1.3- Dicarbonyl compounds from acetals

The wide applicability of the PK reaction is apparent in the synthesis of pyrroles, for example, 45, en route to novel chiral guanidine bases, levuglandin-derived pyrrole 46, lipoxygenase inhibitor precursors such as 47, pyrrole-containing zirconium complexesand iV-aminopyrroles 48 from 1,4-dicarbonyl compounds and hydrazine derivatives. The latter study also utilized Yb(OTf)3 and acetic acid as pyrrole-forming catalysts, in addition to pyridinium p-toluenesulfonate (PPTS). 

Disubstituted furans are available from the combination of P-dicarbonyl compounds with bromoacetaldehyde diethyl acetal (44). For example, dibenzoylmethane (45) reacts with acetal 44 to furnish 2,3-disubstituted furan 46 in 77% yield. This two-... 

The synthesis of 2-substituted pyrimidines from 1,3-dicarbonyl compounds and urea derivatives was first described by Evans2 and was later improved by Hunt, McOmie, and Sayer3 for the preparation of 2-mercapto-4,6-dimethylpyrimidine. Burness4 employed 3-ketobutyraldehyde acetal in this procedure to give 2-mercapto-4-methylpyrimidine. 2-Mercaptopyrimidine has been prepared from 1,1,3,3-tetraethoxypropane and thiourea by variations of this basic method 3 6 6 as well as by the reaction of 2-chloropyrimidine with thiourea 1 or sodium hydrosulfide.8... 

The synthesis of imidazoles is another reaction where the assistance of microwaves has been intensely investigated. Apart from the first synthesis described since 1995 [40-42], recently a combinatorial synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles has been described on inorganic solid support imder solvent-free conditions [43]. Different aldehydes and 1,2 dicarbonyl compounds 42 (mainly benzil and analogues) were reacted in the presence of ammonium acetate to give the trisubstituted ring 43. When a primary amine was added to the mixture, the tetrasubstituted imidazoles were obtained (Scheme 13). The reaction was done by adsorption of the reagent on a solid support, such as silica gel, alumina, montmorillonite KIO, bentonite or alumina followed by microwave irradiation for 20 min in an open vial (multimode reactor). The authors observed that when a non-acid support was used, addition of acetic acid was necessary to obtain good yields of the products. 

A mixture of 1,4-dioxane and water is often used as the solvent for the conversion of aldehydes and ketones by H2Se03 to a-dicarbonyl compounds in one step (Eq. 8.117).331 Dehydrogenation of carbonyl compounds with selenium dioxide generates the a, (i-unsaturated carbonyl compounds in aqueous acetic acid.332 Using water as the reaction medium, ketones can be transformed into a-iodo ketones upon treatment with sodium iodide, hydrogen peroxide, and an acid.333 Interestingly, a-iodo ketones can be also obtained from secondary alcohol through a metal-free tandem oxidation-iodination approach. 

What is described as a domino Knoevenagel-hetero-Diels-Alder reaction , involving the reaction of the glucose-derived aldehyde 93 with a 1,3-dicarbonyl compound in presence of either proline or ethylenediammonium acetate, leads to the doubly annulated 5 6 6-fused compound 94 (Scheme 30) <2004S1150>. If the dicarbonyl compound is Meldmm s acid, however, the sequence is completed by spontaneous elimination of acetone and carbon dioxide from the Diels-Alder adduct, to give compound 95 <2005ASC1353>. 

A large proportion of the condensation products of sugars with dicarbonyl compounds have been obtained in the crystalline state however, some have not yet been crystallized. All are more soluble in hot than in cold water. Those resulting from the condensations with heptoses, hexoses, and pentoses are almost insoluble in benzene. Generally speaking, all are soluble in ethyl acetate. 

In the presence of bis(acetylacetonato)nickel, a-dicarbonyl compounds readily add at the nitrile group of 4-R-substituted l,2,5-oxadiazole-3-carbonitriles 219 to form enaminofurazans 220. The adducts obtained from 4-amino-3-cyanofurazan underwent intramolecular cyclization upon heating with acetic acid in ethanol to give furazano[3,4- ]pyridine 221 derivatives in high yields (Scheme 51) <2001RCB1280>. 

The low yield in this reaction might be caused by a number of reasons. First, the overall reaction is only rapid for readily enolizable compounds. 1,3-Dicarbonyl compounds will therefore be a better choice as compared to acetic acid. Second, to prevent oxidation of radical 54, it is advantageous to work with excess diene and therefore speed up trapping of 54 through diene addition. Finally, lactone 55 can, as an enolizable compound itself, also be oxidized by manganese(III) acetate and form various oxidation products. Shorter reaction time and the use of understoichiometric amounts of oxidant might therefore benefit the overall result. All these factors have been taken into account in the synthesis of bicyclic /-lactone 56, which has been obtained from cyanoacetic acid and 1,3-cyclohexadiene in 78% yield within 15 min reaction time (equation 25)60,88. 

General procedures for the synthesis of the imidazole core have been published in 2000. Solvent-free microwave assisted synthesis of 2,4,5-substituted imidazoles 64 from aldehydes 62 and 1,2-dicarbonyl compounds 63 in the presence of ammonium acetate and alumina has been reported <00TL5031>. V-protected a-amino glyoxals 65 were utilized as potential chiral educts for the synthesis of amino acid-derived imidazoles 66 <00TL1275>. 

Scheme 7.49). The requisite activated double bond is generated in situ from the 1,3-dicarbonyl compound and a one-carbon synthon such as a trialkyl orthoformate, diethoxymethyl acetate or Al,Al-dimethylformamide dimethyl acetal. 

It is not customary to attempt the isolation of ketone or aldehyde intermediates (121) the formula serves merely as a reminder that once hydrolysis of the protecting enol ether or acetal occurs, the same type of structure is formed from any given dicarbonyl compound. Cyclization has been carried out in refluxing ethanolic picric acid or acetic anhydride with a few drops of sulfuric acid, but Hansen and Amstutz (63JOC393) offered excellent theoretical reasons for avoiding an excess of acid, and reported that best results (Table 3) can be obtained by refluxing the dry hydrobromide in acetic anhydride containing no sulfuric acid. 

H-1,4-Benzodioxepin-ones and -diones have been prepared (72HC(26)319, p. 339) sodium salicylate and 2-chloroethanol give (385) (75BSF(2)277) and the methyl ester of 2-acetyl-6-chloro-3,5-dimethoxy-phenoxyacetic acid with hydrochloric acid gives (386). The dicarbonyl compound (387) is prepared by heating 2-carboxy-5,6-dimethoxyphenoxyacetic acid in acetic anhydride. Dicarbonyl compound (388) is prepared from chloroacetylsalicylic acid. 

The reversal of the well-known transformation of sugars into pyrans has been detailed as a method for assembling simple monosaccharides from simple furans (71T1973). A compound of the 2-furylcarbinol type was converted by the Br2/MeOH procedure into a mixture of the cis and trans isomers of the corresponding 2,5-dimethoxy-2,5-dihydrofuran derivative (129). Mild acid hydrolysis of (129) resulted in cleavage of the acetal bonds with formation of the dicarbonyl compound (130) which underwent immediate cyclization to 2,3-dideoxy-DL-alk-2-enopyranos-4-ulose (131 Scheme 29). 

Several significant pyrrole syntheses involve the formal tricomponent cyclization of type III ace (equation 126). The Hantzsch pyrrole synthesis involves a dicarbonyl compound, an a -halo ketone and ammonia or an amine. The mechanistic pattern is similar to that involved in the Knorr synthesis (Section 3.06.3.4.1). In addition to a-halo ketones and a-haloal-dehydes, compounds such as 1,2-dichloroethyl acetate, 1,2-dibromoethyl acetate and 1,2-dichloroethyl ethyl ether can serve as a -haloaldehyde equivalents (equation 127) (70CJC1689, 70JCS(C)285>. It is believed that the initial step in these reactions is the formation of a stabilized enamine from the amine and the /3 -dicarbonyl compound. A structural ambiguity... 

Enamine (235) obtained from cyclic ketones and the acetal of /V-methyl-2-pyrrolidone gave a fused 2-pyrone [83IJC(B)1083]. 2//-Chromenes were obtained from of 3,5-dichlorosalicylaldehyde and enamines (94RRC183) (Scheme 42). The pyran ring is formed by a reaction of aminals of conjugated w-dimethylaminoaldehydes with cyclic /1-dicarbonyl compounds (94IZV285) (Scheme 43). 

Acetals and ketals Acetals and ketals from dicarbonyl compounds... 

Carbanions derived from aldehydes or a-dicarbonyl compounds, with one of the carbonyl groups protected as a dimethyl acetal, also react with o-iodoanilines to give indoles319. 

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