Preparation of .alpha.-trifluoromethyl esters from malonic esters

Everett, Tina; Purrington, Suzanne T.; Bumgardner, Carl L.

doi:10.1021/jo00194a006

Cited by 43 publications

(12 citation statements)

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“…The synthesis and chemical reactivity of such carbanions are of considerable interest. The generation and synthetic applications of these carbanions have been based on several methods: (1) use of nitrotrifluoroethane, (2) the employment of dimethyl 2-(trifluoromethyl)malonate and/or dialkyl 2-bromo-2-(difluoromethyl)malonate, , (3) application of α-CF 3 -silylenol ether and Reformatsky-type reactions of bromotrifluoro propionate, (4) use of 2,3,3,3-tetrafluoropropionate and 2,3,3,3-tetrafluoropropionamide, and (5) indium-mediated allylation using 1,1,1-trifluoro-4-bromo-2-butene .…”

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confidence: 99%

Highly Stereocontrolled Synthesis of Trifluoromethylated Materials with Allylzincs and Allenylzincs Generated by Umpolung of Palladium Complexes

et al. 1999

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The formation and chemical behaviors of trifluoromethylated allylzinc and allenylzinc reagents derived from the umpolung of allyl- or allenylpalladium complexes have been described. The reactions of these reagents with aldehydes proceeded smoothly to afford highly stereocontrolled γ-(trifluoromethyl)-δ-hydroxy α,β-unsaturated materials. Their configurations determined by the spectral data were anti, and Z-isomers were produced from the system of allylzinc reagents.

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confidence: 99%

Highly Stereocontrolled Synthesis of Trifluoromethylated Materials with Allylzincs and Allenylzincs Generated by Umpolung of Palladium Complexes

et al. 1999

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“…CIMS: m/z 185 (( + H)+, 100%). Also prepared by this procedure was ethyl 4,4,4-trifluro-2ethylbutanoate (9c), bp 54-55 °C (15 Torr). NMR (CDClg): 4.17 (q, J = 7.2 Hz, 2H, CtfgCH3), 2.64-2.55 (m, 2H, H-C(3)), 2.17 (t, J = 10.8 Hz, 1H, H-C(2)), 1.66 (m, 2H, CH3CHrC(2)), 1.27 (t, J = 7.2 Hz, 3H, CHgCtfs), 0.93 (t, J = 7.2 Hz, 3H, CH3CHg-C(2)).…”

Section: Methodsmentioning

confidence: 99%

Synthesis, Structure-Activity Relationships, and Pharmacological Evaluation of a Series of Fluorinated 3-Benzyl-5-Indolecarboxamides: Identification of 4-[[5-[((2R)-2-Methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methylindol-3-yl]methyl]-3methoxy-N-[(2-methylphenyl)sulfonyl]benzamide, a Potent, Orally Active Antagonist of Leukotrienes D4 and E4

Jacobs¹,

Bernstein²,

Cronk³

et al. 1994

J. Med. Chem.

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The continued exploration of a series of 3-(arylmethyl)-1H-indole-5-carboxamides by the introduction of fluorinated amide substituents has resulted in the discovery of 4-[[5-[((2R)-2-methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methyli ndol- 3-yl]methyl]-3-methoxy-N-[(2-methyl-phenyl)sulfonyl]benzamide (38p, ZENECA ZD3523), which has been chosen for clinical evaluation. This compound exhibited a Ki of 0.42 nM for displacement of [3H]LTD4 on guinea pig lung membranes, a pKB of 10.13 +/- 0.14 versus LTE4 on guinea pig trachea, and an oral ED50 of 1.14 mumol/kg opposite LTD4-induced bronchoconstriction in guinea pigs. The R enantiomer was found to be modestly more potent than the S enantiomer 38o. Modification of the amide substituent to afford achiral compounds was unsuccessful in achieving comparable levels of activity. Profiling of 38p opposite a variety of functional assays has demonstrated the selectivity of this compound as a leukotriene receptor antagonist. The enantioselective synthesis of 38p, which employed a diastereoselective alkylation of (4R,5S)-3-(1-oxo-4,4,4-trifluorobutyl)-4-methyl-5-phenyl-2-oxazoli dinone (27) as the key step to establish the chirality of the amide substituent, provided an efficient route for generating 38p in > 99% enantiomeric purity.

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“…8,9 Meanwhile, the literature method for the preparation of trifluoromethyl fluorobenzyl ketones generally lacks generality. The only synthetic method currently available for the preparation of 1,3,3,3-tetrafluoro-1-phenyl-2-propanone is based on the reaction of 1-phenyl-pentafluoropropane 10,11 with lithium pyrrolidinoamide. 12 Herein, we described a general synthesis of tetrafluorinecontaining ketones and acetoacetates via the reaction of a-fluorobenzylphosphonate or diisopropyl(fluorocarbeth- …”

Section: Introductionmentioning

confidence: 99%