Indolines intramolecular amination

Buchwald has developed a route to indolines by the Pd-catalyzed intramolecular amination of aryl halides <96T7525> and applied this method to the synthesis of natural products. Thus, cyclization of tetrahydroquinoline 70 provided 71 which was elaborated to a key intermediate in syntheses of damirones A and B and makuluvamine <96JA1028>. 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

Homolytic intramolecular amination allows the synthesis of tetrahydroquinoline 28 from the 3-phenyl-propylamine 27 (n = 2). The yield of indoline 30 is lower because the aminium cation radical 29 generated from A-chloro-2-phenethylamine 27 (n = 1) undergoes an easy jff-scission reaction to form the benzyl radical (Scheme 9). 

Buchwald had previously reported a novel route to indolines by the Pd-catalyzed intramolecular amination of aryl halides. The utility of this methodology was further demonstrated for the case of enantiomerically enriched amines with stereogenic centers adjacent to the nitrogen wherein cyclized products are obtained without erosion of enantiopurity <97JA8451>. For example, Pd2(DBA)3/P(o-tolyl)3 catalyzes the cyclization of 48 (96% ee) to the indoline 49 in high yield and without loss of enantiopurity. 

Reaction of the o-iodoaniline derivative 431 with 1,2-decadiene in the presence of the chiral bisoxazoline 433 as a ligand and Ag salt provided the indoline 432 with 80 % ee [164], Construction of indole skeletons was carried out by intramolecular carbopalladation of allenes followed by amination. The 7r-allylpalladium intermediate 435 was formed from o-iodoaniline derivative 434, and intramolecular amination afforded the indole 436 in 89 % yield [165]. 

Alternatively, the formation of five-, six- and seven-membered rings, such as indoline, quinoline, indolizidine and benzazepine derivatives obtained with [(SIPr)2Ni] by intramolecular amination of appropriated chloro-aromatic amines (Equation (10.7))." ... 

In 2012, Chen and coworkers developed the palladium-catalyzed intramolecular amination of C(sp )-H at y and 5 positions to synthesize a series of nitrogen-containing heterocycles [15], including azetidine (Scheme 2.11), pyrrolidines, and indolines. With the optimal conditions, using catalytic Pd(OAc)2, an oxidant (PhI(OAC)2, 2.5 equiv.) and an acid additive (AcOH) in toluene at llO C, Chen tested them on other picolinamide substrates bearing primary y-C(sp )-H bonds surprisingly, the seemingly unfavorable four-membered azetidine was obtained as the major product. It is possible that a Pd(IV) intermediate was formed via PhI(OAC)2 oxidation of the palladacycle intermediate because the subsequent C-N and C-O reductive elimination pathways would lead to the formation of the cyclized and acetoxylated product. It was also noteworthy that no P H elimination product was detected under the aforementioned reaction conditions. 

Scheme 32 Synthesis of 2-substituted indolines via ring opening of aziridines and subsequent Pd-catalyzed intramolecular amination...

Dineen and Michaelis reported a new method for synthesizing 2-substituted indolines. They prepared the amination substrates 90 via ring opening of aziridines with o-bromophenyl metal reagents, which were subjected to Pd(OAc)2/DPE-Phos-catalyzed intramolecular amination to afford enantiopure indolines 91 (Scheme 32) [65]. 

Conditions were found under which 2,4,6-trinitrostyrene adds nucleophiles (thio-phenol, aniline, and aliphatic amines) at the vinyl moiety to form the corresponding / -X-ethyl-2,4,6-trinitrobenzenes (X = PhS, PhNH, or R2N). In the reactions with primary aromatic amines, the initially formed adducts undergo an intramolecular replacement of the nitro group followed by aromatization of the indolines, giving rise to the corresponding A-substi Luted 4,6-dinitroindoles.219... 

Early examples of intramolecular aryl radical addition reactions to heteroatom containing multiple bonds included cyclizations on N=N and C=S moieties [52, 53]. Recently, cyclizations to imines have been used as part of a new enantio-selective approach to indolines (Scheme 8). In the first step of the sequence, the required ketimines 19 were obtained by phase-transfer catalyzed alkylation of 2-bromobenzyl bromides 20 with glycinyl imines 21 in the presence of a cincho-nidinium salt [54], Due to the favorable substitution pattern on the imine moiety of 19, the tributyltin hydride mediated radical cyclization to 22 occurred exclusively in the 5-exo mode. The indoline synthesis can therefore also be classified as a radical amination. 

Johnston and coworkers reported a base-free aryl amination method based on radical additions to azomethines through nonconventional addition pathways (equation 6)42,43. By this route, the aryl radical adds to nitrogen, rather than to the carbon of the ketimines. For example, the ketimine prepared from o-bromophenethylamine and acetophenone was subjected to tributylstannane and the radical initiator AIBN to give the corresponding indoline in 87% yield. The only side product observed was the directly reduced compound. The fact that only the intramolecular radical addition can afford the high yield limited its application in synthesis of other arylamines. 

Intramolecular addition reactions of arenes and aryl olefins with secondary and primary amines have proven to be of broader scope than the analogous reactions with tertiary amines. The intramolecular addition of nonconjugated o-allylanilines 51 to yield the 2-methylindolines 52 was reported by Koch-Pomeranz et al. in 1977. Intramolecular electron transfer from the singlet aniline to the ground state alkene followed by N-H proton transfer to the alkene terminal carbon was proposed to account for the regioselective formation of indolines. Proton transfer to the internal carbon would yield tetrahydroquinolines, which were... 

Buchwald quickly parlayed this transformation into a versatile indole synthesis via oxidation of intermediate indolines prepared using the above intramolecular Buchwald-Hartwig amination. Variations leading directly to indoles and related nitrogen-containing heterocycles quickly followed and are described below. 

In another approach for intramolecular 1,4-carboamination of 1,3-dienes an o-iodoaniline was employed as substrate. The use of an o-iodoaniline in the Pd(0)-catalyzed reaction with 1,3-dienes results in a cychzation in the second step (amine attack on the Tr-aUyl complex) with the formation of indohnes. "" This reaction was already described in 1986 by Dieck and was further developed by Larock. Recently, the reaction was apphed to l-sulfonyl-l,3-dienes, which afforded synthetically useful 2-(sulfonylvinyl)indolines 2... 

The arylation of aliphatic amines has been difficult under metal-free conditions, but intramolecular arylations using aminoalkyl-substituted iodonium salts to yield indolines were viable (Scheme 5b) [94]. The groups of Olofsson and Adolfsson recently accomplished a metal-free arylation of secondary amides at room temperature (Scheme 5c) [95], A chemoselectivity study revealed a substantial orthoeffect, allowing selective transfer of a TRIP moiety and providing access to sterically hindered tertiary amides that are inaccessible by metal-catalyzed arylations. 

The synthesis of nitrogen heterocycles has been achieved through variations of intramolecular imino-Nazarov cycUzations (Schemes 3.26 and 3.27) [26], A silver-catalyzed version of the reaction generated indolines in moderate to good yields from a range of functionalized aldehydes and secondary amines, while a gadolinium-promoted reaction afforded fused tetrahydroquinoline derivatives in moderate yields. 

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. 

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