Nafion-catalyzed microwave-assisted Ritter reaction: an atom-economic solvent-free synthesis of amides

Article abstract of DOI:10.1016/j.tetlet.2008.02.009

An atom-economic solvent-free synthesis of amides by the Ritter reaction of alcohols and nitriles under microwave irradiation is reported. This green protocol is catalyzed by solid-supported NafionNR50 with improved efficiency and reduced waste production.

Full text of DOI:10.1016/j.tetlet.2008.02.009

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2661–2664
NafionÒ-catalyzed microwave-assisted Ritter reaction:
an atom-economic solvent-free synthesis of amides
Vivek Polshettiwar, Rajender S. Varma *
Sustainable Technology Division, National Risk Management Research Laboratory, US Environmental Protection Agency,
26 W. Martin Luther King Dr., MS 443, Cincinnati, OH 45268, USA
Received 28 January 2008; accepted 4 February 2008
Available online 8 February 2008
Abstract
An atom-economic solvent-free synthesis of amides by the Ritter reaction of alcohols and nitriles under microwave irradiation is
reported. This green protocol is catalyzed by solid-supported NafionÒNR50 with improved efficiency and reduced waste production.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Ritter reaction; Amides; NafionÒNR50; Solvent-free reaction; Microwave irradiation
Amides are common moieties in naturally occurring
substances like peptides and proteins and are also found
in various synthetic materials.1,2 This makes the amide
functionality an important building block in synthetic
chemistry and many methods for its synthesis were
reported in the literature.1 In general, amides are formed
by the condensation of carboxylic acid and amines, using
various coupling agents.3 Although good results were
obtained using this protocol, the reaction conditions were
very harsh. In 1948, Ritter reported the efficient synthesis
of amide by the reaction of alkenes with nitriles,4 in which
alcohols can also be used instead of alkenes.5,6 In recent
years, several alternative methodologies have been devel-
oped for Ritter reaction using sulfuric and other acid cata-
lysts,7–10 metal complexes,11 trifluoromethanesulfonic
anhydride,12 and boron trifluoride etherate.13 The main
disadvantages of these methods are the use of toxic cata-
lysts or corrosive acids.
cient catalyst for the Ritter reaction.15 This is an excellent
protocol in terms of catalyst reusability and product yield;
however, harsh reaction conditions, longer reaction time,
and the use of excessive nitrile make this method non-sus-
tainable. In view of the emerging interest in microwave
chemistry,16,17 and in keeping with our emphasis on the
development of green synthetic methods,17,18 we revisited
this protocol. The primary objective of this project was
to find an economical and greener method for the conver-
sion of nitrile into the corresponding N-monosubstituted
amide, and herein we report NafionÒNR5018a,19-catalyzed
atom-economic solvent-free Ritter reaction under micro-
wave (MW) irradiation (Scheme 1).
After screening a range of MW power, reaction temper-
ature, and time, and exploring the scope of various sol-
vents, we found that the solid-supported NafionÒNR50
was the most efficient catalyst for Ritter protocol at
130 °C under MW irradiation (200 W), in the absence of
any solvent. The efficiency of this protocol was then studied
for the synthesis of various amides, and the results are
summarized in Table 1.
Use of solid-supported acids, such as silica-sulfuric acid,
P2O5/SiO2,10 and Cs2.5H0.5PW12O40, was also made for this
reaction;14 however, reuse of these catalysts is not possible.
Olah et al. in 1987 reported the use of Nafion-H as an effi-
Various alcohols reacted efficiently with nitriles to afford
the corresponding amides in good yields (entries 1–15). The
generality and scope of this protocol was evaluated for a
wide range of alcohols, bearing both electron withdrawing
*
Corresponding author. Tel.: +1 513 487 2701; fax: +1 513 569 7677.
E-mail address: varma.rajender@epa.gov (R. S. Varma).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.009

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V. Polshettiwar, R. S. Varma / Tetrahedron Letters 49 (2008) 2661–2664
O
Nafion®NR50
N
R2
R1
C
N
H
MW, 130 ºC
R1
R2
OH
R1 = H, OMe, Cl
R2 = H, Me, OMe, Cl, naphthyl,
adamantyl etc
Scheme 1. NafionÒNR50-catalyzed solvent-free Ritter reaction under MW irradiation.
Table 1
NafionÒNR50-catalyzed Ritter synthesis of amides under MW irradiationa
Entry
1
Nitrile
Alcohol
Product
Yieldb (%)
92
O
CN
CN
CN
CN
CH2OH
N
H
O
O
O
2
3
4
88
86
86
N
H
Me
Cl
CH2OH
Me
N
H
CH2OH
Cl
N
H
MeO
CH2OH
OMe
O
O
O
5
82
CN
N
H
CH2OH
6
7
90
72
CN
CN
OH
N
H
OH
N
H
O
8
88
N
H
Cl
CN
CH2OH
Cl
O
O
9
86
85
N
H
Cl
Cl
CN
CN
Me
Cl
CH2OH
Cl
Cl
Me
10
N
H
CH2OH
Cl

V. Polshettiwar, R. S. Varma / Tetrahedron Letters 49 (2008) 2661–2664
2663
Table 1 (continued)
Entry
Nitrile
Alcohol
Product
Yieldb (%)
O
O
11
12
13
14
89
70
88
Cl
CN
CN
OH
N
H
Cl
OH
Cl
N
H
Cl
O
N
H
MeO
CN
CH2OH
MeO
O
O
85
86
MeO
MeO
CN
CN
Me
Cl
CH2OH
N
H
MeO
MeO
Me
Cl
15
N
H
CH2OH
a
Reaction temperature 130 °C, time 30 min, and no solvent.
GC yields.
b
(entries 3, 4, 10, 15) and donating (entries 2, 9, 14) substit-
uents, and a variety of aryl nitriles. In all the cases, the Rit-
ter reaction proceeded efficiently and yielded the desired
amides in good to excellent yields, under solvent-free con-
ditions. It is noteworthy to mention that these reactions
proceeded efficiently without any solvent, even though they
involved the use of heterogeneous solid-supported catalyst.
This is due to the selective absorption of microwaves by
reactants, polar intermediates, and Nafion, which acceler-
ated the reaction rate.20 These reactions also get completed
under conventional heating in an oil bath in a sealed tube
but require an extended period of time, 6–8 h.
reactions were conducted under similar conditions (130 °C/
30 min) without any solvent. After the completion of the
first reaction to afford the corresponding amide, the cata-
lyst was recovered by forceps, washed with acetone, and
dried. The catalyst was then used in a new reaction with
fresh reactants under the same conditions; NafionÒNR50
could be used at least 6 times without any change in
activity.
In conclusion, we have demonstrated an atom-economic
Ritter approach for the synthesis of amides, which may
find useful application in sustainable synthetic chemistry.
Also, the use of solid-supported, relatively low toxic, and
inexpensive NafionÒNR50 as a catalyst and the solvent-
free reaction conditions are additional eco-friendly attri-
butes of this synthetic protocol.
Experimental: The alcohol (1 mmol), nitrile (1.1 mmol),
and NafionÒNR50 (50 mg) were placed in a 10 mL crimp-
sealed thick-walled glass tube equipped with a pressure sen-
sor and a magnetic stirrer. The contents were mixed on a
rota-mixer and the reaction tube was placed inside the
cavity of a CEM Discover focused microwave synthesis
system, operated at 130 5 °C (temperature monitored
by a built-in infrared sensor), power 20–200 W, and pres-
sure 5–30 psi for 30 min (Table 1). After the completion
of the reaction, the solid catalyst was physically removed
by forceps, to isolate crude amides, which were further
purified by crystallization/column chromatography.
As compared to Olah’s protocol,15 which requires longer
reaction time (18–48 h) and an excess amount of nitrile, the
present method needs only 30 min for the completion of the
reaction, with stoichiometric amounts of nitrile and alco-
hol. This protocol is also superior to the recently reported
P2O5/SiO2 method,10 in which handling and reuse of the
catalyst is difficult. However, the salient feature of this pro-
cedure is the ease of handling the catalyst NafionÒNR50,
as it involves the simple addition of solid Nafion beads (like
a glass bead) in a reaction vessel, which can be physically
removed by forceps after the completion of the reaction.
For practical applications of the catalyst NafionÒNR50,
the lifetime of the catalyst and its level of reusability are
important factors. The catalyst showed excellent recyclabil-
ity in this Ritter condensation of alcohols with nitriles. The

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V. Polshettiwar, R. S. Varma / Tetrahedron Letters 49 (2008) 2661–2664
13. Firouzabadi, H.; Sardarian, A. R.; Badparva, H. Synth. Commun.
Acknowledgment
1973, 27, 2403.
14. Okuhara, T.; Chen, X. Microporous Mesoporous Mater. 2001, 48, 293
and reference cited therein.
15. Olah, G. A.; Yamato, T.; Iyer, P. S.; Trivedi, N. J.; Singh, B. P.; Surya
Prakash, G. K. Mater. Chem. Phys. 1987, 17, 21.
16. (a) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563; (b) Li,
C.-J.; Chen, L. Chem. Soc. Rev. 2006, 5, 68.
17. (a) Polshettiwar, V.; Varma, R.S. Acc. Chem. Res., in press; (b)
Polshettiwar, V.; Varma, R. S. Curr. Opin. Drug Discovery Dev. 2007,
10, 723; (c) Varma, R. S. Kik-Othmer On-line Encyclopedia of
Chemical Technology, 5th ed.; John Wiley & Sons: Hoboken, New
Jersey, 2006; Vol. 16, p 538; (d) Varma, R. S. Pure Appl. Chem. 2001,
73, 193; (e) Varma, R. S. Green Chem. 1999, 1, 43.
Vivek Polshettiwar was supported, in part, by the Post-
graduate Research Program at the National Risk Manage-
ment Research Laboratory administered by the Oak Ridge
Institute for Science and Education through an interagency
agreement between the US Department of Energy and the
US EPA.
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