Indolines radical cyclization

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. 

The aryl radical cyclization has been successfully used for the preparation of substituted dihydrobenzo[Z)]indoline derivatives [59], An example is shown in Reaction (7.49). The diene 42 was preliminarly subjected to ring-closure metathesis using Grubbs catalyst and then treated with (TMS)3SiH and EtsB at -20 °C, in the presence of air, to provide the compound 43 with an excellent diastereoselectivity. 

The combination of allylic amination, ring-closing metathesis, and a free radical cyclization provides a convenient approach to the dihydrobenzo[b]indoline skeleton, as illustrated in Scheme 10.10. The rhodium-catalyzed aUylic amination of 43 with the lithium anion of 2-iodo-(N-4-methoxybenzenesulfonyl)arrihne furnished the corresponding N-(arylsulfonyl)aniline 44. The diene 44 was then subjected to ring-closing metathesis and subsequently treated with tris(trimethylsilyl)silane and triethylborane to afford the dihydrobenzojhjindole derivative 46a in 85% yield [14, 43]. 

Many methods have been developed for the enantioselective synthesis of unnatural a-amino acids. Jeff Johnston of Indiana University reports (J. Am. Chem. Soc. 125 163,2003) coupling the asymmetric alkylation of O Donnell with intramolecular radical cyclization, leading to what appears to be a general method for the enantioselective construction of indolines. 

Selenides are more readily cleaved by tin radicals than are thioethers. Two examples of the tin radical mediated cleavage of selenides are listed in Table 3.48 (Entries 8 and 9) more examples have been reported [768,773,821-823], The carbon-centered radicals initially formed by homolytic C-Se bond cleavage can either be directly reduced to the alkane by treatment with a tin hydride, or may add to multiple bonds before reduction. Entry 10 in Table 3.48 is an example of the formation of a polycyclic indoline through radical cyclization. Radical-mediated cleavage proceeds under mild,... 

Early examples of intramolecular aryl radical addition reactions to heteroatom containing multiple bonds included cyclizations on N=N and C=S moieties [52, 53]. Recently, cyclizations to imines have been used as part of a new enantio-selective approach to indolines (Scheme 8). In the first step of the sequence, the required ketimines 19 were obtained by phase-transfer catalyzed alkylation of 2-bromobenzyl bromides 20 with glycinyl imines 21 in the presence of a cincho-nidinium salt [54], Due to the favorable substitution pattern on the imine moiety of 19, the tributyltin hydride mediated radical cyclization to 22 occurred exclusively in the 5-exo mode. The indoline synthesis can therefore also be classified as a radical amination. 

Scheme 8 Indoline synthesis via aryl radical cyclization on imines [54]...

Scheme 9 Indoline synthesis as a multicomponent reaction including a radical cyclization step [58]...

Indolines and indoles were prepared by a direct electrochemical reduction of arenediazonium salts. As a result, radical intermediates were generated from which 3,4-disubstituted tetrahydrofuran skeleta were constructed <02OL2735>. A short and stereoselective total synthesis of furano lignans was realized by radical cyclization of epoxides using a transition-metal radical source <02JOC3242>. Other preparations of tetrahydrofurans using radical cyclization include the synthesis of novel amino acids L-bis-... 

Reaction of aryl Grignard compounds, obtained in situ by iodine-magnesium exchange, with C0CI2, presumably generates aryl radicals. In the presence of a double bond or aromatic ring an intramolecular radical cyclization may take place. This reaction was used for the synthesis of spiro-indolines.244 Oshima has applied cobalt-mediated tandem radical cyclization-cross-coupling reaction for the synthesis of benzyl-substituted heterocycles (Scheme 80).245... 

Indolines can also be prepared by radical cyclization. For example, the precursor 62 was annulated to the indoline 63 with incorporation of a N-substituent originating from the ketone component (Equation 16). This reaction seems to proceed via aryl radical addition onto an initially formed imine <20010L1009>. 

Other means for generation and annulation of aryl radicals involve treatment of A -(t>-bromophenyl)propylamides with BusSnH/AIBN, which gives 3-alkylideneoxindoles <2(X)0J(P1)763>, or exposure of A -allyl(t>-iodoanilines) to fluorous tin hydride reagents, affording indolines <1999JA6607>. A set of indolines, for instance 239, have been obtained by radical cyclization of precursors such as 240, which were derived from A -allylanilines (Equation 76) <1999TL2533>. 

Having established that aminyl radicals can undergo cyclization, several different modes of reaction were explored. Allyl sulfenamide 531 was found to participate in a tandem radical cyclization reaction to produce a 2 2 1-mixture of hexahydro-indolines 532 in 30% yield (Scheme 90) (94T1295). The cyclization failed when a related substrate lacking the allyl group was subjected to the same reaction conditions. Sulfenamide 533 underwent a tandem 5-exo/6-endo-trig cyclization to give indolizidine 534 in 64% yield. Substrates that would require a 6-endo/5-exo cascade to form the indolizidine skeleton (i.e. 535) failed to cyclize under the radical conditions. 

Cyclizations. Indanes and indolines are readily formed by treatment of 3-butenylarenes and A-allylaniline derivatives with a stoichiometric amount of dilauroyl peroxide. Formation of a seven-membered ring adjoining an existing aromatic nucleus by radical cyclization of xanthate precursors has a useful scope. Several different functional groups inside the chain are tolerated. 

As a result of the large number of indole and indoline alkaloids present in the literature, many reports and reviews have emerged demonstrating the capabilities of radical cyclization to furnish fused indole structures [25-30]. 

Nicolaou [67, 68] and Fukase [69] have also reported the use of radical cyclization and solid phase methodology to synthesize indoline scaffolds and indol-2-ones. 

Similar radical cyclizations of other five-membered heterocycles such as furan and thiophene also yielded the expected spirooxindoles as the major product without any evidence of rearrangement [79, 80]. However, when the carboxamide group was substituted with an allyl group, i.e., 117b, cyclization of the initially formed aryl radical onto the allyl group generated the indoline 119 in 20% yield. 

In most of the examples outlined in this section, the radical cyclizations were accompanied by oxidation to re-establish the aromatic indole nucleus however, there are some cases where the 2,3-dihydroindoles (indolines) were isolated. It remains unclear which stmcmral features are required in order to facilitate this oxidation especially under reductive tributyltin hydride conditions. 

Pudlo M, Gerard S, Mirand C, Sapi J (2008) A tandem radical cyclization approach to 3-(2-oxopyrrolidin-3-yl)indolin-2-ones, potential intermediates toward complex indole-hetero-cycles. Tetrahedron Lett 49 1066-1070... 

Gribble described a novel radical cyclization of 2-bromoindole-3-carboxamides 160 lo provide a synthesis of hexahydropyrrolo(3,4-h]indoles <01CC805>. It is believed that the reaction involves the sequence (1) generation of the expected indole C-2 radical, (2) 1,5-H atom abstraction to give the a-amidoyl radical, (3), S-endo-trig cyclization to the indole C-2 position, and (4) hydrogen abstraction to give indoline 161. 

An unprecedented domino radical cyclization/Smiles rearrangement process of 175 to give 3-(2-aryl-N-methylacetamido)indolin-2-ones 178 or 180 was reported by Gerard, Sapi, et al. [63] (Scheme 5.38). The reaction proceeds via a 5-exo-trig cyclization followed by radical substitution. The radical intermediate 177, formed via the radicals A and 176, could undergo either a normal termination of a radical to form product 178 in 11-66% yields or an additional amidyl radical cyclization, giving the product 180 in up to 40% yield depending on the reaction conditions. 

More recently, elegant mechanistic studies on intramolecular Meer-wein reactions by Beckwith et al. considerably extended the utility of diazonium salts. They showed that many electron donors could convert an arenediazonium cation into an aryl radical which cyclized in good yield to form dihydrobenzofurans and indolines. The final radical was functionalized as a halide, sulfide, or ferrocene. Thus, the credentials of diazonium salts as electron acceptors were well established, and the stage was set to investigate the interaction between diazonium salts and TTF. 

Cyclization. Allyl o-iodoaryl ethers, A7,Al-diallyl-2-iodoaniline, and related compounds furnish dihydrobenzofuran and indoline products via radical intermediates on reaction with Bu,MnLi. 

Cyclizations. ALDiphenyhnethylene derivatives of obromoarylethylamines form aryl radicals that add to the nitrogen atom to give indolines. ... 

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. 

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