Difluorine synthesis

C-6,209,214 anhydro sugars,branched monosaccharides, fluori-nated amino sugars,difluorinated monosaccharides, and fluorinated monosaccharide phosphates,and phosphonates have been described. Further progress has been achieved in the synthesis and n.m.r.-spectral analysis of fluorinated avermectin Bu, tylono-lide, and neuraminic acid derivatives. " ... 

R. Csuk, E. Prell, C. Korb, R. Kluge, and D. Strohl, Total synthesis of 3,3-difluorinated 1-deoxynojirimycin analogues, Tetrahedron, 66 (2010) 467 472. 

The reaction of hydrazones with elemental fluorine can also be used for the synthesis of gem-in ally difluorinated compounds (Table 4).8 The procedure, however, can have severe limitations it is only applicable to aryl ketone hydrazones (no reaction is observed with the hydrazones of benzaldehyde, cyclohexanone, or cyclopentanone), and mixtures ol di- and monofluorinated compounds are obtained. In some cases, monofluorinated derivatives are the only reaction products (entries 4 and 5). 

A five-step chemical modification of 51 gives A,0-protected a-amino-a -hydroxy-ketone 54. Difluorination of the ketone 54 at the carbonyl carbon with morpho-DAST followed by conventional chemical modification results in the synthesis of P-amino-a,a-difluorocarboxylic acid 55 (see Scheme 9.13) [31]. Enantiomerically pure 5,5,5,5, 5, 5 -hexafluoroleucine 57 is efficiently synthesized from Garner s aldehyde 52 as shown in Scheme 9.14 [32]. Triphenylphosphine-induced reductive coupling of 52 with hexafluo-rothioacetone produces 56 in an excellent yield, which is conventionally transformed to... 

Fokina, N. A., Kornilov, A. M., Kulik, I. B. and Kukhar, V. P. (2002) Towards optically pure mono- and difluorinated amino acids common methodology based on (7 )-2,3-0-isopropyli-deneglyceraldehyde. Synthesis, 2589-2596. 

Fustero, S., Sanchez-Roseflo, M., Rodrigo, V., et al. (2006) Asymmetric synthesis of new P,P-difluorinated cyclic quaternary a-amino acid derivatives. Org. Lett., 8, 4129—4132. 

Synthesis of carbonyl difluoride from phosgene 13.7.S.1 Reaction with difluorine... 

Scheme 2.203 Example of the synthesis of gem-difluorinated carbohydrate analogs via a Reformatsky reaction with ethyl bromodifluoroacetate [41c].

In particular, defluorination brought about by the Mg-TMSCl-DMF system is reliable for the purpose [11]. Difluoroenol silyl ethers [12], enamines [13], phenyl-1,1-difluoroacetate [14], difluorinated Danishefsky diene [15], and trimethylsilyldifluoromethyl benzenes [16] can be prepared in good to excellent yields. The one-pot synthesis of 22 from 21 is of great interest. Defluoro-dechlorinative double silylation occurs under very mild conditions to afford compound 22, a useful synthetic intermediate, in which two different silyl groups can be replaced with various electrophiles in a stepwise manner [17]. Highly functionalized a-iminoesters (27) can be synthesized via 25 and 26 in excellent yields as shown in Scheme 2.15. 

In 1994, Kitazume et al. described the highly stereoselective synthesis of 1,6-dideoxy-6,6-difluoroazasugar analogues starting from the difluorinated building block. 

Construction of furan ring of 131 by acid-catalyzed cyclization of 134 cannot be achieved due to low reactivity of the a,a-difluorinated double bond toward protonation. Therefore, the following sequence was employed for the total synthesis of 131 (Scheme 12.20) fluorination of lactone 133, introduction of a double bond to 136 by Wittig olefination, and modification of R part of O ." " The use of manganese enolate of lactone 133 is useful for one-pot difluorination. The reaction of the lithium enolate of 133 with the conventional electrophilic fluorinating reagent such as N-fluorobenzenesulfonimide provides only monofluoride 135. 

The Ichikawa indole synthesis is the base-induced 5-endo-trig cycUzation of nrtfto-amino-p,p-difluorostyrenes 1 to 2-fluoroindoles 2 (Scheme 1, equation 1) [1-3]. The method is applicable to indolines, which can be oxidized to indoles [4, 5]. This nice chemistry exploits the inherent favorable conversion of a difluorinated sp carbon to an sp carbon, which then expels fluoride to give the aromatic indole. Ichikawa also applied this method to the preparation of 2-fluoiobenzo[fc]furans and 2-fluorobenzo[h]thiophenes [1, 2]. 

The following procedure, adapted from Percy and co-workers synthesis of difluorinated cyclooctenoids, is a useful method when Ti(0/-Pr)4 is to be used as a precatalyst. 

More recent examples of cyclooctene formation have been reported where cyclization was achieved without the need for annulation. For example, Percy has reported the syntheses of difluorinated cyclooctenones en route to conformationaUy locked sugar mimics (Scheme 2.46). " These cy-clizations were aided by a judicious choice of protecting group (vide supra) RCM of benzyl-protected 47 proceeded at 2.2 mmol L in 46% yield, while the benzoyl-protected substrate 45 underwent RCM at 10 mmol in 75% yield. Collectively, these results illustrate that synthesis of cyclooctenes can be challenging, and that the outcome of such reactions can acutely depend on substrate structure. 

Ashworth IW, Miles JAL, Nelson DJ, Percy JM, Singh K. Trisubstituted cyclooctene synthesis at the limits of relay ring-closing metathesis a racemic difluorinated analogue of fucose. Tetrahedron. 2009 65(46) 9637—9646. 

A convenient method for the synthesis of polyfunctionalized 3-fluoropyrroles 243 by Rh2(OAc)4-catalyzed intramolecular N-H insertion reaction of difluorinated diazo compounds 241 was reported [83], The starting compounds can be synthesized by Zn-CuCl-promoted Reformatsky-imine addition reaction of 4-bromo-4,4-difluoroacetoacetate 238 with aldimines 239. Subsequent diazotransfer reaction and Rh2(OAc)4-catalyzed intramolecular N-H insertion allow the preparation of 3-fluoropyrroles 243 in almost quantitative yield. 

A valuable method for the synthesis of 2-aryl-3-fluoropyrroles 247 is based on a gold-catalyzed cyclization and dehydrofluorination of gan-difluorohomopropargylamines 246. Difluorinated homopropargylamines 246 can be prepared by the addition of gem-difluoropropargyllithium reagents to arylated A-tosyUmines 244 [84]. 

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