Ketones Schmidt reaction

Schmidt reaction ketone (etc.) into amide sequence (137) - (129) -> (132) HN3 and H2SO4. von Braun reaction (modified) amide into alkyl halide and nitrile sequence (132) (133) (129)... 

Claisen-Schmidt reaction. Aromatic aldehydes condense with aliphatic or mixed alkyl-aryl ketones in the presence of aqueous alkali to form ap-unsaturated ketones ... 

By catalytic reduction of a p-unsaturated ketones, prepared from aldehydes by the Claisen - Schmidt reaction (see under Aromatic Aldehydes), for example ... 

Schmidt reaction of ketones, 7, 530 from thienylnitrenes, 4, 820 tautomers, 7, 492 thermal reactions, 7, 503 transition metal complexes reactivity, 7, 28 tungsten complexes, 7, 523 UV spectra, 7, 501 X-ray analysis, 7, 494 1 H-Azepines conformation, 7, 492 cycloaddition reactions, 7, 520, 522 dimerization, 7, 508 H NMR, 7, 495 isomerization, 7, 519 metal complexes, 7, 512 photoaddition reactions with oxygen, 7, 523 protonation, 7, 509 ring contractions, 7, 506 sigmatropic rearrangements, 7, 506 stability, 7, 492 N-substituted mass spectra, 7, 501 rearrangements, 7, 504 synthesis, 7, 536-537... 

Claisen-Schmidt reaction (Section 18.10) A mixed aldol condensation in which an aromatic aldehyde reacts with an enolizable aldehyde or ketone. 

The reaction of carboxylic acids, aldehydes or ketones with hydrazoic acid in the presence of a strong acid is known as the Schmidt reaction A common application is the conversion of a carboxylic acid 1 into an amine 2 with concomitant chain degradation by one carbon atom. The reaction of hydrazoic acid with a ketone 3 does not lead to chain degradation, but rather to formation of an amide 4 by formal insertion of an NH-group. 

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. 

There are actually three reactions called by the name Schmidt reaction, involving the addition of hydrazoic acid to carboxylic acids, aldehydes and ketones, and alcohols and alkenes. The most common is the reaction with carboxylic acids, illustrated above.Sulfuric acid is the most common catalyst, but Lewis acids have also been used. Good results are obtained for aliphatic R, especially for long chains. When R is aryl, the yields are variable, being best for sterically hindered compounds like mesi-toic acid. This method has the advantage over 18-13 and 18-14 that it is just one laboratory step from the acid to the amine, but conditions are more drastic. Under the acid conditions employed, the isocyanate is virtually never isolated. 

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 the first step of the mechanism, the OH group is converted by the reagent to a better leaving group (e.g., proton acids convert it to OHj). After that, the mecha-nism follows a course analogous to that for the Schmidt reaction of ketones (18-16) from the formation of 71 on ... 

Section C of Scheme 10.15 shows some Schmidt reactions. Entry 14 is a procedure using polyphosphoric acid, whereas Entry 15 was done in H2S04. Entry 16 is a case of conversion of a cyclic ketone, adamantanone, to the corresponding lactam. 

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... 

The Schmidt reaction of ketones with hydrazoic acid is believed to be a similar rearrangement, again with concerted trans migration and elimination of nitrogen. 

When the two groups of the ketone are para-substituted phenyls, the product of the Schmidt reaction is usually a nearly equimolecular mixture of the two isomeric amides.806 This result, obtained instead of a preferential migration of the more electron-releasing group, is consistent with a mechanism in which the formation of the intermediate rather than its rearrangement is rate determining. 

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>. 

The Claisen-Schmidt reaction (Figure 11-17) produces an a,P-unsaturated aldehyde or ketone, the general structure of which is shown in Figure 11-18. The Claisen-Schmidt reaction is a crossed aldol condensation. 

An example of a Claisen-Schmidt reaction forthe formation of ana,p-unsaturated ketone. 

Claisen-Schmidt Reaction The production of an a,P-unsaturated aldehyde or ketone from an aldehyde or ketone in the presence of strong base. 

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. 

Of equal importance to the Beckmann rearrangement for the preparation of azepines and azepinones is the Schmidt reaction of ketones. Again, however, with unsymmetrically substituted cyclohexanones or with bicyclic ketones such as a-tetralone, two azepines are possible, a -Substituted cyclohexanones invariably yield the product of attack by azide ion at the least hindered side of the protonated ketone as exemplified in Scheme 19 (B-67MI51600). 

As with 1,4-oxazepines the Schmidt reaction of cyclic ketones and the Beckmann rearrangement of their oximes can be applied to the synthesis of monocyclic 1,4-thiazepines, 1,4- and 1,5-benzothiazepines and their 1-oxides and 1,1-dioxides (75CJC276). 

Anm. wahrend d. Korr. 6-Methoxy-l-tetralon, in dem dor clcktronische Eliekt des Aromaten dem in (7) vergleichbar ist, liefert jedoch iibcrvvicgend das Laktam mit CO am Bcnzolring [analog (14)] Evans, D. u. I. M. Lockhart, The Schmidt reaction with aromatic ketones. J. Cheni. Soc. [London] 1965, 4806. 

Amides lactams. Dimethyl thioketals of cyclic or acyclic ketones react with iodine azide to form an a-azido sulfide in 75-95% yield. The product rearranges to an amide or a lactam in high yield in the presence of trifluoroacctic acid. This sequence is an attractive alternative to the Beckmann rearrangement or Schmidt reaction. 

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