Difluoromethyl-substituted

The most common situation where this effect is seen is in a comparison of E- and Z- isomers of trifluoromethyl- or difluoromethyl-substituted alkenes, but as the naphthalene examples indicate, the effect is not unique to that situation. 

T. Michei, B. Koksch, S.N. Osipov, A.N. Golubev, J. Sieler, K. Burger, Peptide synthesis with a-(difluoromethyl)-substituted ot-amino acids. Coll. Czech. Chem. Commun. 67(10) (2002) 1533-1559. 

A novel method for the convenient synthesis of alkenyl fluorides 15, as well as diflu-oromethyl-substituted alcohols 16 and amides 17, via electrophilic fluorination with one equivalent of F-Teda BF4 (6) of alkenyl boronic acids and trifluoroborates, has been reported.87 The alkenyl fluorides 15 are obtained as Z/E mixtures when the reaction is carried out with one equivalent of F-Teda BF4 in acetonitrile at room temperature. When the reaction is performed with two equivalents of F-Teda BF4 in water or a nitrile solvent the difluoromethyl-substituted alcohols 16 or amides 17, respectively, are obtained. 

Difluoromethyl-Substituted Imines, Imidoyl Chlorides, and Nitrones. These CF2H nitrogen-bound building blocks have received much recent interest. A few examples are given in Scheme 4.34, along with their fluorine, proton, and carbon NMR spectral data. 

Various Other Difluoromethyl-Substituted Heterocyclic Systems... 

A series of 2-trifluoromethyl and 2-difluoromethyl substituted benzothiazoles 30 has been synthesized by a one-pot reaction of trifluoroacetic acid and difluoroacetic acid, respectively, with 2-aminobenzenethiol <07TL3251 >. The reaction pathway presumably involves the imidolyl chloride intermediate 29, which undergoes intramolecular nucleophilic substitution by neighbouring thiol under basic conditions to give benzothiazole 30. 

An interesting variation of the aza-Corey-Chaykovsky reaction provides a pathway to difluoromethyl-substituted aziridines. Reduction of trifluoromethylimine 143 with magnesium in the presence of chlorotrimethylsilane gave the enamine 144. Treated with dimethyloxosulfonium methylide in DMSO, 144 hrst underwent desilylation and tautomerization to produce imine 145, which then afforded aziridine 146 via the aza-Corey-Chaykovsky reaction in 92% yield. 

FIGURE 3.96 Synthesis of difluoromethyl-substituted triazoles as potential antitubercular agents. 

As with the other aromatic and heteroaromatic systems, functional group transformations can also be used to produce fluorinated 1,2,3-triazoles. A series of 1-aryl-1,2,3-triazole-4-carbaldehydes were converted to the corresponding difluoromethyl-substituted triazoles by the action of DAST (Fig. 3.96). The difluoromethylene derivatives as well as the precursor aldehydes were studied with respect to antitubercular activity. 

A two-step synthesis of difluoromethyl-substituted 2,3-dihydrobenzo heteroles was also reported in the year 2014 (140L1398).The dihydroben-zothiophenes were synthesized from 2-bromobenzenethiols in two steps, i.e., y-selective allylic substitution of 3-bromo-3,3-difluoropropene with appropriate thiophenes followed by intramolecular radical cyclization of the resulting 3,3-di luoroallylic compounds. 

The Cu" complexes can be prepared directly from trifluoromethyl substituted 1,2-dihalobenzenes in the course of Rosemund-Braun reaction with copper(I) cyanide (Scheme 25). Thus, reaction of 3-, 4-trifluoromethyl and 3,5-difluoromethyl substituted 1,2-dichlorobenzenes 102a-c with CuCN in quinoline (Qn) leads to Cu" complexes of a- or 3-tetrafluoromethyl- or a,p -octatrifluoromethyl-phthalocyanines 103a-c [71],... 

The most massive molecule in this group is the per-difluoromethyl-substituted derivative, molecular weight... 

A possible pathway was proposed to explain the difluoromethylation reaction involving the key initial reduction of PhS02Cp2l 236 by Ru(II) followed by a single-electron oxidation to generate the difluoromethyl-substituted products. 

Reaction of 2 equiv of 2-aminopyridines with 2-hydropolyfluoroalk-2-anoates 351 in MeCN in the presence of NEts at 90 °C for 50 h afforded a mixture of the isomeric 2-oxo-2H- and 4-oxo-4//-pyrido[l,2-n]pyrimidines 110 and 111. Reaction of 3 equiv of 2-amino-pyridines and 2-hydropoly-fluoroalk-2-enoates 351 in MeCN in the presence K2CO3 could be accelerated by ultrasonic irradiation (125W). 2-Amino-6-methylpyridine yielded only 2-substituted 6-methyl-4//-pyrido[l,2-n]pyrimidin-4-ones 111 (R = 6-Me), whereas 2-amino-5-bromopyridine gave a mixture of 7-bromo-4//-pyrido[l,2-n]pyrimidin-4-one (111, R = 7-Br, R = CF2C1) and 2-(chlor-o,difluoromethyl)-6-bromoimidazo[l, 2-n]pyrimidine-3-carboxylate in 44 and 8% yields, respectively (97JCS(P 1)981). Reactions in the presence of K2CO3 in MeCN at 90°C for 60h afforded only imidazo[l,2-n]pyrimidine-3-carboxylates. 

G. Forat, J.-M. Mas, L. Saint-Jalmes (Rhone-Poulenc Chimie). Method for Grafting a Substituted Difluoromethyl Group to a Compound Containing an Electrophilic Group with Microwave Irradiation. PCT International Application WO 5, 609,1998 (FR Application 96/ 9,754, 1 Aug 1996) Chem. Abstr. 1998, 128, 166999u. 

Radical addition of dibromodifluoromethane to alkenes followed by sodium borohydride reduction is a convenient two-step method for the introduction of the difluoromethyl group.5 Either one or both carbon-bromine bonds in the intermediate dibromides may be reduced, depending on the reaction conditions. In the case of acyclic dibromodifluoromethane-alkene adducts, the reduction occurs regioselectively to yield the relatively inaccessible bromodifluoromethyl-substituted alkanes. The latter are potential building blocks for other fluorinated compounds. For example, they may be dehydrohalogenated to 1,1-difluoroalkenes an example of this methodology is illustrated in this synthesis of (3,3-difluoroallyl)trimethylsilane. 

All aromatic aldehydes and heterocyclic aldehydes substituted with strong electron-withdrawing groups react cleanly with sulfur tetrafluoride at elevated temperatures, preferably in the presence of hydrogen fluoride, to give good yields of the respective difluoromethyl derivatives typical examples are given by the formation of 15. 

Substitution of hydrogen by fluorine also occurs, albeit with difficulty, in the formyl group of formates ethyl formate reacts with sulfur tetrafluoride in the presence of potassium fluoride to give a mixture of difluoromethyl ethyl ether (14) and ethyl trifluoromethyl ether (15).175... 

A well-established feature of nucleophilic reactions of fluoroalkenes is that attack occurs exclusively at a difluoromethyl group.61 The order of increasing reactivity is F2C = CF2 < F,C = CFCFj < < F2C = C(CF, )2.61 The primary products of base-catalyzed additions of alcohols to fluoroethenes are saturated ethers 87 however, with higher concentrations of base, unsaturated ethers are formed. Tetrafiuoroethene with sodium methoxide yields a product of substitution, trifluoromethoxyethene (4), and the addition product 1,1,2,2-tetrafluoro-l-methoxyethane (5).62... 

Substituted fluorocarbenes, for example, arylfluorocarbenes 1, (alkoxycarbonyl)fluorocar-benes 2. fluoro(trichlorovinyl)carbene (3). fluoro(trifluoromethyl)carbenc (4). and (difluoromethyl)fluorocarbene (5), have been reported. Their addition to alkenes to give fluo-rinated cyclopropanes has been studied (see Table 2). 

Phillion, D.P., and Cleary. D.G., Disodium salt of 2-[(dihydroxyphosphinyl)difluoromethyl] propenoic acid. An isopolar and isosteric analogue of phosphoenolpyruvate, J. Org. Chem., 57, 2763, 1992. Eymery, F.. lorga, B.. and Savignac, P, Synthesis of phosphonates by nucleophilic substitution at phosphorus. The SNP(V) reaction. Tetrahedron, 55, 13109, 1999. 

Bergstrom, D,E, and Shum, P,W, Synthesis and characterization of a new fluorine substituted nonionic dinucleoside phosphonate analogue, f -deoxy-/ -(difluoromethyl)thymidylyl(3 —>5 )thymidinc, J. Org. Chem., 53, 3953, 1988,... 

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