Acylation Methyl acetoacetate

One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

The reaction of f)-keto esters with primary or secondary amines in the presence of a trace of 4-(dimethylamino)pyridine affords keto amides in good yields. Thus methyl acetoacetate and p-toluidine gave MeCOCT CONHCgTLtMe328. Several selective acylation reactions of amines have been described. Amines are converted into formamides... 

The incorporation of complex side chains at the 7 position based on alkyloximes of 2-amino-thiazole-5-gyloxylamides has provided drugs with very wide antibacterial activity that extend to hitherto resistant species such as pseudomonas. The preparation of one of the simpler side chains involves, first, the formation of the methyl ether from the oxime obtained by the nitrosation of methyl acetoacetate. Chlorination of the product, for example with sulfuryl chloride, gives the intermediate (21-1). The aminothiazole ring is then formed by reaction of that with thiourea to give (21-2). The free acid (21-3) is obtained by saponification of the product. The protected acid chloride (21-5) is obtained by sequential acylation of the amino group with chloroacetyl chloride and then reaction with thionyl chloride. 

Methyl acetoacetate, 60 p-(Tolylsulfinyl)methyllithium, 115 Intramolecular acylation 1,1 -Carbonyldiimidazole, 66 of organometallic reagents to form carbonyl compounds... 

The Reissert reaction would now require a base-catalysed acylation of the methyl group with dimethyl oxalate to give 42. They say All attempts. .. in the presence of various bases to produce intermediate [42] failed. So they used the radical bromination of 43 with NBS (chapter 24) to give 51, alkylated with the anion of methyl acetoacetate to give 52. 

The second route to ipalbidine also provides the first synthesis of its /5-d-glucoside ipalbine.3 2-Methoxypyrroline (4) was condensed with methyl acetoacetate at 85 °C in the absence of solvent to give the keto-ester (5). Acylation of the sodium salt of (5) was achieved with p-methoxyphenylacetyl chloride, but the expected acyl derivative could not be isolated. However, after the addition of a further equivalent of sodium hydride and heating at 80 °C the cyclization product (6) was obtained in moderately good yield. Some of the corresponding carboxylic acid was also isolated. Demethylation and decarboxylation of (6) by means of 48 % hydrobromic acid then gave the tetrasubstituted pyridone (7), which was... 

In continuation of studies on the aromatisation of synthetic polyketides, aryl C-glycosides in the 1,8-dihydroxynaphthalene series were obtained by an approach modelled on biomimetic lines. Thus diethyl 3-hydroxyglutarate (obtained from L-rhamnal) in tetrahydrofuran was added at O C under nitrogen to the lithium-sodium dianion of methyl acetoacetate (15 moles) in tetrahydrofuran/hexamethyl phosphoric triamide (1 1), the mixture was stirred at ambient temperature for 2.5 hours and after acidification the recovered crude diethyl 3,5,9,11-tetraoxo-tridecanedioate was refluxed for 2.5 hours in methanolic solution containing calcium acetate to afford the product shown in 40% yield as a single isomer, after 0-acylation, purification and O-deacylation (ref.61). ( MOM = methoxymethyl)... 

Condensation of ethyl acetoacetate with phenyl hydrazine gives the pyrazolone, 58. Methylation by means of methyl iodide affords the prototype of this series, antipyrine (59). Reaction of that compound with nitrous acid gives the product of substitution at the only available position, the nitroso derivative (60) reduction affords another antiinflammatory agent, aminopyrine (61). Reductive alkylation of 61 with acetone in the presence of hydrogen and platinum gives isopyrine (62). Acylation of 61 with the acid chloride from nicotinic acid affords nifenazone (63). Acylation of 61 with 2-chloropropionyl chloride gives the amide, 64 displacement of the halogen with dimethylamine leads to aminopropylon (65). ... 

The synthesis11 used ethyl acetoacetate which was methylated and cyclised with the guanidine 73 to give the pyrimidone 72 acylation on oxygen gives Aphox directly. 

Carboranyl acid halides can be very easy prepared. We have studied the acylation of malononitrile and acetoacetic ester by methylcarboranyl carboxylic acid chloride (15). The reaction with malononitrile leads to the compound 17a, which exists also as a enol form, similar to compound 13. Compound 17a can be methylated to give compound 17b, a novel synthon for the preparation of wide range of heterocyclic compounds (Scheme 7). 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

The 3-keto reductase step is equivalent to that found in fatty acid synthesis, although it occurs late (and only once) in this process. Indeed, thiol-bound acetoacetate proved inactive as a substrate for the aromatic complex, whereas it was reduced by fatty acid synthetase (Dimrothe/a/., 1972). Thus, the carbonyl group adjacent to the terminal methyl position is not susceptible to reduction by the aromatic synthetase, despite the apparent presence of a suitable reductase, possibly because it is held on the enzyme surface in an inappropriate enolic configuration (Packter, 1973). If so, it may not prove acceptable, since the 3-ketoacyl-acyl carrier protein (ACP) reductase from Escherichia coli only accepts keto substrates and does not react with or bind to the enol form of 3-ketoacyl derivatives (Schulz and Wakil, 1971). 

Acylated acetoacetic esters are cleaved with methanolic potassium hydroxide to give Xn-134, which car be converted to enamines XII-135 with ammonia in the presence of a small amount of ammonium nitrate. Methyl d-alanate and XH 135 in ethanol give the enamines XIl-136, which are cyclized to the 5,6-dihydro-4-pyridones using sodium methoxide in methanol. When the... 

In addition, methyl ketones can be synthesized by the acetoacetic ester synthesis, aromatic ketones can be synthesized by a Friedel-Crafts acylation, and a cyclic ketone, when treated with diazomethane, forms the next-size-larger cyclic ketone. Unless you have an exceptional memory, recalling all the methods you have learned to synthesize a particular functional group might be challenging. Therefore, they are listed for you in Appendix III. 

Michael addition of ethyl [3- C]acetoacetate to ethyl crotonate followed by an intramolecular tandem enolate acylation opens an altemative approach to highly substituted labeled resorcinols (e.g., 3291 (see also Section 6.5.1). Aromatization of the initially formed ethyl 6-methyl-4-hydroxy-2-oxo[l- " C]cyclohex-3-ene-l-carboxylate 13271 is readily... 

Ketoenamine (115), which had previously been used in studies by Lao, Witter and Cheng (c/. Scheme 8) was condensed with ethyl acetoacetate to produce acylpyridone (116) (Scheme 17). Reduction of the acyl group to the alcohol and further treatment with POCk simultaneously dehydrated this alcohol to the vinyl group and converted the pyridone to the chloropyridine (117). Cuprous cyanide served to replace the chlorine with a cyano group giving (118) which was transformed to the methyl ketone (119) with methylmagnesium bromide. 

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