MICHAEL ADDITION, APROTIC

METHYL-l-METHYLENE-2-(r-METHYLETHYL)-, R,R-), 65, 81 MICHAEL ADDITION, APROTIC, 66, 37, 41 cis.cis-Monornethyl muconate (61186-96-7), 66, 180, 184 cis.cis-MONOMETHYL MUCONATE FROM 1,2-DIHYDROXYBENZENE, 66. 180... 

A very efficient method for annulations158 is based on the addition of lithium or silyl enolates to a-silylated enones as a key step. The diastereoselective 1,4-addition is followed by an aldol condensation. This procedure allows Michael additions under aprotic conditions, whereby the silyl substituent stabilizes the enolate of the Michael adduct preventing polymerization of the enone, 59 l63. 

A surprising exception has been reported with evidence for a cleavage reaction in the case of divinyl sulphone. In non-aqueous and slightly acidic media, the behaviour of a., ji-unsaturated aromatic sulphones is also complex (see Table 7) since the cleavage and the saturation may compete. Strongly electrophilic double bonds undergo Michael additions in aprotic solvents by slowly protonated anions. Transfer of labile hydrogen may also lead to unactivated bases. It is noteworthy that in numerous cases (Table 6) the saturation is the preferred route. 

The solvent and temperature effects for the Michael addition of amidoxime 7 to DMAD were probed because the reaction itself occurs without any other catalysts. As shown in Table 6.2, the reaction gave a high ratio of 8E in strongly aprotic polar solvents such as DMF and DMSO (entry 1 and 2). 8E was also found as the major product in MeCN (entry 3), dichloromethane (entry 4), and xylenes (entry 5). To our delight, the desired 8Z was obtained as the major component in methanol (entry 6). The stereoselectivity of 8Z versus 8E was better at low temperature (entry 7). A similar result was observed when the reaction was run in THF or dichlo-roethane in the presence of a catalytic amount of DABCO (entries 9 and 10). 

It should be noted here that a regioselective control may also be exerted by just controlling the experimental conditions. Thus, working under strictly kinetic conditions (low temperature, absence of oxygen and slow addition of the ketone to an excess of a solution of an aprotic base) the less substituted enolate of carvomenthone can also be selectively generated and may be then submitted to different kind of reactions. However, reversible reactions like the Michael addition would equilibrate the reaction mixture to the thermodynamically more stable enolate. 

The fluoride ion is an effective catalyst for Michael additions involving relatively acidic carbon compounds.85 The reactions can be done in the presence of excess fluoride, where the formation of the [F—H—F ] ion occurs, or by use of a tetraalkylammonium fluoride in an aprotic solvent. 

The aprotic double Michael addition was discovered by R. A. Lee and to synthesize functionalized bicyclo[2.2.2]octanes which may serve as starting materials in natural products syntheses (Table I). These ljicyclo[2,2.2]octanes can also be obtained by a Diels-Alder cycloaddition of 2-trimethyl5iloxy-substituted cyclohexadienes and dienophiles H... 

But there are many cases known where the (4+2) cycloaddition fails even with siloxy-activated dienes, e.g., methyl (E)-crotonate does not react with diene 1 at normal pressure and elevated temperature llO C), whereas the aprotic double Michael addition does give the desired bicyclo[2.2.2]octane in high yield. This reaction gives mainly (92%) bicyclic esters with the endo configuration. 

EXAMPLES OF CARBOCYCLIC ESTERS PREPARED BY THE APROTIC DOUBLE MICHAEL ADDITION... 

APROTIC DOUBLE MICHAEL ADDITION PREPARATION OF 1,3-DIMETHYL-5-OXOBICYCLO[2.2.2]OCTANE-2-CAR80XYLIC ACID... 

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

With fluoride ion under aprotic conditions alkylating ring-opening can be performed (equation 94). Similarly, a clever [3 -I- 2] annulation combines a fluoride-induced Michael addition to vinyl phosphonium salts with a subsequent internal Wittig reaction (equation 95) . ... 

Hindered phenolates have low nucleophilicity and in aprotic solvent may act usefully as EGBs. 2,6-Di-t-butyl-/ -cresol = 16.8) was reduced directly with concomitant hydrogen evolution to give, ex situ, the corresponding tetraethylammonium phenolate [59,60], which was clearly capable of deprotonating aromatic ketones and in the presence of aromatic aldehydes promoted aldol reaction to a, /3-unsaturated ketones which underwent Michael addition. The initial proton transfer from the aromatic ketone ] K = 24.7) is thermodynamically very unfavorable. Even so, aldol reaction took place within a matter of hours upon addition of an aromatic ketone together with an aromatic aldehyde leading to or, /3-unsaturated ketones which subsequently underwent Michael addition with a sec-... 

The use of thiazolium salts enables the benzoin condensation to proceed at room temperature. It can also be performed in dipolar aprotic solvents or under phase transfer conditions. Thiazolium salts such as vitamin Bi, thiazolium salts attached to 7-cyclodextrin, macrobicyclic thiazolium salts, thiazolium carboxylate, naphtho[2,l-rf thiazolium and benzothiazolium salts catalyze the benzoin condensation and quaternary salts of 1-methylbenzimidazole and 4-(4-chlorophenyl)-4//-1,2,4-triazole are reported to have similar catalytic activity. Alkylation of 2-hydroxyethyl-4-methyl-l,3-thiazole with benzyl chloride, methyl iodide, ethyl bromide and 2-ethoxyethyl bromide yields useful salts for catalyzing 1,4-addition of aldehydes to activated double bonds. Insoluble polymer-supported thiazolium salts are catalysts for the benzoin condensation and for Michael addition of aldehydes. " Election rich al-kenes such as bis(l,3-dialkylimidazolidin-2-ylidenes) bearing primary alkyl substituents at the nitrogen atoms or bis(thiazolin-2-ylidene) bearing benzyl groups at the nitrogen atoms are examples of a new class of catalyst for the conversion of ArCHO into AiCHOHCOAr. 

The conjugate Michael addition of phosphonate-stabilized anions with dimethyl acetylenedicarboxylate has been described. For example, when the sodium salt of dimethyl l-(methoxycarbo-nyljmethylphosphonate is treated with dimethyl acetylenedicarboxylate, an (fij/CZ) mixture of two isomeric P.y-unsaturated phosphonates is isolated in modest yield (37%). ° Addition of enolates derived from diethyl 2-oxocycloalkylphosphonates to dimethyl acetylenedicarboxylate in aprotic conditions results in [n + 2] ring-expanded products in reasonable yields (Scheme 8.50). The reaction proceeds via a tandem Michael-aldol-fragmentation mechanism to give the ring enlarged products. 

The method of choice for the reaction of diethyl 2-oxocyclohexylphosphonate with ethyl acrylate involves the use of a catalytic amount of EtONa in EtOH. With these conditions, good yields (69%) of Michael adduct are obtained (Scheme 8.59). ° Use of a molar amount of base in an aprotic solvent results in recovery of only unreacted starting material. The reaction of diethyl 2-oxocyclohexylphosphonate is prone to steric factors because no Michael addition occurs when P-substituted Michael acceptors such as methyl crotonatc or ethylidene malonate are used. °... 

The reaction of A -substituted pyrazoles with alkynic esters in the presence of fluoroboric acid yields Michael addition salts and not Diels-Alder adducts as was previously reported in the literature <83T2193>. Addition of 3,5-dimethyl-pyrazole to DMAD (dimethyl acetylenedicarboxylate) is highly stereoselective in aprotic solvents, yielding mono- and bis-adducts <85JCS(P2)427>. 

Initial achievements in this field were carried out by Kobayashi as early as 1978. Copolymerization of 71 with acrylonitrile produced linear polymers 72 (Scheme 10.14), which are soluble in polar aprotic solvents, that were assayed for different Michael additions. In general, good conversions were obtained, but enantioselec-tivities were always below 60% ee [204-206]. In a related approach by Oda, different spacers were introduced between the polyacrylonitrile backbone and the chiral fragment, which resulted in an increase of selectivity up to 65% ee [207]. Addition of thiol groups in PS-DVB resins to the double bond allowed the preparation of the corresponding insoluble polymers 73, which were assayed by Hodge for the addition of thiols to unsaturated ketones and nitrostyrene. Again, selectivities were... 

The product of the Michael addition of 5-aminouracil to dimethyl acetylenedicarboxylate in methanol is the fumarate resulting from the attack of the amino substituent whereas, in aprotic solvents such as dimethyl sulfoxide, the initial adduct is the maleate, which isomerizes within 1 hour to give predominantly the thermodynamically more stable Z-isomer. Upon heating a solution of the fumarate 1 in Dowtherm A at reflux temperature, cyclization occurs to give methyl 2,4,8-trioxo-l,2,3,4,5,8-hexahydropyrido[3,2-r/]pyrimidine-6-carboxylate... 

The hetero-Michael addition of 2,4-dihydropyrazol-3-one 422a-h to trichloro-acetaldimine derivatives 423a-h takes place best in apolar aprotic solvents and the... 

Anions from the Schiffs base (78) can be C- or A -alkylated with ethyl iodide or diethyl sulphate. The ratio of the products depends both on the solvent and on the presence of 18-crown-6. In non-polar solvents, the crown ether increases the solubility of the base, and C-alkylation is the major pathway. In dipolar aprotic solvents, the 18-crown-6 breaks up ion pairs by solvation of the Na" cation, and favours A -alkylation. A nerylsulphonamide, formed from (79), undergoes regiospecific reductive desulphonylation to give nerol (80), which implies that (79) is an effective synthon for cisoid iso-prenoids. Chiral complexes of crown ethers, e.g. (81), catalyse the Michael addition reaction of j3-keto-esters and methyl vinyl ketone to give adducts in high optical yields. ... 

Compound (120) was prepared from 8,10-dihydrosweroside aglucone (32), which could be alkylated in aprotic solvent in the presence of a strong base to (33). However, under the same conditions, but in the absence of the alkylating agent, a sequence of four base-catalyzed reactions (dimerization by a vinylogous Michael addition, intramolecular aldolization, lactonization and cyclization by hetero Michael addition) gave the final product (120). Detailed analysis of its formation would exceed the frame of this paper [result to be published]. 

The use of open-chain precursors for obtaining the benzenoid ring in anacardic and orsellinic acids has proved a fruitful approach. Ethyl 2-methoxy-6-methylbenzoate (synthesised through the Michael addition of ethyl acetoacetate virith but-2-en-al, followed by cyclisation and aromatisation), has been alkylated in an aprotic solvent after formation of the carbanion with lithium di-isopropylamide (refs. 113,114) to give the anacardic after hydrolysis and demethylation (a). In a similar way ethyl 2,4-dimethoxy-6-methylbenzoate (ethyl orsellinate), (formed from ethyl acetoacetate and ethyl crotonate followed by cyclisation aromatisation and methylation (ref. 115)), has been alkylated (ref. 116, 117). In this way the C.,5 orsellinic acid precursor [R = C14H29 in route (b)] of the component phenols in Anacardium occidentale has been synthesised (ref. 118) and the method indirectly affords another route to the cardol series. 

Asymmetric Michael addition. Michael addition of nitromethane to chalcone (equation I) in the presence of a chiral amine (quinine, N-methylephedrine) proceeds in methanol (but not in aprotic solvents) in 60-807) yield, but the optical yield at best is 17>. However, if these amines are converted into aminium fluorides, the addition takes place in aprotic solvents (CaHsCHg, CH3CN) in 50-100% yield of more interest, asymmetric inductions of 207, can be obtained. (- )-BenzyIquininium fluoride (1) is particularly effective. The hydroxyl group in these salts is believed to play an important role in the stereochemical outcome of the reaction. Moreover, the fluoride ion is important as a strong base. 

To further probe the scope of this chemistry, Somei and coworkers studied the reaction of l-methoxy-3-(2-nitrovinyl)indole (103) with nucleophiles [43]. In this substrate, there are two possible sites for the nucleophile to attack. Dipolar aprotic solvents such as DMF or hexamethylphosphoramide (HMPA) encourage attack of the nucleophile at C-2 with concomitant loss of methoxide to form 104. Use of tetrahydrofuran (THF) results in Michael addition of the nucleophile to the p-carbon of the nitrovinyl side chain to produce 105. 

Although the presence of a protic solvent aids these proton-transfer steps, pro-tic solvents are not a necessity for successful Michael addition reactions. Proton abstraction and conjugate addition can be carried out in the presence of a Lewis acid or by using a base in an aprotic solvent. For example, deprotonation of the dicarbonyl compound 19 with sodium hydride in THF and addition of the Michael... 

The direct synthesis of a, unsaturated nitriles occurs in high yields at 40 to 50 °C from aldehydes and acetonitrile or benzyl cyanide in the presence of catalytic amounts of lb or 9b [125]. These reactions take place in both polar protic and non-polar aprotic solvents. Pro-azaphosphatrane 9b, which is a stronger base than lb, effidently catalyzes the condensation/dehydration of aromatic aldehydes and tertiary aliphatic aldehydes. The use of 9b in these reactions gave rise to products with imusuahy high E/Z ratios. With either lb or 9b, ahphatic aldehydes gave aldol products, and secondary aldehydes led to novel Michael addition products which are described in the next section. Ketones do not condense wiA either benzyl cyanide or acetonitrile under our conditions. 

---