Synthesis of Indolines

Recently, the synthesis of indoline derivatives from acetanilides and allylic alcohols was achieved via Rh-catalyzed ortho-C-H bond activation, alkene insertion, and subsequent reductive elimination (Eq. (5.16)) [12a]. Similarly, aryldiazene carboxylates reacted with alkenes to afford diverse 1-aminoindolines without any external oxidant (Eq. (5.17)) [12b]. 

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In the alternate mode of reaction, Zard now reports an expedient and versatile synthesis of indolines by the radical addition of a xanthate to an. AZ-allylanilide 78 (R = Ms, Ac) yielding an adduct 79 which upon further eiqiosure to peroxide generates a radical capable of cyciization onto the aromatic ring to produce foe indolines 80 <99TL2533>. 

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. 

The intramolecular Diels-Alder reaction of 1,2-diazines with an alkyne side chain provides a general synthesis of indolines. The reaction requires a high temperature (200-230°). The most satisfactory solvent is 1,3,5-triisopropylbenzene (b.p. 232-236°). Example ... 

Nicolaou [44-47] has pioneered the use of selenium linkers in soUd-phase synthesis. A selenium linker [44,45], cleaved under radical conditions, has been utilized in a cyclative-capture strategy for the soUd-phase synthesis of indolines (Scheme 61). Treatment of o-allylanihnes with selenenyl bromide resin in the presence of a Lewis acid results in cyclative-capture to give immobilized indoline 240. Further functionalization was then carried out prior... 

Moutrille C, Zard SZ (2004) A new approach for the ortho-substitution of anilines and for the synthesis of indolines. Tetrahedron Lett 45 4631-4634... 

Cossy and cowoikers [52] described a combination of a Mizoroki-Heck and a Suzuki reactiou usiug ynamides and boronic acids to give indole and 7-azaindole derivatives 88, and its application to the total synthesis of the isoindolobenzazepine alkaloid lennoxamine (89) [53]. Thus, reaction of 86 with 87 using Pd(OAc)2 as catalyst led to 88 in moderate to high yield. This strategy was also applied to the synthesis of indoline-based kinase inhibitors by Player and coworkers [54]. Moreover, it has been shown that a carbonylation... 

Although I do not cover the synthesis of indolines, oxin-doles, isatins, and azaindoles in this monograph, some excellent reviews on the synthesis of these indole analogues are available [241-243],... 

Scheme 12.68 Domino synthesis of indoline-spiro benzofurodiazepines.

Furthermore, alcohol and amine have been used as electrophiles in the enantio-selective alkylations of indoles using chiral phosphoric acid as catalyst [78]. In 2011, Yin and You [79] used racemic spiro-indolin-3-ones as substrates to realize the FCA reactions with electron-enriched arenes (indoles, pyrroles, dimethylamino phenols). Catalyzed by 5 mol% 8j, efficient synthesis of indolin-3-ones bearing chiral quaternary stereocenters was established in excellent yields and enantioselectivities (Scheme 9.23). 

A full account of the synthesis of indolin-2-ones and 1,4-dihydro-3(2H)-isoquinolinones by photoinduced cyclization of -acy1-o-chloroanillnes or N-acyl- -chlorobenzylamines has also... 

SCHEME 1.6 Solid-phase synthesis of indoline-like alkaloids. 

FIGURE 11.63 Library synthesis of indoline-derived tricyclic derivatives using a Mitsunobu approach. (From Arya, P. et al., A solid-phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsunobu approach, J. Am. Chem. Soc., 6, 65, 2004.)... 

Katayev D, Lariraiov E, Nakanishi M, Besnard C, Kiindig EP (2014) Palladium-N-heterocyclic carbene (NHC)-catalyzed asymmetric synthesis of indolines through regiodivergent C (sp3)-H activation scope and DFT study. Chem Eur J 20(46) 15021-15030... 

Cross-coupling carboamination reactions between allenes and 2-haloaniline derivatives or halogenated allylic amines have also been employed for the generation of substituted indolines, and use of an appropriate chiral catalyst for these transformations leads to formation of enantioenriched products [52]. For example, Larock has described the synthesis of indoline 56 via the Pd-catalyzed reaction of aryl iodide 54... 

Scheme 2.80 Pd-catal3 ed synthesis of indolines from 1,3-dienes and 2-iodoaniline.

SCHEME 1730 Synthesis of indolines and isoindolines via the metathesis cascade. (Adapted with permission from Ref. [10]. Copyright (2009) American Chemical Society). 

Scheme 8.60 Synthesis of indoline-3-carboxylic acid derivatives, as described by Sole and Serrano [108].

In a same area, an efficient and simple method for the enantioselective synthesis of indolines, isoindolines, tetrahydroquinolines and tetraisoquino-lines was achieved by means of the organocatalytic intramolecular aza-Michael reaction of the corresponding aniline and benzylamine derivatives. " This process was catalysed by a diarylprolinol silyl ether used in the presence of benzoic acid as an additive, which provided the Michael adducts in good yields and excellent enantioselectivities of up to 99% ee (Scheme 1.85). This methodology was applied to the synthesis of the biologically active tetra-hydroquinoline alkaloid (-l-)-angustureine. 

Hsieh J-C, Ebata S, Nakao Y, Hiyama T (2010) Asymmetric synthesis of indolines bearing a benzylic quaternary stereocenter through intramolecular arylcyanation of alkenes. Synlett 2010(11) 1709-1711. doi 10.1055/s-0029-1219964... 

Gilmore CD, Allan KM, Stoltz BM (2008) Orthogonal synthesis of indolines and isoquinolines via aryne annulation. J Am Chem Soc 130 1558-1559... 

SCHEME 26 Synthesis of indolines from arynes and N-Boc enamines [50]. 

The synthesis of indolines through an intramolecular C-H amination reaction has been reported (S cheme 3.65) [71 ]. The reaction was catalyzed by a common palladium compound and promoted by an iodme(lll) reagent. This catalyst system generated good to excellent yields of the heterocycles at 60 °C. 

A ruthenium-catalyzed intramolecular olefin hydrocarbamoylation for the regiodivergent synthesis of indolin-2-ones and 3,4 dihydroquinolin-2-ones was disclosed by Chang and coworkers (Eq. (7.3)) [8]. The reactions underwent smoothly without requiring external CO atmosphere. In the presence of combined catalysts of Ru3(CO)i2/Bu4NI, a 5-exo-type cyclization proceeds favorably to form indolin-2-ones as a major product in good to excellent yields in DMSO/toluene cosolvent (catalytic system A). When the reaction was conducted in the absence of halide additives in NAf-diniethylacetamide (DMA)/PhCl (catalytic system B), 3,4-dihydroquinolin-2-ones were obtained in major in moderate to high yields via a 6-endo cyclization process. An excellent level of regioselectivity was observed with a variety of substrates to deliver 5-exo- or 6-endo-cyclized lactams. 

Scheme 8.37 Cu(OAc)2-catalyzed synthesis of indoline-2,3-dione derivatives from secondary anilines and ethyl glyoxalate.

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