Indolines, preparation

K. Matsui and S. Yoshida, Photochromic film of 6-nitro-r,3, 3 -trimethylspiro[2/7-l-benzopyran-2,2 -indoline] prepared by plasma polymerization, J. Appl. Phys., 64, 2607-2610 (1988). 

Buchwald quickly parlayed this transformation into a versatile indole synthesis via oxidation of intermediate indolines prepared using the above intramolecular Buchwald-Hartwig amination. Variations leading directly to indoles and related nitrogen-containing heterocycles quickly followed and are described below. 

The stronger directing effects present in the indoline ring can sometimes be used to advantage to prepare C-substituted indoles. The aniline type of nitrogen present in indoline favours 5,7-substitution. After the substituent is introduced the indoline ring can be aromatized by dehydrogenation (see Section 15.2 for further discussion). A procedure for 7-acylation of indoline... 

Friedel-Crafts acylation of 3,3-dimethyl-2-indolinone by succinic anhydride gives 3,3-dimethyl-5-(3-catboxyptopionyl)-2-indoline, which is used as an intermediate in the preparation of inotropic agents for treatment of heart failure (94). Antibacterial phlotophenone derivatives have been prepared by Friedel-Crafts acylation with ptopanoyl chlotide (95). 

The reaction of methane tricarboxylate with indoline 342 gave the tricyclic derivative 361 which can be transformed to the amide derivatives 362 (97JHC969). Alkylation of the iV-benzyl indoline 360 with pentafluor-oacetone gave 363 which upon debenzylation and subsequent acylation with diketene followed by cyclization gave 364. Other haloacetones were used to prepare different halogenated derivatives (79BEP872311) (Scheme 63). 

Heterocyclic systems, such as the substituted indoline illustrated below,13 may also be constructed via cyclization of unsaturated organolithiums and a recent review of the preparation of nitrogen- and oxygen-containing heterocycles via this approach is available.14... 

Spiro-(indoline-isoxazolidines) 137, exhibiting interesting biological activities, were prepared in modest yields, by the cycloaddition reaction between ethyl (3-indolylidene)-acetate 135 and various substituted a,N-diphenylnitrones 136 under solvent-free conditions (Scheme 48). The reaction conducted under conventional heating in an oil bath did not proceed even after 20 h, especially when it was carried out without solvent [87]. 

Scheme 1.21 Enzymatic preparation of enantiomerically pure indolines.

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... 

Over the years, many spiropyran structures have been prepared. The pyran component consists of benzopyran or naphthopyran and the heterocyclic part consists of indoline, benzothiazoline, benzoxazoline, benzoselen-azoline, phenanthridine, acridine, quinoline, benzopyran, naphthopyran, xanthene, benzodithiole, benzoxathiole, and saturated heterocyclic rings such as pyrolidine and thiazolidine. 

Fischer s base, a typical starting material, is commercially available and is also obtained in situ from the corresponding quaternary salt, substituted indolines 4 can be prepared by TV-alkylation of 2,3,3-trimethyl-3//-indole followed by alkali treatment, or by exhaustive alkylation of 2,3-dimethylindole (N- and C-alkylation) followed by alkali treatment (Scheme 3). Further, methylation of indoline 5 with methyl iodide leads to C-methylation on the methylene group or the Plancher rearrange-... 

A rich family of diazaphospholes 260-262 having hcxahydro- l//-pyrrolo [l,2-c][l, 3, 2]diazaphosphole backbone was readily prepared by the reaction of phenylphosphorodichloridite or another P(III) precursor with anilides of (iS )-proline, (S)-pyroglutamic acid, and (S)-indoline carboxylic acid in high yields diastereoselectively [95],... 

Pyrano[3,2 ]indolizines such as 120 can be prepared from the reaction of N-( 1 -benzotriazolylmethyl)indolines with 3,4-dihydro-2//-pyran under acidic or Lewis-acidic conditions (Equation 26) <2001T4933>, and a simpler analogue 122 is the end product of an annulation process starting from the enamine 121 and ethyl acrylate <1996H(43)1391> (Scheme 34). Pyrano[4,3-/]indolizinetriones, for example, 124, result from the hydrolysis of protected 2,3-dihydro-l//-indolizincdioncs 123 (Equation 27) <2000H(53)771>. 

A number of novel spiro heterocycles, including the triazepinethione 146 have been derived from 3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one 145 by condensation with active methylene compounds <00SC1257>. A condensation process was also used to prepare tricyclic triazepinones related to the non-nucleoside reverse transcriptase inhibitor nevirapine <00JHC1539>. 

A series of diamine amides based on the phenoxypropyl amine scaffold was reported. Amide 26 displayed an hH3 Ki of 1 nM and was selective versus other histamine receptors [73]. The chirality was removed via cyclic diamines to produce tetrahydroisoquinolines, tetrahydroquinolines, benzazepines and indolines [74]. The benzazepine 27 displayed picomolar hH3 binding affinity. Pharmacokinetic issues were also identified with this diamine series, with i.v. half-lives of 10-12 h in the rat. A strategy to remove the diamine skeleton and prepare new H3... 

Snieckus described short syntheses of ungerimine (121) and hippadine by Suzuki couplings of boronic acid 118 with 7-bromo-5-(methylsulfonyloxy)indoline (116) and 7-iodoindoline (117), respectively [130]. Cyclization and aerial oxidation also occur. Treatment of 119 with Red-Al gave ungerimine (121) in 54% yield, and oxidation of 120 with DDQ afforded hippadine in 90% yield. Indoline 116 was readily synthesized from 5-hydroxyindole in 65% overall yield by mesylation, reduction of the indole double bond, and bromination. Indoline 117 was prepared in 67% yield from N-acetylindoline by thallation-iodination and basic hydrolysis. 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

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]. 

This acylating agent has also been used in the resolution of indolines see Gotor-Fernandez, V., Rebolledo, F. and Gotor, V., Chemoenzymatic preparation of optically active secondary amines a new efficient route to enantiomerically pure indolines. Tetrahedron Lett., 2006,17, 2558. 

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. 

A related approach, developed almost simultaneously by Neuss and co-workers at Eli Lilly (25) and by Kutney et al. in Vancouver (26), utilized as coupling substrate the chloroindoline alkene 17, which, through equilibrium with the corresponding chloroindolenine, was readily prepared by chlorination of dihydrocleavamine 18. Condensation with the 17-deacetyl-16-carboxyhydrazide derivative of vindoline (19) gave a binary indole-indoline product (20) (Scheme 4). The undesired C-16 con-... 

That only the wrong C-16 diastereomer seemed to be produced in this reaction was then demonstrated by the Kutney group, who prepared a series of binary indole-indoline alkaloids using the chloroindolenine approach. The apparent simplicity of this coupling reaction and the rapidity in assembling such binary alkaloids prompted an extensive study of reaction conditions (28), with the desire to find a procedure suitable for generation of the C-16 (S) isomer, required for anticancer activity. Despite the intensive effort involved in this in-depth study, no success could be realized, and it was therefore widely accepted that .. . it is very unlikely that any natural dimer could be obtained in this way (7). At this point it may be noted, however, that we were able to show subsequently that the desired C-16 -C-14 PARF relative stereochemistry can be obtained as a preferential result, albeit only in very low yield [3.6% PARF versus 2.1% PREF (priority reflective)], when the chloroindolenine reaction with vindoline is initiated with silver tetrafluoroborate (13). 

The real breakthrough toward synthesis of vinblastine and, in fact, the first significant laboratory preparation of binary indole-indoline alkaloids with the natural C-16 -C14 PARF configuration, was due to the work of the Potier-Langlois team at Gif (38,39 for reviews, see Refs. 40 and 41), buttressed by results obtained by the Kutney group in Vancouver (42,43,44), and the efforts of Atta-ur-Rahman and associates in Karachi. Their basic idea, which relied on the biogenetic consideration that binary indole-indoline alkaloids are formed in plants by the union of vindoline... 

Kita has introduced a novel one-pot preparation of 5-methoxylated indoline 55 and indole 56 derivatives by intermolecular addition followed by cyclization between A-tosylaniline derivatives 53 and activated olefins 54 using phenyliodine(III) bis(trifluoroacetate) (FIFA) <99H511785>. In the reaction of 53 with phenyl vinyl sulfides, indoles were produced directly by the spontaneous elimination of thiophenol. 

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