Isoquinolines, 1-trifluoromethyl

Keywords Fluorine Isoquinoline Trifluoromethyl group Baltz-Shiemann reaction Halex reaction Bischler-Napieralski reaction Catalysis Addition-elimination Bioactivity Supramolecular chemistry Organic light-emitting diode... 

Bischler-Napieralski reaction conditions can be attributed, again, to the destabilizing ability of the trifluoromethyl group to the cationic transition state of the acid catalyzed elimination. Formation of compound 29 was ultimately accomplished by base catalyzed methanol elimination-conditions conditions that are quite unusual for isoquinoline formation. 

Reaction of 2-cyanomethylpyridine with iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)-iV -(4-methylphenyl)carbodiimides, and with (1,1,2,2,2-pentachloro- and l,l-dichloro-2,2,2-trifluoroethyl)isocyanates or A-methoxycarbonyl-l,2,2,2-tetrachloro-, — l-chloro-2,2-trifluoroacetaldehyde imines afforded 3-aryl-4-cyano-l-(4-methylphenyl)imino-3-trifluoromethyl-2,3-dihydro-17/-pyrido[l,2-f]pyrimidines and 4-cyano-3-trichloro-, 4-cyano-3-trifluoro-17/-pyrido[l,2-4pyrimidin-l-ones, respectively <2004CHE47>. Refluxing 2-cyanomethylpyridine and iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)isocyanates in benzene furnished l-aryl-4-cyano-l-trifluoromethyl-l,2-dihydro-3//-pyrido[l,2-4pyrimidin-3-ones. However, when the solution of the isocyanate was added dropwise to the solution of 2-cyanomethylpyridine, and the reaction mixture was then treated with NEt at room temperature, the isomeric 3-aryl-4-cyano-3-trifluoromethyl-2,3-dihydro-l//-pyr-ido[l,2-dpyrimidin-l-ones were obtained. Reaction of l-(acetyl- and benzoylmethylene)-6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinolines with PhCONCS yielded 1-acetyl-, 1 -benzoyl-9,10-dime thoxy-3-pheny 1-6,7-dihydro-2//-pyrimido[6,l- ]isoquinoline-2-thiones <2003SL2369>. 

Cycloaddition of furans followed by a subsequent transformation is still adopted as a useful strategy to prepare fluorine-containing benzene derivatives and isoquinoline compounds <00SL550>. The cycloaddition adduct can also be converted to a trifluoromethyl substituted cyclohexanone compound via hydrogenation and hydrolysis. Examples of these transformations are illustrated below. 

Unexpected oxazoline formation was observed during a study to prepare nonsedating anxiolytic 1-styrylisoquinolines 27a-h from 2-(trifluoromethyl)aryl-ethylamines 25a-h under Pictet-Gams conditions (POCI3 in refluxing toluene). This deviation from the normal reaction pathway was hypothesized to result from the electron-withdrawing effect of trifluoromethyl group that inhibited the formation of a benzylic cation required for isoquinoline formation (Scheme 8.12). 

The 1-amidino substituent on the isoquinoline system in 7 is oxidized at the amino bond with lead(IV) acetate to give 2-(trifluoromethyl)-l,2,4-triazolo[5,l-a]isoquinoline (8).266... 

JA11707), 4-cyano-3-phenyl-3-trifluoromethyl-2,3-dihydro-lH-pyrido [l,2-c]pyrimidin-l-one (05MI1), and 10-(ferf-butyl)-3-methylene-3,4,4fl,5-tetrahydro-3H-[l,3]oxazino[3,4-b]isoquinolin-l-one (07EJ02015) under either acidic or basic conditions. 

Kaneko, C., Hayashi, S. and Kobayashi, Y. (1974) Photolysis of 2-(trifluoromethyl) quiniline 1-oxides and l-(trifluoromethyl) isoquinoline 2-oxide. Chemical cl Pharmaceutical Bulletin, 22 (9), 2147-2154. 

Oxazoles.—Formation. ci)-Diazoacetophenone reacts with benzonitrile in the presence of trifluoromethanesulphonic acid to give 2,5-diphenyloxazole (514). Bi-, ter-, and quater-oxazoles have been synthesized from a-metallated isocyanides thus lithiobenzyl isocyanide (PhCHLiNC) and dimethyl oxazole-3,4-dicarboxylate afford compound (515). Stable methylene-oxazolines (516 R = Me or Ph) are obtained by heating the iminesHN=C(Ph)OCHRC=CH. The fluorinated oxazoline (518) results from the action of benzonitrile on the oxiran (517), and also from the reaction of bis(trifluoromethyl)carbene with the benzoylimine (CF3)2C=NCOPh/ Treatment of 2-acylamino-l-aryl-alkan-l-ols (519) under the conditions of the Pictet-Gams reaction, i.e. with phosphorus pentoxide in boiling toluene or xylene, results in cis- and trans-2-oxazolines (520), rather than isoquinolines, as claimed previously. The spiro-oxazolines (521 R = Me or Ph) are formed when the lithiated di-isocyanide CN—CH2CH2CHLi—NC is treated with acetone or benzophenone, respec-tively. ... 

Trifluoromethylation reactions of heteroaromatic compounds represent a majority of reported nucleophihc perfluoroalkylations. For example, trifluoromethylation of halogenated quinolines, isoquinolines, or pyridines carried out under pressure using CF3X/CU powder system (X = 1 or Br) in DMF or (Me0)3P=0 solvent affords the corresponding trifluoromethylated heterocycles in 22-60% yield (Fig. 7.21). ... 

N-Trifluoroacetyl-a-homoveratrylaminophenylacetic anilide in coned. HCl and ethanol refluxed 9 hrs. on a water bath -> l-oxo-3-trifluoromethyl-8,9-dimethoxy-2,10b-diphenyl-l,2,3,5,6,10b-hexahydroimidazo[5,l-a]isoquinoline. Y 52%. - Compounds without the fluorine give a different ring closure. G. Hazebroucq, M. Plat, and J. Gardent, Bl. 1968, 2992. 

It should be mentioned that isoquinoUne 2-oxide reacted with perfluorobut-2-yne similarly forming (among other products) l,2,3-tris(trifluoromethyl)- and l,2-bis(trifluoromethyl)-3-trifluoroacethylpyrrolo[2,l-a]isoquinoline [6]. 

A base-promoted conversion of oriho-trifluoromethyl benzyl derivatives of NH-heterocycles into a respective flnorinated isoquinolines (38-57 % isolated yields) was reported [40]. The reaction is general for the benzylated derivatives of the electron-rich NH heterocycles, particularly indoles. The outcome of the reaction... 

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