Ketones with alkyl azides

Variation 2 Intermolecular Reaction of Ketones with Alkyl Azides... 

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. 

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... 

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. 

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

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... 

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>. 

Acetylcarbazole and 9-ethyl-3-propionylcarbazole underwent normal Wilgerodt reactions. The ketone 174 reacted with sodium azide-poly-phosphoric acid with migration of the alkyl substituent generating lactam 203. ... 

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. 

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. 

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... 

Hassner and Belinka118 generated primary enamines in situ by reaction of vinyl azides 67 with alkyl lithium derivatives and converted them to ketones (equation 45). 

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... 

Aube, J., Milligan, G. L., Mossman, C. J. Titanium tetrachloride-mediated reactions of alkyl azides with cyclic ketones. J. Org. Chem. 1992,... 

Fluorenone oxime was recovered unchanged after being heated with PPA at 120°, but at 180° it was rearranged in almost quantitative yield (Conley )- Conley found PPA to be a superior solvent-catalyst for the Schmidt rearrangement. He added sodium azide in portions to a mixture of a diaryl, aryl-alkyl, symmetrical or unsymmetrical ketones with 15-20 parts of PPA at a temperature in the range 25-75° until evolution of nitrogen ceased, and obtained amides in yields mainly of 80-90%. Doorenbos and Wu studied the conversion of cholestanone and... 

To date, four bioorthogonal reactions have been used to label glycans on cells and in lysates hydrazone/oxime formation with ketones, thiol alkylation with maleimides, Staudinger ligation of azides with triaryl phosphines, and copper-catalyzed or strain-promoted [3+2] cycloadditions of alkynes and azides (Figure 5) (25, 26, 32, 34, 35). While each reaction has been used extensively, most recent applications have employed azido- or alkynyl-sugars due to their superior metabolic incorporation and efficient ligations. 

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. 

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