Acetoacetamides

Acetoiicetyliition Reactions. The best known and commercially most important reaction of diketene is the aceto acetylation of nucleophiles to give derivatives of acetoacetic acid (Fig. 2) (1,5,6). A wide variety of substances with acidic hydrogens can be acetoacetylated. This includes alcohols, amines, phenols, thiols, carboxyHc acids, amides, ureas, thioureas, urethanes, and sulfonamides. Where more than one functional group is present, ring closure often follows aceto acetylation, giving access to a variety of heterocycHc compounds. These reactions often require catalysts in the form of tertiary amines, acids, and mercury salts. Acetoacetate esters and acetoacetamides are the most important industrial intermediates prepared from diketene. 

The most important use of diketene is for the preparation of derivatives of acetoacetic acid, such as acetoacetate esters, acetoacetamides, and chloroacetoacetates, which have found many uses in life sciences, dyestuffs, adhesives, and coatings. 

Physical Properties. Acetoacetic esters are high boiling Hquids with pleasant odors. Lower A/-aLkylamides are water-soluble Hquids acetoacetamide and acetoacetaryHdes are soHds. 4-Chloroacetoacetates are high boiling lachrymatory Hquids. Some physical properties are Hsted in Tables 3 and 4. 

Acetoacetamide [5977-14-0] M 101.1, m 54-55, 54-56. Recrystallise from CHCI3, or Me2CO/pet ether. Crystallises from pyridine with 4mol of solvent. Slightly soluble in H2O, EtOH and AcOH but... 

Quinoxalinecarboxamide 1,4-dioxides were prepared in high yields from BFO and acetoacetamides by adding catalytic amounts of a calcium salt and ethanolamine to the... 

The a.a-diethylacetoacetamide used as starting material was obtained by converting diketene with aqueous ammonia to acetoacetamide and alkylating twice with ethyl bromide in the presence of sodium alcoholate. 

Illiopoulos, P. et al., J. Chem. Soc., Dalton Trans., 1986, 437-443 The dihydrated binuclear complexes between copper(II) perchlorate and N-(2-pyridyl)-acetoacetamide and -benzoylacetamide, [Cu2L2(C104)2].2H20, exploded on heating to 260° C. 

Pyridotriazinone 70 was obtained by the reaction of iV-(2-pyridyl)benzoylacetamide 119 with nitrosobenzene in methanol. The reaction probably involves the attack of two molecules of nitrosobenzene at C-2 of 119 with cleavage of C(l)-C(2) and C(2)-C(3) bonds affording diphenylcarbodiimide and 2-pyridylisocyanate, which undergo a [4+2] heterocycloaddition. Interestingly, the reaction of acetyl analog of 119 did not afford the corresponding bicyclic product, instead, 2-methoxy-2-phenylamino-iV-(2-pyridyl)acetoacetamide was obtained (Equation 14) <2004S2975>. 

Ketcha and Wilson reported the solid-phase version of the classic Nenitzescu indole synthesis in a process involving initial acetoacetylation of ArgoPore-NH2 resin with diketene to afford a polymer bound acetoacetamide <00TL6253>. Formation of the corresponding enaminone 102 via condensation with primary amines in the presence of trimethylorthoformate followed by addition of 1,4-benzoquinones 103 leads to formation of polymer bound 5-hydroxyindole-3-carboxamides 104 which could be cleaved from the resin using TFA yielding the indoles 105. 

B Dissolve 4.26 g triethylamine and 8 g (I) in 200 ml CHC13 cool to -5°, add rapidly 4.58 g ethyl-CI-carbonate and agitate fifteen minutes. Bubble dry NH3 through for five minutes (can possibly substitute concentrated NH4OH) and let stand one hour at room temperature. Add water, wash with NaHC03 and water and dry, evaporate in vacuum the CHCI3 to get 5-methoxy-diethyl-indolyl-acetoacetamide(ll). Test this for activity. 

MCRs of aminoazoles and aldehydes with acetoacetamides are also known. For example, combinatorial-oriented synthesis of potentially pharmacologically active dihydrotriazolopyrimidines 13 was described in [38].The authors considered that carrying out S-alkylation at the last step of pathway a (Scheme 6) was more convenient for the combinatorial procedure however, aU attempts to realize three-component condensation of 3-amino-l, 2,4-triazolo-5-thione 8 with aldehydes 9 and... 

As an alternative, initial S-alkylation of aminoazole 8 with appropriate alkyl-bromides (R3CH2Br) was performed. Then 3-amino-5-alkylthio-l,2,4-triazoles 11 were introduced into the MCRs with aromatic aldehydes and acetoacetamides (pathway b ). To sufficiently increase yields of target heterocycles 13, the cyclocondensations were performed under microwave irradiation in ethanol at 120°C. 

Recently, Nakamura and coworkers described a related reaction of the zinc enolates derived from /3-aminocrotonamides of type 395256. In the presence of a stoichiometric amount of Et2Zn, the latter underwent smooth addition to terminal alkynes upon heating in hexane and afforded the corresponding tetrasubstituted 2-alkylidene acetoacetamides 396 (after acidic hydrolysis of the imine) with high (Z)-stereoselectivity (equation 173). 

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... 

Support-bound C,F I-acidic compounds, such as acetoacetamides, react with isocyanates under basic conditions to yield amides through C-carbamoylation [71]. Similarly, polystyrene-bound aryllithium compounds can be converted into benzamides by treatment with isocyanates [111]. These reactions are closely related to C-thiocarbamoyla-tion, which has been used for the solid-phase synthesis of thioamides (see Section 13.9). Amides have also been prepared by C-alkylation of resin-bound N-acylaminals with allyltrimethylsilane or diethylzinc (Entry 11, Table 13.7). 

Various approaches have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

Diketene reacts with Schiff s bases182 to yield a monooxo product (52) [Eq. (39)]. Acetoacetamide reacts similarly.182... 

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