Jonathan M. Percy

Building Block Approaches to Aliphatic Organofluorine Compounds

This review deals with general and significant developments in the area of building block chemistry of lightly-fluorinated aliphatic compounds, that is, those that contain one, two, or three, fluorine atoms. For the purposes of the review, building blocks are small readily-available materials that already contain fluorine atoms. They are classified according to the number of carbon atoms supplied to the target molecule, rather than according to the number of fluorine atoms. Finally, certain fluorinated motifs which may be generated easily, and are then transformable in useful ways, are discussed.

What is the initiation step of the Grubbs-Hoveyda olefin metathesis catalyst?

Density function theory calculations reveal that the Grubbs-Hoveyda olefin metathesis pre-catalyst is activated by the formation of a complex in which the incoming alkene substrate and outgoing alkoxy ligand are both clearly associated with the ruthenium centre. The computed energies for reaction are in good agreement with the experimental values, reported here.

New fluorine-containing building blocks from trifluoroethanol. 1

Abstract A new fluorine containing acyl anion equivalent 1,1-difluoro-2-lithio-2-[(N,N-diethylcarbamato)-ethene 9 has been prepared and trapped with a number of electrophiles in good yields. Transacylation of the first formed lithium alkoxides releases a difluoroenolate, affording difluoromethylketones upon work-up.

A reproducible and high-yielding cerium-mediated route to α,α-difluoro-β-ketophosphonates

Abstract The addition of diethyldifluoromethylphosphonate to LDA containing cerium(III) chloride in THF generates an organometallic nucleophile that reacts efficiently with esters and DMF (1,2-addition) affording moderate to good yields of adducts, and extending considerably the range of compounds available containing the difluoromethylenephosphonate group.

Mapping the potential energy surfaces for ring-closing metathesis reactions of prototypical dienes by electronic structure calculations

The potential energy surfaces for ring-closing metathesis reactions of a series of simple α,ω-dienes which lead to 5-10 membered ring products, have been explored using density functional theory methods. We have investigated both the conformational aspects of the hydrocarbon chain during the course of the reactions, as well as the stationary structures on the corresponding potential energy surfaces. Extensive conformational searches reveal that the reaction proceeds via the conformation that would be expected for the cycloalkene product, though most unexpectedly, cyclohexene forms via complexes in boat-like conformations. The M06-L density functional has been used to map out the potential energy surfaces, and has identified metallocyclobutane fragmentation as being generally the highest barrier along the pathway. The structural variations along the pathway have been discussed for the reactant hydrocarbons of differing chain length to identify points at which cyclisation events may begin to affect reaction rates. Our study provides an excellent starting point from which to begin to learn about the way RCM reaction outcomes are controlled by diene structure.

Synthesis of 8-substituted 1-naphthylamine derivatives. exceptional reactivity of the substituents.

Abstract 8-Lithio-1-N, N-dimethylaminonaphthalene has been prepared, and converted in good yield to the 8-CHO, COCH3, n-Bu2B and OH derivatives. The peri-relationship confers special reactivity on both 1 and 8 substituents: the aldehyde (5) is largely ring-closed in acid, the borane (9) is inert to oxidation because of the B → N interaction, and the 8-methoxymethyl NMe3+ derivative is formed only with difficulty, and readily demethylated.

A RAPID AND CONVENIENT APPROACH TO FUNCTIONALLY DIVERSE MONOFLUORINATED VINYLIC COMPOUNDS

Abstract Monofluorinated allylic ether 3, synthesised in 4 steps from trifluoroethanol, underwent metallation at the CF vinylic position upon treatment with strong base. Monofluoro vinyllithium 4 was trapped efficiently with a variety of electrophiles, including Group (IV) halides, methyl iodide and benzaldehyde. Attempts to couple monofluoro vinyl stannane 5d with aryl iodides and triflates under palladium catalysis proved only moderately successful. Conversion of 4 to the monofluoro vinylzinc reagent allowed access to monofluoro vinyl iodide 5e, which was successfully coupled with a range of terminal alkynes.

Selected substituent effects on the rate and efficiency of formation of an eight-membered ring by RCM.

Studies of a range of reactions forming cyclooctenones highlight a discrepancy between cyclization rate and cyclization efficiency. Cyclization rates change modestly as the oxygen function at the allylic position is varied, and increase upon gem-dimethylation. Cyclization efficiency has also been quantified for four substrates, revealing a range of effective molarities (EMs) of 2 orders of magnitude that are substituent dependent. The most efficient cyclization appears to result from suppression of the cross-metathesis pathway through which oligomerization begins, rather than from a particularly rapid cyclization reaction. In the presence of a Ti(IV) cocatalyst, diene monomers transform smoothly to eight-membered-ring products without the intermediacy of dimers or other oligomers, indicating that the cyclizations are kinetically and not thermodynamically controlled. The gem-dialkyl effect is also shown to be kinetic.

Synthesis of 4,4-difluoroglycosides using ring-closing metathesis

4-Deoxy-4,4-difluoro-glycosides have been synthesised for the first time via a direct sequence involving ring-closing metathesis and indium-mediated difluoroallylation with 1-bromo-1,1-difluoropropene in water. Two protecting group strategies were explored, one to allow protection of the primary C-6 hydroxyl group throughout the sequence, while the second was intended to allow deprotection after RCM and before dihydroxylation. The benzyl ether could be used in the first role, and pivaloyl is effective in the second. Dihydroxylations were highly stereoselective and controlled by the orientation of the glycosidic C-O bond.

Bond length and reactivity: the gauche effect. A combined crystallographic and theoretical investigation of the effects of β-substituents on C–OX bond length

The ‘variable oxygen probe’ is applied to systems with the general structure Y–C–C–OX (Y = F, H, SiR3), using both crystal structure correlations (including 25 new structures) and ab initio calculations (SCF[DZP]), for 20 structures, Y–CH2–CH2–OX: Y = H, F and SiH3(gauche and trans); X = CH3, CHO (E and Z) and NO2. The calculations reproduce conformational preferences well (all our 2-fluoroethyl derivatives crystallise with F gauche to OX). Both crystal and calculated structures give linear bond-length/pKHOX correlations. From the crystal structures: definitive correlations are derived for primary and secondary alcohol derivatives; no significant difference is observed between axial and equatorial cyclohexyl systems; β-fluorine has a small bond-shortening effect on the C–OX bond, which is greatest for the best leaving groups OX; and data for two systems with β-silicon are consistent with a bond-lengthening effect. The inductive effect of β-fluorine, observed as its effect on the C–OX bond length, shows no significant dependence on geometry.Calculated bond lengths give similar results, but show the different sensitivities to varying OX expected from frontier orbital considerations (σY–C–σ*C–OX for Y = Si > H > F). The length of the C–OX bond in Y–CH2–CH2–OX is a linear function of the electronegativity of Y. 1,3-Interaction energies calculated (at the MP2[DZP] level) for the isodesmic reaction Y–CH2–CH2–OX + CH3–CH3→ CH3–CH2–OX + Y–CH2–CH3 give a measure of the destablising effect of β-fluorine and the stabilising effect of β-silicon in these systems. In three different systems which react with participation of adjacent σ-bonds, the lengthening of the C–OX bond, observed in the ground state using the variable oxygen probe, is not accompanied by significant involvement of the adjacent orbitals. It is suggested that C–OX bond breaking, and the further structural reorganisation, are not closely coupled in such reactions.