Synthesis of 1,5-Dicarbonyls

Show the product formed from each Michael reaction in the solution to Example 15.10 after (1) hydrolysis in aqueous NaOH, (2) acidification, and (3) thermal decarboxylation of each /3-ketoacid or /3-dicarboxylic acid. These reactions illustrate the usefulness of the Michael reaction for the synthesis of 1,5-dicarbonyl compounds. 

The synthesis of 4//-pyrans by the ring closure of 1,5-dicarbonyl compounds or their equivalents was the subject of a review <2000CHE1007>. In a specific example, 2,6-bis(silyl)-47/-pyrans 211 are synthesized by the cyclodehydration of the corresponding l,5-bis(silyl)pentane-1,5-diones 210 in good yields (Scheme 116) . 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

Synthesis of 1,4-dicarbonyl compounds and cyclopentenones from furans , Piancatelli, G., D Auria, M., and D Onofrio, F., Synthesis, 1994, 867. 

This reaction has a wide range of application in the preparation of 1,5-dicarbonyl compounds, especially in regard to the synthesis of the smallest known bicyclic compound ([4.3.1] undecane) with trans bridgehead hydrogen. 

MORE ENOLATE REACTIONS SYNTHESIS OF 1,3-DICARBONYLS, 1,5-DICARBONYLS, AND CYCLOHEXENONES... 

Alkylpalladium derivatives formed by the attack of Pd-alkene complexes with stabilized carbanions can undergo carbon monoxide insertion, leading to the formation of 1,5-dicarbonyl derivatives. With enamides as the alkene substrates, nucleophiUc attack occurs exclusively a to N, and the carbonylation produces highly functionalized /3-amino acid derivatives, which can be cyclized to /3-lactams, as indicated by the synthesis of ( )-thienamycin shown in Scheme 19 ... 

Probably the most popular carbon-carbon double-bond-forming reaction involving sulphur proceeds via the elimination of a sulphur-oxygen species. This is illustrated by a synthesis of 1,5-unsaturated dicarbonyl compounds (236) which proceeds by phenylthioalkylation of enolates (236a), using the phenyl-thioalkene (237), followed by ozonolysis and elimination of the sulphoxide moiety to provide the double bond. An alternative method for double-bond formation is shown in the preparation of alkenes R CH=CHR by reductive cleavage of the sulphide (238) with titanium salts, and demonstrates the versatility of sulphur in such double-bond formations. In the latter example... 

Organocopper )V)V-dimethylhydrazone (DMH) derivatives have been used for the synthesis of a variety of 1,5-dicarbonyl compounds. In contrast to the normal Robinson annelation of 2-methylcyclohexanone, which leads to attachment of methyl vinyl ketone analogues at C-(2) and eventual formation of (56), the organocopper DMH derivative of 2-methylcyclohexanone reacts with methyl vinyl ketone to give the 1,5-diketone (57), which undergoes base cyclization to the octalones (58). 

There are few reports in which the 5-lactone ring is constmcted through a samarium iodide-mediated reductive cyclization of 1,5-dicarbonyl compounds. In the first example. Fang, Tsai et al. have reported the synthesis of 5-lactones using samarium... 

Example The lactone (8>, needed for a natural product synthesis, might be made from (6) via epoxide (7) and so a synthesis for (6) was required. Wittlg disconnection reveals a 1,5-dicarbonyl compound (9), best made by Michael addition of a substituted malonate (11) to enone (10). The enone was made by the simple but reliable Grignard route rather than risking a Mannich reaction of unknown regloselectivity. 

An alternative synthesis of (16) is found by disconnecting the 1,5-dicarbonyl relationship in (15),... 

Alkylation of dianions occurs at the more basic carbon. This technique permits alkylation of 1,3-dicarbonyl compounds to be carried out cleanly at the less acidic position. Since, as discussed earlier, alkylation of the monoanion occurs at the carbon between the two carbonyl groups, the site of monoalkylation can be controlled by choice of the amount and nature of the base. A few examples of the formation and alkylation of dianions are collected in Scheme 1.7. In each case, alkylation occurs at the less stabilized anionic carbon. In Entry 3, the a-formyl substituent, which is removed after the alkylation, serves to direct the alkylation to the methyl-substituted carbon. Entry 6 is a step in the synthesis of artemisinin, an antimalarial component of a Chinese herbal medicine. The sulfoxide serves as an anion-stabilizing group and the dianion is alkylated at the less acidic a-position. Note that this reaction is also stereoselective for the trans isomer. The phenylsulfinyl group is removed reductively by aluminum. (See Section 5.6.2 for a discussion of this reaction.)... 

Various variants of this process are presented for pyrrole synthesis. For example, reactions of 1,3-dicarbonyl compounds with P-nitrostyrene followed by treatment with amines give 3-acylpyrroles (Eq. 10.5).7... 

The reaction with the siloxy derivative 29 is an interesting example because the product 30 is a 1,5-dicarbonyl derivative (Equation (36)).96 1,5-Dicarbonyls are classically prepared by a Michael addition, but the synthesis of 30 by a Michael addition is not possible because it would require addition to the keto form of 1-naphthol. The acetoxy derivative 31 resulted in a different outcome, leading to the direct synthesis of the naphthalene derivative 32 (Equation (37)).96 In this case, the combined C-H activation/Cope rearrangement intermediate was aromatized by elimination of acetic acid before undergoing a reverse Cope rearrangement. 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

This selection of diverse MCRs developed in the last 5 years clearly illustrates the high synthetic potential of 1,3-dicarbonyl derivatives in heterocyclic chemistry. These very easily accessible and versatile substrates can be accommodated in many original synthetic pathways. Therefore, they have found numerous applications, especially for the synthesis of complex heterocyclic structures, allowing the facile... 

Intramolecular [2 + 2 + 2] cycloadditions belong to the same type of valence isomerization as those of 1,5-unsaturated compounds to cyclobutanes.70 The cobalt-mediated cyclization of l-en-5-ynes stereoselectively converts enediynes directly to bicyclo[4.2.0]hexa-l,3-dienes, as single diastereomers, when a stoichiometric amount of dicarbonyl(cyclopentadienyl)cobalt is used. This cyclization90 has a high efficiency (92%). An example is the synthesis of the protoilludane framework 23 from the enediyne precursor 22.71... 

The synthesis of 4//-thiopyrans from 1,5-dicarbonyl compounds consists of the cyclization of 1,5-dioxo precursors with hydrogen sulfide in the presence of protic acids or with various phosphorus polysulfides. 

Two typical versions of the synthesis exist two-component and three-component procedures. In many cases, 1,5-dicarbonyl intermediates may be formed (see Section III,A) but when not isolated they are transformed to pyran products. 

Acetylenic compounds may in some cases be suitable sources of 1,3-dioxo precursors as shown for propynal in the synthesis of 85a-d.62,l27 131 Similarly, the preparation of probable 4//-pyran derivative 91 (61.7%) may be explained by a hydration catalyzed with Zn2+ ions, which leads to a 1,5-dicarbonyl intermediate.138... 

The synthesis of pyrylium salts, discovered in a classical study by Dilthey (20JPR(l0l)l77>, involves the facile acid-catalyzed cyclization of a 1,5-dicarbonyl compound. The value of this route stems from the different structural features which are acceptable in the five-carbon unit and from the variety of methods available for their synthesis. The reaction is the reverse of the synthetically useful ring opening of pyrylium salts by nucleophiles. 

A related allylic C-H insertion that has considerable promise for strategic organic synthesis is the reaction with enol silyl ethers [23]. The resulting silyl-protected 1,5-dicarbonyls would otherwise typically be formed by means of a Michael addition. Even though with ethyl diazoacetates vinyl ethers are readily cyclopropanated [l],such reactions are generally disfavored in trisubstituted vinyl ethers with the sterically crowded donor/acceptor carbenoids [23]. Instead, C-H insertion predominates. Again, if sufficient size differentiation exists at the C-H activation site, highly diastereoselective and enantioselective reactions can be achieved as illustrated in the reaction of 20 with 17 to form 21 [23]. 

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