Trifluoromethyl ketones, addition

Trifluoromethylation. Sodium triethylgermanate mediates the transfer of a CFj group from PhSCFj to methyl esters, forming trifluoromethyl ketones. Addition of CFj to imines is also observed. 

Tiifluoromethyl derivatives of tetrahydrothiopyran-4-ols result from the Michael addition of hydrosulfide to a, -unsaturated trifluoromethyl ketones <96JOC1986> and tetrahydro-thiopyran-4-ones arise from the reaction of H2S with l,5-diaryl-2-chloropenta-l,4-dien-3-ones <96PS(108)93>. 

Concurrently, Glorius and co-workers reported the synthesis of y-butyrolactones under similar reaction conditions [122, 123], Glorius has extended this reactivity to include trifluoromethyl ketones (Scheme 36). In addition to intermolecular reactions, intramolecular homoenolate additions are possible in modest yield Eq. 21 [123],... 

More recently, Cassidy et aid conducted additional H NMR experiments to evaluate the basicities of the dyad H57-D102 in the tetrahedral complexes of chymotrypsin with the peptidyl trifluoromethyl ketones (TFKs) N-acetyl-L-Leu-DL-Phe-CFs and A-acetyl-oL-Phe-CFs. The proton bridging His-57 and Asp-102 is part of a low-barrier hydrogen bond (LBHBs). In H NMR spectra at pH 7.0, these protons appear at 8 18.9 and 18.6 ppm. 

Peptidyl fluoromethyl ketones can readily be synthesized by addition of organometallic reagents to peptide aldehydes and other carbonyl compounds 28 one variation of this reaction is suitable for the stereoselective synthesis of trifluoromethyl ketones. 23,31 ... 

The first step in the overall synthetic scheme (Scheme 6) is the condensation of an appropriate carboxylic acid with trifluoroacetaldehyde. The carboxylic acid is chosen to impart specificity for the target enzyme. In one example,[28 the dianion of cyclohexanepropanoic acid (29) was formed by the addition of LDA and then quickly condensed with trifluoroacetaldehyde to form the p-hydroxy acid 30 as a racemic mixture of erythro- and threo-isomers. The p-hydroxy acid 30 is then protected with TBDMSOTf forming 31. Diphenyl phosphorazidate, TEA, and benzyl alcohol were then utilized in a Curtius rearrangement of the protected alcohol 31, which proceeds through an isocyanate intermediate that yields the protected amino alcohol 32 upon reaction with benzyl alcohol. In order for this step to occur at an appreciable rate, a second equivalent of triethylamine had to be added. The amino alcohol 32 was then deprotected and coupled with Boc-Phe-Leu-OH to give the trifluoromethyl alcohol 33, which was oxidized to the corresponding trifluoromethyl ketone 34 as a 1 1.2 mixture of diastereomers using the Dess-Martin periodinane procedure. Thus far, the compound shown in Scheme 6 is the only compound that has been synthesized by this method, but it is reasonable to assume that many other similar fluoro ketones can be produced by this scheme. 

The nucleophilic addition of a trifluoromethyl anion or its equivalent to an activated carboxylic acid derivative is another potential method for the synthesis of trifluoromethyl ketones (Scheme 8). Due to the well-known instability of the trifluoromethyl anion, the organometallic approach (Section 15.1.4.3.3) is often difficult to utilize. However, a trifluoromethyl anion equivalent, (trifluoromethyl)trimethylsilane (CF3TMS), was developed in 1984 by Ruppert and co-workers.[30] This reagent, known as Ruppert s reagent, is stable and does not undergo fluoride elimination like other equivalent trifluoromethyl anions. An obvious limitation to this method is that it is only useful for the synthesis of a-amino trifluoromethyl ketones unless other fluoroalkyl analogues of Ruppert s reagent are developed. 

Two highly unusual reactions were noted in this study which merit attention. First, the treatment of (59) with cuprate (60) gave rise to 1,2-addition of the alkyne as the only product (67% equation 57). Second, when trifluoromethyl ketone (59) was treated with either the higher or lower order methylcu-prates, the cyanohydrin (61) was isolated in addition to the normal 1,4-addition product (equation 58). 

A new, efficient and general synthesis of 4-amino-3-arylcinnolines has been described recently, starting from arylhydrazines and aryl trifluoromethyl ketones, and the following is a typical example. Addition of a THF solution of the hydrazone formed from phenylhydrazine and 2-trifluoroacetylthiophene to 5 equivalents of KHMDS in THF at -78°C, then slow warming of the mixture to room temperature and stirring at room temperature for several hours, gave 4-amino-3-(2-thienyl)cinnoline in 68% yield after work-up (quench with ether, then a wash with brine). 

Zurich, exploit the susceptibility of trifluoromethyl ketones to nucleophilic addition by amines (primary or even secondary) producing hemiaminals 104. Tertiary... 

Alkenylboronic acids and esters underwent conjugated addition to ct,/ -unsaturated ketones in the presence of trifluoroborane etherate589 or cyanuric fluoride (Equation (129)).590,591 Alkadienyl trifluoromethyl ketones were stereoselectively prepared from (2-alkoxyvinyl) trifluoromethyl ketones (Equation (130)).592 Alkynyl boronates can transfer the alkynyl groups regioselectively and enantioselectively to enones (Equation (131 )).593... 

In fact, even very weak bases are enough for most l, 3-dlcarbonyI compounds and piperidine and acetic acid combine to form a mild buffered system that facilitates both conjugate addition and aldol reactions via enol Intermediates. The trifluoromethyl ketone is extremely electrophilic so the aldol reaction proceeds very smoothly. 

Ohkuma T, Kitamura M, Noyori R (2000) In Ojima I (ed) Catalytic asymmetric synthesis, 2nd edn. Wiley-VCH, New York, Chap 1 Pareja C, Martin-Zamora E, Fernandez R, Lassaletta JM (1999) Stereoselective synthesis of trifluoromethylated compounds nucleophilic addition of formaldehyde N,N-dialkylhydrazones to trifluoromethyl ketones. J Org Chem 64 8846-8854 Pellissier H (2005) Tetrahedron 61 6479... 

The reaction of triphenyl-/ -phosphanes with carbonyl compounds, the Wittig olcfmation reaction, involves addition to the carbonyl carbon in a reaction closely related to the aldol condensation. Triphenyl-2 -phosphanes, derived from alkyltriphenylphosphorus salts, react with 1,1,1-trifluoroacetonc or other trifluoromethyl ketones " - to give products 29. 

Aryl difluoroenoxysilanes 20 were prepared by Mg-promoted defluorination of trifluoromethyl ketones, according to Uneyama s procedure [60], Their reaction with DHA acetate appeared to be much more critical than any other Lewis acid-catalyzed reaction and the setup was very troublesome. Each difluoroenoxysilane required specific reaction conditions (e.g., Lewis acid and rate of addition) (see Scheme 6.11 and Table 6.4) [61]. For instance, the best conditions found for the preparation of the difluoroketone 21a (SnCh, 0.4 equivalents) provided a completely rearranged artemisinin skeleton when applied to the enoxysilane 20b. Furthermore, the stereochemical outcome of reactions was unusual difluoroketones 21a-c all possess the epf-artemisinin configuration at C-9 (9a-Me). The mechanism of this epimerization at C-9 is not fully understood, but probably... 

Tlie Kresze reaction has also been used in the synthesis of N phosphinoyl imines derived from nonenolizable aldehydes, although usually in modest yields [25, 26]. The N phosphinoyl imine derived from trifluoromethyl ketones can be prepared via the ethanolate intermediate (Scheme 1.7) [27]. This adduct is directly used in the subsequent nucleophilic addition reaction. 

It was already known that amino alcohols of the kind we have just used 78 were good at this kind of asymmetric addition but this particular combination of an acetylenic nucleophile and an aryl trifluoromethyl ketone was uncharted territory. After some exploration, stoichiometric pyrrolidine alcohol 88 prepared by alkylation of norephedrine 87 from the chiral pool (chapter 23) proved the best and the ketone 85 had to be used as its V-4-methoxybenzyl derivative18 89. 

In a recent report, by making a slight modification in the structure of the parent compound, two additional compounds with slightly higher activity have been synthesized (36). TFT and the aliphatic trifluoromethyl ketones appeared to be classical competitive inhibitors, while many trifluoropropanone sulfides were found to be reversible but slow and tight binding inhibitors of JHE... 

Addition and cycloaddition. Two slightly different protocols are available for achieving addition of 1-alkynes to trifluoromethyl ketones use either CuOTf and t-BuOK with Xantphos in THF at 60°, or Cu(OTf)2 and two equivalents of t-BuOK and 1,10-phenanthro-line in toluene at 100°. Cyanoformate esters can contribute the CN group as an addend to react with organoazides in a [3+2]cycloaddition catalyzed by CuOTf. ... 

The most important synthetic asset of the xanthate transfer methodology lies in its ability to induce carbon-carbon bond formation by intermolecular addition to unactivated olefins. Again, this is possible because the initial radical has a comparatively long lifetime in the medium. Unhindered, terminal olefins are the best substrates, but other types of olefins (especially strained or lacking allylic hydrogens) may be made to react in some cases. Three examples of additions are collected in Scheme 18. The first involves formation and capture of a trifluoroacetonyl radical, a species hitherto only studied by mass spectrometry but never employed in synthesis [34a]. This reaction represents a convenient route to various, otherwise inaccessible, trifluoromethyl ketones. In the second example a tetrazolylmethyl radical, also a previously unused intermediate, is intercepted by a latent allyl glycine [34b]. The amino acid moiety may be part of the xanthate partner as highlighted by the last example [34c]. 

The mode of addition of hydrogenphosphonates to fluorinated ketones can also be complex. The addition of dialkyl, diphenyl or bis(trimethylsilyl) hydrogenphosphonates to methyl trifluoromethyl ketones occurs in the expected manner, but this contrasts with the behaviour of aryl perfluoralkyl ketones in the presence of triethylamine at room temperature, when the products, obtained even under such mild conditions, are phosphate esters (reaction 6), a situation which represents lack of stability of the hydroxyphospho-nate rather than novelty of the reaction under identical conditions, the corresponding alkyl aryl ketones fail to react. The same reaction with mixed-halogen ketones is still more involved, and the nature of the products depends on the reaction conditions if these are of a mild nature, and with catalysis by triethylamine or pyridine (depending on the particular ketone), the product is the expected (hydroxyalkyl)phosphonate 177, whereas with... 

The addition of an aniline to an unsaturated trifluoromethyl ketone 437 or 438 provides a facile preparation of an enaminone 439. In polyphosphoric acid (PPA), this cyclizes to a 4-trifluoromethyl quinoline 440, Scheme 121 (89TL6173 90TL2689). 

Ttifluowmethylr and Perfluoroalkyl-Substituted Pyrazoles Trifluoromethyl-substituted pyrazoles are readily available through reactions of hydrazines with a,[3-unsaturated trifluoromethyl ketones and trifluoromethylated [3-dicarbonyl compounds. In addition, 1,3-dipoIar addition reactions can be applied. Such transformations have been... 

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