Indoline formation

Of the three products, the indoline 19 was the most surprising, since it had been reported [ 12] that aryl radical 22, formed by reduction of the precursor aryl bromide with tributyltin radicals, underwent exclusive cyclization to afford 20, with no indoline formation. However, repeating the tin experiment with the bromide demonstrated that indoline was indeed produced [13] along with 20. Hence the partition between cyclizations onto the aryl ring and onto the alkene is essentially identical regardless of how the radical is generated. 

Figure 1.10 Enantioselective indoline formation from R-26 via Pd-NHC intermediate 27.

An increasing number of examples of ring formation through 1,5-electrocyclization of appropriate carbanions are illustrated in Scheme 27. In the last example the use of a chiral alkoxide (R = menthyl or bornyl) results in the formation of chiral indolines with optical purities ranging from 17 to 31%. 

L-idose 293, 311 ff. imine formation 57 imine-enamine tautomerization 467 iminium-RhH jt complex 351 f. imipenem 348 indoline ligands 681, 684 indolizomycin 47 Iff. -.retrosynthetic analysis 472ff. 

A novel approach to 3-substituted indolines and indoles via the anionic cyclization of 2-bromo-lV,lV-diallyanilines has been developed simultaneously by Bailey <96JOC2596> and Liebeskind <96JOC2594>. Thus, treatment of 2-bromo-lV,lV-diallylanilines 78 with 2 equivalents of BuLi at -78 °C leads to the formation of the intermediate 79 which may be trapped with an electrophile to afford 3-substituted indolines 80. Aside from ease of preparation, an additional benefit of the intramolecular carbolithiation of <7-lithio-W,Al-diallyl-anilines is the production of Al-allyl-protected indolines, which are easily deprotected using... 

The activation energies determined for the conversion of 2-, 3- and 4-NAP to 2-, 3- and 4-aminoacetophenone (AAP) are reported in Table 8.2, as is the activation energy for the formation of 1-indoline. As might have been expected the activation energies for the aminoacetophenone isomers are indistinguishable. However, the activation energy for 1-indoline is significantly different. 

Bailey s group has elaborated a fourfold anionic domino approach leading to a N-allyl-3,4-disubstituted indoline 2-582 from 2-580 (Scheme 2.131) [300]. The central step is the formation of an aryne by treatment of 2-fluoro-N,N-diallylaniline (2-580) with nBuLi followed by a regioselechve intermolecular addition of nBuLi to give 2-581. This then cyclizes to afford a new lithiated species which is intercepted by added TMSCI. 

The unexpected formation of cyclopenta[b]indole 3-339 and cyclohepta[b]indole derivatives has been observed by Bennasar and coworkers when a mixture of 2-in-dolylselenoester 3-333 and different alkene acceptors (e. g., 3-335) was subjected to nonreductive radical conditions (hexabutylditin, benzene, irradiation or TTMSS, AIBN) [132]. The process can be explained by considering the initial formation of acyl radical 3-334, which carries out an intermolecular radical addition onto the alkene 3-335, generating intermediate 3-336 (Scheme 3.81). Subsequent 5-erafo-trig cyclization leads to the formation of indoline radical 3-337, which finally is oxidized via an unknown mechanism (the involvement of AIBN with 3-338 as intermediate is proposed) to give the indole derivative 3-339. 

Alkali metal borohydrides are frequently used for the reduction of rc-electron-deficient heteroaromatic systems, but reduction of jt-electron-excessive arenes is generally possible only after protonation of the systems [e.g. 35-37]. The use of tetra-n-butylammonium borohydride under neutral conditions for the conversion of alkylindoles into indolines [38] is therefore somewhat unusual. Reduction of indoles by diborane under strongly alkaline conditions involves the initial interaction of the indolyl anion with the diborane to form an amino-borane which, under the basic conditions, reacts with a second molecule of diborane to produce the indoline [39]. The reaction of tetra-n-butylammonium borohydride with indoles could also proceed via the intermediate formation of diborane. 

The formation of 2-(indolin-2-yl)indole dimers from indole-3-acetic acid and its propyl ester in trifluoroacetic acid and phosphoric acid has been studied." The reaction involves electrophilic attack of the protonated species (24) on the free substituted indole to give the trans stereochemistry at the C(2)-C(3) bond. 

The synthetic scheme for functionalized indolines shown in equation 83 assumes formation of a doubly metallated intermediate (335), derived from V,iV-diallyl-2,6-dibromo-p-toluidine, that may be quenched to the dehalogenated toluidine 336, or may undergo cyclization to 337. Quenching of 337 with trimethylchlorosilane in the presence of TMEDA leads to formation of indoline derivatives 338 and 339. Apparently a second cyclization of intermediate 337 to compound 340 is hard to accomplish . 

A variety of methods exist for the formation of 1,2-thiazines via the construction of an S-N bond by nucleophilic attack of nitrogen onto a sulfur-bearing leaving group. For example, the reaction of aryl bromide 189 with potassium thiocyanate in the presence of copper(l) iodide and triethylamine affords benzothiazine 190, although in low yield and as a mixture with indoline by-product 191 (Equation 28) <2000JOC8152>. 

The spiro compound 15 is obtained in excellent yield by the cycloaddition of 3-(4-fluorophenylimino)indolin-2-one with mercaptopropionic acid under microwave irradiation <2003SUL201>. Treatment under basic conditions of 2,3-dihalopropylamines with carbon disulfide results in the formation of two isomeric products 5-halotetrahydro-l,3-thiazine-2-thione 204 and 5-(halomethyl)thiazolidine-2-thione 205 <2002CHE1533>. 

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. 

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