Indolines functionalization

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 . 

Fig. 17.5 First- and second-generation functionalized indoline scaffolds.

Hashmi et al. have developed a short and high-yielding synthetic approach towards functionalized indoline derivatives 227 following a reaction sequence that consists of a three-component aza-MBH reaction from furfural catalyzed by La(OTf)3 in combination with 3-HDQ, a simple sulfonamide propargylation and a gold-catalyzed cycloisomerization (Scheme 1.86). ... 

Smith, et al. developed an organocatalyzed 6n electrocyclization of benzaldi-mines, as precursors to 2-aza-pentadienyl anions, prepared in situ from anilines 248 and aldehydes 249, to give functionalized indolines in high yields and enantioselectivities, Scheme 3.80 [101],... 

Maciver EE, Thompson S, Smith MD (2009) Catalytic Asymmetric 6tt Electrocyclization Enantioselective Synthesis of Functionalized Indolines. Angew Chem Int Ed 48 9979... 

Reduction of indolenines with sodium and ethanol gives indolines. The pentachloropyr-role, obtained by chlorination of pyrrole with sulfuryl chloride at room temperature in anhydrous ether, was shown by spectroscopic methods to have an a-pyrrolenine (2H-pyrrole) structure (222). It is necessary, however, to postulate that it is in equilibrium with small but finite amounts of the isomeric /3-pyrrolenine form (3//-pyrrole 223), since pentachloropyrrole functions as a 2-aza- rather than as a 1-aza-butadiene in forming a cycloadduct (224) with styrene (80JOC435). Pentachloropyrrole acts as a dienophile in its reaction with cyclopentadiene via its ene moiety (81JOC3036). 

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). 

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. 

Larock extended this Pd-catalyzed diene heteroannulation to other dienes and anilines [399], including functionalized dienes leading to, for example, ketotetrahydrocarbazoles [400]. Back has employed 1-sulfonyl-l,3-dienes in this 2-vinylindoline synthesis [401], and the use of 1,3-dienes in constructing indolines has been adapted to the solid phase by Wang [402]. Interestingly, Larock has shown that the electronically-related vinylcyclopropanes undergo a similar cyclization with o-iodoanilines to form 2-vinylindolines, e.g., 310 [403, 404]. Vinylcyclobutane also reacts in a comparable manner. 

Reaction of the imine-indoline products 157 and 158 with potassium borohydride in acetic acid resulted in rupture of the C-3 -C-7 bond and reduction of the resulting imonium function (Scheme 45). While the initial C-I6 -C-14 PARF imine-indolines 157 and 158 can be isolated, they are less stable on silica gel chromatography than the corresponding l -vincad-ifformine-derived C-16 -C-14 PREF compounds 145, and consequently purification of the vindoline coupling products and separation of dia-stereomers were best carried out at the indole-indoline stage (162, 163). 

As mentioned in Section 1, molecules as complex as the indole-indoline binary alkaloids warrant an investigation of their critical stereochemistry, including the binary character, with respect to function. The activity profile of the epi C-16, C-14, C-20 -diastereomer of 20 -deoxy VBL is presented in Fig. 5a. The compound inhibits population growth only at micromolar potency, and it lacks detectable antimicrotubule activity. This profile is also typical of the diastereomers of VBL (vincovaline), and of the C-20 congeners examined to date, epideoxy VBL (2), and deoxydesethyl VBL (3). 

The structure-function relationship of the indole-indoline binary alkaloids was relegated to obscurity until the recent achievement of methodologies for their complete syntheses (see Chapter 2, this volume). Our work with C-20 congeners of VBL has established that the complex interactions between this molecule and tubulin or microtubules can be modified by structural alteration. The various, concentration-dependent reactions of VBL with the microtubule system in vitro are sensitive to subtle modifications at a single molecular locus. In addition, these reactions are distinctive on a mechanistic level as seen from the unique activity profiles of most of our C-20 alkyl congeners. At first light, we can look toward the future with secured optimism. 

The procedure has also been applied for the hydroxylation of aromatic amines. Aniline and its /V-alkyl-substimted derivatives show similar behavior under similar conditions to afford the meta-substi tuted aminophenols as the major hydroxylated product.627 Product formation was interpreted by the attack of protonated hydrogen peroxide on the anilinium ion protected by /V-protonation from oxidation or degradation. Indoles, indolines, and tetrahydroquinoline have also been successfully hydroxylated with H202 in HF-SbF5 with the hydroxyl group meta to the nitrogen function.559,628 Hydroxylation of tryptophane and tryptamine derivatives affords pretonine and serotonine derivatives in 42% and 38% yields, respectively.629... 

Thus, the N-protected indoline 211 (Scheme 33), on regiospecific metallation followed by bromination with dibromotetrafluoroethane provided the 7-bromoindoline 212. Removal of the urethane functionality and subsequent benzylation of the free amine formed, furnished the tertiary amine 213. Addition of oxazoline 214 derived from 2,4,5-trimethoxybenzaldehyde to the Grignard reagent prepared from 213, followed by acid hydrolysis of the resulting biaryl 215 afforded the 2-substituted isobutylbenzoate 216. Catalytic N-debenzylation of the methylester 217 obtained by transesterification of 216 yielded oxoassoanine (203). 

Fig. 5 Smart UV-responsive coating on silica nanoparticles with PNIPAM brushes functionalized with FRET donors, 4-(2-acryloyloxyethylamino)-7-nitro-2,l,3-benzoxadiazole (NBDAE), and photoswitchable acceptors, l -(2-methacryloxyethyl)-3, 3 -dimethyl-6-nitro-spiro(2//-l-benzo-pyran-2,2 -indoline) (SPMA). The UV radiation induces the change from colorless spiropyran derivatives in the outer part of the coating (7) to the fluorescent merocyanine form (2). Thus, FRET with the benzoxadiazole moieties in the inner part of the coating is enabled and the fluorescence color changes from green to red. By variation of the temperature and induction of a collapse of the PNIPAM chains (3), the FRET efficiency can be tuned (4). Reprinted, with permission, from [70], Copyright (2009) American Chemical Society...

Similarly, treatment of the 2,6-dibromo-4-methyl-(V,iV-diallylaniline 263 at — 78 °C with r-BuLi gave 264, which was used for the synthesis of indolines 265 functionalized in the 3 and 7 positions (Scheme 82)155. 

In this context, it has been observed that dilithio derivative 333 cyclizes in the presence of TMEDA to give a dilithiated indoline that may be differentially functionalized by sequential addition of electrophiles, affording 1,3-disubstituted indolines 334 (Scheme 86)147. This cyclization reaction also proceeds in an enantioselective way when it is carried out in the presence of the pseudoephedrine ligand 332a. However, (—)-sparteine is in this case not able to promote the carbolithiation step, showing that the substrate structure may have a pronounced effect on the ability of a given ligand to facilitate the cyclization reaction. 

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