Heterocyclization cascades

Scheme 3-32 Heterocyclization cascades triggered by palladium-catalyzed intermolecular coupling reactions [184].

Minfiensine, a secoiridoid indole alkaloid, was isolated from the African plant Strychnos minfiensis by Massiot and co-workers in 1989. The unique structure feature of the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9//-carbazole has received much attention for the synthetic efforts and has culminated in several elegant total syntheses. For example. Overman et al. reported on the first and second total synthesis of (-l-)-minfiensine. " In addition, Qin et al. revealed a synthesis of ( )-minfiensine in 2008. Recently, MacMillan and co-workers reported on a nine-step enantiose-lective total synthesis of (-l-)-minfiensine via the key step reaction of organocatalytic Diels-Alder cyclization and amine heterocyclization cascade (Scheme 21.32). For the key step reaction in their approach, reaction of 2-vinylindole 139 and 3 equivalents of propynal in the presence of secondary amine catalyst 140 followed by the addition of NaBH4, stereoselective afforded the tricyclic alcohol 142 via a iminium activated endo-selectiye Diels-Alder cycloaddition and a 5-exo amine heterocy cliz ation. 

SCHEME 21.32. Diels-Alder/amine heterocyclization cascade for the synthesis of (+)-niinfiensine. 

Eacile approach to highly functionalized N-, 0-, and S-heterocycles using cascade syntheses with cumulated phosphorus ylides 98MI25. 

Cyclization to six-membered rings (Eq. 15) provided modest diastereoselectivity and required the use of bulkier PhMeSiH2 to prevent olefin hy-drosilylation. Propargyl and homopropargyl amines 94 afforded a variety of heterocycles (Scheme 21), if the catalyst was added slowly over the reaction course to diminish side reactions resulting from metal coordination to the basic amine [56]. The reaction procedure was extended to the diastereoselect-ive bicyclization of dienyne substrate 95, giving 96 as product in a cascade fashion (Eq. 16) [57]. 

It was shown that furoxans can be transformed to 1,2,3-triazoles. Thus, 4-acetylamino-3-arylazo-l,2,5-oxadiazole 2-oxides undergo two successive (cascade) mononuclear heterocyclic rearrangements in an aqueous basic medium with the formation of 4-acetylamino-2-aryl-5-nitro-2/7-l,2,3-triazoles (Equation 12) <2001MC230>, or 3,3 -disubsti-tuted 4,4 -azo-l,2,5-oxadiazole 2-oxides were found to undergo a rearrangement into 2-(furoxan-4-yl)-4-nitro-2//-1,2,3-triazole 1-oxides on heating in pertrifluoroacetic or peracetic acids (Equation 13) <2003MC272>. 

The influence of catalytic C,C-coupling of six-membered cyclic nitronates can be used, under more drastic conditions, for the constmction of nitrogen-containing heterocycles via cascade chemical transformations (see, e.g., the coupling reaction of nitronate (368) with silyl enolates (369a-d) in the presence of trimethylsilyl triflate (154) (Scheme 3.211)). 

Isoindolones and Related N-Heterocycles via Palladium Nanoparticle-Catalyzed 3-Component Cascade Reactions... 

A cascade reaction involving multiple C-H functionalizations has been employed for the formation of bicyclic heterocycles with palladium catalysis (Equation (160)).134... 

The formation of the heterocycle 1 from the xylylene-bis-phosphonium salt 2 and PCI3 proceeds via a detectable intermediate 3 in a cascade of condensation reactions that is terminated by spontaneous heterolysis of the last remaining P-Cl bond in a cyclic bis-ylide-substituted chlorophosphine formed (Scheme 1) [15]. The reaction scheme is applicable to an arsenic analogue of 1 [15] and to bis-phosphonio-benzophospholides with different triaryl-, aryl-alkyl- and aryl-vinyl-phosphonio groups [16, 18, 19], but failed for trialkylphosphonio-substituted cations here, insufficient acidity prohibited obviously quantitative deprotonation of the phosphonium salts, and only mixtures of products with unreacted starting materials were obtained [19]. The cations were isolated as chloride or bromide salts, but conversion of the anions by complexation with Lewis-acids or metathesis was easily feasible [16, 18, 19] and even salts with organometallic anions ([Co(CO)4] , [CpM(CO)3] (M=Mo, W) were accessible [20]. 

Keywords Absolute configuration, Amines, Amino acids, Carbenes, Cascade reactions, 2-chloro-2-cyclopropylideneacetates. Combinatorial libraries. Cycloadditions, Cyclobutenes, Cyclopropanes, Diels-Alder reactions. Heterocycles, Michael additions. Nitrones, Nucleophilic substitutions, Peptidomimetics, Palladium catalysis. Polycycles, Solid phase synthesis, Spiro compounds. Thiols... 

Coquerel Y, Bensa D, Doutheau A, Rodriguez J (2006) Synthetic studies on the MARDi cascade stereoselective synthesis of heterocyclic seven-membered rings. Org Lett 8 4819-4822... 

The various, complex, cascade reactions described above converted simple saturated and aromatic heterocycles into polycyclic pentathiepins and their chlorinated and rearranged derivatives this strikingly illustrates the extensive reactivity of S2CI2 and its complexes with bases, particularly DABCO. This reactivity encompassed dehydrogenation of tetrahydroaromatics, chlorination and sulfuration of aromatics and their conversion into SSCl derivatives. 

Chiral l,3-dioxin-4-ones photochemically react intermolecular with (cyclic) ethers, acetals, and secondary alcohols to give the addition products in reasonable yields. The radical addition was completely stereoselective at C-6 of the heterocycle <1999EJO1057>. The exocyclic diastereoselectivity, where relevant, was about 2 1 (Equation 30). In analogy, an intramolecular cascade reaction of a 1,3-dioxin -one derived from menthone was used to get a terpenoid or a steroid framework in optically active form <1997JA1129, 1999JA4894>. 

In the presence of appropriate organometallic compounds, the trapping of organopalladium intermediate can be followed by the carbonylative cross-coupling pathway (Scheme 15)/" The cascade can be applied to the construction of heterocycles (Scheme 16). 

This chapter covers the recent advances in amidocarbonylations, cyclohydrocarbonylations, aminocarbonylations, cascade carbonylative cyclizations, carbonylative ring-expansion reactions, thiocarbonylations, and related reactions from 1993 to early 2005. In addition, technical development in carbonylation processes with the use of microwave irradiation as well as new reaction media such as supercritical carbon dioxide and ionic liquids are also discussed. These carbonylation reactions provide efficient and powerful methods for the syntheses of a variety of carbonyl compounds, amino acids, heterocycles, and carbocycles. 

Westman, J. and Orrling, K., Cascade synthesis with (triphenylphosphoranylidene)-ethenone as a versatile reagent for fast synthesis of heterocycles and unsaturated amides under microwave dielectric heating, Comb. Chem. High Throughput Screening, 2002, 5, 571-574. 

Keywords thioureideo-acetamide, phenacyl bromide, cascade reaction, cycliza-tion, solid-solid reaction, heterocycle... 

The synthesis of A-fused tricyclic (3-lactams involving a radical cascade sequence in enyne 2-azetidinones 114 and 115 bearing a methylenecyclopropane unit has been reported [82]. Slow addition of Bu3SnH/AIBN to a refluxing solution of 114 gave tricyclic vinylstannane 116 as a single stereoisomer in 42% yield, whereas cyclization of 115 under identical conditions gave fused heterocycles 117 and 118 in 73 and 11% yield, respectively, in all three cases via a 7-endo cyclization. Treatment of vinyl stannanes 117 and 118 with PPTS in dichloromethane yielded a common tricyclic product 119 (Scheme 40). 

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