An aerobic and green C-H cyanation of terminal alkynes

Article abstract of DOI:10.1039/d0ob01928c

This study describes a benign C-H cyanation of terminal alkynes with α-cyanoesters serving as a nontoxic cyanide source. In situ generation of the key copper cyanide intermediate is proposed by a sequence of α-C-H oxidation and copper-mediated β-carbon elimination of α-cyanoesters, releasing the α-ketoester byproduct observed experimentally. The ensuing reaction of copper cyanide with terminal alkynes delivers preferentially cyanoalkynes and surpasses the possible Glaser type dimerization of terminal alkynes or the undesired accumulation of HCN under protic conditions. The presence of the co-oxidant K2S2O8 is crucial to this selectivity, probably by promoting oxidative transmetalation and the resulting formation of the Cu(iii)(acetylide)(CN) intermediate. All the reagents and salts used are commercially available, cheap and nontoxic, avoiding the use of highly toxic cyanide salts typically required in cyanation studies. The scope of this reaction is demonstrated with a set of alkynes and α-cyanoesters. The application of this method to late-stage functionalization of the terminal alkyne group in an estrone derivative is also feasible, showing its practical value for drug design.

Full text of DOI:10.1039/d0ob01928c

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An aerobic and green C-H cyanation of terminal alkynes†
View Article Online
DOI: 10.1039/D0OB01928C
a
a
a
Peng-Fei Zhu, Yi-Xin Si, and Song-Lin Zhang*
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
5
Abstract: This study describes a benign C-H cyanation of terminal alkynes with α-cyanoesters serving as a nontoxic cyanide source. In-situ
generation of key copper cyanide intermediate is proposed by a sequence of α-C-H oxidation and copper-mediated β-carbon elimination of α-
cyanoesters, releasing α-ketoesters byproduct observed experimentally. Ensuing reaction of the copper cyanide with terminal alkynes delivers
preferentially cyanoalkynes, and surpasses possible Glaser type dimerization of terminal alkynes or the undesired accumulation of HCN under
protic conditions. The presence of co-oxidant K S O is crucial to this selectivity, probably by promoting oxidative transmetalation and the
1
0
2
2
8
resulting formation of Cu(III)(acetylide)(CN) intermediate. All the reagents and salts used are commercially available, cheap and nontoxic,
avoiding the use of highly toxic cyanides salts typically required in cyanation studies. The scope of this reaction is demonstrated with a set of
alkynes and α-cyanoesters. Application of this method to late-stage functionalization of terminal alkyne group in an estrone derivative is also
feasible, showing its practical value for drug design.
1
2
2
3
3
4
4
5
5
0
5
0
5
0
5
0
The prevalence of nitrile-containing compounds in
intermediate with terminal alkynes to forge the alkynyl-CN
1
pharmaceuticals, agrochemicals and materials, and the 55 bond. While the Glaser type dimerization of terminal alkynes
2
versatile reactivity of cyano group have boosted continuous
efforts to the synthesis of nitriles. Traditionally, nitriles are
prepared by methods such as dehydration of amides or oximes
in the presence of dehydrating agents, or nucleophilic
is a very typical and privileged reaction under Cu/O
2
1
9
oxidative conditions, it requires that reaction of L
n
Cu-CN
intermediate with terminal alkynes is quick enough to
suppress Glaser type dimerization. Finally, the avoidance of
aromatic cyanation of aryl diazonium salts or halides with a 60 generation of flammable HCN is a superior task for any
3
,4
stoichiometric amount of toxic CuCN. Recent endeavor in
transition metal catalysis has allowed catalytic cyanation of
aryl halides or boronic acids/esters by cyanide salts (Scheme
cyanation reactions under protic conditions. This also requires
that L Cu-CN intermediate generated in-situ is consumed
n
quickly through productive reaction with terminal alkynes.
5
-7
1a).
However, inherent drawbacks associated with the
(a) aryl nitriles synthesis
current methods, in particular the need for highly toxic
cyanide salts, have brought about safety concerns, and greatly
impeded the practical application of these methods. This has
prompted recent efforts to pursue safer cyanation chemistry
X
CN
M
+
m-CN
8
-10
X: preinstalled groups
avoiding the manipulation of toxic cyanide salts.
highly toxic
e.g. halo, B(OH)
2
, etc
Cyanoalkynes are useful synthetic building blocks with
broad applications, in particular in the preparation of
heteroarenes. Currently, the preparation of cyanoalkynes has
been dominated by cyanation of terminal alkynes with toxic
cyanide salts (e.g. NaCN, CuCN), I-CN and amino-CN
(b) cyanoalkynes synthesis
m-CN
or
M
H
+
CN
I-CN, N-CN etc
1
1
sources (Scheme 1b), as well as other peculiar methods
highly toxic
1
2,13
using azides.
Direct terminal alkyne C-H cyanation by a
(c) This study: oxidative cyanation of terminal alkynes
1
4
nontoxic organic cyano source remains very rare.
R'
Cu/O2
Our recent efforts using α-cyanoesters as a type of readily
available, green and easy-to-handle cyano source have
enabled the development of efficient and green cyanation of
Ar
H
+
Ar
CN
NC
2
CO R
2 2 8
K S O
Cu / O2
Ar
H
1
5
aryl iodides, boronic acids, and styrenes. These reactions
occur in the presence of a copper salt under aerobic
2 2 8
K S O
O
O
CuL
n
LnCu
R'
1
6
R'
LnCu-CN
conditions to facilitate the C-CN bond cleavage in α-
1
7,18
NC
CO
2
R
NC
CO R
cyanoesters,
thus offering the prerequisite cyanide in a
2
O
safe and green way without the manipulation of toxic cyanide
salts or reagents. To probe the probability of direct C-H
cyanation of terminal alkynes using α-cyanoesters as the
nontoxic source, we noticed that several potential challenges 65 Scheme 1 Methods for nitriles synthesis.
are waiting to be resolved. The first one is the effective in-situ
β-C
elimination
R'
CO R
2
(
Isoated with R' = Ph )
To meet the above demands, we report herein the
development of direct C-H cyanation of terminal alkynes by
α-cyanoesters serving as the safe and convenient cyano source
n 2
formation of the putative L Cu-CN intermediate via Cu/O
accelerated C-CN bond cleavage of α-cyanoesters. Second,
the acceleration and selectivity of reaction of L Cu-CN
n
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 1

Organic & Biomolecular Chemistry
Page 2 of 6
(
Scheme 1c). This reaction is convenient, robust and selective 40 obtained in low yield, byproducts were observed including
View Article Online
diynes arising from Glaser-type dimerization, oligomers of
DOI: 10.1039/D0OB01928C
to produce propiolonitriles, which can suppress potential
Glaser-type oxidative alkyne dimerization and the undesired
formation of flammable and dangerous HCN gas despite the
protic environment. This is a great advantage compared to
alkynes from Sonogashira-type coupling and other identified
byproducts in some cases. This also highlights the optimized
conditions in promoting the selective formation of 3a and
5
methods using cyanides salts where HCN is believed to be a 45 suppressing the formation of byproducts. Finally, it was found
severe byproduct under protic conditions. The choice of a
suitable co-oxidant is crucial to achieve this high reactivity
and selectivity. Interestingly, this method can also allow
cyanation of aryl and vinyl halides and boronic acids,
that the yield can further be improved to 60% with 3
equivalents of cyanoester (entry 14).
Notably, other α-cyanoacetic esters analogous to 2a were
also examined for this cyanation reaction, but gave lower
1
0
significantly broadens the scope of nitriles accessible. The 50 yields than 2a (Table 2). For example, 2b, 2c and 2d gave the
synthetic potential of this method is demonstrated in the late-
stage functionalization of estrone derivatives. Finally, the
mechanism of this reaction is discussed.
desired 3a in 51%, 40% and 46% yields under the conditions
of entry 14.
ae
Table 2. Various α-cyanoesters sources evaluated
1
5
Table 1 Optimization study
CN
CN
CuI
Ligand
O
CuI 1 equiv
O
Phen 1 equiv
NC
+
OR'
+
NC
OEt
Cl
1a (0.5 mmol)
K
2
S
2
O
8
1 equiv
, 130 oC, 12 h
2
Cl
Cl
oxidant, solvent
Cl
R
NMP, O
o
2
O , 130 C, 12 h
1a
2a
2
(1.5 mmol)
3a
3a
yield
(%)
55
entry
1
α-cyanoester 2
yield of 3a
Ligand
Oxidant
solvent
b
entry
O
1
2
3
4
5
6
7
8
9
Phen
K S
2
K S
2
K S
2
K S
2
K S
2
K S
2
K S
2
K S
2
K S
2
2
2
2
2
2
2
2
2
2
O
8
NMP
NMP
NMP
NMP
NMP
DMF
DMSO
DMA
60
NC
PPh
3
O
O
O
O
O
O
O
O
8
8
8
8
8
8
8
8
trace
trace
trace
25
trace
trace
trace
trace
trace
trace
trace
trace
60
OEt
2a
PCy
3
O
DPPF
-
51
2
NC
NC
NC
OMe
OEt
2
b
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
O
3
4
40
46
NMP/DMF(1:1)
Ph
2
c
1
1
1
0
1
2
TBHP
NMP
NMP
NMP
NMP
O
O
H
2
O
2
S
-
c
2d
1
3
K
2
S
2
O
8
d
55
1
4
K
2
S
O
2 8
NMP
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), CuI (0.5 mmol),
ligand (0.5 mmol), co-oxidant (0.5 mmol) and solvent (3 mL) under O
H
CN
2
CuI 1 equiv
Phen 1 equiv
o
b
balloon at 130 C for 12 hours. Isolated yields of 3a by column
O
c
o
d
e
R
+
R
NC
K S O 1 equiv
chromatography. Reaction at RT or 40 C. 2a used in 1.5 mmol. Phen,
1,10-phenanthroline; PCy tricyclohexylphosphane; DPPF,
bis(diphenylphosphanyl) ferrocene; NMP, N-methylpyrrolidinone.
2
2
8
OEt
NMP, O
2
, 130 oC, 12 h
2
0
3
,
1
(0.5 mmol)
2a (1.5 mmol)
3
CN
CN
CN
CN
CN
Our study began by reaction of para-chlorophenyl
acetylene and ethyl α-cyanoacetate under copper/oxygen
condition (Table 1), with the anticipation of generation of
cyanide from α-cyanoacetate via oxidative C-CN bond
Cl
F
2
3
3
5
0
5
3a, 60%
3e, 66%
3b, 49%
3c, 24%
3d, 69%
CN
CN
CN
1
5,16
cleavage.
a was produced in 55% isolated yield promoted with
CuI/phenanthroline (phen) using K S O as the co-oxidant in
After great efforts, it was found that the desired
MeO
3
2
O N
O
2
2
8
3f, 61%
3g, 25%
CN
3h, 44%
NMP (entry 1). Phenanthroline is found to perform better than
other ligands, such as phosphines (entries 2-5). NMP is a
preferred solvent that likely stabilizes the cyanide generated
CN
CN
CN
CN
in situ (entries 6-9). K
2
S
2
O
8
is a crucial co-oxidant for this
Cl
Cl
n-Bu
3
F C
reaction (entries 1 & 10-12), which likely accelerates the
desired reaction of in-situ generated Cu-CN with terminal
alkyne, and thereby minimizes potential side reaction of
Glaser-type dimerization of terminal alkynes toward
conjugated diynes, or cyanide protonation to the undesired
HCN. In cases where the desired cyanoalkyne 3a was
3j, 62%
3k, 61%
3p, 54%
3q, trace
3
i, 56%
poor examples:
CN
CN
S
CN
PhO
N
3l, cpl mix.
3m, cpl mix.
3n, cpl mix.
3o, N.R.
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 6
Organic & Biomolecular Chemistry
Scheme 2 Substrate scope of C-H cyanation of various terminal alkynes.
Isolated yields are reported. Symbol “cpl mix.” means complex mixture;
N.R. means no reaction. 3c suffers from severe lost during workup due to
volatile property.
3
5
tetramethylpiperidinyloxo)
methylphenol) were added in the reaction solution, the desired
or
BHT
(2,6-ditertbutyl-4-
View Article Online
DOI: 10.1039/D0OB01928C
3
a was obtained in trace amounts. Interestingly, a new
compound was found as the major product by TLC and
5
With the optimized conditions developed (entry 14, Table
), terminal alkynes with a range of substituents on the 40 phenyl-α-ketoester 8 (Scheme 4). This finding indicates that
isolated in 49% and 10% yields, which was identified to be α-
2
1
1
aromatic ring were studied (Scheme 2). Substituents including
halo, alkyl, phenyl, nitro and ester are tolerated on the
aromatic ring. Interestingly, substituents at either para-, meta-
or ortho-position have no appreciable impact on the reaction
radical species might probably be involved in the reaction.
Possibly, radical species rad1 is initially generated, followed
by oxygen insertion to give rad2 which can abstract a
1
6
1
1
2
2
0
5
0
5
hydrogen to give a peroxide compound (Scheme 4).
efficiency, as reflected by the yields of 3a, 3i and 3j. However, 45 Oxidation of the Cu(I) precatalyst by this peroxide gives a
2
-thiophenyl and 3-pyridyl acetylenes were poor substrates,
Cu(II)-oxide intermediate Int. Then, β-carbon elimination
occurs from Int through a typical four-membered ring
transition state TS releases α-ketoester 8 observed, and a
giving complex mixtures. This is attributed to the
coordinating ability of the heteroaryl ring to copper that might
trap the Cu-CN generated in-situ and thus impedes the
approach and installment of cyanide to the alkyne terminus.
Gratifyingly, this method was found to also enable
cyanation of aryl and vinyl halides, and boronic acids (please
see ESI† for more details).
1
8
Cu(II)-CN intermediate.
O
O
O
R
I
I
NC
Cu /L
Cu /L
NC
NC
OEt
OEt
OEt
CuII
O2
L
n
O
R
R
O
HO
Int
HO
To show the capability of this method for practical drug
design, late-stage functionalization of an estrone derivative 5
is demonstrated (Scheme 3). The desired product 6 was
obtained introducing a propiolonitrile to replace the original
radical pathway
Oxidation
Ar
H
X
N
C
O
2 2 8
1/2 K S O
II
CuIII CN
L
n
Cu -CN
2
0
L
CuII
L
n
hydroxyl group in estrone.
OEt
O
R
Int2
HSO ꢀ
oxidative
transmetalation
O
4
R
O
TS
Ar
OEt
O
O
O
2 2
i) Tf O, EtN(iPr)
reductive
elimination
β-C elimination
ii) Sonogashira reaction
iii) desilylation
standard
conditions
H
H
H
H
H
H
H
H
H
Ar
CN
HO
50
5
NC
6, 33%
Light yellow solid
estrone
H
Scheme 5 Mechanism proposed.
Scheme 3 Late-stage functionalization of an estrone derivative 5.
Thus, a plausible mechanism is proposed to involve initial
copper-mediated oxidation of the cyanoacetate to produce
copper(II) alkoxide compound Int following
a
radical
H
1
6
5
5
pathway (Schemes 4 and 5). From Int, β-C elimination
CN
II
CuI 1 equiv
Phen 1 equiv
O
occurs to produce key intermediate L
n
Cu -CN through a
17,18
Cl
typical four-membered ring transition state TS,
with the
1
a (0.5 mmol)
+
OEt
2 2 8
K S O 1 equiv
+
NC
O
Cl
release of α-ketoester observed experimentally. This
oxidation/C-C cleavage sequence to generate cyanide is
reminiscent of the metabolism of nitrile compounds in
biological systems. At this stage, the oxidative transmetalation
O
NMP, O
2
,
OEt 130 oC, 12 h
3a
8
Ph
c (1.5 mmol)
6
0
2
49%
10%
TEMPO (2 equiv)
trace
trace
BHT (2 equiv)
II
initiation
of the L Cu -CN with terminal alkyne assisted by K S O
n
2
2
8
III
likely gives preferentially
a
Cu (acetylide)(CN) type
O
O
O
O
2
NC
O
intermediate Int2 (Scheme 5). The K S O co-oxidant plays a
2 2 8
NC
H
NC
O
OEt
OEt
OEt
65 crucial role to promote this oxidative transmetalation, which
thereby suppresses the competing Glaser type dimerization of
alkynes and other side reactions. Finally, reductive
elimination from Int2 produces the cyanoalkyne target
compound.
Ph
rad1
O
Ph
HO
Ph
rad2
CuI
HO
N
O
O
C
NC
O
II
[Cu]
OEt
[
Cu ]-CN
OEt
[
CuII]
Ph
O
Ph
TS
7
0
Conclusions
α-ketoester
Int
8
β-C elimination
In summary, this study reports a copper-mediated C-H
cyanation of terminal alkynes using α-cyanoacetates as the
nontoxic cyano source. A sequence of oxidation/C-CN bond
cleavage is proposed to generate Cu-CN intermediate with the
release of α-ketoesters observed experimentally. This reaction
is robust, selective and most importantly safe, avoiding the
use of toxic cyanide salts previously required. This reaction
3
0
Scheme 4 Radical trapping study and characterization of an α-ketoester
intermediate.
To shed light on the reaction, radical trapping studies were
conducted. Under the optimized conditions, when two
7
5
equivalents
of
additional
TEMPO
(2,2,6,6-
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Organic & Biomolecular Chemistry
Page 4 of 6
1
1
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boronic acids, further broadening the synthetic scope. This
method is also demonstrated in the late-stage functionalization
of estrone derivatives.
DOI: 10.1039/D0OB01928C
6
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0
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0
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0
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MOE@SAFEA for the “111 Project” (B13025) and national
first-class discipline program of Food Science and Technology
1
0
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(
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0
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a
Key Laboratory of Synthetic and Biological Colloids, Ministry of
1
2
2
3
3
4
4
5
5
6
5
0
5
0
5
0
5
0
5
0
Education, School of Chemical and Material Engineering, Jiangnan
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8
5917763; E-mail: slzhang@jiangnan.edu.cn
1
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†
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| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

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Organic & Biomolecular Chemistry
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Review of C-H oxidation by Cu/O
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system, see: R. Trammell, K.
View Article Online
DOI: 10.1039/D0OB01928C
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Minor amounts of byproduct was observed resulting from hydration
of the alkyne in estrone 5, which was not appreciable for other
substrates examined.
The fate of radical scavengers could not be determined after the
reactions despite great efforts.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

Organic & Biomolecular Chemistry
Page 6 of 6
View Article Online
DOI: 10.1039/D0OB01928C
R'
Cu/O2
Ar
H
+
Ar
CN
NC
CO R
2
K S O
8
2
2
Green: using readily available and nontoxic organic cyano source
Selective:
Ar
Ar
(
Glaser type dimerization)
Ar
CN
H CN
(
typical under protic conditions)
This study reports C-H cyanation of terminal alkynes with α-cyanoacetates serving as readily
available and friendly cyano source under Cu/O conditions.
2