Oxindole alkylation

Organometallic compounds asymmetric catalysis, 11, 255 chiral auxiliaries, 266 enantioselectivity, 255 see also specific compounds Organozinc chemistry, 260 amino alcohols, 261, 355 chirality amplification, 273 efficiency origins, 273 ligand acceleration, 260 molecular structures, 276 reaction mechanism, 269 transition state models, 264 turnover-limiting step, 271 Orthohydroxylation, naphthol, 230 Osmium, olefin dihydroxylation, 150 Oxametallacycle intermediates, 150, 152 Oxazaborolidines, 134 Oxazoline, 356 Oxidation amines, 155 olefins, 137, 150 reduction, 5 sulfides, 155 Oxidative addition, 5 amine isomerization, 111 hydrogen molecule, 16 Oxidative dimerization, chiral phenols, 287 Oximes, borane reduction, 135 Oxindole alkylation, 338 Oxiranes, enantioselective synthesis, 137, 289, 326, 333, 349, 361 Oxonium polymerization, 332 Oxo process, 162 Oxovanadium complexes, 220 Oxygenation, C—H bonds, 149... 

Of the five alkaloids with known structures, physostigmine (1), esera-mine (3), and physovenine (4) have been synthesized 1-4). Since the conversion of physostigmine (1), a principal alkaloid, to physovenine (4) (6) and geneserine (S) 7,8) has also been established, synthesis of the former implies acquisition of the latter two alkaloids in a formal sense. Up to 1970, the synthesis of geneserine (5) was not reported because its structure had been considered to be the /V-oxide of physostigmine (1) until 1969 9-II) since its first isolation in 1915 (72), The four approaches to the synthesis of physostigmine (1) may be classified into four types based on the key step employed (i) the Fischer indolization route, (ii) the indole alkylation route, (iii) the oxindole alkylation route [including synthesis of physovenine (4)], and (iv) the oxidative indolization route 1-4) (Scheme I). 

Improved syntheses based on classical routes such as the Fischer indolization route and the oxindole alkylation route have also been reported. The former could provide substantial amounts of the racemic alkaloids, while the latter made possible the practical production of both the natural and the unnatural enantiomers of the alkaloids with the development of a highly efficient method for resolving the racemic intermediate. The latter may be particularly interesting from the pharma-... 

Scheme 86 Phase-transfer catalyzed oxindole alkylation...

Another indole/oxindole synthesis achieves the critical ortho-substitution by Sommelet-Hauser rearrangement of an anilinosiilfonium ion intermediate. Use of P-thioketones (G = R, an alkyl group) generates 2-substituted indoles, whereas P-thioesters (G = OR) lead to oxindoles. In each case, a 3-thio substituent must be removed by desulfuri2ation. 

The mechanism of the rearrangement is explained as shown in Scheme 19. Protonation of the 9-hydroxy group followed by its elimination and subsequent chloride attack at the 4a-carbon generates a chloroindolenine 126. Addition of water to the 9a-imine carbon atom of 126 gives 127. Concerted elimination of the chloride with rearrangement of the alkyl side chain attached to the 9a carbon atom results in 3,3-disubstituted oxindole structure 120a. 

Although geneologically related to indoles, the dihydroindoles behave chemically rather like alkyl anilines. When diphenylamine reacts with chloro-propionyl chloride, amide 40 results this in turn readily cyclizes to oxindole 41. Sodium hydride followed by 2-chloroethyldimethylamine alkylates the 3-position (possibly through an intermediate aziridinium ion) partial demethylation is accomplished by refluxing with ethylchiorocarbonate, followed by hydrolysis of the intermediate carbamate to give indolinone 42, the antidepressant amedalin Repetition of this sequence on the chloropropyl homologue, followed by reduction of the appropriate indolinone produces dihydroindole 43, daledalin, which also has antidepressant activity. ... 

Activated A-alkyl-O-acylhydroxamic acid derivatives 75 undergo base catalysed rearrangement to give 2-acyloxyamides 76 in good to excellent yields (50-100%) (equation 26). These precursors of 2-hydroxy amides (77) are good intermediates to prepare ethanol-amines, oxindoles and oxazolidinediones. 

Other important compounds include oxindole, which is the lactam of 2-aminophenylacetic acid. This compound has an active methylene group, which can be deprotonated with a base such as sodium ethoxide, and the anion that is formed can be alkylated with- a variety of electrophiles (Scheme 7.20). In the case of benzaldehydes, the initially formed aldols are unstable and these dehydrate readily to the corresponding (E)- and (Z)-(benzy lidene)oxindoles. 

Trost and his co-workers succeeded in the allylic alkylation of prochiral carbon-centered nucleophiles in the presence of Trost s ligand 118 and obtained the corresponding allylated compounds with an excellent enantioselec-tivity. A variety of prochiral carbon-centered nucleophiles such as / -keto esters, a-substituted ketones, and 3-aryl oxindoles are available for this asymmetric reaction (Scheme jg) Il3,ll3a-ll3g Q jjg recently, highly enantioselective allylation of acyclic ketones such as acetophenone derivatives has been reported by Hou and his co-workers, Trost and and Stoltz and Behenna - (Scheme 18-1). On the other hand, Ito and Kuwano... 

Oxindole 89 was cleanly demethylated upon treatment with boron tribromide. The resulting oxindole 90 was subjected to the prenylation conditions, and the desired alkylated product 91 was obtained in 52% yield. The epoxidation/Lewis acid-mediated cyclization proved to be successful on this substrate. The epoxide product was directly treated with SnCl4 in THF to provided the desired 92. When oxindole 92 was treated with NaBHt (1.6 equivjand BF3 OEt2 (3.5 equiv) in THF, the desired 93 was obtained. The indole 93 was treated with TBDMSC1 and imidazole in DMF, to provide the required O-silylated indole, which was easily converted to the gramine 94 through the well known Mannich procedure. 

Oxindol (64) reacts at position 3 to give dialkylation with 2 mol of alkyl halide and a cycloaddition with an a,[Pg.195]

The base-catalyzed alkylation of oxindoles favors C-alkylation, and O-alkylation is observed with halides only for particularly favorable intramolecular alkylations (B-70MI30614). Triethyloxonium tetrafluoroborate, on the other hand, gives the O-alkylated... 

The cyclization of iV-allyl-o-haloanilines was adapted to the solid phase for both indoles 1.332, 333] and oxindoles [334], For.example, as illustrated below, a library of l-acyl-3-alkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332]. Zhang and Maryanoff used the Rink amide resin to prepare N-benzylindole-3-acetamides and related indoles via Heck cyclization [333J, and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of c-iodo-A -acryloylanilines [334]. This latter cyclization route to oxindoles is presented later in this section. 

Many early claims of having prepared simple 1-hydroxyindoles have proved to be unfounded, although the unusually stable l-hydroxy-2-phenylindole was obtained in 1895.1-Hydroxyindole itself polymerizes on attempted isolation, while O-acylation, O-alkylation, or the presence of substituents greatly stabilizes the molecule. One 1-hydroxyindole antibiotic has been identified and is the only 1-hydroxyindole derivative isolated from natural sources so far. In contrast, a substantial number of 1-methoxyindoles occurs in various plants, and some of these may inhibit tumor formation in mammals. The biochemistry of these compounds, which include 1-methoxy-indoles, -indolines and -2-oxindoles, has not been widely investigated and could be a very fruitful area for new research which might well lead to novel medicinal agents and other useful compounds. 

The 3-methylene group of l-methoxy-2-oxindole (163) is easily ionized to give a carbanion that undergoes well-known types of reactions with alkyl halides or activated olefins without loss of the methoxyl group (e.g. 

The lithium aluminum hydride reduction of l-acetyloxy-2-oxindole (287) gave a polymer, but that of the 1-methoxy analogue (288) yielded [78JCS(P1)1117] 1-methoxyindole. Application of this method (83H1797) led to a valuable synthesis of lespedamine 291. Alkylation of 288 by 1,2-dibromoethane and sodium hydride gave a 3,3-spiro derivative, which dimethylamine converted to 289. Reduction with lithium aluminum hydride now gave 290, as a mixture of isomers, which was dehydrated instantly by acid to 291 (see Section 1II,E). 

Again, enantioselectivity is sensitive to the a substituent R1 with Me or/trim-alkyl (entries 1-6 and 11) giving very high enantioselectivities under neutral conditions. Most notable, cyclization of 18.1c under neutral conditions in THF (rather than DMA) yielded oxindole 17.3a of 97% ee. Substrates with the bulky a substituents (18.1d,e) gave markedly lower enantioselectivities under both sets of conditions (entries 7-10). Enantioselectivity is less sensitive to the p substituent R2 as can be seen by comparison of cyclizations of substrates 18.1a-c (entries... 

Organocatalytic asymmetric alkylation methodology has also been efficiently applied in a practical multi-gram synthesis of pharmaceutically interesting, optically active (—)-physostigmine analogs [7]. In the presence of 15 mol% of the catalyst 13 alkylation of the oxindole substrate 12 with chloroacetonitrile furnished the desired product 14 in 83% yield and 73% ee (Scheme 3.3, Eq. 2). The counter-ion of the... 

Both 3-alkyl and 3-alkylideneoxindoles have been obtained by carbonylative cyclization of o-alkynylanilines. Carbonylation in the absence of a reducing agent gives the unsaturated oxindole while inclusion of water and Et, N leads to the alkyloxindoles. <95TL6243> Since there are now several reliable syntheses of o-alkylanilines this may be a practical route to oxindoles. 

When the substrate has no alkyl groups on N, the dianion formed by LDA in THF also reacts under irradiation to afford oxindoles in good yields. Photocyclization of 2-chloro-3-(A-methylacetamido)pyridine by means of KNH2 in liquid ammonia or LDA in THF gave azaoxindoles in good yields (62 and 83%, respectively)338. 

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