2.3- Dihydroindoles, preparation from

For the preparation of 2,3-dihydroindoles (8) from indoles (7), two reduction methods are known. In the column Reduction Method in the table, the one indicated A represents use of EtsSiH in TFA (79JOC4809) and the other, indicated B, employs NaBHsCN in AcOH (77S859, 88JMC1746). Although both methods are applicable, the former is generally superior to the latter. In some cases, depending on the substrates structures, the reverse cases are also observed. Examples are the reactions marked B in the column. 

Carbanions derived from side chain tertiary amides have also been cyclized to provide isoquinolones and isoindoles (equation 36).125 126 While benzyne intermediacy in the formation of the former is likely, the latter seems to arise through a SrnI reaction pathway. Synthesis of indole from the meta bromo compound (87), on the other hand, clearly involves an aryne cyclization. 27 A more versatile route to indoles is based on intramolecular addition of aminyl anions to arynes (equation 38).128 A somewhat similar dihydroindole preparation constitutes the first step in a synthesis of lycoranes (equation 39).129 The synthesis of (88) also falls in the same category of reactions, but it is noteworthy because only a few examples of ring closure of heteroarynes are mentioned in literature.27 28... 

Three related alkaloids have been found in the leaves of Pleiocarpa tubicina. One is the known compound 19,20-dihydroakuammicine (CCXXXVII, 70, 69, 137a), while the other two, tubifoline and tubi-folidine, are respectively its decarbomethoxy derivative, the indolenine, CCXXXIX, and the corresponding dihydroindole, CCIII (119). A compound strychene of structure CCXXXIX has been prepared from dihydrodeoxyisostrychnine (67, 125). 

The radical nucleophilic substitution is perfectly suited for tandem reactions [180]. Recent examples have been reported by the Rossi group (Scheme 66). Dihydrobenzofuranes and dihydroindoles substituted at the 3-position were prepared from ortho-functionalized haloaromatic compounds in high yields [181]. The nucleophiles involved in the initial electron transfer and subsequent coupling are varied. In particular, starting form naphthyl derivative 210, phosphinyl anions lead to tricyclic phosphine oxide 211 (after oxidation) in 98% yield. 

The synthesis of 2-vinylindoles continues to be of interest due to the vast potential of these species for further chemical elaboration. In developing a strategy for carbazole synthesis, a Michael-type addition of 4,7-dihydroindole to dimethyl acetylenedicarboxylate was employed to afford, after DDQ oxidation, functionalized 2-vinylindoles <06JOC7793>. In a metal-mediated approach, Nakao, Hiyama, and co-workers prepared propyl-substituted 2-vinylindoles from A-protected 3-cyanoindoles via treatment with 4-octyne in the presence of catalytic nickel <06JACS8146>. Aryl, vinyl, and alkynyl substituents were installed by direct coupling with an A-protected 2-trifluoromethanesulfonyloxyindole, prepared from oxindole <06S299>. 

Inasmuch as the instability of this compound precluded its synthesis in pure form, impure mixtures were used for clinical test (56). Raper (95) had shown that the 5,6-quinone of dihydroindole-2-carboxyIic acid is a product of the action of tyrosinase on tyrosine in the presence of oxygen. Jacobs administered daily such a mixture, prepared from raw potato scrapings and tyrosine, to a pernicious anemia patient. On the fifth day, treatment was interrupted because of the appearance of diarrhea and nausea. The reticulocytes rose from an initial value of 2.8 per cent to 6.0 per cent on the fifth day. 

Indolines are produced in good yield from 1-benzenesulfonylindoles by reduction with sodium cyanoborohydride in TFA at 0°C (Equation 5) (89TL6833). If acyl groups are present at C-2 or C-3 in the substrate, they are reduced to alkyl groups. Indole is also reduced to 2,3-dihydroindole by sodium cyanoborohydride and acetic acid or triethylamineborane and hydrochloric acid. An alternative method for preparing indolines involves treatment of indoles with formic acid (or a mixture of formic acid and ammonium formate) and a palladium catalyst (82S785). Reduction of the heterocyclic ring under acidic conditions probably involves initial 3-protonation followed by reaction with hydride ion. 

Nitroindoles 1155 are prepared in good yields (69-85%) via a thermal 67t-electrocyclization of 2,3-dialkenyl-4-nitropyrroles 1152 in refluxing nitrobenzene (1-5 h), a solvent which causes in situ aromatization of dihydroindoles 1154 resulted from the initially formed dihydroindoles 1153 by [1,5]-H shift (Scheme 224) <1998T1913>. 

Considerable information was obtained from the mass spectra of several derivatives prepared on a 1-2 mg scale specifically for mass spectrometric studies. Henningsamine (M+, 394) was converted by acid hydrolysis to deacetylhenningsamine (M, 310 replacement of two acetyl groups by hydrogens) which on reacetylation with [ HeJ-acetic anhydride gave a product of molecular weight 400. The mass spectra of these derivatives and that of the alkaloid itself, which showed peaks at m/e 130 and 144 characteristic of unsubstituted dihydroindoles, confirmed the above conclusions. 

Dihydroindoles.—new synthesis of 2,2-disubstituted dihydroindoles from enamines and aryl azides has been reported. The reaction is envisioned as proceeding via an unstable triazoline which collapses with loss of nitrogen to give the dihydroindole or an amidine (Scheme 100). A number of eserine derivatives have been prepared by a simple three-stage process (Scheme 101). ... 

---