Difluorocarbene-derived trifluoromethylselenolation of benzyl halides

Article abstract of DOI:10.1039/c8cc09719d

Cu-Promoted difluorocarbene-derived trifluoromethylselenolation of benzyl halides with the Ph₃P⁺CF₂CO₂^-/S_e/F^- system is described. Three new carbon-heteroatom bonds, a Se-CF₂ bond, SeCF₂-F bond, and C-SeCF₃ bond, were sequentially formed in the reaction. This work represents the first trifluoromethylselenolation protocol involving an external fluoride for the generation of the key intermediate, CF₃Se^- anion.

Full text of DOI:10.1039/c8cc09719d

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Difluorocarbene-derived trifluoromethylselenolation
of benzyl halides†
Cite this:DOI: 10.1039/c8cc09719d
b
Xin-Lei Chen,ab Sheng-Hua Zhou,b Jin-Hong Lin,
Qing-Hai Deng *a and
Ji-Chang Xiao*b
Received 7th December 2018,
Accepted 8th January 2019
DOI: 10.1039/c8cc09719d
rsc.li/chemcomm
Cu-Promoted difluorocarbene-derived trifluoromethylselenolation
of benzyl halides with the Ph3P+CF2CO2ꢀ/Se/Fꢀ system is described.
Three new carbon–heteroatom bonds, a Se–CF2 bond, SeCF2–F
bond, and C–SeCF3 bond, were sequentially formed in the reaction.
This work represents the first trifluoromethylselenolation protocol
involving an external fluoride for the generation of the key inter-
mediate, CF3Seꢀ anion.
Scheme 1 The CF3Se incorporation strategies.
Trifluoromethylchalcogeno groups, such as trifluoromethoxy
(CF3O)1 and trifluoromethylthio (CF3S),2 usually possess unique Trifluoromethylation of selenocyanates or diselenides suffers
electronic properties which are of particular interest in life sciences, from the need for the tedious synthesis of selenium-substrates
and thus trifluoromethylchalcogeno-containing pharmaceuticals and a narrow substrate scope. Apparently, direct trifluoromethyl-
and agrochemicals have been continuously developed.1,2 A trifluoro- selenolation is a straightforward and attractive strategy (eqn (2)).
methylseleno group (CF3Se) also shows valuable electronic Since a Cu complex could catalyze trifluoromethylselenolation
properties such as strong electron-withdrawing nature (Hammett with a CF3ꢀ/Se system and [CuSeCF3] was proposed to be a key
constants sp = 0.45, sm = 0.44),3 and its Hansch–Leo parameter intermediate,11 Weng prepared CuSeCF3-type reagents and applied
(p = 1.29) measured recently by Billard is reflective of high them to direct trifluoromethylselenolation.12 [Me4N+ꢀSeCF3]
lipophilicity.4 Compared with CF3O and CF3S, CF3Se has was found to be an effective reagent and has been used in
received much less attention in agrochemical and pharmaceutical trifluoromethylselenolation of a wide range of substrates under
research, probably because it is usually believed that selenium is Pd-catalyzed,13 Ni-catalyzed,14 Cu-catalyzed15 or transition-metal-
toxic to humans.5 However, at low doses selenium is an essential free16 conditions. Based on Wakselman’s approach for the synthesis
nutrient to humans and selenium substances have found applica- of CF3SeCl,17 Billard developed a one-pot method for trifluoro-
tions in drug design,6 such as the drug ebselen.7 Therefore, methylselenolation of arenes,18 alkynyl copper,19 alkenes,20 boronic
determined efforts have been directed towards the development acids,21 organometallic reagents,4 and carbonyl compounds22 via the
of efficient methods for the incorporation of a CF3Se group into in situ generation of CF3SeCl. Interestingly, they further used this
organic molecules.
one-pot strategy to synthesize a new reagent, TsSeCF3, and achieved
Two strategies have been well established for CF3Se incor- various trifluoromethylselenolation reactions by using this reagent.23
poration, trifluoromethylation of selenocyanates8 or diselenides9 Despite this extensive progress, current trifluoromethylselenolation
(Scheme 1, eqn (1)), and direct trifluoromethylselenolation with methods still have significant limitations. For example, the
a CF3Se-containing reagent10 or a CF3ꢀ/Se system11 (eqn (2)). reactions may involve the generation and use of the toxic and
highly volatile CF3SeCl reagent, the [Me4N+ꢀSeCF3] reagent is air
sensitive, and both the CuSeCF3-type reagents and [Me4N+ꢀSeCF3]
have to be prepared from volatile Ruppert–Prakash reagent
(TMSCF3). Therefore, the development of efficient trifluoro-
methylselenolation protocols by using readily accessible and
easily handled reagents is highly desirable.
a College of Chemistry and Materials Science, Shanghai Normal University,
100 Guilin Road, Shanghai, 200234, China. E-mail: qinghaideng@shnu.edu.cn;
Tel: +86 21 64321305
b 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;
Tel: +86 21 54925340
Phosphobetaine salt Ph3P+CF2CO2ꢀ, a reagent that was
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cc09719d developed by us recently24 and also used by others,25 could be
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easily prepared via a one-step reaction. A convenient work-up increasing the loading of CuI to 1 equiv. (entry 6 vs. 4). The
procedure simply by washing could afford the pure phosphobetaine presence of a ligand (2,20-bipyridine) and a suitable Ag complex
salt, which is bench-stable and easy to handle. As a difluorocarbene (2 equiv.) such as Ag2CO3 or AgF further increased the yield
ꢀ
reagent, Ph3P+CF2CO2 could react with elemental sulfur (S8) to (entries 7 and 8). Interestingly, decreasing the loading of
generate thiocarbonyl fluoride in situ, which is electrophilic and Ag2CO3 led to an increase in the yield (entry 10 vs. 7). KF was
would be readily trapped by a nucleophile such as Fꢀ anions.24f–h an inferior fluoride source compared with CsF (entry 11 vs. 10).
Therefore, the Ph3P+CF2CO2ꢀ/S8/Fꢀ system was used as the CF3Sꢀ A lower yield was obtained by using another ligand instead of
source to achieve trifluoromethylthiolation.24e–g Since the reaction 2,20-bipyridine (entry 12). Increasing the reaction temperature
occurred rapidly, 18F-trifluoromethylthiolation by replacing Fꢀ with did not give a higher yield (entry 13). The use of an ammonium
18Fꢀ was investigated and successfully achieved. On the basis of this salt (nBu4NCl) as an additive, which may stabilize the in situ
unprecedented trifluoromethylthiolation process, we envisioned that generated CF3Seꢀ anion, gave a 54% yield of the desired product
the Ph3P+CF2CO2ꢀ/Se/Fꢀ system might be able to act as a CF3Seꢀ (entry 15). A slightly higher yield was given by increasing the
source to realize trifluoromethylselenolation. In this case, although loading of this ammonium salt (entry 18). To our delight, using a
the reaction involved the sequential formation of three new carbon– substoichiometric amount of Ag2CO3 could also give a good
heteroatom bonds, a Se–CF2 bond, SeCF2–F bond, and C–SeCF3 yield (80%) when using excessive CuI (entry 19). But the yield
bond, it occurred fast and was completed within 1.5 h (Scheme 1, was decreased dramatically without the presence of Ag2CO3
eqn (3)).
(entry 20). CuI is essential for this conversion and no desired
As we have found that a copper source may be necessary to product was observed without using this complex (entry 21).
ꢀ
enable the trifluoromethylthiolation with the Ph3P+CF2CO2
/
The ligand 2,20-bipyridine also played an important role, as
S8/Fꢀ system, CuI was then used to promote the trifluoro- evidenced by the lower yield (62%) in its absence (entry 22).
methylselenolation of substrate 1a with the Ph3P+CF2CO2ꢀ/Se/
With the optimized reaction conditions in hand, we then
Fꢀ system (Table 1). A brief survey of the reaction solvent investigated the Cu-mediated trifluoromethylselenolation of
(entries 1–4) revealed that DMA appeared to be a superior benzyl halides with the Ph3P+CF2CO2ꢀ/Se/Fꢀ system. As shown in
choice (entry 4). Almost no product was detected by using CuBr Scheme 2, electron-deficient, -neutral and -rich benzyl bromides
instead of CuI (entry 5). The yield was slightly increased by could all be well converted into the desired products in moderate to
good yields (2a–2m). Although the mixture of Ph3P+CF2CO2ꢀ, Fꢀ
source, and a Cu complex could generate the active trifluoro-
Table 1 Optimization of the reaction conditionsa
methylation intermediate [CuCF3],26 trifluoromethylation byproduct
was not observed in these reactions. Interestingly, the aryl C–X bond
(X = Cl, Br or I) remained intact (2c–2g), even though aryl halides
are reactive toward Cu-mediated trifluoromethylselenolation, as
Entry [Cu] (equiv.) [Ag] (equiv.)
Additive (equiv.)
Yieldb (%)
1cd
2ce
3cf
4c
CuI (0.5)
CuI (0.5)
CuI (0.5)
CuI (0.5)
CuBr (0.5)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (1)
CuI (3)
CuI (3)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
Trace
ND
ND
14
Trace
19
28
26
7
37
20
12
36
17
54
34
35
57
5c
6c
7
8
9
Ag2CO3 (2)
AgF (2)
CF3SO3Ag (2)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (1)
Ag2CO3 (0.2)
—
10
11g
12h
13i
14
15
16
17
18
19
20
21
22j
—
nBu4NF (1)
nBu4NCl (1)
nBu4NBr (1)
nBu4NI (1)
nBu4NCl (2)
nBu4NCl (2)
nBu4NCl (2)
nBu4NCl (2)
nBu4NCl (2)
80
45
ND
62
Ag2CO3 (0.2)
Ag2CO3 (0.2)
CuI (3)
Reaction conditions: substrate 1a (0.2 mmol), Ph3P+CF2CO2ꢀ (2 equiv.),
Se (6 equiv.), CsF (3 equiv.), 2,20-bpy(2,20-bipyridine) (2 equiv.), Cu
complex, and Ag complex in DMA (3 mL) at 70 1C for 1.5 h; ND = not
a
Scheme 2 Cu-Mediated difluorocarbene-derived trifluoromethylselenolation.
Isolated yields. Reaction conditions: substrate 1 (0.2 mmol), Ph3P+CF2COOꢀ
(2 equiv.), Se (6 equiv.), CsF (3 equiv.), 2,20-bipyridine (3 equiv.), CuI (3 equiv.),
Ag2CO3 (0.2 equiv.), nBu4NCl (2 equiv.) in DMA (3 mL) at 70 1C for 1.5 h. a The
yields in parentheses were determined by 19F NMR spectroscopy.
b
c
detected. The yields were determined by 19F NMR spectroscopy. No
d
e
2,20-bpy was used. DMF was used as the reaction solvent. THF was
f
used as the reaction solvent. DMSO was used as the reaction solvent.
KF was used instead of CsF. 1,10-Phenanthroline was used instead of
g
h
i
j
2,20-bpy. The reaction temperature was 90 1C. No 2,20-bpy was used.
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the Chinese Academy of Sciences (XDA02020105, XDA02020106),
and Key Research Program of Frontier Sciences (CAS) (QYZDJ-
SSW-SLH049) for financial support.
Scheme 3 The generation of [CuSeCF3] intermediate. a The yield was
determined by 19F NMR spectroscopy.
Conflicts of interest
The authors declare no competing financial interest.
Notes and references
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has been reported previously.11 Low yields were obtained for the
conversion of allyl bromides and alkyl bromides (2n–2o).
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n
n
the ammonium cation Bu4N+, the source of which is Bu4NCl or
[(nBu4N+)2 CO32ꢀ] that is produced via the reaction of nBu4NCl with
Ag2CO3, to form the [nBu4N+ CF3Seꢀ] intermediate. Ligand exchange
of the copper complex with [nBu4N+ CF3Seꢀ] provides the key
trifluoromethylselenolation intermediate, CuSeCF3, which would
easily convert the substrates into the final products.11
In summary, we have described the Cu-mediated trifluorꢀo-
methylselenolation of benzyl halides with the Ph3P+CF2CO2
/
Se/Fꢀ system. This work represents the first protocol for trifluoro-
methylselenolation by using the combination of a difluorocarbene
intermediate, elemental selenium and fluoride anions as the tri-
fluoromethylseleno anion source. The use of the Fꢀ anion for the
construction of CF3Seꢀ anions may allow the application of this
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The authors thank the National Basic Research Program of
China (2015CB931903), the National Natural Science Founda-
tion (21421002, 21472222, 21502214, 21672242, and 21772122),
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