1,3-Dicarbonyl compound

The second class of 1,3-dixygenated compounds is characterized by two carbonyl groups in the 1,3-position. Depending on the structure of group R , they belong to 

3- dicarbonyl pattern results in two logical synthons, an a-carbanion stabilized by conjugation and an acyl cation. The acyl cation has a number of acceptable reagents in reactive derivatives of carboxylic acids. Reactive enough with carbanions are carboxylic acid esters affording 1,3-dicarbonyl compounds in the well-known ester condensation, also known as Claisen condensation. The next example serves as an introduction to the retrosynthetic analysis of this pattern. 

Example 4.8 Complete the retrosynthetic analysis of TM 4.5 and suggest its synthesis. 

MONOPROTECTION OF DICARBONYL COMPOUNDS Selective Protection of a- and p- Diketones 

Methyl Enol Ether, Ethyl Enol Ether, i-Butyl Enol Ether 

R = (CH3)2CHCH2 (/-BuOH, benzene, reflux, TsOH, 16 h, 100% yield). In Ibis case, 2-metbyl-l,3-cyclopentanedione was monoprotected. 

The best method found for cleavage was MgBr2 Et20, EtSH, Et20, rt. Without EtSH, the released formaldehyde reacts with the p-keto ester. 

Ethyl vinyl ether has been used to prepare a related acetal.  

The compounds described in this section are diketones keto acids and keto esters, which may also be classified as dicarbonyl compounds, are considered in Section 5.14.3, p. 735. The relative location of the two carbonyl groups in the carbon chain may be designated numerically or by letters of the Greek alphabet. The alkyl groups may be the same or different the formulae below also represent keto aldehydes and dialdehydes when one or both of the residues (R), are hydrogen. 

Synthon Some reagent equivalents Cross-references 

Clearly there are a number of possible combinations, particularly when possible strategies for the preparation of unsymmetrical and substituted diketones [e.g. R1,CO,CH2,CO,R2 and R COCHijR -COR3] are considered. A few of these are exemplified in the preparative methods which are discussed below. 

Some typical and important members of this class have structures as follows1 

Ethanedial undergoes an internal Cannizzaro reaction with alkali to give hydroxyethanoic (glycolic) acid  

An analogous reaction occurs with diphenylethanedione, which results in carbon-skeleton rearrangement. This is one of the few carbon-skeleton rearrangements brought about by basic reagents, and is known as the benzilic acid rearrangement.  

Exercise 17-42 What experiments may be done to prove or disprove the following mechanism for rearrangement of ethanedial to hydroxyethanoic acid  

17 Carbonyl Compounds II. Enols Enolate Anions. Unsaturated and Polycarbonyl Compounds 

Ethyl acetoacetate and acetylacetone react very slowly with MA at room temperature. Over 2-3 weeks, both form an adduct containing 2 moles of MA. Berner first examined this reaction in 1946. Acetylacetone gave a 60-70% yield of an adduct 101b. No yield of the adduct from 101a was reported. Interpretation of the structure of these products has caused some difficulties.However, further spectroscopic examination by Bird and 

Molton, as well as Bailey and Stunz, Berner and Kolsaker, and Krow confirm the structure to be 101. 

The products of this reaction are proposed to arise as follows  

Krow has invoked slightly different mechanistic rationalizations involving a Michael addition in the first step. The products of this reaction appear to be very interesting intermediates. 

In the chapter on olefinic reactions, it was observed that mild hydrogenation of MA produces succinic anhydride (SA). Further reduction of SA can give rise to y-butyrolactone 102. This can be accomplished catalytically on a platinum catalyst.y-Butyrolactone 102 can also be further reduced to THF 103. Both these products are commercially significant. In 1976, 83 MM lb of THF were produced in the United States.Most of this is derived from acetylene as raw material. y-Butyrolactone 102 is also a good solvent, intermediate, and monomer, and can be converted to pyrrolidone derivatives. 

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The reaction of diketosulfides with 1,2-dicarbonyl compounds other than glyoxal is often not efficient for the direct preparation of thiophenes. For example, the reaction of diketothiophene 24 and benzil or biacetyl reportedly gave only glycols as products. The elimination of water from the P-hydroxy ketones was not as efficient as in the case of the glyoxal series. Fortunately, the mixture of diastereomers of compounds 25 and 26 could be converted to their corresponding thiophenes by an additional dehydration step with thionyl chloride and pyridine. 

Finally, the Hinsberg synthesis has been extended to the use of a-aryl-a-carboethoxydimethyl sulfide in conjunction with a series of 1,2-dicarbonyl compounds. Specifically, the 4-nitroaryl substituent provides for sufficient activation of the a-proton to allow condensation and ring closure. These examples appear general and suggest future opportunities for the Hinsberg thiophene protocol. 

The Pictet-Spengler reaction is one of the key methods for construction of the isoquinoline skeleton, an important heterocyclic motif found in numerous bioactive natural products. This reaction involves the condensation of a P-arylethyl amine 1 with an aldehyde, ketone, or 1,2-dicarbonyl compound 2 to give the corresponding tetrahydroisoquinoline 3. These reactions are generally catalyzed by protic or Lewis acids, although numerous thermally-mediated examples are found in the literature. Aromatic compounds containing electron-donating substituents are the most reactive substrates for this reaction. 

Model studies directed toward the synthesis of Ecteinascidin 743 employed an elegant Pictet-Spengler cyclization of phenethylamine 54 and the 1,2-dicarbonyl compound 55 to assemble the spiro tetrahydroisoquinoline 56 in a stereospecific fashion. " The silica-catalyzed condensation reaction provided 56 in excellent yield. 

The reactions of heterocyclic 1,2-dicarbonyl compounds with diazomethane, which were studied by Eistert and his co-workers in... 

Benzothiepins 2 can be synthesized by a double Knoevenagel condensation starting from phthalaldehydes I and diesters of thiodiglycolic acid, or diphenacyl sulfide.33-63 " 66 In principle, this is an extension of Hinsberg s synthesis of thiophenes (see Houben-Weyl, Vol. E6a, p 282) which employs 1,4-dialdehydes rather than 1,2-dicarbonyl compounds. 

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. 

The cyclization of 1,2-dicarbonyl compounds with aldehydes in the presence of NH4OAC to give imidazoles was employed in a combinatorial study that compared conventional and microwave heating in the preparation of a library of sulfanyl-imidazoles (Scheme 15). The study employed an array of expandable reaction vessels that could accommodate a pressure build-up system for heating without loss of volatile solvents or reagents. A 24-membered library of imidazoles (48 and 49) was prepared in 16 min instead of the 12 h required using conventional heating [45]. 

Because of the equilibrium between silylated alcohols and free carbonyl compounds, the reaction between silylated alcohols ROSiMe3 13 and free enolized 1,2-dicarbonyl compounds such as 403 in the presence of 1% CF3SO3H results, at... 

Two series of phosphoranes (86 or 87) containing a dioxaphos-pholene ring and a 2-phospholene or 3-phospholene ring have been synthesised from trico-ordinate phospholenes (83) or (84) and 1,2-dicarbonyl compounds (85)1 7. The compounds were characterised by analysis, XH and J1P n.m.r. and, in contrast to earlier work,1 8 were found to be stable towards the retrodiene fragmentation. 

In other cases, oxidation of the rhodium or palladium ketocarbenoid to a 1,2-dicarbonyl compound is well established The Rh2(OAc)4-catalyzed decomposition... 

Several 3-(2H)pyridazinones have been prepared from monophenyl hydrazones of 1,2-dicarbonyl compounds and a variety of active methylene compounds within 1-20 min without solvent under focused irradiation in the presence of carefully adjusted amounts of piperidine or solid potassium tert-butoxide (isolated yields 50-89%), in accordance with Scheme 8.49 [72, 73]. 

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>. 

One of the most common approaches to pyrazine ring construction is the condensation of diaminoethane and 1,2-dicarbonyI compounds such as 206 to provide pyrazines 207 after aromatization. Aromatization was accomplished by treating the dihydropyrazines with manganese dioxide in the presence of potassium hydroxide <00JCS(P1)381>. The N-protected 1,2-dicarbonyl compounds 206 were prepared from L-amino acids by initial conversion into diazoketones followed by oxidation to the glyoxal. 

The traditional method to the construct the pyrazine ring of quinoxalines proceeds by the condensation between an o-phenylenediamine with a 1,2-dicarbonyl compound. For example, the reaction of diamine 240 and glyoxal afforded the pyridoquinoxalines 241 in excellent yields <00H423>. 

Similar chemistry was applied by Heeg and co-workers in their synthesis of substituted quinoxalines 244, which were prepared by condensation of diamine 243 with 1,2-dicarbonyl compounds <00JHC1273>. Vagg utilized analogous chemistry to synthesize phenazines as well as quinoxalines (Section 6.2.8.1). 

Dicarbonyl compounds also act as excellent spin traps for neutral RsM radicals, forming adducts of structure 5, 6 or 7 depending upon the dicarbonyl compound and the nature of the ligand bound to the metal centre. Of course, for cyclic dicarbonyl compounds such as ortho quinones the trans structure 7 is not accessible because of geometric constraints. Data for these radicals are contained in Table 4. 

TABLE 4. ESR spectral data for the radicals formed between 1,2-dicarbonyl compounds and R1R2R3M ... 

Condensation of 1,2-bishydroxylamines (84) with 1,2-dicarbonyl compounds leads to derivatives of 2,3-dihydropyrazine-l,4-dioxides (85) (255), whereas the reaction with ninhydrin gives [1,2-b] pyrazine N,N -dioxides (86) (Scheme 2.32)... 

Highly substituted pyrrolo[l,2- ][l,2,4]triazines were synthesized from pyrrole derivatives, by closure of the triazine ring. Thus, hydrolytic cleavage of some 1,2-diaminopyrroles having a 1-NH-BOC-protected amino function 43 followed by reaction with 1,2-dicarbonyl compounds afforded a one-pot access to the corresponding bicyclic heterocycles 44 (BOC = f-butoxycarbonyl Equation 6) < 1997J(P 1)1829>. 

The interaction of 1,2-dicarbonyl compounds and dihydrazides in 1 1 ratio yields 3,4-dihydro-2/7-l, 2,4,5,3-tetra-azaphosphepine 3-sulphides (10).12... 

The reaction between dialkyl phosphorocyanatidite and acyl cyanides in dichloro-methane at 0 °C parallels that between the same phosphite and 1,2-dicarbonyl compounds, and is probably initiated by attack of tervalent phosphorus on the carbonyl group the formation of O- and V-alkyl products, (30) and (29), is an indication of the probable nature (28) of an intermediate.25 The extension of the reaction (see Organophosphorus Chemistry , Vol. 7, pp. 108, 126) to include ethyl phosphorodicyanatidite and 1-keto-esters provides a route to the 5-phosphabicyclo-[3,2,0]heptanes (31) in high yields.26... 

Anodic oxidation of the monooxime phenylhydrazone of a 1,2-dicarbonyl compound 93 in CH3CN-O.I mol/I Et4NC104 solution gave 2-phenyl-1,2,3-triazol-1-oxide 94 in very good yield [125,126] (Scheme 51). 

Amides of A As react with 1,2-dicarbonyl compounds in a general synthesis to give the corresponding pyrazinones (49JA78 52JA1580 67CB555 78JHC665). 

The versatility and high efficiency coupled with the synthetic significance of 1,2-dicarbonyl compounds make this procedure a powerful tool in organic synthesis. In... 

The preparation of (128) (Scheme 34) highlights the use of the trifluoromethyl group to increase the dipolarophilicity of a ketone. This activating effect of electron withdrawing groups is also taken advantage of in the preparation of 3-carbonyl substituted 1,2,4-trioxolanes (131) via the ozonolysis of a vinyl ethers in the presence of a 1,2-dicarbonyl compound (Scheme 36) <9iJOC659l>. 

Among the four isomers of dihydropyrazines, the 2,3-dihydro isomers are most explored because these reduced pyrazines have been easily prepared by condensation of 1,2-diamines and 1,2-dicarbonyl compounds. This class of compounds is unexpectedly unstable resulting in dimerization at room temperature. Thus, 2,3-dihydropyrazine 97 (R = = Me) gradually dimerizes to form tricyclic system 98, fused with two tetrahydropyrazine units... 

Condensation of 1,2-diaminobenzenes with 1,2-dicarbonyl compounds furnishes a variety of substituted quinoxalines 142 <1995JOC8283>, 143 <2004SC1349>, 144 <1999JHC1271>, 145 <1999JME2266>, 146 <1993JME2335>, 147 <20030L4089>, and 148 <2005TL6155> (Scheme 39). 

In addition to 1,2-dicarbonyl compounds, 1,2-diaminobenzenes condense with a-oximino ketones <2000JHC355>, epoxides <1999SC3459>, ethyl pyruvate <2000H(52)911>, and ethyl carboethoxyformimidate <19978301, 1999J(P1)1789> to produce quinoxaline derivatives. 

An old but practical synthetic method for 2(l//)-pyrazinones is Jones procedure which involves condensation of a-amino amides with 1,2-dicarbonyl compounds (Section 8.03.9.1). A number of stepwise approaches using a-amino acids to 2(177)-pyrazinones have been discussed in Section 8.03.9.4. 

Nair et al. (87,88) achieved a synthesis of spirooxindole-containing molecules by adding isatins to various carbonyl ylides (Scheme 4.46). There has been relatively little research regarding the efficiency of C=0 of 1,2-dicarbonyl compounds as dipolarophiles relative to their olefinic counterparts. As anticipated, Nair found that the more electrophilic carbonyl of the isatin 187 (non-amide carbonyl) reacted smoothly with the carbonyl ylide formed from diazoketone 186 to give the spirocyclic adduct 188. Nair s yields were moderate to good (44—83%), but were based on recovered isatin. 

In the second study, diketones were used as electrophiles and reacted with N-benzoylglycine to give a (Z/E) mixture of oxazolones 366 and 367 derived from condensation at the less hindered carbonyl group of the 1,2-dicarbonyl compound (Scheme 7.116). The ( )-isomers 367 were used as starting materials to prepare (Z) -5 - alky lidene- 3 - (benzoy lamino) -2(5//)-furanones 368... 

The pyrazine ring structure warrants the use of methodology analogous to that of pyridazines for their preparation. Condensation of diaminoethane with 1,2-dicarbonyl compounds 155 provides non-symmetrical pyrazines 156 after aromatization <99SL1203>. 

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