Indole 5-fluoro-3-

Standard Heck conditions were used to introduce the dchydroalanine side-chain with 4-bromo-3-iodo-l-(4-methylphenylsulfonyl)indole[12]. Using 4-fluoro-3-iodo-l-(4-methylphenylsulfonyl)indole as the reactant, Merlic and Semmelhack found that addition of 2 eq, of LiCl or KCl improved yields in reactions carried out with 10% Pd/C as the catalyst[13]. The addition of the dehyroalanine side chain can also be done by stoichiometric Pd-mediated vinylation (see Section 11.2). A series of C-subslituled dehydro tryptophans was prepared in 40-60% yield by this method[14]. 

Recently, the Bartoli indole synthesis was extended to solid supports. In contrast to the earlier reports in the liquid phase, o,o-unsubstituted nitro analogs (see 25) prove to be useful substrates. In addition, fluoro/chloro substituted nitro derivatives are well tolerated, which typically undergo nucleophilic substitution under Bartoli conditions in the liquid phase. 

The aniline derivative 332, prepared from 2-fluoro-6-nitrotoluene, was transformed through successive reactions as shown in Scheme 60 to give the functionalized indole 333. It was then reduced with LiAlH4 to the dimethylaminopropyl derivative which was quaternized with Mel to the trimethyl ammonium salt 334. Subsequent cyclization and functionalization afforded the pyrroloquinoline 335. The latter could be transformed to the tetracyclic acid 336 (90JHC2151). (Scheme 60)... 

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). 

Martin effected the synthesis of several 3,5-diarylated indoles by a tandem Stille-Suzuki sequence [131]. The latter reaction involves exposure of 3-(3-pyridyl)-5-bromo-l-(4-toluenesulfonyl)indole with arylboronic acids (aryl = 3-thienyl, 2-furyl, phenyl) under typical conditions to give the expected products in 86-98% yield [131], Carrera engaged 6- and 7-bromoindole in Pd-catalyzed couplings with 4-fluoro- and 4-methoxyphenylboronic acids to prepare 6- and 7-(4-fluorophenyl)indole (90% and 74% yield) and 6-(4-methoxyphenyl)indole (73% yield) [29]. Banwell and co-workers employed 7-bromoindole in a Suzuki coupling with 3,4-dioxygenated phenylboronic acids en route to the synthesis of Amaryllidaceae alkaloids [132], Yields of 7-arylated indoles are 93-99%. Moody successfully coupled 4-bromoindole... 

Intramolecular cyclization of 2-lithiobenzyl-2-halophenyl amines, ethers, and thioethers—Synthesis of phenanthridine, dibenzopyran, and dibenzothiopyran derivatives Having demonstrated the efficiency of this methodology for the preparation of indole derivatives, we prepared the 2-fluoro-phenyl ether and thioether 22 a, b to study their potential as substrates that could afford oxygen and sulfur heterocycles. However, treatment of 22 a, b with fBuLi afforded, after... 

Jbenzopyrano- [4,3-b] -1,4-oxazin-9-ol (S)-2-(6-chloro-5-fluoro-indol-l-yl)-l-methylethylamine (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-lH-3-benzazepine-7-ol... 

Unsaturated amines are hydrogenated at the multiple bonds by catalytic hydrogenation over any catalyst. The double bond in indole was saturated in catalytic hydrogenation over platinum dioxide in ethanol containing fluoro-boric acid and indoline was obtained in greater than 85% yield [456. AUylic amines such as allylpiperidine are also reduced by sodium in liquid ammonia in the presence of methanol (yield 75%) [709. ... 

Amino-3-fluorobenzoic acid is an important intermediate in the synthesis of derivatives of indole, such as the potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist L-670,596 or the anti-inflammatory agent Etodolac. Compounds of this type have therapeutic applications. 2-Amino-3-fluoro-benzoic add is aiso an important precursor for the synthesis of fluoroacridines, which can be converted to interesting tridentate ligands, such as Acriphos. ... 

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... 

A solution of 1-tosyl-3-(trimethylstannyl)indole (500 mg, 1.15 mmol) in dry MeCN (20 mL) was stirred under N2 at rt. l-(Chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (F-Teda BF4, 6 500 mg, 1.15 mmol) was added in one portion and the solution stirred for 12 h. After 3 h a colorless precipitate began to appear. The mixture was filtered and the filtrate evaporated and purified by chromatography to give a colorless powder yield 70 mg (21 %) mp 87-88 C. 

Chloro-l-(4-fluoro-phcnyl)-4-oxo- -5-fluoro-2-oxo- EI6b. 406 (subst. Indol t snbsl. Ketenimin) 3-Chloro-4-oxo-l-phenyl- -5(or 6)-fluoro-2-oxo- EI6b, 406 (Indol-Der. + subst. Ketenimin) 3-Chloro-4-oxo-l-(4-trifluoromethyl-phenyl)- -5(or 6)-fluoro-2-oxo-EI6b. 406 (Indol-Der, + subst. Ketenimin)... 

---