Radical-Induced Metal and Solvent-Free Cross-Coupling Using TBAI-TBHP: Oxidative Amidation of Aldehydes and Alcohols with N-Chloramines via C-H Activation

Article abstract of DOI:10.1021/jo502464n

A solvent-free cross-coupling method for oxidative amidation of aldehydes and alcohols via a metal-free radial pathway has been demonstrated. The proposed methodology uses the TBAI-TBHP combination which efficiently induces metal-free C-H activation of aldehydes under neat conditions at 50 °C or ball-milling conditions at room temperature.

Full text of DOI:10.1021/jo502464n

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Note
Radical Induced Metal and Solvent free Cross Coupling
using TBAI-TBHP: Oxidative Amidation of Aldehydes
and Alcohols with N-Chloramines via C-H Activation
Tapas Kumar Achar, and Prasenjit Mal
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502464n • Publication Date (Web): 25 Nov 2014
Downloaded from http://pubs.acs.org on November 30, 2014
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Radical Induced Metal and Solvent free Cross Coupling using
TBAI-TBHP: Oxidative Amidation of Aldehydes and Alcohols with
N-Chloramines via C-H Activation
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Tapas Kumar Achar and Prasenjit Mal*
School of Chemical Sciences, National Institute of Science Education and Research (NISER)
Bhubaneswar; Institute of Physics Campus, P.O. Sainik School; Bhubaneswar, Odisha751 005,
India
*Corresponding authors:
Prasenjit Mal, Tel.: +91 674 2304073, E-mail: pmal@niser.ac.in, http://www.niser.ac.in/~pmal/
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ABSTRACT
Solvent free cross coupling method for oxidative amidation of aldehydes and alcohols via metal
free radial pathway has been demonstrated. The proposed methodology uses TBAI-TBHP
combination which efficiently induces metal free C-H activation of aldehydes under neat at 50
ᵒC or ball milling condition at room temperature.
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Amide functionality is well known in peptides and proteins. Due to its stability, high polarity and
conformational diversity, the amide bonds constitute the most abundant motif in various natural
and non-natural products.1 In medicinal chemistry, amides containing bio-active molecules are
also well explored. Development of convenient methodologies for amide functionalities under
catalytic, metal free and chemoselective conditions are highly desirable and much in focus in
recent years. Common methods for the synthesis of amides involve either coupling of carboxylic
acids and amines in presence of a coupling agent2,3 or acylation of amines with activated
carboxylic acid derivatives.4,5 These strategies are efficient but unpopular due to involvement of
hazardous conditions and use of expensive reagents and poor atom economy.3 Therefore handful
of alternatives have been reported such as the Staudinger reaction,6,7 Schmidt reaction,8
Beckmann rearrangement,9,10, aminocarbonylation of haloarenes,11,12 direct synthesis from
alcohols with amines,13 oxidative amidation of aldehydes,14-22 etc. Recently, transition metal
catalyzed aldehyde amidation via oxidation of intermediate carbinolamines has become popular
(Figure 1a).17,19,23-25 One of the recently used catalyst is N-Heterocyclic carbenes (NHCs).26,27 In
addition, N-hydroxyphthalimide28 and N-hydroxysuccinimide29 have also proved to be efficient
as metal free reagents for the amidation of aldehydes. In addition, coupling of acyl- and nitrogen-
centered radicals to construct amide have recently been examined.14,21 Lidia de Luca and co-
workers have shown Cu(II) and Fe(II) catalyzed synthesis of amides from aldehyde and N-
chloramines via radical pathway (Figure 1b).14,16
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Figure 1. a) Known synthesis of amides from aldehydes and amines; b) Metal catalyzed
synthesis of amides using N-chloramine and aldehydes. References are shown as superscript.
Aiming to introduce environmentally benign reagents,30,31 herein we report metal and solvent
free cross coupling oxidative amidation of alcohols and aldehydes with N-chloramines under
neat or ball milling condition. The reagent used here is a TBAI (tetrabutyl ammonium iodide)-
TBHP (tert-butyl hydroperoxide, Caution!!, see experimental section)21,32 combination. Under
neat reaction condition, the substrates were mixed and the reactions were executed at an elevated
temperature (50 °C). However, under ball milling (frequency 21 Hz) the working temperature
was 27 °C (room temperature). Thus we have demonstrated an unprecedented example of TBAI-
TBHP mediated C-H activation33 of aldehydes for oxidative amidation.
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Table 1. Optimization of reaction conditiona
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Entry
Additive Oxidant
(mol%) (equiv)
Yield
(%)b
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2
3
4
5
6
TBAI (25) TBHP (1.5)
TBAI (25) H2O2 (1.5)
TBAI (25) Oxone (1.5)
TBAI (25) PIDA (1.5)
TBAI (25) AgNO3 (1.5)
68
Trace
---
Trace
---
TBAI (25) (NH4)2S2O8
(2)
---
7
TBAI (25)
----
---
59
77
75
---
53
Trace
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38
45
64
73
78
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41
8
TBAI (25) TBHP (1)
TBAI (25) TBHP (2)
TBAI (25) TBHP (2.5)
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19
20c
21d
22e
----
TBHP (2)
TBHP (2)
KI (25)
TBAB (25) TBHP (2)
I2 (25)
NIS (25)
KI/I2
TBHP (2)
TBHP (2)
TBHP (2)
TBAI (10) TBHP (2)
TBAI (15) TBHP (2)
TBAI (20) TBHP (2)
TBAI (20) TBHP (2)
TBAI (20) TBHP (2)
TBAI (20) TBHP (2)
aUnless specified, the reactions were carried out at 50 °C; bIsolated yield; solvent THF solvent
c
d
acetonitrile; eneat at 30 °C
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Reactions were performed for 4-chlorobenzaldehyde, N-benzyl-N-chloro-1-phenylmethanamine
in presence of TBAI (catalyst), TBHP (oxidant) under solvent free (neat) condition at 50 °C.
After which, N,N-dibenzyl-4-chlorobenzamide was isolated in 68% yield (Table 1, entry 1). This
reaction condition was optimized based on screening of various catalysts and the results are
presented in Table 1. TBHP is found to be a superior oxidant (Table 1, entry 1-6) to H2O2
(hydrogen peroxide), oxone, PIDA (phenyliodine diacetate), AgNO3 (silver nitrate) or
(NH4)2S2O8 (ammonium persulfate) etc. In absence of either any of the catalysts or the oxidant
no expected products were identified (entry 7, 11). The roles of counter cations (n-Bu4N+) and
anion (I-) were established by comparing TBAI with different reagents. For example, the
reactions in presence of KI (Potassium iodide), NIS (N-iodosuccinimide, Table 1, entries 12, 15)
and tetrabutyl ammonium bromide (n-Bu4NBr, Table 1, entry 13) resulted in poor yields.
Similarly changing solvents (entry 20, 21), varying temperature (entry 22) and introducing other
reagents like iodine (I2, entry 14), KI-I2 (1:1, entry 16) etc. also did not lead to significant
improvements.
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Figure 2. Results of amidation of aldehydes with N-chloramines under neat condition.
The optimized condition for the oxidative amidation reaction of the aldehyde is shown in Table
1. Aldehydes (1.0 equivalent), N-chloramine (2.0 equivalent), TBAI (20 mol%) and TBHP (2.0
equivalent) led to best results. Using this methodology the amide derivatives were obtained in
good yields with hetero aromatic aldehyde (3f), aliphatic aldehydes (3q, 3r and 3s) and
aldehydes having electron donating (3b, 3e) substituents. Furthermore, aldehydes with electron
withdrawing groups like chloro 3a, trifluoromethyl 3d, bromo 3g and 3i, nitro 3m and 3p, fluoro
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3o etc. were also found to be efficient for the amidation reaction. Similarly, various N-
chloramines like primary (N-chloro-1-phenylmethanamine) and secondary (N-chloro-N-methyl-
1-phenylmethanamine, N-benzyl-N-chloro-1-phenylmethanamine) derivatives have also
facilitated good yields.
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X-Ray crystal structure investigations were done for the synthesized compounds. Good
qualities of crystals were obtained after slow evaporation of the solvent from ethyl acetate-
hexane solution. The structure of the compounds 3c and 3l are shown in supporting information
(SI).
The efficiency and convenience of this methodology encouraged us to further explore the
scope of multistep organic synthesis.34 The oxidative amidation of primary alcohols with N-
chloramines in presence of TBHP (3 equivalent) and TBAI (20 mol%) under neat condition was
performed (Figure 3). We presumed that additional one equivalent of TBHP was consumed for
oxidation of alcohol to the aldehyde. The products were also isolated in good yields in a two-step
process (Figure 3).
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O
TBAI (20 mol%)
TBHP (3 equiv)
R2
Cl
R2
OH
N
N
R4
R4
+
neat, 50 oC, 2.5 h
R3
R3
4
3
2
7
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O
O
N
O
N
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N
O
3e
, 63%
b
3 , 59%
3c
, 52%
O
N
O
O
N
N
NC
Br
3u
3v
, 62%
3t
, 78%
, 69%
O
O
O
N
H
N
H
N
H
Cl
Br
O
3w
3x
3y
,58%
, 67%
, 71%
I
O
N
N
NC
3aa
, 67%
3z
, 73%
Figure 3. Metal free oxidative amidation of alcohols and N-chloramines.
Furthermore, we have also explored this methodology under ball milling (mechanochemical)
condition. The ball milling synthesis35-38 has drawn a significant interest due to its advantages
over traditional solution-based method.39,40 Major benefit of this process is that it is solvent free
and thus minimizes any traditional workup.40,41 Such processes are envisaged to have positive
impact on ecology besides being procedurally as well as time wise economical. Higher
conversion of reaction, less by-products and minimum/no purification requirement are extra
benefits of these procedures.42-44 Under ball milling the reactions were done in absence of any
solvents and at room temperature. Progresses of the reactions were monitored either by TLC or
1H NMR. Products were isolated by dissolving the reaction mixture in ethyl acetate or
dichloromethane and purified by chromatographic methods. The isolated yields for selected
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compounds are shown in Table 2, which are comparable to the results of neat condition (Figure
2).
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Table 2. Under ball milling condition the results for amidation aldehyde and N-chloramines
compound yield entry compound yield
entry
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2
3
4
5
72
75
63
66
64
6
75
69
62
71
68
3c
3e
3f
3i
7
3k
3o
3z
8
9
3u
3v
10
3aa
Control experiments (Scheme 1) under neat condition were performed to shed some light on the
mechanism of the reaction. Upon replacement of N-chloramine with benzylamine, no amide was
obtained (Scheme 1a) due to the formation of imine. And, secondary amine led to only 11% of
amide (Scheme 1b). The combination of TBAI, TBHP, benzaldehyde and TEMPO (2,2,6,6-
tetramethylpiperidin-1-yl-oxy radical) led to the formation of TEMPO adduct (5, Scheme 1c).
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Scheme 1. a) and b) Established that N-chloramine was essential for this reaction; c) Formation
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of TEMPO adduct with aldehyde radical
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In Scheme 2 a plausible mechanism for oxidative amidation reaction has been proposed. The
formation of TEMPO adduct (5, Scheme 1c) clearly establishes that the reaction goes via radical
pathway. The tert-butoxyl and/or tert-butylhydroperoxide radicals were generated from TBHP in
presence of TBAI (Scheme 2b). Further, acyl radical16,21 and amino radicals45 were produced
from the aldehyde and N-chloramine, respectively. Finally, these acyl and amino radicals
combine to results in the amide (Scheme 2c).
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Scheme 2. a) The amidation reaction; b) generation of tert-butoxyl and tert-butylhydroperoxide
radicals; c) formation of acyl radical, amino radical and followed by recombination to the final
product
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O
TBAI
TBHP
a)
b)
Cl
R2
O
R2
N
+
HCl
+
R1
N
R3
R1
H
R3
1/ I2
t-BuOOH
t-BuO
+
OH
2
+
OH
H2O
+
tBuOO
(TBAI)
I
(TBHP)
t-BuOOH
c)
t-BuOO or t-BuO
t-BuOO or t-BuO
R2
Cl
R2
O
O
N
N
+
R3
R3
R1
R1
H
R1
t-BuOOH or t-BuOH
t-BuOOCl or t-BuOCl
O
OH
R2
R1
N
R3
In summary, we have developed a mild, efficient and metal free method for the synthesis of
amides from alcohols and aldehydes using TBHP-TBAI combination under solvent free
conditions. The cross coupling reaction of the aldehydes and N-chloramine is demonstrated as an
example of metal free C-H activation of the aldehydes. This methodology was found to be a
compatible with various functional groups and requires easily accessible starting materials.
Performing the reactions under ball milling condition may constitute an important addition in
mechanochemical synthesis. Hence, we anticipate that our study may draw significant attention
of chemists working on the development of synthetic methodologies as well as the researchers
searching for better methods in organic mechanochemistry.46
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EXPERIMENTAL SECTION
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General Methods. The ball milling (21 Hz) experiments were executed under open atmosphere.
Column chromatographic purification of compounds was performed using silica-gel (mesh 100-
200) and hexane-ethylacetate mixture as eluent, unless otherwise specified. NMR spectra were
recorded on 400 MHz instrument at 25 ⁰C. The chemical shift values are reported in parts per
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million (ppm) with respect to residual chloroform (7.26 ppm for H and 77.16 for C). High-
resolution mass spectra (HRMS) were recorded on ESI-TOF (time of flight) mass spectrometer.
Infrared spectral data are reported in wave number (cm-1). Melting points of the compounds were
determined using digital melting point apparatus and are uncorrected.
Preparation of N-chloramine (Caution!!) derivatives:14
In a representative procedure, dibenzylamine (10.4 mmol) was added to 10 mL of
tetrahydrofuran followed by addition of N-chlorosuccinimide (11.4 mmol). The reaction mixture
was allowed to stir at room temperature for 1 h. After that tetrahydrofuran was evaporated under
reduced pressure and compound was extracted with 50 mL of dichloromethane after successively
washed with water. The organic phase was dried over anhydrous Na2SO4 and solvent was
evaporated under reduced pressure to isolate the desired product N-benzyl-N-chloro-1-
1
phenylmethanamine (2.3 g, 96%). H NMR (400 MHz, CDCl3) δ 7.45-7.34 (m, 10H), 4.19 (s,
4H); 13C NMR (100 MHz, CDCl3) δ 137.1, 129.2, 128.5, 127.9, 67.2.
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Safety issues of N-chloramine (Caution!!). A number of N-chloramines have been reported to
be explosive.47 However, none of the N-chloramine used here have shown any of sign of
explosiveness but they are highly toxic in natureStill, general safety concern at an organic
chemistry laboratory should be carefully exercised. PPEs (personal protective equipment’s)
should be used during preparation and use of N-chloramines. N-Chloramines were stable up to
few weeks when stored at -20 ⁰C without sign of decomposition.
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Procedure for large scale use of TBHP (Caution!!) under ball milling
Safety issues of TBHP (Caution!!). TBHP is a potential shock sensitive chemical. However,
precautions like PPEs should be used during handling under ball milling. Also, very high level
of safety precautions should be exercised during the reaction with TBHP. The ball mill
instrument should be kept under an isolated fume hood and fume hood sashes must be lowered to
fullest extent. The use of blast shields is mandatory at all times during reactions. For large scale
reactions recommended maximum loading should be 1/3 volume of the jar capacity.
Herein, the TBHP was used as 70% in water and the reaction was continued for 3 h
(additional 1.5 h after completion) for synthesis of 0.96 g of 3e using a 25 mL ZrO2 milling jar.
Notably, we did not observe any explosion or decomposition of the materials during the reaction.
In a typical procedure, 4-methoxy benzaldehyde (0.5 mL, 4.1 mmol), N-benzyl-N-chloro-1-
phenylmethanamine (1.9 g, 8.2 mmol), TBAI (0.3 g, 20 mol%), TBHP (70% in water, 1.1 mL,
8.2 mmol) and one grinding ball (15 mm diameter, ZrO2) were placed in a 25 mL ZrO2 milling
jar. After continuous milling of 3 h, the mass was dissolved in dichloromethane and compound
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(N,N-dibenzyl-4-methoxybenzamide, yield 71%) was purified by chromatography. Spectral data
matches with the characterization data provided for 3e.
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Procedure for preparation of amides under neat condition. In a typical run, N-benzyl-N-
chloro-1-phenylmethanamine (0.7 mmol) was added to a 25 mL round bottom flask charged with
magnetic stirring bar and 4-chlorobenzaldehyde (0.35 mmol). TBAI (n-Bu4NI, 20 mol%) and
TBHP (70% in water, 0.7 mmol) were added to the mixture and the round bottom flask was kept
at 50 °C (preheated oil bath). The reaction was monitored by thin layer chromatography (TLC).
After completion of the reaction, the mass was dissolved in dichloromethane and purified by
1
column chromatography to obtain N,N-dibenzyl-4-chlorobenzamide48 (93 mg, 78%). H NMR
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(400 MHz, CDCl3) δ 7.51-7.29 (m, 12H), 7.14 (br s, 2H), 4.71 (br s, 2H), 4.40 (br s, 2H); C
NMR (100 MHz, CDCl3) δ 171.3, 135.9, 134.6, 129.7, 128.9, 128.6, 128.3, 127.8, 126.8, 51.6,
47.2.
Procedure for the preparation of amides under ball milling. Benzaldehyde (0.29 mmol), N-
benzyl-N-chloro-1-phenylmethanamine (0.59 mmol), TBAI (20 mol%), TBHP (70% in water,
0.59 mmol) and one grinding ball (15 mm diameter, ZrO2) were placed in a 10 mL ZrO2 milling
jar. Progress of the reaction under milling condition was checked by thin layer chromatography
1
(TLC) or H NMR. After which the reaction was started and this operation time was excluded
from the reported reaction time. Once the reaction was completed, the mixture was dissolved in
ethyl acetate or dichloromethane and compound (N,N-dibenzylbenzamide, yield 72%) was
purified by column chromatography.
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Monitoring the reaction by TLC or H NMR. To perform this operation, the ball milling
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instrument was stopped and small amount of the sample was collected from the jar to check
either TLC or 1H NMR. After that, the reaction was started and this operation time was excluded
for reporting the reaction timing.
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Trapping of acyl radical by TEMPO. TEMPO (0.54 mmol) was added to a 25 mL round
bottom flask charged with magnetic stirring bar and 4-chlorobenzaldehyde (0.36 mmol). TBAI
(n-Bu4NI, 20 mol%) and TBHP (70% in water, 0.72 mmol) were added to the mixture and the
round bottom flask was kept at 50 °C. The reaction was monitored by thin layer chromatography
(TLC). After completion of the reaction, the mass was dissolved in dichloromethane and purified
by column chromatography to obtain 2,2,6,6-tetramethylpiperidin-1-yl 4-chlorobenzoate (5).
yield: 86% (91 mg); Rf = 0.40 (diethyl ether:hexane = 0.25:4.75); Reddish white solid; mp. 80-
1
82 °C; H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8 Hz, 2H), 7.47 (d, J = 8 Hz, 2H), 1.85-1.45
13
(m, 6H), 1.30 (s, 6H), 1.15 (s, 6H); C NMR (100 MHz, CDCl3) δ 164.8, 138.6, 130.2, 128.1,
~
127.4, 59.7, 38.3, 31.2, 20.1, 16.2; IR (KBr) 3457 (w), 2973 (s), 2935 (s), 1746 (m), 1633 (m),
ν
1252 (m), 1071 (m), 754 (s) cm-1; HRMS (ESI-TOF) calculated for C16H23ClNO2 (M + H+)
296.1412, found 296.1432.
N,N-dibenzyl-4-chlorobenzamide (3a). Rf = 0.17 (Ethyl acetate:hexane = 0.25:4.75); White
1
solid; yield: 78% (93 mg); mp. 102-104 °C (lit.48 103-104 °C); H NMR (400 MHz, CDCl3) δ
7.51-7.29 (m, 12H), 7.14 (br s, 2H), 4.71 (br s, 2H), 4.40 (br s, 2H); 13C NMR (100 MHz,
~
CDCl ) δ 171.3, 135.9, 134.6, 129.7, 128.9, 128.6, 128.3, 127.8, 126.8, 51.6, 47.2; IR (KBr)
ν
3
3459 (w), 3030 (w), 2925 (w), 1637(s), 1450 (m), 1420 (m), 1258 (m), 1089 (m), 750 (m), 700
(m) cm-1; HRMS (ESI-TOF) calculated for C21H19ClNO (M + H+) 336.1150, found 336.1182.
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N,N-dibenzyl-4-methylbenzamide (3b.)49 Rf = 0.20 (Ethyl acetate:hexane = 0.25:4.75); White
solid; yield: 84% (112 mg); mp. 87-90 °C (no literature report on melting points); 1H NMR (400
MHz, CDCl3) δ 7.43-7.28 (m, 10H), 7.19 (d, J = 8 Hz, 4H), 4.71 (br s, 2H), 4.44 (br s, 2H), 2.36
3
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(s, 3H); C NMR (100 MHz, CDCl3) δ 172.6, 144.3, 139.9, 133.2, 130.2, 129.2, 128.8, 127.6,
~
126.9, 51.7, 47.0, 21.4; IR (KBr) 3440 (w), 3028 (w), 2923 (w), 1633 (s), 1449 (m), 1419 (m),
ν
1259 (m), 751 (m) cm-1; HRMS (ESI-TOF) calculated for C22H22NO (M + H+) 316.1696, found
316.1716.
N,N-dibenzylbenzamide (3c). Rf = 0.20 (Ethyl acetate:hexane = 0.25:4.75); White solid; yield:
73% (108 mg); mp. 113-115 °C (lit.50 114-115 °C); 1H NMR (400 MHz, CDCl3) δ 7.52-7.31 (m,
13
13H), 7.16 (br s, 2H), 4.72 (br s, 2H), 4.42 (br s, 2H); C NMR (100 MHz, CDCl3) δ 172.3,
136.2, 129.7, 128.9, 128.8, 128.7, 128.6, 128.5, 128.5, 127.7, 127.6, 127.1, 126.8, 51.6, 46.9; IR
~
(KBr)
3442 (w), 1633 (s), 1494 (m), 1451(m), 1261 (m), 697 (s) cm-1; HRMS (ESI-TOF)
ν
calculated for C21H20NO (M + H+) 302.1539, found 302.1532.
N,N-dibenzyl-4-(trifluoromethyl)benzamide (3d).49 Rf = 0.35 (Ethyl acetate:hexane = 0.5:4.5);
White solid; yield: 73% (99 mg); mp. 88-91 °C (no literature report on melting points); 1H NMR
(400 MHz, CDCl3) δ 7.60-7.53 (m, 4H), 7.33-7.20 (m, 8H), 7.08 (br s, 2H), 4.67 (br s, 2H), 4.30
2
(br s, 2H); 13C NMR (100 MHz, CDCl3) δ 171.0, 139.8, 136.7, 136.0, 131.8 (q, JFC = 65.1 Hz),
3
129.1, 128.9, 128.6, 128.0, 127.9, 127.2, 127.0, 125.8 (q, JFC = 7.4 Hz), 123.8 (d, JFC = 271
1
~
Hz), 51.5, 47.2; IR (KBr) 3473 (w), 3063 (m), 3031 (m), 2927 (m), 1640 (s), 1451 (m), 1425
ν
(m), 1326 (s), 1261 (m), 1167 (s), 1128 (m), 1065 (s), 850 (s), 747 (m) cm-1; HRMS (ESI-TOF)
calculated for C22H19F3NO (M + H+) 370.1413, found 370.1440.
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N,N-dibenzyl-4-methoxybenzamide (3e) Rf = 0.30 (Ethyl acetate:hexane = 1:4); colorless solid;
yield: 82% (112 mg); mp. 118-120 °C (lit.14 120-122 °C); 1H NMR (400 MHz, CDCl3) δ 7.49 (d,
J = 8 Hz, 2H), 7.38-7.23 (m, 10H), 6.88 (d, J = 8 Hz, 2H), 4.66 (br s, 2H), 4.49 (br s, 2H), 3.80
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(s, 3H); C NMR (100 MHz, CDCl3) δ 172.3, 160.8, 137.0, 128.8, 128.7, 128.3, 127.6, 113.9,
~
55.4, 51.8, 47.2; IR (KBr) 3440 (w), 2054 (w), 1632 (s), 1451 (m), 1420 (m), 1249 (s), 1029
ν
(m), 992 (m), 839 (m), 699 (m) cm-1; HRMS (ESI-TOF) calculated for C22H22NO2 (M + H+)
332.1645, found 332.1665.
N,N-dibenzylthiophene-2-carboxamide (3f) Rf = 0.24 (Ethyl acetate:hexane = 0.5:4.5); White
1
solid; yield: 76% (125 mg); mp. 46-47 °C (lit.50 48-50 °C); H NMR (400 MHz, CDCl3) δ 7.45
(d, J = 8 Hz, 1H), 7.39-7.27 (m, 11H), 6.96 (dd, J1 = J2 = 4 Hz, 1H), 4.73 (s, 4H); 13C NMR (100
MHz, CDCl3) δ 165.2, 137.8, 136.7, 129.5, 128.9, 128.7, 127.7, 127.0, 126.8, 51.7, 49.2; IR
~
(KBr) 3444 (w), 2880 (m), 1620 (s), 1615 (s), 1452 (m), 1427 (m), 1252 (m), 975 (s), 735 (m)
ν
cm-1; HRMS (ESI-TOF) calculated for C19H18NOS (M + H+) 308.1109, found 308.1093.
N-benzyl-4-bromo-N-methylbenzamide (3g).51 Rf = 0.22 (Ethyl acetate:hexane = 0.5:4.5);
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Colorless oil; yield: 74% (61 mg); 1:1 mixture of rotamers ; H NMR (400 MHz, CDCl3) δ 7.59-
7.44 (m, 4H), 7.39-7.30 (m, 12H), 7.16 (br s, 2H), 4.74, 4.50 (two singlets for two rotamers, 4H),
3.03, 2.86 (two singlets for two rotamers, 6H); 13C NMR (100 MHz, CDCl3) δ 169.9, 133.5,
~
131.8, 130.2, 128.9, 128.5, 128.3, 127.8, 124.1, 55.3, 51.0, 37.1, 33.5; IR (KBr)
3466 (w),
ν
3062 (m), 3030 (m), 2924 (s), 2854 (s), 1714 (s), 1633 (m), 1453 (m), 1402 (s), 1264 (s), 1073
(s), 1012 (s), 836 (s), 734 (m), 699 (m) cm-1; HRMS (ESI-TOF) calculated for C15H15BrNO (M +
H+) 304.0332, found 304.0358.
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N-benzyl-3-bromo-4-methoxy-N-methylbenzamide (3h). Rf = 0.20 (Ethyl acetate:hexane = 1:4);
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6
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Colorless oil; yield: 78% (60 mg); 1:1 mixture of rotamers; H NMR (400 MHz, CDCl3) δ 7.69
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8
9
(s, 1H), 7.42-7.18 (m, 6H), 6.89 (br s, 1H), 4.69, 4.58 (two singlets for two rotamers, 2H), 3.90
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(s, 3H), 2.94 (br s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.7, 157.0, 136.8, 132.6, 129.6, 128.9,
~
128.2, 128.0, 128.0, 127.7, 111.6, 111.4, 56.4, 55.4, 51.1, 37.2, 33.6; IR (KBr) 3459 (w), 2924
ν
(s), 2853 (s), 1632 (m), 1600 (s), 1454 (m), 1402 (m), 1293 (s), 1262 (m), 1052 (m), 816 (m),
730 (m), 698 (m) cm-1; HRMS (ESI-TOF) calculated for C16H17BrNO2 (M + H+) 334.0437,
found 334.0453.
N-benzyl-3-bromo-N-methylbenzamide (3i).52 Rf = 0.40 (Ethyl acetate:hexane = 1:4); Colorless
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oil; yield: 82% (107 mg); 1:1 mixture of rotamers; H NMR (400 MHz, CDCl3) δ 7.60-7.52 (m,
4H), 7.45-7.28 (m, 12H), 7.23-7.15 (m, 2H), 4.74, 4.49 (two singlets for two rotamers, 4H), 3.02,
13
2.85 (two singlets for two rotamers, 6H); C NMR (100 MHz, CDCl3) δ 170.6, 169.9, 138.1,
136.6, 136.1, 133.2, 132.7, 130.1, 130.0, 128.9, 128.8, 128.3, 128.2, 127.7, 126.7, 125.6, 125.2,
~
122.6, 55.2, 50.9, 37.0, 33.3; IR (KBr) 3459 (w), 3063 (m), 3030 (m), 2925 (m), 1713 (m),
ν
1633 (s), 1562 (m), 1495 (m), 1452 (m), 1400 (m), 1255 (m), 1077 (m), 735 (m), 699 (m) cm-1;
HRMS (ESI-TOF) calculated for C15H15BrNO (M + H+) 304.0332, found 304.0363.
N-benzyl-N-methylbenzamide (3j).53 Rf = 0.27 (Ethyl acetate:hexane = 1:4); Colorless oil; yield:
1
81% (180 mg); 1:1 mixture of rotamers; H NMR (400 MHz, CDCl3) δ 7.55-7.27 (m, 18H), 7.17
(br s, 2H), 4.77, 4.51 (two singlets for two rotamers, 4H), 3.04, 2.86 (two singlets for two
13
rotamers, 6H); C NMR (100 MHz, CDCl3) δ 172.4, 171.7, 137.0, 136.5, 136.1, 133.0, 130.2,
~
130.0, 129.7, 128.8, 128.4, 128.3, 128.2, 127.6, 127.0, 126.8, 55.2, 50.8, 37.0, 33.2; IR (KBr)
ν
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3468 (w), 3060 (m), 3029 (m), 2923 (m), 1631 (s), 1450 (m), 1401 (s), 1264 (m), 1070 (s), 717
(m), 698 (m) cm-1; HRMS (ESI-TOF) calculated for C15H16NO (M + H+) 226.1226, found
226.1223.
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N-benzyl-4-chloro-N-methylbenzamide (3k)53 Rf = 0.38 (Ethyl acetate:hexane = 1:4); Colorless
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oil; yield: 77% (70 mg); 1:1 mixture of rotamers; H NMR (400 MHz, CDCl3) δ 7.47-7.29 (m,
16H), 7.16 (br s, 2H), 4.74, 4.51 (two singlets for two rotamers, 4H), 3.03, 2.86 (two singlets for
two rotamers, 6H); 13C NMR (100 MHz, CDCl3) δ 171.4, 170.6, 135.8, 133.2, 131.4, 130.1,
129.7, 128.8, 128.7, 128.6, 128.5, 128.4, 128.2, 127.7, 127.0, 126.8, 126.6, 55.2, 51.0, 37.0,
~
33.5; IR (KBr) 3449 (w), 3062 (m), 3029 (m), 2925 (s), 2855 (m), 1717 (m), 1632 (s), 1478
ν
(m), 1451 (m), 1401 (s), 1263 (m), 1090 (s), 1069 (s), 734 (m), 700 (s) cm-1; HRMS (ESI-TOF)
calculated for C15H14ClNNaO (M + Na+) 282.0656, found 282.0687.
N-benzyl-3,4,5-trimethoxybenzamide (3l). Rf = 0.20 (Ethyl acetate:hexane = 1:4); White solid;
yield: 72% (55 mg); mp. 139-140 °C (lit.54 141 °C); 1H NMR (400 MHz, CDCl3) δ 7.37-7.29 (m,
13
5H), 7.02 (s, 2H), 6.38 (br s, 1H), 4.645 (d, J = 4 Hz, 2H), 3.89 (s, 6H), 3.87 (s, 3H); C NMR
(100 MHz, CDCl3) δ 167.1, 153.3, 141.1, 138.3, 129.9, 128.9, 128.1, 127.8, 104.5, 61.0, 56.5,
~
44.4; IR (KBr) 3321 (w), 2941 (m), 2838 (m), 1697 (m), 1644 (s), 1585 (s), 1500 (s), 1463
ν
(m), 1415 (s), 1334 (s), 1232 (s), 1127 (s), 1002 (s), 764 (m), 699 (m) cm-1; HRMS (ESI-TOF)
calculated for C17H20NO4 (M + H+) 302.1392, found 302.1407.
N-benzyl-4-nitrobenzamide (3m). Rf = 0.25 (Ethyl acetate:hexane = 1:4); White solid; yield:
1
68% (58 mg); mp. 134-137 °C (lit.55 136-137 °C); H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8
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Hz, 2H), 7.95 (d, J = 8 Hz, 2H), 7.39-7.37 (m, 5H), 6.46 (br s, 1H), 4.67 (d, J = 8 Hz, 2H); C
3
4
5
6
NMR (100 MHz, CDCl3) δ 165.4, 149.8, 140.0, 137.5, 129.1, 128.3, 128.2, 128.1, 124.0, 44.6;
7
8
9
IR (KBr) 3449 (w), 2923 (s), 2848 (s), 1638 (m), 1344 (s), 1018 (s), 703 (s) cm-1; HRMS
~
ν
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(ESI-TOF) calculated for C14H13N2O3 (M + H+) 257.0926, found 257.0912.
N-benzyl-4-methoxybenzamide (3n). Rf = 0.20 (Ethyl acetate:hexane = 1:4); White solid; yield:
1
69% (61 mg); mp. 128-131 °C (lit.56 129-130 °C); H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8
Hz, 2H), 7.36-7.28 (m, 5H), 6.92 (d, J = 8 Hz, 2H), 6.33 (br s, 1H), 4.635 (d, J = 4 Hz, 2H), 3.84
13
(s, 3H); C NMR (100 MHz, CDCl3) δ 167.0, 162.3, 138.5, 128.9, 128.9, 128.0, 127.7, 126.7,
~
113.9, 55.5, 44.2; IR (KBr) 3521 (w), 3294 (m), 1633 (s), 1538 (m), 1505 (s), 1255 (s), 1180
ν
(m), 846 (m), 726 (m), 696 (m) cm-1; HRMS (ESI-TOF) calculated for C15H16NO2 (M + H+)
242.1176, found 242.1189.
N-benzyl-4-fluorobenzamide (3o). Rf = 0.30 (Ethyl acetate:hexane = 1:4); Colorless solid;
yield: 73% (79 mg); mp. 140-141 °C (lit.57 143-144 °C); 1H NMR (400 MHz, CDCl3) δ 7.80 (d,
13
J = 8 Hz, 2H), 7.33 (br s, 5H), 7.08 (d, J = 8 Hz, 2H), 6.59 (br s, 1H), 4.61 (s, 2H); C NMR
(100 MHz, CDCl3) δ 166.5, 164.8 (d, 1JFC = 250.4 Hz), 138.2, 130.6 (d, 4JFC = 3.1 Hz), 129.5 (d,
2
3JFC = 8.8 Hz), 128.9, 128.0, 127.7, 115.7 (d, JFC = 21.8 Hz), 44.3
;
~
IR (KBr) 3323 (m), 3068
ν
(s), 2927 (s), 2848 (s), 1639 (m), 1544 (s), 1421 (s), 1360 (s), 1255 (s), 1057 (s), 854 (s), 723 (s)
cm-1; HRMS (ESI-TOF) calculated for C14H13FNO (M + H+) 230.0981, found 230.0954.
N-benzyl-3-nitrobenzamide (3p). Rf = 0.20 (Ethyl acetate:hexane = 1:4); White solid; yield: 71%
1
(60 mg); mp. 100-103 °C (lit.58 100-101 °C); H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.36-
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8.33 (m, 1H), 8.18-8.16 (m, 1H), 7.63 (t, J = 8 Hz, 1H), 7.38-7.28 (m, 5H), 6.73 (br s, 1H), 4.655
5
6
(d, J = 4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 165.1, 148.3, 137.6, 136.0, 133.4, 130.0,
7
8
9
~
129.0, 128.1, 128.0, 126.2, 121.9, 44.6; IR (KBr)
3322 (w), 3087 (m), 1720 (m), 1644 (s),
ν
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1528 (s), 1350 (s), 1322 (m), 1080 (m), 911 (m), 815 (m), 719 (m) cm-1; HRMS (ESI-TOF)
calculated for C14H13N2O3 (M + H+) 257.0921, found 257.0948.
N-benzyldecanamide (3q). Rf = 0.33 (Ethyl acetate:hexane = 1:4); Colorless solid; yield: 64%
1
(75 mg); mp. 60-61 °C (lit.59 60-62 °C); H NMR (400 MHz, CDCl3) δ 7.35-7.28 (m, 5H), 5.74
(br s, 1H), 4.445 (d, J = 4 Hz, 2H), 2.21 (t, J1 = J2 = 8 Hz, 2H), 1.67-1.64 (m, 2H), 1.29-1.26 (m,
13
12H), 0.88 (t, J1 = J2 = 8 Hz, 3H); C NMR (100 MHz, CDCl3) δ 173.2, 138.4, 128.8, 128.0,
~
127.6, 43.8, 37.0, 32.0, 29.5, 29.4, 29.4, 29.4, 25.9, 22.8, 14.2; IR (KBr) 3438 (w), 2919 (m),
ν
2850 (m), 1633 (m), 695 (w) cm-1; HRMS (ESI-TOF) calculated for C17H28NO (M + H+)
262.2165, found 262.2189.
N,N-dibenzylcyclohexanecarboxamide (3r). Rf = 0.34 (Ethyl acetate:hexane = 1:4); Colorless
solid; yield: 53% ; mp. 118-120 °C; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.27 (m, 6H), 7.25 –
7.15 (m, 4H), 4.58 (s, 2H), 4.46 (s, 2H), 2.58 – 2.52 (m, 1H), 1.81-1.63 (m, 7H), 1.30 – 1.19 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 177.0, 137.7, 137.0, 129.0, 128.6, 128.1, 127.7, 127.3,
~
126.5, 77.4, 77.1, 76.8, 49.7, 47.8, 40.9, 29.8, 25.8; IR (KBr)
ν
3059 (s), 3029 (s), 2927 (m),
2854 (m), 1643 (m), 1494 (s), 1450 (m), 1359 (s), 1244 (s), 1205 (m), 1176 (s), 1079 (s), 1028
(s), 948 (s), 731 (s) cm-1; HRMS (ESI-TOF) calculated for C21H26NO (M + H+) 308.2009, found
308.2026.
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N-benzylcyclohexanecarboxamide (3s). Rf = 0.30 (Ethyl acetate:hexane = 1:4); Colorless solid;
yield: 58%; mp. 110-114 °C (lit.60 113 °C); 1 : 4 mixture of rotamers (data for major isomer); 1H
NMR (400 MHz, CDCl3) δ 7.37-7.27 (m, 10H), 7.25 (s, 1H), 5.73 (br s, 1H), 4.43 (d, J = 4 Hz,
2H); 2.18-2.05 (m, 1H), 1.99-1.85 (m, 2H), 1.84-1.75 (m, 2H), 1.73-1.61 (m, 2H), 1.54-1.39
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(m, 2H), 1.35-1.15 (m, 2H); C NMR (100 MHz, CDCl3) δ 176.0, 138.6, 128.8, 127.8, 127.5,
~
45.7, 44.3, 43.5, 29.8, 25.8; IR (KBr)
ν
3286 (m), 3085 (s), 3028 (s), 2927 (m), 2851 (s), 1639
(m), 1543 (m), 1492 (s), 1449 (s), 1311 (s), 1258 (s), 1219 (s), 1140 (s), 1079 (s), 991 (s) cm-1;
HRMS (ESI-TOF) calculated for C14H20NO (M + H+) 218.1539, found 218.1545.
N,N-dibenzyl-4-isopropylbenzamide (3t). Rf = 0.30 (Ethyl acetate:hexane = 0.5:4.5); Colorless
solid; yield: 78% (89 mg); mp. 80-83 °C; 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8 Hz, 2H),
7.34-7.28 (m, 4H), 7.24-7.18 (m, 6H), 7.13 (br s, 2H), 4.66 (br s, 2H), 4.40 (br s, 2H), 2.95-2.78
(m, 1H), 1.19 (d, J = 8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 172.5, 150.8, 137.1, 136.7,
~
133.6, 128.9, 128.8, 128.5, 127.7, 127.5, 127.1, 127.0, 126.7, 51.7, 46.9, 34.1, 23.9; IR (KBr)
ν
3442 (w), 3031 (m), 2961 (m), 1633 (m), 1452 (m), 1417 (m), 1258 (m), 1148 (m), 993 (m), 842
(s), 733 (m), 699 (s) cm-1; HRMS (ESI-TOF) calculated for C24H26NO (M + H+) 344.2009, found
344.2042.
N,N-dibenzyl-2-bromobenzamide (3u).61 Rf = 0.30 (Ethyl acetate:hexane = 0.5:4.5); Colorless
1
solid; yield: 69% (70 mg); mp. 130-134 °C (no literature report on melting points); H NMR
(400 MHz, CDCl3) δ 7.54-7.51 (m, 2H), 7.40-7.30 (m, 10H), 7.17 (br s, 2H), 4.73 (s, 2H), 4.42
13
(s, 2H); C NMR (100 MHz, CDCl3) δ 172.3, 136.2, 129.7, 128.9, 128.7, 128.6, 128.4, 127.7,
~
127.6, 127.1, 126.7, 51.6, 46.9; IR (KBr) 3436 (w), 3081 (s), 3059 (s), 3028 (s), 2923 (s), 1637
ν
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(m), 1420 (m), 1248 (m), 1144 (s), 1027 (s), 990 (s),732 (m) cm-1; HRMS (ESI-TOF) calculated
for C21H19BrNO (M + H+) 380.0650, found 380.0629.
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N,N-dibenzyl-4-cyanobenzamide (3v). Rf = 0.40 (Ethyl acetate:hexane = 1:4); Colorless solid;
yield: 62% (76 mg); mp. 115-117 °C (lit.50 114-116 °C); 1H NMR (400 MHz, CDCl3) δ 7.675 (d,
J = 12 Hz, 2H), 7.57 (d, J = 8 Hz, 2H), 7.39-7.30 (m, 8H), 7.11 (br s, 2H), 4.72 (br s, 2H), 4.34
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(br s, 2H); 13C NMR (100 MHz, CDCl3) δ 170.3, 140.6, 136.5, 135.8, 132.5, 129.2, 128.9, 128.6,
~
128.1, 127.9, 127.5, 126.9, 118.1, 113.6, 51.5, 47.4; IR (KBr) 3442 (w), 2927 (s), 2229 (s),
ν
1638 (m), 1425 (s),1261 (s), 1077 (s), 991 (s), 847 (s), 750 (s) cm-1; HRMS (ESI-TOF)
calculated for C22H19N2O (M + H+) 327.1497, found 327.1482.
N-benzyl-4-chlorobenzamide (3w). Rf = 0.27 (Ethyl acetate:hexane = 1:4); Colorless solid;
yield: 67% (58 mg); mp. 158-160 °C (lit.62 162 °C); 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8
Hz, 2H), 7.39 (d, J = 8 Hz, 2H), 7.36-7.30 (m, 5H), 6.46 (br s, 1H), 4.625 (d, J = 4 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 166.5, 138.0, 137.9, 132.8, 131.6, 128.9, 128.5, 128.0, 127.8, 44.3;
IR (KBr) 3317 (w), 1634 (m), 1416 (m), 1093 (s), 849 (s), 711 (m) cm-1; HRMS (ESI-TOF)
~
ν
calculated for C14H13ClNO (M + H+) 246.0686, found 246.0672.
N-benzylbenzamide (3x). Rf = 0.3 (Ethyl acetate:hexane = 1:4); Colorless solid; yield: 71% (69
mg); mp. 105-107 °C (lit.53 106 °C); 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8 Hz, 2H), 7.52-
13
7.27 (m, 8H), 6.49 (br s, 1H), 4.645 (d, J = 4 Hz, 2H); C NMR (100 MHz, CDCl3) δ 167.5,
~
138.3, 134.5, 131.6, 128.9, 128.7, 128.0, 127.7, 127.0, 44.2; IR (KBr)
3329 (w), 1641 (s),
ν
1577 (m), 1547 (m), 1418 (m), 1258 (m), 727 (m), 692 (m) cm-1; HRMS (ESI-TOF) calculated
for C14H14NO (M + H+) 212.1070, found 212.1065.
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N-benzyl-4-bromobenzamide (3y). Rf = 0.40 (Ethyl acetate:hexane = 1:4); Colorless solid; yield:
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58% (45 mg); mp. 157-160 °C (lit.63 160-162 °C); H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8
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Hz, 2H), 7.56 (d, J = 8 Hz, 2H), 7.38-7.29 (m, 5H), 6.37 (br s, 1H), 4.635 (d, J = 4 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 166.5, 138.0, 133.3, 131.9, 129.0, 128.7, 128.1, 127.9, 126.4, 44.4;
IR (KBr) 3437 (w), 2918 (s), 1634 (m), 1550 (m), 1257 (s), 846 (s), 731 (s), 701 (s) cm-1;
~
ν
HRMS (ESI-TOF) calculated for C14H13BrNO (M + H+) 290.0181, found 290.0164.
N-benzyl-4-cyano-N-methylbenzamide (3z).64 Rf = 0.20 (Ethyl acetate:hexane = 1:4); Colorless
1
oil; yield: 73% (67 mg); 1:1 mixture of rotamers; H NMR (400 MHz, CDCl3) δ 7.71-7.64 (m,
4H), 7.54 (d, J = 8 Hz, 4H), 7.38-7.28 (m, 8H), 7.12 (d, J = 8 Hz, 2H), 4.74, 4.44 (two singlets
for two rotamers, 4H), 3.05, 2.82 (two singlets for two rotamers, 6H); 13C NMR (100 MHz,
CDCl3) δ 170.3, 169.6, 136.4, 132.4, 129.1, 128.9, 128.8, 128.2, 128.0, 127.8, 127.7, 127.5,
~
126.5, 118.1, 113.4, 55.0, 50.9, 36.8, 36.4; IR (KBr) 3454 (w), 3085 (s), 3063 (s), 3028 (s),
ν
2925 (m), 2230 (m), 1633 (m), 1451 (m), 1402 (m), 1264 (m), 1070 (s), 850 (s), 702 (s) cm-1;
HRMS (ESI-TOF) calculated for C16H15N2O (M + H+) 251.1184, found 251.1201.
N-benzyl-2-iodo-N-methylbenzamide (3aa).65 Rf = 0.40 (Ethyl acetate:hexane = 1:4); Colorless
1
oil; yield: 67% (60 mg); 1:1 mixture of rotamers; H NMR (400 MHz, CDCl3) δ 7.47-7.29 (m,
16H), 7.18 (br s, 2H), 4.77, 4.52 (two singlets for two rotamers, 4H), 3.03, 2.86 (two singlets for
two rotamers, 6H); 13C NMR (100 MHz, CDCl3) δ 172.5, 171.7, 139.3, 137.1, 136.7, 136.2,
133.2, 130.1, 129.7, 128.9, 128.7, 128.5, 128.4, 128.3, 127.9, 127.6, 127.3, 127.1, 126.9, 55.3,
~
50.9, 37.1, 33.3; IR (KBr) 3459 (w), 3061 (m), 3029 (m), 2923 (m), 1631 (s), 1479 (m), 1450
ν
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(m), 1400 (m), 1264 (m), 1069 (s), 718 (m), 698 (s) cm-1; HRMS (ESI-TOF) calculated for
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C15H15INO (M + H+) 352.0193, found 352.0165.
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ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for all compounds; crystal data (CIF) for 3c
and 3l. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author: Prasenjit Mal pmal@niser.ac.in.
Notes. The authors declare no competing financial interest.
ACKNOWLEDGEMENT
We are thankful to DST (New Delhi, India; Grant no. INT/FINLAND/P-06 and SR/S1/IC-
59/2010) for financial support. TKA is thankful to UGC (India) for fellowship.
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