Nucleophilic substitution Lewis acid-mediated

Other types of heterofunctionalized cyclopropane derivatives used as starting materials in transition metal mediated conversions are acylcyclopropanes and similar systems. These systems, being electrophilic cyclopropanes, are opened by carbanion nucleophiles (e.g. cuprates, see Section l.B.2.1.3.) or nucleophilic transition-metal centers. In combination with siloxy groups, push-pull (capto-dative) substituted cyclopropanes are available as homoenolate precursors via Lewis acid mediated ring opening (see Section 1. B.2.1.4.).. This latter procedure has been used in tetrahydrofuran synthesis. 

A new reaction of diazo compounds was discovered when a-aryliodonio diazo compounds were prepared and treated with nucleophiles. a-Aryliodonio diazo compounds (160) are readily accessible by treatment of bis(pyridino)aryliodine(III) salts with alkyl diazoacetates, or by the Lewis acid mediated (MesSiOTf) reaction of diacetoxyiodobenzene with alkyl diazoacetates. Nucleophilic substitution at the a-carbon was carried out by reaction with a series of neutral nucleophiles under mild neutral conditions to lead to the a-oniosubstituted diazo compounds (161). ... 

Allyltributylstannanes are common reagents in both radical and Lewis acid-mediated reactions, although they are unknown to react with enones. However, there has been the first report of a reaction of an electrophilic allylstannane with an enone (Scheme 1). While the parent allylstannane does not react with enones, those substituted with an ester substitute smoothly at the y3-position of enones. The authors claim this to be the first non-basic and non-nucleophilic alternative to the Michael reaction. 

Activation of C-X Bonds. The activation of C-X single bonds toward nucleophilic substitution is also mediated by the Lewis acidic character of ZnCl2. Benzylic (eq 33), allylic (eq 34), propargylic, and tertiary halides (eq 35) undergo substitution with mild carbon and heteroatom nucleophiles. 

Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity. 

C-Ring substituted indoles, including 4-nitroindole, are also allylated under these conditions. The reaction is believed to proceed by an Sa I mechanism, with the Zn(03SCF3)2 acting as a Lewis acid catalyst. There may also be some N-H deprotonation by the amine. 1-Methylindole reacts under these conditions, but with reduced yield. The Zn(03SCF3)2-mediated reaction was used in tandem with intramolecular nucleophilic capture to synthesize the flustramine structure [89]. 

In general, these alcohol-based dehydrative A-alkylation reactions can be classified into two categories. One is the direct nucleophilic substitution of the hydroxy group by amines/amides mediated/catalyzed by Bronsted acids, Lewis acids, or TM complexes via formation of carbocation or coordinated cationic metal complexes under acidic conditions (Scheme 2) [16-20]. The famous Ritter reaction of nitriles and alcohols giving alkylated amides may be classified as one of these reactions, in which the nitriles serve as the A-nuleophile (Eq. 2) [21, 22]. 

In N-acyliminium ion-mediated functionalization of 2- or 6-alkoxy-substituted piperidines, Sc(OTf)3 was found to be an excellent Lewis acid with a silyl enol ether nucleophile, and moderate diastereoselectivities were obtained (trans/cis = 26/74 and 78/22, respectively) [158]. Sc(OTf)3 was found to be a more efficient metal tri-flate in the nucleophilic substitution of N-benzyloxycarbonyl-2-methoxypiperidine and 3-substituted-2-acyloxy-N-benzyloxy-carbonylpiperidine with silylicon enolates [159]. 2-Acetoxy-3-benzyloxy-N-benzyloxycarbonylpiperidine afforded the 2-alkylat-ed adducts in high cis selectivity (cis/trans = 71/29), while 2,3-diacyloxy-N-benzyl-oxycarbonylpiperidines showed trans selectivity (trans/cis = 80/20-100/0). Febri-fugine, a potent malarial alkaloid, was successfully synthesized from 2,3-diacetoxy car bony Ipiperidine on the basis of these diastereoselective nucleophilic substitution reactions. 

Planar chiral orf/to-substituted (arene)Cr(CO)3-stabilized a-propargylic cations (67) may be generated from (66) in 5n1 fashion mediated by Lewis acid. They are in principle ambident electrophiles, susceptible to nucleophilic attack at the propar-gyl or allenyl positions. However, they react with 5-, N-, and jr-nucleophiles to give regioselectively the propargyl derivatives (68) in good yields and excellent diastereoselectivities, overall a process of retention by double inversion. Without the orf/to-substituent nucleophilic attack at both possible positions occurs. 

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