Difluorocarbene-Based Cyanation of Aryl Iodides

Article abstract of DOI:10.1055/s-0039-1691590

A large number of efficient cyanation methods have been developed because of the wide range of applications of nitriles, but conventional methods usually suffer from the need for a toxic cyanation reagent. Although difluorocarbene chemistry has received increasing attention, the use of difluorocarbene as a sources of the nitrile carbon for nitrile groups remains largely unexplored. We describe a difluorocarbene-based cyanation of aryl iodides promoted by a cheap copper source, Cu(NO ₃) ₂ ·2.5H ₂ O, under an air atmosphere. Ph ₃ P ⁺ CF ₂ CO ₂^-, an easily available and shelf-stable difluorocarbene reagent, and NaNH ₂ are used as the carbon source and the nitrogen source for the nitrile group, respectively. The cyanation protocol is attractive because no toxic reagent is used and performing the reactions under an air atmosphere is operationally convenient.

Full text of DOI:10.1055/s-0039-1691590

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
A
en
Synlett
Y.-X. Zhang et al.
Letter
Difluorocarbene-Based Cyanation of Aryl Iodides
Yin-Xiang Zhanga,b◊
Xuan Xiaoa,b◊
Zhi-Hong Fub,c◊
Jin-Hong Lin*b
Yu Guo*a
Xu Yao*a
Yu-Cai Caod
Ruo-Bing Dub
Xing Zheng*a
R
R
Cu(NO3)2
I
+
CF2
+
NaNH2
CN
Ji-Chang Xiao*b
18 examples
R = aryl, alkyl, alkoxy, CO2Et, NO2, or I
up to 78% yield
a
Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center
for Molecular Target New Drug Study, Hunan Provincial Key Laboratory of Tumor Microen-
vironment Responsive Drug Research, University of South China, 28 Western Changsheng
Road, Hengyang, Hunan 421001, P. R. of China
guoyuhy@126.com
yaoyao19840415@126.com
zhengxing9166@sohu.com
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
b
University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, P. R. of China
jlin@sioc.ac.cn
jchxiao@sioc.ac.cn
c
School of Materials Science and Engineering, Southwest Petroleum University, Xindu,
Chengdu 610500, P. R. of China
State Key Laboratory of Polyolefins and Catalysis, Shanghai Key Laboratory of Catalysis
Technology for Polyolefins, Shanghai Research Institute of Chemical Industry Co. Ltd.,
Shanghai, P. R. of China
d
◊
These authors contributed equally to this work.
Received: 15.01.2020
Accepted after revision: 15.01.2020
Published online: 03.02.2020
therefore significant efforts have been devoted to the devel-
opment of efficient cyanation reagents. Commonly used
3
4
DOI: 10.1055/s-0039-1691590; Art ID: st-2019-r0642-l
nucleophilic cyanation reagents such as TMSCN, KCN, or
5
CuCN are highly toxic and are prone to undergo hydrolysis
Abstract A large number of efficient cyanation methods have been
developed because of the wide range of applications of nitriles, but con-
ventional methods usually suffer from the need for a toxic cyanation re-
agent. Although difluorocarbene chemistry has received increasing at-
tention, the use of difluorocarbene as a sources of the nitrile carbon for
nitrile groups remains largely unexplored. We describe a difluorocarbe-
ne-based cyanation of aryl iodides promoted by a cheap copper source,
with generation of hazardous HCN gas. Electrophilic cyana-
tion can deliver products that cannot be easily obtained by
using nucleophilic reagents, and consequently various elec-
trophilic cyanation reagents have been developed, includ-
6
7
8
9
ing X–CN (X = Cl, Br), N–CN, I–CN, and S–CN reagents.
However, the X–CN (X = Cl, Br) reagents are volatile and
highly toxic, and the preparation of the other reagents re-
quire the use of poisonous nucleophilic cyanation reagents.
+
–
Cu(NO ) ·2.5H O, under an air atmosphere. Ph P CF CO , an easily
3
2
2
3
2
2
available and shelf-stable difluorocarbene reagent, and NaNH are used
2
as the carbon source and the nitrogen source for the nitrile group, re-
spectively. The cyanation protocol is attractive because no toxic re-
agent is used and performing the reactions under an air atmosphere is
operationally convenient.
Recently, many easily handled cyanation reagents have
10
emerged, such as CH CN, DMF alone or in combination
3
11
12
with a nitrogen source, or DMSO with a nitrogen source.
The emergence of these large numbers of reagents has al-
lowed the development of a variety of cyanation methods
for the synthesis of various nitrile-containing molecules.
Key words difluorocarbene, cyanation, nitriles, copper, aryl iodides
13
Nitriles are widely present as key structural motifs in
Because of the wide availability of aryl halides, the cya-
nation of aryl halides, catalyzed or promoted by a complex
natural products, pharmaceuticals, and agrochemicals, and
they have emerged as versatile intermediates in organic
of a transition metal such as Pd,14 Cu,
10c,11c,15
or Ni, serves
16
1
synthesis. Consequently, the incorporation of a nitrile
as an effective protocol for the synthesis of aryl nitriles
(Scheme 1, eq 1). However, Pd catalysts are quite expensive
and Pd catalysts can be readily deactivated due to the
group into organic molecules has received increasing atten-
2
tion. Cyanation is apparently one of the most straightfor-
–
14a,b
ward strategies for the installation of a cyano group, and
strong binding ability of the CN anion.
The
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
Y.-X. Zhang et al.
Letter
Rosenmund–von Braun reaction is a classic method for the
Cu-promoted cyanation of aryl halides,17 but requires the
use of the toxic reagent CuCN in excess. In early studies on
transition-metal-catalyzed or -promoted cyanations of aryl
halides, toxic inorganic cyanide salts were frequently
ed by the cheap copper complex Cu(NO ) ·2.5H O, under an
3
2
2
+
–
air atmosphere by using Ph P CF CO as the difluorocarbe-
3
2
2
ne source (Scheme 1, eq 2).
Our initial attempts at difluorocarbene-based cyanation
of 4-iodobiphenyl (1a) using sodium amide (NaNH ) as the
2
4,14c
used.
K [Fe(CN) ] is a safe inorganic salt, but its low sol-
nitrogen source successfully gave the desired product 2a,
but only in a low yield (Table 1, entry 1). A brief survey of
transition-metal compounds, including Cu and Pd complex-
es (entries 1–6), revealed that Cu(NO ) ·2.5H O was a suit-
4
6
ubility and its low rate of transmetalation limit its wide-
18
spread application. Organic cyanide precursors, such as
TMSCN, acetone cyanohydrin,20 or alkyl nitriles,
1
9
16a,d
and
or
3
2
2
+
– 11c,21
combined cyanide sources, including DMF/[NH X ],
able choice (entry 4). Because the use of a ligand might be
favorable, we screened various ligands L1–L4 (entries 7–
10). The yield was significantly increased by using L4 as a
ligand (entry 10). Other reaction solvents were found to be
inferior to DMF (entries 10–14), although a moderate yield
was obtained in hexamethylphosphoramide (HMPA; entry
4
1
3g
CO /NH , have also proved to be quite effective for the cy-
2
3
anation of aryl halides, but some reagents, such as TMSCN
and acetone cyanohydrin are toxic, and the reactions can
require an inert atmosphere, the handling of gases, or the
use of an expensive catalyst or ligand. It is therefore appar-
ent that it is highly desirable to develop operationally con-
venient protocols for the cyanation of aryl halides by using
easily available reagents.
Table 1 Optimization of the Reaction Conditionsa
[M], ligand
Ph3P CF2CO2–
+
Ph
I
+
+
NaNH2
Ph
CN
Previous work:
DMF, 130 °C
10 h
1a
2a
L4
R
R
[Pd], [Cu], or [Ni]
X
+
[CN]
CN
(1)
t-Bu
t-Bu MeO2C
CO2Me
X = I, Br or Cl
CN]:
N
N
N
N
N
N
N
N
[
L1
L2
L3
Inorganic salts: NaCN, KCN, Zn(CN)2, CuCN
K4Fe(CN)6
highly toxic
weakly reactive
Metal compound [M] Ligand (mol%) Ratiob
Yield (%)
c
Organic precusors and combined sources:
Entry
HO CN
toxic or
expensive transition metal
TMSCN R-CN DMF + NH4HCO3 CO2 + NH3
1
2
Cu(OAc)2
CuOAc
–
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:2:3.5:1.8
1:1.5:2:1.3
1:1.5:2:1.3
1:1.5:2:0.5
1:1.5:2:1.3
22
10
30
44
13
12
34
47
42
66
2
–
This work:
R
3
CuI
–
R
Cu(NO3)2
I
+
CF2
+
NaNH2
CN
(2)
4
Cu(NO ) ·2.5H O
–
3
2
2
5
PdCl
PdCl
2
(PPh
3
)
2
–
Scheme 1 Cyanation of aryl halides
6
2
(dppf)
–
7
Cu(NO
Cu(NO
Cu(NO
3
3
3
)
)
)
2
2
2
·2.5H
·2.5H
·2.5H
2
2
2
O
O
O
L1 (10)
L2 (10)
L3 (10)
L4 (10)
L4 (10)
L4 (10)
L4 (10)
L4 (10)
L4 (5)
L4 (5)
L4 (5)
L4 (5)
As an active intermediate, difluorocarbene has found
8
22
widespread applications in synthetic chemistry. Typical
transformations of difluorocarbene include [2+1] cycliza-
9
23
10
11d
Cu(NO ) ·2.5H O
tion with alkenes or alkynes, insertion into X–H bonds (X
3
3
3
3
3
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2a,24
25
=
N, O, S),
coupling with other carbenes, and transi-
Cu(NO
Cu(NO
Cu(NO
Cu(NO
Cu(NO
)
)
)
)
)
·2.5H
·2.5H
·2.5H
·2.5H
·2.5H
O
O
O
O
O
26
tion-metal-catalyzed transfer reactions. We recently de-
veloped the mild difluorocarbene reagent Ph P CF CO ,
2e
1
1
1
1
ND
22
52
70
34
12
11
+
–
3
2
2
3f
27
which is easily accessible and shelf stable. The use of this
reagent as a difluorocarbene source allowed us to discover
that difluorocarbene can be captured by a suitable source of
sulfur, selenium, or nitrogen to generate thiocarbonyl
fluoride (CF =S), selenocarbonyl fluoride (CF =Se), and cya-
nide anion (CN ), respectively, thereby offering new possi-
bilities for difluorocarbene chemistry. The transformation
into CN was developed into a synthetic tool to enable the
incorporation of a nitrile groups into alkanes. These find-
ings prompted us to investigate the installation of cyano
groups into arenes to provide aryl nitriles. Here we describe
a difluorocarbene-based cyanation of aryl iodides promot-
4g
5h
28
29
30
16
17h
i
3 2 2
Cu(NO ) ·2.5H O
Cu(NO ) ·2.5H O
3
2
2
2
2
–
8h
1
CuI
a
3 2 2
Reaction conditions: 1a (0.2 mmol), Ph CO
P+CF –, metal complex, ligand,
–
NaNH , anhyd DMF (1.5 mL), under air, 130 °C, 10 h.
2
b
c
d
e
f
+
–
30
3 2 2 2
Molar ratio 1a/Ph P CF CO /NaNH /[M].
Determined by GC/MS analysis. ND = Not Detected
Dimethyl carbonate was used as the reaction solvent.
DME was used as the reaction solvent.
NMP was used as the reaction solvent.
HMPA was used as the reaction solvent.
Reaction time 15 h.
g
h
i
Reaction time 6 h.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
Synlett
Y.-X. Zhang et al.
Letter
+
–
trile group, respectively.30 Indeed, in this aryl halide cyana-
tion process, the desired conversion was almost completely
suppressed without their presence (Scheme 3). Almost no
1
4). Decreasing the loadings of Ph P CF CO , NaNH , and
3
2
2
2
the Cu complex resulted in slight increases in the yield on
prolonging the reaction time to 15 hours (entries 10 and
15). The yield markedly decreased on shortening the reac-
product 2a was observed when NaNH was not used, fur-
2
tion time (entry 16). A catalytic amount of the Cu source
did not promote this reaction effectively (entry 17). Al-
though a 30% yield was obtained by using CuI (1.8 equiv) as
the copper source (entry 3), the yield was not increased by
concurrently using L4 as a ligand with 1.3 equivalents of
CuI (entry 18).
ther indicating that NaNH is the nitrogen source. In the ab-
2
+
–
sence of Ph P CF CO , product 2a was obtained in low
3
2
2
yield, suggesting that the predominant carbon source is
+
–
Ph P CF CO . DMF might also serve as a nonnegligible
3
2
2
source of carbon,1
1b,c,21
A 52% yield was obtained by using
HMPA as the reaction solvent instead of DMF (Table 1, entry
+
–
With the optimal reaction conditions in hand (Table 1,
entry 15), we investigated the substrate scope of the difluo-
rocarbene-based cyanation of aryl halides promoted by
14), further confirming that Ph P CF CO and NaNH are,
3 2 2 2
respectively, the sources of the C and N atoms of the CN
group.
31
Cu(NO ) ·2.5H O under an air atmosphere (Scheme 2).
3
2
2
optimal conditions
+
Ph3P CF2CO2–
(x equiv)
The process could be extended to a wide range of aryl
iodides 1a–o. Electron-rich, -neutral, and -deficient aryl
iodides were all converted into the desire products 2a–o in
moderate to good yields. Various functional groups were
tolerated under these conditions, including ether, ester,
nitro, and hetaryl groups. Aryl bromides showed a low re-
activity, and a low yield (25%) of 2a was obtained from bro-
mobenzene. When the substrate contained both Br and I
atoms, a mixture of the C–I and C–Br cyanation products 2p
and 2q was produced. In this case, although a dicyanation
product was detected by GC/MS analysis, it was produced
only in a trace amount and could not be isolated. Aryl chlo-
rides were inert toward this cyanation transformation.
Ph
I
+
+
NaNH2
Ph
CN
(
0.2 mmol)
(y equiv)
2a
Yielda (%)
x
y
0
0
0
2
trace
trace
17
1.5
0
Scheme 3 The identification of the carbon source and the nitrogen
source for the CN group. The optimal conditions were those shown in
Table 1, entry 15. a Determined by GC/MS analysis.
On the basis of the above results and our previous stud-
30
ies on difluorocarbene-based cyanation of alkenes, we
propose the plausible mechanism shown Scheme 4. Difluo-
+
–
rocarbene generated from Ph P CF CO reacts with NaNH2
3
2
2
+
–
–
We have previously reported that Ph P CF CO and
to produce a CN anion through sequential formation of in-
3
2
2
30
NaNH can act as sources of carbon and nitrogen for a ni-
termediates A, B, and C (major pathway). The generation
2
of CN– from the DMF/NaNH system cannot be excluded
2
11b,c
(
minor pathway).
Because of its strong oxidizing power,
Cu can be readily reduced to Cu in the reaction system.
The coordination of a ligand and CN gives the Cu CN com-
X
Cu(NO ) •2.5H O, L4
CN
3
2
2
II
I
32
+
–
+
Ph3P CF2CO2
+
NaNH2
R
R
DMF, 130 °C, 15 h
–
I
1
2
2
plex D. Oxidative insertion of CuI into the Ar–I bond deliv-
X = I
III
ers ArCu CN (intermediate E), reductive elimination from
CN
CN
CN
CN
CN
CN
which affords the final product. Although the last reductive
Ph
MeO
BnO
EtO2C
2d, 40%
CN
t-Bu
I
elimination also releases the catalyst Cu , a stoichiometric
a, 68%
2b, 62%
2c, 71%
2e, 63%
II
amount of the Cu source is still necessary, probably be-
CN
CN
O2N
CN
cause the reductive elimination proceeds quite slowly
and/or the Cu is deactivated by coordinating ligands.
O2N
I
I
2f, 64%
2g, 54%
2h, 36%
2i, 74%
2j, 41%
CN
Major pathway for CN– generation:
NaNH2
H
N
CN
CN
H
F
N–
F
– F–
NC
Ph P+CF CO
–
CF2
F
H
HN
3
2
2
H
H
B
F
F
NC
2l, 73%
S
O
Minor pathway for CN– generation:
A
C
n, 66%a
2o, 50%a
X = Cl
[Cu]
2k, 65%
2m, 78%
2
– HF
O
O
O
NH
NaNH2
– H+
X = Br
CH3
CN–
N
CH
CN
CN
H
N
H
N
H
N
NC
Br
I
CN
CH3
CuII
CuI
CH3
CH3
CuI
ligand
CuII
Ph
2p
2q
b
Ph
2a, 25%
2a, 0%
L
2
p + 2q: 50% yield; 2p:2q = 1.6:1
Ar-I
Ar-CN
ArCuIIICN
L-Cu CN
I
Scheme 2 Difluorocarbene-based cyanation of aryl halides. Reagents
E
D
+
–
and conditions: 1 (0.5 mmol), Ph P CF CO (1.5 equiv),
3
2
2
Scheme 4 The proposed mechanism
Cu(NO ) ·2.5H O (1.3 equiv), L4 (5 mol%), NaNH (2 equiv), dry DMF (4
3
2
2
2
mL), under air, 130 °C, 15 h. Isolated yields are reported.
a
For products 2n and 2o, the reaction time was 20 h. b Both 2p and 2q
In summary, we have described a difluorocarbene-
based cyanation of aryl iodides promoted by a cheap copper
source, Cu(NO ) ·2.5H O, under an air atmosphere.
were obtained from the conversion of 4-bromo-4′-iodobiphenyl; the
molar ratio (1.6:1) was determined by H NMR spectroscopy.
1
3
2
2
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
Synlett
Y.-X. Zhang et al.
Letter
+
–
Ph P CF CO , an easily available and shelf-stable reagent,
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3
2
2
and NaNH act as the sources of carbon and nitrogen, re-
2
(
spectively, for the CN group. This convenient cyanation pro-
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find application in the synthesis of aryl nitriles.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691590.
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©
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(31) Cyanation of Aryl Iodides 1; General Procedure
Under air atmosphere, a reaction tube was charged with the
+
–
appropriate aryl iodide 1 (0.5 mmol), Ph P CF CO (268 mg,
3
2
2
(24) (a) Thomoson, C. S.; Dolbier, W. R. Jr. J. Org. Chem. 2013, 78,
0.75 mmol, 1.5 equiv), ligand L4 (6.3 mg, 5 mol%), Cu(NO ) ·2.5
3 2
8904. (b) Xie, Q.; Ni, C.; Zhang, R.; Li, L.; Rong, J.; Hu, J. Angew.
H O (143 mg, 0.65 mmol, 1.3 equiv), NaNH (39 mg, 1.0 mmol,
2 2
Chem. Int. Ed. 2017, 56, 3206.
25) (a) Hu, M.; Ni, C.; Li, L.; Han, Y.; Hu, J. J. Am. Chem. Soc. 2015,
2.0 equiv), and anhyd DMF (4 mL). The mixture was stirred at
130 °C for 15 h, then cooled to rt and filtered through a pad of
Celite that was washed with CH Cl . The combined organic
(
137, 14496. (b) Zheng, J.; Lin, J.-H.; Yu, L.-Y.; Wei, Y.; Zheng, X.;
2
2
Xiao, J.-C. Org. Lett. 2015, 17, 6150. (c) Zhang, Z.; Yu, W.; Wu, C.;
Wang, C.; Zhang, Y.; Wang, J. Angew. Chem. Int. Ed. 2016, 55, 273.
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phase was washed with H O (3 × 15 mL), and the organic layer
2
was further washed with sat. aq Na SO and sat. brine, then
2
3
(
dried (Na SO ) and concentrated under vacuum. The residue
2 4
(
(
b) Feng, Z.; Min, Q.-Q.; Zhang, X. Org. Lett. 2016, 18, 44.
c) Feng, Z.; Min, Q. Q.; Fu, X. P.; An, L.; Zhang, X. Nat. Chem.
was purified by flash column chromatography.
9,9-Dimethyl-9H-fluorene-3-carbonitrile (2k)
2
017, 9, 918. (d) Fu, X.-P.; Xue, X.-S.; Zhang, X.-Y.; Xiao, Y.-L.;
Zhang, S.; Guo, Y.-L.; Leng, X.; Houk, K. N.; Zhang, X. Nat. Chem.
019, 11, 948.
27) (a) Zheng, J.; Cai, J.; Lin, J.-H.; Guo, Y.; Xiao, J.-C. Chem. Commun.
013, 49, 7513. (b) Deng, X.-Y.; Lin, J.-H.; Zheng, J.; Xiao, J.-C.
The reaction was performed on a 0.6 mmol scale. Yellow oil;
yield: 85 mg (65%). IR (neat): 3062, 2962, 2924, 2866, 2223,
1609, 1485, 1471, 1447, 1416, 1302, 1283, 1219, 1077, 1023,
2
–1 1
(
893, 835, 783, 759, 737 cm
. H NMR (400 MHz, CDCl ):  =
3
2
7.80–7.72 (m, 2 H), 7.69 (s, 1 H), 7.62 (d, J = 7.9 Hz, 1 H), 7.46 (d,
13
Chem. Commun. 2015, 51, 8805.
J = 7.1 Hz, 1 H), 7.43–7.34 (m, 2 H), 1.48 (s, 6 H). C NMR (101
(
28) (a) Zheng, J.; Wang, L.; Lin, J.-H.; Xiao, J.-C.; Liang, S. H. Angew.
Chem. Int. Ed. 2015, 54, 13236. (b) Zheng, J.; Cheng, R.; Lin, J.-H.;
Yu, D. H.; Ma, L.; Jia, L.; Zhang, L.; Wang, L.; Xiao, J.-C.; Liang, S.
H. Angew. Chem. Int. Ed. 2017, 56, 3196. (c) Yu, J.; Lin, J.-H.; Xiao,
J.-C. Angew. Chem. Int. Ed. 2017, 56, 16669.
MHz, CDCl ):  = 154.19, 154.16, 143.8, 137.2, 131.4, 129.1,
3
127.5, 126.4, 122.9, 121.1, 120.5, 119.7, 110.1, 47.1, 26.8. HRMS
+
(EI); m/z [M] calcd for C16H13N: 219.1048; found: 219.1054.
(32) Shi, R.; Zhang, H.; Lu, L.; Gan, P.; Sha, Y.; Zhang, H.; Liu, Q.;
Beller, M.; Lei, A. Chem. Commun. 2015, 51, 3247.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–E