Imines trifluoromethylation

Isocyanides react with fluorine [75 to yield difluoromethylene imines, which tend to dimerize In an inert solvent, imines accept fluorine fioin trifluoromethyl hypofluorite [76, 77] (equation 11)... 

Reactions offluorinated dipoles. In recent years, much effort has been devoted to the preparation of tnfluoromethyl-substituted 1,3-dipoles with the goal of using them to introduce trifluoromethyl groups into five-membered nng heterocycles Fluorinated diazoalkanes were the first such 1,3-dipoles to be prepared and used in synthesis A number of reports of cycloadditions of mono- and bis(tnfluo-romethyl)diazomethane appeared prior to 1972 [9] Other types of fluonne-substi-tuted 1,3-dipoles were virtually unknown until only recently However, largely because of the efforts of Tanaka s group, a broad knowledge of the chemistry of tnfluoromethyl-substituted nitrile oxides, nitnle imines, nitnle ylides, and nitrones has been accumulated recently... 

Similarly, 1-alkylpyrroles, indoles, furans, thiophenes [60], a-picoline [61], enols, malonates [76], and organometallic compounds [56, 62] react with acyl imines of trifluoropyruvates to give derivatives of a-trifluoromethyl a-amino acids... 

Likewise, trifluoromethyl-substituted nitrile imines [172] and nitnle oxides [173,174, 7 75] have been used to synthesize tnfluoromethyl substituted five-membered ring systems of the pyrazole, isomzole, isoxazohne, and 1,2,4-oxadiazole... 

Trifluoromethyl-substituted 1,3-dipoles of the allyl type. Trifluoromethyl-substituted azomethine imines ate readily available on reaction of hexafluo-... 

Trifluoromethyl-substitutedazimines are surprisingly stable compounds. They are accessible by 1,3-dipole metathesis from tnfluoromethyl-substituted azomethine imines and certain nitroso compounds [187, 188] On photolysis, an electrocyclic ring closure first gives the triaziridines, which are stable at room temperature. On heating above 80-100 C, a valence tautomenzation takes place and azimines are formed [189] (equation 43). 

An unusual 1,4-migration of a trifluoromethyl group was observed when azomethine imines were synthesized from hexafluoroacetone azine and alkoxy-acetylenes The rearrangement, which occurs at temperatures as low as 0 "C, results in the formation of A-(perfluoro-ferf-butyl)pyrazoles [207] (equation 46)... 

Cycloaddition reactions where bis(trifluoromethyl)-substituted hetero-1,3-dienes act as dienophiles have been descnbed for open-chain and cyclic dienes [115, 126, 127] The balance of the diene -dienophile activity of bis(tnfluoro-methyl)-substituted hetero-l,3-dienes can be influenced strongly by the substituents bonded to the inuno nitrogen atom For instance, A/-(arylsulfonyl) denvatives of tnfluoroacetaldimine and hexafluoroacetone imine do not act as dienes but exhibit only the dienophile reactivity of electron deficient imines [5 229, 234,235, 236 237] (equation 52)... 

Photochemical [2 + 2] cycloaddition of ketene and (trifluoromethyl)tria-zinone 25 gave 26 (88CPB3354). The role of the CF3 group in the activation of the imine function of 25 was investigated (Scheme 7),... 

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>. 

Raasch, and Schaumann and co-workers, have studied the reactions of bis (trifluoromethyl)thioketene (83 R1 = CF3) with alkenes, with thioketones, and with carbodiimides or Schiff-base imines. The products were, respectively, thietans, 1,3-dithietans (84 R1 = CF3), and 1,3-thiazetidines (85 R1 = CF3) (from the carbodiimide).114,115 With phenyl azide the 1,2,3,4-thiatriazoline (86 R = CF3) is formed subsequent pyrolysis yields2,l-benzisothiazole.114... 

Two other results should be reviewed here, too. The substituted thiadiazolo[3,2-trifluoromethyl groups) was described by Sokolov and Aksinenko <2003IZV2053> 2-amino-5-methyl[l,3,4]thiadiazole 165 was heated with iV-ethoxycarbonyl-bis-trifluoroacetone imine in DMF in the presence of />-toluenesulfonic acid to yield the cyclized product 166 in good yield (77%). 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

Imines and (Af,(9)-acetals from fluoral are useful precursors of trifluoromethyl nitrogen-containing molecules amines, amino alcohols, amino acids, peptidomimetic units, heterocycles, and so on (Figure 2.50). These simple Af-derivatives of fluoral are easily prepared from the hydrate or the hemiacetal. Imines of fluoral react in [2 + 1 ]... 

Trifluoroalanine has also been prepared by reducing trifluoropyruvate imines (ethyl trifluoropyruvate is available commercially it is prepared either from per-fluoropropene oxide or by trifluoromethylation of ethyl or f-butyl oxalate). These imines are obtained by dehydration of the corresponding aminals or by Staudinger reaction. They can also be obtained by palladium-catalyzed carbonylation of trifluoroacetamidoyl iodide, an easily accessible compound (cf. Chapter 3) (Figure 5.4). Reduction of the imines affords protected trifluoroalanines. When the imine is derived from a-phenyl ethyl amine, an intramolecular hydride transfer affords the regioisomer imine, which can further be hydrolyzed into trifluoroalanine. ... 

Cycloaddition reactions were also carried out using l,2-bis(trifluoromethyl)-fumaronitrile (137,138,191,192). Seven-membered cychc ketene imines (186-188) could actually be isolated in good yields from the reactions with 69,... 

In accordance with expectations, the isolable trifluoromethyl substituted ketene imines (186-188) were found to react readily with nucleophilic agents. In the case of 186, the reaction with methanol and aniline led to lactim ether 187a and amidine 187b, respectively (137). 

The furo[3,4-ri]oxazoie 54, constracted by cyclisation of a rhodium carbenoid, is a useful compound for the production of unusual benzoxazoles for example, cycloaddition of Al-phenylmaleimide gave the benzoxazole 55 <98JOC7680>. Simpler benzoxazole syntheses include the base catalysed cyclizsation (with loss of the trifluoromethyl anion) of the imines 56 <99TL4119> and the acid catalysed cyclisation of diacylated aminophenols 57 <99H(51)979>. ... 

A rather more complex scheme is required for the preparation of a derivative that bears a trifluoromethyl substituent on one of the benzene rings. The scheme starts with the condensation of the nitrile group in (32-1) with phenyhnagnesium bromide to give the corresponding imine treatment with aqueous acid leads to the substituted benzophenone (32-2). The future methyl on one of the bridges is introduced in a sequence involving the addition of a trimethylsulfonium yhde. 

Tetrakis(trifluoromethyl)-l,3-dithietanes react with nucleophiles to give products expected from monomeric bis(trifluoromethyl)thione. In fact, fluoride ion in DMF produces monomer (76BCJ2491), anilines give imines, and phenylhydrazine gives hydrazone (73BCJ3260). Triphenylphosphine gives a Wittig ylide that reacts with aldehydes to produce... 

Bis(trifluoromethyl)thioketene reacts with some imines to form 1,3-thiazetidines (78JOC2500). One derivative has been used by Dupont in surface treatment of water-repellent textiles (71USP3592811). 

Recently, Ishihara and coworkers demonstrated that zinc-mediated reaction of 2-bromo-2,3,3,3-tetrafluoropropanoate with chiral imines afforded three- and erythro-i omscs, of a-fluoro-a-(trifluoromethyl)-/3-amino esters in good yields with high diastereomeric excess (equation 121)178. 

A number of imines have also been fluorinated. Typical reactions are the fluorination of N-(trifluoromethyl)difluoromethanimine (21) and 7V,7V,N -tris(trifluoromethyl)fluoroform-imidamide (22).103... 

The periluorinated aliphatic imine, periluoro-3-methyl-2-azabut-2-ene is epoxidized using 50 % hydrogen peroxide in alkaline acetonitrile solution to afford 2,3,3-tris(trifluoromethyl)oxa-ziridine in 22% yield (Table 14).236... 

Attempts to prepare the A -benzylimine of hexafluoroacelone by treatment of the latter with (benzylimino)triphenyl-/. ,-phosphane give. /V-benzylidene-1,1,1,3,3,3-hexafluoropropan-2-amine [(CF,)2CHN = CHPh] in 56% yield, which results from complete isomerization of /V-benzyl-2,2,2-trifluoro-l-(trifluoromethyl)ethanimine [(CF3)2C = NCH,Ph] under the reaction conditions.12 Taking this into account, the reactivity of substituents R at the imine carbon of compounds 14 follows the order perfluoroalkyl > > aryl > > hydrogen > alkyl benzyl.14 11 as described below, alkoxycarbonyl as the R group in structure 14 (x-oxo ester derivatives) activates as effectively as perfluoroalkyl. 

Ethoxyearbonyl-5-(2-furyl)-2-methoxycarbony l-2-mel hyl-3-trifluoromethyl- ElOb,. 546 (FjC-en-COOR + Imin)... 

---