Grignard with amides

Heterocyclic structures analogous to the intermediate complex result from azinium derivatives and amines, hydroxide or alkoxides, or Grignard reagents from quinazoline and orgahometallics, cyanide, bisulfite, etc. from various heterocycles with amide ion, metal hydrides,or lithium alkyls from A-acylazinium compounds and cyanide ion (Reissert compounds) many other examples are known. Factors favorable to nucleophilic addition rather than substitution reactions have been discussed by Albert, who has studied examples of easy covalent hydration of heterocycles. 

For an improved procedure with amides, see Olah, G.S. Prakash, G.K.S. Arvanaghi, M. Synthesis, 1984, 228. See Martin, R. Romea, R Tey, C. Urpi, R Vilarrasa, J. Synlett, 1997, 1414 for reaction with an amide derived from morpholine and Grignard reagents, whch gives the ketone in good yield. See Kashima, C. Kita, I. Takahashi, K. Hosomi, A. J. Heterocyclic Chem., 1995, 32, 25 for a related reaction. 

The most popular method these days for the acylation of Grignard or organolithium reagents is the Weinreb amide (also discussed in chapter 8). Acylation of vinyl Grignard with the complex intermediate 60 was part of a synthesis of ( )-fumagillolB 62. 

It is possible that the ketone product formed by reaction of a Grignard with an acid chloride or anhydride is. css reactive than those starting materials. If so, significant amounts of the ketone product can be isolated, but the yields are often low. With esters and amides, the ketone product is usually more reactive, very little ketone 1 isolated from the reaction mixture, and the ketone reacts further to form a tertiary alcohol. If a large excess... 

Related isoflavones have been prepared, using SPOS, by Harikrishnan and Showalter. Resin-bound salicyl aldehyde derivatives 336, immobilized via a traceless silyl linker unit, were prepared and treated with a Grignard reagent to introduce the first point of diversity. Subsequent re-oxidation with 2-iodoxybenzoic acid (IBX), and deprotection of the methoxymethyl (MOM) group provided ketone 338. Treatment of ketone 338 with amide acetals promoted an unusual cyclization, which concurrently installed R to give 339. Final traceless cleavage with CsF or TBAF releases isoflavones 340 (Scheme 3.59). 

Ketones. Reaction of 2-pyridylthiol esters with Grignard reagents occurs rapidly to give ketones in almost quantitative yields (eq 5). In all studies, less than 1% of the tertiary alcohol is observed. This procedure works reasonably well with a suitably protected amino acid to give the ketone (eq 6). Phthaloyl protection of the amine is required since esters with amide NH groups decompose when treated with Grignard reagents. ... 

Alkynyl anions are more stable = 22) than the more saturated alkyl or alkenyl anions (p/Tj = 40-45). They may be obtained directly from terminal acetylenes by treatment with strong base, e.g. sodium amide (pA, of NH 35). Frequently magnesium acetylides are made in proton-metal exchange reactions with more reactive Grignard reagents. Copper and mercury acetylides are formed directly from the corresponding metal acetates and acetylenes under neutral conditions (G.E. Coates, 1977 R.P. Houghton, 1979). 

Hydroperoxides have been obtained from the autoxidation of alkanes, aralkanes, alkenes, ketones, enols, hydrazones, aromatic amines, amides, ethers, acetals, alcohols, and organomineral compounds, eg, Grignard reagents (10,45). In autoxidations involving hydrazones, double-bond migration occurs with the formation of hydroperoxy—azo compounds via free-radical chain processes (10,59) (eq. 20). 

Other Rea.ctlons, The anhydride of neopentanoic acid, neopentanoyl anhydride [1538-75-6] can be made by the reaction of neopentanoic acid with acetic anhydride (25). The reaction of neopentanoic acid with acetone using various catalysts, such as titanium dioxide (26) or 2irconium oxide (27), gives 3,3-dimethyl-2-butanone [75-97-8] commonly referred to as pinacolone. Other routes to pinacolone include the reaction of pivaloyl chloride [3282-30-2] with Grignard reagents (28) and the condensation of neopentanoic acid with acetic acid using a rare-earth oxide catalyst (29). Amides of neopentanoic acid can be prepared direcdy from the acid, from the acid chloride, or from esters, using primary or secondary amines. 

The other three methods have not been studied extensively. The dimethyl-cadmium route has been used on a 17a-methyl-17 -carboxylic acid. ° The reaction of the acid amide with a Grignard reagent is described only in a Spanish patent,with a high yield claimed, and the methyllithium reaction has apparently been tried only on D-norsteroids. ... 

Formally analogous to the foregoing Grignard additions are the intramolecular condensations of amides with aromatic systems, found in the Bischler-Napieralski reaction 101), which is of particular interest in isoquinoline and indole alkaloid syntheses (102). Condensations of amidines with reactive methylene compounds also led to enamines (103-106). 

Grignard and alkyl lithium reagents were found to add to the carbonyl group of a tricyclic vinylogous amide. However, the same compound underwent the usual vinylogous reduction with lithium aluminum hydride (712). Grignard additions to di- and trichloroenamines gave a-chloro- and dichloroketones (713). 

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