Ketones intramolecular ketone-alkyl azide

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>. 

Sha et al. (45) reported an intramolecular cycloaddition of an alkyl azide with an enone in an approach to a cephalotaxine analogue (Scheme 9.45). Treatment of the bromide 205 with NaN3 in refluxing methanol enabled the isolation of compounds 213 and 214 in 24 and 63% yields, respectively. The azide intermediate 206 underwent 1,3-dipolar cycloaddition to produce the unstable triazoline 207. On thermolysis of 207 coupled with rearrangement and extrusion of nitrogen, compounds 213 and 214 were formed. The lactam 214 was subsequently converted to the tert-butoxycarbonyl (t-Boc)-protected sprrocyclic amine 215. The exocyclic double bond in compound 215 was cleaved by ozonolysis to give the spirocyclic ketone 216, which was used for the synthesis of the cephalotaxine analogue 217. 

Variation 3 Intramolecular Reaction of Ketones with Alkyl Azides (Aube )... 

As compared with the intermolecular reaction of ketones with alkyl azides, the corresponding intramolecular version provides a reliable approach to... 

The intramolecular reaction of ketones with alkyl azides is quite general in terms of the ketone moiety, but the distance between the carbonyl group and the azide moiety is critical. Thus, a good yield of lactam 6 is formed with a span of four carbons between the carbonyl and the azido group, and in contrast, no rearrangement occurs with a span of either three or five carbons. 

The first synthetically useful Schmidt reactions of alkyl azides with ketones were intramolecular. Thus, it was shown that azido-tethered ketones, when treated with Brpnsted or Lewis adds in CH2CI2 at room temperature, were converted to lactams in good to excellent yields (Table 7.1). Mono- and bicyclic ketones are attractive substrates for the preparation of fused bi- and tricyclic lactams and the range of ring sizes accommodated... 

Aube and his team have used their trademark intramolecular Schmidt reaction of azidoketones in their synthesis of (—)-indolizidine 223A (1556) and (—)-6-epi-indohzidine 223A ent-2041) (Scheme 261). Commencing with norbomadiene (2077), they used a precedented enantioselective hydrosilylation—oxidation procedure to prepare the (S)-(- -)-norbomeol 2078 in 72% yield and an er of 96 4. Oxidation to the ketone, exo-selective alkylation with l-chloro-3-iodopropane, and substitution of chloride with azide afforded the key azidoketone (+)-2079, which underwent the intramolecular Schmidt reaction when treated with titanium tetrachloride to... 

Additionally, 1,2-dihydroxyethylene dipeptide analogues without the C-terminal carboxylic acid have been used to obtain aspartyl proteases inhibitors.[641 These efforts include stereoselective alkylation of imines, one-pot reductive amination of epoxy ketones, ring opening of epoxides with sodium azide, diastereoselective dihydroxylation of allylic amines, and enzymatic resolution and stereocontrolled intramolecular amidation. 

Later,triplet alkylititrenes 12a-c were generated by intramolecular sensitization in solution. The photochemistry of three a-benzoyl-ft)-azidoalkanes (PhCO(CH2)oN3 (13a-c, n = 3-5) was studied and two competitive processes were found to proceed from the triplet ketone (Scheme 11.8) energy transfer to azide to yield triplet alkyl nitrene and 7-hydrogen abstraction to yield Norrish type II products. Photolysis of azides with a longer methylene chain (13b,c) yields mainly acetophenone, a product of Norrish type II reaction. The major products of the azide 13a photolysis were substituted pyrrole and pyr-roline derived from triplet nitrene 12a. ... 

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