Intramolecular Schmidt reactions

Both inter- and intramolecular variants of the Schmidt reaction in which an alkyl azide effects overall insertion have been observed. 

Nitrones derived from 2-azabicyclo[5.3.0]decane give quinolizidine compounds by photochemical Beckmann rearrangement which implies simultaneous ring expansion and ring contraction reactions. Intramolecular Schmidt reactions in 2(4-azidobutyl)-cyclopentanones also give quinolizidinone derivatives by ring expansion. Examples of both types of reactions are given in Sections 12.01.11.1 and 12.01.11.3, respectively. 

Aube took advantage of an intramolecular Schmidt reaction of azide 129 to provide the fused ring heterocyclic lactam 130 as a key step in a total synthesis of (+)-aspidospermidine... 

In an investigation of the intramolecular Schmidt reaction of alkyl azides for the synthesis of benzo-fused l-azabicyclo[m.n.O]alkanes, the perhydrobenzo[/]pyrrolo[l,2-a] azepine 29 was prepared in 72% yield . 

Alkyl azides have been involved in the synthesis of indolizidinone derivatives in several ways. One example (Scheme 7) is the intramolecular Schmidt reaction between alkyl azides and ketones which can be used to transform azidoketone 24 into the corresponding indolizidinones 26 through intermediate 25 <2001JOC886> or with epoxides to obtain the indolizidine 27 <2004JOC3093>. 

An example of ring enlargement is the intramolecular Schmidt reaction of azidoalkyl ketone 53 that gives, by the action of titanium tetrachloride, through intermediate azidohydrin, lactam 20 (95JA10449). Because of the large distance between keto and azido groups, the usual catalyst trifluoroacetic acid does not work. 

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 acid-catalyzed ring expansions of tertiary cyclohexylazides to tetrahydroazepines may be viewed as an intramolecular version of the Schmidt reaction and in general proceed in high yield. Unfortunately, the reaction is of little synthetic value as the imines formed are readily hydrolyzed to w-aminoketones in the strong acid media (B-67MI51600). However, the reaction is successful with 9-azido-9-phenylacridone, which on thermolysis or photolysis ring-expands to a mixture of 9-phenyliminoacridone (15-35%) and 6-phenyl-11//-dibenz[6,e]azepin-ll-one (65-85%) (76TL3141). 

In a one-pot process which has been described as an intramolecular Schmidt reaction it has been shown that treatment of ketals or enol ethers of 1,5-azidoketones with Lewis or protic acids followed by sodium iodide in acetone results in formation of lactams in 68-95% yield. 

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). 

A new one-pot tandem C-C coupling intramolecular acetylenic Schmidt reaction using Pd/C-Cu catalysis was developed to afford 3-substituted I (2/7)-isoquinolones 139 <07CC1966>. In this one-pot procedure, 2-iodobenzoyl azide 140 and the appropriate alkyne were reacted in the presence of Pd/C, PPh3, Cul and TEA to provide the products in good to high yields. 

An example of intramolecular aminomercuration has been reported by Weimeb as part of the synthetic strategy to the tricyclic nucleus of madangamine A - an alkaloid that shows cytotoxicity toward a number of tumor cell lines (equation 15). Pearson has recently reported the first example of an azidomercuration involving aliphatic azides (see equation 16) according to a protocol that exhibits wider applicability and is, therefore, more convenient than the analogous acid-promoted Schmidt reaction. ... 

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>. 

Iyengar, R., Schiidknegt, K., Aube, J. Regiocontrol in an Intramolecular Schmidt Reaction Total Synthesis of (+)-Aspidospermidine. Org. Lett. 2000, 2,1625-1627. 

Mossman, C. J., Aube, J. Intramolecular Schmidt reactions of alkyl azides with ketals and enol ethers. Tetrahedron 1996, 52, 3403-3408. 

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