Indole fluorination

There have been few reports of indole fluorination. 2-Methylindole was largely destroyed by cobalt(V) fluoride treatment, giving perfluorocyclo-hexane and perfluoromethylcyclohexane among the products [70MI2 72HC(25-2)127]. 4-Fluoro-3-indoleacetonitriles have been prepared from the diazonium fluoroborates (85CPB3696). 

Keywords Indole Fluorine Trifluoromethyl group Synthesis Fluorinated... 

Two closely related indoles fused to an additional saturated ring have been described as CNS agents. The first of these is obtained in straightforward manner by Fischer indole condensation of functionalized cyclohexanone 0 with phenyl hydrazine (19). The product, cyclindole (21) shows antidepressant activity. The fluorinated analogue flucindole (26) can be prepared by the same scheme. An alternate route starting from a somewhat more readily available intermediate involves as the first step Fischer condensation of substituted phenyl hydrazine with 4-hydroxycyclohexanone (23). The resulting alcohol (24) is then converted to its tosylate (25). Displacement by means of dimethyl amine leads to the antipsychotic agent flucindole (26). ... 

Racemic fluorinated tryptophan derivatives 31 were obtained from 3-methylene indole 29 and fluorinated imines 30 using the imino-ene reaction (Equation (18)).28 The highest yields were obtained for the more electrophilic imines (R2 = SC>2Ph, Ts, SC Me). Moreover, these reactions took place at ambient temperature. 

For the formation of indoles 2 and 3 we assumed that amines 1 first reacted with fBuLi at -110°C to give N-(2-lithioallyl)amines 4, through halogen-metal exchange 23 this was confirmed by deuteration and isolation of the deuteriated amine 5 a (Scheme 2). Intermediate 4, which is stable for several hours at —110 °C, probably undergoes proton-abstraction ortho to the fluorine atom by the additional equivalents of fBuLi when the temperature is raised to — 40 °C giving the intermediate 6. The subsequent elimination of LiF produces a benzyne intermediate 7, which is efficiently... 

In Figure 6.22, the product ion scan of (M—H) mIz 352, C17H10N1O2F3CI, showed three major product ions at miz 286 (loss of F2CO) with the fluorine migrating to the indole ring, miz 283 (loss of CF3 radical) and m z 266 (loss of CF3OH). Using the (M—H) ion at miz 352 as the reference mass the measured exact masses were all within 5.8 ppm of the theoretical value for the proposed formula. 

A. Fleaid, K.L. Locker, A.M. MacLeod, D. Morrison, C.R. Moyes, D. O Connor, A. Pike, M. Rowiey, M.G.N. Russell, B. Sohal, J.A. Stanton, S. Thomas, FI. Verrier, A.P. Watt, J.L. Castro, Fluorination of 3-(3-(piperidin-1-yl)propyl)indoles and 3-(3-(piperazin-1-yl) propyl)indoles gives selective human 5-FITid receptor ligands with improved pharmacokinetic profiles, J. Med. Chem. 42 (1999) 2087-2104. 

Vinca dimer indole alkaloids (e.g., vinblastine) act as spindle poison. They bind tubulin, inhibiting polymerization into microtubules, major elements of the cytoske-Vinblastine itself and its analogue vinorelbine (Navelbine ) are marketed for cancer therapies (Figure 4.48). Because of the obvious difficulty in synthesizing such highly complex structures, there were no reports on the preparation of fluorinated derivatives until the remarkable work of Jacquesy s group on the synthesis in super-acidic media. 5 ... 

The Fischer indole synthesis is quite tolerant of additional functional groups in the starting material. Thus reaction of 4-dimethylaminocyclohexanone (18-2) with phe-nylhydrazine (18-1) in acetic acid leads directly to cyclindole (18-3) [18], a compound described as an antidepressant. A shghtly different approach is used to prepare the fluorinated analogue. The tricyhc indole (18-5), in this case, is obtained by reaction of 2,4-diiluorophenylhydrazine (18-4) with 4-hydroxy-cyclohexanone. The hydroxyl... 

Protected and unprotected indole derivatives dissolved in hydrogen fluoride are also fluorinated by 18F-F. The relatively stable melatonin (10), a neurohormone responsible for the biological clock and other brain functions, gave only the 6-[l8F]fluoro derivative 11, but even the more fragile 5-hydroxytryptophan (12) could be fluorinated under these conditions resulting in a mixture of 4- and 6-[l8F]fluorohydroxytryptophan 13.54... 

Regioselective fluorodestannylation of alkenyl and heteroaryl molecules to give 34 can be achieved under mild conditions with cesium fluoroxysulfate, while x-fluoro ketones, e.g. 35, are formed when the tin group is attached to the benzylic position.42 The pyrrole ring in indole derivatives is also successfully fluorinated using this method, e.g. formation of 36.42-45... 

The fluorination of 1-substituted indole 32 with F-Teda BF4 (6) in acetonitrile or acetonitrile/ methanol gives 3-fluoro-2-methoxy-l-tosyl-2,3-dihydroindole (33) in 48% isolated yield.87 Relative stereochemistry about the 2,3-bond in the dihydropyrrole ring was confirmed as trans by X-ray crystallographic analysis. F-Teda BF4 (6) reacts with 2- and 3-trimethylstannyl-sub-stituted 1-tosylindoles to give the corresponding fluoroindoles in 40 and 21 % yield, respectively.108... 

Fischer indole synthesis, 157 fluorinated phosphine, 136 fuostifoline, 276 furo[2,3- ]pyridine, 281 furopyrimidine, 281, 393 furo[2,3-c]quinoline, 274 furylaniline, 272 furylboronic acid, 274 furylpyridine, 274 furylstannane, 277-9 2-furylzinc chloride, 271-4... 

Intramolecular replacement of fluorine by nitrogen has been used for the formation of fused heterocycles, i.e. derivatives of indole,187 - 189 2,3-dihydroindole.190 benzopyrazole.191 benzo-pyridazine,192 benzoxazine,193194 bcnzothiadiazole,193 quinoline,196-198 and benzothiazinc (e.g., 9).194 1"-200... 

Intramolecular cyclization in perfluoroaromatic systems proves useful for the synthesis of heterocyclic compounds [72] For example, the Fischer indole synthesis, which normally requires the presence of an ortho proton, occurs satisfactorily with an ortho fluorine in theperfluoronaphthalene senes [73] (equation 37)... 

Dandia, A., Singh, R., Sachdeva, H. and Arya, K., Microwave-assisted one pot synthesis of a series of trifluoromethyl substituted spiro [indole triazoles], /. Fluorine Chem., 2001, 111,61-67. 

Joshi et al. [81] have incorporated azetidin-2-one moiety into indole nucleus and synthesized several fluorine containing spiro-(3-lactams (Scheme 9). The synthesis involved the condensation of primary amines with an appropriate indole-2,3-dione... 

Jouannetaud and co-workers229 have explored electrophilic trifluoromethylation under superacidic conditions of aniline derivatives229 and /V-heterocycles. Methyl-substituted anilines and substituted acetanilides [Eq. (5.85)] react with the CC13+ cation generated from CC14 in HF-SbF5 followed by fluorination to yield the corresponding trifluoromethyl derivatives. Under similar conditions, indolines are transformed to the 6-triluoromethyl derivatives, whereas substituted indoles yield 5-triluoromethyl derivatives.230... 

The fluorines of a CF2H group at the 2-position of an imidazole or benzimidazole are more highly shielded than those at the 2-position of indole (Scheme 4.76). Included are compounds with the CF2H group bound to nitrogen. 

Preparation of fluorinated organic compounds is important. Uneyama and co-workers have investigated the generation and reactions of trifluroacetimidoyl radicals [95BCSJ1497], The imidoyl radicals can be generated under three different conditions and it undergoes clean 5-exo cyclizations to provide 3-substituted indoles in moderate yields. 

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