Oxindole, fluorination

Anodic regioselective fluorination of a-phenylsulphenylated ethyl acetates, 1-naphthalene and 2-pyridine derivatives [80], l-aryl-3-(phenylthio)oxindoles and 2-substituted-3-oxo-4-(phenylthio)-l, 2, 3,4-tetrahydroisoquinolines [81], 2-benzo-thiazolyl and 5-chloro-2-benzothiazolyl sulfides [82], a-(phenylsulfenyl)lactams [83], as well as various heterocycles such as thiolanones, oxathiolanones, dithi-olanones, 3Fl-l,4-benzoxathian-2-ones [84] in Et3N-3HF or Etr NF- HF [n = 3,4), has been reported. 

Both experimental and theoretical studies have been reported of fluoro-denitration and fluoro-dechlorination reactions using anhydrous tetrabutylammonium fluoride in DMSO. The absences of ion pairing and strong solvation are critical in contributing to the reactivity of the fluorinating agent24 Quaternary ammonium salts derived from cinchona alkaloids have been shown to be effective catalysts in an improved asymmetric substitution reaction of /1-dicarbonyl compounds with activated fluoroarenes. The products may be functionalized to yield spiro-oxindoles.25... 

Interestingly, cyclic / -keto esters, e.g. 69, can be also fhiorinated with enantioselectivity up to 80% ee, although the yield and enantioselectivity depend strongly on the type of substrate. A representative example of asymmetric fluorination of a cyclic ester is shown in Scheme 3.27, Eq. (2). In addition, oxindoles 71 have been successfully fhiorinated, as shown in Scheme 3.27, Eq. (3). Under optimized conditions, the desired 3-substituted 3-fluorooxindole, 72, was obtained in 79% yield and with enantioselectivity of 82% ee. 

Catalytic enantioselective fluorination using chiral Pd complexes (59) and (60) has been reported.166,167 This method has provided various fluorinated compounds, includ- ing /3-keto phosphonates, oxindoles, and phenylacetate derivatives, in a highly enantioselective manner (75-96% ee). 

Recent additional work by Shibata [13b] has shown that related compounds such as oxindoles 20 can also be employed as substrates. Fluorinated oxindole 22 could be obtained with up to 82% ee when the preformed N-F ammonium salt of the Sharpless ligand (DHQD)2PYR (21) was used. 

The electrochemical and chemical stability of diamond makes it an ideal electrode material for electrochemical fluorination reactions. The installation of fluorine a to heteroatom-substituted positions can be anodically performed by hydrogen fluoride/triethylamine mixtures. The Fuchigami group studied several electrode materials for the fluorination of oxindole 20. In this transformation to 21 only a... 

This group continuously enlarged the scope of substrate to allylsilane, silyl enol ether 113 and oxindoles 115 for enantioselective catalytic a-fluorination (Scheme 6.34) [62]. They employed N-fluorobenzenesulfonimide (NFSI) as a fluorinating reagent with bis-cinchona alkaloid catalysts and excess base to provide the corresponding fluorinated compounds 114,115 in excellent enantioselectivities up to 95% ee. 

Scheme 9 Enantioselective fluorination of oxindoles and transition state model...

When the reaction of 3-methylindole is done in a 1 1 mixture of methanol and the ionic solvent [bmim BF4 ] an essentially quantitative yield of the 3-fluorooxindole is obtained [41]. Combining Selectfluor with dihydroquinidine acetate leads to fluori-nation of oxindoles in up to 80% ee. The reaction is believed to proceed by transfer fluorination in which the iV-fluoro alkaloid is the immediate fluorinating agent [42]. 

Acid-base catalysis of as5rmmetric fluorination of oxindoles 05YZ785. 

Enantioselective fluorination reactions of active methine compounds, particularly, oxindole derivatives catalyzed by chiral palladium complexes 06SL1467. 

Shibata et al. [2,6] further extended this Cinchona alkaloid-mediated asymmetric transfer fluorination reaction to substrates with activated methylene groups, including acyclic (3-cyanoesters, cyclic (3-ketoesters, and oxindole substrates. Representative products, along with the optimal Cinchona alkaloids for these reactions, are shown in Scheme 13.3. Reaction conditions for the acyclic (3-cyanoesters and the cyclic (3-ketoesters used both (a) Selectfluor as the achiral electrophilic fluorine source in MeCN/CHaCla (3 4) at — 80 C and (b) dihydroquinidine acetate (DHQDA) in stoichiometric quantities. The oxindole substrates required the use of stoichiometric bis-Cinchona alkaloids, (DHQlaAQN or (DHQDlaPYR, to obtain useful yields and selectivities. Reactions of these substrates were run in MeCN at 0°C and also employed Selectfluor as the achiral electrophilic fluorine source. 

Shibata s Cinchona alkaloid-mediated asymmetric fluorination of oxindoles was used in the first enantioselective synthesis of BMS-204352 (MaxiPost), a potent opener of maxi-K channels developed by Bristol-Myers Squibb Pharmaceutical Research Institute for the treatment of acute ischemic stroke [7]. The Togni group [8] developed a similar method for the asymmetric fluorination of another class of substrates with activated methylene groups, a-nitroesters however, usefiil levels of enantioinduction were not obtained. 

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]. 

In 2012, Dorta and coworkers reported other interesting chiral Pd-NHC complexes with naphthyl side chains, which are easily accessed as a single diastereomer from the NHC salt. The enantiose-lective construction of carbon-fluorine bonds via an asymmetric a-arylation is also a nice efficient approach to the direct synthesis of 3-flouro-3-aryl oxindoles (Scheme 8.46) [85]. 

Scheme 5.3 Fluorinations of allyl silanes, silyl enols and oxindoles.

These ligands were initially tested in the nickel(ll)-catalyzed enantioselec-tive fluorination of oxindoles and P-ketoesters, yielding the corresponding products with enantioselectivities of up to >99% ee and high yields. Application of the chiral pincer ligands in the chromium-catalyzed enantioselective Nozaki-Hiyama-Kishi reaction of aldehydes gave the corresponding alcohols with a maximum enantioselectivity of 93% [34]. 

Oxindoles are fluorinated by NFSi with excellent enantioselec-tivity in the presence of bis-cinchona alkaloid, (DHQD)2AQN, to furnish (5)-fluorinated oxindole in 87% yield with 87% ee. In the presence of (DHQ)2 AQN, (/ )-fluorinated oxindole was obtained in 85% yield with 89% ee (eq 22). This enantioselective... 

The cyclization of oxindoles generated cyclic lactams with large ring sizes [30], There was considerable substrate-specific reactivity noted in this work, and each substrate should be evaluated against the reported work for best results A copper-catalyzed aminofluorination works quite well for these substrates and incorporates the fluorine in the a-position [33]... 

The iron-catalyzed aryldifluoromethylation of activated alkenes with PhS02CF2l and aryl C(sp )-H bonds to difluoromethylated oxindoles has also been established by Wang and coworkers (Scheme 9.19) [22]. This method provides a useful route to fluorine-containing oxindoles. 

SCHEME 44.14. Catalytic enantioselective fluorination of silyl enol ethers and oxindoles. 

The ease of preparation and generality of fluorination make the [N-F] class of reagents an excellent choice for enantioselective electrophilic fluorination. Advantageously, enantioselective electrophilic fluorination was also achieved with silyl enol ethers and oxindoles as substrates using a catalytic amount of bis-cinchona alkaloids and NFSI in the presence of excess base (Scheme 44.14). Applications of these [N-F] reagents include the enantioselective syntheses of a-fluoro-a-amino acid derivatives (Scheme 44.15), a potent opener of maxi-K channels (BMS-204352, MaxiPost Xi an Unique Electronics Chemical Co., Ltd, Xi an, P.R. China), and 20-deoxy-20-fluorocamptothecin (see section 3). 

Following this pioneering work, other metals with various chiral ligands were added to the list of successful systems able to catalyze electrophilic fluorination on a wide range of substrates in particular, this includes Pd, Ni, Cu, Zn, and Ru catalysts. Indeed, efficient enantioselective fluo-rinations of various p-keto esters, oxindoles, rcrt-butoxy-carbonyl lactones and lactams, and p-keto phosphonates... 

The catalytic enantioselective fluorination of oxindoles by using a BINAP-palladium catalyst also proceeded highly efficiently without exclusion of air and moisture to give the corresponding fluorinated oxindoles in good yields with high-to-excellent enantioselectivities (up to 96%... 

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