One-pot synthesis of N-tert-butyl amides from alcohols, ethers and esters using ZnCl2/SiO2 as a recyclable heterogeneous catalyst

Article abstract of DOI:10.1016/j.molcata.2011.01.013

ZnCl₂/SiO₂ has been found to be an efficient and reusable catalyst for conversion of alcohols, ethers and esters to corresponding amides via the Ritter reaction in high yield. It was found that benzonitrile reacted with tert-butyl acetate faster than the other sources of tert-butyl carbocation.

Full text of DOI:10.1016/j.molcata.2011.01.013

Journal of Molecular Catalysis A: Chemical 337 (2011) 52–55
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Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
One-pot synthesis of N-tert-butyl amides from alcohols, ethers and esters using
ZnCl2/SiO2 as a recyclable heterogeneous catalyst
Fatemeh Tamaddon∗, Fatemeh Tavakoli
Department of Chemistry, Yazd University, Yazd 89195-741, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
ZnCl2/SiO2 has been found to be an efficient and reusable catalyst for conversion of alcohols, ethers and
esters to corresponding amides via the Ritter reaction in high yield. It was found that benzonitrile reacted
with tert-butyl acetate faster than the other sources of tert-butyl carbocation.
© 2011 Elsevier B.V. All rights reserved.
Received 7 November 2010
Received in revised form
28 December 2010
Accepted 7 January 2011
Available online 21 January 2011
Keywords:
Ritter reaction
Nitriles
Carbocation source
ZnCl2/SiO2
1. Introduction
neous acidic catalysts. These methods often led to the development
of more eco-friendly protocols. We have also developed a useful
Heterogeneous supported catalysts have been gained much
attention in recent years, as they posses a number of advantages
[1–3]. Immobilization of catalysts on solid support improves the
available active site, stability, hygroscopic properties, handling and
reusability of catalysts [4] which all factors are important in indus-
try. Therefore, use of supported and recoverable catalysts in organic
transformations has economical and environmental benefits. Due
to the stability and high surface area, silica has been widely used as
support [5–7]. Among silica impregnated catalysts, silica supported
zinc chloride (ZnCl2/SiO2, silzic) has been prepared and character-
ized by Upadhyaya and Samant [8]. In spite of ZnCl2, silzic is highly
water tolerant, non-corrosive and stable solid catalyst with ele-
vated Lewis acid property. Silzic has been used as a recoverable
Lewis acid catalyst in the Pinacol–Pinacolone rearrangement [8],
Biginelli reaction [9], protection of heteroatoms [10] and Mannich
reaction [11].
heterogeneous alternative for the Ritter reaction using heteroge-
neous catalyst P2O5/SiO2 [5]. Meanwhile, some of these methods
are limited by use of excess harmful organic reagents or mineral
acids, low yield of products and long reaction times. Thus, develop-
ment of modified efficient and reliable Ritter reaction remains as a
field of researches. In continuation of our interest in the use of sup-
ported catalysts [5], herein we report the Ritter reaction of various
nitriles with tert-butyl alcohol, esters and ethers using silzic as an
efficient heterogeneous catalyst (Scheme 1).
2. Experimental
2.1. Preparation of catalyst
Supported ZnCl2 on silicagel was prepared according to the pre-
vious procedure [8]. Thus, 10% (w/w) ZnCl2/silica gel (silzic 10%)
was easily prepared by co-grinding of anhydrous zinc chloride (1 g)
with dry silica gel (9 g) in an agate mortar at room temperature for
20–25 min. Careful mixing is required to attain uniform dispersion
of ZnCl2 over silica surface. This results in formation of homoge-
nized, white free flowing powder which was further activated in
vacuum at 80 ◦C for 2 h [8].
The classical Ritter reaction is the reaction of tertiary or benzylic
alcohols with nitriles in concentrated sulfuric acid [12]. Recently,
various modified versions of this reaction have been reported for
amidation of nitriles by relatively stable in situ-generated carboca-
tions from alcohols, ethers, silyl ethers, alkylborons, esters, alkenes
and carbonium salts [13–21] by using heterogeneous and homoge-
2.2. General experimental procedure for the Ritter reaction
∗
Corresponding author. Tel.: +98 3518122666; fax: +98 3518210644.
E-mail addresses: ftamaddon@yazduni.ac.ir (F. Tamaddon), fa t23@yahoo.com
To a stirred mixture of the tert-butyl acetate (10 mmol) and
(F. Tavakoli).
nitrile (5 mmol) was added 0.15 mol% of supported ZnCl2 on SiO2
1381-1169/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2011.01.013

F. Tamaddon, F. Tavakoli / Journal of Molecular Catalysis A: Chemical 337 (2011) 52–55
53
100
90
80
70
60
50
40
O
R2
ZnCl2/SiO2 (15 mol%)
100 oC
R3= H, R, COR, SiR3
R2OR3
N +
R1
R
N
H
R1= Alkyl, Aryl
Scheme 1. The Ritter reaction in the presence of silzic catalyst.
(10%, w/w) in a round bottom flask equipped with condenser at
100 ◦C for the given times (Table 2). For microwave-assisted reac-
tions the above premixed mixture irradiated at 500 w in a domestic
MW oven. Progress of the reaction was followed by TLC. After com-
pletion of the reaction, the resulting mixture was extracted with
EtOAc (5 × 10 ml). Then the organic layer was washed with 10%
NaHCO3 and water, dried over Na2SO4 and concentrated to give
the products.
10
20
30
% Loading of ZnCl2 On SiO2
Fig. 1. Effect of catalyst loading on the yield of N-tert-butylbenzamide.
2.3. Reusability of catalyst
amounts of unsupported ZnCl2 at 100 ◦C under solvent-free con-
ditions. Despite of the progress of reactions (TLC monitoring) a
sticky reaction mixture was obtained in all cases, while reaction
yielded a mixture of N-tert-butyl benzamide and benzamide in 60%
yield using 10 ml% of unsupported ZnCl2 after 5 h. Increasing the
amounts of catalyst and reaction time not only did not raise the
reaction yield but also resulted in the hydration of benzonitrile
and formation of benzamide as competitive product. These results
prompted us to focus our attention on the Ritter reaction using
heterogeneous ZnCl2. However, we studied the catalytic effect of
10 ml% of ZnCl2 dispersed on 0.1 g of silicagel, alumina and Celite
for the similar reaction. We found that dispersed ZnCl2 on silicagel
gave the better results in terms of reaction time and yield. Then, 10%
and 30% (w/w) ZnCl2/silicagel was carefully prepared according to
the previous reported procedure by co-grinding of anhydrous zinc
chloride with dry silicagel [9].
The recovered catalyst was regenerated by washing with EtOAc
and drying under microwave irradiation. Using the recycled cata-
lyst for two consecutive times in the Ritter reaction of benzonitrile
and tert-butyl acetate furnished the product with no significant
decreasing of reaction yield.
2.4. Selected spectral data
2.4.1. N-tert-Butyl-3-nitrobenzamide (Table 2, Entry 3)
White needles (EtOH:H2O), 90% yield, mp = 128–130 ◦C. FT-IR:
ꢀmax (neat) 3359, 1644, 1520, 1348 cm−1. 1H NMR (500 MHz, CDCl3)
ı: 1.56 (s, 9H, (CH3)3), 6.06 (br s, 1H, NH), 7.77 (t, 1H, J = 8 Hz),
8.15 (d, 1H, J = 8 Hz), 8.36 (d, 1H, J = 8 Hz), 8.55 (s, 1H, ph) ppm. 13C
NMR (125 MHz, CDCl3) ı: 29.2, 52.7, 121.93, 126.11, 130.18, 131.07,
133.51, 138, 164.82 ppm.
As % yield and selectivity of the obtained products depends on
the loading of catalyst, we studied the effect of % loading ZnCl2
onto SiO2 on % yield for the Ritter reaction of benzonitrile with
tert-butyl acetate as model substrates at 100 ◦C (Fig. 1). Monitor-
ing of the reactions showed that use of 30% (w/w) ZnCl2/silicagel
contributed to the lower yield of N-tert-butylbenzamide, due to the
formation of undesired benzamide product via competitive hydra-
tion of benzonitrile.
Owing to the best yield of N-tert-butylbenzamide (1a), the Ritter
reaction of benzonitrile with various sources of tert-butyl cation
include tert-butyl methyl ether, tert-butyltrimethyl silyl ether, tert-
BuOH and tert-butyl acetate was investigated in the presence of 10%
(w/w) of supported ZnCl2 on SiO2 in comparison to unsupported
ZnCl2 at various conditions (Table 1).
2.4.2. N-tert-Butyl-4-(trifluoromethyl)-benzamide (Table 2,
Entry 6)
White needles (EtOH:H2O), 86% yield, mp = 135 ◦C. FT-IR: ꢀmax
(neat) 3266, 1641 cm−1 1H NMR (500 MHz, DMSO-d6) ı: 7.79 (d,
.
2H, J = 10 Hz), 7.97 (d, 2H, J = 10 Hz), 8.03 (br s, 1H, NH) ppm.
2.4.3. N-tert-Butyl-2-(4-chlorophenyl)-acetamide (Table 2, Entry
13)
White needles (EtOH:H2O), 85% yield, mp = 122–126 ◦C. FT-IR:
ꢀmax (neat) 3302, 1636 cm−1 1H NMR (500 MHz, CDCl3) ı: 1.32
.
(s, 9H, (CH3)3), 3.45 (s, 2H, CH2), 5.29 (br s, 1H, NH), 7.21 (d, 2H,
J = 8.35 Hz), 7.34 (d, 2H, J = 8.35 Hz) ppm. 13C NMR (125 MHz, CDCl3),
ı: 29.1, 44.4, 51.8, 129.4, 131, 133.4, 134.3, 170.1 ppm.
The illustrated results in Table 1 obviously reveals that 15 mol%
of supported ZnCl2 on SiO2 (10%, w/w) is an advanced alterna-
tive. The optimized conditions for reactions were the molar ratio
of 2:1:0.15 for tert-butyl cation generator, benzonitrile and silzic at
100 ◦C and solvent-free conditions. Although silzic provides a het-
erogeneous media for the amidation of nitriles with various sources
of tert-butyl cation, the reaction of tert-butyl acetate was superior.
Subsequently, the Ritter reaction of tert-butyl acetate and cyclo-
hexyl acetate was extended to the various aromatic and aliphatic
nitriles and a range of tert-butyl and cyclohexyl amides were iso-
lated in good to excellent yields under these conditions (Table 2).
Acrylonitrile converted to acrylamide and amidation of malonon-
itrile with tert-butyl acetate produced the desired monoamide
(Table 2, entries 15 and 16). No Ritter reaction took place with
cyano pyridines as well as simple primary alcohols under these
conditions, even after along reaction times.
2.4.4. N-tert-Butyl-4-methylbenzamide (Table 2, Entry 11)
White needles (EtOH:H2O), 92% yield, mp = 116 ◦C. FT-IR: ꢀmax
(neat) 3352, 1634 cm−1 1H NMR (500 MHz, DMSO-d6) ı: 1.36 (s,
.
9H, (CH3)3), 2.38 (s, 3H, CH3), 7.22 (d, 2H, J = 10 Hz), 7.69 (d, 2H,
J = 10 Hz), 7.66 (br s, 1H, NH) ppm.
2.4.5. N-((2-hydroxynaphthalen-1-yl)(phenyl)methyl)
benzamide (Compound 2)
1H NMR (500 MHz, DMSO-d6): ı 2.25 (3H, s); 7.00 (2H, d,
J = 8.0 Hz), 7.20–7.50 (m, 11H), 7.60–7.90 (2H, m), 8.14 (d, 1H,
J = 8.0 Hz), 8.86 (d, 1H, J = 8.0 Hz), 9.88 (br s 1H, NH).
3. Results and discussion
In our preliminary experiments and in order to optimize the
reaction conditions, a model reaction between benzonitrile and
tert-butyl acetate was carried out in the presence of various
Furthermore, microwave assisted silzic catalyzed Ritter reac-
tions of propionitrile and benzonitrile with tert-butyl acetate were

54
F. Tamaddon, F. Tavakoli / Journal of Molecular Catalysis A: Chemical 337 (2011) 52–55
Table 1
Ritter reaction of PhCN.
O
O
Ph
C
C
N
N
Ph
Silzic, 100 oC, 2h
N
Catalyst
100 oC
H
91%
Me
tert-Butyl acetate
+
N
Ph
+
OR
H
Ph
N
H
N
Me
1a
.
0 %
O
Entry
R
Catalyst (mol%)
Time/yielda (h)/(%)
1
2
3
4
5
6
7
8
9
H
CH3
t-Bu
t-Bu
COCH3
COCH3
COCH3
COCH3
COCH3
SiMe3
H
ZnCl2/SiO2 (15)
ZnCl2/SiO2 (15)
ZnCl2/SiO2 (15)
ZnCl2/SiO2 (10)
ZnCl2/SiO2 (20)
ZnCl2/SiO2 (15)
SiO2 (15)
4/85
4/82
3.5/87
3.5/80
3/88
Scheme 2. The chemoselectivity of the silzic-catalyzed Ritter reaction.
Table 3
Recyclability of the ZnCl2/silicagel in the Ritter reaction of benzonitrile and tert-butyl
acetate.
2/91
12/40
4/78b
4/81
Run no.
Time (h)
Yield (%)
ZnCl2 (15)
ZnCl2/HOAc (15)
ZnCl2/SiO2 (15)
ZnCl2/HOAc (15)
ZnCl2 (15)
1
2
3
4
2
2
3
5.5
90
89
88
83
10
11
12
4/86
6/82b
4/74b
H
a
Isolated yield.
As a mixture with benzamide.
b
attempted at different powers ranging from 500 to 950 w. In the
most appropriate power 500 w, microwave irradiation of reaction
mixtures produced the corresponding amides in 90 and 93% yields
at short times (∼120 s). The speeding up of the reaction under
microwave irradiation possibly will be streamlined on the basis
of the huge polarity of the reaction mixture.
The chemoselectivity of the silzic-catalyzed Ritter reaction was
examined by parallel reactions of tert-BuOH, tert-BuOCOCH3 and
tert-BuOCH3 with benzonitrile for 2 h. It was found that benzoni-
trile reacted with tert-butyl acetate much faster than the other
sources of tert-butyl carbocation. Greatly facilitated heterolytic
cleavage of C–O bond of tert-butyl acetate by silzic is rationalized by
the leaving group superiority of acetate than OH or OR groups. In
addition, competitive silzic-catalyzed Ritter reaction of tert-butyl
Scheme 3. Proposed mechanism for silzic-catalyzed Ritter reaction.
acetate (1 mmol) with a mixture of benzonitrile and acetonitrile
under optimized conditions led to the selective formation of N-tert-
butylbenzamide in high yield. However, no chemoselectivity was
observed for cyclohexanol versus dicyclohexyl ether (Scheme 2).
Reusability of catalyst is an important factor for its upgrade use.
The recovered silzic from the Ritter reaction of benzonitrile and
tert-butyl acetate was reused successfully two times and it was
found that more than this, elongation of the reaction time up to
2 h was observed due to the significant loss of activity of catalyst
(Table 3).
From mechanistic point of view, the catalytic efficiency of sup-
ported Zn2+ in this reaction maybe attributed to its Lewis acidity
and oxophilicity which both promote the Ritter reaction via coor-
dination to oxygen atoms of ester and facilitation of C–O cleavage
by attack of nitrile group. Thus, according to the electronic effects,
we proposed the following mechanism (Scheme 3).
Table 2
Preparation of N-tert-butyl amides using silzic (ZnCl2/SiO2).
O
O
ZnCl2/SiO2 (15 mol%)
H3C
O
R1
R
N
R1
R
C
N
+
H
.
Entry
R
R1
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
C6H5
C6H5
tert-Butyl
Cyclohexyl
tert-Butyl
tert-Butyl
Cyclohexyl
tert-Butyl
tert-Butyl
tert-Butyl
Cyclohexyl
tert-Butyl
tert-Butyl
tert-Butyl
tert-Butyl
Cyclohexyl
tert-Butyl
tert-Butyl
2
3.5
11
10
10
8
5
6
8
6
5
5.5
5
6
6
8
89
78b
90
3-NO2–C6H4
4-NO2–C6H4
4-NO2–C6H4
4-CF3–C6H4
4-Cl–C6H5
3-Cl–C6H5
3-Cl–C6H5
4-MeO–C6H4
4-Me–C6H4
Terephthalonitrile
CH3
87
75b
85b
90
90
76b
92
Finally, Ritter type reaction of PhCN, ˇ-naphtol and ben-
zaldehyde in the presence of ZnCl2/SiO2 (20 mol%) produced the
corresponding amidoalkyl naphthol in 70% isolated yield which
structurally confirmed by its 1H NMR spectra (Scheme 4).
92
88
85
CH3
78b
85
4-Cl–C6H4CH2
2-Cl–C6H4CH2
85
PhCHO
CH2
NHCOPh
17
tert-Butyl
4
90
Ph
+
OH
CN
OH
CH
2
18
tert-Butyl
tert-Butyl
5
91
86
Silzic (20 mol%)
Me
CH
2
19
4.5
+
2
a
PhCN
Isolated yield.
b
30% (w/w) ZnCl2/silicagel was used and product was purified by recrystalliza-
tion.
Scheme 4. Ritter-type three-component condensation.

F. Tamaddon, F. Tavakoli / Journal of Molecular Catalysis A: Chemical 337 (2011) 52–55
55
4. Conclusion
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In conclusion, we have developed a simple chemoselective
methodology for modified Ritter reaction using silzic as a reusable
catalyst. The products were obtained in high yields and could be
used in the synthesis of biologically active compounds.
Acknowledgement
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We gratefully thank the Yazd University Research Council for
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Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molcata.2011.01.013.
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