Imidazolium salt-supported Mukaiyama reagent: An efficient condensation reagent for amide bond formation

Article abstract of DOI:10.1039/c4ra14856h

A novel imidazolium salt-supported Mukaiyama reagent (2-chloropyridinium salt) has been developed and explored as an efficient coupling agent for amide bond formation. The use of an ionic liquid-supported reagent enabled isolation of the amide products by simple extraction with organic solvents in high purity and avoiding column chromatography purification. This journal is

Full text of DOI:10.1039/c4ra14856h

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: K. Pandey, M. K.
Muthyala, S. Sunita Choudhary and A. Kumar, RSC Adv., 2015, DOI: 10.1039/C4RA14856H.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 8
RSC Advances
View Article Online
DOI: 10.1039/C4RA14856H
Graphical Abstract
A novel imidazolium salt-supported Mukaiyama reagent has been synthesized and utilized as coupling agent
for synthesis of amides.
N
O
N
Cl
OTf
IL
IL
O
O
R'
R'NH2
R
N
R
OH
H
NEt3, THF,
N2 atm, reflux
16 examples
48-95% yield

View Article Online
DOI: 10.1039/C4RA14856H
RSC Advances
Page 2 of 8
Dynamic Article Links ►
Journal Name
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
Imidazolium Salt-supported Mukaiyama Reagent: An Efficient
Condensation Reagent for Amide Bond Formation
Khima Pandey, Manoj Kumar Muthyala, Sunita Choudhary and Anil Kumar*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
years different approaches have been reported to address these
A novel imidazolium salt-supported Mukaiyama reagent (2-
chloropyridinium salt) has been developed and explored as an
efficient coupling agent for the amide bond formation. The
use of ionic liquid-supported reagent enabled isolation of the
10 amide products by simple extraction with organic solvents in
high purity and avoiding column chromatography
purification.
problems associated with Mukaiyama reagents (Figure 1). For
50 example, Xu et. al.19 have synthesized a novel N-ethyl-2-
bromopyridinium tetrafluoroborate as an excellent coupling
reagent for peptide synthesis with high activity and a low level of
racemisation. The Tye,20 Taddei21 and Swinnen22 groups have
independently developed polymer-supported Mukaiyama
55 reagents (2 & 3) and demonstrated their application for the
synthesis of carbodiimide, guanylation of primary amines,
synthesis of amide & esters and generation of ketenes for
Staudinger cycloaddition reactions, respectively. Although
polymer-supported reagents have addressed some of the issues of
60 2-chloropyridinium salts, low loading capacity, high cost and
slower reaction rates makes these approaches less attractive.
Nagashima23 and Matsugi24 groups have independently reported
fluorous tagged Mukaiyama reagents 4 and 5, respectively for the
amide bond formation. The reactivity of reagent 5 was found to
65 be dependent on the length of the fluorous tag in molecule.24b In
the case of fluorous-supported synthesis, special solvent
requirements and cost are serious concerns.25 Onium salt-
supported reagents have gained considerable interest as a
promising alternative soluble support for reagents owing to their
70 high loading capacity, tuneable solubility, homogeneity and easy
monitoring of the reaction by various analytical techniques such
as NMR, IR and mass spectroscopy.26
Introduction
The amide bond is an significant building unit in many natural
15 and synthetic compounds.1 Amide bond has a unique role in
peptides and proteins. Molecules possessing amide bonds have
shown wide range of biological properties.2 Establishing
synthetic methods for amides are immensely important pursuit in
organic synthesis. The most prevalent strategy for amide bond
20 formation relies heavily upon the interconversion of activated
carboxylic acid derivatives with an amine. However, other
methodologies to access amide functionality have been also
developed like Staudinger reaction,3 hydrative amide syntheses
with alkynes,4 the Schmidt reaction,5 Beckmann rearrangement6
25 and amidation of aldehydes catalyzed by transition metals and
hypervalent iodine reagents.7 Although these methods are highly
efficient but has an innate drawback of using expensive transition
metals, hazardous oxidants, longer reaction time and waste
generation. Formation of amide bonds from carboxylic acids is
30 not a spontaneous process at ambient temperature and generally it
relies on activation of a carboxylic acid using a coupling reagent.
To address these challenging problems several coupling and
activating reagents such as 2-chloropyridinium salts,
dicyclohexylcarbodiimide (DCC),8 1-ethoxycarbonyl-2-ethoxy-
35 1,2-dihydroquinoline
(EEDQ),9
the
boron
reagent
B(OCH2CF3)3,10 nano-Mgo11 and 1-[bis(dimethylamino)-
methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide
hexafluorophosphate (HATU) have been described in literature
for this reaction.12 Among these coupling reagents, N-methyl-2-
40 chloropyridinium iodide (Mukaiyama reagent) (1) is an efficient
activating agent for the formation of esters,13 carboxamides,14
ketenes,15 lactones16 and lactams17 from carboxylic acids. Despite
its great success, it is also associated with some issues of
solubility, stability and purification of coupled products.18 In
45 most of the reactions using Mukaiyama reagent, cumbersome
chromatographic separation is mandatory to separate the product
from the by-product, N-alkylpyridone. Over the last couple of
75
Fig. 1: Some solid-supported and fluorous-supported Mukaiyama
reagents
In continuation to our interest towards ionic liquid-supported
reagents in organic synthesis,27 herein we report the synthesis of
novel imidazolium salt-supported Mukaiyama reagent (2-
80 chloropyridinium salt) and its application in amide bond
formation. To the best of our knowledge this is the first report of
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

View Article Online
DOI: 10.1039/C4RA14856H
Page 3 of 8
RSC Advances
the synthesis of an imidazolium salt-supported Mukaiyama
reagents.
agreement with the proposed sturcture. Presence of the peaks at
m/z 502.4 [M-CF3SO3]+ and 506.3 [M-PF6]+ in the mass spectrum
45 of 15 conformed the formation of 15.
In order to explore synthetic applicability of the reagent, coupling
of 4-nitrobenzoic acid (16) and 4-bromoaniline (17) was
performed without additive in DCM as a prototype reaction.
DCM was the first solvent of choice and this proved to work
50 efficiently showing completion of reaction within 2 h. However,
the choice of DCM was not optimal, because many carboxylic
acids are insoluble in it, while it is too volatile for parallel
synthetic use. Various solvents were screened to circumvent the
issue. Among the various solvents evaluated for the reaction,
55 THF proved to be the best choice in terms of yield and reaction
time (Table 1, entry 4). Although the reagent was soluble in
acetonitrile the yield of product was less even after longer
reaction times. In methanol, the yield of the desired product was
poor, probably because the nucleophilicity of the methanol also
60 lead to the formation of the ester as a by-product.
Result and discussion
Our initial investigation to synthesize an imidazolium salt-
supported Mukaiyama reagent by the reaction of 1-(3-
chloropropyl)-2,3-dimethylimidazolium tetrafluoroborate (6) with
2-chloropyridine (7) in the presence of KI or by the reaction of 2-
chloro-1-(3-chloropropyl)pyridin-1-ium bromide (8) with 1,2-
dimethylimidazole (9) followed by anion exchange (Scheme 1)
5
10 failed to give a substantial amount of imidazolium salt-supported
Mukaiyama reagent 10.
Table 1: Optimization of reaction conditions for amide bond formation
Entry
Solvent
DCM
CH3CN
CH3CN
THF
Time (h)
Yield (%)
72 (62)a
55
1
2
3
4
5
6
2
2
4
2
2
2
65
85
Methanol
H2O
43
20 (53)b
Scheme 1: Synthesis of imidazolium salt-supported Mukaiyama reagent
10 and 15.
a room temperature, bstirring for 5 h
65 Having identified optimum reaction conditions, the scope of
reagent was examined by employing different substituted
carboxylic acids and amines and results are summarized in table
2. For the synthesis of amide, a mixture of benzoic acid (16),
15 We envisioned the reaction of imidazolium salt-supported benzyl
alcohol 14 with 2-chloropyridine (7) and triflic anhydride would
afford us the desired imidazolium salt-supported Mukaiyama
reagent.22 Synthesis of 14 was achieved from 4-hydroxy-
benzaldehyde (12) as shown in Scheme 1. Reaction of 12 with 1-
20 bromo-3-chloropropane (11) in the presence of potassium
carbonate gave monoalkylated aldehyde, which on subsequent
reduction resulted into the monoalkylated benzyl alcohol 13.
Reaction of 13 with 1,2-dimethylimidazole (9) at 110 °C gave the
corresponding chloride salt. Anion exchange of the chloride salt
25 with aqueous KPF6 resulted in corresponding imidazolium salt-
supported benzyl alcohol (14). Reaction of 14 and 7 in the
presense of triflic anhydride under nitrogen atmosphere in
dichloromethane for 10 h resulted in the imidazolium salt-
supported Mukaiyama reagent 15 in good yield (55%). It is
30 believed that sequential in situ formation of imidazolium salt-
supported triflic acid ester followed by quaternization of 2-
chloropyridine gave 15 (IL-supported Mukaiyama reagent). This
reaction proved to be convenient and fast compared to our earlier
attempts. The structure of reagent 15 was confirmed by 1H NMR,
35 13C NMR and HRMS (Supporting information). Presence of two
singlets at 3.73 ppm (NCH3) and 5.92 ppm (PhCH2), two
doublets at 7.60 ppm and 7.64 ppm for the imidazolium protons
along with characteristic double doublet at δ 9.27 for the ortho-
protons adjacent to nitrogen of pyridinium and other peaks in the
40 1H NMR spectrum of 15 clearly indicated that the 2-
chloropyridne has been tagged with imidazolium ion. Similarly,
the number of peaks in the 13C NMR spectrum of 15 were well in
imidazolium
salt-supported
Mukaiyama
reagent
(15),
70 triethylamine were suspended in THF and amine (17) was added
to mixture. The reaction mixture was refluxed for an optimal
time. It was observed that aromatic amines having electron
donating substituents like methyl and methoxy group furnished
better yields of product as compared to aniline with electron
75 withdrawing bromo substituents (Table 2, entries 2, 3 & 6, 7). On
the other hand aromatic acid with electron donating as well as
withdrawing groups showed excellent reactivity (Table 2, entries
1, 5 & 2, 6). However, 3,4,5-trimethoxybenzoic acid gave a lower
yield even after longer reaction time (Table 2, entry 11).
80 Aliphatic acid, propionic acid also furnished low yield of
corresponding N-phenylpropionamide (Table 2, entries 13). The
lower yield in case of 3,4,5-trimethoxybenzoic acid and propionic
acid may be attributed to their lower reactivity towards first step
of substitution. n-Butylamine also coupled with benzoic acid
85 giving good yield of N-butylbenzamide (Table 2, entry 12). The
heterocyclic amine, 2-aminobenzothiazole and 6-aminoquinoline
also coupled with benzoic acid to give desired amide in moderate
to good yield (48-59%) in 4-6 h using 15 as coupling reagent
(Table 2, entry 14, 16). Nicotinic acid also coupled with aniline
90 affording good yield of the desired product in 4h. The longer
reaction time taken by heteroaromatic acids and amines is
attributed to lesser reactivity of acid and lower nucleophilicity of
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
RSC Advances
DOI: 10.1039/C4RA14P85a6gHe 4 of 8
heteroamines. All the amides were obtained in excellent purity
structure of imidazolium salt-supported pyridone 20 was
after simple workup without additional chromatography. The
confirmed by 1H NMR, 13C NMR and IR spectroscopy
(Supporting information). It is worth to mention that recovered
1
melting point and H NMR data for the synthesized amides were
in agreement with the reported data in the literature. The by- 10 IL-supported pyridone (20) can be easily converted to reagent 15
5
product imidazolium salt-supported pyridone 20 was easily
removed from the reaction mixture by simple washing. The
by reacting with phosphorus oxychloride followed by anion
metathesis with sodium trifluoromethanesulfonate.24a
Table 2: Substrate scope for amide formation using reagent 15
Entry
1
R
Rˈ
Product
Time (h)
3
Yield (%)a
87
C6H5
C6H5
2
3
C6H5
C6H5
4-CH3C6H4
4-BrC6H4
2
3
93
70
4
5
C6H5
C6H5CH2
3
3
68
90
4-NO2C6H4
C6H5
6
7
8
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-CH3C6H4
4-BrC6H4
C6H4CH2
3
2
3
95
84
90
9
4-CH3OC6H4
C6H5
3
3
5
92
95
60
10
11
C6H5
4-CH3OC6H4
4-CH3C6H4
3,4,5-(CH3O)3C6H4
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

View Article Online
DOI: 10.1039/C4RA14856H
Page 5 of 8
RSC Advances
Dynamic Article Links ►
Journal Name
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
ARTICLE TYPE
12
13
C6H5
C2H5
C4H9
C6H5
4
82
2.5
56
14
15
C6H5
C7H4NS
4
4
48
63
C5H4N
C6H5
16
C6H5
C9H6N
6
59
aIsolated yield.
chloropropane (6.46 mL, 65 mmol) and potassium carbonate
It is believed that the reaction proceeds through initial activation 30 (9.05 g, 65 mmol) were taken in dry acetone (25 mL) in a 250 mL
of carboxylic acid (16) by IL-supported 2-chloropyridinium
triflate to give intermediate ester (19) which on subsequent
reaction with amine (17) by nucleophilic attack furnishes amide
(18) as product and IL-supported pyridone (20) as by-product
(Scheme 2)
round bottom flask. The reaction mixture was refluxed for 12 h.
After completion of reaction, acetone was evaporated and residue
was washed with water (20 mL) and extracted by ethyl acetate
(15 mL × 2). The organic layer was dried with anhydrous sodium
35 sulphate and evaporated under reduced pressure to get crude
product. Crude product was purified by column chromatography
on silica (60-120 mesh) using hexane and ethyl acetate as eluent
(9:1, v/v) to get 7.86 g of pure 4-(3-chloropropoxy)benzaldehyde.
It was further dissolved in dry THF (15 mL) at 0 C, then sodium
40 borohydride (2.24 g, 59 mmol) was added in pinches. After
addition the resulting mixture was stirred at room temperature for
3 h. On completion of reaction, methanol was evaporated and
water (15 mL) was added to the viscous residue. The solution was
neutralized to pH 7 by 2N HCl and extracted in ethyl acetate (15
45 mL × 2). The organic layer was washed with brine water and
dried with anhydrous sodium sulfate and concentrated under
reduced pressure to get pure product as white solid.
5
10 Scheme 2: Plausible mechanism for the amide formation using reagent 15
Experimental
General
The NMR (1H and 13C) spectra were recorded on 300 MHz and
400 MHz spectrometer in CDCl3 and DMSO-d6. The chemical
15 shifts were expressed in ppm and coupling constants (J) in Hz.
The IR spectra were recorded on ABB Bomen MB3000 FTIR
spectrophotometer. The progress of the reaction was determined
on thin-layer chromatography (TLC) performed on Merck-
precoated silica gel 60-F254 plates. Melting points were
20 determined on open capillary tube on MPA-120G EZ-Melt
automated melting point apparatus and are uncorrected. 1,2-
Dimethylimidazole, 2-chloropyridine, trifluoromethanesulfonic
acid and other reagents and solvents were purchased from
commercial sources and used without further purification unless
25 otherwise specified
(4-(3-Chloropropoxy)phenyl)methanol (13): Yield: 6.80 g (86%);
50 mp: 53-55 °C; 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 8.7 Hz,
2H), 6.92 (d, J = 8.7 Hz, 2H), 4.65 (d, J = 5.9 Hz, 2H), 4.14 (t, J
= 5.8 Hz, 2H), 3.78 (t, J = 6.3 Hz, 2H), 2.31 – 2.20 (m, 2H); 13
C
NMR (101 MHz, CDCl3) δ 158.4, 133.4, 128.7, 114.6, 65.0, 64.3,
41.5, 32.3.
55 General procedure for the synthesis of imidazolium salt-
supported benzyl alcohol (14)
A mixture of 13 (6.00 g, 30 mmol) and 1,2-dimethylimidazole
(2.87 g, 30 mmol) was heated at 110 °C for 3 h to give thick
viscous liquid. The viscous liquid was washed with ethyl acetate
60 (3 × 20 mL) to remove unreacted starting materials to give pure
General
procedure
for
the
synthesis
of
(4-(3-
chloropropoxy)phenyl)methanol (13)
4-Hydroxybenzaldehyde (8.00 g, 65 mmol), 1-bromo-3-
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 4

View Article Online
RSC Advances
DOI: 10.1039/C4RA14P85a6gHe 6 of 8
chloride salt (8.56 g, 96%). Ion exchange of chloride was
performed using (20 mL) aqueous potassium
hexafluorophosphate (6.37 g, 35 mmol) solution at room
N-p-Tolylbenzamide (18b): Yield 93%; Crystalline solid; mp:
o
158-160 C(lit.30 158 C ); IR (KBr, cm-1): 3319, 2910, 1649,
1580, 1521, 1404, 1315, 812; 1H NMR (400 MHz, CDCl3) δ 7.96
temperature for 1 h. The resulting solid precipitate was filtered 60 (s, 1H), 7.90 – 7.85 (m, 2H), 7.57 – 7.52 (m, 3H), 7.50 – 7.44 (m,
5
and washed with water and dried in vacuum to get pure 14.
2H), 7.18 (d, J = 8.2 Hz, 2H), 2.36 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 165.8, 135.4, 135.0, 134.2, 131.7, 129.5, 128.7, 127.0,
120.4, 20.94.
1
Yield: 11.37 g, 97%; mp: 115 °C; H NMR (300 MHz, DMSO) δ
7.65 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 8.5
Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.05 (t, J = 5.6 Hz, 1H), 4.41
10 (d, J = 5.6 Hz, 2H), 4.29 (t, J = 6.8 Hz, 2H), 3.97 (t, J = 5.9 Hz,
2H), 3.73 (s, 3H), 2.55 (s, 3H), 2.19 (p, J = 6.4 Hz, 2H); 13C
NMR (75 MHz, DMSO) δ 157.4, 144.9, 135.3, 128.4, 122.9,
121.4, 114.4, 64.5, 62.9, 45.3, 35.1, 29.1, 9.5.
N-(4-Bromophenyl)benzamide (18c): Yield 70%; Off-white solid;
o
65 mp: 196-198 C (lit.31 200-202 C); IR (KBr, cm-1): 3322, 2935,
1644, 1588, 1530, 1360, 830; 1H NMR (400 MHz, CDCl3) δ 7.88
(d, J = 8.4 Hz, 2H), 7.82 (s, 1H), 7.61 – 7.56 (m, 3H), 7.52 (dd, J
= 12.2, 5.3 Hz, 4H); 13C NMR (101 MHz, CDCl3) δ 165.6, 137.0,
134.6, 132.1, 128.9, 127.0, 121.7, 117.1.
General procedure for the synthesis of imidazolium salt-
15 supported Mukaiyama reagent (15)
70 N-Benzylbenzamide (18d): Yield 68%; Yellow crystalline; mp:
102-103 C (lit.32 100-101 oC); IR (KBr, cm-1): 3325, 3055, 2924,
1643, 1551, 1319, 800, 694; H NMR (300 MHz, CDCl3) δ 7.79
(d, J = 7.2 Hz, 2H), 7.53 – 7.46 (m, 1H), 7.41 (t, J = 7.3 Hz, 2H),
7.35 (d, J = 4.1 Hz, 2H), 7.32 – 7.28 (m, 4H), 6.49 (s, 1H), 4.64
75 (d, J = 5.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 167.3, 138.2,
134.4, 131.5, 128.8, 128.6, 127.9, 127.6, 126.9, 44.1.
1
A mixture of 14 (11.00 g, 27 mmol) and 2-chloropyridine (14 g,
135 mmol) was suspended in 20 mL DCM at 0 °C under N2
atmosphere. Triflic anhydride (6.40 mL, 38 mmol) was added
drop wise over 5 min. After complete addition, the resulting
20 reaction mixture was allowed to stir at room temperature for 10 h.
Reaction was monitored by TLC. On completion, the reaction
mixture was filtered and thoroughly washed with 20% DCM-
Methanol solution (20.0 mL) to furnish pure 15.
4-Nitro-N-phenylbenzamide (18e): Yield 90%; Yellow solid; mp:
210-212 C (lit.33 211 C); IR (KBr, cm-1): 3317, 3078, 2924,
1
1651, 1597, 1528, 1350, 1319, 856; H NMR (400 MHz, CDCl3)
1
Yield (9.68 g, 55%); mp 120 °C; H NMR (300 MHz, DMSO-d6)
80 δ 8.38 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 7.84 (s, 1H),
7.67 (d, J = 8.0 Hz, 2H), 7.44 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.4
Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 164.0, 149.3, 140.8,
138.5, 129.1, 128.6, 124.4, 123.2, 120.9.
25 δ 9.27 (dd, J = 6.2, 1.3 Hz, 1H), 8.65 (td, J = 8.1, 1.5 Hz, 1H),
8.40 (dd, J = 8.2, 1.0 Hz, 1H), 8.21 – 8.14 (m, 1H), 7.65 (d, J =
2.0 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H),
6.99 (d, J = 8.7 Hz, 2H), 5.90 (s, 2H), 4.28 (t, J = 6.9 Hz, 2H),
4.02 (t, J = 5.9 Hz, 2H), 3.73 (s, 3H), 2.55 (s, 3H), 2.20 (p, J =
30 6.3 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 159.2, 148.2,
148.1, 146.8, 144.9, 131.0, 130.8, 127.3, 124.8, 122.8, 121.4,
115.4, 64.7, 62.4, 45.2, 35.2, 29.0, 9.5.; ESI-MS (m/z): 502.4 [M-
OTf]+ and 506.3 [M-PF6]+.
4-Nitro-N-p-tolylbenzamide (18f): Yield 95%; Yellow solid; mp:
85 200-203 C (lit.28 201-203 C); IR (KBr, cm-1): 3317, 2924, 2854,
1
1651, 1597, 1528, 1350, 1319, 849; H NMR (300 MHz, CDCl3)
δ 8.33 (d, J = 8.7 Hz, 2H), 8.03 (d, J = 8.6 Hz, 2H), 7.82 (s, 1H),
7.51 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 2.36 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 163.4, 149.7, 140.6, 135.1, 134.6,
90 129.7, 128.2, 124.0, 120.4, 20.9.
Representative procedure for the amide bond formation
35 using 15
N-Benzyl-4-nitro benzamide (18h): Yield 90%; Off-white solid;
mp: 137-138 C (lit.33 136-137 C); IR (KBr, cm-1): 3279, 2924,
1628, 1597, 1535, 1342, 872; 1H NMR (300 MHz, CDCl3) δ 8.17
(d, J = 8.7 Hz, 2H), 7.86 (d, J = 8.7 Hz, 2H), 7.33 – 7.21 (m, 5H),
95 6.62 (s, 1H), 4.56 (d, J = 5.7 Hz, 2H), 13C NMR (75 MHz,
CDCl3) δ 165.3, 149.6, 139.9, 137.4, 128.9, 128.2, 127.9, 127.9,
123.8, 44.4.
A mixture of 4-nitrobenzoic acid (0.030 g, 0.17 mmol) and
imidazolium salt-supported Mukaiyama reagent 15 (0.1404 g,
0.21 mmol) was suspended in THF (5.0 mL) under nitrogen
atmosphere. To this reaction mixture were added triethylamine
40 (0.044 g, 0.43 mmol) and 4-bromoaniline (0.030 g, 0.17 mmol) in
sequence. The resulting reaction mixture was allowed to reflux
for 2 h. After completion of reaction, THF was evaporated to
obtain viscous mixture. Product was extracted with 30% ethyl
acetate: hexane (10 mL × 2) from viscous mixture and washed
45 with 2M HCl solution (5.0 mL  3) and saturated bicarbonate
solution (5.0 mL  3) in order to remove any unreacted amine and
by-products. The organic layer was washed with brine and dried
over sodium sulphate and concentrated in vacuum to get pure
amide 18g in 0.048 g (84%).
N-(4-Bromophenyl)-4-nitrobenzamide (18g): Yield 84%; Yellow
solid; mp: 236-238 C (lit.28 238-240 C); IR (KBr, cm-1): 3296,
100 2839, 1659, 1597, 1529, 1389, 1342, 840, 825; 1H NMR (300
MHz, DMSO-d6) δ 10.68 (s, 1H), 8.42 – 8.33 (m, 2H), 8.22 –
8.14 (m, 2H), 7.80 – 7.72 (m, 2H), 7.61 – 7.52 (m, 2H); 13C NMR
(101 MHz, CDCl3) δ 163.9, 149.2, 140.4, 137.8, 131.4, 129.1,
123.2, 122.4, 116.5.
50 N-Phenylbenzamide (18a): Yield 87%; Pale yellow solid; mp:
157-159 C (lit.29 162-164 oC); IR (KBr, cm-1): 3298, 3075, 1670,
1556, 1450, 728; H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.2
105 N-(4-Methoxyphenyl)benzamide (18i): Yield 95%; Off-white
solid; mp: 154-157 C (lit.29 156-157 C); IR (KBr, cm-1): 3325,
1
1
3047, 2839, 1643, 1612, 1026, 825; H NMR (400 MHz, CDCl3)
Hz, 2H), 7.84 (s, 1H), 7.67 (d, J = 7.7 Hz, 2H), 7.62 – 7.56 (m,
1H), 7.52 (t, J = 7.3 Hz, 2H), 7.41 (t, J = 7.9 Hz, 2H), 7.19 (t, J =
55 7.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 165.7, 137.9, 135.0,
131.8, 129.1, 128.8, 127.0, 124.6, 120.2.
δ 7.89 (dd, J = 7.0, 1.5 Hz, 2H), 7.74 (s, 1H), 7.59 – 7.54 (m,
3H), 7.53 – 7.48 (m, 2H), 6.97 – 6.88 (m, 2H), 3.84 (s, 3H); 13C
110 NMR (101 MHz, CDCl3) δ 165.6, 156.6, 135.0, 131.7, 131.0,
128.7, 127.0, 122.1, 114.2, 55.5.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

View Article Online
DOI: 10.1039/C4RA14856H
Page 7 of 8
RSC Advances
4-Methoxy-N-p-tolylbenzamide (18j): Yield 97%; White solid;
139.4, 130.2, 129.8, 122.8, 121.4, 120.3, 114.9, 105.9, 64.6, 50.9,
45.2, 35.1, 29.1, 9.5.
mp: 186-188 C (lit.34 169-170 C); IR (KBr, cm-1): 3340, 2916,
2839, 1651, 1605, 1520, 841, 818; 1H NMR (400 MHz, CDCl3) δ
7.85 (d, J = 8.8 Hz, 2H), 7.80 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H),
7.18 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H),
2.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.2, 162.4, 135.5,
133.9, 129.5, 128.8, 127.2, 120.3, 113.9, 55.4, 20.9.
Representative procedure for the regeneration of 15 from 20
5
A 10 ml clean oven dried round bottom flask was charged with
60 IL-supported pyridone 20 (168 mg, 0.347 mmol) and phosphorus
oxychloride (95 µL, 1.04 mmol) was added dropwise at room
temperature. The reaction mixture was then heated at 80 ᴼC for 8
h. After completion of the reaction, the volatile impurities were
removed under reduced pressure. To the residue was added dry
65 acetonitrile (5 mL) and sodium triflouromethansulfonate (80 mg).
The reaction mixture was again refluxed for 12 h. After complete
anaion metathesis, the reaction mixture was filtered through a
thin pad of silica to remove solid impurity and the filtrate was
concentrated to get viscous product. The viscous liquid on
3,4,5-Trimethoxy-N-phenylbenzamide (18k): Yield 60%; Yellow
solid; mp: 139-140 C (lit.35 137-139 C); IR (KBr, cm-1): 3249,
10 2924, 1682, 1643, 1589, 841, 756; 1H NMR (400 MHz, CDCl3) δ
8.00 (s, 1H), 7.68 – 7.63 (m, 2H), 7.41 – 7.35 (m, 2H), 7.17-7.15
(m, 1H), 7.08 (s, 2H), 3.91 (s, 3H), 3.90 (s, 6H); 13C NMR (101
MHz, CDCl3) δ 165.6, 153.3, 141.2, 137.9, 130.4, 129.1, 124.6,
120.3, 107.9, 104.5, 60.9, 56.3.
1
15 N-Butylbenzamide (18l): Yield 82%; Colourless liquid; H NMR 70 washing with ethyl acetate (5 mL × 3) resulted into desired
(400 MHz, CDCl3) δ 7.80 – 7.76 (m, 2H), 7.50 – 7.45 (m, 1H),
7.40 (dd, J = 8.6, 7.2 Hz, 2H), 6.48 (s, 1H), 3.44 (dd, J = 13.0, 7.2
Hz, 2H), 1.60 (dt, J = 14.9, 7.5 Hz, 2H), 1.40 (dq, J = 14.5, 7.3
Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
20 167.7, 134.8, 131.2, 128.4, 126.9, 39.8, 31.7, 20.1, 13.7.
reagent 15.
Conclusion
In conclusion, we have developed a shelf stable and efficient
imidazolium salt-supported Mukaiyama reagent. This reagent is
75 utilized for amide bond formation between carboxylic acids and
amines. The significance of this protocol is evading column
chromatography, shorter reaction time and good to excellent
yields of amides. The isolated by-product imidazolium salt-
supported pyridone 19 can be further utilized in regeneration of
80 Mukaiyama reagent.24a
N-Ethylbenzamide (18m): Yield 56%; Off-white solid; mp: 110-
114 C (lit.36 106-108 C); IR (KBr, cm-1): 3294, 2978, 2932,
1666, 1605, 1551; 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J = 7.9
Hz, 2H), 7.23 (dd, J = 15.5, 7.4 Hz, 2H), 7.02 (t, J = 7.3 Hz, 1H),
25 2.32 (q, J = 7.5 Hz, 2H), 1.18 (dd, J = 9.0, 6.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 172.0, 137.9, 128.9, 124.1, 119.7, 30.7, 29.7,
9.6.
Acknowledgements
N-(Benzo[d]thiazol-2-yl)benzamide (18n): Yield 48%; Off-white
solid; mp: 188-191 C (lit.37 188-190 C); IR (KBr, cm-1): 3225,
30 3055, 2962, 1674, 1597, 1551; H NMR (300 MHz, CDCl3) δ
12.66 (s, 1H), 8.22 (d, J = 6.4 Hz, 1H), 8.09 (d, J = 6.5 Hz, 1H),
7.85 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.52 – 7.39 (m, 3H), 7.33
(s, 2H); 13C NMR (75 MHz, CDCl3) δ 165.8, 147.4, 133.1, 131.9,
130.0, 128.9, 128.4, 128.0, 126.2, 124.0, 121.4, 120.4.
The authors sincerely acknowledge the financial support from
Council of Scientific and Industrial Research (CSIR), New Delhi
(01(115)/13/EMR-II) for this research. KP thanks UGC, New
85 Delhi for junior research fellowship (JRF) and MMK and SC
thank CSIR, New Delhi for providing senior research fellowship
(SRF).
1
35 N-Phenylnicotinamide (18o): Yield 63%; off white solid; mp:
112-115 °C; 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.91 (s,
1H), 8.67 (s, 1H), 8.17 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 7.8 Hz,
2H), 7.33 (t, J = 7.7 Hz, 3H), 7.16 (t, J = 7.3 Hz, 1H); 13C NMR
(101 MHz, CDCl3) δ 164.2, 152.1, 147.9, 137.6, 135.6, 130.9,
40 129.0, 125.0, 123.7, 120.7.
Notes
aDepartment of Chemistry, Birla Institute of Technology and Science,
90 Pilani, Rajasthan, India, PIN-333031. Phone: +91-1596-245652. Fax:
+91-1596-244183.
E-mail: anilkumar@pilani.bits-pilani.ac.in.
†Electronic Supplementary Information (ESI) available: [Copies of 1H
and 13C NMR spectra for compounds 13, 14, 15, 18a-p and 19]. See
95 DOI: 10.1039/b000000x/
N-(Quinoline-6-yl)benzamide (18p): Yield 59%; yellow solid;
1
mp: 155-158 °C; H NMR (400 MHz, CDCl3) δ 8.84 (d, J = 2.8
Hz, 1H), 8.50 (s, 1H), 8.47 (s, 1H), 8.128.05 (m, 2H), 7.94 (d, J
= 7.4 Hz, 2H), 7.72 (dd, J = 8.9, 1.9 Hz, 1H), 7.56 (t, J = 7.2 Hz,
45 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.38 (dd, J = 8.2, 4.2 Hz, 1H); 13C
NMR (101 MHz, CDCl3) δ 166.1, 149.5, 145.6, 135.9, 134.6,
133.8, 132.0, 130.1, 128.8, 127.14, 123.5, 121.6, 116.6, 107.4.
References
1. (a) B. Rogge, Y. Itagaki, N. Fishkin, E. Levi, R. Rühl, S.-S. Yi, K.
Nakanishi and U. Hammerling, J. Nat. Prod., 2005, 68, 1536-1540;
(b) S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54,
100
3451-3479; (c) S. Ahmed, J. H. Mondal, N. Behera and D. Das,
Langmuir, 2013, 29, 14274-14283; (d) C. Yu and K. Mosbach, J.
Org. Chem., 1997, 62, 4057-4064.
IL-supported pyridone (19): White solid; mp: 70-72 C; IR (KBr,
1
cm-1): 3140, 2932, 1659, 1582, 1535, 1250, 841, 771; H NMR
2. (a) D. Fattori, M. Porcelloni, P. D’Andrea, R.-M. Catalioto, A.
Ettorre, S. Giuliani, E. Marastoni, S. Mauro, S. Meini, C. Rossi, M.
Altamura and C. A. Maggi, J. Med. Chem., 2010, 53, 4148-4165;
(b) K. Lee, C. W. Park, W.-H. Jung, H. D. Park, S. H. Lee, K. H.
Chung, S. K. Park, O. H. Kwon, M. Kang, D.-H. Park, S. K. Lee, E.
E. Kim, S. K. Yoon and A. Kim, J. Med. Chem., 2003, 46, 3612-
3622.
50 (400 MHz, DMSO-d6) δ 7.80 – 7.75 (m, 1H), 7.66 (d, J = 2.0 Hz,
1H), 7.61 (d, J = 2.0 Hz, 1H), 7.40 (m, 1H), 7.27 (d, J = 8.6 Hz,
2H), 6.88 (d, J = 8.6 Hz, 2H), 6.40 (d, J = 9.1 Hz, 1H), 6.23 (t, J
= 7.2 Hz, 1H), 5.02 (s, 2H), 4.28 (t, J = 6.8 Hz, 2H), 3.97 (t, J =
5.9 Hz, 2H), 3.73 (s, 3H), 3.34 (s, 3H), 2.19 (p, J = 6.3 Hz, 2H);
55 13C NMR (101 MHz, DMSO-d6) δ 161.8, 158.0, 144.9, 140.4,
105
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

View Article Online
RSC Advances
DOI: 10.1039/C4RA14P85a6gHe 8 of 8
3. F. Damkaci and P. DeShong, J. Am. Chem. Soc., 2003, 125, 4408-
34. Y. Wu, S. Wang, L. Zhang, G. Yang, X. Zhu, Z. Zhou, H. Zhu and
S. Wu, Eur. J. Org. Chem., 2010, 2010, 326-332.
35. J. Pharm. Pharmacol., 1960, 12, 82-86.
36. L.-F. Liu, H. Liu, H.-J. Pi, S. Yang, M. Yao, W. Du and W.-P.
Deng, Synth. Commun., 2011, 41, 553-560.
37. D. Fajkusova and P. Pazdera, Synthesis, 2008, 2008, 1297-1305.
4409.
75
80
4. M. P. Cassidy, J. Raushel and V. V. Fokin, Angew. Chem. Int. Ed.,
2006, 45, 3154-3157.
5 5.
T. Ribelin, C. E. Katz, D. G. English, S. Smith, A. K. Manukyan, V.
W. Day, B. Neuenswander, J. L. Poutsma and J. Aubé, Angew.
Chem. Int. Ed., 2008, 47, 6233-6235.
6. M. Hashimoto, Y. Obora, S. Sakaguchi and Y. Ishii, J. Org. Chem.,
2008, 73, 2894-2897.
10 7.
(a) T. M. U. Ton, C. Tejo, S. Tania, J. W. W. Chang and P. W. H.
Chan, J. Org. Chem., 2011, 76, 4894-4904; (b) V. Prasad, R. R.
Kale, B. B. Mishra, D. Kumar and V. K. Tiwari, Org. Lett., 2012,
14, 2936-2939; (c) S. Muthaiah, S. C. Ghosh, J.-E. Jee, C. Chen, J.
Zhang and S. H. Hong, J. Org. Chem., 2010, 75, 3002-3006; (d) S.
C. Ghosh, J. S. Y. Ngiam, C. L. L. Chai, A. M. Seayad, T. T. Dang
and A. Chen, Adv. Synth. Catal., 2012, 354, 1407-1412.
8. J. Xiao, G. Yuan, W. Huang, A. S. C. Chan and K. L. D. Lee, J.
Org. Chem., 2000, 65, 5506-5513.
15
20
9. B. Zacharie, T. P. Connolly and C. L. Penney, J. Org. Chem., 1995,
60, 7072-7074.
10. R. M. Lanigan, P. Starkov and T. D. Sheppard, J. Org. Chem., 2013,
78, 4512-4523.
11. V. K. Das, R. R. Devi and A. J. Thakur, Appl. Catal., A, 2013, 456,
118-125.
25 12. (a) G. Quéléver, S. Burlet, C. Garino, N. Pietrancosta, Y. Laras and
J.-L. Kraus, J. Comb. Chem., 2004, 6, 695-698; (b) C. A. G. N.
Montalbetti and V. Falque, Tetrahedron, 2005, 61, 10827-10852.
13. T. Mukaiyama, M. Usui, E. Shimada and K. Saigo, Chem. Lett.,
1975, 4, 1045-1048.
30 14. E. Bald, K. Saigo and T. Mukaiyama, Chem. Lett., 1975, 4, 1163-
1166.
15. R. L. Funk, M. M. Abelman and K. M. Jellison, Synlett, 1989, 1989,
36-37.
16. T. Mukaiyama, M. Usui and K. Saigo, Chem. Lett., 1976, 5, 49-50.
35 17. H. Huang, N. Iwasawa and T. Mukaiyama, Chem. Lett., 1984, 13,
1465-1466.
18. H. L. Bradlow and C. A. Vanderwerf, J. Org. Chem., 1951, 16,
1143-1152.
19. P. Li and J.-C. Xu, Tetrahedron, 2000, 56, 8119-8131.
40 20. E. Convers, H. Tye and M. Whittaker, Tetrahedron Lett., 2004, 45,
3401-3404.
21. D. Donati, C. Morelli, A. Porcheddu and M. Taddei, J. Org. Chem.,
2004, 69, 9316-9318.
22. S. Crosignani, J. Gonzalez and D. Swinnen, Org. Lett., 2004, 6,
45
50
55
60
65
4579-4582.
23. T. Nagashima, Y. Lu, M. J. Petro and W. Zhang, Tetrahedron Lett.,
2005, 46, 6585-6588.
24. (a) Y. Sugiyama, Y. Kurata, Y. Kunda, A. Miyazaki, J. Matsui, S.
Nakamura, H. Hamamoto, T. Shioiri and M. Matsugi, Tetrahedron,
2012, 68, 3885-3892; (b) M. Matsugi, S. Nakamura, Y. Kunda, Y.
Sugiyama and T. Shioiri, Tetrahedron Lett., 2010, 51, 133-135.
25. R. Berger, G. Resnati, P. Metrangolo, E. Weber and J. Hulliger,
Chem. Soc. Rev., 2011, 40, 3496-3508.
26. (a) N. V. Plechkova and K. R. Seddon, Chem. Soc. Rev., 2008, 37,
123-150; (b) M. Pucheault and M. Vaultier, in Ionic Liquids, ed. B.
Kirchner, Springer Berlin Heidelberg, 2010, vol. 290, pp. 83-126.
27. (a) M. K. Muthayala, B. S. Chhikara, K. Parang and A. Kumar, ACS
Comb. Sci., 2011, 14, 60-65; (b) M. K. Muthayala and A. Kumar,
ACS Comb. Sci., 2011, 14, 5-9; (c) M. K. Muthyala, S. Choudhary
and A. Kumar, J. Org. Chem., 2012, 77, 8787-8791; (d) M. Kumar
Muthyala, S. Choudhary, K. Pandey, G. M. Shelke, M. Jha and A.
Kumar, Eur. J. Org. Chem., 2014, 2014, 2365-2370.
28. J. Gao and G.-W. Wang, J. Org. Chem., 2008, 73, 2955-2958.
29. Z. Zhang, Y. Yu and L. S. Liebeskind, Org. Lett., 2008, 10, 3005-
3008.
30. V. K. Haridasan, A. Ajayaghosh and V. N. R. Pillai, J. Org. Chem.,
1987, 52, 2662-2665.
31. L. Kumar, T. Mahajan and D. D. Agarwal, Green Chem., 2011, 13,
2187-2196.
70 32. C. L. Allen, S. Davulcu and J. M. J. Williams, Org. Lett., 2010, 12,
5096-5099.
33. A. R. Katritzky, C. Cai and S. K. Singh, J. Org. Chem., 2006, 71,
3375-3380.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7