil
bath in a sealed tube, 70 °C, 36 h, isolated yield.
Scheme 2. Additional Experiments
D
DOI: 10.1021/acs.joc.7b02211
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The Journal of Organic Chemistry
Note
Scheme 3. Control Experiments for Oxidative Amidation
Scheme 4. Control Experiments for Amidation of Benzyl Cyanides
the corresponding secondary amides N-benzylbenzamide 5m
and N-(4-bromophenethyl)benzamide 5n in 54% and 50% yield.
To amplify the scope of the process, representative nitriles
and different amines such as 4-chlorobenzylamine, phenylethyl-
amine, and morpholine were subjected to the present pro-
cedure, secondary (5o and 5p) and tertiary 5q amides were
obtained in 50%, 60%, and 43% yields, respectively. However,
N-methylbenzylamine does not give the oxidative amidation
product 5r under the present conditions.
We have not extensively evaluated the scope of this amidation
process; a brief study indicates that a range of primary, secondary,
and tertiary amide derivatives would be accessible using the
E
DOI: 10.1021/acs.joc.7b02211
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The Journal of Organic Chemistry
Note
Scheme 5. Plausible Mechanism
present protocol. The mild reaction conditions, transition metal-
free and base-free conditions, good functional-group tolerance,
and accessibility of broad range of amides make this proto-
col applicable for the practical synthesis of desired amides.
The optimized conditions were applied for the oxidation of
dibenzyl amine 6; selectively mono-oxidation product 7 was
isolated in 47% yield (Scheme 2). When 2-(p-tolyl)isoindoline 8
was subjected to the optimized conditions only traces of product
9 formation was observed. Further, to check the decarboxylative
amidation of amino acid 10, under the same conditions but at
100 °C, no decarboxylative amidation was observed. These studies
indicate that, present conditions are applicable for selective
monobenzylic oxidation only, but does not affect dibenzylic, cyclic,
or amino acid moieties (Scheme 2).
α- methyl benzyl cyanide 17 with aqueous ammonia under the
conditions of Scheme 3, led to no formation of the desired amide.
The reactions of substrates 11 and 17 suggest that the free
benzylic carbon only undergoes oxidation to yield desired amide.
The reaction of 3a with TEMPO (3.0equiv) and aqueous
ammonia led to 35% yield of desired amide 2q (along with 18
and 19 were observed by GC−MS), but no TEMPO adduct
formation was observed. When the reaction of benzoyl cyanide
20 was subjected to the above conditions, 92% of 2q was
isolated in 18 h of reaction time. This reaction clearly indicates
that, it goes through benzoyl cyanide formation (Scheme 4).
Further, benzaldehyde 21 was subjected to the above reaction
conditions, and 99% of benzonitrile 22 formation was observed
(GC−MS).
To understand the reaction mechanism, we performed some
control experiments using benzylamines and benzyl cyanides.
First, we performed the reaction of α-methyl benzyl amine 11
(Scheme 3) under the optimal reaction conditions; we did not
observe the formation of amide 2q product. To gain insight
into the reaction mechanism under the optimized conditions,
the reaction of 4-methylbenzylamine 12 along with TEMPO
(3.0 equiv) was performed, and the TEMPO adduct 13 formation
was observed by HRMS (see the Supporting Information), which
indicates the reaction may proceed by a radical mechanism.
Further, to learn the reaction path, 4-methylbenzonitrile 14
and 4-methylbenzaldehyde 15 were subjected under the
optimized conditions, no reaction was observed with nitrile,
and 52% of amide 2r was observed in the latter case with aqueous
ammonia. With 4-methylbenzylimine 16, the desired amide 2r
was obtained in 40% yield with the optimized conditions
(Scheme 3). It gives an idea that the reaction goes through the
imine intermediate. In order to establish the reaction route for
the amidation of benzyl cyanide via decyanation, some con-
trol experiments were conducted (Scheme 4). The reaction of
On the basis of the above control experiments (Schemes 3 and 4),
a probable reaction mechanism was proposed (Scheme 5). Initially,
the reaction of benzylamine with iodine and TBHP generated the
benzyl radical intermediate I, which readily underwent oxidation
to yield imine intermediate II. The imine intermediate II may
proceed through path A or B via the intermediate III or IV, and
their subsequent oxidation yields the desired amide. On the
other hand, reaction of benzyl cyanide with iodine and TBHP
generates benzyl cyanide radical I′, and its reaction with tert-butyl
peroxy radical may generate tetrahedral intermediate II′ upon
elimination of tert-butyl alcohol give the stable aroyl cyanide III′.
Nucleophilic addition of amine to the intermediate III′ may
generate another tetrahedral intermediate IV′. Finally, decyana-
tion through the oxidation yield the desired amide.
In conclusion, we have developed a metal- and base-free oxi-
dative amidation of arylmethylamines as well as aryl acetonitriles
into the corresponding primary benzamides under mild reaction
conditions. To the best of our knowledge, this is the first report
on benzylic oxidation of amines and cyanides to amides under
metal-free conditions. The present I2−TBHP system is accessible
F
DOI: 10.1021/acs.joc.7b02211
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The Journal of Organic Chemistry
Note
4-Methoxy-N-methylbenzamide (2c). Eluent: 40% EtOAc/
hexane. 71% yield (116.0 mg). White solid. Observed mp 96−99 °C.
1H NMR (500 MHz,CDCl3): δ 7.74 (d, J = 8.5 Hz, 2H), 6.91 (d, J =
8.0 Hz, 2H), 6.21 (br, NH, 1H), 3.84 (s, 3H),2.99 (d, J = 4.0 Hz, 3H).
13CNMR (125 MHz, CDCl3): δ 167.8, 162.0, 132.1, 128.7, 128.6,
126.9, 113.8, 113.7, 55.3, 26.7. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C9H12NO2 166.0868, found 166.0869.
for a range of primary, secondary, and tertiary amide derivatives in
good to excellent yields.
EXPERIMENTAL SECTION
■
General Methods. All commercially available chemicals and reagents
were used without any further purification unless otherwise indicated.
1H and 13C NMR spectra were recorded at 500, 600, and 125 MHz and
150 MHz, respectively. The spectra were recorded in CDCl3 as solvent.
Multiplicity is indicated as follows: s (singlet); d (doublet); t (triplet);
m (multiplet); dd (doublet of doublets), etc., and coupling constants
(J) are given in Hz. Chemical shifts are reported in ppm relative to TMS as
1
an internal standard. The peaks around δ values of H NMR (7.2) and
13C NMR (77.0) correspond to deuterated solvent chloroform,
respectively. Mass spectra were obtained using an electron-impact (EI)
ionization method. Progress of the reactions was monitored by thin-layer
chromatography (TLC). All products were purified through column
chromatography using silica gel 100−200 mesh size using hexane/ethyl
acetate as eluent unless otherwise indicated.
4-tert-Butyl-N-methylbenzamide (2d). Eluent: 30% EtOAc/
hexane. 77% yield (148.0 mg). White solid. Observed mp 101−103 °C.
1H NMR (500 MHz, CDCl3): δ 7.70 (d, J = 8.0 Hz, 2H), 7.44 (d, J =
7.5 Hz, 2H), 6.18 (br, NH, 1H), 3.01 (d, J = 3.5 Hz,3H), 1.32 (s, 9H).
13C NMR (125 MHz, CDCl3): δ 168.1, 154.8, 131.7, 130.0, 126.6,
125.4, 34.8, 31.1, 26.7. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C12H17NONa 214.1208, found 214.1204.
General Procedure for the Synthesis of N-Methylbenzamide
(2a). To a reaction tube equipped with a magnetic stir bar were added
N-methylbenzylamine 1a (121.0 mg, 1.0 mmol), iodine (50.6 mg,
0.2 mmol), and aq TBHP (10.0 mmol) in 2.0 mL of acetonitrile.
The mixture was heated in an oil bath at 70 °C for 18 h in a sealed tube.
The reaction was monitored by TLC; after completion of the reaction,
it was allowed to attain room temperature. The reaction mixture was
quenched by saturated Na2SO3 solution, extracted with ethyl acetate
(15 mL × 3), and dried with anhydrous K2SO4. Removal of the solvent
under reduced pressure left a residue which was purified by column
chromatography using silica gel (40% EtOAc/hexane) to afford 2a
(111.2 mg; 82% yield).
General Procedure for the Synthesis of Benzamide from
Benzyl Cyanide (5). A mixture of benzyl cyanide (58.5 mg,
0.5 mmol), 25% aq NH3 (1.5 mL), and 20 mol % of I2 (25.3 mg,
0.1 mmol and aq TBHP (8.0 mmol) in 1.5 mL of acetonitrile
was taken in an oven-dried reaction tube. The reaction mixture was stirred
at 70 °C for 36 h. This reaction was monitored by TLC. After completion
of the reaction, the solvent was removed on a rotary evaporator.
The reaction mixture was quenched by saturated Na2SO3 solution and
extracted by ethyl acetate. The organic extract was dried over K2SO4, and
the final residue was purified by column chromatography using 40%
EtOAc in hexane to afford 5a (45.6 mg; 75%yield).
4-Fluoro-N-methylbenzamide (2e). Eluent: 35% EtOAc/hexane.
68% yield (104.2 mg). White solid. Observed mp 121−124 °C.
1H NMR (500 MHz, CDCl3): δ 7.77 (d, J = 5.5 Hz, 2H), 7.09 (t, J =
8.5 Hz, 2H), 6.20 (br, NH, 1H), 3.01 (t, J = 5.0 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 167.2, 165.6, (d, J = 250.25 Hz) 163.6, 130.8,
129.17, (d, J = 10.2 Hz), 129.10, 115.6, (d, J = 21.62 Hz), 115.5, 26.9.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H9NOF 154.0668, found
154.0662.
4-Chloro-N-methylbenzamide (2f). Eluent: 35% EtOAc/hexane.
62% yield (105.1 mg). White solid. Observed mp 171−174 °C. 1H NMR
(600 MHz,CDCl3): δ 7.70 (d, J = 6.5 Hz, 2H), 7.40 (d, J = 7.5 Hz, 2H),
6.27 (br, NH, 1H), 3.00 (d, J = 3.5 Hz, 3H). 13CNMR (150 MHz,
CDCl3): δ 167.2, 137.6, 132.0, 128.8, 128.3, 26.9. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C8H9NOCl 170.0373, found 170.0368.
N-Methylbenzamide (2a).8 Eluent: 30% EtOAc/hexane. 82%
1
yield (111.2 mg). White solid. H NMR (500 MHz, CDCl3): δ 7.77
(d, J = 7.0 Hz, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.0 Hz, 2H), 6.36
(br, NH, 1H), 3.00 (d, (t, J = 5.0 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ 168.2, 134.6, 131.3, 128.5, 126.8, 26.8.
4-Bromo-N-methylbenzamide (2g). Eluent: 35% EtOAc/hexane.
52% yield (111.4 mg). White solid. Observed mp 170−172 °C. 1H NMR
(600 MHz, CDCl3): δ 7.61 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.1 Hz, 2H),
6.23 (br, NH, 1H), 2.98 (d, J = 4.9 Hz, 3H). 13CNMR (151 MHz,
CDCl3): δ 167.3, 133.5, 131.8, 128.5, 126.1, 26.9. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C8H8NONaBr 235.9687, found
235.9689.
N,4-Dimethylbenzamide (2b). Eluent: 35% EtOAc/hexane. 51%
yield (89 mg). White solid. H NMR (500 MHz, CDCl3): δ 7.66
1
(d, J = 7.5 Hz, 2H), 7.22 (d, J = 7.5 Hz, 2H), 6.17 (br, NH, 1H), 3.17
(d, J = 3.5 Hz, 3H), 2.38 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 168.1,
141.7, 131.7, 130.1, 129.2, 127.4, 126.8, 26.8, 21.4. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C9H12NO 150.0919, found 150.0916.
N-Methyl-3-nitrobenzamide (2h). Eluent: 30% EtOAc/hexane.
68% yield (123 mg). Observed mp 162−166 °C. 1H NMR (500 MHz,
CDCl3): δ 8.58 (s, 1H), 8.37−8.35 (m, 1H), 8.17 (d, J = 8.0 Hz, 1H),
7.67 (t, J = 8.0 Hz, 1H), 6.34 (br, NH, 1H), 3.07 (d, J = 5.0 Hz, 3H).
G
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Note
13C NMR (125 MHz, CDCl3): δ 164.3, 148.1, 136.1, 133.1, 129.8, 126.0,
121.6, 27.0. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H9N2O3
181.0613, found 181.0611.
(125 MHz, CDCl3): δ 167.5, 134.7, 133.4, 131.3, 130.1, 128.5, 128.4,
126.8, 34.9, 14.8.
N-Phenylbenzamide (2p).12b Eluent: 20% EtOAc/hexane. 48%
1
yield (94.6 mg). H NMR (600 MHz, CDCl3): δ 7.90 (s, 1H), 7.85
4-Cyano-N-methylbenzamide (2i). Eluent: 30% EtOAc/hexane.
55% yield (87.4 mg). Observed mp 203−205 °C. 1H NMR (500 MHz,
CDCl3): δ 7.87 (d, J = 7.5 Hz, 2H), 7.74 (d, J = 7.5 Hz, 2H),
6.23 (br, NH, 1H), 3.04 (s, 3H). 13C NMR (125 MHz, CDCl3):
δ 166.3, 138.5, 132.4, 127.5, 117.9, 115.0, 27.0. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C9H9N2O 161.0715, found161.0723.
(d, J = 6.7 Hz, 2H), 7.63 (d, J = 7.1 Hz, 2H), 7.53 (s, 1H), 7.47 (d, J =
6.2 Hz, 2H), 7.36 (s, 2H), 7.14 (s, 1H). 13C NMR (150 MHz, CDCl3):
δ 165.8, 138.0, 131.9, 129.1, 128.8, 127.1, 124.6, 120.3.
Benzamide (2q).15d Eluent: 40% EtOAc/hexane. 58% yield
1
(70.5 mg). White solid. H NMR (500 MHz, CDCl3): δ 7.82 (t, J =
7.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 6.12 (br, NH, 2H). 13C NMR
(125 MHz, CDCl3) δ 169.5, 133.3, 132.0, 128.6, 127.3.
N-Methyl-(1,1′-biphenyl)-4-carboxamide (2j). Eluent: 35%
EtOAc/hexane. 57% yield (121.2 mg). White solid. Observed mp
167−168 °C. 1H NMR (600 MHz,CDCl3): δ 7.84 (d, J = 6.5 Hz, 2H),
7.65 (q, J = 7.0 Hz, 4H), 7.47 (t, J = 6.5 Hz, 2H), 7.39 (t, J = 5.0 Hz, 1H),
6.31 (br, NH, 1H), 3.04 (d, J = 4.0 Hz, 3H). 13C NMR (150 MHz,
CDCl3): δ 168.0, 144.2, 140.0, 133.3, 128.9, 128.0, 127.4, 127.2, 127.2,
26.9. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H14NO 212.1075,
found 212.1069.
4-Methylbenzamide (2r).15d Eluent: 35% EtOAc/hexane. 54% yield
(73.3 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.72 (d, J = 8.5 Hz,
2H), 7.26 (d, J = 8.0 Hz, 2H), 6.06 (br, NH, 2H), 2.40 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 169.4, 142.5, 130.4, 129.2, 129.0, 127.3, 21.4.
3-Fluoro-N-methylbenzamide (2k). Eluent: 30% EtOAc/hexane.
65% yield (98.9 mg). White solid. 1H NMR (600 MHz, CDCl3):
δ 7.52 (q, J = 8.0 Hz, 2H), 7.37 (q, J = 10.0, 7.8 Hz, 1H), 7.20−7.15
(m, 1H), 6.65 (br, NH, 1H), 2.99 (d, J = 4.6 Hz, 3H). 13C NMR
(150 MHz, CDCl3): δ 167.1, 163.6, 161.96 (d, J = 246 Hz), 136.93
(d, J = 7.5 Hz), 136.88, 130.27 (J = 7.5 Hz), 130.22 122.4, 118.46
(J = 21.0 Hz), 118.32, 114.4, 26.9. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C8H9NOF 154.0668, found 154.0665.
3-Methylbenzamide (2s).15d Eluent: 30% EtOAc/hexane. 88%
yield (119 mg). White solid. H NMR (600 MHz, CDCl3): δ 7.54
(s, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.23 (d, J = 5.5 Hz, 2H), 6.19 (br, NH,
2H), 2.29 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.1, 138.5, 132.8,
128.5, 128.1, 124.3, 21.4.
1
3-Methoxybenzamide (2t).15e Eluent: 40% EtOAc/hexane. 55%
1
yield (82.4 mg). White solid. H NMR (500 MHz, CDCl3): δ 7.40
(m, 1H), 7.34 (m, 2H), 6.10 (br, NH, 2H), 3.85 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 169.1, 159.9, 134.8, 129.7, 119.2, 118.4, 112.6, 55.5.
N-Methyl-1-naphthamide (2l). Eluent: 30% EtOAc/hexane. 44%
yield (81.2 mg). White solid. Observed mp 152−154 °C. H NMR
1
(600 MHz, CDCl3): δ 8.26 (d, J = 6.5 Hz, 1H), 7.87 (q, J = 7.0 Hz, 2H),
7.51 (m, 3H), 7.39 (t, J = 6.0 Hz, 1H), 6.25 (br, NH, 1H), 3.01
(s, 3H).13C NMR (150 MHz, CDCl3): δ 170.4, 130.5, 128.3, 127.0,126.4,
125.5, 124.9, 124.7, 26.8. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C12H12NO 186.0919 found 186.0926.
4-Chlorobenzamide (2u).15e Eluent: 40% EtOAc/hexane. 60%
yield (93.7 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J =
7.5 Hz, 2H), 7.43 (d, J = 7.0 Hz, 2H), 6.08 (br, NH, 2H). 13C NMR
(125 MHz, CDCl3): δ 168.3, 138.4, 131.7, 128.9, 128.8.
N-Ethylbenzamide (2n).15b Eluent: 30% EtOAc/hexane. 63%
1
yield (94.5 mg). White solid. H NMR (500 MHz, CDCl3): δ 7.77
4-Fluorobenzamide (2v).15d Eluent: 40% EtOAc/hexane. 55%
yield (76.7 mg). White solid. H NMR (500 MHz, CDCl3): δ 7.84
(d, J = 7.0 Hz, 2H), 7.48 (m, 1H), 7.43 (q, J = 7.0 Hz, 2H), 6.22 (br, NH,
1H), 3.50 (pent, J = 7.0 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H). 13C NMR
1
H
DOI: 10.1021/acs.joc.7b02211
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Note
(m, 2H), 7.12 (t, J = 7.0 Hz, 2H), 6.74 (br, NH, 2H). 13C NMR
(125 MHz, CDCl3): δ 168.7, 166.1 (d, J = 251.2 Hz), 164.0, 132.5,
129.82, (d, J = 8.8 Hz), 129.75, 115.82 (d, J = 21.87 Hz), 115.65.
3-Methoxylbenzamide (5d).15e Eluent: 40% EtOAc/hexane. 63%
yield (47.3 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.40 (m,
1H), 7.36−7.32 (m, 2H), 7.07 (m, 1H), 6.16 (br, NH, 2H), 3.85 (s, 3H).
13C NMR (150 MHz, CDCl3): δ 169.4, 159.9, 134.8, 129.7, 119.2, 118.3,
112.6, 55.5.
Nicotinamide (2w).15e Eluent: 1:1 EtOAc/hexane. 40% yield
(48.8 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 9.04 (s, 1H),
8.75 (d, J = 3.5 Hz, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.43 (q, J = 4.0 Hz,
1H),6.45 (br, NH, 2H). 13C NMR (150 MHz, CDCl3): δ 167.6, 152.7,
148.3, 130.6, 129.2, 123.6.
4-tert-Butylbenzamide (5e).15d Eluent: 30% EtOAc/hexane. 52%
yield (45.6 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.73 (d, J =
7.0 Hz, 2H), 7.43 (d, J = 7.0 Hz, 2H), 6.15 (br, NH, 2H), 1.30 (s, 9H).
13C NMR (150 MHz, CDCl3): δ 169.7, 155.6, 130.5, 127.3, 125.6,
35.0, 31.2.
Furan-2-carboxamide (2x).15e Eluent: 40% EtOAc/hexane. 36%
1
yield (17.6 mg). White solid. H NMR (600 MHz, CDCl3): δ 7.39
(s, 1H), 7.09 (d, J = 3.5 Hz, 1H), 6.48−6.41 (m, 1H), 6.32−5.88 (m,
2H). 13C NMR (150 MHz, CDCl3): δ 160.3, 147.4, 144.5, 115.3, 112.40.
3, 4-Dimethoxybenzamide (5f).15f Eluent: 40% EtOAc/hexane.
53% yield (47.6 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 7.42
(d, J = 1.5 Hz, 1H), 7.31 (dd, J = 8.1, 2.0 Hz, 1H), 6.84 (d, J = 8.1 Hz,
1H), 6.07 (s, 2H), 3.89 (s, 6H). 13C NMR (151 MHz, CDCl3): δ 169.2,
152.2, 149.0, 126.0, 120.2, 110.8, 110.3, 56.1.
Thiophene-2-carboxamide (2y).15e Eluent: 40% EtOAc/hexane.
30% yield (18.9 mg). White solid. 1H NMR (600 MHz, CDCl3):
δ 7.51 (dd, J = 7.9, 4.4 Hz, 2H), 7.12−7.04 (m, 1H), 5.84 (s, 2H).
13C NMR (150 MHz, CDCl3): δ 163.8, 137.8, 131.0, 129.3, 127.8.
4-Bromobenzamide (5g).15d Eluent: 40% EtOAc/hexane. 79%
yield (79.2 mg). White solid. 1H NMR (500 MHz, CDCl3): δ 7.69 (d, J =
7.5 Hz, 2H), 7.60 (d, J = 7.0 Hz, 2H), 6.51 (br, NH, 2H). 13C NMR
(125 MHz, CDCl3): δ 169.2, 132.0, 129.0, 127.0.
Benzamide (5a).15d Eluent: 40% EtOAc/hexane. 75% yield
1
(45.6 mg). White solid. H NMR (500 MHz, CDCl3): δ 7.82 (t, J =
7.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 2H), 6.12 (br, NH, 2H). 13C NMR
(125 MHz, CDCl3): δ 169.5, 133.3, 132.0, 128.6, 127.3.
4-Chlorobenzamide (5h).15d Eluent: 40% EtOAc/hexane. 72%
1
yield (55.6 mg). White solid. H NMR (500 MHz, CDCl3): δ 7.75
(d, J = 7.5 Hz, 2H), 7.43 (d, J = 7.0 Hz, 2H), 6.08 (br, NH, 2H).
13C NMR (125 MHz,CDCl3): δ 168.3, 138.4, 131.7, 128.9, 128.8.
2-Methylbenzamide (5b).15d Eluent: 40% EtOAc/hexane. 70%
yield (47.3 mg). White solid. 1H NMR (500 MHz, CDCl3):δ 7.46 (d, J =
7.5 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.23 (pent, J = 8.5 Hz, 2H), 5.94
(br, NH,2H), 2.50 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 172.0,
136.3, 135.1, 131.2, 130.3, 126.9,125.7, 19.9.
4-Fluorobenzamide (5i).15d Eluent: 40% EtOAc/hexane. 56%
1
yield (38.9 mg). White solid. H NMR (500 MHz, CDCl3): δ 7.84
(q, J = 5.5 Hz, 2H), 7.13 (t, J = 8.5 Hz, 2H), 6.22 (br, NH, 2H). 13CNMR
(125 MHz, CDCl3): δ 168.7, 166.1, (d, J = 251.2 Hz), 164.0, 132.5,
129.82, (d, J = 8.8 Hz), 129.75, 115.82 (d, J = 21.87 Hz), 115.65.
3-Methylbenzamide (5c).15d Eluent: 40% EtOAc/hexane. 66%
yield (44.8 mg). White solid. H NMR (600 MHz, CDCl3): δ 7.54
1
(s, 1H), 7.49 (d, J = 5.5 Hz, 1H), 7.23 (d, J = 5.5 Hz, 2H), 6.19 (br, NH,
2H), 2.29 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.1, 138.5, 132.8,
128.5, 128.1, 124.3, 21.4.
4-Nitrobenzamide (5j).15d Eluent: 40% EtOAc/hexane. 84% yield
1
(69.5 mg). White solid. H NMR (500 MHz, CDCl3): δ 8.32 (d, J =
7.5 Hz, 2H), 7.99 (d, J = 6.5 Hz, 2H), 6.14 (br, NH, 2H). 13C NMR
(125 MHz,CDCl3): δ 165.1, 150.1, 128.6, 123.9.
I
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Note
Nicotinamide (5k).15e Eluent: 1:1 EtOAc/hexane. 49% yield
(29.8 mg). White solid. 1H NMR (600 MHz, CDCl3): δ 9.04 (s, 1H),
8.75 (d, J = 3.5 Hz, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.43 (q, J = 4.0 Hz,
1H), 6.45 (br, NH, 2H). 13C NMR (150 MHz, CDCl3): δ 167.6, 152.7,
148.3, 130.6, 129.2, 123.6.
(4-Chlorophenyl)(morpholino)methanone (5q).12b Eluent:
30% EtOAc/hexane. 43% yield (48.3 mg). White solid. Observed mp
72−75 °C. 1H NMR (500 MHz, CDCl3): δ 7.40−7.35 (m, 4H), 3.75−
3.65 (m, 3H), 3.44 (s, 2H), 1.30 (s, 9H). 13C NMR (125 MHz, CDCl3):
δ 168.3, 134.9, 132.5, 127.8, 127.6, 65.7, 47.2, 41.5.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b02211.
Picolinamide (5l).15e Eluent: 1:1 EtOAc/hexane. 33% yield
Effective solvents for the reaction, H and 13C NMR
1
1
(20.4 mg). White solid. H NMR (500 MHz, CDCl3) δ 8.59 (d, J =
spectra for all compounds, and HRMS spectra for new
products (PDF)
4.5 Hz, 1H), 8.22 (t, J = 8.0 Hz, 1H), 7.86 (m, 2H), 5.87 (br, NH, 2H).
13C NMR (125 MHz, CDCl3): δ 166.8, 149.5, 148.3, 137.3, 126.4, 122.4,
133.4, 131.3, 130.1, 128.5,128.4, 126.8, 34.9, 14.8.
AUTHOR INFORMATION
Corresponding Author
*E-mail: adimurthy@csmcri.res.in.
■
ORCID
N-Benzylbenzamide (5m).12b Eluent: 30% EtOAc/hexane. 54%
yield (57.4 mg). 1H NMR (500 MHz, CDCl3): δ 7.79 (s, 2H),
7.48−7.28 (m, 8H), 6.67 (br, NH, 1H), 4.61 (s, 2H). 13C NMR
(125 MHz, CDCl3): δ 166.9, 137.7, 133.8, 131.0, 128.2, 128.0, 127.3,
127.0, 126.5, 43.5.
Subbarayappa Adimurthy: 0000-0001-5320-4961
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
CSIR-CSMCRI Communication No. 115/2017. S.N.R.,
N.N.K.R., and S.S. are thankful to AcSIR for their Ph.D.
enrollment and the “Analytical Discipline and Centralized
Instrumental Facilities” for providing instrumentation facilities.
S.N.R. and S.S. are thankful to CSIR, New Delhi, for their
fellowships. We thank DST, Government of India (EMR/2016/
000010), and CSIR-CSMCRI (OLP-087 and OLP-088) for
financial support.
N-(4-Bromophenethyl)benzamide (5n).12b Eluent: 30% EtOAc/
1
hexane. 54% yield (81.5 mg). Observed mp 151−153 °C. H NMR
(500 MHz, CDCl3): δ 7.70 (d, 2H), 7.50 (m, 1H), 7.44−7.39 (m, 4H),
7.11 (d, 2H), 6.27 (br, NH, 1H), 3.69 (m, 2H), 2.90 (m, 2H). 13C NMR
(125 MHz, CDCl3): δ 166.5, 136.8, 133.4, 130.7, 129.5, 127.5, 125.7,
119.4, 39.9, 34.1.
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■
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K
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