Photocatalyzed Cyanodifluoromethylation of Alkenes

Article abstract of DOI:10.1002/anie.201900466

Difluoromethylation is a straightforward and widely applied strategy used to incorporate HCF₂ into organic molecules. In contrast, cyanation reagents are typically volatile or highly toxic, or they require harsh reaction conditions. Incorporation of both CN and HCF₂ into organic molecules, such as alkenes, is a worthwhile but challenging task. A method for photocatalyzed cyanodifluoromethylation of alkenes has been developed, which employs a Ph₃P⁺CF₂CO₂^?/NaNH₂ (or NH₃) reagent system. Ph₃P⁺CF₂CO₂^? functions as both the HCF₂ and CN carbon source. A cyanide anion is generated in situ under mild conditions, thereby avoiding the use of toxic cyanation reagents. The photocatalytic method permits cyanodifluoromethylation of a range of alkenes under mild room temperature conditions. The CN group within the products may be further derivatized by standard methods.

Full text of DOI:10.1002/anie.201900466

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Accepted Article
Title: Photocatalyzed Cyanodifluoromethylation of Alkenes
Authors: Ji-Chang Xiao
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900466
Angew. Chem. 10.1002/ange.201900466
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Photocatalyzed Cyanodifluoromethylation of Alkenes
Min Zhang, Jin-Hong Lin, and Ji-Chang Xiao*
Dedicated to Professor Qing-Yun Chen on the occasion of his 90th birthday
Abstract: Photocatalyzed cyanodifluoromethylation of alkenes with
tool and Ir(ppy)3 has become one of the most commonly used
-
a Ph3P+CF2CO2 /NaNH2 (or NH3) system is described. Ph3P+CF2CO2-
photocatalysts.[14]
Therefore,
we
screened
the
-
acted as both the HCF2 source and CN carbon source, and the
cyanide anion was generated in situ under mild conditions, avoiding
the use of toxic cyanation reagents.
cyanodifluoromethylation of alkene 1a with the Ph3P+CF2CO2
/NaNH2 system under photocatalytic conditions by using Ir(ppy)3
as the photocatalyst. Because a copper source is usually
required in cyanotrifluoromethylation of alkenes,[13] various Cu
complexes were examined (entries 1–4) and CuI was found to
be a superior choice (entry 1). Increasing the loading of
The difluoromethyl group (HCF2) can act as a lipophilic
hydrogen bond donor and a bioisostere of hydroxyl or thiol
groups,[1] and it has found widespread application in
pharmaceutical chemistry and agrochemistry.[2] During the past
Ph3P+CF2CO2 led to an increase in the yield (entries 6–8). A
-
78% yield was obtained when 3 equiv. of NaNH2 (entry 9) was
used. The use of 10 mol % of CuI afforded an 83% yield of the
corresponding product (entry 10), whereas almost no desired
product was detected without the addition of CuI (entry 11). Both
a photocatalyst [Ir(ppy)3] and light source (blue LED) were
essential for this reaction, and the expected conversion was
completely suppressed when one of them was not used (entries
12–13). The use of TMSCN as the cyanide source only gave a
low yield under these conditions (entry 14). Other nitrogen
sources of the nitrile group were also screened (entries 15–19),
and ammonia (NH3) was also an efficient source (entry 15). In
the case of ammonium carbamate (NH2CO2NH4) as a nitrogen
source, the yield was decreased dramatically (entry 16).
decades,
a number of HCF2-based pharmaceuticals and
agrochemicals, such as Eflornithine, Deracoxib, Sedaxane,
Isopyrazam, Bixafen, and Thiazopir, have been developed.[2]
The incorporation of a HCF2 group into organic molecules has
garnered significant attention.[2-3] Because difluoromethylation is
the most straightforward strategy for incorporation of HCF2 in
organic molecules, many difluoromethylation reagents have
been developed,[4] such as TMSCF2H[5] and XCF2H (X=F, Cl, or
Br)[6]. Simultaneous incorporation of a second functional group
into molecules would allow further transformation; the second
functional group could also have excellent potentials for the
design of pharmaceuticals and agrochemicals. Therefore, much
effort has been devoted to the development of efficient methods
for difluoromethylative difunctionalization of alkenes, including
Table 1. Optimization of reaction conditions[a]
hydrodifluoromethylation,[7]
carbodifluoromethylation,[8]
oxydifluoromethylation,[9] and halodifluoromethylation[10]
.
The nitrile group (CN) is a versatile functionality in synthetic
chemistry and life sciences, and thus cyanation has received
increasing attention.[11] Various cyanation reagents have been
developed, such as NaCN, KCN, and TMSCN.[11] However,
many of these reagents are volatile or highly toxic, or harsh
reaction conditions such as a high reaction temperature (130–
150 °C) are required for the cyanation reaction. Considering the
importance of HCF2 and the potential derivatization of CN, the
incorporation of both of these groups into organic molecules
Entry
3
[Cu]
1a:2:3:[Cu]
Yield (%)[b]
1
2
NaNH2
NaNH2
NaNH2
NaNH2
NaNH2
NaNH2
NaNH2
NaNH2
NaNH2
NaNH2
NaNH2
NaNH2
NaNH2
TMSCN
CuI
CuCN
CuBr2
Cu(OAc)2
CuI
1:2:2:0.2
1:2:2:0.2
28
13
3
1:2:2:0.2
21
would
be
worthwhile.
However,
efficient
4
1:2:2:0.2
21
cyanodifluoromethylation of alkenes under mild conditions
remains a challenging task. On the basis of our recent
5
1:1.5:2:0.2
1:3:2:0.2
16
6
CuI
57
-
observation that Ph3P+CF2CO2 reacts with elemental sulfur (S8)
7
CuI
1:4:2:0.2
64
to generate thiocarbonyl fluoride (CF2=S),[12] we envisioned that
Ph3P+CF2CO2- could be trapped by a suitable nitrogen source to
produce a cyanide anion (CN-). Inspired by the discovery of
cyanotrifluoromethylation of alkenes,[13] we investigated the
8
CuI
1:4.5:2:0.2
1:4.5:3:0.2
1:4.5:3:0.1
1:4.5:3:0
66
9
CuI
78
10[c]
11[c]
12[c][d]
13[c][e]
14[c]
15[f]
16[c]
17[c]
18[c]
19[c]
CuI
83
-
trace
ND
ND
38
-
cyanodifluoromethylation of alkenes with Ph3P+CF2CO2 in the
CuI
1:4.5:3:0.1
1:4.5:3:0.1
1:4.5:3:0.1
1:4.5:4.9:0.1
1:4.5:3:0.1
1:4.5:3:0.1
1:4.5:3:0.1
1:4.5:3:0.1
presence of a nitrogen source and without external addition of
any CN- source.
CuI
CuI
Photoredox catalysis has proven to be a valuable synthetic
NH3
CuI
83
NH2CO2NH4
NH4BF4
CuI
42
CuI
trace
trace
trace
[*]
Min Zhang, Dr. Jin-Hong Lin, Prof. Dr. Ji-Chang Xiao
Key laboratory of organofluorine chemistry, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences,
Chinese Academy of Science, 345 Lingling Road, Shanghai
200032, China, E-mail: jchxiao@sioc.ac.cn
NH4Br
CuI
NH4H2PO4
CuI
[a] Reaction conditions: Substrate 1a (0.2 mmol), Ph3P+CF2CO2 , [N] source,
Ir(ppy)3 (2 mol%) and Cu complex in DMAc (2 mL) irradiated with blue LED at
room temperature under a N2 atmosphere for 12 h; [b] The yields were
determined by 19F NMR spectroscopy; [c] 3 mL of DMAc was used instead of
-
Supporting information for this article is given via a link at the end of
the document.
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2 mL; [d] Ir(ppy)3 was not used; [e]The light source (blue LED) was not used;
[f] DMF (3 mL) was used instead of DMAc.
allowed further C–C coupling transformations. The HCF2/CN-
containing estrone derivatives were synthesized by this
cyanodifluoromethylation conversion, further demonstrating the
synthetic utility of this protocol (4-18, 4-19). Internal alkenes
showed low reactivity, which resulted in a lower yield (4-25).
Besides aryl alkenes, alkyl alkenes were also reactive and
smoothly converted into the expected products (4-19, 4-20, 4-27
~ 4-29).
It has been reported that the generation of cyanide anion
(CN-) can be detected by a CN- indicator, sodium picrate,[15] and
therefore this method was adopted to identify the sources of the
CN- anion [Please see Supporting Information (SI) for
experimental details]. No CN- anion was detected in the absence
-
of Ph3P+CF2CO2 (Table 2, entries 1-2) or NaNH2 (entry 3), but
-
the anion was formed when both Ph3P+CF2CO2 and NaNH2
were present (entry 4), indicating that Ph3P+CF2CO2- and NaNH2
are the carbon source and the nitrogen source of the CN- anion,
respectively. Furthermore, the CN- anion can also be produced
in THF or CH3CN, suggesting that DMAc is not a source of the
CN- anion (entries 5-6).
Table 2. Detection of CN- by indicator paper[a]
-
NaNH2
(0.6 mmol)
Ph3P+CF2CO2
(0.9 mmol)
CuI
(10 mol%)
Solvent
(3 mL)
CN-
produced
Entry
1
2
3
4
5
6
√
√
×
√
√
√
×
×
√
√
√
√
×
√
×
×
×
×
DMAc
DMAc
DMAc
DMAc
THF
–
–
–
+
+
+
CH3CN
[a] “√” means the reagent was used; “×” means the reagent was not used; “+”
means positive result; “−” means negative result.
Besides the cyanide detection test, other experimental
evidence was collected. The reaction of phenyl amine 5 with
Scheme 1. Substrate scope of the photocatalyzed cyanodifluoromethylation of
-
Ph3P+CF2CO2 gave isocyanobenzene 6 (Scheme 2). The
alkenes. Isolated yields. Reaction conditions: substrate
1 (0.4 mmol),
-
Ph3P+CF2CO2 (4.5 equiv.), NaNH2 (3 equiv.) or NH3 (5 ~ 7.5 equiv.), Ir(ppy)3
(2 mol %), CuI (10 mol %), in DMAc (6 mL) or DMF (6 mL) irradiated with blue
LED at room temperature under a N2 atmosphere for 12 h. [a] A gram-scale
reaction (1.12 g of 1a) gave 4-1 in 69% isolated yield. [b] The dr value was
determined by 19F NMR spectroscopy.
formation of the isocyano (NC) moiety also indicated that both
Ph3P+CF2CO2- and NaNH2 were sources of the nitrile group.
With the optimal reaction conditions in hand (Table 1, entry
10 or entry 15), we investigated the substrate scope of the
photocatalyzed cyanodifluoromethylation of alkenes. As shown
in Scheme 1, various aryl alkenes could be converted into the
desired products in moderate to good yields. A gram-scale
conversion was performed and a 69% isolated yield of 4-1 was
obtained, revealing the potential application of this reaction. An
examination of the substituent effects in aryl alkenes showed
that neither electron-withdrawing nor -donating groups had an
obvious impact on the yields. A variety of functional groups were
tolerated, such as ether, ester, ketone, chloride, bromide, iodide,
boronic acid ester and amide groups. The compatibility of this
reaction with the reactive functional groups, including bromide
(4-14, 4-15, 4-24), iodide (4-16), and boronic acid ester (4-12),
Scheme 2. Formation of an isocyano moiety
-
Ph3P+CF2CO2 was not only the carbon source of the nitrile
group, but also the source of the HCF2 group. The proton in the
HCF2 group should be from the NaNH2 reagent, or a trace
amount of water present in the reaction system, as evidenced by
the observation that the presence of D2O generated
deuterated product (Scheme 3, eq 1). A radical scavenger such
as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO),
dibutylhydroxytoluene (BHT), or hydroquinone could
a
dramatically suppress the formation of the desired product. A
TEMPO-CF2H byproduct was produced in 32% yield (by 19F
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NMR) when TEMPO was used, suggesting that a radical
reaction mechanism was operative (Scheme 3, eq 2).
The possibility of generating cation intermediate F (path b in
Scheme 4) was excluded based on the following evidence. If this
cation was generated, it might be trapped by the ambient
nucleophiles. NaNH2 is
a
good nucleophile, but no
aminodifluoromethylation product was detected (Scheme 5, eq
1). Besides, the in situ generated CN- was also a nucleophile.
However, almost no cyanodifluoromethylation product was
formed if CuI was not used (see Table 1, entry 11), suggesting
that the cyanodifluoromethylation was not from
a direct
nucleophilic attack of CN- on the cation F. Furthermore, the
external addition of a nucleophile, H2O or MeOH, did not afford
hydroxylation or methoxylation byproduct (eq 2).
Scheme 3. Experimental evidence. [a] The D/H ratio was determined by 19F
NMR spectroscopy. [b] Determined by 19F NMR spectroscopy.
On the basis of the above results, we proposed a plausible
reaction mechanism, as shown in Scheme 4. Difluorocarbene
-
generated from Ph3P+CF2CO2 is readily trapped by NaNH2 to
produce carbon anion A. Hydrogen migration from the N-H
moiety to the carbon anion provides intermediate B, which
undergoes β-fluorine elimination to afford formimidoyl fluoride C.
Further F-elimination generates a proton and furnishes hydrogen
cyanide, and the deprotonation of hydrogen cyanide gives a
Scheme 5. The capture of a possible cation F. R = 4-tBuC6H4. [a] The yield
was determined by 19F NMR spectroscopy.
We
developed
an
efficient
protocol
for
-
cyanodifluoromethylation of alkenes. This approach is highly
attractive as the simultaneous incorporation of both HCF2 and
CN groups could be achieved under mild conditions and the use
of highly toxic or volatile cyanation reagents was avoided. To
demonstrate the synthetic versatility of the HCF2/CN-containing
products, diversifications of product 4-1 were performed
(Scheme 6). HCF2-tetraazole (7a) was obtained in a high yield
through cyclization of 4-1 with sodium azide. Some other typical
transformations into an ester (7b), amide (7c), and aldehyde (7d)
were also illustrated.
cyanide anion. Ph3P+CF2CO2 could also abstract a proton to
form the phosphonium salt [Ph3P+CF2H X-].[16] The cyclic
voltammetry studies and Stern–Volmer measurements (Please
see SI for experimental details) reveals that the phosphonium
salt [Ph3P+CF2H X-] (Epred = -0.959 V vs. SCE, See SI) could be
easily reduced by the photoexcited complex [Ir(ppy)3*]
(E1/2red[IrIV/Ir*III] = −1.73 V vs. SCE)[14a] to generate an IrIV
10a, 17]
complex and the HCF2· radical.[4f,
The capture of this
radical by an alkene substrate gives radical intermediate D. The
IrIV complex is an oxidant (E1/2ox[IrIV/IrIII] = +0.77 V vs. SCE),[14a]
and would therefore oxidize CuI into CuII (E1/2ox[CuII/CuI] = +0.71
V vs. SCE, See SI). Rapid ligand exchange affords CuIICN
complex, the combination of which with radical intermediate D
13e, 18]
produces CuIII complex
E
(path a).[13d,
Reductive
elimination of complex E furnishes the final product 4 and re-
generates the CuI catalyst.
Scheme 6. Representative transformations of product 4-1.
In summary, we have described the photocatalyzed
-
cyanodifluoromethylation of alkenes with
a
Ph3P+CF2CO2
/NaNH2 (or NH3) reagent system. Ph3P+CF2CO2 acted as a
difluoromethylation reagent and carbon source of the nitrile
group in the reaction. This work represents the first example of
efficient cyanodifluoromethylation using easy-to-handle reagents
-
Scheme 4. The proposed reaction mechanism.
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Acknowledgements
The authors thank the National Natural Science Foundation
(21421002, 21672242), Key Research Program of Frontier
Sciences (CAS) (QYZDJSSW-SLH049), National Basic
Research Program of China (2015CB931903), and the Chinese
Academy of Sciences (XDA02020105, XDA02020106) for
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Keywords: Difluorocarbene
•
Cyanodifluoromethylation
•
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Min Zhang, Jin-Hong Lin, and Ji-Chang
Xiao*
Page No. – Page No.
Photocatalyzed
Cyanodifluoromethylation of Alkene
-
Photocatalyzed cyanodifluoromethylation of alkenes with a Ph3P+CF2CO2 /NaNH2
(or NH3) system is described. The use of toxic cyanation reagents were avoided
-
because Ph3P+CF2CO2 acted as both the HCF2 source and CN carbon source.
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