Oxa-Michael Addition of Alcohols

Oxa-Michael addition reactions are well known and the protected j0-hydroxy carbonyl compounds so produced are of significant importance in organic synthesis [127]. To our knowledge, however, no general reaction has been reported in which j8-alkoxy ketones can be prepared via Michael addition. We first detect- 

Transesterification of Esters and the Acyiation and Deacyiation of Protected Aicohois 

Transesterification is an important transformation in organic synthesis in industrial as well as in academic laboratories [138]. There are many catalysts available for such reactions and the most common procedure is to reflux the ester with a catalytic amount of Ti(0-/-Pr)4 in an alcohol solvent. Other catalysts include DBU/LiBr [139] as well as several organometallic compounds [138]. 

The acyl group is a common protecting group for alcohols that can be incorporated using several methods[138]. The most common acylation method involves the reaction of an alcohol with acetic anhydride in the presence of pyridine. But for some acid- or base-sensitive alcohols, the common procedures do not work very well. Transesterification using vinyl acetate offers an alternate route which is very mild and can be catalyzed by Cp2 Sm THF, enzymes, and acids. 

Deacylation of protected alcohols is an important deprotection reaction [138]. Here, K2C03/Me0H has been a widely used reagent, and recently DIBAL-H has been shown to effect clean deacetylation. Although the latter reagent is effective, it is pyrophoric. 

---

Scheme 3.29 Some examples of oxa-Michael additions of alcohols to a,P-unsaturated aldehydes.

Chiral cyclohexene derivatives were also constructed by an asymmetric four-component quadruple domino reaction initiated by oxa-Michael addition of alcohols to acrolein. The other two components were another equivalent of acrolein and a nitroalkene. Enders has shown that cyclohexene derivatives can also be assembled by a domino reaction of y-nitroketones and enals. Domino Michael/aldol condensation of 5-oxoalkanals and a,p-unsaturated aldehydes afforded densely functionalised cyclohexenes. Combination of unsaturated aldehydes with unsaturated p-ketoesters resulted in the formation of chiral cyclohexene derivatives via a Michael/ Morita-Baylis-Hillman sequence (Scheme 8.21). ... 

Remaining in the field of hetero-Michael reaction, Gong et al. disclosed a four-component quadruple cascade reaction activation initiated by oxa-Michael addition of alcohol to acroleins providing an easy and direct access to highly functionalized chiral trisubstituted cyclohexene derivatives 170 (Scheme 2.54) [81]. 

In an effort to develop new cascade reactions, Zhang et al. envisioned that a linear aldehyde can also be genaated in situ via an extra iminium catalysis from an ot,p-unsaturated aldehyde prior to the triple cascade reaction. Therefore, there would be a possibility of extending the triple cascade reactions to four-component cascade reactions. Based on this design, a four-component quadruple cascade reaction through iminium-enamine-iminium-enamine sequential activation initiated by oxa-Michael addition of alcohol to acrolein in moderate yield (about 50%), excellent diastereoselectivities (>20 1), and excellent enantioselectivities (>99% ee) was accomplished (Scheme 1.33) [47]. 

Hassner et aL reported an oxa-Michael addition of allyl alcohols 150 to nitroalkenes 75 followed by ISOC reaction (Scheme 40) [141]. The ISOC reaction conducted without isolating the intermediate nitroalkane 151 was superior to the stepwise mode in most cases in terms of its one-pot nature and product yield. 

Recently, Lin et al. demonstrated that the propargyl alcohol could participate in such a transformation for the synthesis of chiral dihydrofurans [53]. The reaction began with a challenging oxa-Michael addition to cinnamaldehyde derivatives, which was followed by a secondary amine/Pd complex-catalyzed nucleophilic addition/ isomerization of the alkyne moiety in excellent yields and enantioseleclivities (Scheme 9.58). Since the oxa-Michael addition of propargyl alcohol to 0[,P-unsaturated aldehydes was a slow process, this cascade reaction proceeded through a dynamic kinetic asymmetric transformation (DYKAT) process, whereby it made the overall reaction proceed efficiently and with high stereocontrol using the second reaction with precise stereocontrol to shift the first reversible oxa-Michael addition selectively. 

Abstract Progress in the field of metal-catalyzed redox-neutral additions of oxygen nucleophiles (water, alcohols, carboxylic acids, and others) to alkenes, alkynes, and allenes between 2001 and 2009 is critically reviewed. Major advances in reaction chemistry include development of chiral Lewis acid catalyzed asymmetric oxa-Michael additions and Lewis-acid catalyzed hydro-alkoxylations of nonacti-vated olefins, as well as further development of Markovnikov-selective cationic gold complex-catalyzed additions of alcohols or water to alkynes and allenes. 

The conjugate addition of oxygen nucleophiles to acceptor-substituted olefins is the oxa-Michael reaction (Scheme 15). The term is derived from heteroatom replacement nomenclature, meaning that oxygen takes the place of a CH2 unit (RCH2 RO ). Oxa-Michael reactions have been known for many years and are often catalyzed by bases or acids [7]. Catalysis by metals has been reported sporadically in the older literature, e.g. for the case of alcohol addition to vinyl ketones with a Nieuwland catalyst (HgO, BF3-OEt2, ROH) [75-77]. A patent describes a PdCl2-catalyzed addition of alcohols to acrolein or methacrolein [78]. 

High yields of 2-substituted chromans are readily attained from the asymmetric intramolecular oxa-Michael addition reaction of phenols bearing an (f -a,P-unsaturated ketone or thioester moiety mediated by a cinchona-alkaloid-urea-based bifunctional organocatalyst (140BC119). Molecular iodine-catalyzed reaction of phenols with a,P-unsaturated alcohols affords a wide range of 2,2-disubstituted chromans (14T5221). Chiral derivatives result from the intramolecular allylic alkylation of phenols bearing an... 

In 2008, the group of Williams [15] reported the first total synthesis of ( )-2-0-methylneovibsanin H (33) (Scheme 14.6). The diterpene, isolated from the leaves of Viburnum awabuki [16], was prepared by employing an acid-catalyzed domino sequence. Thus, the key transformation was the conversion of advanced intermediate 28 to cyclohexene 32 upon treatment with an excess of sulfuric acid in anhydrous methanol. Acid-mediated silyl deprotection first revealed alcohol 29, which readily underwent an intramolecular oxa-Michael addition to yield tricyclic 30. It was postulated that solvolysis and nucleophilic addition of methanol to the intermediary allyl cation then furnished acid 31, which underwent Fischer esterification. The resultant highly functionalized cyclohexene 32 was isolated in 50% yield as a mixture of diastereomers at C2 (diastereomeric ratio (dr) = 85 15). The observed stereochemistry at the newly created stereocenters, i.e., at C2 and C5, was postulated to arise from the preexisting sterically congested stereocenters in the starting material (i.e., 28). Cyclohexene 32 was eventually taken on to provide the natural... 

The synthesis of unique seven-membered ring sultams has been reported, by an intramolecular oxa-Michael addition reaction from vinyl sulfonamides 248 via a one-step or two-step method, both of which give similar yields of sultams, 249 (13T2369).The intramolecular oxa-Michael reaction was initiated by either TBS-deprotection (with TBAF) to form alkoxide intermediates (Method A), or by removal of the protecting group by HCl to give vinyl sulfonamide alcohols which, upon reaction with NaH, the oxa-Michael reaction is initiated (Method B). 

We also found that 2-R -chromones 130 react with salicylaldehydes in the presence of piperidine to afford 207 via oxa-Michael addition followed by intramolecular Mannich condensation [27], Treatment of 130 with pyridoxal hydrochloride in the presence of NaOH (2.6 equiv.) gave oxepines 208 in moderate yields. In this case, the reaction proceeded at the alcoholic hydroxyl. Interestingly, using 1.3 equiv. of NaOH, it was possible to obtain 209 [103] (Scheme 67). 

The addition of alcohols to aUcenes is a valuable approach to the synthesis of ethers. One of the most popular alkenes for this addition reaction is dihydropyran. The addition reaction is commonly catalyzed by p-toluenesulfonic acid, and a vast array of alcohols including tertiary systems are converted into the THP etliers under mild conditions. When activated alkenes are used in the O—H addition reactions, the process is commonly referred to as an oxa-Michael addition and is a valuable approach to the synthesis of ethers due to the atom-efficient nature of the chemistry. While Michael additions using carbon-based nucleophiles have been well studied, less attention has been given to these oxa-Michael processes due to issues related to the reversibility of the addition reaction as well as the poor nucleophilicity of the alcohols and related neutral oxygen nucleophiles. The reaction can be promoted by a wide range of catalysts and has been reviewed [19]. 

An example of a successful approach to the oxa-Michael addition reaction used copper salts to catalyze the addition of primary alcohols to acrylamide derivatives (Scheme 2.14) [20]. The reaction was carried out under mild conditions using a... 

The oxa-Michael reaction is particularly suitable for the rapid generation of molecular complexity when it is embedded in domino reactions. The enolates generated by addition of alcoholates to conjugate acceptors are potent nucleophiles that can further react with suitable electrophiles. Wang and Menche used this reactivity to combine an oxa-Michael reaction with a Tsuji-Trost coupling (Scheme 5-211). " ... 

Oxa- and aza-Michael additions followed by intramolecular cyclizations occur when propargyl alcohols are treated with a, -unsaturated nitroalkenes in the presence of t-BuOK in THF. Although exo-3-methylene tetrahydrofurans are usually the major products of these reactions, 3,4-dihydropyrans are also obtained in some cases, depending upon the substituents present within the donor and acceptor. Equation 59 shows the results of the reactions of propargyl alcohol with four nitroalkenes. Similar reactions of methyl propargylamine with these same acceptors give exclusively 3-methylenepyrrolidines."... 

---