Indoline derivatives, synthesis

The strategies used in the synthesis of polymethine dyes are illustrated for a series of indoline derivatives in Scheme 6.1. There is an even wider range of synthetic routes to polymethine dyes than is described here, but they are based for the most part on a similar set of principles. The starting material for the synthesis of this group of polymethine dyes is invariably 2-methylene-1,3,3-trimethylindolenine (121), known universally as Fischer s base. As illustrated in the scheme, compound 121 may be converted by formylation using phosphoryl chloride and dimethylformamide into compound 122, referred to as Fischer s aldehyde, which is also a useful starting material for this series of polymethine dyes. When compound 121 (2 mol) is heated with triethylorthoformate (1 mol) in the presence of a base such as pyridine, the symmetrical cyanine dye, C. I. Basic Red 12 109 is formed. The synthesis of some hemicyanines may be achieved by... 

Miscellaneous Iminium Catalyzed Transformations The enantioselective construction of three-membered hetero- or carbocyclic ring systems is an important objective for practitioners of chemical synthesis in academic and industrial settings. To date, important advances have been made in the iminium activation realm, which enable asymmetric entry to a-formyl cyclopropanes and epoxides. In terms of cyclopropane synthesis, a new class of iminium catalyst has been introduced, providing the enantioselective stepwise [2 + 1] union of sulfonium ylides and ot,p-unsaturated aldehydes.As shown in Scheme 11.6a, the zwitterionic hydro-indoline-derived catalyst (19) enables both iminium geometry control and directed electrostatic activation of sulfonium ylides in proximity to the incipient iminium reaction partner. This combination of geometric and stereoelectronic effects has been proposed as being essential for enantio- and diastereocontrol in forming two of the three cyclopropyl bonds. 

The major isomer 34 is desilylated with TBAF, and oxidative cleavage of the diol with sodium periodate generates the corresponding aldehyde 35, the racemic form of which is a known intermediate in the total synthesis of racemic CP compounds. The conversion to the indoline derivative mt-31 therefore follows the strategy of the racemic route. Circular dichroism (CD) spectroscopy verified the identity of the synthetic mt-31 as the enantiomer of the naturally derived indoline (—)-31. Synthetic ent-31 was also processed to give ent-1 and ent-2. 

Geissoschizoline [= pereirine (106)] is an indoline derivative with a Strychnos carbon keleton. The complete structure was elucidated by partial synthesis from (—)-akuammicine (117) the latter on reduction with zinc and acid forms 2/ ,16jS-dihydroakuammicine which on lithium aluminium hydride reduction followed by catalytic hydrogenation gives geissoschizoline (106). The base can also be obtained by degradation of the strychnine derivative (1IS). " ... 

A synthesis (Scheme 3) of the perhydrocyclopenta[c,d]indoline derivative (66), which represents the skeleton of dendrobine (43 R = H), has been reported.72 Condensation of carvotanacetone (61) with butadiene gave the adduct (62) which was converted into the ring-contracted product (63) using a well-known reaction sequence. The latter was readily transformed to a stereoisomeric mixture of... 

Oxidation of 3,3-disubstituted indoline derivatives (121) with 5 equiv of H202 H2NC0NH2 complex in the presence of a catalytic amount of Na2W04 (82b) also affords the A a-hydroxyoxindole derivatives (118) in moderate yield (84a). By applying this procedure, the synthesis of a new humantenine-type alkaloid, 20-hydroxydihydrorankinidine (26), starting from ajmaline (66) was achieved (84b). 

This methodology with some variations has been utilized in the synthesis of numerous heterocyclic systems, such as heterocycle-fused quinolinone derivatives [391], l,4-benzodiazepin-2-ones [392], benzo-, naphtho- and heterocycle-fused pyrrolo[2,l-c][l,4]diazepines [393], quinolinone or pyrrolidinone derivatives [394], dibenzo[fl,c]phenanthridines [395], thiazolo-fused quinolinones [396], isoindolinone and isoquinolin-2-one derivatives [397], indoline derivatives [398], 5-aroyl-pyrrolidinones [399,400], indazolone derivatives [401,402], substituted indolizidinones [403], 1-arylpyrrolopyrazinones [404], stmcturally diverse... 

As described in the definition of Buchwald indoline synthesis, this reaction involves the formation of a zirconocene-stabilized benzyne complex that intramolecularly inserts to an A-allyl group to give a tricyclic indoline zirconacycle. In the presence of oxidating reagent or electrophiles, the indoline zirconacycle decomposes into indoline derivatives. ... 

This reaction has general application for the synthesis of indole and indoline derivatives. 

FIGURE 11.63 Library synthesis of indoline-derived tricyclic derivatives using a Mitsunobu approach. (From Arya, P. et al., A solid-phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsunobu approach, J. Am. Chem. Soc., 6, 65, 2004.)... 

Additionally, the intramolecular cyclization of 2-halo-AT-allylanilines provides optional proeedures for indole derivative synthesis. Many transition metal eatalysts have been developed in this field, such as cobalt, nickel and palladium, but stoichiometric amounts of catalysts are needed. In 1987, a eatalytie version was developed by Laroek and Babu. In the pres-enee of a eatal54ie amount of Pd(OAe)2, indoles, indolines, oxindoles, qui-nolones, isoquinolines and isoquinolones were formed in high yields in short reaetion times under mild temperatures (Seheme 2.106). 

Scheme 25 Synthesis of highly fused indoline derivatives...

Recently, the synthesis of indoline derivatives from acetanilides and allylic alcohols was achieved via Rh-catalyzed ortho-C-H bond activation, alkene insertion, and subsequent reductive elimination (Eq. (5.16)) [12a]. Similarly, aryldiazene carboxylates reacted with alkenes to afford diverse 1-aminoindolines without any external oxidant (Eq. (5.17)) [12b]. 

Julia s synthesis of lysergic acid 2 jj based on internal nucleophilic trapping of a benzyne intermediate in the ring C-seco intermediate (A). As in an earlier approach, the synthesis proceeds via indoline derivatives and formation of the indole nucleus is deferred until the very end. ... 

The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

An efficient chemoenzymatic route for the synthesis of optically active substituted indolines has been recently developed (Scheme 7.27), and also the alkoxycarbonyla-tion process is more efficient than the acylation reaction. Different lipases have been tested in the alkoxycarbonylation of these secondary amines, GALA being found to be the best biocatalyst for 2-substituted-indolines, and CALB for 3-methylindoline. The combination of lipases with a variety of allyl carbonates and TBME as solvent has allowed the isolation of the carbamate and amine derivatives in a high level of enantiopurity [51]. 

A few examples of the photocyclization of A,iV-diarylamines or related species have been applied to the synthesis of spirocyclic indoline precursors <96TL37> and carbazole derivatives <96SC657, 96JCS(P1)669>. 

In the course of our successful synthesis, we identified several limitations of our new method and associated strategy (1) the harsh conditions of the bicyclization reaction do not tolerate base-sensitive functionality such as vinyl halides (2) post-cyclization manipulations such as iododesilylation reactions are complicated by the sensitive/ reactive functionality of the products (a,p-unsaturated aldehyde, indoline, etc.) and (3) the incorporation of the required functionality into the Zincke aldehyde requires the synthesis of a complex tryptamine derivative, resulting in a lengthy, non-convergent route. In order to develop a concise route to strychnine, we would have to address each of these issues, and a straightforward solution to obviate all of these is described below. 

A novel procedure for the synthesis of an indole skeleton 81 was developed by Mori s group (Scheme 13).16e,16f Enantioselective allylic amination of 78 with A-sulfonated < r/ < -bromoaniline 79 followed by Heck cyclization of 80 provided chiral indoline 81. The treatment of a cyclohexenol derivative 78 with 79 in the presence of Pd2(dba)3-GHGl3 and ( )-BINAPO gave compound 80 with 84% ee in 75% yield. Total syntheses of (—)-tubifoline, (—)-dehydrotubifoline, and (—)-strychnine were achieved from compound 80. 

JPS 62,490(1973) gives an indoline synthesis which can be carried one step further (dehydrogenation described in this chapter) to give DMT derivatives. See JOC 41,1118(1976) for indoles from betaketosulfoxides. 

In addition, due to the proximity and inductive effect of the indoline nitrogen, a metalation strategy provides for a facile synthesis of 7-bromoindoline, as well as other 7-substituted indolines. Thus, Iwao and Kuraishi find that IV-Boc-indoline (22) is smoothly lithiated at C-7 to give 7-lithio 23. Quenching 23 with suitable electrophiles gives 7-haloindolines 24-26, and quenching with tri-n-butylstannyl chloride affords the corresponding tin derivative in 65% yield [31]. 

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