Direct and facile synthesis of primary amides from carboxylic acids via acyl isocyanate intermediates using mukaiyama reagent

Article abstract of DOI:10.2174/1570178615666180212152643

A very simple and efficient procedure for the preparation of primary amides is described from carboxylic acids using Mukaiyama reagent/KNCO in aqueous acetonitrile. Availability of the reagents, simplicity, and easy workup of the reaction crude make this method attractive for organic chemists.

Full text of DOI:10.2174/1570178615666180212152643

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Letters in Organic Chemistry, 2018, 15, 801-804
RESEARCH ARTICLE
ISSN: 1570-1786
eISSN: 1875-6255
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Direct and Facile Synthesis of Primary Amides from Carboxylic Acids via
Acyl Isocyanate Intermediates Using Mukaiyama Reagent
BENTHAM
S
CIENCE
Roya Azadi* and Zahra Motamedpoor
Chemistry Department, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
Abstract: A very simple and efficient procedure for the preparation of primary amides is described
from carboxylic acids using Mukaiyama reagent/KNCO in aqueous acetonitrile. Availability of the
reagents, simplicity, and easy workup of the reaction crude make this method attractive for organic
chemists.
A R T I C L E H I S T O R Y
Received: June 28, 2017
Revised: December 20, 2017
Accepted: January 21, 2018
DOI:
10.2174/1570178615666180212152643
Keywords: 2-Chloro-1-methylpyridinium iodide, acyl isocyanate, amide, carboxylic acid, mukaiyama reagent.
1. INTRODUCTION
acids via acyl isocyanate intermediates using Mukaiyama
reagent.
In synthetic chemistry, primary amides are characterized
by a functional group allowing their easy transformation into
nitriles, primary amines, and heterocycles. The preparation
of primary amides from the corresponding carboxylic acids
is an important and major transformation in organic synthe-
sis [1]. This conversion requires preactivation of the free
carboxylic acid with stoichiometric activating reagents such
as N,N-dicyclohexylcarbodiimide [2]. Other coupling rea-
gents that have been used for this purpose include ammo-
nium bicarbonate or ammonium carbamate [3], N-acylben-
zotriazoles [4], ammonium chloride in the presence of pep-
tide synthesis coupling agents [5], activated phosphate [6],
PPh3/N-halosuccinimide [7], PPh3/trichloroacetonitrile [8],
ArB(OH)2 [9], imidazole/urea under microwave irradiation
[10], and borate esters [11]. Thus, the development of
greener and more eꢀcient methods to prepare primary am-
ides from readily available carboxylic acids is still a big
challenge for synthetic organic chemistry.
2. RESULTS AND DISCUSSION
In a continuation of our studies on the use of the Mukai-
yama reagent in organic transformations [17], we became
interested in evaluating it as a reagent for the conversion of
carboxylic acids into corresponding primary amides via acyl
isocyanate intermediates (Scheme 1).
As a model reaction for our studies, we chose benzoic
acid as the substrate, and its reaction with Mukaiyama rea-
gent, potassium isocyanate and pyridine as a base in aqueous
acetonitrile was studied in detail. In our preliminary investi-
gations, we applied a 2:3:1:2 molar ratio of Mukaiyama rea-
gent / KNCO / benzoic acid / pyridine in aqueous acetonitrile
at reflux conditions. The results showed nearly complete
conversion of benzoic acid to benzamide.
Instead of pyridine, we used other bases such as 4-
dimethylaminopyridine (DMAP), triethylamine and imida-
zole. According to the results shown in Table 1, the best
conversion of benzoic acid to benzamide was observed in the
presence of pyridine.
The Mukaiyama reagent (2-chloro-1-methylpyridinium
iodide) is one of the most useful reagents in organic synthesis
and there are many reports of its use for the conversion of
carboxylic acids into esters [12], amides [13], lactones [14],
lactams [15], and ketenes [16]. There have been some reports
for the preparation of secondary and tertiary amides using
Mukaiyama reagent [13]. However, there is no report avail-
able for direct synthesis of primary amides from carboxylic
acids using this reagent. In this communication, we report
direct and facile synthesis of primary amides from carboxylic
To investigate the generality and the scope of this
method, the reaction was examined with various structurally
diverse carboxylic acids. As it is clear from Table 2, the re-
actions proceeded cleanly and the desired carboxamides
were obtained in good yields. In the case of substituted ben-
zoic acids, as expected, the presence of electron-withdrawing
groups on the aromatic ring accelerated the reactions and
increased their yields (Table 2, entries 5-8).
*Address correspondence to this author at the Chemistry Department, Fac-
ulty of Science, Shahid Chamran University of Ahvaz, P.O. Box: 61357-
43169, Ahvaz, Iran; Tel/Fax: +98-061-33331042; +98-061-33331042;
E-mail: razadi@scu.ac.ir
Based on our finding, we suggest that this reaction may
proceed firstly by the formation of a pyridinium carboxylate
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802 Letters in Organic Chemistry, 2018, Vol. 15, No. 9
Azadi and Motamedpoor
O
O
O
Mukaiyama reagent, pyridine
OH
KNCO, CH3CN, reflux
H2O
R
N
R
C
R
NH2
O
Scheme (1). Synthesis of primary amides from carboxylic acids.
Table 1. Optimization of base for conversion of benzoic acid to benzamide.
Entry
Base
Time (h)
Yield (%)a
1
2
3
4
Et3N
8
5
7
5
50
70
75
89
DMAP
Imidazole
Pyridine
aIsolated yields.
Table 2. Preparation of primary amides from carboxylic acids using Mukaiyama reagent/KNCO.
Entry
Product
m.p. (ºC) (Lit) [Refs.]
Time (h)
Yields (%)a
O
1
127-129 (127) [18]
5
89
NH2
Cl
O
2
3
142-144 (144) [18]
176-178 (179) [18]
5
4
85
80
NH2
O
NH2
NH2
Cl
Br
O
4
5
6
190-193 (191) [18]
174-178 (174) [18]
140-143 (140) [18]
4
3
3
75
80
85
NO2
O
NH2
O
O
O2N
NH2
NH2
7
200-202 (200) [18]
183-185 (187) [18]
3
85
89
O2N
O2N
O
NH2
8
1.5
NO2
(Table 2) Contd….

Direct and Facile Synthesis of Primary Amides from Carboxylic Acids
Letters in Organic Chemistry, 2018, Vol. 15, No. 9 803
Entry
Product
m.p. (ºC) (Lit) [Refs.]
Time (h)
Yields (%)a
O
NH2
O
9
159-162 (160) [18]
7
56
H3C
NH2
10
11
195-200 (199-201) [19]
6
65
H3CO
NH2
154-156 (152) [18]
128-129 (128) [18]
6
3
80
85
O
O
12
NH2
N
aIsolated yields.
N
CH3
Cl
I-
O
N
O
O
+
N
CH3
O
R
I-
N
N
Cl-
R
OH
R
O-
H+
H+
(I)
KNCO
N
O
+
R
N
O
C
CH3
O
H2O
O
R
NH2
Scheme (2). The suggested mechanism of conversion of carboxylic acid to primary amide using Mukaiyama reagent.
3.1. Preparation of Benzamide from Benzoic Acid Using
Mukaiyama Reagent as Typical Procedure
salt. In the second step, nucleophilic attack of carboxylate
anion on the C2 of Mukaiyama reagent produces intermedi-
ate I, in turn the intermediate reacts directly with isocyanate
anion to give acyl isocyanates and N-methyl-2-pyridinone.
Acyl isocyanates in the presence of water could produce the
corresponding primary amides (Scheme 2).
A suspension of Mukaiyama reagent (0.511 g, 2 mmol),
potassium isocyanate (0.242 g, 3 mmol), benzoic acid (0.122
g, 1 mmol) and pyridine (0.16 g, 2 mmol) in 1% aqueous
acetonitrile (7 mL) was magnetically stirred at reflux condi-
tions. After completion of the reaction (10 min) and evapora-
tion of acetonitrile, aqueous HCl (5%, 10 mL) was added
and the organic layer extracted with CH2Cl2 (3 × 5 mL). The
combined organic extracts were dried over Na2SO4, filtered,
and concentrated. Purification of the crude product by short
column chromatography on silica gel (hexane/EtOAc 5:3)
provided benzamide (0.107 g, 88%) as a white solid: mp
127-129oC (lit. [18] 127oC); 1H NMR (DMSO-d6, 250 MHz)
8.11 (brs, 2H), 7.65 (d, J = 8.0 Hz, 2H, H-2',6'), 7.32 (t, J =
7.8 Hz, 2H, H-3',5'), 7.05 (t, J = 7.4 Hz, 1H, H-4').
3. EXPERIMENTAL SECTION
Products were characterized by comparison of their spec-
troscopic data (1H and 13C NMR, IR) with those reported in
the literature. All yields refer to isolated products. The FT-IR
spectra of neat samples between NaCl disks were obtained
on a BOMEM 450 instrument. The high-field NMR spectra
were obtained on a Bruker 400 MHz Avance ultrashield in-
1
strument. H chemical shifts are quoted relative to solvent
resonance(s) as internal standard.

804 Letters in Organic Chemistry, 2018, Vol. 15, No. 9
Azadi and Motamedpoor
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In conclusion, we have disclosed a new procedure for
obtaining primary amides from the corresponding carboxylic
acids via acyl isocyanate intermediates using Mukaiyama
reagent/KNCO in aqueous acetonitrile. Among the attractive
features of this protocol, the use of inexpensive and com-
mercially available reagent, simplicity, easy workup, and
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ACKNOWLEDGEMENTS
We thank Shahid Chamran University of Ahvaz Research
Council, Ahvaz, for financial support of this investigation
(grant 1396).
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