The direct electrophilic cyanation of β-keto esters and amides with cyano benziodoxole

Article abstract of DOI:10.1039/c4ob02032d

The direct electrophilic α-cyanation of β-keto esters and amides has been developed using a hypervalent iodine benziodoxole-derived cyano reagent. The procedure is accomplished within 10 min and without the use of any catalyst in DMF, at room temperature. Thus, the highly functionalized quaternary carbon-centered nitriles were produced in high to excellent yields.

Full text of DOI:10.1039/c4ob02032d

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The direct electrophilic cyanation of β-keto esters
and amides with cyano benziodoxole†
Cite this: DOI: 10.1039/c4ob02032d
Received 24th September 2014,
Accepted 15th October 2014
Yao-Feng Wang, Jiashen Qiu, Dejie Kong, Yongtao Gao, Feipeng Lu,
Pran Gopal Karmaker and Fu-Xue Chen*
DOI: 10.1039/c4ob02032d
www.rsc.org/obc
The direct electrophilic α-cyanation of β-keto esters and amides
has been developed using a hypervalent iodine benziodoxole-
derived cyano reagent. The procedure is accomplished within
10 min and without the use of any catalyst in DMF, at room temp-
erature. Thus, the highly functionalized quaternary carbon-
centered nitriles were produced in high to excellent yields.
The introduction of a cyano group into various substrates has
received considerable research attention because it was discov-
ered to be an important functional group among natural pro-
ducts, pharmaceuticals, materials, agrochemicals as well as
versatile intermediate with diverse transformations.1 In
general, the strategies for cyanation mainly include nucleophi-
lic and electrophilic reactions. Typically, nucleophilic substi-
tution of RX (X = leaving group) with inorganic cyanides is
widely employed in both lab and industry (Scheme 1A). In the
last decade, considerable progress has been achieved in
nucleophilic addition of cyanide to electrophiles (Scheme 1B).
Among them, racemic and asymmetric synthesis of cyano-
hydrins through 1,2-addition of cyanide to aldehydes and
ketones,2 synthesis of α-amino-nitriles with imines (Strecker
reaction),2g,3 and preparation of β-cyano-carbonyl compounds
via 1,4-addition of cyanide with α,β-unsaturated carbonyl sub-
strates,4 have been well established and/or comprehensively
reviewed (Scheme 1B). In contrast, electrophilic cyanation has
been less explored in previously studied reports5 and mostly
accomplished under strong basic conditions (Scheme 1C).
On the other hand, α-functionalization of carbonyl com-
pounds could directly produce large numbers of interesting
synthetic building blocks and molecules.6 Various transform-
ations, particularly through the electrophilic reaction pathway,
have been developed such as α-fluorination,7 halogenation,8
hydroxylation,9 arylation,10 trifluoromethylation,7b,11 trifluoro-
Scheme 1 Strategies for direct cyanation.
methylthiolation,12 and azidation.13 Therefore, it was hypo-
thesized that direct cyanation could be achieved through
electrophilic substitution of carbonyl compounds with a hyper-
valent iodine(III)-CN reagent (Scheme 1D). Herein, we report
for the first time α-cyanation of β-keto esters and amides
within 10 min using cyano benziodoxole C1 as the electrophi-
lic cyanating agent.
Considering the high reactivity of the hypervalent iodine
reagent,6c,d,14 hypervalent iodine(III)-CN reagents (C1, C2) were
prepared by the following modified procedures.15 Addition of
1.5 mol% of CsF made the synthesis of cyano benziodoxole C1
from acetoxyiodinane precursor and Me3SiCN complete in a
School of Chemical Engineering & the Environment, Beijing Institute of Technology,
5 South Zhongguancun street, Haidian district, Beijing 100081, China.
E-mail: fuxue.chen@bit.edu.cn; Fax: (+86)10-68918296
†Electronic supplementary information (ESI) available: Experiment procedure,
characterization data, 1H and 13C NMR spectra. See DOI: 10.1039/c4ob02032d
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Table 1 Optimization of the cyanation of 1aa
Scheme 2 Control experiments.
Yieldb (%)
Entry
Cyanide
Solvent
Time (h)
2a
4a
1
2
3
4
5
6
7
C1
C2
C3
C4
C1
C1
C1
C1
C1
C1
DMF
DMF
DMF
DMF
CH2Cl2
Toluene
THF
CH3CN
CH2Cl2
DMF
0.15
3
3
83
—
Trace
—
Trace
—
—
68
23
Trace
—
27
36
—
3
12
12
12
12
12
0.15
9
8
Trace
17
95
9c
10d
—
—
a Unless otherwise noted, the reaction conditions are as follow: 1a
(0.1 mmol), cyanide (0.12 mmol, 1.2 equiv.), solvent (0.5 mL), room
temperature. b Isolated yield. c 20 mol% Cu(OTf)2 was used. d Solvent
(0.2 mL).
short time and improved yield on gram scale, which was
reported by Zhdankin16a in the direct cyanation of methyl of
N,N-dimethylaryl amines and by Kita.16b The treatment of the
chloroiodinane precursor with KF was followed by a substi-
tution reaction with Me3SiCN to produce the desired cyano-
iodinane C2 in 45% yield (not optimized).15
Scheme 3 Substrate scope of the electrophilic cyanation.a,b aUnless
otherwise noted, the reaction conditions are as follow: 1 (0.1 mmol), C1
(0.12 mmol, 1.2 equiv.), DMF (0.2 mL) at room temperature for 10 min.
bIsolated yield. cC1 (0.2 mmol, 2 equiv.); reaction time: 1 h. dReaction
time: 0.5 h. Ad = adamantyl.
With these electrophilic cyanating agents in hand, acidic
β-keto ester 1a was chosen as the model substrate to establish
the direct cyanation reaction with the results listed in Table 1.
To our delight, a complete conversion of 1a to the desired
nitrile 2a, in 83% yield, was initially observed with C1 in DMF
without any catalyst (entry 1). Surprisingly, only the hydroxyl
product 4a was isolated in 68% yield with C2 (entry 2). Then,
other known cyanating agents, cyanogen bromide (C3)5g and
1-cyanobenzotriazole (C4),5h,i were examined, and it was found
that they did not give the desired product 2a but instead gave
4a to some extent (entries 3–4). Subsequently, screening of
different solvents was carried out. Poor yields were obtained in
CH2Cl2 and CH3CN, whereas toluene and THF gave 4a as the
main product (entries 5–8). Other non-polar solvents hardly
yielded any conversion due to the poor solubility of C1 in
them. Interestingly, in CH2Cl2, Lewis acid Cu(OTf)2 catalyzed
the title reaction to some extent (entry 9 vs. 5), which could be
a clue to the asymmetric version. DMF was found to be the
best solvent, partially because of the good solubility of C1 in it.
Excellent yield (95%) was achieved in concentrated reaction
medium (entry 10).
over, the yield of 4a increased with prolonged reaction time in
each solvent, which could possibly be explained by the slow
hydrolysis of these cyano hypervalent iodine reagents in the
presence of moisture in the solvent.17 Such hydroxylation reac-
tion was shown in previously studied reports using N-sulfonyl-
oxaziridines, and other compounds.9 To further verify it,
hydroxy hypervalent iodine reagents 3a and 3b were prepared
and applied to the reaction affording 4a in 45% and 77%
yield, respectively (Scheme 2). And the prepared 3b produced
4a more quickly than C2 (Scheme 2, 3b vs. entry 2, Table 1).
With the optimized conditions, the substrate scope of the
direct electrophilic cyanation of keto esters and amides was
investigated, and the results are shown in Scheme 3. Various
β-keto esters derived from indanone gave the corresponding
products with excellent yields (2a–2i). The nitrile product
derived from tetralone (2j) was obtained in good yield, though
As shown in Table 1, C2 and C3 gave more byproduct 4a
than C1, which was attributed to their low stabilities. More-
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the reaction was a little slower. Cyanation of keto amides
1k–1o was also accomplished in good to excellent yields.
However, this protocol has its limitation: no conversion was
observed in the case of acyclic keto ester (1r).
In summary, we have developed an efficient direct electro-
philic cyanation of β-keto esters and amides with a cyano
benziodoxole reagent without any catalyst. The cyano hyper-
valent iodine(III)-CN (C1) was used as the electrophilic cyanat-
ing agent for the first time. The highly functionalized
quaternary carbon-centered nitriles were obtained in excellent
yields within 10 minutes. Further studies are underway to
expand the reaction scope and develop the asymmetric
version.
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Acknowledgements
The authors thank the National Natural Science Foundation of
China (21172018, 20972016) for financial support.
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