Schmidt reactions ketones-alkyl azides

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>. 

Ketones generally fail to react with alkyl azides under standard Schmidt conditions. However, when these reactions are conducted in the presence of Lewis acid instead of the protic conditions used in the standard Schmidt reactions, the intermolecular Schmidt reactions can be carried out in moderate to good yields. Titanium(IV) chloride (> 1.0 equiv) in dichloromethane is the best reagent for effecting this type of reactions. The best substrates include the sterically unhindered ketones, especially cyclohexanones. This transformation is sensitive to steric effects, and even the a-substituted ketones may lead to poor yields and require long reaction time. The intermolecular Schmidt reaction with alkyl azides is still limited to a small range of cyclic ketones. For example, cyclopentanones do not react well with alkyl azides. 

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... 

Reaction of RN, with ketones.2 TiCl4 (2.5 equiv.) can effect a Schmidt type reaction of alkyl azides with cyclic ketones to afford N-alkyllactams. An aldol-typc reaction can also occur bul can be suppressed by use of excess (2 equiv.) of the alkyl azide. Highest yields are obtained with cyclohcxancs, but ring expansion products can be obtained in 20-25% yield from cyclopcntanonc and cyclobutanoncs. 

Schmidt Rearrangement Reactions with Alkyl Azides 201 Table 7.3 Reactions of hydroxyalkyl azides with ketones... 

The Schmidt reaction of ketones works best with aliphatic and alicyclic ketones alkyl aryl ketones and diaryl ketones are considerably less reactive. The reaction is only seldom applied to aldehydes as starting materials. The hydrazoic acid used as reagent is usually prepared in situ by treatment of sodium azide with sulfuric acid. Hydrazoic acid is highly toxic, and can detonate upon contact with hot laboratory equipment. 

With alkyl aryl ketones, it is the aryl group that generally migrates to the nitrogen, except when the alkyl group is bulky. The reaction has been applied to a few aldehydes, but rarely. With aldehydes the product is usually the nitrile (16-21). Even with ketones, conversion to the nitrile is often a side reaction, especially with the type of ketone that gives 17-31. A useful variation of the Schmidt reaction treats a cyclic ketone with an alkyl azide (RN3) in the presence of TiCU, generating a... 

In addition to the Beckmann reaction, the Schmidt rearrangement is used to generate M-alkylated lactams, too. Alkyl azides 231 react with the cyclic ketones (and aldehydes) in the presence of proton or Lewis acids. On running the inter-molecular reactions, in most cases symmetric ketals 230 have been converted... 

Nitrilium salts, e.g., 66, prepared from the alkylation of nitriles, react with sodium azide to yield 1,5-disubstituted tetrazoles, e.g., 67 (Scheme 7).121 The Schmidt reaction,122 a versatile method for the preparation of 1,5-disubstituted tetrazoles from ketones and hydrazoic acid, can now be regarded as a special case of azide addition to nitrilium salts.123... 

Aube and co-workers have found that enolizable ketones react with benzyl azide in triflic acid to yield /V-(phenylamino)-methylated products [Eq. (5.354)]. The transformation is an aza-Mannich reaction interpreted with the involvement of the Mannich reagent A -phenyl iminium ion 295 formed in situ in a Schmidt rearrangement. Cyclic tertiary alcohols react with alkyl azides in triflic acid to yield N-alkylamines (296, 297)983 [Eq. (5.355)]. The Schmidt rearrangement was used to transform Merrifield resin into amino-polystyrene resin by reacting the azido derivative in excess triflic acid (CH2CI2, 0°C).984... 

The Schmidt reaction of cyclic ketones with hydrazoic acid affords convenient access to ring-expanded N-unsub-stituted lactams but extension of this process to alkyl azides to provide Aralkyl lactams is capricious in nature. A protocol... 

Two reportshave appeared concerning an extension of the Schmidt reaction of aryl aUcyl ketones in which the ketone was treated with an alkyl azide to give benzaldehyde, an aliphatic aldehyde and an amine. The yields of benzaldehyde were claimed to range from... 

About 15 years ago, Aube et al. reported that alkyl azides undergo Lewis acid-mediated reactions with ketones 76 to give the corresponding lactams 78 via 77 (Azido-Schmidt reaction Scheme 14A) [44-48]. However, this reaction pathway does not proceed when a,/3-unsaturated ketones are used. It was recently shown that Lewis acid-activated enones like 79 undergo a [3-P2] cycloaddition with alkylazides, likely via an 1,2,3-triazoline intermediate 80, to give the corresponding enaminone 80 (Scheme 14B) [49]. 

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... 

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