Keto esters, brominated

The bromine adds on at the ethylenic linkage to form thedibromo compound (I), which easily loses hydrogen bromide to give the mono-bromo keto ester (II) ... 

A structurally unrelated agent is tazadolene (40). The synthesis of tazadolene begins with P-keto ester 37 and subsequent enamine formation with 3-amino-1-propanol followed by hydrogenolysis to give 38. This phenylhydroxymethyl compound is then dehydrated with hydrochloride acid to form olefin 39. Treatment with bromine and triphenylphosphine effects cycliza-tion to form the azetidine ring of tazadolene [10]. 

A piridazine ring forms the nucleus for a rather unusual nontricyclic antidepre.ssant. Condensation of the keto ester 136 with hydrazine leads to the cyclic hydrazide 137. Oxidation, for example with bromine, gives the corresponding pyridazone 138. The oxygen is then replaced by chlorine by reaction with phosphorus oxychloride. Displacement of the halogen in 139 with N-ethylami-nomorpholine affords minaprine 140 [30]. 

The finding that the anthelmintic thiazoloimidazole levamisole showed immunoregulatory activity spurred further investigation of this heterocyclic system. Synthesis of a highly modified analogue starts by displacement of bromine in keto ester 149 by sulfur in substituted benzimidazole 148. Cyclization of the product (150), leads initially to the carbinol 151. Removal of the ester group by saponification in base followed by acid-catalyzed dehydration of the carbinol affords the immune regulator tilomisole (152) [28]. 

Another Lewis acid-catalyzed atom-transfer domino radical cyclization, to produce various bicyclic and tricyclic ring skeletons, has been developed by Yang and coworkers [54]. Reactions of the a-bromo-(3-keto ester 3-125 with Yb(OTf)3 and Et3B/02 led to the bicycle 3-126 in 85 % yield (Scheme 3.33). The reaction proceeds via a (>-endo-Irig and 5-exo-trig cyclization after initial abstraction of the bromine... 

Condensation of 3-nosyloxy-2-keto esters 305 with methyl carbamate in refluxing toluene in the presence of p-toluenesulfonic acid provides 2(3/7)-oxazolone -carboxylates 306 in good yields (41-80%). Alternatively, condensation of 3-bromo-2-keto esters 307, derived from the bromination of a-keto esters with CuBr2, with methyl carbamate in the presence of AgOTf and p-toluenesulfonic acid under similar conditions provides the 2(3//)-oxazolone-4-carboxylates 306 in comparable yields (30-79%) (Fig. 5.78 Table 5.15, Fig. 5.79). ... 

Bromination of Beta Keto Esters. The work of K. A. Pedersen on the bromination of beta keto esters in the presence of copper(II) and other divalent metal ions provides several examples of reactions proceeding via complexes (29), The complexes provide an alternative and much more rapid route for the bromination reaction. These reactions are accelerated by bases which take up a proton from the beta keto esters. For such substrates, e.g. ethyl acetoacetate, the general expression for the pseudo first order rate constant in the presence of copper has the form ... 

Complexes of related species such as keto acids, keto esters, and acetoacetanilides are known, particularly for beryllium.93 270 285 286,287 Bromination and nitration studies have been carried out on a wide range of -substituted N-acetoacetamides of beryllium and show introduction of bromo and nitro groups at the 3-position.285,286... 

A useful route to a,/(-acetylenic acids, illustrated by the preparation of but-2-ynoic acid (Expt 5.217), involves the base-induced decomposition of the dibromopyrazolone which is obtained by brominating pyrazol-5-one, which is itself prepared by the reaction of a / -keto ester with hydrazine. 

Sideritis canariensis contains trachylobane, (—)-kaurene, and some 7)S,18-dihydroxy-( — )-kaur-16-ene, together with trachinodiol [(7fi, 18-dihydroxytrachyl-obane (93)] and trachinol (7)5-hydroxytrachylobane). The structure of trachinodiol was established by interconversion with trachylobane. Oxidation gave a keto-ester, which on bromination and dehydrobromination afforded an a -unsaturated ketone whose substitution pattern located the carbonyl group at C-7. 

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

The bromination of j8-keto esters is quite similar to that of /3-diketones. Ethyl acetoacetate was found to undergo electrophilic substitution at the... 

The effect of a number of metal ions on the rate of bromination of 2-carbethoxycyclopentanone (XI) was studied, since the presence of only one a-hydrogen atom in this /3-keto ester should considerably simplify the kinetics (164) ... 

Copper complexes bearing bisoxazolines were described by Cahard [44]. Ligand 7 induces moderate to good enantiomeric excesses in the fluorination of 3-keto esters. Bolm described the application of chiral sulfoximine 8 as ligand for copper triflate and subsequent application of this catalyst in all three halogenation reactions of chlorination, bromination and fluorination employing various 3-keto esters [45]. 

Bromination of Carbonyl Derivatives. Reaction of a complex silyl enol ether with NBS leads to an a-bromo ketone in the Ogasawara synthesis of (—)-morphine. Amberlyst-15 promotes the bromination of 1,3-keto esters and cychc ketones with NBS. a-Bromination of carbonyl compounds has been achieved using NBS in the presence of silica-supported sodium hydrogen... 

A process of selenocatalytic a-halogenation using NBS has been reported. A catalytic enantioselective bromination of -keto esters has been achieved using a combination of NBS and TiCl2(TADDOLato) complexes as enantioselective catalyst modest enantiomeric excesses were obtained. 

Dianions of /8-keto-esters can be alkylated with a-chloro-ethers to give 5-alkoxy-jS-keto-esters in ca. 70% yield. These compounds serve as useful alternatives to y5-unsaturated-/8-keto-esters in the Robinson annelation reaction.Clean nucleophilic displacement of bromine from y-bromoacetoacetates can be effected by prior protection of the keto-ester system as the sodium enolate. ... 

If both the radical source and the radical trap are in the same molecule, then an intramolecular atom-transfer radical cyclisation reaction occurs. In 2001, Yang et al. reported the oxazoline 39d-magnesium-catalysed bromine atom-transfer radical cyclisation reaction of unsaturated p-keto ester 49 for... 

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