Conjugate addition of methanol

Maruoka has found that simple alcohols can also be used in the oxy-Michael reaction [107], Using the axially chiral biaryl catalyst 67 (1 mol%) the conjugate addition of methanol, ethanol and aUyl alcohol to a, 3-unsaturated aldehydes was examined (Scheme 29). Despite moderate yields (55-83%) and enantioselectivities (16-53% ee), the high activity of this catalyst suggests that further optimisation... 

C.2. Conjugate Addition of Methanol to a, (i-unsatumted Carbonyl Compounds... 

Conjugate addition of methanol to a,/l-unsaturated carbonyl compounds forms a new carbon-oxygen bond to yield valuable ethers (Scheme 26). Kabashima et al. (12) reported the conjugate addition of methanol to 3-buten-2-one on alkaline oxides, hydroxides, and carbonates at a temperature of 273 K. The activities of the catalyst follow the order alkaline earth metal oxides > alkaline earth metal hydroxides > alkaline earth metal carbonates. All alkaline earth metal oxides exhibited high catalytic activities and, as in alcohol condensations and nitroaldol reactions, their catalytic activities were not much affected by exposure to CO2 and air. 

According to the Lewis theory, alkaline earth metal hydroxides are weaker bases than their oxides, the order of the strength of the basic sites being Ba(OH)2> SrO(OH)2 > Ca(OH)2 > Mg(OH)2. The hydroxides have been used recently as solid catalysts for organic transformations, such as the conjugate addition of methanol to a, S-unsaturated carbonyl compounds (12), cyanoethylation of alcohols (163,164), and transesterification reactions (166,167,171,172) which are described above. The extensive work of Sinisterra et al. (282) on the number and nature of sites and on the catalytic activity of the most basic alkali metal hydroxide, Ba(OH)2, is emphasized. It was found that commercial barium hydroxide octahydrate can be converted into... 

Z. BenkO, B. Fraser-Reid, P. S. Mariano, and A. L. Beckwith, Conjugate addition of methanol to a-enones Photochemistry and stereochemical detail, J. Org. Chem. 53 2066 (1988). 

Kabashima, H., Katou, T. and Hattori, H. Conjugate addition of methanol to 3-buten-2-one over solid base catalysts. Appl. Catal., A, 2001, 214, 121-124. 

Acid-catalyzed removal of a TMS protecting group from a bicyclic lactone in methanol solution proceeded with intramolecular acetylation after conjugate addition of methanol to an a,/ -unsatu-rated ketone side chain. By this route the 6-5-5 tricyclic acetal (27) is obtained in excellent yield (Equation (7)) <90JCS(Pl)75i>. Hemiacetal derivatives of the acetals were also prepared, and were found to exist in equilibrium with their open hydroxy-ketone forms by H NMR. 

In this group of reactions we can cite cyanoethylation of alcohols such as methanol, ethanol and 2-propanol with acrylonitrile [261] (Figure 17a) and conjugate addition of methanol to 3-buten-2-one (Figure 17b) [17.66]. 

Only preussomerins D, G-I and deoxypreussomerins A and B that were isolated as antagonists of FPTase activity are reported here. Preussomerins D, G, and H differ only in their oxidation levels. Preussomerin G contains an epoxy-ketone in the upper decalin and an aromatic enone in the lower decalin unit. The enone unit is saturated in preussomerin H and the epoxy-ketone unit is converted to epoxy-alcohol in preussomerin D. Conjugate addition of methanol to the enone unit of preussomerin G would produce preussomerin I. Deoxypreussomerin B is the de-epoxy analog of deoxypreussomerin A [127]. The enone unit of the preussomerin G readily reacts with dithiothreitol (DTT) or N-acetylcysteine to form Michael adducts, with the latter reaction being much slower than the DTT reaction (Scheme 10). 

Some attempts to use aliphatic alcohols as nucleophiles in the enantioselec-tive conjugate addition to enals have been carried out, but with no success with regard to the stereochemical control (Scheme 3.29). For example, the conjugate addition of methanol to several aliphatic enals using axially chiral amines derived from BINOL as catalysts proceeded with enantioselectivities around 50% ee and also a 31c-catalyzed intramolecular reaction leading to the formation of the tetrahydropyrane skeleton has been reported to proceed with 57% ee. 

Conjugate addition of strong nucleophiles to the >C=N—C=C< moiety, followed by ring opening of the resulting saturated 5 4H)-oxazolone. Thus, 57 reacts with simple or peptidic amino acid esters [Eq. (31)]. Similarly, 62 gives 63 in methanolic 7i-propylamine, and... 

The reaction of butyllithium with 1-naphthaldehyde cyclohexylimine in the presence of (/C )-l,2-diphenylethane-1,2-diol dimethyl ether in toluene at —78 °C, followed by treatment with acetate buffer, gave 2-butyl-1,2-dihydronaphthalene-l-carbaldehyde, which was then reduced with sodium borohydride in methanol to afford (1 R,2.S)-2-butyl-1 -hydroxymcthyl-1,2-dihydronaphthalene in 80% overall yield with 91 % ee83. Similarly, the enantioselective conjugate addition of organolithium reagents to several a,/J-unsaturated aldimines took place in the presence of C2-symmetric chiral diethers, such as (/, / )-1,2-butanediol dimethyl ether and (/, / )- ,2-diphenylethane-1,2-diol dimethyl ether. 

In neutral solvent, nitrosamides LXII readily undergo photolysis to give N-acylimines as the primary products which are susceptible to nucleophilic attack due to the conjugated C=N-C0 group (44). Photolysis of nitrosamide LXIIa in methanol gives LXVII (45%) and LXVIII (23%) obviously derived from the nucleophilic addition of methanol to and proton migration of LXVI, respectively. Photolysis of LXIIa in ether gives LXVIII (27%)... 

The addition of methanol to give a 50 % solution did, however, result in a very considerable increase in the rate of coupling of bilirubin. Under these conditions they considered that a 5-minute reading for conjugated bilirubin and a further 5-minute reading for total bile pigments, after the addition of methanol, gave satisfactory values. 

Statine was synthesised from the oxazolidine derivative 201 obtained through a stereoselective conjugate addition of an hydroxymethyl group in a basic methanolic solution. The conjugate addition proceeded faster than the dehydroxymethylation<02OL1213>. 

Acid catalysts promote conjugate addition of alcohols to a, p unsaturated carbonyl compounds by protonating the carbonyl group and making the conjugated system more electrophilic. Methanol adds to this ketone exceptionally well, for example, in the presence of an acid catalyst known as Dowex 50 . This is an acidic resin—just about as acidic as sulfuric acid in fact, but completely insoluble, and therefore very easy to remove from the product at the end of the reaction by filtration. 

However, the enone is not the only product of this reaction. A methanol adduct is also formed by Michael addition of methanol to the conjugated enone. 

In this series of reactions, conjugate addition of an amine to an a,(3-unsaturated ester is followed by nucleophilic addition of the amine to a second ester, with loss of methanol. 

The Michael conjugate addition of an oxygen to an activated double bond has also been exploited in order to obtain 2,5-disubstituted tetrahydrofurans. The diacetoxynonenoate 1 is cyclized with methanolic potassium hydroxide to give the tetrahydrofuranyl derivative 2 in 97 % yield after esterification with diazomethane. The 1,3-asymmetric induction is low as indicated by the cisf trans diastereomeric ratio (67 33) which was determined by a GLC comparison with known material50. 

The intramolecular conjugate addition of a nucleophilic oxygen to a chiral precursor allows tctrahydro-2//-pyrans to be prepared with high stereochemical control. Treatment of the carbohydrate derivative 1 with methanolic potassium hydroxide immediately gives an equimolar, inseparable mixture of products, however, by successive equilibration, there is formation of the 2,6-cw-disubstituted diastereomer 2 in which the less slcrically encumbered equatorial orientation of the methoxycarbonylmethyl group is reached88. 

There appears to exist only one single example of substrate-controlled diastereoselection in the conjugate addition to allenoates7 Base-catalyzed addition of methanol to the steroid allene 11 afforded only one of the two possible diastereomeric products in 95% yield. Unfortunately, the configuration around the exocyclic C —C double bond [( )/(Z)] of 12 was not established7. 

A highly stereoselective synthesis of yy/j-/l-hydroxy-o -arnino acids, with complete 1,2-syn diastereoselectivity, can be achieved by intramolecular conjugate addition of substituted hetero alkenes with an allylic aminocarbonyloxy group (e.g., 10). The reaction occurs smoothly by-treatment with potassium carbonate in methanol/dichloromethane to give predominantly the 1,2-yytt-isomer 11 A102. 

Piperidine and benzylamine have been utilized in diastereoselective addition reactions to other a,/ -unsaturated vinyl sulfoxides bearing the R absolute configuration92,93 at sulfur. A conjugate addition of piperidine to (f )-l-methyl-4-[(Z)-l-propenylsulfinyl]benzene (20) in a polar solvent such as methanol gives an 83 17 (21A/21B) diastereomeric mixture of adducts94,95. 

---