The Nucleophilic 5-endo-trig Cyclization of 1,1-Difluoro-1-alkenes: Ring-Fluorinated Hetero- and Carbocycle Synthesis and Remarkable Effect of the Vinylic Fluorines on the Disfavored Process

Abstract

The disfavored 5-endo-trig cyclizations have been accomplished for 1,1-difluoro-1-alkenes with nitrogen, oxygen, sulfur, and carbon nucleophiles by taking advantage of the properties of fluorine. b,b-Difluorostyrenes bearing tosylamido, hydroxy, or methylsulfinyl group at the o-position undergo intramolecular nucleophilic substitution with a loss of the vinylic fluorine, leading to 2-fluorinated indole, benzo[b]furan, and benzo[b]thiophene in high yields. 1,1-Difluoro-1-butenes bearing homoallylic tosylamido, hydroxy, mercapto, or iodomethyl group also successfully cyclize via a 5-endo-trig process with the in situ generated intramolecular nucleophiles to afford 2-fluoro-2-pyrroline, 5-fluoro-2,3-dihydrofuran, 5-fluoro-2,3-dihydrothiophene, and 1-fluorocyclopentene. The two vinylic fluorines proved to be essential and play a critical role in these 'anti-Baldwin' cyclizations.

The nucleophilic addition reactions of difluorovinyl tosylates with O- and S-nucleophiles

“…2,2-Difluorovinyl tosylate 1 was prepared by reported method [11]. Melting points were taken on a Melt-Temp apparatus and are uncorrected.…”

Ring-fluorinated naphthalene and indene synthesis via 6- and 5-endo-trig cyclizations of gem-difluoroalkenes by carbon nucleophiles

“…Since we have already accomplished this type of 5-endo-trig cyclization by sp 3 carbanions [26] (see also [27] for 5-endo carbocyclization of gem-difluoroalkenes in the presence of SnCl 4 ), a phenyl anion of an sp 2 carbon nucleophile was adopted to broaden the scope of the nucleophilic 5-endo-trig ring closures (for the nucleophilic 5-endo-trig cyclization, see [9] and references therein). We expected the nucleophilic 5-endo-trig cyclization to proceed due to the unique properties of gem-difluoroalkenes: (i) the electrostatic attraction between the cationic CF 2 carbon and nucleophilic center (anion) would allow initial ring formation and (ii) the successive elimination of fluoride ion could suppress the reverse ring opening, thus functioning as a ''lock''.…”

“…However, lack of regioselectivity, the necessity of multistep procedures, and difficulties in handling these fluorinating reagents continue to be problems with these conventional methods. Therefore, the development of efficient methods for the selective construction of those fluorinated carbocycles remains a highly desirable goal.Recently, we have introduced a new concept for the synthesis of five-and sixmembered ring-fluorinated heterocyclic compounds, such as indoles, benzo[b]furans, benzo[b]thiophenes, 2-pyrrolines, 2,3-dihydrofurans, 2,3-dihydrothiophenes, isochromenes, isothiochromenes, quinolines, and isoquinolines [6][7][8][9][10][11]. This flexible methodology is based on vinylic nucleophilic substitution (SNV) of the fluorines in gem-difluoroalkenes via intramolecular addition-elimination processes [12][13][14].…”

Recent progress in the use of fluoroorganic compounds in pericyclic reactions

“…An illustrative example is shown in Scheme 1. 18 The nonfluorinated and the fluorinated amino-diesters 1a,b exhibit opposite ring-closing reactivities. The former substrate 1a was used by Baldwin and coworkers 19 to illustrate the difficulty of 5-endo-trig processes.…”