Nucleophilic substitution three-component coupling reactions

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

The potential of one-pot three-component coupling reaction was further explored by the same group for the synthesis of substituted tetrahydropyranols 207 Ishikawa [96]. As for the two previous examples, the isolation of the Michael products A in suitable yields is only allowed when the addition of the different starting materials proceeds in a well-established order, thus avoiding undesired side reactions. Furthermore, this three-component coupling process could be successfully combined with an additional nucleophilic addition step to allow an asymmetric one-pot four-component coupling reaction to give rise to tetrahy-dropyrans 208 that are present in many natural products (Scheme 2.70). 

Previously, Ohashi and his co-workers reported the photosubstitution of 1,2,4,5-tetracyanobenzene (TCNB) with toluene via the excitation of the charge-transfer complex between TCNB and toluene [409], The formation of substitution product is explained by the proton transfer from the radical cation of toluene to the radical anion of TCNB followed by the radical coupling and the dehydrocyanation. This type of photosubstitution has been well investigated and a variety of examples are reported. Arnold reported the photoreaction of p-dicyanobenzene (p-DCB) with 2,3-dimethyl-2-butene in the presence of phenanthrene in acetonitrile to give l-(4-cyanophenyl)-2,3-dimethyl-2-butene and 3-(4-cyanophenyl)-2,3-dimethyl-l-butene [410,411], The addition of methanol into this reaction system affords a methanol-incorporated product. This photoreaction was named the photo-NO-CAS reaction (photochemical nucleophile-olefin combination, aromatic substitution) by Arnold. However, a large number of nucleophile-incorporated photoreactions have been reported as three-component addition reactions via photoinduced electron transfer [19,40,113,114,201,410-425], Some examples are shown in Scheme 120. 

The synthesis of substituted tetrahydropyranylidene acetates such as 465 and 466 can be accomplished by TiCU-promoted carbon-carbon bond-forming reactions of ethyl glyoxylate, 3,4-dihydro-2/7-pyran 455, and oxygen or sulfur nucleophiles (Scheme 82). The reaction is an efficient three-component coupling process and the overall outcome of the reaction is dependent upon reaction temperature <1999TL4751>. 

The key element of this protocol is the initial addition of cationic electrophiles such as rerr-alkyl or acyl cations to the double bond of a DCHC complex of the conjugated enyne 118, which results in the formation of the substituted propargylic cation intermediate 119, Subsequent reaction with pre-selected external nucleophiles, for example allylsilanes or silyl enol ethers, leads to the formation of the final adducts 120. The reaction is carried out as a one-pot, three-component coupling and can be used for the creation of two novel C-C bonds. It is a process somewhat complementary to the stepwise Michael addition described earlier (Scheme 2.31), with a reverse order of E and Nu addition. Oxidative decomplexation of 120 yields the product 121. The overall... 

Micalizio and coworker reported a three-component coupling sequence for the synthesis of substituted pyridines in 2012 [121]. The reaction proceeded through nucleophilic addition of a dithiane anion to an Q ,/3-unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed trimethylsilane-imines (generated in situ by the low temperature reaction of lithium hexamethyldi-silazide with an aldehyde) and Ag(I)- or Hg(II)-mediated ring closure. Good yields of substituted pyridines were isolated. 

In 2005, Xi and coworkers reported that 1,1-cycloaddition of oxalyl chloride with l,4-dilithio-l,3-dienes 379 or zirconcyclopentadienes 397 afford CPDNs 399 in the presence of CuCl (Scheme 6.100a), in which the carbon-carbon bond of the 1,2-dicarbonyl component cleaves during nucleophilic addition [239]. They also found that no reaction is observed when 397 is treated with isocyanates. However, multiply substituted ICPDs 400 are formed from Lewis acid-promoted reactions (BF3-Et20) by a one-pot three-component coupling process (Scheme 6.100b) [240]. 

Smith and coworkers next extended Type II ARC domino protocol beyond dithiane arena by designing a variety of effective ARC linchpins with different ASGs capable of three and four component couplings. In their first effort toward this goal, they developed readily available 2-bromoallylsilane [62a], and subsequently, allyltrimethylsilane 185 [63], and recently o-TMS (trimethylsilyl) benzaldehyde 188 as promising linchpins for Type II ARC process [64, 65]. However, domino anionic relay reactions with these linchpins 185 and 188 are not discussed in this chapter, since they are not initiated by nucleophilic substitution as the first step. 

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