Alkyl Acetoacetate

Routes 1-6 can also be used for the preparation of a broad range of carbon-14-labeled /8-keto esters and acids by replacing [ C]acetyl chloride with other acyl chlorides. Alternatively, higher homologs can be prepared by alkylation of doubly deprotonated alkyl acetoacetates (see Section 6.4.1) 

---

The starting semicarbazones were most often prepared directly from the a-keto acids. Godfrin proceeded from a-alkyl acetoacetates, which were converted by oxidation with nitrosylsulfuric acid to a-keto-acid oximes and the latter transformed to semicarbazones or thioseraicarbazones by applying semicarbazide or thiosemicarbazide. For glyoxylic acid semicarbazone a very convenient procedure was employed, making use of the hydrolysis of nonisolated chloral semicarbazone. ... 

The synthesis of 4-unsubstituted DHPs in a focused microwave reactor has been reported using alkyl acetoacetates and hexamethylenetetramine 19 as the source of both formaldehyde and ammonia, with additional ammonium acetate to maintain the stoichiometry [57], Irradiation for 100 s under solvent-free conditions gave, for example, 1,4-DHP 20 in 63% isolated yield (Scheme 5). 

Fig. 13 Synthesis of oxazoles on JandaJel. Reagents and conditions a toluene, alkyl acetoacetate (R0(C0)CH2C0R R =t-Bu), reflux, 6h or alkyl acetoacetate (R = Me, Et), toluene, LiC104, reflux, 6h fc dodecylbenzenesulfonyl azide, EtsN, toluene, rt, 16 h c benzamide, Rh2(oct)4, toluene, 65 °C, Ih rf Burgess reagent, pyridine, chlorobenzene, MW 100 °C, 15 min (or 80 °C, 4 h with conventional heating) e AICI3, piperidine, CH2CI2, rt, 16 h...

This general procedure is effective for the preparation of many types of phenylhydrazones. For example, a substituted diazo compound can be employed.2 Alkylated acetoacetic esters 8 and ethyl benzoylacetate 4 may be used. For the higher homologs, the a-formyl derivatives of ketones may be used in place of ethyl acetoacetate.6 6 Ethyl pyridylacetates may also be substituted for ethyl acetoacetate.7 The products in these cases are the phenylhydrazones of 2-acylpyridines. 

The route a where an alkyl aminocrotonate 3 was condensed with a substituted benzaldehyde 4 and an alkyl acetoacetate 5 at reflux in a suitable solvent (i.e. methanol, ethanol), to give the corresponding 1,4-dihydropyridine 2 in c.a. 35% yields. Whereas the route b involves the reaction of an alkyl benzylideneacetoacetate 1 with an alkyl B-aminocrotonate 3 appears to afford consistently better yields (34-71%) and easier purification was generally used [ref. 16],... 

Other mono-alkyl acetoacetic esters may be prepared in an exactly... 

In the preparation of some of the higher mono-alkyl acetoacetic esters the yield is sensibly lowered, owing to the formation of di-alkyl compounds due to secondary reactions of the same type as those described on p. 137. This in like manner can be remedied by using only half the calculated quantity of sodium and alkyl halide. The unattacked acetoacetic ester is recovered by distillation. 

Fig. 13.26. Acetoacetic ester synthesis of methyl ketones I preparation of an alkylated acetoacetic ester.

Hantzsch dihydropyridine synthesis. The original Hantzsch synthesis2 involves condensation of two equivalents of a keto ester with an aldehyde in the presence of ammonia. In an enantioselective version.5 the chirality is introduced by use of a chiral hydrazone (2) of an alkyl acetoacetate prepared from 1. The anion of 2 is then treated with Michael acceptors to form adducts (3), which cyclize to 4-aryl-l,4-dihydropyridines (4), in 64-72% overall yield and in 84-98% ee. 

Diketo esters.1 Various N-methoxy-N-methyl amides couple with the dianion of alkyl acetoacetates to form 0,8-diketo esters in 42-91% yield. These... 

Ester-substituted ketone enolates are stabilized, and these enolates can be alkylated (acetoacetic ester synthesis). Alkylation is, however, also possible for enolates that are not stabilized. In the case of the stabilized enolates, the alkylated ketones are formed in two or three steps, while the nonstabilized enolates afford the alkylated ketones in one step. However, the preparation of nonstabilized ketone enolates requires more aggressive reagents than the ones employed in the acetoacetic ester synthesis. 

Disubstituted acetones are formed by alkylating acetoacetic ester a second time before the hydrolysis and decarboxylation steps, as shown in the following general synthesis. 

An acetoacetic ester synthesis goes through alkylation of the enolate, hydrolysis, and decarboxylation.To design a synthesis, look at the product and see what groups are added to acetone. Use those groups to alkylate acetoacetic ester, then hydrolyze and decarboxylate. 

Similar to the Combe synthesis, primary aromatic amines condense with alkyl acetoacetates at lower temperatures to give / -anilinocrotonates, which can be used as precursors for cyclization to 4-hydroxyquinolines177 by action of hot sulphuric acid or hydrochloric acid in a Conrad-Limpach synthesis. 

Ammonolysis of alkyl acetoacetates with 15% aqueous ammonia at 25 °C initially led to the formation of alkyl /3-aminocrotonates 372a,b, which slowly converted into the iminodiazocine 53, as the main product. A plausible mechanism is depicted in Scheme 73. Once formed, the aminocrotonates underwent further ammonolysis to give /1-arni nocroton amide, which cyclodimerized to give the diazocinedione 373, which, in the presence of ammonia, finally underwent a transannular Michael addition to give 53 <2002T55>. 

Acetylacetone and alkyl acetoacetates, both (1,3 nn) species, and per-fluorobut-2-ene, a masked (1,2 ee) compound, react in the presence of sodium hydride at room temperature to give 2,3-bis(trifluoromethyl)furans [83JCS(P1)1239] (Scheme 27). 

Table 5 Hydrogenation of Alkyl Acetoacetate over Raney Nickel Modified with (+)-Tartaric Acid and NaBr...

As with diazo ketones, an a-diazo ester (126) can be prepared by nitrosation of the corresponding a-amino acid (125) or a derivative (equation 51). Alternatively, an a-diazo ester (128) can be prepared by diazo transfer to an alkylated acetoacetate (127), with concomitant deacylation (equation 52). ... 

The fe-carbanions derived from alkyl acetoacetates 17a-e add on the A2-imidazolinium cation 3a to form adduct imidazolidines 18a-e, which could not be obtained in a pure state and were isolated as tautomeric enaminoketoesters 19a e (82TL3301, 83H2129, 85T3345). The formation of homologous enaminoketo-ester 20 from 15 and the fe-carbanion of ethyl acetoacetate 17a is also reported (91T4155). 

Heating 6-amino-l,3-dimethyluracil together with 2-chlorobenzaldehyde and a 4-substituted benzoylacetic ester in refluxing ethanol directly leads to the corresponding 5,8-dihydropyrido-[2,3-(7]pyrimidine.273 Similarly, other uracils react with aromatic aldehydes and various alkyl acetoacetates in propan-2-ol.235... 

---