Catalytic Cyanation Using CO2 and NH3

Article abstract of DOI:10.1016/j.chempr.2018.09.009

Li and co-workers describe the catalytic cyanation of organic halides with CO₂ and NH₃. In the presence of Cu₂O/DABCO as the catalyst, a variety of aromatic bromides and iodides were transformed to the desired nitrile products with broad functional-group tolerance. Both ¹³C- and/or ¹⁵N-labeled nitriles were obtained conveniently with appropriately isotope-labeled CO₂ and NH₃. Construction of functionalized chemical compounds from small molecules in a highly selective and efficient manner is crucial for sustainable development. The chemical-based manufacturing sector of the future should aim to produce chemicals from very simple and abundant resources, just as nature uses CO₂ and N₂ to generate sugars, amino acids, and so forth. In practice, however, the utilization of CO₂ for the generation of industrial products, such as drugs and related intermediates, still remains a major challenge. Here, we describe the facile cyanide-free production of high-value nitriles with CO₂ and NH₃ as the sole sources of carbon and nitrogen, respectively. This practical and catalytic methodology provides a unique strategy for the utilization of small molecules for sustainable and cost-effective applications. Selective cyanation of aryl halides was achieved with CO₂ and NH₃ as the only sources of carbon and nitrogen, respectively. In the presence of Cu catalysts under low pressure (3 atm), a variety of aromatic iodides and bromides were transformed to the desired nitrile products without the use of toxic metal cyanides. Notably, olefins, esters, amides, alcohols, and amino groups were tolerated. Mechanistic studies suggest that Cu(III)-aryl insertion by isocyanate intermediates is involved. [¹³C,¹⁵N]-labeled nitriles were conveniently accessible from the respective isotope-labeled CO₂ and NH₃ via this methodology.

Full text of DOI:10.1016/j.chempr.2018.09.009

Article
Catalytic Cyanation Using CO and NH3
2
Hua Wang, Yanan Dong,
Chaonan Zheng, Christian A.
Sandoval, Xue Wang, Mohamed
Makha, Yuehui Li
zhengcn@suda.edu.cn (C.Z.)
yhli@licp.cas.cn (Y.L.)
HIGHLIGHTS
A highly efficient cyanide-free
protocol for cyanation of aryl
halides
2 3
CO and NH are the only sources
of carbon and nitrogen,
respectively
Cyanation based on copper
catalysis for small-molecule
activation
This method allows for facile
generation of isotope-labeled
nitriles
DATA AND SOFTWARE
AVAILABILITY
1
589821
Li and co-workers describe the catalytic cyanation of organic halides with CO
NH . In the presence of Cu O/DABCO as the catalyst, a variety of aromatic
bromides and iodides were transformed to the desired nitrile products with broad
2
and
3
2
1
3
15
functional-group tolerance. Both C- and/or N-labeled nitriles were obtained
conveniently with appropriately isotope-labeled CO and NH
2
3
.
Wang et al., Chem 4, 1–11
December 13, 2018 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.09.009

Please cite this article in press as: Wang et al., Catalytic Cyanation Using CO
j.chempr.2018.09.009
2 3
and NH , Chem (2018), https://doi.org/10.1016/
Article
Catalytic Cyanation Using CO and NH3
2
Hua Wang,1,5 Yanan Dong,1,4,5 Chaonan Zheng, * Christian A. Sandoval, Xue Wang,
2,
3
1
Mohamed Makha, and Yuehui Li1,6,*
1
SUMMARY
The Bigger Picture
Selective cyanation of aryl halides was achieved with CO
2
and NH
3
as the only
Construction of functionalized
chemical compounds from small
molecules in a highly selective and
efficient manner is crucial for
sustainable development. The
chemical-based manufacturing
sector of the future should aim to
produce chemicals from very
simple and abundant resources,
sources of carbon and nitrogen, respectively. In the presence of Cu catalysts un-
der low pressure (3 atm), a variety of aromatic iodides and bromides were trans-
formed to the desired nitrile products without the use of toxic metal cyanides.
Notably, olefins, esters, amides, alcohols, and amino groups were tolerated.
Mechanistic studies suggest that Cu(III)-aryl insertion by isocyanate intermedi-
1
3
15
ates is involved. [ C, N]-labeled nitriles were conveniently accessible from
2 3
the respective isotope-labeled CO and NH via this methodology.
2 2
just as nature uses CO and N to
INTRODUCTION
generate sugars, amino acids, and
so forth. In practice, however, the
Efficient C–C bond formation methods are fundamental for organic synthesis. For C1
chemicals, such as CO, HCHO, MeOH, and CO , their selective C–C coupling reaction
with other reagents represent powerful methodologies for the construction of structur-
2
utilization of CO for the
2
generation of industrial products,
such as drugs and related
1
–3
ally versatile products. Here, however, the organic chemists’ toolbox is rather limited.
Known strategies focus on the electrophilic property of the central carbon atom (for
intermediates, still remains a
major challenge. Here, we
2 3
CO , HCHO, and CH OH) or migratory insertion of CO to metal-carbon bonds. Carbon
describe the facile cyanide-free
production of high-value nitriles
dioxide is the most abundant carbon source and is thus regarded as the most promising
4
nontoxic C1 feedstock for the production of value-added chemicals. In the past de-
2 3
with CO and NH as the sole
cades, many strategies using organometallic chemicals or high-energy compounds
sources of carbon and nitrogen,
respectively. This practical and
catalytic methodology provides a
unique strategy for the utilization
of small molecules for sustainable
and cost-effective applications.
(
e.g. H
2 2
, silane, or borane) have been developed to transform CO into functionalized
compounds such as carboxylic acids, ureas, carbonates, and carbamates in both aca-
5
–13
demic laboratories and industry.
CO capture via C–N bond formation occurs conveniently to generate ureas, carba-
mates, formamides, and even isocyanates. Hence, C–C bond formation of CO in the
presence of amines is desirable for direct integration of the C–N moiety into organic
In the presence of amine nucleophiles, chemical
2
2
1
4–16
compounds, albeit highly challenging.
Ammonia is a similarly abundant small molecule used as an N-source feedstock for
the industrial production of fertilizers and as precursor for a variety of nitrogenous
2 3
compounds. Despite the various types of reactions utilizing CO and/or NH , their
use as carbon and nitrogen source for catalytic cyanation reactions remains un-
known. Cyanation of the carbon-halide bond is of significant importance in organic
1
7–22
synthesis and post-stage modification of complex molecules.
Despite this rele-
vance, industry predominately utilizes conventional cyanation methods based on
metal cyanides, which suffer from high toxicity and limited availability because of
2
3
handling restrictions.
As an important intermediate in biosystems, carbamoyl phosphate (CP) is synthesized
from bicarbonate and NH . Viewed as an active intermediate, CP is reported to be
3
24
the ‘‘CN’’ source of the [NiFe]-hydrogenase cyanide ligands. Here, enzyme-thiocarba-
mate dehydration to enzyme-thiocyanate, followed by 2e-reduction to cyanide ligand,
Chem 4, 1–11, December 13, 2018 ª 2018 Elsevier Inc.
1

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A
biosynthesis of CN
O
2
e-
enzyme
[NiFe]
[Co]
CN
CN
X
C
enzyme
CO2
NH3
+
NH2
- H O
2
X = O, S or NH
... ...
C-N intermediate
B
this work:
bio-inspired design
O
reductant
R
NH2
catalyst
Ar-X
CO2
NH3
+
Ar
C
N
-
H O
2
R = NH , H
2
C-C formation
C-N intermediate
CO /NH as the CN source
2
3
New route for C-C coupling
Ar
Ar
NH2
NH2
CO, HCO H
O
... ...
Broad functional group tolerance
Cu(III)-mediated catalysis
2
HCHO, CH OH
3
other C1 sources
related products
Figure 1. Cyanation Using CO
2
and NH
A) Natural cyanide generation involving multi-enzyme cooperation.
B) C–C bond formation of C–N-containing intermediates.
3
(
(
25,26
yields the iron-cyano complexes (hydrogenases) (Figure 1A).
elegant process in nature, we considered that a similar CO -to-intermediate strategy
can be developed for catalytic cyanation reactions, whereby CO (a bicarbonate equiv-
alent) and NH act as desirable cyanation reagents (Figure 1B). We herein disclose CO
and NH utilization for the cyanation of aryl and alkenyl halides via copper(III)-mediated
Inspired by this
2
1State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Suzhou Research Institute of
LICP, Center for Excellence in Molecular
2
3
2
Synthesis, Lanzhou Institute of Chemical Physics
3
(
LICP), Chinese Academy of Sciences, Lanzhou
C–C bond formation of isocyanate intermediates.
730000, P.R. China
2Laboratory of Molecular Neuropathology,
College of Pharmaceutical Sciences, Soochow
University, Suzhou 215123, P.R. China
RESULTS AND DISCUSSION
3Curiolex Ltd. (Shanghai), Shanghai 200120, P.R.
China
We began our study by investigating catalytic cyanation of o-methyliodobenzene
with 3 atm of CO
2 3
and NH (15/15 mL) and different metal salts and oxides. Among
4University of Chinese Academy of Sciences,
Beijing 100049, P.R. China
the tested metal sources, the desired product o-methylbenzonitrile was produced in
3
1%–40% yield when copper salts and oxides were used as catalyst in the presence
5These authors contributed equally
6Lead Contact
2
7,28
of PhSiH
3
as reductant under heating conditions (Table 1, entries 1–5).
The addi-
tion of amine ligand 1,4-diazabicyclo[2.2.2]octane (DABCO; 25 mol %) to the
cuprous oxide accelerated the reaction, giving 76% yield (Table 1, entry 6). Further
screening of other amine ligands, phenanthroline and tris(2-pyridylmethyl)amine,
*
Correspondence: zhengcn@suda.edu.cn (C.Z.),
yhli@licp.cas.cn (Y.L.)
https://doi.org/10.1016/j.chempr.2018.09.009
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2 3
Table 1. Catalytic Cyanation of o-Methyliodobenzene with CO and NH : Optimization of the
Reaction Conditions
Entry
Catalyst
PdCl
Ni(acac)
Ligand
–
Conversion (%)
Yield (%)
trace
2
a
1
2
100
96
42
42
51
87
30
36
66
55
62
96
2
3
4
5
6
7
8
2
–
Cu(OAc)
CuO
2
–
31
–
35
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
O
O
O
O
O
O
O
O
–
40
DABCO
Phen
TPMA
DABCO
DABCO
DABCO
DABCO
76
22
33
b
9
60
c
1
1
1
0
1
2
52
d
e
42
94
2 3 3
Reaction conditions: ArI (0.125 mmol), CO /NH (15/15 mL), Cat. (10 mol %), ligand (25 mol %), PhSiH (6.0
ꢀ
equiv) and NMP (0.5 mL), 130 C, 24 hr; GC yield. NMP, N-methyl-2-pyrrolidone; DABCO, 1,4-diazabicyclo
[2.2.2]octane; TPMA, tris(2-pyridylmethyl)amine; DMP, N,N-dimethylpropionamide; DMI, 1,3-dimethyl-2-
imidazolidinone. See also Figure S1 and Tables S1–S3.
a
5
2
mol % PdCl .
b
5
mol % Cu
2
O.
c
DMP as solvent.
d
e
DMI as solvent.
ꢀ
1
80 C.
revealed less efficiency than DABCO, resulting in moderate yields of 22% and
3%, respectively (Table 1, entries 7–8). Moderate reactivity was achieved
when the loading of Cu O was lowered to 5 mol % (60% yield; Table 1, entry 9).
3
2
Among screened solvents, moderate yields were obtained in N,N-dimethylpropio-
namide (DMP) and 1,3-dimethyl-2-imidazolidinone (DMI) for the desired product
(
42%–52% yields; Table 1, entries 10–11; see also Table S2). Increasing the initial re-
ꢀ
action temperature to 180 C with DABCO as ligand led to significant improvement
in the reactivity (76% versus 94% yields; Table 1, entries 6 and 12). Further lowering
the pressure to 1 or 2 atm resulted in decreased yields.
As described in Figure 1B, urea or carbamates could be formed from the condensa-
2 3 2 3
tion of CO and NH . Accordingly, a range of CO and NH substitutes such as urea,
isocyanates, or carbamates were identified as suitable CN sources (26%–86%
yields). Moreover, industrial waste polymethoxylsiloxane (PMHS, 78% yield) could
be used as the reductant, highlighting the application potential of this reaction sys-
2
9
tem. Importantly, such nitrile products can be transformed conveniently to many
3
0
nitrogenous compounds.
Encouraged by these results, we investigated the cyanation of different aryl iodides
with CO and NH (Scheme 1) under optimized conditions. Generally, moderate to
2
3
good reactivity was obtained for different kinds of substrates (40%–76% yields). This
system tolerates substrates with o-substitution better than m- or p-substitution on
the aryl ring. Specifically, both 2-iodotoluene and 2-iodo-1,3-dimethylbenzene
were smoothly transformed (64%–76% yields). Meanwhile, we found that the elec-
tronic effect of substituents varied. For example, in the presence of alkyl, chloro,
or alkoxy substituents, slightly lower yields were obtained. Notably, most of the
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I
CN
Cu O, DABCO
2
R
ꢀ
CO2/NH3
atm
R
o
PhSiH , 130 C
3
3
CN
CN
CN
CN
H C
3
CN
H C
3
Et
CH3
45%a
43%
51%
76%
52%
CN
CN
CN
CN
CN
O
EtO
N
N
H
HO
Ph
O
c
b,c
6
2%b
72% (88%)
b
b,c
68% (90%)
c
b,c
7
1% (89%)
0%b
4
CN
CN
CN
CN
O
O
CN
N
Cl
H
CN
56%
4
5%b
75% (94%)
b
b,c
43%
55%
CH3
F3C
CN
CN
CN
CN
CN
MeO
OMe
CH3
CF3
EtO
Cl
7%
4
4%b
5
62%
64%
61%
Scheme 1. Copper-Catalyzed Cyanation of Organic Iodides
ꢀ
Reaction conditions: Ar-I (0.125 mmol), Cu
2
3 2 3
O (10 mol %), DABCO (25 mol %), PhSiH (6.0 equiv), CO /NH (15/15 mL), NMP (0.5 mL), 130 C, 24 hr; GC
ꢀ
ꢀ
yield. Note a: 150 C. Note b: isolated yield. Note c: 180 C.
starting materials were recovered, showing excellent chemoselectivity. The incom-
plete conversions might be due to the consumption of CO
2
3
via reduction by PhSiH
3
,
1
leading to less efficient generation of active intermediates. Functional groups such
as hydroxyl, ester, amino, cyano, and amide groups were tolerated. Reactions under
ꢀ
elevated temperatures (180 C) gave the corresponding products in excellent yields
(
88%–94% yield).
The synthetic utilization of this cyanation system was further explored with readily
available aryl bromides as substrates. Here, a ‘‘one-pot two-step’’ procedure
4
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Br
CN
1
)
CuI, NaI, DMEDA
R
R
2
) Cu O, DABCO
2
PhSiH , CO /NH
3
2
3
CN
CN
CN
CN
H C
3
CN
EtO
N
CH3
H3C
O
6
8%
58%a
41%a
45%
47%b
CN
CN
MeO
CN
CN
NC
CN
Cl
N
npentyl
H
OMe
41%
4
6%
76%b
5
6%
55%
CN
CN
CN
CN
N
N
H
H C
3
CH3
O
Ph
3%b
54%b
4%b
6
2%
5
&&1F
5
3
Scheme 2. Copper-Catalyzed Cyanation of Organic Bromides
Reaction conditions: (1) Ar-Br (0.125 mmol), NaI (2.0 equiv), CuI (5 mol %), DMEDA (10 mol %), dioxane (0.2 mL), 24 hr, 120 C. (2) Cu
ꢀ
2
O (10 mol %), DABCO
(15/15 mL), NMP (0.5 mL), 130 C, 24 hr; GC Yield. Note a: 150 C for the second step. Note b: isolated yields.
Note c: solid-state structure of 9-phenyl-9H-carbazole-3-carbonitrile (PCCN; Table S6).
ꢀ
ꢀ
(
3 2 3
25 mol %), PhSiH (6.0 equiv), CO /NH
3
2
was developed to overcome the lower observed reactivity. Thus, initial treatment
0
of aryl bromide with NaI, CuI, and ligand N,N -dimethylethylenediamine (DMEDA)
ꢀ
in dioxane at 120 C, followed by the in situ addition of CO
2
and NH
3
, Cu
2
O,
ꢀ
DABCO, and PhSiH
3
at 130 C for 24 hr, gave product (o-methyl benzonitrile) in
moderate yield (68%). Generally, this method produced moderate reactivity
(
(
41%–76% yields) for various kinds of aryl and heteroaromatic bromides
Scheme 2).
Next, we carried out mechanistic studies to understand the catalytic reaction
1
3
13
pathway. As expected, in situ C nuclear magnetic resonance (NMR) using CO
2
and ammonia as reactants showed the formation of urea, whereas gas chromatog-
raphy-mass spectrometry (GC-MS) analysis of reaction mixtures under optimized
conditions exhibited trace amounts of silyl isocyanates. Control experiments using
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A
Li
Cu
CN
Et O
TMS-N=C=O
2
+
CuBr
Cu(0)
n.d.
o
o
-
10 C
NMP, 130 C
B
C
CN
I
TMS-N=C=O
Phen
Ar Cu(II)
+
o
o
NMP, 180 C, 2 hr
NMP, 180 C, 8 hr
CH3
CH3
step 2
n.d.
step 1
TMS-CF3
TMS-N=C=O
CN
I
Phen
Ar Cu(III)
+
CH3
CuI
o
o
NMP, 180 C, 2 hr
NMP, 180 C, 8 hr
CH3
step 1
step 2
detected (2% yield)
n.d. (no TMS-CF3)
D
E
PhSiH3
TMS-N=C=O
CN
N
N
I
Cu
+
o
NMP, 130 C, 24 hr
F3C
CF3
CH3
CH3
CF3
yield: 30%
CN
N
N
B(OH)2
CH3
TMS-N=C=O
+
Cu
o
F3C
CF3
DMF, 130 C, 24 hr
CH3
yield: 4%
CF3
N-N = 1,10-Phenanthroline (Phen)
Scheme 3. Mechanistic Study: Control Experiments for Active Copper Species
Aryl-Cu(I) species (A), aryl-Cu(II) species (B), aryl-Cu(III) species (C), use of preformed Cu(III)-complex (D), and aryl-Cu(III) species via transmetalation (E).
trimethylsilyl isocyanate (TMS-NCO) as the CN source gave the desired product o-
methylbenzonitrile (19% yield). Considering the ease with which urea can decom-
3
3
pose to isocyanic acid and ammonia at elevated temperatures, the formation of
silyl isocyanate intermediates was reasonable. Meanwhile, to better understand
the active copper species involved, we performed reactions by using organocopper
reagents with different valencies. As shown in Scheme 3, the in situ formation of
plausible Cu(I)-, Cu(II)-, or Cu(III)-aryl species could not lead to the desired cyano
product with trimethylsilyl isocyanate (Schemes 3A–3C). Alternatively, the cyanated
product was detected only by the addition of trimethyl(trifluoromethyl)silane to the
reaction of aryl iodide and cuprous iodide with isocyanates (Scheme 3C). Because it
3ꢁ
is well known that trifluoromethyl CF can stabilize Cu(III) complexes and that
3
4,35
organometallic Cu(III) species participated in many Cu-catalyzed reactions,
this result gave us the hint that Cu(III) species were critically involved in the catalytic
pathway for our system. Next, copper(III) complex [Phen]Cu(III) (CF was prepared,
and its reduced form was found to be active in mediating the coupling of aryl iodide
o-methyliodobenzene) and isocyanate (trimethyl silylisocyanate) such that o-meth-
3 3
)
(
ylbenzonitrile was generated in 30% yield (Scheme 3D). It is noteworthy that once
silane was added, an immediate change of color from yellow to brown was observed,
6
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CO2
+
NH3
silane via urea
I
N
C
O
LnCu (III)
[
Si]
c
Ar
Ar
I
b
GC-MS detected
Ar
O
LnCu(I)
Cu(III)
control experiments
a
N
'
CN' source
yield (Ar-CN)
[
Si]
d
urea
26% yield
19% yield
silane
TMS-NCO
[
Si]-O-Cu(III)
[
Si]: silyl groups; anions on Cu omitted
e
Ar CN
2 3
Figure 2. Plausible Reaction Pathway for Cyanations Using CO and NH
indicating the in situ formation of Cu(I) species. At the same time, the observed
mediation of complex [Phen]Cu(III) (CF in the coupling reaction of o-methylbenze-
3 3
)
neboronic acid and trimethyl silylisocyanate gave further positive results to support
2
the selective insertion of isocyanates into the sp C–Cu(III) bonds (Scheme 3E).
Thus, we propose the reaction mechanism as shown in Figure 2. First, the oxidative
3
6
addition of Cu(I) intermediates a to aryl iodides leads to the active Cu(III) species b.
3
7
Silyl isocyanates c formation is followed by copper-carbon insertion to generate
proposed transient imidate species d, which yields the cyano product via a plausible
1
,3-silyl N-to-O migration whereby Cu(III) intermediate e is released and rapidly
3
8–42
reduced by silanes to Cu(I) species.
Furthermore, we pursued the application of this methodology for the production of
diverse biorelevant compounds. Isotope-labeled compounds are important tracers in
biological and pharmaceutical studies. Using the appropriately isotope-labeled CO
2
1
3
15
13
and NH
labeled CO
0% yield and 98% C incorporation (determined by C NMR and GC-MS; see Fig-
3
can conveniently yield both C- and N-labeled nitriles. Treatment of C-
13
2
3
with iodobenzene and NH for 6 hr gave C-labeled benzonitrile in
1
3
13
2
1
3
15
ure S2). Hence, the multi-step synthesis of [ C, N]-labeled azilsartan was performed
1
3
15
(
2 3
Figures 3A and S3–S5). Using CO and NH , the reaction of o-tolyl bromobenzene
1
3
15
gave isotope-labeled intermediate [ C, N]-o-tolyl cyanobenzene in 72% yield,
resulting in an overall yield of 13% for isotope-labeled azilsartan over five steps.
Considering the isotope effect in biochemical reactions, we further explored the phar-
1
3
15
macokinetics of the [ C, N]-azilsartan (Figures 3B and S6). Interestingly, the isotope-
labeled compound had a slower elimination rate in Sprague-Dawley rats than the
non-labeled drug with half-life (t1/2) values of 7.42 G 1.19 versus 8.60 G 1.33 hr, respec-
tively (Table S5). Such characteristics are valuable in drug design and development.
Building on the good functional-group tolerance performance and the facile synthe-
sis of azilsartan, we pursued the modification and synthesis of several relevant drug
intermediates to further showcase our methodology. The acrylic nitrile group is a key
moiety for many bioactive compounds (e.g., rilpivirine and entacapone) and is typi-
cally limited to the use of cyanide reagents. For instance, bioactive alkaloid
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A
I
B(OH)2
Pd(Cl)2(PPh3)2
K2CO3
CuI, NaI
Cu2O, DABCO
13CO , 15NH
+
2
3
Br
NH HN
15N13
C
Br
PhSiH3
step 1
step 2
N
N
N
N
N
O
Br
O
O
N
H
OH
Et3N
N
15NH2
NBS
NH2OH
O
O
13C15
13C
N
O
O
O
O
AIBN
K CO , DMF
DMSO
step 5
2
3
1
5N13
step 3
C
step 4
O
N
N
O
O
O
O
O
N
N
O
N
N
N
N
15NH
15NH
N
N
NaOH
CH OH
HCl
13C
13C
HO
O
O
O
DMSO, K2CO3
step 6
3
step 7
[13
C, 15N]-azilsartan
B
3000
Azilsartan
13C,15N]-labelled azilsartan
3000
Azilsartan
[
[13
C, N]-labelled azilsartan
15
2000
2000
1000
1000
0
0
0
2
4
6
0
10
20
30
40
50
Time (h)
Time (h)
Figure 3. Synthesis and Pharmacokinetics of Isotope-Labeled Azilsartan
1
3
15
(
(
(
2 3
A) Application of Cu-catalyzed CO and NH cyanation in the multi-step synthesis of isotope-labeled azilsartan.
1
3
15
B) Plasma concentration versus time profiles of azilsartan and [ C, N]-labeled azilsartan after oral administration (1.5 mg/kg) to Sprague-Dawley rats
data are mean G SD, n = 3).
cyanations to yield the corresponding nitriles suffer from low functional tolerance
4
3
and require palladium-catalyzed processes using metal cyanides. Here, the repre-
sentative alkaloid 17-iodoandrosta-5,16-dien-3b-ol (a key intermediate for abirater-
one) was transformed easily to the corresponding nitriles under the optimized con-
ditions (N-methyl-2-pyrrolidone [NMP] as solvent), and no negative effects due to
the hydroxyl group were observed. Alternatively, abiraterone intermediate was
also transformed to the corresponding nitrile product in 54% yield in DMP
(
Scheme 4A). Similarly, with DMP as the solvent, the presence of both amino and
CF groups in bicalutamide intermediate did not influence the reactivity, yielding
-trifluoromethyl-4-cyanoaniline in 76% yield (Scheme 4B).
3
3
In summary, we have demonstrated catalytic cyanation of halides with CO
the cyano (CN) source. In the presence of Cu O/DABCO catalyst, various aryl and
alkenyl iodides and bromides were transformed into the desired aryl nitriles in moderate
2 3
and NH as
2
8
Chem 4, 1–11, December 13, 2018

Please cite this article in press as: Wang et al., Catalytic Cyanation Using CO
j.chempr.2018.09.009
2
and NH
3
,
Chem (2018), https://doi.org/10.1016/
A
I
C
N
H
H
standard conditions
H
H
+
CO /NH3
2
5
4% yield
H
H
HO
3 atm
HO
abiraterone intermediate
B
F
I
C
N
CF3
CF3
CF3
CN
standard conditions
6% yield
O
+
CO2/NH3
atm
7
3
S
N
O
H
NH2
NH2
OH
bicalutamide
O
Scheme 4. Modification of Functionalized Intermediates
Cyanation of abiraterone intermediate (A) and preparation of bicalutamide intermediate (B).
Standard conditions: 0.125 mmol substrate, Cu
6.0 equiv), CO /NH
2
O (10 mol %), DABCO (25 mol %), PhSiH
3
ꢀ
(
2
3
(15/15 mL), DMP (0.5 mL), 180 C, 20 hr.
ꢀ
to excellent yields (up to 94%). Notably, under relatively mild conditions (e.g., 130 C,
atm pressure), functional groups including hydroxyl, ester, amino, amide, and olefin,
3
1
3
15
as well as heterocycles, were tolerated. In addition, C- and N-labeled nitrile products
were conveniently obtained. This cyanide-free cyanation methodology is versatile and
1
3
15
was applied in the synthesis of [ C, N]-labeled azilsartan. Mechanistic studies demon-
strate that the insertion of isocyanate intermediates into Cu(III)-aryl is involved and crit-
ical for the high chemoselectivity of cyanation reactions.
EXPERIMENTAL PROCEDURES
General Procedure for Cyanation Reaction Using CO
Under nitrogen atmosphere, Cu-catalyst, ligand, and a stirring bar were added into a
0 mL oven-dried sealed glass tube. Desired solvent, aryl iodide (0.125 mmol, 1.0 equiv)
and silane were then injected via syringe. The tube was then sealed and both CO and
NH were injected by syringe after N was removed under vacuum. Finally, the mixture
2 3
and NH
1
2
3
2
ꢀ
was stirred for 24 hr in an alloyed block preheated to 130 C. After the reaction was com-
plete, the tube was cooled to room temperature and the pressure carefully released.
The result was measured by GC and GC-MS analysis using dodecane as the internal
standard. For pharmacokinetic studies, care and handling of all animals were approved
by the Institutional Animal Care and Use Committee of Soochow University.
DATA AND SOFTWARE AVAILABILITY
The structure of 9-phenyl-9H-carbazole-3-carbonitrile (PCCN) in this article has been
deposited in the Cambridge Crystallographic Data Center under accession number
CCDC: 1589821.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 42 fig-
ures, 6 tables, and 1 data file and can be found with this article online at https://doi.
org/10.1016/j.chempr.2018.09.009.
ACKNOWLEDGMENTS
th
This article is dedicated to Professor Ryoji Noyori on the occasion of his 80
birthday. The authors acknowledge financial support from the National Natural
Chem 4, 1–11, December 13, 2018
9

Please cite this article in press as: Wang et al., Catalytic Cyanation Using CO
j.chempr.2018.09.009
2 3
and NH , Chem (2018), https://doi.org/10.1016/
Science Foundation of China (21633013, 21101109, and 21602228), the National
Science Foundation of Jiangsu Province (BK20160394), and the National Program
for Thousand Young Talents of China.
AUTHOR CONTRIBUTIONS
Y.L. directed and coordinated the project. Y.D., H.W., X.W., and C.Z. performed the
experiments, analyzed the data, and prepared the supporting information. Y.L.,
C.A.S., M.M., and C.Z. wrote the paper. C.A.S. contributed valuable discussions.
DECLARATION OF INTERESTS
The authors declare no competing financial interests.
Received: December 20, 2017
Revised: August 24, 2018
Accepted: September 18, 2018
Published: October 11, 2018
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11