Indoline derivatives

Pd2(dba)3/l,4-bis(diphenylphosphino)butane (DPPB) in the presence of 2-mercaptobenzoic acid <95TL1267>. The Af-allylindolines can be easily oxidized to the corresponding indoles at room temperature with o-chloranil. Additionally, Al-allylanilines were also found to undergo aromatic 3-aza-Cope rearrangements in the presence of Zeolite catalysts to give indoline derivatives as the major product <96TL5281>. 

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... 

This indoline derivative has antihypertensive and diuretic actions. Indapamide (233) in methanol under nitrogen was irradiated with a medium-pressure mercury lamp through a copper sulphate filter solution for 12 h. The filter removed wavelengths below 300 nm. Products were separated by preparative TLC and identified as 2-methylindoline (234), the formylhydrazide (235), the amide (237) and semicarbazide. The procedure was repeated under oxygen to give the above products plus the urethane (236), acid (238), ester (239) and TV-acetylanthranilic acid [146]. 

More recently, an efficient transformation of 6-nitro-C-glycofuranosyl derivative 96 into indoline derivatives 99 and 100 has been reported. Treatment of 96 with a base (4% NaOMe or 1% K2C03 in MeOH) at room temperature produced nitro cyclohexanols 97 and 98, via (1-elimination followed by an intramolecular Michael addition (Scheme 31).71... 

Palladium complexes have been used for the electroreductive cycliza-tion of Ai-alkenyl-2-bromoanilines to the corresponding indoline derivatives (Scheme 69) [101]. The postulated carban-ion intermediate undergoes a reaction with the electrophiles (H+, CO2). 

Intramolecular C-N bond coupling in arylazides via C-H bond activation catalyzed by [Ir(COD)(OMe)]2 was recently reported [131]. The intermediate iridium nitrenoid complex (50) formed after the extrusion of dinitrogen is proposed as a reactive species, which can cleave the benzylic C-H bond to yield indoline derivatives (31). 

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. 

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 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 . 

The ene-reaction, which is mechanistically related to the Diels-Alder reaction, has also been reported. The thermal addition of 3-ferf-butoxycarbonyl-2(3//)-oxazolone 236 to 2,2 -biindole 235 affords 4-(2,2 -biindol-3-yl)-2-oxazolidinone 237, probably via the indoline derivative. The product is further converted to the fused aromatic compound 238 by bromination with NBS and AIBN, followed by dehydrobromination (Fig. 5.58). ... 

Japanese workers reported in 1956 (J. Pharm. Soc. Jpn., 76, 966 (1956)) that phosphorus trichloride-catalysed cyclisation of A-(3,4-dimethoxyphenylacetyl)tryptamine in boiling benzene gave the expected dihydro-p-carboline derivative. A recent reinvestigation of this reaction, however, showed that the major product, formed in 46% yield, is in fact the spirocyclic indoline derivative 1. When TFAA in benzene was used for the cyclisation, the indoline 2 was obtained in quantitative yield. 

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. 

This reaction was exploited by Pass, Amit and Patchornik to directly couple two peptide fragments (Scheme 13.30) [117]. However, one of the main issues to date has been the preparation of such activable amino acids. Two approaches (which, unfortunately, are limited in their scope) are nitration of the parent indoline derivative after acylation with the amino acid, or use of the amino acid chloride prepared in situ. 

S.-R. Keum and K.-W. Lee, Unusual solvatochromic behavior of the open-chain merocyanine forms of 5-chlorinated l,3,3-spiro(2/7-l-benzo-2,2 -indoline) derivatives, Bull. Korean Chem. Soc., 14, 16-18 (1993). 

S.-R. Keum, K.-B. Lee, P. M. Kazmaier, and E, Buncel, A novel method for measurement of the merocyanine-spiropyran interconversion in nonactivated l,3,3-trimethylspiro(2/7-l-benzopyran-2,2 -indoline) derivatives, Tetrahedron Lett., 35, 1015-1018 (1994). 

Furthermore, Pd-catalyzed aminations can be sequentially coupled with alkene insertion and amination. Wolfe and Lira [102] have established a transformation involving two different sequential metal-catalyzed reactions that lead to AT-aryl-2-benzylindolines 125 in moderate to excellent yields upon formation of two C - N bonds and one C - C bond in a one-pot process (Scheme 45). Interestingly, the selective installation of two different aryl groups in this sequence can be accomplished by in situ modification of the Pd catalyst system Pd-126 upon addition of the chelating ligand dpephos prior to addition of the second aryl bromide (Scheme 46). The selectively substituted indoline derivatives 127 were isolated in good to excellent yields. 

The limited amount of experimental work that has been carried out recently on akuammine shows that its behavior is exactly analogous to that of pseudoakuammigine (49). Thus, the UV-spectrum of 0-methyl-akuammine in neutral and in dilute acid solution is typical of an indoline derivative a marked bathochromic shift is observed in concentrated hydrochloric acid, and the spectrum is now characteristic of the 3-H-indolium ion. The recovery of O-methylakuammine from this solution shows that no rearrangement of the molecule has occurred, and suggests further that the readily reformed carbinolamine ether ring is five- or six-membered. 

This chapter has illustrated the numerous advances made toward identifying selective PDE inhibitors. Despite the heterogeneity that may appear at first glance, several common structural features have become clear. The majority of compounds can be grouped into families of common substructures that address conserved features of the PDE active site. Most notably, the substrate-like cGMP-PDE5 inhibitors, the structurally unrelated indoline derivatives, and the cAMP-PDE4... 

Tetrahydrocarbazoles and related fused systems have been accessed by a route relying on palladium-catalyzed tandem formation of alkenyl and aryl C-N bonds. For instance, the starting triflate 477 could be efficiently transformed into the target system 478 by amination with aniline (Equation 133) <2005AGE403>. Annulation of (2-triflyloxy)phenethyl carbonates with amides in the presence of a palladium catalyst has been used as a route to various N-substituted indoline derivatives <2005OL4777>. 

The preparation of stereospecific indoline derivatives was also provided by the author as illustrated in Eq. 2 ... 

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