Acetoacetic esters diketene

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. 

Another important reaction of diketene derivatives is the Hant2sch pyridine synthesis (101). This synthesis is the preparation of 1,4-dihydropyridines (14) starting either from two acetoacetic esters, which react with an aldehyde and ammonia or a primary amine or from 3-aminocrotonates and 2-alkyhdene acetoacetic esters, both diketene derivatives. Several such dihydropyridines such as nifedipine [21829-25-4] (102), nimodipine [66085-59-4] and nicardipine [55985-32-5] exhibit interesting pharmaceutical activity as vasodilators (blood vessel dilation) and antihypertensives (see Cardiovascularagents). 

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. 

Manufacture and Uses. Acetoacetic esters are generally made from diketene and the corresponding alcohol as a solvent ia the presence of a catalyst. In the case of Hquid alcohols, manufacturiag is carried out by continuous reaction ia a tubular reactor with carefully adjusted feeds of diketene, alcohol, and catalyst, or alcohol—catalyst blend followed by continuous purification (Fig. 3). For soHd alcohols, an iaert solvent is used. Catalysts used iaclude strong acids, tertiary amines, salts such as sodium acetate [127-09-3], organophosphoms compounds, and organometaHic compounds (5). 

Likewise, heterocyclic coupling components are derived from acetoacetic ester, diketene, or 2-hydroxy-3-naphthoic acid and a heterocyclic amine ... 

Bisacetoacetarylide pigments are considered disazo pigments that are obtained from bifunctional coupling components. The latter are obtained by bisacetoace-tylation of aromatic diamines, especially of 4,4 -diaminodiphenyl or 1,4-di-aminophenyl derivatives with 2 equivalents of diketene or acetoacetic ester ... 

The synthesis of the coupling component 5-acetoacetylaminobenzimidazolone (25) corresponds to the preparation of acetoacetarylides (Sec. 2.1.2) from 5-aminobenz-imidazolone by reaction with diketene or acetoacetic ester ... 

Diketene is of course a masked form of acetoacetic ester, and as such reacts in much the expected manner with a variety of mono- and di-nucleophiles. Aromatic and heteroaromatic amines, and phenols, for example, give acetoacetanilides and aryl acetoacetates the latter can be cyclized in excellent yield to coumarins while reaction of the former with excess of diketene followed by cyclization gives dioxopyridines (e.g. equation 164). Amidines, ureas, thioureas, S- alkylthioureas and carbodiimides also react with diketene to give pyrimidines e.g. equation 165), although in the case of amidines, S- alkylthioureas and carbodiimides the initially formed products are 1,3-oxazines which are converted into pyrimidines on subsequent treatment with acid or base. 

The enolate ions of acetoacetic ester and other active methylene compounds react with 0-propiolactone to give the ethoxycarbonyl derivative, but the yields are generally not high. Application of this reaction to 2-ethoxycarbonyldodecanone (equation 53) has been recently patented, with the product reported to be a useful perfume intermediate (77JAP(K)77133952). The reaction is used quite widely with diketene, which gives C-acylation rather than alkylation of the enolate ion, followed by cyclization (72CPB1574). 

Diketene reacts as a masked form of acetoacetic ester with a variety of mono- and di-nucleophiles. Aromatic and heteroaromatic amines give acetoacetanilides which with more diketene cyclize to dioxopyridines, e.g. (170) is formed from 4-aminopyridine. 

Fig. 6.25. Acylation of alcohols with a diketene (A preparation Section 15.4). The reaction product is the acetoacetic ester F.

Reaction of 272 with acrylic acid, /9-chlorobutyric acid, /9-diketones, or a,/9-unsaturated ketones gave the expected diazepines, while acetoacetic ester and diketene reacted only at the primary amino group.323 Similarly, 273 was obtained from acetylacetone and 2,3-dimethyl - 7- aminoindole.32 4... 

An important method for the preparation of /3-keto esters is by the action of alcohols on ketene dimers in the presence of acid catalysts. Diketene and alcohols give acetoacetic esters in 60-80% yields. Dimers of higher ketenes are made by dehydrohalogenation of acyl halides and are converted to /S-keto esters in one operation (cf. method 245). 

The rDA route to isopropenyl acetoacetate and to vinyl acetoacetate was apparently the first synthesis of acetoacetate esters of enols. The reaction between diketene (26) and norbomenols (25a) and (25b) generated the protected ethylene cycloadducts (27), which upon FVP gave the desired isopropenyl acetoacetate (28a) in 48% yield and vinyl acetoacetate (28b) in 61% yield (equation 20). ... 

Treatment of alcohols with diketene in the presence of tertiary amines is a simple and efficient method for the preparation of P-keto esters. As illustrated below, this method is specific for the formation of acetoacetic esters. ... 

An alternative route to y,5-unsaturated ketones is via the Carroll-Claisen rearrangement, which uses allylic esters of 3-keto acids (which exist mainly in the enol form) as substrates. These are readily prepared by condensation of allylic alcohols with acetoacetic esters or diketene. Following rearrangement, the intermediate keto acid undergoes in situ decarboxylation on heating. 

Chemical acetylation of the 3-hydroxymethyl to reform cephalosporin C is complicated by the competing lactonization reaction. This problem is avoided by reacting a desacetyl cephalosporin C derivative salt with acetic anhydride in a non-aqueous system. In the example shown in Figure 15, the triethylamine salt of N-phthaloyl desacetyl cephalosporin C is converted to N-phthaloyl cephalosporin C in dimethylformamide. If the acetoxy group is to be subsequently displaced, other acid anhydrides can be used to prepare other C-3 esters (64). A variation of this approach, also shown in Figure 15, is to react the desacetyl derivative with diketene, which yields the acetoacetate ester (65). 

The substrates can easily be prepared by the condensation of an allylic alcohol with acetoacetic ester. Another approach is the reaction of 5-acyl Meldrum s acid with allylic alcohols214. Treatment of diketene with an allylic alcohol in the presence of catalytic amounts of 4-(dimeth-ylaminojpyridine215 at 20 SC followed by stirring at 20 C makes the generation of the substrates routine (80-93 %100). 

The Carroll reaction uses an acetoacetate ester (54), made by ester exchange or with diketene (Chapter 33), to give enol (55) which can do the [3,3] sigmatropic shift and give keto acid (56) which decarboxylates under the reaction conditions. The synthesis of (53) is standard acetylene chemistry (Chapter 16). 

Acetoacetic ester s. y -Keto-carboxylic acid esters C-Acetoacetylation with diketene 24,708 N-Acetoacetylation with diketene 24, 334, 708 Acetone as reagent (s. a. under Sensitizers) 22, 324 Acetonitrile... 

According to a Hoffmann-la-Roche patent procedure, acetylene is added to acetone in the presence of a base. Reduction with a Lindlar catalyst gives 2-methylbut-3-en-2-ol. Treatment of this with diketene and sodium methoxide renders an isolable acetoacetate ester, which undergoes at 160 °C a Carroll reaction [58] (a Claisen rearrangement with loss of carbon dioxide) to yield the desired intermediate product. 

Structure (332) in which either R or R is H and one of the three dotted lines represents a double bond. As discussed above and shown in Fig. 8.10, dehydrolinalool (46) can be treated with an acetone equivalent, such as 2-methoxypropene, to yield il -ionone directly without going through citral, if the desired product is an ionone as opposed to a methylionone (402). Diketene (403) and acetoacetate esters (403) have also been used. Similarly, the methyl enol ether of 2-butanone can react with dehydrolinalool to give o-methyl-i >-ionone (404). 

Pyrrole itself undergoes a,a -disubstitution. Diazo-acetoacetic ester can be used in this reaction. The mechanism of this reaction, which may be a radical substitution or involve the intermediate formation of a ketene, is uncertain, but it is interesting to note that a number of pyrroles react readily with diketene, giving G-acetoacetyl derivatives, and that ketene converts 2,4-dimethylpyrrole into 2-acetyl-3,5-dimethylpyrrole . In view of these results, the earlier report that diphenylketene converted pyrrole into 1-diphenylacetylpyrrole must be questioned. 

The reaction of diketene with aryl isocyanates in an acid medium furnished derivatives of 50.180,181 It was also found that acetoacetic and benzoylacetic esters react with unsymmetrical dimethylurea to yield 50 and 51, respectively [Eq. (38)]. 

The Carroll rearrangement, a variation on the ester Claisen rearrangement, is a useful method for the preparation of y, 8-unsaturated ketones from allyl acetoacetates, and has been adapted to provide a method for the synthesis of a number of specific arylacetones. Thus, treatment of the p-quinol 1 with diketene and a catalytic amount of DMAP at room temperature gave a 72% yield of the arylacetone 2 together with 5% of the benzofuran 3. 

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