Enones 1,3-dicarbonyl compounds

A route to pyridines which involves an isolated 1,5-dicarbonyl compound, has been reported. Aldol reaction of enone 57 with methylketone 58 generated 1,5-diketone 59. When this was submitted to the reaction conditions for a Krohnke reaction, thiopyridine 60 was isolated. 

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. 

Friedel-Crafts disconnection (38a) Is unambiguous because of the synunetry of (39). Further disconnection requires FGA. A carbonyl group next to the aromatic ring gives a 1,4-dicarbonyl compound (40) and allows disconnection of an acyl anion equivalent to give an enone (41). This can be made by Mannich reaction from (42). 

On the other hand, the enantioselective 1,4-addition of carbanions such as enolates to linear enones is an interesting challenge, since relatively few efficient methods exist for these transformations. The Michael reaction of p-dicarbonyl compounds with a,p-unsaturated ketones can be catalysed by a number of transition-metal compounds. The asymmetric version of this reaction has been performed using chiral diol, diamine, and diphosphine ligands. In the past few years, bidentate and polydentate thioethers have begun to be considered as chiral ligands for this reaction. As an example, Christoffers et al. have developed the synthesis of several S/O-bidentate and S/O/S-tridentate thioether... 

The Michael addition of nitroalkanes to a,P-unsaturated ketones followed by the Nef reaction has been extensively used as a method for the conjugated addition of acyl anions to enones (see Section 6.1, Nef Reaction). This strategy is one of the best methods for the preparation of 1,4-dicarbonyl compounds.156a h Various natural products have been prepared via this route.157 For example, r/.v-jasmone is prepared from readily available materials, as shown in Scheme 4.19.156f... 

Selective formation of 1,5-dicarbonyl compounds by 1,4-addition (Michael addition) of enolates to enones is facilitated by the use of enol silyl ethers as enolate equivalents [37]. The reaction is catalyzed by... 

The cationic iridium complex [Ir(cod)(PPh3)2]OTf, when activated by H2, catalyzes the aldol reaction of aldehydes 141 or acetal with silyl enol ethers 142 to afford 143 (Equation 10.37) [63]. The same Ir complex catalyzes the coupling of a, 5-enones with silyl enol ethers to give 1,5-dicarbonyl compounds [64]. Furthermore, the alkylation of propargylic esters 144 with silyl enol ethers 145 catalyzed by [Ir(cod)[P(OPh)3]2]OTf gives alkylated products 146 in high yields (Equation 10.38) [65]. An iridium-catalyzed enantioselective reductive aldol reaction has also been reported [66]. 

The asymmetric allylic C-H activation of cyclic and acyclic silyl enol ethers furnishes 1,5-dicarbonyl compounds and represents a surrogate of the Michael reaction [136]. When sufficient size discrimination is possible the C-H insertion is highly diastereoselective, as in the case of acyclic silyl enol ether 193 (Eq. 22). Reaction of aryldia-zoacetate 192 with 193 catalyzed by Rh2(S-DOSP)4 gives the C-H insertion product 194 (>90% de) in 84% enantiomeric excess. A second example is the reaction of the silyl enol ether 195 with 192 to form 196, a product that could not be formed from the usual Michael addition because the necessary enone would be in its tautomeric naphthol form (Eq. 23). 

Wang XS, Zhang MM, Jiang H, Shi DQ, Tu SJ, Wei XY, Zong ZM (2006) An improved and benign synthesis of 9,10-diarylacridine-l,8-dione and indenoquinoline derivatives from 3-anilino-5,5-dimethylcyclohex-2-enones, benzaldehydes, and 1,3-dicarbonyl compounds in an ionic liquid medium. Synthesis 4187 199... 

Reduction of enediones. 1,4-Encdioncs and 4-oxo-2-alkenals are reduced to saturated 1,4-dicarbonyl compounds in nearly quantitative yield by a large excess of Nal-HCl (1 1) in acetone. The method is ineffective with butenedioic acids and 3,/J-enones and a,/J-enals. 

Acylcuprate reagents.1 The reaction of cuprates of the type R2(CN)CuLi2 with carbon monoxide at -110° results in carbonylated reagents, possibly with the composition (RCO)R(CN)CuLi2. In any case, these cuprates effect 1,4-acylation of a,p-enones and -enals to provide 1,4-dicarbonyl compounds. 

In the Weiss reaction (Scheme 4), an 7-dicarbonyl compound (38) condenses with two molecules of dimethyl 3-oxoglutarate (39 E = CC Me) to give a c w-bicyclo [3.3.0] oct-ane-3,7-dione tetraester (40) the one-pot reaction produces considerable complexity, with the sequential formation of four C—C bonds. Simple acid treatment removes the carbomethoxy groups, if deshed. While die reaction involves aldol and Michael sequences, die intermediacy of a cyclopentenone [4-hydroxycyclopent-2-enone (41)] has up to now been unproven. A series of such 1 1 adducts has now been reported for a variety of diketones, together with evidence diat diey are indeed intermediates en route to the bicyclo system.62 Electronic and steric effects on the reaction are also discussed in detail. 

In addition to an earlier report by another group,84 FeCh has now been found to catalyse Michael addition of /1-dicarbonyl compounds to highly reactive enones (CH2=CHCOMe, PhCH=CHCOMe, PhCH=COPh).85... 

Conjugate addition. The reagent (1) undergoes selective 1,4-addition to enones to give potential precursors to 1,5-dicarbonyl compounds.1 Example ... 

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

Closely related to the Robinson annelation is the sequence of conjugate addition and acylation used to make dimedone 83. Either disconnection of the 1,5-dicarbonyl compound 84 is good but we prefer 84a as the enone 85 is the aldol dimer of acetone (chapter 19) and is readily available. 

If the 1,4-dicarbonyl compound is unsymmetrical, it will have to be made by methods such as those described in chapter 25. Examples such as 22 appear in papers by Yadav.3 The 1,4-diketone 23 can be disconnected at a branchpoint with the idea of using a d1 reagent for BuCHO in conjugate addition to the enone 24. 

Nitroolefins are attractive alternative acceptors to enones. In 1999, Barnes and Ji reported an efficient catalyst system for reaction of nitroolefins with 1,3-dicarbonyl compounds with high enantioselectivity (up to 97% ee Scheme 19) [22], Using this method, a highly functionalized nitro compound 38, an important intermediate in the synthesis of an endothelin-A antagonist, was prepared on a large scale in 88 % ee. In this case, the formation of a chiral Mg enolate as a reactive intermediate was proposed. 

Michael Reaction of a,/Mlnsaturated Enones with Cyclic 1,3-Dicarbonyl Compounds... 

Dioxins behave as masked cis y-hydroxy enones and as such are an excellent source of y-lactones, notably in an enantio-enriched form <02JOC5307>. Treatment of the dioxin with an amine base results in rearrangement to 1,4-dicarbonyl compounds from which pyrroles and thiophenes are available in a one-pot synthesis <02TL3199>. Stabilised phosphonates add to 1,2-dioxins to yield diastereo-pure substituted cyclopropanes <02JOC3142>. 

The synthetic interest of the reaction is even broader since several functional groups in the substrate, such as C=C double bond, ether, halogen, ester, and amide groups (entries 6-10) can be present in the carbon skeleton. Chemose-lective cyclopropanation reactions involved the enone functionality in the presence of a saturated ketone group (Scheme 9). Recently, the reaction was applied to the conversion of 1,3-dicarbonyl compounds into 2-alkoxyalkenyl cyclopropanes (Scheme 10) [15]. These molecules having both vinylcyclopropane and enol ether moieties are supposed to be versatile synthetic intermediates. 

Carbon-carbon bond formation via the Michael addition of a,P-unsaturated ketone and 1,3-diketone is achieved in high yields and short times to give (61) by employing catalytic amounts of EUCI3 in dry media under microwave irradiation (Soriente et al, 1997). Ranu et al. (1997) reported the Michael addition of ethyl acetoacetate, acetyl acetone, and ethyl cyanoacetate to cycloalkenones, P-substituted enones and enal. The reaction accomplished efficiently on the surface of alumina under microwave irradiation in dry media. Baruah et al. (1997a,b) also demonstrated the BiClj and Cdl2 catalyzed solvent-free Michael addition of 1,3-dicarbonyl compounds under microwave irradiations with good yields. 

Dicarbonyl compounds.4 Michael addition of a-nitro ketones to methyl vinyl ketone (la) or acrylaldehyde (lb) catalyzed by P(QH5)3 provides the adducts 2, which are reduced by Bu3SnH to 1,5-dicarbonyl compounds (3). Additions to the enal proceed more rapidly than ones to the enone. 

Selenenyl halides are relatively stable, though moisture sensitive, compounds that are generally prepared by the reactions shown in Scheme 7 and behave as electrophihc selenium species. " They react with ketones and aldehydes via their enols or enolates to afford a-seleno derivatives (e.g. (17) in equation 11). Similar a-selenenylations of /3-dicarbonyl compounds, esters, and lactones can be performed, although the latter two types of compounds require prior formation of their enolates. Moreover, the a-selenenylation of anions stabilized by nitrile, nifro, sulfone, or various types of phosphorus substituents has also been reported (equation 12). In many such cases, the selenenylation step is followed by oxidation to the selenoxide and spontaneous syn elimination to provide a convenient method for the preparation of the corresponding a ,/3-unsaturated compound (e.g. 18 in equation 11). Enones react with benzeneselenenyl chloride (PhSeCl) and pyridine to afford a-phenylselenoenones (equation 13). 

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. 

Ni(II)(OAc)2bpy and Co(II)(OAc)2bpy catalyze the Michael addition of nitro-methane, malononitrile, and aniline to a,j8-unsaturated ketones, methyl acrylate, and acrylonitrile in DMF under neutral conditions [116]. FeCls 6H2O is a highly efficient catalyst of Michael reaction of 1,3-dicarbonyl compounds with a,/3-unsaturated ketones under mild and neutral conditions (Sch. 24) [117]. There is literature precedent for this reaction with dual catalysis Ni(II) immobilized on a clay support and FeCl3 to activate the enone [118]. The mechanism proposed for the single-center catalysis involves coordination of the enone to a diketonato complex [119]. The chemo-... 

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