3-allyl oxindole

In 2010, Dorta and coworkers [83] reported a new synthetic strategy to access functionalizable 3-allyl oxindoles bearing a chiral quaternary carbon stereocenter via a direct palladium-catalyzed a-arylation protocol. This elegant methodology, previously accessible only via a two-step procedure involving a Pd-catalyzed intramolecular a-arylation followed by an asymmetric Pd-catalyzed allylic alkylation [84], afforded impressive reactivities, and high chemoselectivities and enantioselectivities were also achieved in the synthesis of oxindoles using a new chiral Pd-NHC catalyst (Scheme 8.45). 

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

Trost and his co-workers succeeded in the allylic alkylation of prochiral carbon-centered nucleophiles in the presence of Trost s ligand 118 and obtained the corresponding allylated compounds with an excellent enantioselec-tivity. A variety of prochiral carbon-centered nucleophiles such as / -keto esters, a-substituted ketones, and 3-aryl oxindoles are available for this asymmetric reaction (Scheme jg) Il3,ll3a-ll3g Q jjg recently, highly enantioselective allylation of acyclic ketones such as acetophenone derivatives has been reported by Hou and his co-workers, Trost and and Stoltz and Behenna - (Scheme 18-1). On the other hand, Ito and Kuwano... 

In the event, formation of the enolatc of 18 using lithium hcxamethyldisilazide in THF at -78 "C followed by quenching with allyl bromide gave oxindole 19 in 88% yield, establishing the quaternary center at the C(3) position. Since the conversion from oxindole 19 to geneserine (20) was known [18], this constitutes a formal total synthesis of the natural product. 

When reacted with allyl/propargyl bromide in the presence of indium and sodium iodide, isatins undergo efficient allylation/propargylation to afford the corresponding 3-substituted 3-hydroxy-oxindoles (Scheme 50).206 Indium-mediated Barbier reaction of ninhydrin with benzyl bromide in DMF gives 45 and O-benzylated compound 46. Similarly, the reaction of isatin with allyl bromide affords 47 and 48.207... 

Chen and coworkers employed the cinchona alkaloid-derived catalyst 26 to direct Mannich additions of 3-methyloxindole 24 to the A-tosylimine 25 to afford the all-carbon quaternary center of oxindole 27 with good enantioselectivity (84% ee) [22]. The outcome of this Mannich reaction is notable in that it provided very good selectivity for the anti diastereomer (anti/syn 94 6). The mechanism of asymmetric induction has been suggested to involve a hydrogen bonding network between the cinchona alkaloid 26, the oxindole enolate of 24, and the imine electrophile 25 (Scheme 7). Asymmetric allylic alkylation of oxindoles with Morita-Baylis-Hillman carbonates has been reported by the same group [23]. 

An intermolecular cyclization approach to C3 asymmetric oxindoles has been devised by Smith and coworkers who paired chiral A-phenylnitrone nucleophiles with ketene electrophiles, e.g., intermolecular fusion of 54 and 55 [37]. As illustrated in Scheme 16, the oxindole skeleton 57 materialized in 87% ee following a proposed sequence of nitrone addition to the ketene, a hetero-Claisen rearrangement, imine hydrolysis and, finally, cyclization to generate the lactam linkage. As an extension of this methodology, (5)-3-allyl-3-phenyloxindole 57 was transformed into enantiopure 3-phenyl-hexahydropyrroloindole scaffold 58. 

Using molecular oxygen as the oxidizing agent, the Itoh group has achieved the enantioselective preparation of 3-allyl-3-hydroxyoxindole 90 (85% ee) under phase-transfer conditions with the cinchonidine derived catalyst 89 [54]. The oxindole 90 was further manipulated to a key intermediate that has been applied in a prior synthesis of the hexahydropyrroloindole CPC-1 [55] (Scheme 24). 

Silvani and coworkers have converted isatin to the chiral imines 94 and 97 that were employed as electrophiles for the diastereoselective addition of Grignard reagents [60]. As illustrated in Scheme 26, addition of allyl Grignard to 94 or 97 afforded the amino-substituted quaternary oxindoles 95 or 98 with good diastereos-electivity (80 20 and 89 11 dr, respectively). Grignard adducts 95 and 98 were further manipulated to afford the enantiomeric pair of 3-amino-3-allyloxindoles (5)-96 and (R)-99, respectively. 

The Kobayashi group has observed the intramolecular diastereoselective spirocyclization of racemic 2-haloindoles bearing a C3-tethered allylic alcohol [71, 72]. For example, CuCl-catalyzed intramolecular Ullmann coupling of 117 followed by spontaneous Claisen rearrangement of the intermediate pyranoindole 118 afforded, in a one-pot synthesis, the all-carbon quaternary center of spiro-oxindole 119 in 95% de (Scheme 31). The methodology has been extended to the synthesis of hexahydropyrroloindoles, e.g., ( )-debromoflustramine B and E. 

Chen et al. have found that commercially available modified cinchona alkaloids [(DHQD)2AQN] are outstanding catalysts for the asymmetric allylic alkylation (AAA) reaction of MBH carbonates with a,a-dicyanoolefins 268 or 3-substituted oxindoles 269. Enantioenriched compounds 270 and 271, respectively, with multifunctional frameworks bearing adjacent stereogenic centers were obtained in excellent stereoselectivities (Scheme 3.107). 

Shibata successfully adapted the asymmetric transfer fluorination to cyclic silyl enol ethers, cyclic allyl silanes and oxindoles, illustrated in Schemes 13.1-13.3, as a catalytic method (Scheme 13.6) [16]. Similar reaction conditions were identified for all three substrates, including the use of stoichiometric NFSI as the electrophilic fluorine source and a stoichiometric inorganic base additive. It was observed that bis-Cinchona alkaloid (DHQ)2PHAL was best for cyclic silyl enol ethers (X = 0), (DHQ)2PYR (Scheme 13.2) was best for cyclic allyl silanes (X = CH2), while (DHQD)2AQN was best for oxindoles. A similar method was applied to cyclic enol ethers, providing products in modest ee s [17]. 

Indoles. A soln. of N-allyl-o-iodoaniline, 2.5 eqs. Na2C03, 1 eq. Bu4N CL, and a little Pd(OAc)2 in DMF stirred at 25° for 1 day - 3-methylindole. Y 97%. Quinolines and isoquinolines are also obtainable under these conditions. F.e. inch indolines and oxindoles, and bases. (NaOAc, EtjN), s. R.C. Larock, S. Babu, Tetrahedron Letters 28, 5291-4 (1987) review of palladium-catalyzed synthesis of condensed heteroarenes s. T. Sakamoto et al.. Heterocycles 27, 2225-49 (1988). 

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