Fluorinated dipolarophiles

Reactions of fluorinated dipolarophiles. Electron-deficient unsaturated species generally make better dipolarophiles, therefore, fluonnated alkenes become better dipolarophiles when vinylic fluonnes are replaced by perfluoroalkyl groups For example, perfluoro-2-butene is unreactive with diazomethane, but more highly substituted perfluoroalkenes, such as perfluoro-2-methyl-2-pentene, undergo cycloadditions in high yields [5] (equation 2) Note the regiospecificity that IS observed in this reaction... 

The synthesis of biologically significant fluorinated heterocyclic compounds has been accomplished by 1,3-dipolar cycloaddition of nitrones to fluorinated dipolarophiles [51], This reaction was noticeably improved under solvent-free conditions and using microwave irradiation (Eq. (8) and Tab. 3.5). 

Loupy, A., Petit, A., and Bonnet-Delpon, D. 1995. Improvements in 1,3-dipolar cycloaddition of nitrones to fluorinated dipolarophiles under solvent-free microwave activation. Journal of Fluorine Chemistry, 75 215-16. 

The selected examples by Studer et al. [97-99] reported the synthesis of two small, discrete libraries of isoxazolines (eight compounds) and of amides derived from a Ugi 4CC reaction (10 compounds). The synthesis of the tagging silicon derivative and the scheme for isoxazoline synthesis are reported in Figure 16. A known silane [100] was coupled quantitatively with bromine in the fluorinated solvent FC-72 [101] and the tagging reagent was used to protect and label the allyl alcohols in THF. After the cycloaddition of the fluorinated dipolarophiles with the nitrile oxides, the protected isoxazolines were finally cleaved with HF/pyridine complex in ethyl ether. The scheme of the purification for each synthetic step is depicted in Figure 17. 

Banks RE, Mohialdin SN (1986) Synthesis of indolizines from pyridinium (trifluoroacetyl) methyUde and fluorinated dipolarophiles. J Fluor Chem 34 275-280... 

The first section of this chapter describes the preparation and several synthetic applications of a-fluoroalkyl P-sulfmyl enamines and imines the second deals with the chemistry of di- and trifluoropyruvaldehyde A, 5-ketals, stereochemically stable synthetic equivalents of P-di and P-trifluoro a-amino aldehydes, which can be prepared from the corresponding p-sulfinyl enamines the third overviews the preparation of chiral sulfinimines of trifluoropyruvate and their use to prepare a library of a-trifluoromethyl (Tfm) a-amino acids the fourth section is mainly dedicated to the asymmetric synthesis of monofluorinated amino compounds, using a miscellany of methods such as MifstmobuAike azidation of P-hydroxy sulfoxides, ring opening of fluoroalkyl epoxides with nitrogen-centered nucleophiles and 1,3-dipolar cycloadditions with chiral fluorinated dipolarophiles. 

Some monofluoro amino derivatives have been prepared with excellent stereocontrol exploiting the potential of inter- and intra-molecular 1,3-dipolar cycloadditions (72) with fluorinated dipolarophiles. An intermolecular application is shown in Scheme 19 (73J4). Nitrile oxides 78 were reacted with fluorinated chiral enol ethers 79 4,5-dihydroisoxazoles 80 were obtained with total regio- and stereo-selectivity. By subsequent elimination of methanol and reductive opening of the isoxazole ring 81, fluoroiminoalcohol 82 was obtained in fair yield. 

Perfluorinated and partially fluorinated substituents directly bonded to hetero multiple bond systems lower the energies of FMOs Consequently, they are highly reactive in H0MO (l,3-dipole)-LUMO (dipolarophile)-controlled [3+2] cycload-... 

Polyfluoroalkyl- andperfluoroalkyl-substituted CO and CN multiple bonds as dipolarophiles. Dmzo alkanes are well known to react with carbonyl compounds, usually under very mild conditions, to give oxiranes and ketones The reaction has been interpreted as a nucleophilic attack of the diazo alkane on the carbonyl group to yield diazonium betaines or 1,2,3 oxadiazol 2 ines as reaction intermediates, which generally are too unstable to be isolated Aromatic diazo compounds react readily with partially fluorinated and perfluorinated ketones to give l,3,4-oxadiazol-3-ines m high yield At 25 °C and above, the aryloxa-diazolines lose nitrogen to give epoxides [111]... 

Unsaturated electron-deficient compounds are excellent dipolarophiles. This is especially true for fluorinated alkenes, in which the perfluoroalkyl group lies at the multiple bond. They react with diazomethane, forming heterocyclic compounds. The nature of the perfluoroalkyl group, however, plays an important role. Thus perfluorobut-2-ene is unreactive with diazomethane, whereas perfluoroolefins with sterically hindered perfluoroalkyl groups give cycloaddition products in high yields (83JCS(CC)5). 

Fluorinated cz/kunsaturated carbonyl compounds acting as dipolarophiles react with diazomethane, giving 1,3-dipolar cycloaddition products with high regioselectivity (76T1995, 00IZV1770). 

Incorporation of perfluoroalkyl groups into 1,3-dipoles usually increases reactivity, i.a. by lowering the energies of the frontier orbitals and reducing the LUMO 1,3-dipole/HOMO dipolarophile energy gap. On the other hand, when perfluoroalkyl and partially fluorinated substituents are directly bonded to the dipolarophile skeleton, cycloaddition reactions occur preferentially under HOMO 1,3-dipole/LUMO dipolarophile control. Furthermore, perfluoroalkyl groups often stabilize the newly formed ring systems. 

Introduction of Fluorine-containing Substituents into Five-Membered Heterocycles via Dipolarophiles... 

The activation of the trifluoromethyl substituent is strong enough to allow the 1,3-dipolar reaction to occur with trisubstituted dipolarophiles, provided a second electron-withdrawing substituent is present in the molecule (Table 11). Under similar conditions non-fluorinated analogs are unreactive (entry 3).The cycloaddition with ethyl trifluoroacctoacetate is a striking example (Table 11, entry 2) in this case, the dipolarophile reacts in its enolic form (Z-isomer). 

These fluorinated Dewar benzenes are also reactive as dipolarophiles in the 1,3-dipolar reactions 63). 

Cyclic sulfonamides are Lermed sultams. From the enantiomeric 10-camphorsulfonic acids, both enantiomers of camphorsultam (49) are readily available by reduction of the intermediate sulfon-imide 484fi 50 and are commercially available. They have been used for the formation of amides with unsaturated acids, which are useful chiral dienophiles and dipolarophiles (Sections D. 1.6,1.1.1- and D. 1.6.1.2.1.) or undergo osmium tetroxide catalyzed dihydroxylations (Section D.4.4.). Other amides may be used for enolate reactions (Sections D.1.1.1.3.1., D.l.5.2.1. and D.4.3.). The. V-fluorinated derivative was obtained by direct fluorination of the sultam with 10% fluorine in nitrogen at low temperature5 , and has been used for the enantioselective formation of C —F bonds (Section D.3.). 

Indolizines, indolizidines, indoles, and other bicyclic or polycyclic compounds containing a fused pyrrole or pyrrolidine moiety often possess potent and useful biological activities. There have been several approaches to the preparation of fluorinated analogues of these heterocycles, mainly based on 1,3-dipolar addition reactions using fluorinated synthons either as the dipole or as the dipolarophile. Several examples of this strategy are given below. 

Wang and co-workers developed an elegant catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with low reactive fluorinated imines as the dipolarophiles catalyzed by Cu(MeCN)4BF4/PPFOMe complex for the synthesis of 2,4-frans-fluorinated imidazolidines (Scheme 25) [45]. This catalytic system exhibited high reactivity, excellent stereoselectivity, and broad substrate scope. 

The 1,3-dipolar cycloaddition using fluoroalkylacetylenes as dipolarophiles represents the key method to preparing diverse 4-fluoroalkylpyrazoles. The addition of ethyl diazoacetate to fluorine-containing acetylenes 105, in diethyl ether at room temperature, afforded mixtures of 4- and 3-fluoroalkylpyrazoles 106 and 107 in high yield but with poor control over the regioselectivity in general (Schane 34). Both products were easily separated chromatographically [57]. 

The synthetic procedures for the preparation of C-F derivatives of tri- and tetrazoles are more developed compared to the synthesis of the derivatives with the N-F bond. The preparation methods of C-F derivatives are known not only for 1,2,3-and 1,2,4-triazoles, but also for tetrazoles. The C-F bond is successfully formed by the replacement of hydrogen atom or various leaving groups under the action of the fluorination reagents. Along with the above methods diverse versions are applied of 1,3-dipolar cycloaddition of azides to dipolarophiles containing fluorine. Also very useful approach is oxidative cychzation of molecules with the hnear structure containing a C-F bond. 

Trifluoromethyl group is one of the important functional groups, which improves liphophilicity and stability of drug molecules. Benoit et al. S5mthesized a series of 3-trifluoromethyl-2-isoxazolines 74 and 3-trifluoromethyl-2-isoxazoles 72 by utilizing DIB-induced oxidation of trifluoromethyl aldoximes 70 followed by 1,3-dipolar cycloaddition of the resulhng nitrile oxides with different dipolarophiles (alk5mes 71 and alkenes 73). This developed a metal-free DIB-mediated 1,3-dipolar cycloaddition protocol to prepare valuable fluorinated bioactive oxazoles and isoxazolines (Scheme 13) [29]. 

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