Transition-Metal-Free Deacylative Cleavage of Unstrained C(sp3)-C(sp2) Bonds: Cyanide-Free Access to Aryl and Aliphatic Nitriles from Ketones and Aldehydes

Article abstract of DOI:10.1021/acs.orglett.5b03367

A transition-metal-free deacylative C(sp³)-C(sp²) bond cleavage for the synthetically practical oxidative amination of ketones and aldehydes to nitriles is first described, using cheap and commercially abundant NaNO₂ as the oxidant and the nitrogen source. Various nitriles bearing aryl, heteroaryl, alkyl, and alkenyl groups could be smoothly obtained from ketones and aldehydes in high yields, avoiding highly toxic cyanides or transition metals.

Full text of DOI:10.1021/acs.orglett.5b03367

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Deacylative Cleavage of Unstrained C(sp3)−
C(sp2) Bonds: Cyanide-Free Access to Aryl and Aliphatic Nitriles from
Ketones and Aldehydes
Jing-Jie Ge,†,§ Chuan-Zhi Yao,†,§ Mei-Mei Wang,† Hong-Xing Zheng,† Yan-Biao Kang,*,†
and Yadong Li†,‡
†Center of Advanced Nanocatalysis, Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026,
China
‡Department of Chemistry, Collaborative Innovation Center for Nanomaterial Science and Engineering, Tsinghua University, Beijing
100084, China
S
* Supporting Information
ABSTRACT: A transition-metal-free deacylative C(sp3)−C(sp2)
bond cleavage for the synthetically practical oxidative amination of
ketones and aldehydes to nitriles is first described, using cheap and
commercially abundant NaNO2 as the oxidant and the nitrogen
source. Various nitriles bearing aryl, heteroaryl, alkyl, and alkenyl
groups could be smoothly obtained from ketones and aldehydes in
high yields, avoiding highly toxic cyanides or transition metals.
thioamides, acids, esters, heterocyclic compounds, etc.5,6
he selective cleavage of unstrained C−C bonds has been
1−4 The cleavage of unstrained
Tprogressing in recent years.
Conventional methods to access nitriles, such as the Sandmeyer
and Rosenmund von Braun reactions, were widely employed in
the early years.7 Recently, metal cyanides, metalloid cyanides
C−C single bonds2 has always been a critical issue due to its
uncontrollable selectivity and inertness compared to the strained
C−C bonds such as cyclopropanes with strained small rings or
tertiary alcohols with high steric repulsion.3,4 Transition-metal-
catalyzed C−C bond activation has been frequently reported
using palladium and copper as catalysts. For example, Murakami
and co-workers developed palladium-catalyzed C−C bond
cleavage of three to five membered rings.3 Jiao and co-workers
reported copper-catalyzed deacylative C−C bond cleavage under
oxidative conditions, patterned in a Bayer−Villager type of
oxidative C−C bond cleavage.2 To date, the deacylative C−C
bond cleavaging oxidative amination reaction toward nitriles
under transition-metal-free conditions has not yet reported.
Nitriles are ubiquitous building blocks in organic synthesis,
pharmaceutics (Figure 1), and chemical engineering, as they can
be easily transformed into aldehydes, amines, amides,
n
[MCN (M = Na, K, Zn, Cu), TMSCN, Bu3SnCN, K3Fe-
(CN)6],8 and organonitriles9,10 as direct CN sources have also
been established. Other methods have also been reported.11,12
Nevertheless, to the best of our knowledge, no example has been
reported to date in which nitriles were directly prepared through
C−C bond cleavage from carbonyl compounds under transition-
metal-free conditions. Herein, we report a practical AlCl3-
promoted oxidative amination of ketones and aldehydes using
NaNO2 via unstrained C(sp3)−C(sp2) bond cleavage.
Initially, using the oxidative amination of 1-phenyl-2-actone
(1a) as a model reaction, different nitrogen sources were selected
to optimize conversions (Table 1). Using anhydrous aluminum
chloride as the Lewis acid and NaNO2 as the oxidant as well as
nitrogen source, 1a was obtained in 90% conversion (entry 1). It
was found out that both AlCl3 and NaNO2 were necessary for the
oxidative amination of 1a to 2a (entries 2 and 3). One advantage
for this approach was that the reaction was not air or moisture
sensitive and could be run under open air. The reaction under
argon atmosphere afforded the same conversion as that under
open air (entries 5 and 1), indicating that air was not the oxygen
source. Other nitrogen sources such as NaNO3 and t-BuONO
gave much lower conversions (entries 6 and 7). Using
ammonium hydroxide as the nitrogen source was not successful
(entry 8). The radical trapping agent TEMPO could partially
inhibit the reaction (entry 9). Brønsted acids such as acetic acid
Received: November 24, 2015
Figure 1. Nitrile-containing pharmaceuticals.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03367
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Organic Letters
Letter
a
a
Table 1. Reaction Conditions
Scheme 1. Reaction Scope
b
entry
Lewis acid (equiv)
AlCl3 (2)
[N]
atmosphere
conv (%)
1
2
3
4
5
6
7
8
NaNO2
NaNO2
open air
open air
open air
argon
90
0
AlCl3 (2)
AlCl3 (1)
AlCl3 (2)
AlCl3 (2)
AlCl3 (2)
AlCl3 (2)
AlCl3 (2)
AcO2H (1)
TfOH (1)
BF3·OEt2 (1.0)
0
NaNO2
NaNO2
NaNO3
tBuONO
NH3·H2O
NaNO2
NaNO2
NaNO2
NaNO2
53
90
53
39
0
argon
open air
open air
open air
open air
open air
open air
open air
c
9
16
1
10
11
12
11
16
a
Reaction conditions: 1a (0.5 mmol), AlCl3 (2 equiv), [N] (10 equiv),
b
DMF (0.5 M), 90 °C, open air, 1.5 h. Determined by GC using
dioxane as the internal standard. With 1.6 equiv TEMPO to NaNO2.
c
See the Supporting Information for details.
and TfOH and BF3·OET2 fail to promote this reaction (entries
10−12). The conditions described in entry 1 were chosen as the
standard conditions for further study.
The scope of this deacylative C−C bond cleavage oxidative
amination of ketones and aldehydes to nitriles was then
investigated. Aryl and alkyl ketones and aldehydes could be
smoothly converted to the desired nitriles (Scheme 1). For
example, various aryl and heteroaryl nitriles were obtained in
high isolated yields (1b−m). The substrates bearing other
carbonyl groups instead of an acetyl group could also give the
desired nitriles in high yields (Scheme 1, 1n and 1o). Similar to
the reaction of 1o, both PhCN and MeCN have been detected by
GC. Actually, under open air, most MeCN was evaporated.
However, acetic acid was also afforded. After workup, only PhCN
was isolated in 91% yield. The unstable enone substrate 1p could
give the corresponding product in acceptable yield. Besides
(hetero)aryl ketones, this method is also suitable for conversion
of aliphatic ketones to the corresponding nitriles in high yields
(Scheme 1, 1q−t). What should be noted is that aldehydes 1u
and 1v were also successfully converted to nitriles.
a
Reaction conditions: 1 (2 mmol), NaNO2 (10 equiv), AlCl3 (2.0
b
equiv), DMF (0.5 M), 90 °C, monitored by TLC; isolated yields. 120
°C. 100 °C. Determined by GC using dioxane as an internal
standard. See the Supporting Information for details.
c
d
The kinetic isotope effect (KIE) for 1a is described in Scheme
2. A second-order KIE with a value of 0.7 was found for 1a-D
(Scheme 2, top). For the compound 1a′-D, a kH/kD of 1 was
observed. No KIE of 1a-D or 1a′-D indicates the rate-
determining step is a C−H cleavage step. Compound 3 was
initially hypothesized as a possible intermediate for the
conversion to nitrile 2a, and a first-order KIE was observed
(Scheme 2, bottom). Another possible intermediate 4a was
observed by GC−MS. Compound 4a could not be directly
detected by 1H NMR, whereas 1,2-dione 5a was observed by 1H
NMR. Oxime 4a could be converted to nitrile 2a in 78% yield
under standard reaction conditions, but the substrate 1a′ bearing
an α-methyl group is difficult to convert to 2a (Scheme 3).
Therefore, 4a could be the intermediate in this reaction.
Scheme 2. Kinetic Isotope Effects
A possible reaction mechanism is proposed in Scheme 4. First,
1a reacts with NaNO2 and AlCl3 probably via nitric oxide radical
to form intermediate A,4a which quickly tautomerized to B. The
existence of B is supported by observation of 4a by GC−MS
experiments (Scheme 3). Intermediate B transforms to final
target nitrile 2a via Beckmann fragmentation.
B
DOI: 10.1021/acs.orglett.5b03367
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Organic Letters
Letter
Funds for the Central Universities of China (WK2060190022,
Scheme 3. Control Experiments
WK2060190026, WK3430000001) for financial support.
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unstrained C−C bond cleavage which provides highly efficient
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amination of ketones and aldehydes to nitriles in high yields
and wide scope. The use of cheap and commercially abundant
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nitrogen source avoids highly toxic cyanides and expensive
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03367.
Experimental details and spectroscopic data for all
products (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ybkang@ustc.edu.cn.
Author Contributions
§J.-J.G. and C.-Z.Y. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(NSFC 21404096, U1463202) and the Fundamental Research
■
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