2- substituted indolin-3-ones

An aza-analogue of the functionalized dihydrocoumarin 2b, the 3-benzyl-3,4-dihydro-1 //-quinolin-2-one 8b, and its five-membered analogue, a substituted indolin-2-one 8a, were synthesized (Fig. 11.6). 

Alkylation of 8-(un)substituted-10,10,10a-trimethyl-1,2,3,4,10-1 Oa-hexahydro-pyrimido[l,2-a]indol-2-ones (46) gave (unlike the five-membered ring case) chiefly the O-ethers (47), and gave them exclusively when triethyloxonium fluoroborate was the alkylating agent. Upon treatment with acid, these similarly gave the 1-alkoxy-carbonylethyl-2-methylene-3,3-dimethyl-5-substituted indolines (45, n = 2).50... 

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 cascade sequence that affords bicyclic systems fails with the lithium derivatives of 2-bromo-iV,iV-diallylaniline. The methodology is useful for the synthesis of 3-substituted indolines and indoles, but the substrate undergoes only one anionic cyclization. Alkenyl vinyllithiums and alkenyl aryllithiums have also been employed in the preparation of alkylidenecyclopentanes and indanes. The intramolecular addition of vinyllithium reagents... 

Karp, G. M., Condon, M. E. Preparation and alkylation of regioisomeric tetrahydrophthalamide-substituted indolin-2(3H)-ones. J. 

A number of interesting one-pot or two-pot sequences of Pdarylation processes [14]. For example, a two flask sequence of Negishi coupling followed by intramolecular C—N bond formation has been employed for the synthesis of substituted indolines (Eq. (1.4)) [14a]. Lautens has recently described an elegant one-flask sequence of intermolecular C H bond functionalization followed by intramolecular N-arylation for the preparation of substituted indolines [14b]. As shown below (Eq. (1.5)), the Pd-catalyzed coupling of 2-iodotoluene with 2-bromopropylamine 5 in the presence of norbornene provided indoline 6 in 55% yield. 

Jin, H., Zhou, B., Wu, Z., Shen, Y., and Wang, Y. (2011). One-pot synthesis of substituted indolines via a copper-catalyzed sequential multicomponent/C-N coupling reaction. Tetrahedron Lett., 67, 1178-1182. 

The same strategy has been employed successfully for the KR of mono-2- or mono-3-substituted indolines [214] and 2,3-disubstituted indolines [215] using CAL-A or CAL-B (Figure 9.30). Similarly, cyclic a-amino esters derived from the 2,3-dihydroindole and octahydroindole cores have also been resolved successfully using allyl carbonates and CAL-A, attaining excellent selectivity and conversion values [216]. Although less explored, complementary hydrolytic processes have also been reported, as, for instance, Ostaszewski and coworkers used "homemade" animal liver acetone powders for the KR of 2-acetyl-4-phenyl-l,4-dihy-dro-2H-isoquinolin-3-one [217]. 

Aromatization of indolines is important in completing synthetic sequences in which the directive effects of the indoline ring have been used to achieve selective carbocyclic substitution[l]. Several methods for aromatization have been developed and some of these are illustrated in Table 15.2. A range of reagents is represented. One type of procedure represents use of oxidants which are known to convert amines to imines. Aromatization then provides the indole. Such reagents must not subsequently oxidize the indole. Mereuric acetate (Entry 1) is known to oxidize other types of amines and presumably reacts by an oxidative deprotonation ot- to the complexed nitrogen. 

The extension of the use of lactams to include indolin-2-ones provides a Vilsmeier-type methodology for the construction of biindolyl systems, which are of considerable current interest.37,39-43 In this situation, the initially formed imines are indolenines, which readily isomerize to the related 2-indolyl derivatives.43 In view of our general interest in activated indoles, as well as a specific interest in continuing to synthesize structures containing indoles directly linked to each other, we investigated not only reactions with indolinone itself but also with substituted derivatives. These were variously methoxy-substituted at C-4 and C-6, and in some cases substituted also at C-3 with methyl, phenyl, or dithiolan groups. 

The Fischer indole synthesis. The Fischer acid-catalyzed conversion of an 7V-arylhydrazone 42 into an indole is one of the most powerful and versatile methods for the preparation of indoles . The mechanism involves a [3,3] sigmatropic Claisen-type rearrangement of a protonated enehydrazine tautomer 43 to give intermediate 44, which spontaneously cyclizes by loss of ammonia, probably via indoline 45, to an indole 46 (Scheme 27). For unsymmetrical ketones, two isomeric indoles are possible and the general result is that the indole derived from the more stable (usually the more highly substituted) enehydrazine is formed. 

Quite early in the chemical studies of Wieland and King, evidence accumulated that the calabash curare alkaloids are indole derivatives, and with present knowledge it is possible to correlate the UV-spectra of many of them with one or another of the following related chromo-phores formally derived from the indole nucleus by oxidation, reduction, and substitution, or combinations of these processes. They are the indoline (II), 2-hydroxyindoline and the derived ethers (III), iV-hydroxy-alkylindoline and its ethers (IV), 2-methyleneindoline or 1-vinylindoline (Va or Vb, respectively), indole (VI), oxindole or 1-acylindoline (Vila or Vllb, respectively), -indoxyl (VIII), and /J-carbolinium (IX) systems it is not possible to distinguish with certainty by spectroscopic methods between the chromophores III and IV, between Va and Vb, or between Vila and Vllb. 

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