Substitution indolines

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... 

An efficient chemoenzymatic route for the synthesis of optically active substituted indolines has been recently developed (Scheme 7.27), and also the alkoxycarbonyla-tion process is more efficient than the acylation reaction. Different lipases have been tested in the alkoxycarbonylation of these secondary amines, GALA being found to be the best biocatalyst for 2-substituted-indolines, and CALB for 3-methylindoline. The combination of lipases with a variety of allyl carbonates and TBME as solvent has allowed the isolation of the carbamate and amine derivatives in a high level of enantiopurity [51]. 

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... 

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). 

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-... 

Substituent effects on the are remarkable. Electron-withdrawing groups at the 5 -position, e.g., 5 -nitro-substitution (indoline component), and donor substituent at the 8-position (benzothiopyran component) in 44 leads to a longer wavelength shift. As the polarity of the solvent increases, the max of the colored form of spiroindolinobenzothiopyran results in hypsochromic shift. This can be interpreted as the existence of a polar structural component of the colored form in the ground state. Kinetic study has suggested that the zwitterionic structure largely contributes to the colored form of 6-nitrospiroindolinobenzothiopyran, as well as spiropy-rans.97 Based on H-NMR and X-ray analysis,98 99 the existence of an... 

Methods for the enantioselective synthesis of 3-substituted indolines by means of the asymmetric intramolecular carbolithiation of 2-bromo-A,-allylanilines in the presence of (-)-sparteine were reported simultaneously by Bailey <00JA6787> and Groth <00JA6789>. Thus, addition of 89 to 2.2 equiv of /BuLi in the presence of the chiral ligand generates the lithium intermediate 90 which upon quenching with methanol affords the chiral indoline 91 in a process that is highly solvent dependent. 

In addition, due to the proximity and inductive effect of the indoline nitrogen, a metalation strategy provides for a facile synthesis of 7-bromoindoline, as well as other 7-substituted indolines. Thus, Iwao and Kuraishi find that IV-Boc-indoline (22) is smoothly lithiated at C-7 to give 7-lithio 23. Quenching 23 with suitable electrophiles gives 7-haloindolines 24-26, and quenching with tri-n-butylstannyl chloride affords the corresponding tin derivative in 65% yield [31]. 

Current studies43,44 show that a range of isatogens can now be prepared in good yield by the oxidation of 2-substituted 1-hydroxyindoles and 2-substituted indolines with perbenzoic acids. Until this work, 2-phenylisatogen was reported as only a minor product from a number of reactions of 2-phenylindole derivatives with a variety of oxidizing agents. 

The carbocyclic ring of substituted indolines can be constructed by intramolecular Diels-Alder reactions of 2-(Af-pent-3-ynylamino)pyridazines (Scheme 10) (84JOC2240). 

Scheme 22)87 The intramolecular 4 + 2-cycloaddition of ynamides with conjugated enynes produces substituted indolines that can be oxidized to indoles with o-chloranil.88 The double Diels-Alder cycloaddition of the linear conjugated tetraene... 

Recently Liu and coworkers used (porphyrin)iron(III) chloride complex 96 to promote 1,5-hydrogen transfer/SHi reactions of aryl azides 95, which provided indolines or tetrahydroquinolines 97 in 72-82% yield (Fig. 24) [148]. The reaction starts probably with the formation of iron nitrenoids 95A from 95. These diradicaloids undergo a 1,5- or 1,6-hydrogen transfer from the benzylic position of the ortho-side chain. The resulting benzylic radicals 95B react subsequently with the iron(IV) amide unit in an Sni reaction, which liberates the products 97 and regenerates the catalyst. /V,/V-Dialkyl-w// o-azidobenzamides reacted similarly in 63-83% yield. For hydroxy- or methoxy-substituted indolines 97 (R2=OH or OMe) elimination of water or methanol occurred from the initial products 97 under the reaction conditions giving indoles 98 in 74—78% yield. 

A stereoselective method for the synthesis of 2-substituted indolines 88 has been developed based on a sequence involving palladium-catalyzed coupling of zinc reagents... 

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... 

M. A. GaTbershtam, N. N. Artamonova, and N. P. Samoilova, Synthesis of 3 -acyl-substituted indoline spiropyrans, Chem. Heterocycl. Cpds., 1975, 167-172. 

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... 

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>. 

SYNTHESIS OF 7-SUBSTITUTED INDOLINES Via DIRECTED LITHIATION OF 1-(tert-BUTOXYCARBONYL)INDOLINE 7-IN DO LIN EC A R BOX ALDEHYDE... 

The procedure described here offers a general route to 7-substituted indolines.3 The method is based on the directed ortho-lithiation of N-(tert-butoxycarbonyl)aniline derivatives.4 The teri-butoxycarbonyl group seems to be essential for C-7 selective lithiation, since other directing groups so far reported promote C-2 metalation on the Indoline ring.5 The C-7 selective lithiation of 1-(tert-butoxycarbonyl)indoline is in contrast to the C-2 selective lithiation of 1-(tert-butoxycarbonyl)indole.6... 

Masatomo Iwao and Tsukasa Kuraishi 85 SYNTHESIS OF 7-SUBSTITUTED INDOLINES via DIRECTED LITHIATION OF l-(tert-BUTOXYCARBONYL)-INDOLINE 7-INDOLINECARBOX-ALDEHYDE... 

A series of 1-substituted indolines such as 79 has been synthesized via aryl radieal cyclizations of acetophenone imines 80, providing an enantioselective route to indoline a-amino acids <03JA163>. Aluminum chloride-induced cyclization of imine precursors derived by condensation of p-anisidine and a-phosphorylated-a-chloro aldehydes provided 3-phosphorylated 5-methoxyindoles <03CHE1521>. 

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

Heating of A-aryl-l-alkynesulfenamides 203 in benzene for 3 hours resulted in smooth transformation into the substituted indoline-2-thiones 204290 (equation 78). 

L. A. Ulanova, E. V. Pykhtina, andB. V Tolkachev, EPR spectra and re-electronic structure of anion radicals ofnitro-substituted indoline spiropyran, Khim. Geterotsikl. Soedin. 11,1477-1481 (1984) Chem. Abstr. 102, 112743a (1985). 

Synthesis of A-alkynyl-substituted indolines by Ti-catalyzed intermolecular hy-droamination of alkynes 04SL1653. 

The Pd-catalyzed coupling of substituted indoline 145 with diaryl-2,3-dicyanopy-... 

Other approaches to indoles based on transition metal-mediated couplings have been outlined in Sections 4.2.2 and 4.2.4. Nicolaou et al. recently described a novel solid-phase synthesis of substituted indolines and indoles [414]. 

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