Fluorinated cyclohexanes: Synthesis of amine building blocks of the all-cis 2,3,5,6-tetrafluorocyclohexylamine motif (original) (raw)
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An Improved Synthesis of 2-, 3-, and 4-(Trifluoromethyl)cyclohexylamines
Synthesis, 2012
An improved synthesis of 2-, 3-, and 4-trifluoromethylcyclohexylamines on a multigram scale via PtO 2 -mediated hydrogenation of the corresponding trifluoromethylanilines in trifluoroacetic acid at room temperature under atmospheric pressure is reported. The hydrogenation occurred with a remarkable stereoselectivity favoring the formation of cis-isomers.
A new synthesis of trifluoromethylated cyclohexenes
Journal of Fluorine Chemistry, 1993
1,3-Dimethyl-2-ethoxycarbonyl-1-(trifhroromethyl)cyclohex-4-ene is prepared by the cycloaddition of 1 , 1,l-trifhroro-2-methyl-2-butenoic acid ethyl ester with 1,3-pentadiene. The dienophile is prepared by the reaction of CF,C(O)CH, with BrCH&(0)OC2H5 in the presence of (CeH,),Sb or (C,H&As. An extension of this procedure to hexafluoroacetone has provided 1,l,l-trifluoro-2-hydroxy-2-(trifhroromethyl)-4-butanoic acid ethyl ester. *Author to whom all correspondence should be addressed. +The proposed structures for compounds 1, 2 and 3 are given in Scheme 1.
Nature Chemistry
Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl-and fluoro-substituent stereogenic carbon centre are far less common. This potentially impactful set of molecules thus remains severely underdeveloped. Here we introduce a catalytic regio-, diastereoand enantioselective strategy for the preparation of homoallylic alcohols bearing a stereogenic carbon centre bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalysed by an in situ-formed organozinc complex, can be used for diastereodivergent preparation of tetrafluoro-monosaccharides, including ribose core analogues of the antiviral drug sofosbuvir (Sovaldi). Unexpected reactivity/selectivity profiles, probably originating from the trifluoromethyl-and fluoro-substituted carbon site, are discovered, foreshadowing other unique chemistries that remain unknown. The ease, economy, efficiency and selectivity with which organofluorine compounds are accessed is in the exclusive purview of chemical synthesis 1,2. Efficient transformations that deliver valuable fluoro-organic products with high diastereo-and/or enantioselectivity open fresh vistas in drug discovery 3-5 , and facilitate the development of improved agrochemicals 6 and/or superior polymeric materials 7. Among the areas to be impacted are oligonucleotide therapeutics and glycomimetic drug design 8-11 , where 2-fluoro-substituted monosaccharides are key (Fig. 1a). An example is sofosbuvir, sold under the name Sovaldi, which is used for the treatment of chronic hepatitis C virus infection 12-15. A more potent derivative of Sovaldi has a fluoro,bromo-substituted stereogenic C2 (ref. 16). Bioactive pyranosides with a fluoro-substituted C2 are similarly sought-after, a prominent member being sialyltransferase inhibitor 3F ax-Neu 5 Ac 17,18. These latter compounds are components of cancer vaccine candidates 19,20 that can be used discretely, or in combination with other drugs, to counter viral infections 21 , including COVID-19 (refs. 22-24). In light of evidence vis-à-vis the beneficial impact of a trifluoromethyl group on bioavailability and/or metabolic stability of a therapeutic candidate 2,3 , the development of efficient and stereoselective pathways for the synthesis of unexplored furanosides and pyranosides with a trifluoromethyl-and fluoro-substituted C2 (refs. 2,25) is particularly desirable (Fig. 1a). Oxonium ion generation and the ensuing saccharide ring cleavage, a preamble to depurination 26,27 , might then be thwarted by the strong electronic pull caused by the trifluoromethyl-and fluoro-substituted stereogenic carbon (compared
Journal of Organic Chemistry, 1980
Sodium trifluoroacetate reacts with fluorine in the presence of traces of water or H F to give mainly trifluoroacetyl hypofluorite, CF,COOF (1). This uncommon reagent was reacted in situ with a number of stilbenes and with diphenylacetylene. The oxygen-bound fluorine clearly acts as an electrophile, since Markownikoff addition of 1 to the double bond was observed. However, in cases where the Hammett constant up+ of the ring substituent is low, as in 4-ChlOrO-(15) or 4-methyl-(32) stilbenes, some of the regioselectivity is lost. Usually only syn adducts were found except in cases where the 1-fluor0 carbocation is stabilized, as in the case of trans-4-methoxystilbenes (23), or more than usual sterically hindered, as in trans-2-(carbomethoxy)stilbene (20). The stereoselectivity achieved in the reaction of 1 with stilbenes was compared with the stereoselectivity of fluoroxyperfluoroalkanes, R P F , with the same olefins. In the light of this comparison it seems to us that the oxygen-bound fluorine in 1 is more electrophilic in character than in R P F compounds. The reaction products of diphenylacetylene (28) with 1, which are in sharp contrast to the products of the parallel reaction of 28 with CF,OF, support this observation. The strong electrophilic character of the oxygen-bound fluorine of 1 is also demonstrated by aromatic electrophilic fluorination taking place on the activated ring of 4-methoxystilbene (23). In almost all cases the 1-fluoro-2-hydroxy (or 2-trifluoroacetoxy) compounds adopt the more stable gauche conformation as is evident from their NMR ('H and 19F) spectra. In the case of steric disturbance, however, as in 21b and 22b, a deviation from the gauche conformation was observed and discussed. The 1-fluoro-2-trifluoroacetoxy compounds were readily hydrolyzed to the corresponding a-fluorohydrins, thus opening a new route for the synthesis of this important group.