Difluorocarbene-based cyanodifluoromethylation of alkenes induced by a dual-functional Cu-catalyst

Article abstract of DOI:10.1039/d1cc00160d

Although cyanofluoroalkylation has received increasing attention, a toxic cyanation reagent is usually required. Herein, a Cu-catalyzed difluorocarbene-based cyanodifluoromethylation of alkenes with BrCF₂CO₂Et/NH₄HCO₃under photocatalytic conditions is described. BrCF₂CO₂Et and NH₄HCO₃serve as a carbon source and a nitrogen source of the nitrile group, respectively, avoiding the use of a stoichiometric toxic cyanation reagent. The Cu-complex plays a dual role. It is not only a photocatalyst, but also a coupling catalyst for the formation of a C-CN bond.

Full text of DOI:10.1039/d1cc00160d

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Difluorocarbene-based cyanodifluoromethylation
of alkenes induced by a dual-functional
Cu-catalyst†
Cite this: Chem. Commun., 2021,
7, 2649
5
Received 11th January 2021,
Accepted 29th January 2021
a
a
b
a
Min Zhang, Jin-Hong Lin,
Chuan-Ming Jin * and Ji-Chang Xiao
*
DOI: 10.1039/d1cc00160d
rsc.li/chemcomm
Although cyanofluoroalkylation has received increasing attention, a develop cyanofluoroalkylation approaches. Cyanotrifluoro-
toxic cyanation reagent is usually required. Herein, a Cu-catalyzed methylation of alkenes has been independently reported by
6
7
8
9
difluorocarbene-based cyanodifluoromethylation of alkenes with the groups of Szab o´ , Liang, Liu, and others (Scheme 1a). All
BrCF
2
CO
2
Et/NH
4
HCO
3
under photocatalytic conditions is described. of these reactions are very efficient for the incorporation of both
serve as a carbon source and a nitrogen CF and CN groups, and some processes have been extended
BrCF
2
CO
2
Et and NH
4
HCO
3
3
9
b–d
source of the nitrile group, respectively, avoiding the use of a to other fluoroalkyl groups,
4 9 2 2
such as C F and CF CO Et.
stoichiometric toxic cyanation reagent. The Cu-complex plays a dual However, these approaches suffer from the stoichiometric
role. It is not only a photocatalyst, but also a coupling catalyst for the use of a toxic cyanation reagent (mostly TMSCN), and the
formation of a C–CN bond.
fluoroalkyl groups are mainly limited to the CF3 group.
Recently, Zhu and co-workers developed an effective cyano-
Owing to the unique properties of the fluorine element, such as fluoroalkylation of alkyl alkenes via an intramolecular CN
1
0
high electronegativity and small atomic radius, the incorporation migration (Scheme 1b). A wide substrate scope was demon-
of a fluorinated group into organic molecules would usually strated and high yields were obtained, but the pre-installation
1
lead to profound changes in their physicochemical properties.
of a CN group into substrates by using a toxic cyanation reagent
Fluoroalkyl groups, which usually show high lipophilicity (TMSCN) is required.
2
and strong electron-withdrawing nature, are commonly found
Difluorocarbene has served as a valuable intermediate in
1
1
in pharmaceuticals, such as Gemcitabine, Tafluprost and organic synthesis. This reactive species can be used to enable
Lubiprostone. Therefore, significant efforts have been directed many reactions, such as [2+1] cyclization of alkenes, difluoro-
towards the development of efficient methods for the installation methylation of X–H bonds (X = carbon or heteroatom), and
of fluoroalkyl groups. Among them, fluoroalkylative difunctiona- difluorocarbene transfer by transition metal catalysis. Recently,
lization of alkenes has received increasing attention because this we disclosed that difluorocarbene can be trapped by NaNH or
type of reaction has been proved to be a powerful tool for NH to generate a cyanide anion, a process which was developed
1
2
1
3
3
14
2
3
constructing two vicinal chemical bonds in a single step from into a synthetic tool to achieve cyanodifluoromethylation of
4
simple precursors.
As the nitrile group (CN) has served as an important moiety
in a large number of pharmaceuticals, such as Verapamil and
Anastrozole, and can be further transformed into many other
functional groups, many cyanation reagents and cyanation
5
methods have been developed. Since the incorporation of both
fluoroalkyl and nitrile groups may provide more opportunities
for drug/agrochemical development, it is highly desirable to
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China. E-mail: jchxiao@sioc.ac.cn
b
Department of Chemistry and Chemical Engineering, Hubei Normal University,
1
1 Cihu Road, Huangshi, 435002, Hubei, China
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1cc00160d
Scheme 1 Cyanofluoroalkylation of alkenes.
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1
5
alkenes (Scheme 1c). Although no toxic cyanation reagent was involves sequential deprotonation processes. A base could
used, the protocol may suffer from strongly basic conditions obviously accelerate deprotonation, and is thus favorable for the
(
NaNH ) or the use of NH , which is a gas with a characteristic final cyanation. Other bases led to a slight decrease in the yield
2 3
pungent smell. Furthermore, the difluorocarbene source, (entries 6 and 7). Cu sources were also screened (entries 8–10), and
+
ꢀ
Ph P CF CO (PDFA), has to be used in a large excess (4.5 equiv.), CuCN was found to be a better choice (entry 8). The yield was
3
2
2
0
0
and an expensive Ir complex has to be used as a photocatalyst. further increased by adding a ligand, 1,1 -binaphthalene-2,2 -
Due to these deficiencies, we further develop a mild cyanodi- diylbis-diphenylphosphine (BINAP) (entry 11). Other ligands
fluoromethylation reaction of alkenes with BrCF
NH HCO under visible-light induced photocatalytic conditions to be a superior choice. Surprisingly, the absence of Ir(ppy)
Scheme 1d). NH HCO can act the nitrogen source of the CN not dramatically decrease the yield, probably because the
group, and BrCF CO Et is not only the carbon source of the CN (BINAP)Cu complex can act as a photocatalyst (entry 12).
2
CO
2
Et/ were also examined (please see the ESI†) but BINAP was found
4
3
3
did
(
4
3
1
6
A
2
2
group, but also the difluoromethyl source. In this process, the high yield (85%) was obtained when H O and diglyme (DG) were
2
Cu-catalyst plays a dual role, as both a photoredox catalyst for used as additives (entry 13). These two additives may easily
+
ꢀ
single electron transfer and a cross-coupling catalyst for C–CN dissolve the inorganic salts, such as M CN and K
bond formation. therefore favor the participation of these inorganic salts in the
For our previous cyanodifluoromethylation of alkenes with reaction. Under these conditions, the side bromination product
PDFA/NaNH , Ir(ppy) was used as a photocatalyst and CuI was (3a) was almost completely suppressed. No desired product was
3 4
PO , and
2
3
1
5
used as a cross coupling catalyst (Scheme 1c). In the initial observed without the irradiation of blue LEDs, indicating that
attempts by using BrCF CO Et instead of PDFA as a difluoro- this is a photocatalyzed process.
2
2
carbene source, the expected product 4a was obtained in a very
With the optimal conditions in hand (Table 1, entry 13), we
low yield under similar conditions (Table 1, entry 1). An then investigated the substrate scope of the Cu-catalyzed
undesired bromination compound, 3a, was produced as a difluorocarbene-based cyanodifluoromethylation of alkenes.
major product. A brief survey of the nitrogen sources revealed As shown in Table 2, the process could be extended to a wide
that the yield of 4a could not be significantly increased variety of alkenes, including aryl and alkyl alkenes. Various
(
entries 2–4). A 13% yield was obtained with the use of
NH HCO as the nitrogen source (entry 2). To our delight, the
presence of a base, K PO , gave product 4a in 43% yield (entry
4
3
3
4
Table 2 Difluorocarbene-based cyanodifluoromethylation of alkenes
5
). The formation of a cyanide anion from CF /NH HCO
2 4 3
a
Table 1 The optimization of reaction conditions
b
Yield (%)
Entry
[N]
[Cu]
3a
4a
c
1
NaNH
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCN
60
55
16
38
26
30
44
13
21
23
10
12
Trace
ND
6
13
3
c
2
NH
(NH
4
HCO
CO
CO NH
3
c
3
4
)
2
3
c
4
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
2
4
4
4
4
4
4
4
4
4
4
2
4
6
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
3
3
3
3
3
3
3
3
3
3
43
42
27
57
43
49
68
50
85
ND
d
8
9
CuBr
2
10
11
12
13
14
Cu(OTf)
CuCN
CuCN
CuCN
CuCN
2
f
fg
fgh
fghi
a
Reaction conditions: substrate 1a (0.2 mmol), BrCF
(1 mol%), Cu complex (10 mol%)
(2 equiv.) in DMF (2 mL) irradiated with blue LEDs at 35 1C
2
COOEt (5.0 equiv.),
a nitrogen source (2 equiv.), Ir(ppy)
and K PO
under a N
3
3
4
b
19
2
atmosphere for 12 h. The yields were determined by
F
NMR spectroscopy with 1-fluoronaphthalene as the internal standard. Reaction conditions: substrate 1 (0.4 mmol), BrCF
2
CO
(0.8 mmol), CuCN (5 mmol%), BINAP (6 mmol%), DG
5 mol% CuCN and 6 mol% BINAP were used. (1.0 mmol) and H O (1.2 mmol) in DMF (4 mL) irradiated with blue
was not used and the loading of BrCF CO
Et was decreased to LEDs at 35 1C under a N atmosphere for 12 h. Isolated yields are
O (3 equiv.) and DG (2.5 equiv.) were added. No blue LED shown. The yields in parentheses are determined by F NMR
was used. ND = not detected.
spectroscopy.
2
Et (1.0 mmol),
c
d
e
Without K
used instead of K
3
PO
4
.
KHCO was used instead of K PO . K HPO
3 3 4 2 4
was NH HCO
4 3
f
3
4
PO .
2
g
Ir(ppy)
.5 equiv.
3
2
2
2
h
i
a
19
2
H
2
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functional groups could be tolerated under these conditions,
such as ether, ester and halide groups. Electron-rich, -neutral
and -deficient aryl alkenes could all be converted into the
desired products in moderate to good yields. Alkyl alkenes
show similar reactivity to aryl alkenes, and moderate yields
were obtained (4u–4x). An estrone derivative was synthesized,
which may show biological activity. The reaction is sensitive to
steric effects, and thus a low yield was obtained in the case of
internal alkenes (4z). a,b-Unsaturated alkenes also show low
reactivity (4ab).
a
Scheme 3 The evidence for a radical mechanism. The yields were
19
determined by F NMR spectroscopy with 1-fluoronaphthalene as the
internal standard.
absorptions in the visible light range (please see the ESI†).
Since the cyanodifluoromethylation proceeded under visible
light irradiation and it has been reported that a Cu complex
we propose that the (BINAP)-
CuCN complex should be the photocatalyst for this difluorocarbene-
based cyanodifluoromethylation. Stern–Volmer measurements
please see the ESI†) revealed that BrCF CO Et could effectively
2 2
quench the excited state of the (BINAP)CuCN complex gener-
ated in situ, reflecting that a single electron transfer between
The reaction should involve the generation of a cyanide
anion from the difluorocarbene source, BrCF CO Et, and the
2
2
nitrogen source, NH HCO , like our previous difluorocarbene-
4
3
1
6,17
1
5
ꢀ
could act as a photocatalyst,
based cyanodifluoromethylation process. Indeed, CN was
not detected using an indicator paper in the absence of either
2 2 4 3
BrCF CO Et or NH HCO (Table 3, entries 1 and 2), and the
anion could be clearly detected only when both of them were
(
present (entry 3) (please see the ESI† for experimental details).
ꢀ
In addition, CN was produced not only in DMF, but also in
BrCF
generate a CF
2
CO
2
Et and the (BINAP)CuCN complex would occur to
DMAc, MeCN, and DG (entries 4–6), reflecting that the reaction
solvent DMF is neither a carbon source nor a nitrogen source of
ꢁ
2
CO
2
Et radical under visible light irradiation.
A radical scavenger, including 2,2,6,6-tetramethyl-1-piperidinyloxy
TEMPO), hydroquinone or 1-hydroxybenzotriazole (HOBt), could
dramatically suppress the desired cyanodifluoromethylation
process, indicating that a radical process is indeed operative
ꢀ
the CN .
(
During the optimization of reaction conditions, we found
that bromination compound 3a was produced as a side product
under some conditions (Table 1). A question arises whether this
compound is an intermediate of the final product 4a. Compound
(Scheme 3).
On the basis of the above results and our previous studies on
3a was then subjected to the optimized conditions shown in
1
5
cyanodifluoromethylation, we propose the plausible reaction
mechanism as shown in Scheme 4. BrCF CO Et is not only the
carbon source of the nitrile group, but also the source of the
terminal CF CO Et group in the final products. First,
BrCF CO Et hydrolyzes to give BrCF CO , which could readily
undergo decarboxylation to release difluorocarbene. Difluoro-
carbene is an electrophilic species, and would be easily trapped
Table 1, entry 13, and it was found that no product 4a was
formed (Scheme 2). Instead, a dehydrobromination compound
2
2
5a was obtained, indicating that 3a is not a necessary
intermediate.
2
2
ꢀ
The analysis of UV-VIS absorption spectra of BINAP, CuCN
and (BINAP)CuCN showed that only (BINAP)CuCN has
2
2
2
2
by NH
3
produced from NH
4
HCO
3
to form intermediate A.
+
ꢀ
ꢀ
a
A proton transfer from the NH
moiety to the CF
group
Table 3 Detection of CN using indicator paper
3
2
provides intermediate B, and the subsequent defluorination
delivers intermediate C, which would further undergo deproto-
nation and defluorination to afford HCN. Neutralization of HCN
ꢀ
Entry
NH
4
HCO
3
BrCF
2
CO
2
Et
Solvent
CN produced
1
2
3
4
5
6
O
ꢂ
O
O
O
O
ꢂ
O
O
O
O
O
DMF
DMF
DMF
DMAc
MeCN
DG
ꢀ
ꢀ
+
+
+
+
a
‘
‘O’’ means the reagent was used; ‘‘ꢂ’’ means the reagent was not
ꢀ
ꢀ
used; ‘‘+’’ means CN was produced; ‘‘ꢀ’’ means CN was not
produced.
a
Scheme 2 The exclusion of the possible reaction path. The yield was
19
determined by F NMR spectroscopy with 1-fluoronaphthalene as the
internal standard.
Scheme 4 The plausible reaction mechanism.
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Notes and references
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Scheme 5 Diversification of cyanodifluoromethylation product 4a.
2
ꢀ
delivers the CN anion. On the other hand, the coordination of
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BINAP to CuCN produces the (BINAP)–CuCN complex. The
photoexcitation of this complex could easily reduce BrCF CO Et
2
2
ꢁ
II
to give the CF CO Et radical and Cu complex. The ligand
2
2
ꢀ
exchange between CN and the Br ligand generates the
II
ꢁ
2 2 2
complex. The addition of the CF CO Et radical to
LCu (CN)
a double bond provides an alkyl radical. The interaction of the
II
alkyl radical with the Cu (CN)
product and releases the catalyst. As we have described
before, a Cu complex is essential for the transfer of a CN group
to the alkyl radical. Therefore, the Cu catalyst plays a bifunctional
role in this transformation. It is not only a photocatalyst, but also
2
complex furnishes the final
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a coupling catalyst for C–CN bond formation.
ꢀ
Since CN and CF
2
groups are both incorporated under mild
6
conditions, this cyanodifluoromethylation protocol may find
potential applications in the synthesis of unique molecules.
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CN and CF CO Et could be easily transformed, and various
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1
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ꢁ
functional Cu-catalyst. BrCF
2
CO
2
Et is not only the CF
2
CO
2
Et
radical source, but also a difluorocarbene reagent, which
releases difluorocarbene to serve as the carbon source of the
nitrile group. No stoichiometric toxic cyanation reagent was
used, and a cheap Cu complex, playing a dual role, could
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Conflicts of interest
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2652 | Chem. Commun., 2021, 57, 2649ꢀ2652
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