Sulphuric acid immobilized on silica gel (H2SO4-SiO2) as an eco-friendly catalyst for transamidation

Article abstract of DOI:10.1039/c4ra16571c

A novel method of transamidation of carboxamides with amines by using catalytic amounts of H₂SO₄-SiO₂ has been developed under solvent free conditions. The transamidation is compatible with a wide range of aromatic, heteroaromatic, aliphatic, cyclic/acyclic primary or secondary amines. The metal/solvent-free conditions represent a significant improvement over other existing methods as the reaction can be performed in open air conditions and no column purification is required. The versatility of this methodology was further demonstrated by synthesizing the commercially available drug procainamide.

Full text of DOI:10.1039/c4ra16571c

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Graphical Abstract
Sulphuric acid immobilized on silica gel (H2SO4-SiO2) as an
eco-friendly catalyst for transamidation
Sk. Rasheed, D. Nageswar Rao, A. Siva Reddy, Ravi Shankar and Parthasarathi Das*
O
N
O
O
N
H
R1
R1
H2SO4-SiO2 (cat)
Me
+
HN
R
N
R
N
H2N
No metal
No solvent
R2
R2
Procainamide
Me
No column purification
yield upto 98%
44 examples
R= H, CH3, t-Bu, Aryl
Amine = Aryl, het-
aryl,alkyl,cycloalkyl
A novel method of transamidation of carboxamides with amines using catalytic amounts of H2SO4-SiO2 under
solvent-free conditions has been developed. The scope of the methodology has been demonstrated with
aromatic/heteroaromatic, cyclic/acyclic, primary, and secondary amines. Versatility of this methodology has further
been demonstrated by the synthesis of commercially available drug procainamide.

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PAPER
Sulphuric acid immobilized on silica gel
(H2SO4-SiO2) as an eco-friendly catalyst for
transamidation
Cite this: DOI: 10.1039/x0xx00000x
Sk. Rasheed,a,b D. Nageswar Rao,a,b A. Siva Reddy,a,b Ravi Shankar,b and
Parthasarathi Das a,b,
*
Received 00th January 2014,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A novel method of transamidation of carboxamides with amines by using catalytic amount of H2SO4ꢀ
SiO2 has been developed under solvent free conditions. The transamidation is compatible with wide
range of aromatic, heteroaromatic, aliphatic, cyclic/ acyclic primary or secondary amines. The metal/
solventꢀfree conditions represent a significant improvement over other existing methods as it can be
performed in open air conditions and no column purification is required. The versatility of this
methodology was further demonstrated by synthesizing commercially available drug procainamide.
www.rsc.org/greenchemistry
important organic reactions under solventꢀfree conditions.15 The
Introduction
high catalytic activity, the operational simplicity and the
recyclability of H2SO4ꢀSiO2 make this reagent attractive for
industrial use.16 To the best of our knowledge, H2SO4ꢀSiO2
catalyzed transamidations have not been reported yet. Considering
the economic attractiveness and environmental friendliness of
H2SO4ꢀSiO2 as catalyst, we became interested in developing a
general transamidation methodology of carboxamides with amines.
Herein, we report our results for the first time (Scheme 1).
Previous work
The amide bond is widely present both in natural products and
synthetic compounds. Presence of amide functionality in top
selling pharmaceutical products, makes the amidation reaction one
of the most commonly used reactions in medicinal chemistry.1,2
Traditionally, amides have been synthesized by the reactions of
carboxylic acids3 and their derivatives4 with amines, which in
general suffers from harsh reaction conditions and large amount of
byꢀproducts, thus severely impedes the large scale production.
Therefore, atomꢀeconomical synthesis of amides without use of
hazardous reagents or without generating waste is a formidable
challenge in organic synthesis. The transamidation process has
emerged as an alternative and attractive protocol for amide bond
formation.5 Recently, elegant examples of transamidation reaction
from the groups of Stahl,6 Williams,7 Myers,8 Beller9 and other
groups have been reported.10 Despite their wide scope these
reactions suffer from high temperature and required transitionꢀ
metal catalyst to promote the transamidation. Boronꢀmediated
transamidation has been reported in the literature,11 where the
boron reagents has been used either in stoichiometric or in
catalytic amounts. Metalꢀfree methods utilizing catalytic
hydroxylamine hydrochloride12, Lꢀproline13 and ammonium
chloride14 have also been reported. But these catalysts are active
only in organic solvents except few are reported under solventꢀfree
conditions.10d,13 Moreover, the scope of these methods are only
limited to primary amides and most cases to primary amines.
Clearly there is a lack of an efficient, general and environmentally
benign protocol for transamidation.
O
O
R1
R1
Me
Fe(III)
i (ref10b)
ii (ref11c)
iii (ref13)
+
+
HN
HN
R
R
N
R
R
N
solvent/reflux
R2
R2
Me
O
O
R1
R2
B(OCH2CF3)3
solvent/reflux
R1
Me
N
N
R2
Me
O
O
R1
B(OH)3
R1
Me
+
HN
R
N
R
N
solvent/reflux
R2
R2
Me
This work
O
O
R1
R1
H2SO4-SiO2 (cat)
Me
R
N
+
HN
R
N
No metal
No solvent
No column purification
R2
R2
Me
yield upto 98%
44 examples
R= H, CH3, t-Bu, Aryl
Amine = Aryl, het-
aryl,alkyl,cycloalkyl
Scheme 1 Methods for transamidation
Results and discussion
Our initial studies focused on developing an efficient catalytic
system for transamidation and we used N, Nꢀdimethylbenzamide
In the recent years, H2SO4ꢀSiO2 has shown great potentiality as an
efficient and easily retrievable solid catalyst in promoting various
This journal is © The Royal Society of Chemistry 2013
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with pꢀtoluidine as model system (Table 1). At first the reaction
was performed in presence of silica (SiO2) without solvent
unfortunately no transamidation happened even at 100 oC (entry 1,
Table 1). But to our delight use of H2SO4ꢀSiO2 (100 mol %) at 100
oC gave transamidation product 1a in 50 % yield. Temperature
variation revealed that SiO2ꢀH2SO4 works more efficiently at 70 oC
(entry 3, Table 1). At room temperature (entry 4, Table 1) the
corresponding transamidation products in very good yields (70ꢀ
90%) (1a-f). Interestingly, sterically hindered arylamines like 2,6
dimethyl aniline undergoes the reaction smoothly and the resulted
amide (1c) isolated in good yield (82%). Less reactive
heteroaromatic like 2ꢀaminopyrimidine gave the transamidation
product (1d), albeit in low yield (70%) and in larger reaction time.
To enhance the further substrate scope N,Nꢀdimethyl napthamides
were subjected for transamidation raction with various amines. To
our delight aromatic/heteroaromatic/aliphatic amines undergoes
smooth transamidation (1g-m) with excellent yields (75ꢀ87%). It is
noteworthy to mention that functional groups like bromo (1k) or
chloro (1l) are tolerable under these reaction conditions.
o
reaction was not moving even after 12 h where as at 50 C lower
yield (50%) was obtained (entry 5, Table 1). Encouraged with this
results, we performed the reaction by using 20 mol% H2SO4ꢀSiO2
o
at 70 C (entry 6, Table 1) and the transamidation product was
isolated in 63% yield. The yield of product was further increased
(70%) when the catalyst loading decreased to 10 mol% (entry 7,
Table 1). The optimum condition was obtained when we
Synthesis of benzamides/napthamide via transamidationa
Table 2
O
O
R1
o
R1
H2SO4-SiO2(5 mol%)
70 oC, 6-8 h
performed the reaction by using 5 mol% H2SO4ꢀSiO2 at 70 C and
Me
N
N
+
HN
Ar
Ar
R2
R2
the isolated yield was 90 % (entry 8, Table 1). Interestingly, when
the reaction temperature was increased to 100 oC (entry 9, Table 1)
yield was decreased due to hydrolysis of corresponding amide.
The catalytic potential of other protic acid on silica (TfOHꢀSiO2;
AcOHꢀSiO2; HClO4ꢀSiO2) was also assessed found are less effective
(entries 10ꢀ12, Table 1). When we used only H2SO4 (5 mol%) the
yield was decreased to 73% (Table 1, entry 13).
Me
1a-m
CO2Me
Me
Me
O
O
O
MeO
MeO
N
N
N
H
Me
H
H
1c
, 7 h, 82%
1a, 6 h, 90%
1b, 8 h, 89%
O
O
N
O
MeO
MeO
N
N
H
MeO
N
N
H
O
a
Table 1
Optimization studies for transamidation
Me
O
1f
, 6 h, 87%
O
1e, 6 h, 85%
O
1d
, 12 h, 70%
H2N
Me
conditions
Me
N
H
+
N
O
O
N
7 h, 86%
O
Me
N
H
1a
O
N
N
H
1i
,
Temp [oC] Time (h) Yield(%)b
1h
,
6 h, 87%
1g, 8 h, 85%
Entry
Catalyst(mol%)
1
2
SiO2 (100)
100
100
12
6
n.r
50
Br
O
O
H2SO4ꢀSiO2 (100)
N
H
N
H
N
N
H
N
Cl
3
4
70
rt
6
12
12
12
12
6
60
n.r.
50
63
70
90
75
45
25
H2SO4ꢀSiO2 (100)
H2SO4ꢀSiO2 (100)
H2SO4ꢀSiO2 (100)
H2SO4ꢀSiO2 (20)
H2SO4ꢀSiO2 (10)
H2SO4ꢀSiO2 (5)
H2SO4ꢀSiO2 (5)
TfOHꢀSiO2 (100)
AcOHꢀSiO2 (100)
1l, 10 h, 75%
1j, 10 h, 80%
1k
, 10 h, 80%
N
O
5
50
N
N
H
6
70
1m
, 12 h, 75%
7
70
aReaction conditions: amine (0.93 mmol.), N,N- dimethyl benzamide (2.8 mmol), H2SO4-SiO2
8
70
(5 mol%), 70 oC, air.
9
100
100
100
6
Nꢀaryl/heteroaryl pivalamides are important in organic synthesis as
they works as directing group in many transitionꢀmetal catalyzed
reactions.18 Further Nꢀaryl pivalamides also found in many
medicinally important compounds.19
10
11
12
3
12
13
HClO4ꢀSiO2 (100)
H2SO4 (5)
100
70
6
6
40
73
Table 3 Synthesis of N-aryl/hetaryl pivalamide via transamidationa
aReaction conditions: amine (0.93 mmol), N, Nꢀdimethyl benzamide (2.8
mmol) H2SO4ꢀSiO2 (5 mol%), temp = 70 C, air; b = isolated yield; n.r.=
H
O
o
N
NH2
H2SO4ꢀSiO2(5 mol%)
Me
+
N
O
70 oC, 6-12 hr
no reaction.
R
R
R
Me
2a-j
H
N
H
N
H
N
With the optimized catalytic conditions in hand at first the scope of
the amidation reactions were explored with a wide range of amines
and various N, Nꢀdimethyl benzamides results are summarized in
Table 2. Nꢀaryl/heteroaryl benzamides are the important structural
core of many FDA approved drugs.17 Thus, finding a general route
for this kind of amide bond formation will definitely add value to
drug discovery process. In general, the transamidation of N, Nꢀ
dimethyl benzamide with aryl/heteroaryl amines (electronꢀneutral,
ꢀrich, ꢀdeficient), aliphatic and cyclic secondary amines gave
R
O
O
N
O
N
Cl
2g, R= H, 10 h, 80%
2h, R= 5-Br 12 h, 75%
2i, 12 h, 74%
2a, R= H, 6 h, 95%
2b
, R= 4-Me, 7 h, 93%
2c, R= 4-OMe, 7 h, 94%
2d, R= 2,6 di-Me, 6 h, 82%
2e
S
H
N
, R= 3-OMe-4-CO2Me, 8 h, 85%
N
2f, R= 2-I, 8 h, 80%
O
2j
, 10 h, 80%
aReaction conditions: amine (0.93 mmol), N ,N ꢀdimethylpivalamide (2.8 mmol),
H2SO4ꢀSiO2 (5 mol%), 70 oC, air
2 | J. Name., 2012, 00, 1-3
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Thus, finding general synthetic protocol for this kind of amide
bond formation will be interesting in organic synthesis. Here, we
have applied this optimized transamidation conditions in synthesis
of various Nꢀaryl/heteroaryl pivalamides (Table 3). The versatility
of this reaction was demonstrated with different aryl amines
undergoes transamidation reaction with N, Nꢀdimethyl pivalamide
to give the corresponding Nꢀaryl pivalamides (2a-f) in excellent
yields (80ꢀ95%). Under these conditions heteroaromatic amines
also been tested and the resulted Nꢀheteroaryl pivalamides are
isolated (2g-j) in good yields (74ꢀ80%).
Procainamide21 an antiarrhythmic drug used for treatment of
cardiac arrhythmias prepared by following these optimized
transamidation protocol (Scheme 2). In this synthesis nitro
benzamide derivative (4) under goes smooth transamidation with
diamine (5) to give benzamide 6 in very good yield (82%).
Subsequent reduction of nitro group gave the desired procainamide
(7).
O
O
N
Me
+
H2SO4-SiO2 (5 mol%)
70 oC, 8 h
N
N
N
H
H2
N
Me
O2N
O2N
82%
5
6
4
O
Typically, the Nꢀacetylation and Nꢀformylation of an amine is
carried out using hazardous, toxic, and unstable reagents.20 This
led us to carry out a more comprehensive study of scope and
limitation of acetylation/formylation using the present
methodology. As shown in Table 4 the aromatic/heteroaromatic
amines bearing either electronꢀrich or electronꢀdeficient
substituent in the aromatic ring all underwent the reactions
smoothly to give the desired Nꢀaryl formamides (3a-i) in excellent
yields (78ꢀ98%). Functional groups like ꢀCO2Me (3b-c), hydroxyl
(3d) and iodo (3e) are tolerable under this optimized conditions. In
this context, we performed the formylation of methyl ester of Lꢀ
tryptophan and the corresponding formylated product (3k) was
obtained in good yield (85%).
N
Fe-powder (2equiv.)
N
H
EtOH, reflux, 2 h
95%
H2
N
Procainamide
7
Scheme 2
Synthesis of Procainamide
Based on the results and the fact that H2SO4ꢀSiO2 plays the role of
transferring protons from its solid surface.15b
plausible
A
mechanism for the transamidation has been presented in Scheme 3.
The protonation and activation of the amide bond of N, Nꢀdimethyl
benzamide by sulfonic group of H2SO4ꢀSiO2 generates the cationic
intermediate 8. Now, the cationic intermediate reacts with amine
nuclophiles, which on further elimination of ꢀNHMe2 provides the
transamidation product 1a.
Acetylation and formylation of amines via transamidationa
Table 4
Me
:N
H
Me
Me
O
N
R
NH2
O
H2SO4ꢀSiO2(5 mol%)
O
Me
N+
Me
R
N
H2N
+
O
+
Me
70 oC, 6-12 hr
Me
H
N
O
+
R
SiO2-H2SO4
R
Me
O
3a-v
R= H, Me
S
Me
OH
8
O
OSO3H
O
HO3SO
Nucleophilic addition of amine to
carbonyl group of amide activated by
H2SO4-SiO2
H
N
H
H
N
H
N
H
H
R
R
N
O
H
Me
O
O
Br
O
Me
N
N
O
N
H
Me
3h, 8 h, 78%
3f, R= H, 8 h, 86%
3g, R= 2-Cl, 10 h, 80%
3a
, R= H, 6 h, 98%
3b, R= 4-CO2Me, 7 h, 95%
3c, R= 3-OMe-4-CO2Me, 8 h, 95%
3d,
HN
-NHMe2
1a
Me
R= 2-OH-4-Me, 8 h, 90%
Scheme 3 Plausible transamidatiom mechanism
3e, R= 2-Iodo, 8h, 90%
COOMe
H
S
H
N
H
Conclusion
HN
H
N
H
O
N
N
O
O
H
3j
, 6 h, 96%
H
3i, 12 h, 80%
3k
We have developed an environment friendly H2SO4ꢀSiO2 catalytic
system for transamidation. Presented catalytic system explored
with substituted aromatic, heteroaromatic, and aliphatic/alicyclic
primary amines, as well as secondary amines with carboxamides.
The scope of H2SO4ꢀSiO2 catalytic system was also examined
further for acetylation and formylation. Due to its manipulation
ease, lowꢀcost, and benign character, the H2SO4ꢀSiO2 catalytic
system described here represents an excellent complement to the
previously reported protocols. This methodology is general and
definitely will add value into the fastest growing area of
transamidation chemistry.
, 12 h, 85%
X
H
N
N
Me
Me
N
H
R
R
O
N
O
O
3n
, R= 4-Me, 6 h, 98%
3s, R= H, 10 h, 80%
, R= 5-Br, 10 h, 75%
3t
3o, R= 4-OMe, 6 h, 97%
3p
3q
3l,
X= H, 7 h, 87%
3m, X= O, 7 h, 88%
, R= 4-F, 7 h, 95%
, R= 4-OCF3, 8 h, 86%
3r, R= 4-NO2, 8 h, 85%
H
N
Me
O
N
3u, 10 h, 78%
aReaction conditions: amine (1.05 mmol), DMF/DMA( 3.22 mmol & 3.12 mmol), H2SO4ꢀSiO2
(5 mol%), 70 oC, air.
Experimental Section
General Information
Finally, under these optimized conditions the transamidation of N,
Nꢀdimethyacetamide with various amines was examined. The
results presented in Table 4 revealed that both the aryl and hereto
aryl amines underwent smooth transamidation to give the desired
products (3n-u) in high yields (75ꢀ98%). It is important to
highlight that this result represents a useful method for the
protection of primary amines with excellent functional group
tolerability.
Analytical thin layer chromatography (TLC) was performed
on preꢀcoated silica gel plates (60 F254; MERCK). TLC
plates were visualized by exposing UV light or by iodine
vapors or immersion in ninhydrin followed by heating on hot
plate. 1H and 13C NMR spectra were recorded with BRUKER
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1
500 and 400 MHz NMR instruments. Mass spectra were
recorded with VARIAN GCꢀMS instrument. HRMS spectra
were recorded with LCMSꢀQTOF Module No. G6540 A
(UHD) instrument. IR spectra were recorded on Jasco FT/ IRꢀ
5300 spectrophotometer. Melting points were measured in
open capillary tubes and are uncorrected. Unless otherwise
indicated, chemicals and solvents were purchased from
commercial suppliers.
1040, 993, 877, 755; H NMR (400 MHz, CDCl3) δ 7.49 (d, J =
2.0 Hz,1H), 7.46 (d, J = 7.7 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J = 7.6
Hz, 1H), 7.13 (m, 3H), 3.88 (s, 3H), 2.28 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 165.8, 159.9, 135.9, 135.6, 133.8, 129.7, 128.2,
127.4, 118.9, 117.9, 112.6, 55.5, 18.4; HRMS (ESI): m/z Calcd.
for C16H18NO2 [M+H]+ : 256.1332; found: 256.1336.
3-Methoxy-N-(pyrimidin-2-yl)benzamide (1d): Colourless solid
(70%); mp. 110ꢀ112 oC; IR (NaCl) ν(cmꢀ1) 3436, 2924, 2853,
1694, 1599, 1583, 1567, 1487, 1452, 1430, 1408, 1290, 1265,
1212, 1180, 1123, 1083, 1041, 995, 801, 768; 1H NMR (400 MHz,
CDCl3) δ 8.64 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 6.1 Hz, 1H), 7.24
(td, J = 8.1, 1.2 Hz, 2H), 7.13 (t, J = 5.4 Hz, 1H), 7.02 (dd, J = 8.2,
2.0 Hz, 1H), 3.77 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 172.4,
160.6, 159.7, 158.8, 135.5, 129.6, 121.6, 119.5, 118.8, 113.8, 55.4;
HRMS (ESI): m/z Calcd. for C12H12N3O2 [M+H]+ : 230.0924;
found: 230.0918.
Preparation of Sulphuric acid adsorbed on silica gel
(SiO2-H2SO4):
The preparation of H2SO4ꢀSiO2 was carried out by following
reported procedure.15a To a suspension of silica gel (29.5 g,
230–400 mesh size) in EtOAc (60 mL) was added H2SO4 (1.5
g, 15.5 mmol, 0.8 mL of a 98% aq. solution of H2SO4) and
the mixture was stirred magnetically for 30 min at rt. The
EtOAc was removed under reduced pressure (rotary
evaporator) and the residue was heated at 100 °C for 72 h
under vacuum to afford H2SO4ꢀSiO2 as a free flowing
powder.
N-(Cyclopropylmethyl)-3-methoxybenzamide (1e): Colourless
solid (85%); mp. 60ꢀ62 oC; IR (NaCl) ν(cmꢀ1) 3321, 2921, 2851,
1637, 1601, 1582, 1540, 1485, 1464, 1430, 1340, 1300, 1242,
1
1125, 1045, 1018, 876, 804; H NMR (400 MHz, CDCl3) δ 7.37
(m, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.04
(dd, J = 7.9, 2.5 Hz, 1H), 6.22 (s, 1H), 3.86 (s, 3H), 3.31 (dd, J =
7.1, 5.5 Hz, 2H), 1.06 (m, 1H), 0.56 (q, J = 4.4 Hz, 2H), 0.28 (q, J
= 4.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 167.3, 159.8, 136.2,
129.5, 118.6, 117.5, 112.3, 55.4, 44.9, 10.7, 3.5; HRMS (ESI): m/z
Calcd. for C12H16NO2 [M+H]+ : 206.1176; found: 206.1195.
General Procedure:
To a mixture of aniline (0.93 mmol) and N, Nꢀdimethyl amide (2.8
mmol) H2SO4ꢀSiO2 (5 mol%) was added. The mixture was stirred
o
at 70 C and progress of the reaction monitored by TLC. After
completion of the reaction, the mixture was diluted with EtOAc
(20 ml), filtered, water (30 ml) added, the solution extracted with
EtOAc (3 x 15 ml), and the combined organic layers were dried
over anhydrous Na2SO4 and concentrated. The residue was
subjected to column chromatography to obtain the pure desired
product.
(3-Methoxyphenyl)(morpholino)methanone (1f):22c Yellow oil
(87%); IR (NaCl) ν(cmꢀ1) 3257, 2964, 2919, 2854, 1643, 1580,
1577, 1488, 1454, 1363, 1288, 1185, 1141, 1114, 1070, 1044,
1
1022, 995, 946, 742; H NMR (400 MHz, CDCl3) δ 7.38 (m, 1H),
6.95 (d, J = 7.4 Hz, 3H), 3.82 (s, 3H), 3.77 (d, J = 3.0 Hz, 4H),
3.45 (d, J = 76.0 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 170.1,
159.6, 136.5, 129.6, 119.0, 115.6, 112.4, 66.8, 55.3, 48.1; HRMS
(ESI): m/z Calcd. for C12H16NO3 [M+H]+ : 222.1125; found:
222.1122.
N-(p-tolyl)benzamide (1a):22a Colourless solid (90%); mp. 133ꢀ
o
135 C ; IR (NaCl) ν(cmꢀ1) 3339, 2923, 1650, 1597, 1579, 1514,
1404, 1320, 1121, 1018, 926, 813, 772, 713; 1H NMR (500 MHz,
CDCl3) δ 7.87 (d, J = 7.5 Hz, 2H), 7.77 (s, 1H), 7.52 (m, 5H),
7.18 (d, J = 8.2 Hz, 2H), 2.35 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 165.7, 135.3, 135.0, 134.2, 131.7, 129.6, 128.78, 127.0,
120.2, 20.9; HRMS (ESI): m/z Calcd. for C14H14NO [M+H]+ :
212.1070; found: 212.1073.
N-(Naphthalen-2-yl)-1-naphthamide (1g): Colourless solid
(85%); mp. 198ꢀ200 oC; IR (NaCl) ν(cmꢀ1) 3224, 2923, 1651,
1583, 1548, 1470, 1429, 1356, 1292, 1258, 1221, 898, 781; 1H
NMR (400 MHz, CDCl3) δ 8.43 (d, J = 9.0 Hz, 2H), 8.00 (d, J =
8.2 Hz, 1H), 7.93 (d, J = 7.3 Hz, 1H), 7.87 (m, 3H), 7.81 (d, J =
7.4 Hz, 1H), 7.60 (m, 4H), 7.52 (m, 1H), 7.45 (t, J = 7.0 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ 167.6, 135.4, 133.8, 133.7, 131.1,
130.8, 130.0, 128.9, 128.4, 127.7, 127.6, 127.4, 126.6, 125.2,
125.2, 125.1, 124.7, 119.7, 116.7; HRMS (ESI): m/z Calcd. for
C21H16NO [M+H]+ : 298.1227; found: 298.1227.
Methyl 4-(3-methoxybenzamido)benzoate (1b):22b Colourless
solid (89%); mp. 112ꢀ114 oC; IR (NaCl) ν(cmꢀ1) 3440, 2923,
1682, 1609, 1585, 1491, 1457, 1439, 1308, 1282, 1236, 1194,
1103, 1049, 1018, 749; 1H NMR (400 MHz, CDCl3) δ 7.74 (t, J =
8.5 Hz, 2H), 7.64 (dd, J = 11.8, 2.9, 2H), 7.43 (t, J = 8.1 Hz, 1H),
7.38 (d, J = 7.9 Hz, 1H), 7.19 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 162.2, 159.8 , 159.5, 130.0, 129.8,
129.5, 122.9, 122.6, 121.1, 120.4, 114.8, 114.3, 55.5, 55.4; HRMS
(ESI): m/z Calcd. for C16H16NO4 [M+H]+ : 286.1074; found:
286.1079.
N-(Cyclopropylmethyl)-1-naphthamide (1h): Colourless solid
o
(87%); mp. 123ꢀ124 C; IR (NaCl) ν(cmꢀ1) 3299, 2923, 2851,
1635, 1620, 1592, 1578, 1539, 1428, 1385, 1338, 1300, 1268,
1207, 1163, 1018, 806, 778; 1H NMR (400 MHz, CDCl3) δ 8.31
(d, J = 8.0 Hz, 1H), 7.88 (m, 2H), 7.62 (d, J = 7.0 Hz, 1H), 7.54
(m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 6.12 (s, 1H), 3.41 (t, J = 8.2 Hz,
2H), 1.10 (m, 1H), 0.57 (q, J = 4.9 Hz 2H), 0.31 (q, J = 4.8 Hz,
2,6-Dimethyl-N-phenylbenzamide (1c): Colourless solid (82%);
mp. 149–152 oC ; IR (NaCl) ν(cmꢀ1) 3261, 2913, 2835, 1644,
1585, 1513, 1485, 1470, 1446, 1376, 1328, 1302, 1242, 1182,
4 | J. Name., 2012, 00, 1-3
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View ArticAle ROnTliInCeLE
DOI: 10.1039/C4RA16571C
2H); 13C NMR (125 MHz, CDCl3) δ 169.5, 134.7, 133.6, 130.4,
130.1, 128.3, 127.0, 126.4, 125.4, 124.8, 124.7, 44.8, 10.8, 3.5;
HRMS (ESI): m/z Calcd. for C15H16NO [M+H]+ : 226.1227;
found: 226.1231.
135.0, 133.9, 133.4, 129.6, 128.8, 128.3, 127.8, 126.9, 126.3,
125.1, 124.7, 124.5, 123.2; HRMS (ESI): m/z Calcd. for
C15H12N3O [M+H]+ : 250.0975; found:250.0969.
N-Phenylpivalamide (2a):23a Colourless solid (95%); mp. 134ꢀ
Naphthalen-1-yl(piperidin-1-yl)methanone (1i):22c Yellow color
gel (86%); IR (NaCl) ν(cmꢀ1) 3055, 2918, 2854, 1634, 1592, 1508,
1466, 1432, 1361, 1300, 1281, 1267, 1249, 1154, 1114, 1067,
o
136 C; IR (NaCl) ν(cmꢀ1) 3435, 2921, 2851, 1653, 1613, 1598,
1
1460, 1431, 1018, 745, 669 566; H NMR (400 MHz, CDCl3) δ
7.53 (d, J = 7.7 Hz, 2H), 7.32 (t, J = 7.9 Hz, 2H), 7.10 (t, J = 7.4
Hz, 1H), 1.32 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 176.6,
138.0, 128.9, 124.2, 119.9, 39.6, 27.6. HRMS (ESI): m/z Calcd.
for C11H16NO [M+H]+ : 178.1227; found: 178.1227.
1
1044, 1018, 994, 847, 799, 780; H NMR (400 MHz, CDCl3) δ
7.85 (t, J = 6.9 Hz, 3H), 7.51 (dd, J = 11.3, 4.2 Hz, 2H), 7.47 (dd,
J = 8.1, 4.8 Hz, 1H), 7.41 (d, J = 6.9 Hz, 1H), 3.82 (t, J = 8.5 Hz,
4H), 3.49 (t, J = 8.7 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ
169.3, 133.6, 133.4, 129.5, 129.3, 128.5, 127.1, 126.5, 125.2,
124.6, 123.9, 66.9, 47.5; HRMS (ESI): m/z Calcd. for C15H16NO2
[M+H]+ : 242.1176; found: 242.1176.
N-(p-Tolyl)pivalamide (2b):23a Colourless solid (93%); mp. 116ꢀ
o
118 C; IR (NaCl) ν(cmꢀ1) 3429, 2921, 2849, 1644, 1583, 1515,
1484, 1467, 1303, 1240, 1157, 1112, 1019, 769, 753, 721; 1H
NMR (500 MHz, CDCl3) δ 7.41 (d, J = 8.3 Hz, 2H), 7.12 (d, J =
8.3 Hz, 2H), 2.31 ( s, 3H), 1.31 (s, 9H). 13C NMR (125 MHz,
CDCl3) δ 176.4, 135.4, 133.7, 129.4, 120.0, 39.5, 27.6, 20.8.
HRMS (ESI): m/z Calcd. for C12H18NO [M+H]+ : 192.1383;
found: 192.1387.
22d
N-(Pyridin-2-yl)-1-naphthamide (1j):
Colourless solid
(80%); mp. 103ꢀ105 oC; IR (NaCl) ν(cmꢀ1) 3438, 2924, 1680,
1609, 1580, 1488, 1455, 1432, 1422, 1318, 1292, 1226, 1184,
1113, 1041, 1028, 928, 749; 1H NMR (400 MHz, CDCl3) δ 9.35
(s, 1H), 8.41 (d, J = 6.9 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 7.89 (d,
J = 8.2 Hz, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.67 (dd, J = 16.6, 7.5
Hz, 2H), 7.48 (m, 2H), 7.40 (t, J = 7.6 Hz, 1H), 6.86 (t, J = 8.1 Hz,
1H); HRMS (ESI): m/z Calcd. for C16H13N2O [M+H]+ : 249.1023;
found: 249.1018.
23a
N-(4-Methoxyphenyl)pivalamide (2c):
Colourless solid
(94%); mp. 115ꢀ116 C; IR (NaCl) ν(cmꢀ1) 3441, 2921, 2851,
1670, 1619, 1594, 1544, 1404, 1237, 1018, 779, 669; H NMR
o
1
(400 MHz, CDCl3) δ 7.42 (d, J = 8.9 Hz, 2H), 7.27 (s, 1H), 6.85
(d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 1.30 (s, 9H). 13C NMR (125
MHz, CDCl3) δ 176.5, 156.3, 131.1, 121.9, 114.0, 55.5, 39.4, 27.6.
HRMS (ESI): m/z Calcd. for C12H18NO2 [M+H]+ : 208.1332;
found: 208.1328.
N-(4-Bromopyridin-2-yl)-1-naphthamide (1k): Colourless solid
(80%); mp. 164ꢀ165 oC ; IR (NaCl) ν(cmꢀ1) 3439, 2924, 1706,
1673, 1592, 1574, 1509, 1459, 1396, 1367, 1345, 1320, 1293,
1271, 1233, 1193, 1123, 1092, 783; 1H NMR (400 MHz, CDCl3) δ
8.61 (s, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.94 (dd, J = 8.4, 2.4 Hz,
1H), 7.75 (d, J = 7.1 Hz, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.53 (d, J =
8.2 Hz, 1H), 7.42 (m, 3H), 7.10 (t, J = 7.7 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 172.5, 151.9, 150.8, 141.0, 133.2, 133.1, 131.7,
129.9, 128.1, 127.5, 127.2, 126.5, 124.9, 124.0, 123.8, 119.5;
HRMS (ESI): m/z Calcd. for C16H12BrN2O [M+H]+ : 327.0128;
found: 327.0127.
23b
N-(2,6-Dimethylphenyl)pivalamide (2d):
Colourless solid
(82%); mp. 203ꢀ204 C; IR (NaCl) ν(cmꢀ1) 3271, 2928, 2871,
o
1650, 1592, 1514, 1478, 1439, 1400, 1367, 1297, 1222, 1177,
1
1091, 1036, 937, 913, 809, 764, 722; H NMR (400 MHz, CDCl3)
δ 7.08 (m, 3H), 6.89 (s, 1H), 2.20 (s, 6H), 1.36 (s, 9H). 13C NMR
(125 MHz, CDCl3) δ 176.5, 135.4, 133.9, 128.1, 127.1, 39.2, 27.8,
18.2. HRMS (ESI): m/z Calcd. for C13H20NO [M+H]+ : 206.1540;
found: 206.1546.
N-(2-Chloropyridin-3-yl)-1-naphthamide (1l): Colourless solid
(75%); mp. 139ꢀ141 oC; IR (NaCl) ν(cmꢀ1) 3408, 2926, 2854,
1678, 1615, 1580, 1510, 1453, 1400, 1383, 1297, 1245, 1194,
Methyl 2-methoxy-4-pivalamidobenzoate (2e): Colourless solid
(85%); mp. 128ꢀ129 oC; IR (NaCl) ν(cmꢀ1) 3358, 2958, 287, 1707,
1672, 1608, 1590, 1523, 1479, 1451, 1434, 1398, 1291, 1250,
1209, 1180, 1144, 1090, 1034, 961, 916, 856, 824, 778; 1H NMR
(400 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 1.7 Hz,
1H), 7.60 (s, 1H), 6.83 (dd, J = 8.5, 1.8 Hz, 1H), 3.90 (s, 3H), 3.86
(s, 3H), 1.33(s, 9H). 13C NMR (125 MHz, CDCl3) δ 177.4, 166.1,
160.5, 143.5, 132.6, 114.3, 110.6, 103.2, 55.8, 51.8, 39.9, 27.4.
HRMS (ESI): m/z Calcd. for C14H20NO4 [M+H]+ : 266.1387;
found: 266.1395.
1
1137, 1080, 1053, 1019, 869, 779; H NMR (400 MHz, CDCl3) δ
9.72 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.34 (d, J = 8.2 Hz, 1H),
7.90 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 6.7 Hz, 1H), 7.71 (m, 2H),
7.45 (m, 3H), 6.90 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 168.5,
146.0, 143.8, 134.7, 133.4, 133.3, 132.0, 131.1, 129.3, 128.4,
128.0, 127.4, 126.8, 126.2, 125.8, 124.2; HRMS (ESI): m/z Calcd.
for C16H12ClN2O [M+H]+ : 283.0633; found: 283.0639.
N-(Pyrimidin-2-yl)-1-naphthamide (1m): Colourless oil (75%);
IR (NaCl) ν(cmꢀ1) 3323, 2931, 1703, 1631, 1591, 1509, 1476,
1460, 1434, 1381, 1364, 1237, 1216, 1172, 1127, 1098, 1017, 863,
N-(2-Iodophenyl)pivalamide (2f): 23c Colourless solid (80%); mp.
o
70ꢀ72 C; IR (NaCl) ν(cmꢀ1) 3274, 2925, 2859, 1654, 1583, 1503,
1469, 1457, 1437, 1366, 1238, 1221, 1175, 1017, 928, 739, 753;
1H NMR (500 MHz, CDCl3) δ 8.29 (dd, J = 8.3, 1.4 Hz, 1H), 7.81
(s, 1H), 7.77 (dd, J = 8.0, 1.3 Hz, 1H), 7.34 (m, 1H), 6.83 (td, J =
7.8, 1.5 Hz, 1H), 1.37 (s, 9H). 13C NMR (125 MHz, CDCl3) δ
176.8, 138.6, 138.2, 129.2, 125.7, 121.7, 90.1, 40.1, 27.7. HRMS
1
801, 781, 746; H NMR (400 MHz, CDCl3) δ 8.99 (d, J = 8.6 Hz,
1H), 8.29 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.85 (dd, J
= 8.8, 3.4 Hz, 2H), 7.60 (d, J = 7.3 Hz, 1H), 7.50 (m, 3H), 7.41
(dd, J = 7.0, 1.1 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 170.5,
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

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1
(ESI): m/z Calcd. for C11H15INO [M+H]+ : 304.0193; found:
304.0197.
1223, 1188, 1148, 1089, 842, 775; H NMR (400 MHz, CDCl3) δ
8.43 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.55 (s, 1H),
6.87 (dd, J = 8.4, 1.6 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 166.1, 161.9, 159.4, 142.2, 132.8, 115.2,
103.5, 56.0, 51.9; HRMS (ESI): m/z Calcd. for C10H12NO4
[M+H]+ : 210.0761; found: 210.0765.
N-(Pyridin-2-yl)pivalamide (2g): 23d Colourless solid (80%); mp.
68ꢀ70 o C; IR (NaCl) ν(cmꢀ1) 3333, 2931, 2872, 1690, 1593, 1578,
1513, 1478, 1457, 1430, 1399, 1367, 1302, 1225, 1149, 1096,
1051, 1026, 992, 922, 778; 1H NMR (400 MHz, CDCl3) δ 8.25 (d,
J = 8.1 Hz, 2H), 8.04 (s, 1H), 7.71 (dd, J = 12.1, 5.2 Hz, 1H), 7.03
(dd, J = 6.9, 5.4 Hz, 1H), 1.33 (s, 9H). HRMS (ESI): m/z Calcd.
for C10H15N2O [M+H]+ : 179.1179; found: 179.1179.
N-(2-Hydroxy-5-methylphenyl)formamide (3d):24a Colourless
solid (90%); mp. 120ꢀ121 oC; IR (NaCl) ν(cmꢀ1) 3435, 2955, 2923,
2852, 1741, 1657, 1596, 1455, 1378, 1243, 1156, 1019, 771, 668;
1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.66(d, J = 8.4 Hz,
1H), 6.75 (s, 1H), 6.65 (d, J = 7.8 Hz, 1H), 2.23 ( s, 3H); 13C NMR
(125 MHz, Acetoneꢀd6) δ 160.6, 147.8, 135.8, 122.0, 121.9, 121.1,
118.0, 20.9.
23e
N-(5-Bromopyridin-2-yl)pivalamide (2h):
Colourless solid
(75%); mp. 61ꢀ63 C; IR (NaCl) ν(cmꢀ1) 3437, 2964, 2931, 2871,
1693, 1584, 1567, 1503, 1398, 1369, 1295, 1224, 1154, 1127,
1093, 1019, 1002, 925, 834, 743, 666; 1H NMR (500 MHz,
CDCl3) δ 8.29 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.17 (s, 1H), 7.79
(t, J = 7.3 Hz, 1H), 1.31 (s, 9H). 13C NMR (125 MHz, CDCl3) δ
177.2, 150.3, 148.4, 140.8, 115.2, 114.4, 39.8, 27.4. HRMS (ESI):
m/z Calcd. for C10H14BrN2O [M+H]+ : 257.0284; found: 257.0287.
o
N-(2-Iodophenyl)formamide (3e):24b Colourless solid (90%); mp.
110ꢀ112 oC; IR (NaCl) ν(cmꢀ1) 3439, 2955, 2923, 2852, 1739,
1618, 1460, 1383, 1153, 1117, 1019, 773, 669; 1H NMR (400
MHz, CDCl3) δ 8.49 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.83 (dd, J
= 21.4, 8.0 Hz, 1H), 7.45 (s, 1H), 7.36 (t, J = 7.7 Hz, 1H), 6.91 (dt,
J = 24.4, 7.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 160.0,
157.0, 138.1, 137.2, 127.8, 127.6, 125.2, 124.6, 120.4, 117.3, 88.8,
87.4;
N-(2-Chloropyridin-3-yl)pivalamide (2i):23f
Colourless oil
(74%); IR (NaCl) ν(cmꢀ1) 3435, 2955, 2923, 2853, 1741, 1594,
1506, 1457, 1385, 1301, 1260, 1205, 1153, 1120, 1073, 1019, 858,
1
799, 669; H NMR (500 MHz, CDCl3) δ 8.76 (d, J = 6.7 Hz, 1H),
8.10 (d, J = 8.4 Hz , 1H), 8.01 (s, 1H), 7.27 (d, J = 8.2 Hz, 1H),
1.36 (s, 9H). HRMS (ESI): m/z Calcd. for C10H14ClN2O [M+H]+ :
213.0789; found: 213.0783.
N-(Pyridin-3-yl)formamide (3f): 24c Colourless solid (86%); mp.
94ꢀ96 C; IR (NaCl) ν(cmꢀ1) 3234, 2922, 2852, 1692, 1588, 1544,
1484, 1426, 1412, 1329, 1286, 1241, 1192, 1154, 1125, 1020, 864,
803, 781; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.47 (s, 2H),
8.25 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H). 13
o
N-(Thiazol-2-yl)pivalamide (2j): 23g Colourless solid (80%); mp.
C
o
136ꢀ138 C; IR (NaCl) ν(cmꢀ1) 3380, 2922, 2854, 1651, 1598,
NMR (125 MHz, CDCl3) δ 162.2, 159.6, 146.4, 140.7, 127.5,
126.1.
1
1536, 1419, 1402, 1320, 1291, 1247, 1109, 1018, 949, 873; H
NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 7.45 (d, J = 3.6 Hz, 1H),
6.98 (d, J = 3.5 Hz, 1H), 1.33 (s, 9H). 13C NMR (125 MHz,
CDCl3) δ 176.4, 159.0, 137.2, 113.7, 39.1, 27.2. HRMS (ESI): m/z
Calcd. for C8H13N2OS [M+H]+ : 185.0743; found: 185.0736.
N-(2-Chloropyridin-3-yl)formamide (3g):
Colourless solid
o
(80%); mp. 145ꢀ147 C ; IR (NaCl) ν(cmꢀ1) 3440, 2927, 2837,
1698, 1599, 1582, 1488, 1429, 1410, 1330, 1290, 1264, 1229,
1212, 1064, 1036, 994, 868, 781, 752, 688; H NMR (400 MHz,
CDCl3) δ 8.77 (d, J = 8.1 Hz, 1H), 8.56 (s, 1H), 8.13 (d, J = 8.8
Hz, 1H), 7.77 (s, 1H), 7.29(m, 1H). 13C NMR (125 MHz, CDCl3) δ
172.2, 159.6, 148.9, 129.7, 121.4, 119.2; HRMS (ESI): m/z Calcd.
for C6H6ClN2O [M+H]+ : 157.0163; found: 157.0164.
1
24a
o
N-Phenylformamide (3a):
Beige solid (98%); mp. 48ꢀ51 C
IR (NaCl) ν(cmꢀ1) 3439, 2955, 2920, 2849, 1730, 1610, 1540,
1439, 1397, 1383, 1276, 1133, 1121, 1089, 953, 879, 773, 678; 1H
NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.69 (d, J = 11.3 Hz, 1H),
8.33 (s, 1H), 8.18 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.32 (m, 4H),
7.18 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 8.1 Hz, 3H). 13C NMR (125
MHz, CDCl3) δ 163.3, 159.9, 137.1, 136.8, 129.7, 129.0, 125.3,
124.8, 120.2, 118.8.
N-(5-Bromopyridin-2-yl)formamide (3h):
Colourless solid
(78%); mp. 141ꢀ143 oC; IR (NaCl) ν(cmꢀ1) 3440, 2922, 2852,
1690, 1593, 1579, 1535, 1463, 1404, 1375, 1306, 1220, 1171,
1094, 1014, 825; 1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 9.30
(d, J = 10.5 Hz, 1H), 8.87 (s, 1H), 8.51 (s, 1H), 8.36 (s, 2H), 8.18
(d, J = 8.8 Hz, 1H), 7.84 (dd, J = 8.8, 2.2 Hz, 1H), 7.78 (dd, J =
8.6, 2.1 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ 162.8, 159.2, 149.5, 149.5, 149.3, 148.5, 141.2, 141.1,
116.1, 115.1, 111.9; HRMS (ESI): m/z Calcd. for C6H6BrN2O
[M+H]+ : 202.9637; found: 202.9642.
11a
Methyl 4-formamidobenzoate (3b):
Colourless solid (95%);
mp. 119ꢀ122 oC; IR (NaCl) ν(cmꢀ1) 3264, 2924, 2853, 1714, 1612,
1539, 1436, 1409, 1307, 1282, 1218, 1191, 1177, 1145, 1115,
1016, 846, 765; 1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.44
(s, 1H), 8.03 (t, J = 8.5 Hz, 4H), 7.65 (d, J = 8.0 Hz, 2H), 7.16 (d,
J = 7.9 Hz, 2H), 3.91 (s, 6H). 13C NMR (125 MHz, CDCl3) δ
166.7, 166.4, 162.4, 159.6, 141.2, 141.1, 131.5, 130.8, 126.4,
125.9, 119.2, 117.2, 52.2, 52.1.
N-(Thiazol-2-yl)formamide (3i): Colourless solid (80%); mp.
159ꢀ161 oC; IR (NaCl) ν(cmꢀ1) 3440, 2921, 2852, 1693, 1681,
1597, 1436, 1386, 1352, 1319, 1288, 1169, 1140, 1049, 1018, 854,
Methyl 4-formamido-2-methoxybenzoate (3c): Colourless solid
(95%); mp. 130ꢀ132 oC ; IR (NaCl) ν(cmꢀ1) 3283, 2923, 2852,
1698, 1607, 1595, 1532, 1511, 1453, 1435, 1412, 1326, 1255,
1
834, 748, 726, 672; H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H),
7.48 (d, J = 3.6 Hz, 1H), 7.06 (d, J = 3.6 Hz, 1H). 13C NMR (125
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C4RA16571C
MHz, CDCl3) δ 163.7, 161.7, 142.4, 118.2; HRMS (ESI): m/z
Calcd. for C4H5N2OS [M+H]+ : 129.0117; found: 129.0123.
N-(4-(Trifluoromethoxy)phenyl)acetamide (3q): Colourless
solid (86%); mp. 114ꢀ115 oC; IR (NaCl) ν(cmꢀ1) 3435, 2920, 2851,
1672, 1609, 1541, 1512, 1457, 1407, 1377, 1284, 1208, 1162,
1019, 852; 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 9.0 Hz, 2H),
7.48 (s, 1H), 7.16 (d, J = 8.5 Hz, 2H), 2.18 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 168.9, 145.2, 136.5, 128.6, 121.4, 119.4, 24.3;
HRMS (ESI): m/z Calcd. for C9H9F3NO2 [M+H]+ : 220.0579;
found: 220.0582.
11a
N-Phenethylformamide (3j):
Colourless oil (96%); IR (NaCl)
ν(cmꢀ1) 3285, 3061, 3029, 2931, 2864, 1666, 1604, 1532, 1497,
1454, 1384, 1237, 1198, 1156, 1085, 1031, 779, 748, 700; 1H
NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.30 (d, J = 5.8 Hz, 2H),
7.22 (dd, J = 15.3, 7.7 Hz, 3H), 5.98 (s, 1H), 3.54 (t, J = 6.0 Hz,
2H), 2.83 (t, J = 5.6 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ
164.8, 161.6, 138.6, 137.7, 128.9, 128.8, 128.7, 128.6, 126.8,
126.6, 43.3, 39.2, 37.6, 35.4.
N-(4-Nitrophenyl)acetamide (3r):24f Colourless solid (85%); mp.
o
210ꢀ212 C; IR (NaCl) ν(cmꢀ1) 3345, 2921, 2851, 1684, 1617,
1598, 1568, 1507, 1404, 1345, 1304, 1269, 1115, 1018, 849, 750,
1
Methyl 2-formamido-3-(1H-indol-3-yl)propanoate (3k):24d Pale
668, 513; H NMR (400 MHz, DMSOꢀd6) δ 10.31 (s, 1H), 8.14
o
yellow solid (85%); mp. 114ꢀ117 C; [α]20 = + 55 (0.5 CHCl3);
(dd, J = 9.2, 1.9 Hz, 2H), 7.83 (dd, J = 9.2, 2.1 Hz, 2H), 2.17 (s,
3H). 13C NMR (125 MHz, DMSOꢀd6) δ 169.1, 145.0, 142.0,
124.2, 118.4, 24.0.
D
IR (NaCl) ν(cmꢀ1) 3346, 2952, 2854, 1739, 1667, 1618, 1512,
1457, 1437, 1382, 1342, 1213, 1180, 1096, 1018, 746; H NMR
1
(400 MHz, CDCl3) δ 8.32 (s, 1H), 8.13 (s, 1H), 7.53 (d, J = 7.9 Hz,
1H), 7.35 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 13.1, 5.8 Hz, 1H), 7.12
(t, J = 7.5 Hz, 1H), 6.98 (d, J = 1.6 Hz, 1H), 5.01 (dd, J = 11.9, 6.5
Hz, 1H), 3.71 (s, 3H), 3.34 (dd, J = 5.1, 2.3 Hz, 2H). 13C NMR
(125 MHz, CDCl3) δ 172.0, 161.1, 136.1, 127.5, 123.1, 122.2,
119.6, 118.4, 111.4, 109.3, 52.5, 51.6, 27.5.
N-(Pyridin-2-yl)acetamide (3s):24g Colourless solid (80%); mp.
o
70ꢀ72 C; IR (NaCl) ν(cmꢀ1) 3244, 2924,2850, 1690, 1640, 1601,
1584, 1551, 1482, 1424, 1366, 1328, 1288, 1244, 1195, 1133,
1108, 1036, 1020, 918, 855, 838, 818, 706; 1H NMR (400 MHz,
CDCl3) δ 8.74 (s, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 3.8
Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.27 (dd, J = 8.2, 4.9 Hz, 1H),
2.20 (s, 3H).
Piperidine-1-carbaldehyde (3l):11a Colourless oil (87%); IR
(NaCl) ν(cmꢀ1) 3298, 2930, 2819, 1720, 1638, 1610, 1538, 1502,
1496, 1428, 1385, 1318, 1257, 1189, 1125, 1083, 1030, 994, 892;
1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 3.47 (m, 4H), 1.59 (m,
6H).
N-(4-Bromopyridin-2-yl)acetamide (3t): Colourless solid (75%);
mp. 122ꢀ123 oC; IR (NaCl) ν(cmꢀ1) 3241, 2923, 2852, 1681, 1588,
1574, 1540, 1456, 1378, 1304, 1093, 1018, 973, 830, 764; 1H
NMR (400 MHz, Acetoneꢀd6) δ 8.51 (s, 1H), 8.34 (d, J = 2.2 Hz,
1H), 8.20 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 2.5 Hz, 1H), 2.20(s,
3H). 13C NMR (125 MHz, acetoneꢀd6) δ 172.5, 170.9, 149.7,
149.3, 141.2, 115.8, 21.5.; HRMS (ESI): m/z Calcd. for
C7H8BrN2O [M+H]+ : 216.9799; found: 216.9798.
Morpholine-4-carbaldehyde(3m):24a Colourless oil (88%); IR
(NaCl) ν(cmꢀ1) 3320, 2920, 2821, 1710, 1640, 1590, 1520, 1472,
1
1390, 1327, 1254, 1208, 1176, 1109, 1049, 973; H NMR (400
MHz, CDCl3) δ 8.06 (s, 1H), 3.70 (m, 2H), 3.67 (m, 2H), 3.58 (m,
2H), 3.40 (m, 2H).
N-(Pyridin-3-yl)acetamide (3u):24h Colourless solid (78%); mp.
129ꢀ131 oC; IR (NaCl) ν(cmꢀ1) 3256, 2955, 2924, 2853, 1682,
1597, 1578, 1531, 1463, 1434, 1372, 1302, 1239, 1150, 1082,
N-(p-Tolyl)acetamide (3n):24e Colourless solid (98%); mp. 148ꢀ
151 oC ; IR (NaCl) ν(cmꢀ1) 3361, 2916, 2849, 1702, 1685, 1610,
1597, 1526, 1443, 1408, 1368, 1314, 1289, 1253, 1175, 1118,
1000, 856, 768; 1H NMR (400 MHz, CDCl3) δ 7.43 ( br, 1H), 7.37
(d, J = 8.3 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H), 2.30 (s, 3H), 2.14 (s,
3H).
1
1017, 965, 740; H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.26
(m, 2H), 7.73 (m, 1H), 7.05 (m, 1H), 2.21 ( s, 3H).
N-(2-(Diethylamino)ethyl)-4-nitrobenzamide (6):25 Transamide
product 6 was prepared by following general procedure. Viscous
yellow oil; (82%); IR (NaCl) ν(cmꢀ1) 3416, 2970, 2929, 1658,
1650, 1600, 1556, 1537, 1488, 1470, 1381, 1346, 1301, 1262,
N-(4-Methoxyphenyl)acetamide(3o):24e Colourless solid (97%);
o
mp. 128ꢀ129 C ; IR (NaCl) ν(cmꢀ1)
3242, 2934, 2836, 1647,
1
1177, 1087, 1067, 1014, 870; H NMR (400 MHz, CDCl3) δ 8.24
1605, 1562, 1513, 1456, 1441, 1369, 1319, 1285, 1246, 1176,
1113, 1030, 970, 838, 773; 1H NMR (400 MHz, CDCl3) δ 7.49 (br,
1H), 7.38 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 3.77 (s,
3H), 2.13 (s, 3H).
(d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 3.62 (dd, J = 10.4,
5.0 Hz, 2H), 2.84 (t, J = 5.5 Hz, 2H), 2.74 (q, J = 7.1 Hz, 4H), 1.13
(t, J = 7.1 Hz, 6H); HRMS (ESI): m/z Calcd. for C13H20N3O3
[M+H]+ : 266.1499; found: 266.1501.
N-(4-Fluorophenyl)acetamide (3p):24f Colourless solid (95%);
Procainamide (7):25 To a suspension of 6 (1.88 mmol ) in ethanol
(10 mL) was added reduced iron powder (3.77 mmol). The
resulting suspension was reflux for 2h with TLC analysis
monitoring for completion of the reaction. The reaction mixture
was filtered through celite to remove the iron residue which was
washed with ethyl acetate (3x10 mL). The filtrate was partitioned
with (2M) KOH solution and the basic layer was further extracted
mp. 152ꢀ154 oC; IR (NaCl) ν(cmꢀ1) 3267, 2923, 1660, 1613, 1565,
1
1540, 1507, 1400, 1316, 1237, 1208, 1017, 834; H NMR (400
MHz, CDCl3) δ 7.50 (s, 1H), 7.45 (m, 2H), 6.99 (t, J = 8.7 Hz,
2H), 2.16 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.3, 160.6,
133.9, 121.8, 115.6, 24.3.
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DOI: 10.1039/C4RA16571C
M. Hoerter, I. A. Guzei, Q. Cui, S. H. Gellman, and S. S. Stahl, J.
Am. Chem. Soc 2007, 129, 1776.
) A. J. A. Watson, A. C. Maxwell and J. M. J. Williams, Org.
Lett., 2009, 11, 2667; ( ) B. N. Atkinson, A. R. Chhatwal, H. V.
with ethyl acetate (3 x 25 mL). The combined organic extracts
were washed with brine, dried over Na2SO4 and concentrated
under reduced pressure. The crude residue was then subjected to
flash silica gel column chromatography to obtain the pure desired
product. Orange oil (95%); IR (NaCl) ν(cmꢀ1) 3443, 2917,
2849,1679, 1633, 1587, 1509, 1497, 1467, 1390, 1327, 1298,
,
7
(a
b
Lomax, J. W. Walton and J. M. J. Williams, Chem. Commun.
,
2012, 48, 11626.
T. A. Dineen, M. A. Zajac, and A. G. Myers, J. Am. Chem. Soc.,
2006, 128, 16406.
8
1
1189, 1109, 1074, 949, 847; H NMR (400 MHz, acetoneꢀd6) δ
8.38 (s, 1H), 7.70 (d, J = 8.5 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H),
3.82 (d, J = 4.6 Hz, 2H), 3.50 (dd, J = 9.3, 4.5 Hz, 2H), 3.44 (m,
4H), 1.40 (t, J = 7.2 Hz, 6H). 13C NMR (100 MHz, acetoneꢀd6) δ
171.3, 153.6, 130.2, 120.7, 114.0, 56.0, 49.1, 37.5, 9.5; HRMS
(ESI): m/z Calcd. for C13H22N3O [M+H]+ : 236.1758; found:
236.1784.
9
M. Zhang, S. Imm, S. Bahn, L. Neubert, H. Neumann and M.
Beller, Angew. Chem., Int. Ed., 2012, 51, 3905.
10
(a
) M. Tamura, T. Tonomura, K.ꢀi. Shimizu and A. Satsuma,
Green Chem., 2012, 14, 717; ( ) L. BecerraꢀFigueroa, A. Ojedaꢀ
Porras and D. GambaꢀSanchez, J. Org. Chem., 2014, 79, 4544; (
D. P. Singh, B. K. Allam, K. N. Singh and V. P. Singh, RSC Adv.
2014, , 1155; ( ) S. N. Rao, D. C. Mohan and S. Adimurthy,
Green Chem., 2014, 16, 4122. ( ) S. P. Pathare, A. K. H. Jain and
K. G. Akamanchi, RSC Adv. 2013, , 7697.
) T. B. Nguyen, J. Sorres, M. Q. Tran, L. Ermolenko, and A. Alꢀ
Mourabit, Org. Lett., 2012, 14, 3202; ( ) P. Starkov and T. D.
Sheppard, Org. Biomol. Chem., 2011, , 1320; ( ) R. M. Lanigan,
P. Starkov, and T. D. Sheppard, J. Org. Chem., 2013, 78, 4512.
b
c
)
4
d
e
Acknowledgements
3
Sk. R., N.R. and A. S. R. thanks CSIRꢀNew Delhi and UGC for
their research fellowship respectively. This research work
financially supported by CSIRꢀNew Delhi (BSC0108). IIIM
communication no IIIM/1730/2014
11
(a
b
9
c
12 C. L. Allen, B. N. Atkinson, and J. M. J. Williams, Angew. Chem.
Int. Ed., 2012, 51, 1383.
13
Notes and references
(a) S. N. Rao, D. C. Mohan, and S. Adimurthy, Org. lett., 2013,
15, 1496; (b) X. Yang, L. Fan and Y. Xue, RSC Adv., 2014, 4,
30108.
14 A. Galat and G. Elion, J. Am. Chem. Soc., 1943, 65, 1566.
aAcademy of Scientific and Innovative Research(AcSIR); bMedicinal
Chemistry Division, Indian Institute of Integrative Medicine(CSIR), Canal
Road, Jammu-180001, India; Tel: 91-191-2560000; Fax:91-191-2569019;
E-mail: partha@iiim.ac.in
15
(a
) D. Kumar, M. Sonawane, B. Pujala, V. K. Jain, S. Bhagat, A.
K. Chakraborti, Green Chem., 2013, 15, 2872; ( ) S. Pathak, K.
Debnath and A. Pramanik, Beilstein J. Org. Chem. 2013, , 2344;
) A. K. Chakraborti, B. Singh, S. V. Chankeshwara and A. R.
Patel, J. Org. Chem., 2009, 74, 5967.
) P. Salehi, M. Dabiri, M. A. Zolfigol and M. A. B. Fard,
Tetrahedron Lett., 2003, 44, 2889; ( ) P. Salehi, M. Dabiri, M. A.
b
†
Electronic
Supplementary
Information
(ESI)
available:
9
[experimental details and spectroscopic data for all compounds]. See
DOI: 10.1039/c000000x/
(c
16
(a
1
2
(a) A. Greenberg; C. M. Breneman and J. F. Liebman The amide
b
Linkage: Structural Significance in Chemistry, Biochemistry and
Materials Science; WileyꢀInterscience: New York, 2000; (b) J. S.
Carey, D. Laffan, C. Thomson, and M. T. Williams, Org. Biomol.
Zolfigol and M. Baghbanzadeh, Tetrahedron Lett., 2005, 46
,
7051.
17 http://www.drugs.com/top200html, Pharmaceutical Sales 2010.
Chem., 2006,
For reviews see: (
Tetrahedron, 2005, 61, 10827; (
Soc. Rev., 2009, 38, 606; ( ) A. ElꢀFaham, and F. Albericio,
Chem. Rev., 2011, 111, 6557; ( ) C. L. Allen, and J. M. J.
Williams, Chem. Soc. Rev., 2011, 40 3405. V. R.
Pattabiraman, and J. W. Bode, Nature, 2011, 480, 471.
From carboxylic acids, selected recent examples see: (a) N.
Gernigon, R. M. AlꢀZoubi, D. G. Hall, J. Org. Chem 2012, 77,
4
, 2337.
) C. A. G. N. Montalbetti, and V. Falque,
) E. Valeur, M. Bradley, Chem.
18
(
(
a
b
) J. Zhou, B. Li, F. Hu and B.ꢀF. Si, Org. Lett., 2013, 15, 3460;
) S. Cai, C. Chen, Z. Sun and C. Xi, Chem. Commun., 2013, 49
a
,
b
4552.
c
19 K. C. Coffman, H. H. Nguyen, P.ꢀW. Phuan, B. M. Hudson, G. J.
Yu, A. L. Bagdasarian, D. Montgomery, M. W. Lodewyk, B.
Yang, C. L. Yoo, A. S. Verkman, D. J. Tantillo and M. J. Kurth, J.
Med. Chem., 2014, 57, 6729.
20 T. W. Green, and P. G. M. Wuts, Protective groups in organic
Synthesis, 3rd ed.; Wiley: New York, 1999, p 150.
21 J. W. Noneman and M. D. Jones, In Drug Treatment of cardiac
Arrhythmias; Gould, L. A., Ed.; Futura Publishing Co., Inc.:
Mount Kisco, New York, 1983; pp 193ꢀ223
d
,
(e)
3
4
.
,
8386; (b) M. Kitamura, F. Kawasaki, K. Ogawa, S. Nakanishi, H.
Tanaka, K. Yamada, and M. Kunishima, J. Org. Chem., 2014, 79,
3709.; (c) C. L. eꢀAboussafy, B. P. Jones, K. E. Price, M. A.
Hardink, R. W. Mclaughlin, B. M. Lillie, J. M. Hawkins, and R.
Vaidyanathan, Org. Lett., 2010, 12, 324.
22
(a
) M. B. M. Reddy, V. P. Jayashankara, M. A. Pasha, Green
Chemistry Letters and Reviews, 2013, , 107; ( ) S. Kim, H. Ko,
Sh. Kim, and T. Lee, J. Comb. Chem., 2002, , 549; ( ) T. T.
Dang, Y. Zhu, S. C. Ghosh, A. Chen, C. L. L. Chai, and A. M.
Seayad, Chem. Commun., 2012, 48, 1805; ( ) S. Ko, H. Han, and,
S. Chang, Org. Lett., 2003, , 2687.
) N. Hazarika, and G. Baishya, Eur. J. Org. Chem., 2014, 26
5686. ( ) H. Suzuki, J. Tsuji, Y. Hiroi, N. Sato, A. Osuka, Chem.
Lett., 1983, 12, 449; ( ) C. Gimbert, and A. Vallribera, Org. Lett.
2009, 11, 269; ( ) M. L. H. Mantel, A. T. Lindhardt, D. Lupp,
and T. Skrydstrup, Chem. Eur. J., 2010, 16, 5437. ( ) J. Zhou, B.
Li, F. Hu, and B. F. Shi, Org. Lett., 2013, 15, 3460; ( ) L. Estel, F.
Linard, F. Marsais, A. Godard, and G. Queguiner, J. Heterocyclic
Chem., 1989, 26, 105; ( ) B. Sachiavi, A. Ahond, A. AlꢀMourabit,
6
b
From carboxylic acid derivatives, selected recent examples see (
B. R. Kim, H.ꢀG. Lee, S.ꢀB. Kang, G. H. Sung, J.ꢀJ. Kim, J. K.
Park, S.ꢀG. Lee, Y.ꢀJ. Yoon, Synthesis, 2012, 44, 42; ( ) J. M.
Munoz, J. Alcazar, A. D. Hoz, A. diazꢀOrtiz, and, S. A. De Diego,
Green Chem., 2012, 14, 1335. ( ) W. Wu, Z. Zhang, and L. S.
a)
4
c
b
d
5
c
23
(a
,
Liebeskind, J. Am. Chem. Soc., 2011, 133, 14256.
For review on transamidation see: R. M. lanigan, and T. D.
Sheppard, Eur. J. Org. Chem., 2013, 7453.
b
5
6
c
,
d
(a
) N. A. Stephenson, J. Zhu, S. H. Gellman, and S. S. Stahl, J.
Am. Chem. Soc., 2009, 131, 10003; ( ) J. M. Hoerter, K. M. Otte,
S. H. Gellman, Q. Cui, and S. S. Stahl, J. Am. Chem. Soc., 2008,
130, 647; ( ) J. M. Hoerter, K. M. Otte, S. H. Gellman, and S. S.
Stahl, J. Am. Chem. Soc., 2006, 128, 5177; ( ) D. A. Kissounko, J.
e
f
b
c
g
d
8 | J. Name., 2012, 00, 1-3
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Page 10 of 10
Journal Name
View ArticAle ROnTliInCeLE
DOI: 10.1039/C4RA16571C
C. Poupat, A. Chiaroni, C. Gaspard, P. Potier, Tetrahedron, 2002,
58, 4201.
24
(
a
) M. H. Sarvari, and H. Sharghi, J. Org. Chem., 2006, 71, 6652;
) T. Kesharwani, A. K. Verma, D. Emrich, J. A. Ward, and R.
) B. P. Fors, P. Krattiger,
E. Strieter, and S. L. Buchwald, Org. Lett., 2008, 10, 3505; ( ) M.
Suchy, A. A. H. Elmehriki, and R. H. E. Hudson, Org. Lett., 2011,
(b
C. Larock, Org. Lett., 2009, 11, 2591; (
c
d
13, 3952; (
e
) R. Vanjari, B. Kumar Allam, K. N. Singh, RSC.
, 1691; ( ) Xi sun, M. Wang, P. Li, X. Zhang, and L.
) C. Abate, S. Ferorelli,
M. Niso, C. Lovicario, V. Infantino, P. Convertini, R. Perrone,
and F. Berardi, Chem. Med. Chem, 2012, , 1847; ( ) J. A. A. W.
Adv., 2013,
3
f
Wang, Green Chem., 2013, 15, 3289. (
g
7
h
Elemans, E. J. A. Bijsterveld, A. E. Rowan, and R.J.M. Nolte,
Eur. J. Org. Chem., 2007, 751.
25 S. K. Shannon, M. J. Peacock, S. A. Kates, and G. Barany, J.
Comb. Chem, 2003, , 860.
6
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