A facile tandem decyanation/cyanation reaction of α-iminonitriles toward cyano-substituted amides

Article abstract of DOI:10.1039/c8ob02186d

A new tandem decyanation/cyanation reaction of α-iminonitriles has been developed. A variety of cyano-substituted aryl amides and heteroaryl amides are synthesized in good yields. Both electron-rich and electron-deficient groups are compatible with the standard conditions. This reaction features a nonmetallic cyano source, tandem decyanation and cyanation reaction, waste utilization of the HCN from the hydrolysis of α-iminonitriles, formation of two important functional groups in one-step operation, etc.

Full text of DOI:10.1039/c8ob02186d

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Biomolecular Chemistry
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A facile tandem decyanation/cyanation reaction of
α-iminonitriles toward cyano-substituted amides†
Zhengwang Chen,
Xiaowei Wen,a Tanggao Liua and Min Ye*a
Cite this: Org. Biomol. Chem., 2018,
16, 8481
*
a,b Pei Liang,a Botao Liu,a Haiqing Luo,a Jing Zheng,a
Received 5th September 2018,
Accepted 23rd October 2018
DOI: 10.1039/c8ob02186d
rsc.li/obc
A new tandem decyanation/cyanation reaction of α-iminonitriles CNCH2CN, CNCH2CO2Et, BnCN, HCONH2, DMF/NH4X, and so
has been developed. A variety of cyano-substituted aryl amides on.5 Despite the significance of these methods, continuing to
and heteroaryl amides are synthesized in good yields. Both elec- explore new nonmetallic cyano-group sources involving high
tron-rich and electron-deficient groups are compatible with the efficiency and practicability would be highly desirable.6
standard conditions. This reaction features a nonmetallic cyano
Amides are ubiquitous in natural products, pharmaceuti-
source, tandem decyanation and cyanation reaction, waste utiliz- cals, polymers and synthetic intermediates.7 Accordingly,
ation of the HCN from the hydrolysis of α-iminonitriles, formation above 50% of known drugs contain amide moieties.8 As a
of two important functional groups in one-step operation, etc.
result, over the past decades many efforts have been devoted to
the acquisition of amide compounds. Considering the impor-
tance of these kinds of compounds, the alternative platform
for their preparation is of great interest in organic synthesis.
Typically, pyridyl benzamides and cyano-substituted aryl-
amides are frequently found in a variety of natural products,
pharmaceuticals and bioactive molecules.9 Conventionally, the
construction of cyano-substituted amides needs multistep pro-
cesses and metal cyanides to introduce different functional
groups.10 Consequently, the development of efficient and ver-
satile methods for organic molecules with nitrile and amide
functionalities presents an important synthetic challenge.
α-Iminonitriles are valuable synthetic intermediates for the
preparation of amidines, α-keto acids, amides, N-alkyl ketene
imines, cyanoenamides, triazoles, aminopyrroles, and nitrogen
heterocycles.11 Several mild and practical routes have been
established and thus have increased the attractiveness of
α-iminonitriles in organic synthesis.12 Recently, Zhu’s group
reported an unprecedented alumina-promoted hydrolysis of
α-iminonitriles to amides with microwave irradiation.13
However, the production of the HCN byproduct may cause
environmental issue and limit the application in large scale
synthesis. In contrast, there are few reports involving the reten-
tion of the CN group in the product through the activation of
the C–CN bond.14 Herein, we present the first cyanation reac-
tion of iodo-substituted α-iminonitriles via the cleavage and
formation of the C–CN bond, thereby providing an effective
and unusual strategy for the synthesis of cyano-substituted
amides.
Nitrile and amide groups are considered as one of the most
fundamental groups in organic chemistry. Aryl and heteroaryl
nitriles are well represented throughout natural products,
pharmaceuticals, agrochemicals, and electronic materials.1
Moreover, the nitrile moiety is a versatile precursor for the
preparation of aldehydes, amides, amines, amidines, tetra-
zoles, and other carboxy derivatives.2 The Sandmeyer reaction
and Rosenmund–von Braun protocol are the most convention-
al methods to aryl nitriles, which require stoichiometric
amounts of CuCN and relatively harsh reaction conditions.3
Transition-metal-catalyzed cyanation of aromatic halides with
a range of cyanating reagents has made great progress in the
past decades.4 However, most of these approaches use highly
toxic and environmentally hazardous metal cyanide sources
such as CuCN, KCN, NaCN, Zn(CN)2, etc., restricting their
widespread applications. Recently, nonmetallic organic cyano-
group sources in the metal-catalyzed cyanation of aryl halides
have attracted significant attention, as they avoid producing
hazardous HCN gas and stoichiometric metal waste. These cya-
nating reagents include NCTS, acetone cyanohydrin, MeCN,
aKey Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan
Normal University, Ganzhou, 341000, China. E-mail: chenzwang@126.com,
yemin811@gnnu.cn; Fax: +86 797-8793670; Tel: +86 797-8793670
bKey Laboratory of Functional Molecular Engineering of Guangdong Province,
South China University of Technology, Guangzhou, 510640, China
†Electronic supplementary information (ESI) available: Experimental section,
characterization of all compounds, and copies of 1H and 13C NMR spectra of
selected compounds. CCDC 1844390. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c8ob02186d
Our investigation began with an unexpected discovery; the
original purpose was to carry out the Suzuki reaction between
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Scheme 1 Cyanation reaction of iodo-substituted α-iminonitriles to
cyano-substituted amides.
an iodo-substituted α-iminonitrile and phenylboronic acid
under palladium-catalyzed conditions. However, the cyanation
reaction occurred to afford cyano-substituted amides instead
of the Suzuki reaction (Scheme 1). Firstly, the reaction of (Z)-N-
(5-iodopyridin-2-yl)benzimidoyl cyanide 1a and Pd(PPh3)4 cata-
lyst was chosen as the model reaction to optimize the reaction
conditions. As shown in Table 1, the solvent played an impor-
tant role in transformation, and besides that THF–H2O can
promote the reaction, other co-solvents or water led to signifi-
cantly lower yields (entries 1–7). Then a variety of common in-
organic and organic bases were probed, and K2CO3 was found
to give the best results with the isolated yield improved to 92%
(entries 8–14). The reaction temperature was also evaluated,
and decreasing the temperature resulted in declined yields
(entries 15 and 16). Finally, it was unfavorable when the reac-
tion time was shortened to 8 hours (entry 17). Thus, it was
determined that K2CO3 at 70 °C in THF–H2O for 12 h was the
optimal reaction condition (entry 10).
Scheme 2 The synthesis of cyano-substituted pyridyl amides from
iminonitriles. Isolated yields. a10 mmol scale of the reaction.
With the optimal reaction conditions available, we next
investigated the scope and generality of this facile tandem
decyanation/cyanation approach to cyano-substituted amides.
The iodo-substituted pyridyl α-iminonitriles were prepared
conveniently based on our procedure.15 Initially, the phenyl
moiety was evaluated and the results are summarized in
Scheme 2. Both electron-rich and electron-deficient groups on
the benzene ring were well tolerated and furnished the corres-
ponding products in good yields (Scheme 2, 3b–g). The sub-
strates bearing a bulky tert-butyl group provided the product in
satisfactory yield (Scheme 2, 3c). To our excitement, the reac-
tion could be carried out on gram scale, furnishing the
product in high yield (3a). The structure of 3a was further
determined based on X-ray diffraction (Fig. 1).16
Table 1 Optimization of the reaction conditionsa
Next, we tested the substrate scope of the 2-amino pyridine
moiety under the standard conditions (Scheme 3, 4a–h). The
reaction conditions were compatible with a series of substitu-
ents, such as methyl, methoxy, fluoro, chloro, bromo and tri-
fluoromethyl functional groups. We were pleased to find that
the bromo group was able to maintain in the palladium-cata-
lyzed cross coupling reaction. Especially aryl bromide can be
used for further synthetic application under transition-metal-
catalyzed conditions (Scheme 3, 4g). Moreover, the strong elec-
tron-withdrawing group, trifluoromethyl group, was also suit-
able for the reaction and gave high yield (Scheme 3, 4h).
Entry
Solvent
Base
Temp.
Yieldb (%)
1
H2O
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOt-Bu
Cs2CO3
K2CO3
K3PO4
TEA
DABCO
DBU
K2CO3
K2CO3
K2CO3
70
70
70
70
70
70
70
70
70
70
70
70
70
70
50
25
70
n.p
65
26
2c
THF/H2O
DMF/H2O
DMSO/H2O
EtOH/H2O
Dioxane/H2O
CH3CN/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
3c
4c
n.p
n.p
n.p
n.p
Trace
95
98(92)
n.p
30
50
n.p
90
52
78
5c
6c
7c
8c
9c
10c
11c
12c
13c
14c
15c
16c
17c,d
a Reaction conditions: 1a (0.2 mmol) with catalyst (5 mol%) in 1 mL
solvent for 12 h. b Determined by GC with mesitylene as the internal
standard. Number in parentheses is isolated yield. c The volume ratio
of water and other solvents is 1 : 1. d Reacted for 8 h.
Fig. 1 X-ray crystal structure of 3a.
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Scheme 5 The synthesis of 3a from bromo or chloro-substituted
α-iminonitriles.
tuted product was obtained in high yield (Scheme 4, 5g).
Interestingly, the reaction worked well when ortho iodo substi-
tuted aniline was employed, and gave better yield compared
to the meta iodo substrate (Scheme 4, 5e and 5h).
Disappointingly, the reaction failed to work when the iodo was
attached to the benzoyl moiety.
Besides iodo-substituted α-iminonitriles, bromo or chloro-
substituted substrates were also tried under the standard con-
ditions, however, 1x afforded 3a in moderate yield and 1y furn-
ished the product in low yield (Scheme 5). Moreover, when the
substrates contained I and Br or I and Cl, the cyanation reac-
tion mainly happened with the C–I bond.
Scheme 3 The synthesis of cyano-substituted pyridyl amides from
iminonitriles. Isolated yields.
On the other hand, we continued to extend the strategy to
N-phenyl α-iminonitriles. The α-iminonitrile substrates were
synthesized according to Zhu’s oxidative Strecker approach.12a
We tried the palladium-catalyzed intramolecular cyanation
reaction under the standard conditions mentioned above,
however, it failed to form the desired products. After some
attempts, we found that solvent is essential to the transform-
ation, and the reaction proceeded smoothly in acetonitrile
solvent. As illustrated in Scheme 4, substituted α-iminonitriles
with the iodo group at different positions of the aniline moiety
underwent smooth reaction to afford the products in moderate
to good yields (Scheme 4, 5a–h). Irrespective of the electronic
nature of the substituents, the reactions were well tolerated
(Scheme 4, 5b–e). To our delight, the trifluoromethyl substi-
To understand the origin of the carbonyl oxygen atom in
the amide product, an isotope-labeled reaction was performed
to gain evidence under standard conditions with H218O, and
GCMS spectra demonstrated that 3a-O18 was obtained in 95%
yield. This isotope-labeled experiment showed that the oxygen
was from water (Scheme 6, eqn (1)). Moreover, 1a could be
hydrolysed to the corresponding amide under the standard
conditions without palladium catalyst with 98% yield for 8 h
(Scheme 6, eqn (2)). Based on the previous reports4,13 and our
experimental observations, we proposed a possible mechanism
shown in Scheme 7. Initially, α-iminonitrile 1a was hydrolysed
to amide 6a and the CN anion was released under base con-
ditions. Then oxidative addition of palladium to aryl iodide to
formed intermediate B, which via transmetalation yielded
intermediate C. Finally, reductive elimination afforded product
3a and regenerated the palladium catalyst to complete the
catalytic cycle (Scheme 7).
In conclusion, we have developed a novel tandem decyana-
tion and cyanation reaction with various iodo-substituted
α-iminonitriles. Under mild conditions, a broad range of
cyano-substituted aryl amides were obtained in good yields.
This methodology will prevent or reduce the release of hazar-
dous HCN gas in the hydrolysis of α-iminonitriles through
Scheme 4 The synthesis of cyano-substituted phenyl amides from
iminonitriles. Isolated yields.
Scheme 6 Controlled experiments.
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Acknowledgements
We are grateful for financial support from the the NSFC
(21562003), the NSF of Jiangxi Province (20171ACB21048), and
the NSF of Jiangxi Provincial Education Department
(GJJ160924, GJJ160956). This research was also partially sup-
ported by the Open Fund of the Key Laboratory of Functional
Molecular Engineering of Guangdong Province, South China
University of Technology (2017kf04).
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