An efficient synthesis of N-tert-butyl amides by the reaction of tert-butyl benzoate with nitriles catalyzed by Zn(ClO4)2·6H2O

Article abstract of DOI:10.1007/s11696-018-0586-4

An efficient, mild and inexpensive synthesis of N-tert-butyl amides from the reaction of nitriles (aryl, benzyl and sec-alkyl nitriles) with tert-butyl benzoate catalyzed by the employment of 2?mol% Zn(ClO₄)₂·6H₂O at 50?°C

Full text of DOI:10.1007/s11696-018-0586-4

Chemical Papers
https://doi.org/10.1007/s11696-018-0586-4
SHORT COMMUNICATION
An efcient synthesis of N‑tert‑butyl amides by the reaction
of tert‑butyl benzoate with nitriles catalyzed by Zn(ClO4)2·6H2O
Cheng‑Liang Feng1 · Bin Yan1 · Min Zhang1 · Jun‑Qing Chen2 · Min Ji2
Received: 12 June 2018 / Accepted: 31 August 2018
© Institute of Chemistry, Slovak Academy of Sciences 2018
Abstract
An efcient, mild and inexpensive synthesis of N-tert-butyl amides from the reaction of nitriles (aryl, benzyl and sec-alkyl
nitriles) with tert-butyl benzoate catalyzed by the employment of 2 mol% Zn(ClO4)2·6H2O at 50 °C under the solvent-free
conditions is described. The reaction with aryl nitriles was carried out well and aforded the N-tert-butyl amides in 87–97%
yields after 1 h. The benzyl and sec-alkyl nitriles also proceeded well and produced the N-tert-butyl amides in 83–91%
yields after 5 h.
Keywords Ritter reaction · Tert-butyl benzoate · Zn(ClO4)2·6H2O · Amides · Solvent-free
Introduction
and Al-Abd 2018) and Epristeride (Baine et al. 1994) have
been developed for the treatment of benign prostatic hyper-
plasia. On the other hand, Indinavir (Rossen et al. 1995),
nelfnavir (Sanchez et al. 2018) and Saquinavir (Ghosh et al.
1997) have been used as a component to treat HIV, whereas,
CPI-1189 (Hensley et al. 2000) is a candidate for neuro-pro-
tective therapy in humans with HIV-associated CNS disease.
The N-tert-butyl amide compounds have wide application in
organic synthesis (Clayden et al. 2007) and drug synthesis
(Mao et al. 2017). Especially, a lot of drug molecules con-
taining N-tert-butyl amide functionality have been explored
to cure various diseases. For example, Finasteride (Ahmed
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s11696-018-0586-4) contains
supplementary material, which is available to authorized users.
* Min Ji
fcl085620@163.com
1
Institute of Pharmaceutical Engineering, Jiangsu College
of Engineering and Technology, Nantong, Jiangsu 226000,
People’s Republic of China
2
School of Biological Sciences and Medical Engineering,
Southeast University, Nanjing, Jiangsu 211189,
People’s Republic of China
Vol.:(0123456789)
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Chemical Papers
(a)
(b)
(c)
(d)
(e)
Scheme 1 Synthesis of N-tert-butyl amides by Ritter reaction
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Table 1 Optimization of reaction conditionsa
Usually, the N-tert-butyl amide compounds were synthe-
sized by acylation of amines (Valeur and Bradley 2009).
On the other hand, various alternative methodologies like
Staudinger reaction (Gololobov and Kasukhin 1992), the
Schmidt reaction (Lang and Murphy 2006), the oxidative
amidation of aldehydes and alcohols (Chang et al. 2010;
Krabbe et al. 2016), aminocarbonylation reaction (Wannberg
and Larhed 2003), amidation of aryl halides (Jiang et al.
2011), and oxidation of imines (Larsen et al. 1991) were
also used to form amides. Although efective, the strategies
often used highly hazardous reagents following a stoichio-
metric amount of and difcultly separated byproducts. In
recent years, direct amides from nitriles via Ritter reaction
have gained much attention for its atomic economy (Jiang
et al. 2014). In general, tert-butanol was employed to react
with nitriles to form N-tert-butyl amides in the presence of
acids (Callens et al. 2006; Indalkar et al. 2017). Further-
more, some alternatives including tert-butyl acetate (Baum
et al. 2009; Hazarika and Baishya 2014), tert-butyl bromide
(Qu et al. 2012) and methyl tert-butyl ether (Tamaddon and
Tavakoli 2011) also have been developed for this transforma-
tion. Despite convenient, some drawbacks like using solvents
and acids, high reaction temperature, long reaction time and
high catalyst loading led to restrict its application on large
scale. For example, Milne et al. (Baum et al. 2009) used tert-
butyl acetate in acetic acid along with an excess amount of
corrosive H2SO4 to synthesize N-tert-butyl amides. Hazarika
et al. (2014) reported one-pot sequential Schmidt and Ritter
reactions with tert-butyl acetate for the synthesis of N-tert-
butyl amides in acetic acid. Tamaddon’s group (Tamaddon
and Tavakoli 2011) transformed methyl tert-butyl ether to
N-tert-butyl amides in the presence of ZnCl2/SiO2 as a recy-
clable heterogeneous catalyst at 100 °C under solvent-free
condition. Moreover, Qu et al. (2012) adopted tert-butyl bro-
mide to produce N-tert-butyl amides at 100 °C. Hence, the
need for the development of a novel, mild, efective, Lewis-
catalyzed synthetic method for the synthesis of N-tert-butyl
amides is in demand.
Entry
Catalyst (mol%)
T °C
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
ZnCl2 (5)
Zn(OTf)2 (5)
Zn(OAc)2·2H2O (5)
ZnO (5)
ZnBr2 (5)
Zn(ClO4)2·6H2O (5)
Zn(AcAc)2 (5)
ZnSO4·H2O (5)
Zn(ClO4)2·6H2O (1)
Zn(ClO4)2·6H2O (2)
Zn(ClO4)2·6H2O (10)
Zn(ClO4)2·6H2O (2)
Zn(ClO4)2·6H2O (2)
Zn(ClO4)2·6H2 (2)
Zn(ClO4)2·6H2O (2)
60
60
60
60
60
60
60
60
60
60
60
12
6
12
12
12
1
12
12
1
1
1
1
1
41
84
36
NR
44
88
NR
NR
54
86
89
Trace
69
94
9
10
11
12
13
14
15
RT
40
50
80
1
1
93
aTert-butyl benzoate (5.5 mmol) and benzonitrile (5 mmol) were used
bIsolated yields
1
are uncorrected. H NMR and 13C NMR spectra were
recorded on a Bruker Avance DPX-400 MHz instrument in
CDCl3; chemical shifts (δ) were given in part per million
(ppm) relative to TMS as an internal standard. All reac-
tions were monitored by TLC on silica gel GF-254 glass
plates (E.Merck) and viewed under UV light at 254 nm.
The HRMS spectra were obtained on a Thermo Finnigan
spectrometer, model MAT 95XP.
In this paper, we wish to report a new and efcient proce-
dure for the transformation of nitriles with tert-butyl benzo-
ate by the use of Zn(ClO4)2·6H2O as a catalyst under sol-
vent-free conditions (Scheme 1, path (e)). And our research
expands the scope of the substrates and tert-butyl benzoate
is frst used in Ritter reaction to form N-tert-butyl amides.
Typical experimental procedure for the reaction
of nitriles and tert‑butyl benzoate
A mixture of nitrile (5 mmol), tert-butyl benzoate
(5.5 mmol) and Zn(ClO4)2·6H2O (2 mol%) was placed in a
round bottom fask. Then, the reaction mixture was heated
at 50 °C for the given time. After completion of the reac-
tion monitored by thin layer chromatography (TLC), the
reaction mixture was quenched with 5-ml water. Then the
reaction system was added 10 ml aqueous NaOH solution
(1 mol/L) and continued to be stirred 5 min and extracted
with ethyl acetate (3 × 10 ml). The organic layers were
collected, combined, washed with water (3 × 10 ml), dried
over anhydrous Na2SO4, and concentrated under vacuum.
Experimental
Materials and instruments
All reagents were purchased from commercial sources
and used without further purification. Melting points
were determined on a RY-1 hot stage microscope and
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Table 2 Reaction of nitriles and
tert-butyl benzoatea
Entry
1
R
Time(h)
1
Product
Yield(%)b
94
C6H5
1a
2
4-NO2C6H4
1
87
1b
1c
1d
3
4
5
3-CH3C6H4
2-CH3C6H4
4-CH3OC6H4
1
1
1
95
93
90
1e
1f
6
7
8
3-FC6H4
4-CH3C6H4
4-F3CC6H4
1
1
1
95
92
97
1g
1h
9
3-BrC6H4
C6H5CH2
1
5
94
89
1i
1j
10
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Chemical Papers
Yield(%)b
Table 2 (continued)
Entry
R
Time(h)
Product
11
4-ClC6H4CH2
5
85
1k
1l
12
2-CH3C6H4CH2
5
90
13
3,4-Cl2C6H4CH2
5
84
1m
1n
14
15
4-NO2C6H4CH2
4-BrC6H4CH2
5
5
87
89
1o
1p
16
17
3-ClC6H4CH2
2-FC6H4CH2
5
5
91
83
1q
1r
1s
1t
18
19
20
21
3-FC6H4CH2
C6H5CHCH3
Cyclopentyl
Cyclopropyl
5
5
5
5
87
86
89
90
1u
aTert-butyl benzoate (5.5mmol), nitriles (5mmol) and Zn(ClO4)2·6H2O (2 mol%) were used
bIsolated yields
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Chemical Papers
Scheme 2 Tert-butyl 4-methylbenzoate and tert-butyl 4-chlorobenzoate reacted with benzonitrile
Scheme 3 The reaction of tert-
butyl acetate with benzonitrile
Scheme 4 Proposed mechanism
for Zn(ClO4)2·6H2O-catalyzed
Ritter reaction
The pure product was obtained by directly passing through
a silica gel (200–300 mesh) column using petroleum ether/
ethyl acetate and identifed by 1H NMR and 13C NMR.
Characterization of new compound
N-(tert-butyl)-2-(3, 4-dichlorophenyl) acetamide (1 m)
1
White powder. M.p. 148–150 °C. HNMR (400 MHz,
CDCl3): δ 7.41–7.35(m, 2H), 7.12–7.10(m, 1H), 5.31(s,
1H), 3.40(s, 2H), 1.32(s, 9H). 13CNMR (100 MHz, CDCl3):
δ 168.89, 135.56, 132.66, 131.24, 131.16, 130.63, 128.60,
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Chemical Papers
51.61, 43.53, 28.71. HRMS calcd. for C12H15Cl2NO[M+H]+
requires 259.0531, found 259.0533.
benzamide(1a) was improved dramatically to 94% (Table 1,
entry 14). When the reaction was conducted at 80 °C, a
93% yield of N-(tert-butyl)benzamide(1a) was obtained
(Table 1, entry 15). Therefore, 50 °C was sufcient for this
transformation.
N-(tert-butyl)-2-(3-chlorophenyl) acetamide(1p) White
powder. M.p. 127–129 °C. 1HNMR (400 MHz, CDCl3) δ:
7.29–7.14(m, 4H), 5.28(s, 1H), 3.43(s, 2H), 1.31(s, 9H).
13CNMR (100 MHz, CDCl3) δ: 169.36, 137.38, 134.55,
130.04, 129.37, 127.39, 127.31, 51.48, 44.26, 28.70. HRMS
calcd. for C12H16ClNO[M+H]+ requires 225.0920, found
225.0922.
The generality of this Zn(ClO4)2·6H2O-mediated efec-
tive synthesis of N-tert-butyl amides with tert-butyl ben-
zoate and nitriles was subsequently investigated. The
substrate scope for the nitriles is summarized in Table 2.
The reaction was compatible with a variety of substituents
on the nitrile substrates including aryl nitriles and benzyl
nitriles and aforded the corresponding N-tert-butyl amides
in good–excellent yields (Table 2, 1a–1s). Moreover, the
substituents on the para, meta and ortho site of the aryl
nitriles and benzyl nitriles could not infuence the reaction
and furnish the products with high yields. It was observed
that the reaction of tert-butyl benzoate with 3-methylb-
enzonitrile, 4-methylbenzonitrile, 4-methylbenzonitrile
afforded the N-(tert-butyl)-3-methylbenzamide(1c),
N-(tert-butyl)-2-methylbenzamide(1d), and N-(tert-butyl)-
4-methylbenzamide(1g) in 95%, 93% and 92% yields,
respectively. What is more, the reaction of benzyl nitriles
prolonged the reaction time to 5 h for obtaining the best
yield. On the other hand, sec-alkyl nitriles also could be
carried out well and aforded the N-tert-butyl amides in
excellent yields (Table 2, entries 20, 21).
N-(tert-butyl)-2-(2-fuorophenyl) acetamide(1q) White
powder. M.p. 102–103 °C. 1HNMR (400 MHz, CDCl3) δ:
7.31–7.23(m, 2H), 7.11–7.04(m, 2H), 5.40(s, 1H), 3.48(s,
2H), 1.30(s, 9H). 13CNMR (100 MHz, CDCl3) δ: 169.08,
162.13(q, JC–F =244 Hz), 131.59(q, JC–F =4 Hz), 129.05(q,
JC–F =9 Hz), 124.48(q, JC–F =4 Hz), 122.78(q, JC–F =16 Hz),
115.57(q, JC–F =22 Hz), 51.34, 37.93, 28.66. HRMS calcd.
for C12H16FNO[M+H]+ requires 209.1216, found 209.1217.
Results and discussion
To explore the procedure, benzonitrile was employed as a
model compound for the reaction with tert-butyl benzoate to
screen the reaction conditions (Table 1). The results are sum-
marized in Table 1. At the beginning, 5 mol% of ZnCl2 was
frst used in this transformation at 60 °C; fortunately, the cor-
responding N-(tert-butyl)benzamide(1a) was obtained with
moderate yield in 41% after 12 h (Table 1, entry 1). Then,
a range of Zn catalysts like Zn(OTf)2, Zn(OAc)2·2H2O,
ZnO, ZnBr2, Zn(ClO4)2·6H2O, Zn(AcAc)2 and ZnSO4 were
checked again for this reaction, in which Zn(ClO4)2·6H2O
showed the best catalytic efect and aforded an excellent
yield of the desired product N-(tert-butyl)benzamide(1a)
(Table 1, entry 6). However, the catalysts like Zn(OTf)2,
Zn(OAc)2·2H2O, and ZnBr2 produced the N-(tert-butyl)
benzamide(1a) in moderate–good yields (Table 1, entries
2, 3 and 5). Whereas, ZnO, Zn(AcAc)2 and ZnSO4 did not
work in this transformation (Table 1, entries 4, 7 and 8).
The further optimization revealed that the yield was criti-
cally afected by the amount of catalyst employed. The yield
decreased to 54% by employment of 1 mol% catalyst. By
switching the amount of Zn(ClO4)2·6H2O to 2 mol% and
10 mol%, the N-(tert-butyl)benzamide(1a) was obtained
with 86% and 89% yield, respectively (Table 1, entries 10,
11). Although yields by employment of 5 mol% (88%) and
10 mol% (89%) catalyst were slightly increasing, 2 mol%
catalyst was thought to be enough for this reaction. When
the reaction was carried out at room temperature, only
trace amount of N-(tert-butyl)benzamide(1a) was detected
by TLC after 1 h. By raising the temperature to 40 °C, the
reaction aforded a good yield of the product (1a) with 69%
after 1 h (Table 1, entry 13). Moreover, it was worth noting
that while operating at 50 °C, the yield of N-(tert-butyl)
This method was also suitable to other liquid tert-butyl
benzoate. For example, tert-butyl 4-methylbenzoate and
tert-butyl 4-chlorobenzoate were used to react with ben-
zonitrile and aforded the corresponding N-(tert-butyl)
benzamide(1a) in 92% and 94% yields, respectively
(Scheme 2). It was noted that there were no remarkable
electronic efects on this reaction.
Furthermore, the catalyst Zn(ClO4)2·6H2O was also
used to check the reaction of tert-butyl acetate with benzo-
nitrile. It was found that a moderate yield of N-(tert-butyl)
benzamide(1a) was obtained at 50 °C after 5 h. Then rais-
ing the reaction temperature to 80 °C, an excellent yield of
N-(tert-butyl)benzamide(1a) could also be obtained after
5 h (Scheme 3).
The mechanism for this sequential reaction can be
explained by the already established mechanisms of the
Ritter reaction (Tamaddon and Tavakoli 2011), involved
in this novel method (Scheme 4).
Conclusions
In summary, we devised an efective and mild protocol for
the synthesis of N-tert-butyl amides from nitriles with tert-
butyl benzoate using Zn(ClO4)2·6H2O as a catalyst under
solvent-free condition. The present work involves several
practical advantages like the employment of mild reaction
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Chemical Papers
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Acknowledgements We are grateful to Nantong City Science Founda-
tion (No. 2015) and Science program of Jiangsu College of Engineering
and Technology for fnancial support.
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