Cu-catalyzed aerobic oxidative C-CN bond cleavage of benzyl cyanide for the synthesis of primary amides

Article abstract of DOI:10.1039/c7ra02207g

An efficient method via copper-catalyzed aerobic oxidative amidation of benzyl cyanide for primary amides is successfully developed. Using readily available NH₄Cl as a nitrogen source and Cu/O₂ as a catalytic oxidation system offers new opportunities for C-CN bond cleavage and primary amide bond formation.

Full text of DOI:10.1039/c7ra02207g

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Cu-catalyzed aerobic oxidative C–CN bond
cleavage of benzyl cyanide for the synthesis of
Cite this: RSC Adv., 2017, 7, 18588
primary amides†
*
Xiuling Chen,
Yanhong Peng, Yan Li, Minghu Wu, Haibing Guo, Jian Wang
*
and Shaofa Sun
Received 22nd February 2017
Accepted 20th March 2017
An efficient method via copper-catalyzed aerobic oxidative amidation of benzyl cyanide for primary amides
is successfully developed. Using readily available NH4Cl as a nitrogen source and Cu/O2 as a catalytic
oxidation system offers new opportunities for C–CN bond cleavage and primary amide bond formation.
DOI: 10.1039/c7ra02207g
rsc.li/rsc-advances
Primary amides are prevalent organic motifs in peptide, protein continued interest in Cu or Fe-catalyzed aerobic oxidative C–C
synthesis, intensiers of perfume, anti-block reagents, color bond cleavage reaction,15 we developed a Cu-catalyzed aerobic
pigments for inks, detergents, and lubricants.1 Generally, the oxidative C–C bond cleavage of benzyl cyanide for the synthesis
synthetic procedures for the preparation of primary amides are of primary amides. Using readily available NH4Cl as a nitrogen
rely on the reaction of carboxylic acid,2 or its derivatives with source and a Cu/O2 catalytic oxidation system offers new
ammonia or ammonium salt.3 However, toxic and corrosive, opportunities for primary amide bond formation. The devel-
materials, low functional groups tolerance and complex opera- oped methodology tolerated a wide range of functional groups
tion are generally required in conventional synthetic proce- and produced high yields for the synthesis of primary amides.
dures. To overcome these problems, alternative methods for
primary amide synthesis have been developed. The direct ami-
dation of aldehydes,4 alcohols,5 or methylarenes6 to primary
(1)
amides represents an interesting topic in this area, however,
hazardous peroxides (TBHP), the toxic halogens, or an excess
amount of molecular sieves were required. Other attractive
approaches include the hydration of nitriles,7 oxidative amida-
We carried out experiments to test the reactivity of benzyl
tion of terminal alkynes,8 transition-metal-catalyzed C–H acti-
cyanide 1a with ammonium salts in the presence of a metal
vation and amidation9 and catalytic oxidation C–C bond
catalyst under an oxygen atmosphere and the obtained results
cleavage of ketones into benzamides.10 Although great progress
are compiled in Table 1. First, our studies started with the
has been achieved in this eld, there still remains signicant
reaction between benzyl cyanide 1a and 5.0 equiv. of ammonia
challenges for synthetic organic chemists in reactivity, effi-
(25% aqueous) in CH3CN at 120 ꢀC (Table 1, entries 1–5). When
ciencies, and high functional group tolerance.
5 mol% of CuCl was used as catalyst, the benzamide 2a was
Recently, C–C bond cleavage has become an attractive topic
obtained in 38% yield along with the hydration of nitrile
because of its potential usage in new chemical bond formation
products 2b (Table 1, entry 1). We then screened the types of
via inert starting materials.11 Also molecular oxygen has been
catalysts, and discovered that CuCl2 or Cu2O produces higher
considered as an ideal oxidant due to its atom-economical,
yields (Table 1, entries 4–5). However the products 2b was
environmentally benign, and abundance.12 However, few reac-
always by a product. Then, optimization studies were performed
tions are compatible with aerobic oxidation13 and C–C bond
to improve the yield of 2a. To our surprise, when ammonia was
cleavage in one transformation.14 Therefore, the development of
replaced with NH4Cl, 2a was obtained in 50% yield, and only
an efficient catalytic system towards aerobic oxidative
trace amounts 2b was observed (Table 1, entry 6). Four bases
unstrained C–C bonds cleavage is always highly desired. As our
were tested using Cu2O as the catalyst in CH3CN, and NaOH
showed the highest yield (Table 1, entries 6–9). Several copper
salts and amine salts were screened (Table 1, entries 10–16), and
Life Science, Hubei University of Science and the best result was obtained under Cu2O/NH4Cl/NaOH system
Non-power Nuclear Technology Collaborative Innovation Center, School of Nuclear
Technology and Chemistry
&
Technology, Xianning 437100, China. E-mail: cxl828800@163.com; sunshaofa@
mail.hbust.com.cn; Fax: +86-715-8338007
(Table 1, entry 9). Noteworthily, NaOH is essential for this
reaction. In the absence of NaOH, 2a could not be obtained at
all (Table 1, entry 17). The reaction did not proceed in the
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data for the products. See DOI: 10.1039/c7ra02207g
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Table 1 Optimization of the reaction conditionsa
Table 2 Cu-catalysed aerobic oxidative amidation of benzyl cyanide
with NH4Cl producing primary amidesa
Entry
1
Benzonitriles
Products
Yieldb
Entry
Cat
[N] source
Base
2ab%
2bb%
1
2
3
4
5
6
7
8
CuCl
Cu(OAc)2
CuO
NH3$H2O
NH3$H2O
NH3$H2O
NH3$H2O
NH3$H2O
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4Cl
NH4OAc
(NH4)2SO4
(NH4)2CO3
Urea
NH4Cl
NH4Cl
NH4Cl
NH4Cl
—
—
—
—
35
25
40
50
50
50
58
20
88
71
65
58
63
50
71
<1
—
20
30
41
25
31
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
Trace
<1
<1
1a
2a, 82%
CuCl2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuCl
CuCl2
Cu(OAc)2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
—
Ba(OH)2
KOH
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
2b, 81%
2c, 79%
2d, trace
2e, 81%
2f, 78%
2g, 83%
2h, 69%
Ca(OH)2
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
—
9
10
11
12
13
14
15
16
17
18
19c
20d
21e
NaOH
NaOH
NaOH
NaOH
—
Cu2O
Cu2O
Cu2O
Trace
20
13
NH4Cl
a
Reaction conditions: 2-benzyl cyanide 1a (0.2 mmol), cat (5 mol%), N
source (0.3 mmol), base (0.4 mmol), CH3CN (2 mL), in 25 mL Schlenk
b
tube, 120 ꢀC, O2 (1 atm), 30 h. Yields were determined by GC using
c
n-hexadecane as an internal standard. Air was used as oxidant.
d
Toluene as solvent. e DMF as solvent.
absence of copper catalyst (Table 1, entry 18). The reaction was also
dependent on dioxygen; when air was used as the oxidant, only
trace of 2a was obtained (Table 1, entry 19). Other solvents such as,
toluene and DMF gave lower yields (Table 1, entries 20–21).
With the optimal conditions in hand, the scope of copper-
catalyzed aerobic oxidative amidation of substituted 2-benzyl
cyanides with “NH2” producing primary amides was investi-
gated, the results were compiled in Table 2. A variety of 2-benzyl
cyanide with either an electron-donating or an electron-
withdrawing group, were all converted readily to the corre-
sponding primary amides efficiently. Thus, in addition to 2-
benzyl cyanide, benzyl cyanide with electron-donating substit-
uents methyl (–CH3), methoxy (–OCH3) reacted smoothly with
NH4Cl/NaOH to provide the corresponding primary amides 2a–
2c (Table 2, entries 1–3). However, when hydroxyl (–OH)
substituted 2-benzyl cyanide was used as a substrate, none of
the expected products were detected. This may have been due to
the interaction between the hydroxyl and base or oxidizing
agent, which would hinder the C–CN bond activation (Table 2,
entry 4). Benzyl cyanide with uoro (–F), chloro (–Cl), bromo
(–Br), iodo (–I), triuoromethyl (–CF3) or phenyl (–Ph) electron-
withdrawing groups served as good substrates to produce the
corresponding primary amides 2e–2j in excellent yields (Table 2,
1g
1h
9
1i
1j
2i, 78%
2j, 73%
2k, 92%
10
11c
1k
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Table 2 (Contd.)
used as a substrate under the standard reaction conditions, while
2a was not detected at all (eqn (2)). Benzaldehyde 1s was treated
under the optimized conditions, 2a was obtained in 15% yield
(eqn (3)), indicating that an aldehyde or acid was not the efficient
intermediate. The reaction of benzonitrile 1t with NH4Cl/NaOH
under standard conditions was also explored, and the desired
benzamide 2a was not detected at all, showing that benzyl
cyanide was not converted to benzonitrile via hydration of nitriles
to primary amides (eqn (4)). The reaction of benzoyl cyanide 1u
and NH4Cl/NaOH was performed in the absence of Cu2O, the
corresponding primary amide 2a was obtained in 89% yield (eqn
(5)). The results indicated that benzoyl cyanide 1u was the effi-
cient intermediate for this transformation, at rst benzyl cyanide
was converted to benzoyl cyanide via sp3 C–H bond oxygenation.
Under dry conditions and in the absence of air, the desired
product 2a was also generated in 82% yield under the optimal
conditions, thus the oxygen atoms of the product amides should
originate from molecular dioxygen (eqn (6)).
Entry
12
Benzonitriles
Products
Yieldb
1l
2l, 57%
13
14
15
1m
1n
1o
2m, 71%
2n, 63%
2o, 72%
(2)
(3)
(4)
(5)
16
1p
1q
2p, 71%
2q, 35%
17d
a
Reaction conditions: substrate 1a–1q (0.2 mmol), Cu2O (5 mol%),
NH4Cl (0.3 mmol), NaOH (0.4 mmol), CH3CN (2 mL), O2 in 25 mL
Schlenk tube, 120 ꢀC, 24 h. Isolated yield. c 16 h. d 48 h.
b
entries 5–10), and there is no sharp difference. Interestingly,
when nitro (–NO2) substituted 2-benzyl cyanide were used, the
corresponding 4-nitrobenzamide was obtained in high yield
and with short time (Table 2, entry 11).
Even the 1-(naphthalen-2-yl)acetonitrile and 2-(naphthalen-2-
yl)acetonitrile furnished the corresponding primary amide 2l and
2m in 57% and 71% yield respectively. The heteroaryl-substituted
primary amide 2n and 2o were obtained from the corresponding
2-(thiophen-2-yl)acetonitrile or 2-(pyridin-2-yl)acetonitrile under
the present Cu2O/NH4Cl/NaOH system. While, the reaction was
inuenced by the substituent steric effects. For example, the yield
of 2q was decreased for ortho-substituted 2-benzyl cyanide
contrast to para-substituted and meta-substituted 2-benzyl
cyanide (Table 2, entry 2, entries 16–17).
(6)
To get more information of the reaction mechanism, a few
potential intermediates were subjected to the reaction under
standard conditions. As shown below, phenylacetic acid 1r was
*The solvent CH3CN and 1a were dried, degassed by stan-
dard methods before use, and stored under nitrogen using
standard Schlenk techniques.
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amides is suggested in Scheme 1. The catalytic cycle reaction
involved sp3 C–H bond oxygenation of benzyl cyanide to the
intermediate benzoyl cyanide M and with the Cu catalyst being
regenerated, NH3 was generated from the heating of NH4Cl and
NaOH. Then intermediate benzoyl cyanide M was attacked by
NH3 to generate I, followed by C–CN bond cleavage affording
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Using readily available NH4Cl as a nitrogen source, conversion
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utilize inert starting materials to construct amides bond. The
present method is practical and economical, and the starting
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Financial supports by National Natural Science Foundation of
China (21603068), Science and Technology Innovation Team
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and research fund for the doctoral program of Hubei University
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