An efficient regioselective hydrodifluoromethylation of unactivated alkenes with TMSCF2CO2Et at ambient temperature

Article abstract of DOI:10.1039/c4cc04591b

A mild, versatile and efficient method for the regioselective hydrodifluoromethylation of unactivated alkenes has been developed. This Ag-mediated Csp³-CF₂ bond forming reaction provides easy access to a variety of vicinal α-difluoro

Full text of DOI:10.1039/c4cc04591b

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An efficient regioselective
hydrodifluoromethylation of unactivated alkenes
with TMSCF2CO2Et at ambient temperature†
Cite this: Chem. Commun., 2014,
50, 9749
Received 17th June 2014,
Accepted 7th July 2014
Guobin Ma,a Wen Wan,*a Jialiang Li,a Qingyang Hu,a Haizhen Jiang,a
Shizheng Zhu,b Jing Wanga and Jian Hao*ab
DOI: 10.1039/c4cc04591b
www.rsc.org/chemcomm
A mild, versatile and efficient method for the regioselective hydro- For instance, Burton developed nickel catalyzed reaction of
difluoromethylation of unactivated alkenes has been developed. alkenes with iododifluoroacetates to afford a-difluoroesters.10a
This Ag-mediated Csp3–CF2 bond forming reaction provides easy Fuchigami described photoinitated S–CF2 bond cleavage in the
access to a variety of vicinal a-difluoroacetate-containing alkanes. presence of olefins to obtain regioselective addition products.10b
Ryu demonstrated a reductive bromine atom-transfer reaction of
Owing to the unique properties of the difluoromethylene group alkenes with bromodifluoroacetate through photoirradiation to
(CF2), which can function as a bioisostere for mimicking the steric give hydroalkylation products of alkenes.10c Despite significant
and electronic features of an oxygen atom or a carbonyl group, the advances in the construction of Csp3–CF2COOEt, the difluoro-
incorporation of functionalized difluoromethylene groups in small methylation process still remains challenging, and only a handful
molecules has a profound impact on the pharmaceuticals and of examples have been developed so far.11
agrochemicals.1 It has been of great synthetic interest to develop
efficient methods for the introduction of a difluoromethylated the copper-catalyzed cross-coupling reaction of aryl iodides with
group into diverse organic structures.
a-silyldifluoroacetates (TMSCF2COOEt) described by Amii12a
The transition-metal-mediated or catalyzed fluoroalkylation for and a silver-mediated aromatic C–H difluoromethylation with
Recently, the radical aromatic difluoromethylation through
the construction of Csp2–CF3 or Csp2–CF2 bonds has been a-silyldifluoroacetates reported by Brase,
respectively, paved
2,3
4–6
12b
¨
intensively documented. The past three years has witnessed rapid the way for the novel construction of Csp2–CF2COOEt in
advances in copper or palladium-catalyzed trifluoromethylation aromatic rings. It was reasonably envisioned that the novel
reactions for the construction of Csp3–CF3 bonds from alkenes.7 construction of Csp3–CF2 could be considerably expanded if a
Very recently, groups led by Qing, Buchwald, and Nicewicz devel- difluoromethyl radical generated by the a-silyldifluoroacetates
oped Ag(I)-catalyzed, visible-light-mediated, or metal-free hydro- could undergo a hydrodifluoromethylation type addition on
trifluoromethylation of unactivated olefins in order to build alkenes. Herein, we report the development of a net regioselec-
Csp3–CF3 bonds.8 These synthetic strategies provide a novel tive addition of H–CF2COOEt onto unactivated alkenes.
protocol for the construction of a vicinal Csp3–CF3 bond in a TMSCF2COOEt works as an efficient (ethoxycarbonyl)difluoro-
wider range of molecular context. In contrast to the significant methylating reagent and Hanztsch ester as a useful hydrogen
achievements that have been made in the trifluoromethylation donor in this reductive intermolecular hydrodifluoromethyla-
studies, the transition-metal-mediated hydrodifluoroalkylation to tion. This operationally simple protocol can be readily applied
construct Csp3–CF2 bonds is still underdeveloped, because of the to the introduction of a terminal CF2COOEt group into a broad
instability of difluoroalkyl intermediates.
range of simple and complex alkenes under very mild reaction
Among the reported functionalized difluoro moieties, the conditions. More interestingly, the incorporation of the terminal
ethoxycarbonyldifluoromethyl (CF2COOEt) moiety is extremely difluoroacetate group into alkenes in this reaction provides easy
appealing due to the huge possibility of postfunctionalization.9 access for further chemical modification of these fluorine-
containing compounds, which overcomes the drawbacks of the
a Department of Chemistry, School of Materials Science and Engineering,
Shanghai University, Shanghai 200444, China. E-mail: jhao@shu.edu.cn,
wanwen@staff.shu.edu.cn
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc04591b
recently reported trifluoromethylation of terminal alkenes.
We initially examined the reaction of compound 1a with
TMSCF2COOEt in the presence of AgNO3 or PhI(OAc)2 as an
oxidant, respectively, and NaOAc as a base in DMF at ambient
temperature (Table 1, and see Tables S1 and S2 in ESI† for the
screening of oxidants and bases). Unfortunately, this reaction
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Table 1 Optimization of hydrodifluoromethylation of alkenesa
Table 2 Scope of regioselective hydrodifluoromethylation of terminal
alkenesa
Yieldb (%)
H donor PhI(OAc)2 Solvent 3a 4a 5a
Entry Ag salts
1
2
3
4
5
6
7
8
20% AgNO3
/
/
/
I
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
2 eq.
DMF
DMF
DMF
DMF
DMF
DMF
THF
DMPU 11
CH3OH
DCE
1
25
47
67
56
72
3
—
—
3
7
3
1
1
2
100% AgNO3
250% AgNO3
250% AgNO3
Trace
1
2
—
3
—
—
2
3
5
250% AgNO3 II
250% AgNO3 III
250% AgNO3 III
250% AgNO3 III
250% AgNO3 III
250% AgNO3 III
250% AgNO3 III
250% AgNO3 III
250% AgNO3 III
250% AgOAc III
250% Ag2CO3 III
250% Ag2O
250% AgF
250% AgBF4
250% AgSbF6 III
250% AgOTf III
250% AgOTf III
8
—
—
—
—
4
5
8
9
—
—
10
11
12
13
14
15
16
17
18
19
20
21
22
CH3CN 54
DMSO 70
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
79
34
—
3
12
68
80
86
—
—
6
3
—
—
—
8
3
7
—
Trace
Trace
4
1
3
III
III
III
—
—
—
—
0% AgOTf
III
a
Reaction conditions: 1a (0.3 mmol), 2 (1.5 mmol, 5 eq.), NaOAc
(0.9 mmol), 12 h, N2 atmosphere. Determined by 19F NMR spectro-
b
scopy; H donor (0.3 mmol): I = triethylsilane, II = 1,4-cyclohexadiene,
III = Hantzsch ester.
did not work under these conditions. Pleasingly, a mixture of
hydrodifluoromethylated compound 3a as the major product,
with the deprotonated a-difluoromethylated side products of
4a and 5a, was obtained, when the combination of 1 equiv.
of AgNO3 and 2.0 equiv. of PhI(OAc)2 as a co-oxidant, and
3.0 equiv. of NaOAc as a base was applied (entry 2). Increasing
the loading of AgNO3 to 2.5 equiv. provided the desired product
3a with 47% yield (entry 3). In order to improve the efficiency
of the hydrodifluoromethylation, a H-donor was used to suppress
the difluoromethylated alkenes in this reaction. To our delight,
a
Isolated yields.
the addition of Et3SiH (1.0 equiv.) and 1,4-cyclohexadiene alkenes in good to high yields. In all of the reactions, the
(1.0 equiv.) in this reaction remarkably increased the yield of hydrodifluoromethylated compounds 3 (i.e. 3a–3u) are found to
the a-adduct product (entries 4, 5), while Hantzsch ester constitute the major products, whereas compounds 4 and 5 are
(1.0 equiv.) provided the yield of the desired product up to 72% obtained as the side products with very low yields. In addition, the
(entry 6). The use of solvents, such as MeOH, THF, DCE, and mild reaction conditions of hydrodifluoromethylation of alkenes
DMPU, did not give acceptable results (entries 7–10). However, the are found to allow high tolerance for a wide range of substrates
reaction could proceed smoothly in polar solvents of CH3CN, and functional groups, including esters, sulfonic esters, ethers,
DMSO and NMP, while NMP proved to be the best (entries 11–13). amides, imides, (hetero)arenes, ketones, and protected amines.
Finally, a variety of silver(I) salts were further evaluated (entries Moreover, arene rings containing chloro, bromo or iodo substitu-
14–19) and AgOTf was found to work more efficiently to afford the ents, which are prominent leaving groups in a variety of transition-
desired product in 86% yield (entry 20).
metal catalyzed cross-coupling reactions, are compatible with the
With the optimized protocol in hand, we examined the range of reaction in good yields within the range of 64–81% (3d, 3e, and 3f).
unactivated terminal monosubstituted alkenes that are capable of Terminal alkenes derived from coumarin 1r, 3-hydroxyflavone 1s
undergoing silver(I)-mediated hydrodifluoromethylation with and 4-methyl-umbelliferone 1t, which contain two inequivalent
TMSCF2COOEt (Table 2). The reactions afford highly regioselective alkenyl groups, showed excellent chemoselectivity to afford the
products with the hydrodifluoromethylation of the unactivated hydrodifluoromethylation of the vicinal alkenyl group. To expand
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Scheme 1 Hydrodifluoromethylation of biologically active compounds.
Scheme 2 Proposed reaction mechanism.
the scope of the method, a disubstituted alkene was tested under
the same reaction conditions. 1,1-Disubstituted alkene 1u was
smoothly converted to the desired product 3u in 76% yield.
In regard to the reaction mechanism through a probable
Late-stage modification of drug candidates is valuable for radical process, we conducted the reaction by replacing the
structure–activity relationship studies, since the complex target solvent of NMP with DMSO-d6 in the absence of a H-donor
molecules are more challenging to obtain. The protocol in this (see ESI†). DMSO is known to have the ability to generate the
work offers the possibility of late-stage functionalization of methylsulfinic methyl radical CH3S(QO)CH2ꢀ via abstraction of
biologically active compounds that contain an alkenyl group a methyl hydrogen atom by an active radical, such as HOꢀ, Clꢀ,
14 To our surprise, we did not observe any incorpora-
ꢀ
(Scheme 1). For example, a quinine derivative, which has been and Ralkyl .
used as an effective antimalarial drug, was smoothly converted tion of deuterium information in the hydrodifluoromethylation
to its difluoromethylated product 3v (48% yield). Also, an product.
estrone derivative was transferred to the desired product 3w
Despite the successful capture of ꢀCF2COOEt by TEMPO, the
(81% yield). It should be pointed out that the versatile functio- high selectivity for the formation of a-difluoroacetate alkane
nalization of the terminal ester in the above synthesized over that of the a-difluoroacetate alkenes in this reaction
biologically active compounds could be readily realized, making suggested that the possible hydrogen abstraction of an alkyl
it possible to incorporate another pharmacophore into one cation intermediate from the Hanztsch ester may be the major
molecule. Thus, novel identical or non-identical twin drugs route involved in the reaction.
linked by the unusual difluoromethylene group are anticipated
Thus, the collective mechanistic evidence, including the
to show two different pharmacological activities stemming from control experiments, suggested the critical roles of the
the individual pharmacophores (dual action).13 In addition, ꢀCF2COOEt radical and the subsequently formed alkyl cation
enhanced potent or selective pharmacological effects could also in this reaction. Based on these results, we proposed a working
be expected.
hypothesis for the reaction mechanism, as illustrated in
To figure out whether the in situ generated (ethoxycarbonyl)- Scheme 2. A pathway of one-electron oxidation of the radical
difluoromethyl radical species (ꢀCF2COOEt) would be involved intermediate by oxidative hypervalent iodine was reasonable in
in the reaction, we conducted an inhibition experiment of the hydrodifluoromethylation process. Firstly, the ꢀCF2COOEt
alkene 1b with the addition of the known radical scavenger of radical intermediate is generated by the coꢀmbination of Ag(I)
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy, 1.0 equiv.) under and PhI(OAc)2. Subsequent addition of the CF2COOEt radical
the standard reaction conditions (see ESI†). The TEMPO– intermediate onto the CQC bond of the vicinal alkene affords
CF2COOEt was afforded in 76% yield with greatly suppressed the alkyl radical C. The alkyl radical C will be rapidly oxidized to
formation of the desired product 3b. Furthermore, addition an alkyl cation D by the oxidative hypervalent iodine centered
of the radical inhibitor hydroquinone or the ET scavenger radical B. The generated cation intermediate D undergoes
1,4-dinitrobenzene to the reaction mixture led to a significant abstraction from the known H-donor, such as Hantzsch esters,
decrease of the reaction efficiency. These results suggested that providing the main a-difluoromethylated alkane 3. Deprotona-
a CF2COOEt radical species would play an important role in the tion of the alkyl cation D gives the side products of a-difluor-
current reaction.
omethylated alkenes 4 and 5.
To obtain some information on the reaction pathway, we
In summary, we have described a mild and efficient procedure
investigated the reaction of 1b with AgOTf or PhI(OAc)2 as an of silver-mediated hydrodifluoromethylation of diverse unacti-
oxidant, respectively, in the presence of TMSCF2COOEt and vated alkenes. This reaction affords a practical instance of
NaOAc (Table 1, entries 21, 22, and see ESI†). The control hydro-(ethoxycarbonyl)difluoromethylation of the vicinal CQC
experiments authenticated the importance of the combination bond to construct the Csp3–CF2 bond in molecules. The primary
of both AgOTf and PhI(OAc)2. The possible formation of mechanistic investigations suggest that a CF2COOEt radical
CF2COOEt radical species generated independently from oxidative species is involved, followed by one-electron oxidation to afford
AgOTf or PhI(OAc)2, respectively, was ruled out.
an alkyl cation intermediate, in the current transformation.
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