Highly efficient synthesis of amides via Ritter chemistry with ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2010.12.028

The utility of Br?nsted-acidic imidazolium ionic liquid [BMIM(SO₃H)][OTf] as catalyst for the high yield synthesis of a wide variety of amides under mild conditions via the Ritter reaction of alcohols with nitriles has been demonstrated. As alternative methods for the carbocation generation step, NOPF₆ immobilized in [BMIM][PF₆] ionic liquid was used in the Ritter reaction of bromides with nitriles and for the synthesis of adamantyl amides from adamantane and nitriles.

Full text of DOI:10.1016/j.tetlet.2010.12.028

Tetrahedron Letters 52 (2011) 867–871
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly efficient synthesis of amides via Ritter chemistry with ionic liquids
⇑
Rajesh G. Kalkhambkar, Sarah N. Waters , Kenneth K. Laali
Department of Chemistry, University of North Florida, 1, UNF Drive, Jacksonville, FL 32224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The utility of Brønsted-acidic imidazolium ionic liquid [BMIM(SO3H)][OTf] as catalyst for the high yield
synthesis of a wide variety of amides under mild conditions via the Ritter reaction of alcohols with
nitriles has been demonstrated. As alternative methods for the carbocation generation step, NOPF6 immo-
bilized in [BMIM][PF6] ionic liquid was used in the Ritter reaction of bromides with nitriles and for the
synthesis of adamantyl amides from adamantane and nitriles.
Received 28 October 2010
Revised 1 December 2010
Accepted 6 December 2010
Available online 21 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ritter reaction
Amides
Ionic liquids
Carbocations
First reported over 60 years ago,1,2 the classical Ritter reaction
involves condensation of alcohols, suitably substituted alkenes,
or tertiary halides, with nitriles in the presence of stoichiometric
amount of a strong acid, typically H2SO4 and often together with
a highly ionizing solvent such as AcOH, forming amides upon
hydrolysis. Mechanistically, the success of the Ritter reaction
hinges on the formation and subsequent chemistry of two key
reactive intermediates, a relatively stable alkyl or benzhydril car-
bocation, and the nitrilium ion formed by N-alkylation of RCN
( Fig. 1). The reaction typically requires elevated temperatures,
and depending on the structure of the reactants, is accompanied
by rearrangement and side products. Ritter reaction is suited to
the synthesis of sterically crowed amides and hindered amines,
following amide hydrolysis.
Given the importance of amides as building blocks in organic
and medicinal chemistry, there is continuing interest in this trans-
formation, and over the years numerous variations to the Ritter
reaction have been reported with the goal to perform this transfor-
mation in higher yields, with better chemoselectivity, and under
milder, environmentally more acceptable, conditions. These varia-
tions have included the use of: Nafion-H as a solid catalyst,3,4 Naf-
ion-H along with microwave irradiation,5 formic acid under
reflux,6 HBF4ꢀEt2O,7 2,4-dinitrobenzenesulfonic acid,8 HClO4-func-
tionalized silica-coated nanoparticles,9 liquid HF,10 TMS-CN/
H2SO4 as reagent for synthesis of formamides,11 tBuOAc instead
of tBuOH as carbocation precursor,12 Tf2O/ROH as an in situ source
of ROTf,13 metal complexes,14 Bi(OTf)3 and other metallic tri-
flates,15 nitrosonium salt to effect Ritter reaction of halides with ni-
triles,16 and hydride abstraction from adamantane to synthesize
adamantly amides.17
In 2002 Forbes, Davis and co-workers,18a reported a facile two-
step process for the synthesis of Brønsted acidic ILs, by alkylation
of N-alkyl-imidazole or Ph3P with sultones, followed by proton-
ation of the resulting zwitterion with TfOH. The utility of the
resulting ILs in representative acid-catalyzed reactions as dual sol-
vent/catalysts was demonstrated.18a
Brønsted acidic ILs, including those bearing other counteri-
ons,18b,c have since been employed in: aromatic nitration,19a alkyl-
ation with olefins,19b Beckmann rearrangement,19c esterification,20
olefin oligomerization,20 condensation reactions,21 esterification/
O
R
R
R'
R
R
H2O
R
R
R'
N
R
R
R
NH
R
N
R'
R
R
OH
Figure 1. The Ritter reaction.
⇑
Corresponding author. Tel.: +1 904 620 1503; fax: +1 904 620 3535.
E-mail address: kenneth.laali@UNF.edu (K.K. Laali).
S.W. is a UNF senior undergraduate participant.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.028

868
R. G. Kalkhambkar et al. / Tetrahedron Letters 52 (2011) 867–871
ent study complements and greatly extends a recent report on Rit-
SO3H
CF3
ter reaction in Brønsted acidic ILs.38
Using tBuOH as the carbocation source, a variety of cyclic, acy-
clic, aromatic, and heteroaromatic nitriles reacted under mild con-
ditions to give their corresponding amides in very good isolated
yields after hydrolysis (Fig. 3 and Table 1).
N
O
S
O
N
O
[BMIM(SO3H)][OTf]
In the second set of experiments adamantanol was used as a
carbocation precursor (Fig. 4 and Table 2).
In the third set of experiments, methylcyclopentanol was used
as a carbocation precursor (Fig. 5 and Table 3).
Figure 2. Brønsted acidic IL employed.
trans-esterification,22 carbonyl protection,23 synthesis of beta-ami-
do-ketones,24 and 3-component synthesis of hindered pyridines.25
In continuation of our studies focusing on onium ion chemistry
and electrophilic aromatic substitution in ILs,26–37 we report herein
a convenient method for the high yield synthesis of amides from a
variety of cyclic and acyclic tertiary alcohols and a host of nitriles
under mild conditions, employing [BMIM(SO3H)][OTf] (Fig. 2) as
the catalyst.
We also report on the utility of [BMIM][PF6]/NOPF6 system for
amide synthesis via the reaction of bromides with nitriles and for
the synthesis of adamantylamides from adamantane and nitriles.
The experimental procedures and product characterization data
are gathered in the accompanying Supplementary data. The pres-
It should be pointed out that because in these reaction [BMIM(-
SO3H)][OTf] was used in catalytic amounts, in small scale experi-
ments, it was not deemed essential to recover the IL for re-use.
However, as it has been reported in other works,20b this ionic liquid
can be conveniently recovered and reused, making this chemistry
economically viable for scale-up.
The nitrosium ion-induced amide synthesis from halides and
nitriles was reported by Olah et al. over three decades ago.16 NOPF6
is poorly soluble in most organic solvents but has adequate solubil-
ity in acetonitrile and nitromethane. Using MeCN is convenient for
amide synthesis if this nitrile is to be employed, but is problematic
when other nitriles are to be used, in which case MeNO2 should be
used as the solvent.
[BMIM-SO3H][OTf]
O
H
N
[BMIM(SO3H)][OTf]
R
R
R
N
HO
OH
R
N
HN
ACOH
40-850C
13-24 h
50-800C
3-18 h
O
61 - 87%
77 - 98%
Figure 3. Ritter reaction using tBuOH.
Figure 4. Ritter reaction using AdOH.
Table 1
[BMIM(SO3H)][OTf] catalyzed Ritter reaction of tBuOH with nitriles
Entry
Nitriles
N-tert-Butyl-amide
IL:nitriles ratio
0.450
Temp (°C)
Time (h)
8
Isolated yield (%)
95
H
N
1
70
N
O
H
N
2
3
0.277
0.444
50
60
3
5
77
98
N
O
H
N
N
O
O
N
4
0.571
60
5
96
HN
O
5
6
0.666
0.444
80
50
18
3
92
94
N
HN
O
O
O
N
HN
H
N
7
8
0.444
0.571
50
60
4
5
92
91
O
O
O
N
N
O
N
N
HN

R. G. Kalkhambkar et al. / Tetrahedron Letters 52 (2011) 867–871
869
Table 2
[BMIM(SO3H)][OTf] catalyzed Ritter reaction of AdOH with nitriles
Entry
Nitriles
Product
IL:nitriles ratio
0.615
Temp (°C)
Time (h)
24
Isolated yield (%)
NH
O
N
9
40
84
87
82
NH
O
10
11
0.666
0.666
75
85
18
13
N
NH
O
N
NH
O
12
1
80
14
76
N
NH
O
13
14
15
16
N
0.7
80
75
80
70
18
24
16
13
74
61
71
77
NH
O
0.9
O
N
O
NH
O
O
0.777
0.657
O
N
N
NH
O
N
N
NOPF6 can be immobilized in imidazolium ILs and this increases
its synthetic utility as reagent, eliminating the need to employ
molecular solvents that will then have to be disposed of. In addi-
tion, the IL-version offers the possibility of recycling and reuse.
In the context of the present study, tBu-Br and Ad-Br were used
for carbocation generation induced by NO+ for reaction with repre-
sentative classes of nitriles, to furnish amides in reasonable iso-
[BMIM(SO3H)][OTf]
O
R
N
HO
N
H
R
ACOH
40-850C
12-24 h
60 - 82%
Figure 5. Ritter reaction using methylcyclopentanol.
Table 3
[BMIM(SO3H)][OTf] catalyzed Ritter reaction of methylcyclopentanol with nitriles
Entry
Nitriles
Product
IL:nitriles ratio
0.666
Temp (°C)
Time (h)
24
Isolated yield (%)
73
H
N
17
40
N
O
H
N
18
19
0.733
0.666
65
75
24
16
81
66
N
O
H
N
N
O
O
20
0.750
85
18
67
HN
N
(continued on next page)

870
R. G. Kalkhambkar et al. / Tetrahedron Letters 52 (2011) 867–871
Table 3 (continued)
Entry
Nitriles
Product
IL:nitriles ratio
0.626
Temp (°C)
Time (h)
24
Isolated yield (%)
65
H
N
N
21
80
O
O
H
N
O
N
22
23
24
0.5
70
80
80
12
12
13
82
78
60
O
H
N
0.490
0.75
O
O
N
N
O
N
H
N
N
O
R
O
[BMIM][PF6]
NOPF6
R'
H
R'-Br
R
N
HN
O
N
H
[BMIM][PF6]
NOPF6
70-900C
14-18 h
R
R
N
0-RT
2.5-24 h
60 - 77%
Figure 6. NO+ induced Ritter reaction with bromides.
59 - 75%
Figure 7. NO+ induced Ritter reaction via hydride abstraction from adamantine.
lated yields after hydrolysis (Fig. 6 and Table 4). The IL was recycled
and reused in subsequent runs.
Utility of [BMIM][PF6]/NO+PF6 system for hydride abstraction
ꢁ
elevated temperatures to reach acceptable yields, it offers the pos-
sibility of recycling/reuse that was successfully tested in the two
subsequent cycles.
In summary, the Brønsted-acidic imidazolium ionic liquid
[BMIM(SO3H)][OTf] represents a convenient and recyclable cata-
from adamantane to generate Ad+ for reaction with representative
nitriles was also examined in the present study (Fig. 7 and Table 5).
This reaction had previously been reported by Olah and Gupta in
MeCN or MeNO2 as solvent at rt.17 Whereas the IL-version requires
Table 4
Nitrosonium-induced Ritter reaction of RBr with nitriles in [BMIM][PF6]
Entry
1
Nitriles
R0
Product
NOPF6
2.35
Temp (°C)
Time (h)
18
Isolated yield (%)
71
H
N
N
0–30
Br
O
O
H
N
N
2
3
-do-
-do-
2.35
2.47
0–rt
0–rt
24
20
66
62
O
H
N
O
O
N
Br
NH
O
N
4
5
6
2
0–25
0–25
0–25
2.5
7.6
9
77
60
62
NH
O
-do-
-do-
2
N
NH
O
2.15
N

R. G. Kalkhambkar et al. / Tetrahedron Letters 52 (2011) 867–871
871
Table 5
Nitrosonium-induced Ritter reaction of adamantane with nitriles in [BMIM][PF6]
Entry
Nitriles
Product
NOPF6
2.5
Temp (°C)
Time (h)
14
Isolated yield (%)
N
NH
O
1
90
60
75
59
N
NH
O
2
3
3.3
3.5
90
90
18
18
N
NH
O
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