Microwave assisted, Ca(II)-catalyzed Ritter reaction for the green synthesis of amides

Article abstract of DOI:10.1016/j.tetlet.2014.06.068

An efficient solvent-free synthesis of amides by Ca(II) catalyzed Ritter reaction has been reported under microwave irradiation. This green protocol tolerates the substrate diversity and delivers the high yielding amides with minimal loading of inexpensive and more abundant Ca(II) catalyst.

Full text of DOI:10.1016/j.tetlet.2014.06.068

Tetrahedron Letters xxx (2014) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted, Ca(II)-catalyzed Ritter reaction for the green
synthesis of amides
⇑
Srinivasarao Yaragorla , Garima Singh, Pyare Lal Saini, M. Kesava Reddy
Department of Chemistry, Central University of Rajasthan, Bandarsindri, NH-8, Ajmer-distt., Rajasthan 305817, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient solvent-free synthesis of amides by Ca(II) catalyzed Ritter reaction has been reported under
microwave irradiation. This green protocol tolerates the substrate diversity and delivers the high yielding
amides with minimal loading of inexpensive and more abundant Ca(II) catalyst.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 28 May 2014
Revised 14 June 2014
Accepted 17 June 2014
Available online xxxx
Keywords:
Ritter reaction
Microwave irradiation
Ca(II) catalysis
Atom economy
Green synthesis
Amide bond formation is one of the very important tools in the
organic synthesis and subsists in the nature (living and non-living
organisms) in many forms like peptides, proteins, polymers, mate-
rial, and in many of the natural and synthetic molecules.1 Due to its
potential importance,2 many synthetic methodologies have been
discovered for the amide bond formation.3 Most of the times, it
is formed from the reaction between carboxylic acids or acid chlo-
rides or acid anhydrides and the amine functionality under the
influence of several catalysts and various conditions. Some meth-
ods were also reported by the condensation of aldehydes with
hydroxylamine to form the primary amides.4 Another very impor-
tant method for the amide (peptide) bond formation is by the reac-
tion between alcohols and nitriles, which is well known by the
name ‘Ritter reaction’.5 The first report of Ritter reaction published
in the year 1948, involved the condensation of the alcohols, or suit-
able alkenes with nitriles in the presence of stoichiometric amount
of sulfuric acid and glacial acetic acid.5
Due to the excess use of corrosive sulfuric acid in the classical
Ritter reaction it was limited to the substrates with acid tolerant
functionalities only. Due to this major drawback, scientists around
the globe realized the importance to improve this methodology
Table 1
Optimization of the reaction conditions for the Ca(II) catalyzed synthesis of amides by
Ritter reaction
Entry Catalyst-Ca(OTf)2
(mol %)
Additive-Bu4NPF6
(mol %)
Conditions
Yield (3a)
(%)
1
2
3
10
10
10
10
10
10
rt, 24 h
Trace
92
93
120 °C, 8 h
MW, 120 °C,
15 min
4
5
6
—
10
5
10
—
5
MW, 120 °C,
15 min
MW, 120 °C,
15 min
MW, 120 °C,
15 min
No
reaction
05
93
N
CH3
OH
CH3 O
Ca(OTf)2,
Bu4NPF6
Bold values show the best result/optimum condition for the transformation.
N
H
H2O, conditions
N
CH3
OH
CH3 O
Ca(OTf)2 (5 mol%)
Bu4NPF6 (5 mol%)
N
H
1a
2a
3a
H2O, MW,
Scheme 1.
120 oC, 15 min
1a
2a
3a
⇑
Corresponding author. Tel.: +91 463 238535; fax: +91 463 238722.
E-mail address: Srinivasarao@curaj.ac.in (S. Yaragorla).
Scheme 2. Optimum conditions.
http://dx.doi.org/10.1016/j.tetlet.2014.06.068
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
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S. Yaragorla et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 2
List of the amides synthesized by Microwave assisted, Ca(II)-catalyzed Ritter reactiona
Ca(OTf)2 (5 mol%)
R3
O
R3
R2
R1
Bu4NPF6 (5 mol%)
R2
R1
OH
N
R
N
H
R
H2O, MW, 120 oC, 15 min
1
2
3
CH3
O
CH3
O
CH3
O
CH3 O
N
H
N
H
N
H
N
H
CH3
CH3
Ph
NO2
3b
3c
Yield: 76%
3d
Yield: 95%
3a
Yield: 93%
Yield: 90%
Ph
Ph
CH3
O
O
O
O
CH3
O
N
H
N
Ph
N
H
CH3
N
H
N
H
Bn
H
3f
Yield: 75%
3g
Yield: 96%
3h
Yield: 94%
3ib
Yield: 90%
3e
Yield: 94%
Ph
Ph
O
O
CH3
O
CH3
O
CH3 O
H3C
CH3 H3C
H3C
CH3 H3C
H3C
H3C
N
H
Ph
N
H
N
H
N
H
N
H
Bn
H3CO
H3CO
3jb
Yield: 91%
3k
Yield: 86%
3l
3m
Yield: 90%
3n
Yield: 88%
Yield: 94%
CH3
O
CH3
O
Ph
O
Ph
O
Ph
O
H3C
H3C
H3C
H3C
Ph
Ph
Ph
CH3 Ph
Ph
Ph
N
H
N
H
N
H
N
H
N
H
CH3
3o
Yield: 92%
3p
Yield: 90%
3q
Yield: 70%
3r
3s
Yield: 78%
Yield: 65%
O
O
O
O
N
H
N
H
N
CH3
N
H
H
CH3
3tc
Yield: 90%
3uc
Yield: 92%
3vc
Yield: 95%
3wc
Yield: 88%
O
O
O
O
N
H
N
H
N
H
N
H
CH3
Cl
CH3
3x
3y
3z
Yield: 90%
3aa
Yield: 75%
Yield: 78%
Yield: 82%
a
b
c
Conditions are 1 equiv of alcohol, 2 equiv of nitrile.
Reaction required to be run at 150 °C.
Reaction required to be run at 140 °C for 25 min.
and hence by the completion of six and half decades of the discov-
ery of Ritter reaction, several publications have appeared with the
betterment in terms of milder reaction conditions, better catalysts,
substrate diversities, increased yields etc. To list some of them, acid
catalyzed methods,6 solid supported-acid catalysts,6d triflamides,7
metal complexes,8 Nafion-H9 catalyzed methods, and many oth-
ers.10 Nevertheless, some of these methods still have the limita-
tions in terms of high amounts of catalyst loading, longer
reaction times, and lesser scope for the substrate diversity and also
in terms of poor yields. Very recently, the more abundant and envi-
ronmentally benign alkaline earth metal triflate-Ca(OTf)2 has been
proved to be inexpensive and alternative to the transition metal
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S. Yaragorla et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
catalysis.11 It has been efficiently utilized in Luche-type reduc-
tion.12a Many other Ca(II) catalyzed reactions like Friedel–Crafts
alkylation of alcohols with electron rich aromatic compounds,12b
and intramolecular hydroalkoxylation,12c have been reported. As
part of our research aimed toward the development of environ-
mentally benign synthetic transformations,13 herein we report
the Ca(II) catalyzed, microwave assisted solvent-free synthesis of
primary amides by Ritter reaction.
To check the generality of this methodology we extended this
method to tertiary alcohols, tert-butanol (1d), 1-adamantylalcohol
(1e), and triphenylmethanol (1f). All these three 3°-alcohols also
reacted well under the similar conditions with the above nitriles
and yielded the respective amides (Table 2, entries 3l–3w). But
in case of amides 3t–3w (Table 2), we realized that the reaction
should be irradiated at 140 °C, for 25 min. Encouraged by these
results we further checked the scope of this methodology with pri-
mary alcohols like benzyl alcohol (1g) and 4-chlorobenzyl alcohol
(1h) with acetonitrile (2b), benzonitrile (2a), and 4-methylbenzo-
nitrile (2c). Under similar microwave irradiation conditions we
obtained the corresponding benzamides (3x, 3y, 3z, and 3aa,
Table 2) in excellent yields.
Our initial studies for the synthesis of amides by Ca(II)-cata-
lyzed Ritter reaction commenced with the optimization of reaction
conditions for the model reaction (Scheme 1) which are shown in
Table 1. As shown in Table 1, 1-phenylethanol (2°-alcohol, 1a)
and benzonitrile (2a) were treated with water, Ca(OTf)2, and Bu4-
NPF6 (additive) at various conditions to obtain N-(1-phenyl-
ethyl)benzamide (3a). The following points emerged from
Table 1—that microwave irradiation is faster (entries 3–6) and
saves lot of time when compared to conventional heating (entry
2, Table 1), it is very clear that both catalyst and the additive are
compulsory for the reaction (Table 1, entries 4 and 5). Overall,
the optimum conditions are shown in entry 6, which specifies that
5 mol % of each catalyst and the additive under microwave irradia-
tion for 15 min provide the desired amide in 93% yield (Scheme 2).
After discovering the suitable conditions, we found that the
alcohol 1a was also reacted with (aliphatic) acetonitrile (2b) under
similar conditions to give N-(1-phenylethyl)acetamide (3d,16
Table 2) in 95% yield. Encouraged by these results, we extended
this methodology to the other 2°-alcohols, diphenylmethanol
(1b) and (4-methoxyphenyl)(phenyl)methanol (1c) with benzoni-
trile (2a) and obtained the respective amides in high yields (Table 2,
entries, 3a, 3f, and 3i). These 2°-alcohols were also treated with dif-
ferent aliphatic and aromatic nitriles like, acetonitrile (2b), 4-
methylbenzonitrile (2c), acrylonitrile (2d), 4-nitrobenzonitrile
(2e), and benzylnitrile (2f) and obtained the corresponding amides,
that too in good yields (Table 2, entries 3d, 3b, 3e, 3c, 3f, 3h, 3g, 3i,
3j, and 3k). In case of amides 3i and 3g (Table 2), we found that the
reactants (alcohols) are giving corresponding ethers as the major
products at 120 °C, but when the reaction temperature is increased
to 150 °C, we observed the formation of the desired products only.
This could be due to the fact that at high temperatures ethers
revert back to the carbocation intermediate,14 which further reacts
with nucleophilic nitriles to give the respective amides as shown in
Scheme 3.
As shown in Scheme 3, the combination of Ca(OTf)2 and Bu4-
NPF6 activates the hydroxyl group.11 The active catalyst is regener-
ated by the protonation of hydroxide at Ca2+
.
In summary, we have developed a solvent-free, green synthetic
protocol for Ca(II) catalyzed Ritter reaction to synthesize various
primary amides from alcohols and nitriles. We believe that our
methodology enables the synthesis of new libraries of amides
(NCE’s) which may find their importance in medicinal chemistry
due to the simpler and environmentally benign reaction conditions
and more abundance of the inexpensive catalyst.
Acknowledgments
S.Y. and G.S. thank the Central University of Rajasthan for the
support and fellowship, respectively. P.S. thanks UGC for the fel-
lowship and M.K.R. thanks the Chemistry department for support.
We dedicate this work to Dr. S. Chandrasekhar on the occasion of
his 50th birthday.
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Ca(OTf)2 (5 mol%)
O
Bu4NPF6 (5 mol%)
OH
N
R
N
H
R
H2O, MW, 120 oC, 10 min
1d
2
3
-
- Ca2+ (OTf)2
PF6
PF6
N
R
-OH-
H O
H+
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N
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H2O
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N
N
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N
R
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H
OH2
H
Scheme 3. Plausible mechanism for the Ca(II) catalyzed atom-economy in the
synthesis of amides by Ritter reaction.
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16. General experimental procedure:
A mixture of alcohol (1.0 equiv), nitrile
(2.0 equiv), water (2.0 equiv), Ca(OTf)2 (5 mol %), and additive-Bu4NPF6
(5 mol %) was subjected to microwave irradiation for 15 min at 120 °C. After
the completion of the reaction (monitored by TLC), the reaction mixture was
diluted with minimum amount of water and extracted into ethylacetate,
combined organic layers were dried over anhydrous Na2SO4, solvent was
removed under reduced pressure, and the crude reaction mass was purified by
column chromatography on silica gel using ethylacetate and hexanes as the
eluents to yield the amides. Spectral data of all the compounds were in
agreement with the reported data. Spectral data of representative
compounds:10,15 3h. 1H NMR (400 MHz, CDCl3): d 7.36–7.22 (m, 10H), 6.88
(br s, 1H), 6.23 (d, J = 8 MHz, 1H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3): d
169.5, 141.6 (2C), 129.0 (4C), 128.6 (4C), 127.1 (2C), 56.9, 23.1; IR (KBr): mmax
3262, 3050, 2924, 1644, 1547, 1494, 1372, 1244 cmÀ1; mp: 144–146 °C; 3d-1H
NMR (400 MHz, CDCl3): d 7.38–7.23 (m, 5H), 6.15 (br s, 1H), 5.12 (m, 1H), 1.98
(s, 3H), 1.44 (d, 3H); 13C NMR (100 MHz, CDCl3): d 169.2, 143.2, 128.5 (2C),
13. (a) Yaragorla, S.; Kumar, G. S. Indian J. Chem., Sect. B 2014 (3/4OC1661); (b)
Yaragorla, S.; Sudhakar, A.; Kiranmai, N. Indian J. Chem., Sect. B 2014 (3/
4OC1688).
127.2 (2C), 126.1, 48.7, 23.2, 21.6; IR (KBr): mmax 3273, 3065, 2980, 1651, 1547,
1449, 1378, 1287 cmÀ1; mp: 72–74 °C.
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