Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Single C(sp3)−F Bond Activation in a CF3 Group: IpsoDefluorooxylation of (Trifluoromethyl)alkenes with Oximes Hao Zeng, Chuanle Zhu,* and Huanfeng Jiang* Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P.R. China
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ABSTRACT: The first defluorinative ipso-functionalization reaction of (trifluoromethyl)alkenes is reported. This exclusively regioselective ipsodefluorooxylation of (trifluoromethyl)alkenes with oximes affords various attractive O-(1,1-difluoroallyl)oxime ethers efficiently via a chemoselective single C(sp3)−F bond activation in the CF3 group. Primary mechanism studies indicated an anionic SN2-type substitution pathway might be involved in this transformation.
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Scheme 1. Functionalization of (Trifluoromethyl)alkenes via Single C(sp3)−F Bond Activation
he selective activation of strong chemical bonds has become the subject of active investigation in chemical synthesis. Though considerable progress has been achieved in the functionalization of C(sp2)−F bonds,1 the defluorinative functionalization of the C(sp3)−F bond in CF3 group decorated compounds has been a highly challenging task2 because of the shielding effect of the three fluorine atoms3 and the high bond dissociation energies of the C−F bonds.4 Particularly, owing to the C−F bond strength decreases as defluorination proceeds, the trifluoromethyl moiety is intrinsically favored to perform over- or exhaustive defluorination under the conditions to cleave the first C(sp3)−F bond.5,6 Thus, the methods for selective single C(sp3)−F bond activation in the CF3 group while retaining the other two C−F bonds have not been well developed.2e,7 Such a strategy would facilitate the straightforward synthesis of fluorine-containing molecules, which is highly attractive. (Trifluoromethyl)alkenes are readily available substrates that have been successfully utilized in the transformations of C(sp3)−F bonds activation in a CF3 group.5,8−11 Cleavage of a C(sp3)−F bond in (trifluoromethyl)alkenes can be accomplished using anionic SN2′-type substitution (Scheme 1a),8 Lewis acid promoted cationic SN1′-type substitution (Scheme 1b),9 transition-metal-catalyzed defluorinative functionalization (Scheme 1c),10 and photocatalysis via radical-polar crossover (Scheme 1d).11 Intrinsically, the attached trifluoromethyl group lowers the LUMO of the double bond in the (trifluoromethyl)alkene. Thus, although these defluorinative functionalizations of (trifluoromethyl)alkenes are diverse in nature, they are united in their destination to functionalize the γ carbon to the fluorine atoms and provide gem-difluoroalkene products with retaining of two C(sp2)−F bonds. However, due to their intrinsic properties, control over the regioselectivity in defluorinative functionalization of (trifluoromethyl)alkenes still remains an unsolved challenge. To the best of our knowledge, the defluorinative ispo-functionalization of (trifluoromethyl)alkenes has not been developed, which would afford gem-difluoroalkylated compounds with retainment of two C(sp3)−F bonds. © XXXX American Chemical Society
The impressive effect of fluoroalkyl groups on the biological and physical properties of molecules has inspired substantial research effort to construct novel fluoroalkylated compounds,12 especially for gem- or 1,1-difluoroalkylated molecules.13 Consequently, the synthesis and application of novel 1,1difluoroalkylated compounds have been extensively investigated in library design and drug discovery.14 We herein report a catalyst-free exclusively ispo-selective defluorinative functionalization of (trifluoromethyl)alkenes via a chemoselective single C(sp3)−F bond activation in the CF3 group. This ispoReceived: January 7, 2019
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DOI: 10.1021/acs.orglett.9b00074 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
worth mentioning that the γ-selective product 3a′ was not detected in all these cases. With the optimized reaction conditions in hand, we then turned our attention to the generality of oximes in this ipsodefluorooxylation reaction with terminal (trifluoromethyl)alkene 2a as the reaction partner. The results are illustrated in Scheme 2. In general, substituted oximes with electron-donating
defluorooxylation of (trifluoromethyl)alkenes with readily available oximes provides various attractive and novel O-(1,1difluoroallyl)oxime ethers in high yields with retainment of two C(sp3)−F bonds (Scheme 1e). As part of our recent interest in the synthetic applications of oxime acetates,15 as well as synthetic applications of trifluoromethylated compounds,16 an experiment was carried out with acetophenone-derived oxime acetate and (trifluoromethyl)alkene 2a. A new species was detected by GC−MS analysis with a base peak at m/z = 287.14. Unexpectedly, control experiments showed this new species was derived from the corresponding oxime 1a and (trifluoromethyl)alkene 2a (Table 1, entry 1).
Scheme 2. Substrate Scope of Oximesa
Table 1. Optimization of the Reaction Conditionsa
entry
base
solvent
temp (°C)
yield of 3ab (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
t-BuOLi t-BuONa t-BuOK Cs2CO3 K2CO3 Li2CO3 Et3N DBU DABCO
DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMF 1,4-dioxane MeCN DCE toluene EtOH H2O DMF DMF
90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 90 80 100
57 (55) 30 45 81 30 12
