Cesium Fluoride Catalyzed Trifluoromethylation of Esters, Aldehydes, and Ketones with (Trifluoromethyl)trimethylsilane

Singh, Rajendra Prasad; Cao, Ganfeng; Kirchmeier, Robert L.; Shreeve, Jean’ne M.

doi:10.1021/jo982494c

Cited by 174 publications

(76 citation statements)

References 25 publications

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“…The intermediate acetals 170 can be hydrolyzed by acid. 69 The reactions of the acyl chlorides with trifluoromethylsilver generated in situ proceed selectively in EtCN giving the corresponding trifluoromethylketones 171 in moderate yields. 70 …”

Section: Scheme 48mentioning

confidence: 99%

Preparation of α,β-unsaturated trifluoromethylketones and their application in the synthesis of heterocycles

Nenajdenko¹,

Баленкова²

2011

Arkivoc

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Section: Scheme 48mentioning

confidence: 99%

Preparation of α,β-unsaturated trifluoromethylketones and their application in the synthesis of heterocycles

Nenajdenko¹,

Баленкова²

2011

Arkivoc

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“…The incorporationoffluorine into molecules results in profound changes in the physicaland chemicalproperties [2]. The changes also affect the biologicalactivity of the molecules.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-5-((4-trifluoromethyl) methyleneimino)-1H-pyrazole-3-carbonitrile, C19H8Cl2F6N4

Zhang¹,

Chen²,

Hu³

et al. 2007

Zeitschrift Für Kristallographie - New Crystal Structures

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C 19H 8 Cl 2 F 6 N 4 ,triclinic, P 1 (no. 2), a =6.8064(7) Å, b =11.599(1) Å, c =13.421(1) Å, a =72.683(2)°, b =84.523(2)°, g =83.237(2)°, V =1002.4 Å 3 , Z =2, R gt(F) =0.085, wRref(F 2 ) =0.217, T =298 K. Source of materialFollowing the literaturemethod [1] the reactionof2,6-dichloro-4-(trifluoromethyl)aniline (10 mmol, 2.3 g) with asuspensionof sodium nitrite (10 mmol,0 .69 g) and sulfuric acid (3 ml), followed by reaction with asolutionofethyl 2,3-dicyanopropionate (10 mmol, 1.52 g) in acetic acid (5 ml), gave 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole. The compound wasthen reacted with 4-trifluoromethylbenzaldehyde (10 mmol, 1.74 g) to give the title compound. Single crystals suitable for Xrayanalysis were obtained by slow evaporation from amethanol solution. Experimental detailsAll Hatoms were positioned geometrically and allowed to ride on their parent atoms atdistances of C sp2 -Hof 0.93 Åwith U iso = 1.2U eq (parent atom), C sp3 -Hof 0.97 Åwith U iso =1.5U eq (parent atom), and N-Hof 0.86 Åwith U iso =1.2U eq(parent atom).The large displacement parameters of the fluorine atoms and the high R values resulted from either intense thermalmotion or rotationaldisorder of the two trifluoromethylgroups. DiscussionThe incorporationoffluorine into molecules results in profound changes in the physicaland chemicalproperties [2]. The changes also affect the biologicalactivity of the molecules. Asaconsequence, trifluoromethyl-containing molecules have been found considerable utilization in pharmaceuticaland agrochemicalindustry [3,4]. The title compound is akey intermediate in the synthesis of trifluoromethyl-containing pyrazole derivatives,which are good insecticides [5]. The title compound contains two trifluoromethyl groups and consists of threedifferent rings, the first phenyl ring (C2 ® C7), the second phenyl ring (C13® C18) and the pyrazolyl ring (N2, N3, C9 ® C11), which are each almost planar. The dihedralangles of the pyrazolyl ring with the phenylrings C2 ® C7and C13® C18 are 19.2(2)°and 74.8(2)°, respectively. Inthe crystalstructure, all bond lengths and angles are normal, and there are no obvious p -p interactions between pyrazolyl ring and phenyl rings.

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“…Reaction of the methyl ester (17) with trifluoromethyltrimethylsilane in the presence of cesium fluoride [Singh et al, 1999] gave the trifluoromethyl ketone (18, 68%). Subsequent reaction of this ketone (18) with hydroxylamine hydrochloride afforded 4-hydroxylamino-3-(4-methylthiophenyl)-4-phenyl-1,1,1-trifluorobutan-2-one (19, 86%), which was cyclized to the isoxazole product (20, 85%) using potassium iodide, sodium bicarbonate, and iodine.…”

Section: Discussion Chemistrymentioning

confidence: 99%

Design and syntheses of diarylisoxazoles: Novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

Habeeb

Rao

Knaus

2000

Drug Development Research

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A group of 4,5-diphenylisoxazoles (11ap), 3,4-diphenyl-5-trifluoromethylisoxazoles (15, 21), and 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) possessing a variety of substituents (H, F, MeS, MeSO, MeSO 2 ) at the para-position of one of the phenyl rings were synthesized for evaluation as analgesic, and selective COX-2 inhibitory antiinflammatory (AI), agents. Although the 4,5-diphenylisoxazole group of compounds (11ap) exhibited potent analgesic and AI activities, those compounds evaluated (11a, 11b, 11m) were more selective inhibitors of COX-1 than COX-2, with the exception of 4-(4-methylsulphonylphenyl)-5-phenylisoxazole (11n) that showed a modest COX-2 selectivity index (SI) of 2.1. In contrast, 3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole (15), which retained good analgesic and AI activities, was a highly potent and selective COX-2 inhibitor (COX-1 IC 50 > 500 µM; COX-2 IC 50 < 0.001 µM) with a COX-2 SI of > 500,000, relative to the reference drug celecoxib (COX-1 IC 50 = 22.9 µM; COX-2 IC 50 = 0.0567 µM) with a COX-2 SI of 404. The 3-phenyl-4-(4-methylsulphonylphenyl) regioisomer (21) was a less potent inhibitor (COX-1 IC 50 = 252 µM; COX-2 IC 50 = 0.2236 µM) with a COX-2 SI of 1122, relative to the regioisomer (15). The related compound 4,5-diphenyl-3-methylsulfonamidoisoxazole (23) exhibited similar (to 21) potency and COX-2 selectivity (COX-1 IC 50 > 200 µM; COX-2 IC 50 = 0.226 µM) with an SI of 752. A molecular modeling (docking) study for the most potent, and selective, COX-2 inhibitor (15) in the active site of the human COX-2 enzyme showed the C-5 CF 3 substituent is positioned 3.37 Å from the phenolic OH of Tyr 355 , and 6.91 Å from the Ser 530 OH. The S-atom of the MeSO 2 substituent is positioned deep (7.40 Å from the entrance) inside the COX-2 secondary pocket (Val 523 ). These studies indicate a C-5 CF 3 (15, 21), or C-3 NHSO 2 Me (23), central isoxazole ring substituent is crucial to selective inhibition of COX-2 for this class of compounds. Drug Dev. Res. 51:273-286, 2000.

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Cesium Fluoride Catalyzed Trifluoromethylation of Esters, Aldehydes, and Ketones with (Trifluoromethyl)trimethylsilane

Cited by 174 publications

References 25 publications

Preparation of α,β-unsaturated trifluoromethylketones and their application in the synthesis of heterocycles

Preparation of α,β-unsaturated trifluoromethylketones and their application in the synthesis of heterocycles

Crystal structure of 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-5-((4-trifluoromethyl) methyleneimino)-1H-pyrazole-3-carbonitrile, C19H8Cl2F6N4

Design and syntheses of diarylisoxazoles: Novel inhibitors of cyclooxygenase‐2 (COX‐2) with analgesic‐antiinflammatory activity

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