Intramolecular, addition Schmidt reaction

Nucleophilic addition to C=0 (contd.) ammonia derivs., 219 base catalysis, 204, 207, 212, 216, 226 benzoin condensation, 231 bisulphite anion, 207, 213 Cannizzaro reaction, 216 carbanions, 221-234 Claisen ester condensation, 229 Claisen-Schmidt reaction, 226 conjugate, 200, 213 cyanide ion, 212 Dieckmann reaction, 230 electronic effects in, 205, 208, 226 electrons, 217 Grignard reagents, 221, 235 halide ion, 214 hydration, 207 hydride ion, 214 hydrogen bonding in, 204, 209 in carboxylic derivs., 236-244 intermediates in, 50, 219 intramolecular, 217, 232 irreversible, 215, 222 Knoevenagel reaction, 228 Lewis acids in, 204, 222 Meerwein-Ponndorf reaction, 215 MejSiCN, 213 nitroalkanes, 226 Perkin reaction, 227 pH and, 204, 208, 219 protection, 211... 

The intramolecular carbon-carbon bond-forming reactions considered in this section are based on the aldol condensation (see Section 5.18.2, p. 799), the Claisen-Schmidt reaction (see Section 6.12.2, p. 1032), the Claisen ester condensation (see Section 5.14.3, p. 736), and the Claisen reaction (see Section 6.12.2, p. 1032). Since these carbonyl addition reactions are reversible, the methods of synthesis are most successful for the formation of the thermodynamically stable five- and six-membered ring systems. The preparation of the starting materials for some of these cyclisation reactions further illustrates the utility of the Michael reaction (see Section, 5.11.6, p. 681). 

Another fascinating intramolecular process involves the spirocyclic epoxide 103, which carries a pendant azide group. Under the influence of ethylaluminum chloride, this substrate undergoes Lewis acid assisted cyclization followed by an intramolecular Schmidt reaction and subsequent in situ reduction of the intermediate iminium species 105 upon addition of sodium borohydride. This protocol was used as a key step in a novel synthesis of indolizidine alkaloids of pharmaceutical interest <03OL583>. 

A related transformation of azides has been reported by the group of Toste to afford pyrroles by an acetylenic Schmidt reaction (equation 30).In an intermolecular-related addition, gold triazolates are obtained. The intramolecular hydroamination of trichloroacetimidates derived from propar-gyl and homopropargyl alcohols also proceeds with cationic Au(I) as catalysts. ... 

Somewhat similar results are obtained with a Hojfman reaction on polyacrylamide [279]. A Schmidt reaction on poly (acrylic acid) also yields mixed results [250]. When it is run in acetic acid, the intermolecular reactions appear to predominate over the intramolecular ones. Also, the products formed in acetic acid have higher nitrogen content that those formed in dioxane [250]. The NMR spectra show presence of some acid anhydride groups. This has an additional effect of lowering the yield. 

Toste has reported a gold(I)-catalyzed protocol for the intramolecular addition of an alkyl azide to an alkyne with loss of dinitrogen (acetylenic Schmidt reaction) to form pyrrole derivatives [19]. For example, treatment of homopropargyl azide 16 with a catalytic 1 2 mixture of (dppm)Au2Cl2 (dppm = l,2-bis(diphenylphosphino)meth-ane) and AgSbFfi in methylene chloride at 35 °C led to isolation of2,5-dibutylpyrrole in 82% yield (Eq. (11.13)). The method was also effective for the cyclization of a-unsubstituted homopropargyl azides and tolerated both alkyl and aryl substitution of the alkyne. 

Enones are not useful substrates for intramolecular Schmidt reactions as azide addition to the olefin predominates over attack at the enone carbonyl. Thus, enone 7 undergoes Michael addition followed by loss of nitrogen to give the icyclic enone 10 in moderate yield. 

The gold(I)-catalyzed intramolecular Schmidt reaction of azido alkynes 49 provides easy entry to a series of pyrroles 54 with a variety of substitution patterns. The proposed mechanism involves gold(I)-induced activation of the alkyne toward addition by the proximal nitrogen of the azide. Subsequent loss of nitrogen leads to cationic intermediate 52, which is... 

The power of the intramolecular Schmidt reaction is demonstrated in the concise synthesis of the Stemona alkaloid stenine. Reaction of trimethylsilyloxy diene 79 with cyclohexenone 80 and tin(IV) tetrachloride brings about a tandem Diels-Alder/Schmidt reaction to give adducts 82 and 83 in 52% and 17% yields, respectively, with the exo addition product 83 predominating. Adduct 83 contains three rings and four stereocenters present in stenine. The intramolecular Schmidt reaction is also employed as a key step in the total syntheses of 251 F (84 to 85) and (+)-aspidospermidine (87 to 88). ... 

The development of this version of the Schmidt reaction predates the experience of anyone working in organic chemistry today (Schmidt s original report was in 1924) but the extension of the concept to nucleophilic alkyl azides is a decidedly contemporary development. For example, if one compares the two reactions shown in Scheme 7.2, it is clear that the direct insertion of an alkyl azide into cyclohexanone allows for the introduction of additional nitrogen atom substitution and, in the case of an alkyl azide tethered to a carbonyl substrate, the possibility of an intramolecular reaction. The goal of this chapter... 

The reaction of trienyl azide 76 was noteworthy as the first reported example of a combined Diels-Alder/Schmidt reaction of any type (see Section 7.7 above). In addition, the isolation of compound 77b represented the first known observation of a bridged lactam from an intramolecular Schmidt reaction (in contrast to the formation of bridged ortho-amide 62 shown in Scheme 7.40). Mechanistically, an endo Diels-Alder leads to 77a and 77b (box at bottom of Scheme 7.43), while an exo transition state leads to 77c (transition state not shown). The formation of fused or bridged lactam depends on antiperiplanar migration of carbon from the equatorially or axially disposed N2 groups in the intermediates shown. 

Polar Cycloadditions R. R. Schmidt, Angew. Chem., Int. Ed. Engl., 1973, 12, 212-224. Addition Reactions with Intramolecular Cyclisation V. I. Staninets and E. A. Shilov, Russ. Chem. Rev. (Engl. Transl.), 1971, 40, 272-283. 

Flavanones 25 are often synthesized by Claisen-Schmidt condensation followed by intramolecular Michael addition reaction of the corresponding chalcone derivative. Climent et al. reported a new environment-friendly method to prepare flavanones 25 by the reaction of 5-substituted-2-hydroxyacetophenones and benzaldehydes using hydro-talcites as basic catalysts (Scheme 16) [81]. Substitution over both aromatic rings influenced the reaction coxu-se leading to flavanones 25 in 7-45% of yields in only Ih of reaction time. 

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