Azides, alkyl reactions with ketones

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]. 

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... 

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. ... 

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. 

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

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. 

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 addition of ozone (O3) to alkenes to give a primary ozonide (molozonide), which rearranges to an ozonide and eventually leads, on reduction, to carbonyl compounds (aldehydes and/or ketones), has already been mentioned and the reaction itself is shown in Scheme 6.11. However, it is important to recognize that this is only one example of a 4th- 2n electrocyclic addition and that orbital overlap for many sets of these reactions dictates their courses as well. Thus, to show the similarity of some of these dipolar 3 -f 2 addition reactions Equations 6.53-6.56 are provided. Although any alkene might be used as an example, (Z)-2-butene is used in each to emphasize that aU of them occur with retention of stereochemistry and, in the first (Equation 6.53), the reaction with ozone to form the primary ozonide (molozonide) is presented again (i.e., see Scheme 6.11). In a similar way, with a suitable azide, R-N3, readily prepared from an alkyl halide (Chapter 7), the same alkene forms a triazoline (Equation 6.54) and with nitrous oxide (N2O) the heterocycle (Chapter 13) cis -4,5-dimethyl-A -l,2,3-oxadiazoline (ds-4,5-dihydro-4,5-dimethyl-l,2,3-oxadiazole) (Equation 6.55). Finally, with a nitrile oxide, such as the oxide derived from ethanenitrile (acetonitrile [CH3ON]), the same alkene yields a different heterocycle, the dihydroisoxazole, 3,4,5-trimethyl-4,5-dihydroisoxazole (Equation 6.56). 

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... 

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

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