Difluorocyclopropanation

Table 1. gem-Difluorocyclopropanes from Bromo(difluoromethyl)-triphenylphosphonium Bromide... 

Table 2. gem-Difluorocyclopropanes from Alkenes and Hexafluoropropylene Oxide... 

Simultaneous elimination of chloride ion and carbon dioxide occurs dunng heating of methyl chlorodifluoroacetate with lithium chloride in hexamethyl-phosphoric tnamide (HMPA) The difluorocarbene generated in this way is trapped by electron-rich alkenes to form 1,1-difluorocyclopropanes [26] (equation 24)... 

On the contrary, the cathodic reduction of dibromodifluoromethane generates difluorocarbene, which was successfully trapped with reactive olefines yielding 1,1-difluorocyclopropanes (Scheme 3.3.) [13]. 

Sigma lone pair nonbonded interaction in 1,2-difluorocyclopropane presents a similar situation to that observed in 1,2-difluoroethane (see Pattern b Scheme 1). Specifically, sigma nonbonded attraction may favor the trans isomer. This can be seen in the results of CNDO/2 calculations shown above where it appears that the sigma nonbonded interaction is repulsive in the cis isomer. 

Consider the simplest disubstituted cyclic system, difluorocyclopropane. The two geometrical isomers are shown below and the a a interactions are enumerated, neglecting those involving the central methylene group since they will be identical for both isomers. 

Experimentally, trans 1,2-difluorocyclopropane is more stable than the cis isomer372. Fluorine and hydrogen charges for cis and trans 1,2-difluorocyclopropane as calculated by the CNDO/2 method are shown below ... 

Difluorocarbene cannot be generated (<1%) under liquiddiquid phase-transfer catalytic conditions [29] owing to the rapid hydrolysis of the carbene at the interface [30], although it has been indicated that it is possible to obtain low yields of 1,1-difluorocyclopropanes under soliddiquid conditions [1]. More successful is the reaction of dibromomethane and dibromodifluoromethane under basic conditions. It is assumed that the initially formed dibromomethyl anion is transported into the organic phase where an equilibrium reaction with dibromodifluoromethane produces the bromodifluoromethyl anion and, subsequently, the difluorocarbene [31]. 

Fluorocyclopropanss Monofluoro- and difluorocyclopropanes are new structural moieties used in medicinal chemistry. 

The difluorocyclopropane motif is found in zusuquidar, an inhibitor of the efflux pump (Figure 8.10). 

Calculations and Experiments on the Stereomutation of 1,1-Difluorocyclopropanes. C—F bonds have low-lying unfilled, ct orbitals therefore, C—F bonds are strong, hyperconjugative electron acceptors. Consequently, as shown schematically in Figure 22.9, hyperconjugative interaction with... 

Figure 22.9. Disrotatory ring opening of 1,1-difluorocyclopropane (9) to 2,2-difluorocyclo-propane-l,3-diyl (10). The in-phase comhination of 2p-n AOs in the highest occupied molecular orbital (HOMO) is stabilized by a bonding interaction with the 2p AO at C2 in the n combination of low-lying, C—F, antibonding orbitals.

Dolbier WR, Sellers SF (1982) J. Am. Chem. Soc. 104 2494. A review of the authors works on thermal rearrangements of gem-difluorocyclopropanes covering, inter alia, cyclopropane thermolysis, methylene cyclopropane and spiropentane rearrangements, vinyl-cyclopropane and cyclopropylcarbinyl isomerizations has been published Dolbier WR (1981) Acc. Chem. Res. 14 195... 

Trialkyl(trifluoromethyl)tin reacted with sodium iodide at 80 °C to form difluorocarbene in situ, which gave the difluorocyclopropane derivatives in the presence of olefins [108-110] (Scheme 39). 

Methylene difluorocyclopropanes are relatively rare and their rearrangement chemistry has been reviewed recently [14]. In addition, electron deficient alkenes such as sesquiterpenoid methylene lactones may be competent substrates. Two crystal structures of compounds prepared in this way were reported recently [15,16]. Other relatively recent methods use dibromodifluoromethane, a relatively inexpensive and liquid precursor. Dolbier and co-workers described a simple zinc-mediated protocol [17], while Balcerzak and Jonczyk described a useful reproducible phase transfer catalysed procedure (Eq. 6) using bromo-form and dibromodifluoromethane [18]. The only problem here appears to be in separating cyclopropane products from alkene starting material (the authors recommend titration with bromine which is not particularly amenable for small scale use). Schlosser and co-workers have also described a mild ylide-based approach using dibromodifluoromethane [19] which reacts particularly well with highly nucleophilic alkenes such as enol ethers [20], and remarkably, with alkynes [21] to afford labile difluorocyclopropenes (Eq. 7). 

Difluorocyclopropane has a lengthened distal C2-C3 (1.533 A), and shortened proximal C1-C2, C1-C3 bonds (1.464 A) in comparison with cyclopropane (1.514 A).3 In all other fluorinated cyclopropanes for which data is available, all of the ring bonds are slightly shorter than those of cyclopropane. Data for fluorocyclopropane is not available, but the crude assumption is that the distal C2-C3 bond has an average value between that of 1,1-difluorocyclopropane... 

The chemical effect of a gem-difluoro group on cyclopropane is to facilitate the thermal cleavage of the distal ring bond. This is illustrated by the facile endojexo isomerization of tricyclic cTO-difluorocyclopropane 1, which occurs at 60 C.4... 

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