Diketene synthesis

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). 

Diketene reacts with imines to give l,3-oxa2inones (16) (105). This reaction has been used in the synthesis of the tranquili2er Keta2olam... 

Ketene trimer can be recovered from the tarry residue of diketene distillation and converted into valuable building blocks like 1,3-cyclobutanedione and squaric acid [2892-51-5] (140,141), an important intermediate in the synthesis of pharmaceuticals and squaryHum dyes used in photostatic reproduction (142,143). 

The synthesis of a large number of y-pyrones and y-pyranols from enamines has been brought about through the use of a wide variety of bifunctional molecules. These molecules include phenolic aldehydes (126,127), phenolic Mannich bases (128), ketal esters (129), and diketene (120-132). All of these molecules have an electrophilic carbonyl group and a nucleophilic oxygen center in relative 1,4 positions. This is illustrated by the reaction between salicylaldehyde (101) and the morpholine enamine of cyclohexanone to give pyranol 102 in a quantitative yield (127). 

More and more emphasis has recently been placed on the synthesis of fibre-forming AN copolymers containing reactive groups8. Among the monomers used to obtain reactive copolymers of considerable interest is diketene (1) (2-methylene-4-oxooxe-tane). 

Because the condensation between a diketene acetal and a diol proceeds without the evolution of volatile byproducts, this method allows the preparation of dense, crossUnked materials by using reagents having a functionality greater than 2 (15). Even though either or both the ketene acetal and alcohol could have functionalities greater than 2, only triols were investigated because the synthesis of trifunctional ketene acetals is extremely difficult. 

Materials. Ketene was synthesized as described by Andreades and Carlson ( ) from diketene. Diazomethane was synthesized from N-methyl-N-nitroso-pi-toluenesulfonamide as outlined by Hudlicky (10). A typical synthesis of cyclopropanone involved the slow addition of 400 mL of a 1.0 M diethyl ether solution diazomethane to a 2-3-fold molar excess of ketene at -78°C. This synthesis was based on the... 

An effective two-step synthesis of isobellendine (114) starting from tropi-none (124) has been described by Lounasmaa and co-workers (95). Tropinone (124) is transformed to the corresponding enamine (191), which is then treated with diketene to yield isobellendine (114) in over 30% total yield (Scheme 16). 

Scheme 16. Lounasmaa synthesis of isobellendine (114). Reagents i, morpholine ii, diketene.

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. 

P-Lactams. Diketene can function as an equivalent to acetylketene, CH3C0CH=C=0, to provide 3-acetyl-p-lactams by [2 + 2]cycloaddition with imines.1 A stereoselective cycloaddition of this type can furnish a useful precursor (2) to lp-methylcarbapenems. Thus reaction of diketene with the chiral imine 1, prepared in a few steps from the readily available methyl (S)-3-hydroxy-2-meth-ylpropionate (Aldrich), can provide the desired 3,4-frpreviously developed for synthesis of the antibacterial carbapenem 4. 

The fourth synthesis, developed by the Swiss Lonza company and known as the diketene process, resembles the succinic acid ester process of DuPont in that the central ring of the... 

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 ... 

Shaabani et al. developed a one-pot MCR for the synthesis of 1,6 dihydropyrazine derivatives from condensation reactions among diketene 42, an isocyanide 40, and 2,3-diaminomaleonitrile 41 (Scheme 7) [27]. 

Terpenoid Synthesis from Isoprene.—Syntheses of the useful synthons (33) and (34) have been reported. The vinyl-oxygen bond of diketen is selectively cleaved by Me3SiCH2MgCl-NiCl2 to yield the synthon (35) which is readily converted into the dicopper dienolate (Vol. 7, p. 14) and prenylated to yield (36 X = C02H) after hydrolytic work-up and desilylation (36 X = C02H) yields... 

Solid-phase synthesis of pyrido[2,3 pytirtiidines 514 was achieved by Hantzsch condensation of Wang resin-supported Knoevenagel derivative 513 with 6-aminouracil derivatives 512 as an a-oxo enamine component in the presence of ceric ammonium nitrate (CAN) in DMA followed by hydrolysis with TFA in CH2GI2. Compound 513 was prepared by treatment of a hydroxylated polymer, such as Wang or Sasrin resin, with diketene, followed by condensation with benzaldehyde (Equation 41) <1996TL4643>. 

Industrial synthesis of nerolidol starts with linalool, which is converted into ger-anylacetone by using diketene, ethyl acetoacetate, or isopropenyl methyl ether, analogous to the synthesis of 6-methyl-5-hepten-2-one from 2-methyl-3-buten-2-ol. Addition of acetylene and partial hydrogenation of the resultant dehydroner-olidol produces a mixture of cis- and trans-nerolidol racemates. 

In the synthesis of vitamin A, the dependence on natural sources as well as steadily increasing production via /3-ionone as an intermediate have led to the development of a method for synthesizing citral from dehydrolinalool (see p. 37). More recent routes employ dehydrolinalool as the starting material for pseudoionone. Dehydrolinalool is converted into pseudoionone by using either diketene [92] or a suitably substituted acetoacetate (Carroll reaction) [93] ... 

Diketene also is widely employed as a natural and synthetic fiber cross-linking agent, wood preservative and paper-sizing agent. Both it and /3-propiolactone have wide application as chemical intermediates. The synthetic applications of diketene for the synthesis of aromatic, heterocyclic and aliphatic compounds is exceptionally extensive (74ACR265). 

The construction of the furan ring in a Feist-Benary type reaction starting from 4-hydroxy-6-methylpyran-2-one (66) has also proved to be useful for the synthesis of furo[3,2-c]pyridines (Scheme 14) (75JHC461, cf. 71BSF4041). Quite recently the synthesis of the hitherto unknown furo[3,2-c]pyridin-3-ols has been described (79LA371). 4-Hydroxypyridine-3-carboxylates (e.g. 69), which are available from diketene and /3-aminocrotonic esters, react with a-halogenoketones in the presence of potassium carbonate to give compounds of type 70. 

Diketene is very useful in synthesis, particularly through its reactions with alcohols and amines to give derivatives of 3-oxobutanoic acid ... 

---