Michael addition of alcohol

Although the unsaturated nitrile oxides 124 can be prepared via the aldoxime route (see Scheme 8), the older procedure suffers from the disadvantage that a tenfold excess of allyl alcohol and two additional steps are required when compared to Scheme 15. Therefore, unsaturated nitro ether 123 that can be prepared by condensation of an aldehyde 120 and a nitro alkane followed by Michael addition of alcohol 122, was a useful precursor to nitrile oxide 124 [381. The nitrile oxide 124 spontaneously cyclized to ether 125. This procedure is particularly suitable for the synthesis of tetrahydrofurans (125a-h) and tetrahydropyrans (125i-k) possessing Ar substituents in 72-95% yield (Table 12). The seven-membered ether 1251 was obtained only in 30% yield on high dilution. The acetylenic nitro ether 126 underwent INOC reaction to provide the isoxazole 127. 

Michael addition of alcohols, thiols and amides expectedly gave high yields with all three sulfur derivatives 2-4 of trifluoropropene and interestingly the sulfoxide 2 furnished with thiophenol beyond the expected monoaddition the dithioacetal of trifluoropropanal (Scheme 21). 

P-Alkoxy carboxylic acids. The Michael addition of alcohols to unsaturated acids is catalyzed by La(III) salts. 

A fluorous trialkylphosphine was used as a base catalyst for Michael addition of alcohols (Scheme 14). The fluorous phosphine exhibits a 60- to 150-fold increase in solubility in octane between 20-80°C and 20-100°C, respectively. Utilizing the dramatic temperature dependence of the solubility of this compound, it could be recycled by cooling to lower temperatures. Thus, after completion of the reaction, the solution was cooled to -30°C and the precipitated catalyst isolated by decantation, permitting it to be recycled four times without any deterioration in yields. 

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]. 

Roberto Fernandez de la PradUla of the CSIC, Madrid established Tetrahedron Lett. 2008, 49, 4167) the diasteieoselective intramolecular hetero Michael addition of alcohols to enantiomericaUy-pure acychc sulfoxides such as 4 to give the aUylic sulfoxide 5. Mislow-Evans rearrangement converted 5 into 6, the enantiomericaUy-pure core of Ethyl Deoxymonate B 7. 

In the same year, Maruoka and coworkers developed an alternative for the Michael addition of alcohols [66], Using a biphenyl catalyst derivative, methanol, ethanol, and allylic alcohol react with aliphatic enals, albeit with moderate yields and enantioselectivities. 

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]. 

Torgov introduced an important variation of the Michael addition allylic alcohols are used as vinylogous a -synthons and 1,3-dioxo compounds as d -reagents (S.N. Ananchenko, 1962, 1963 H. Smith, 1964 C. Rufer) 1967). Mild reaction conditions have been successful in the addition of ],3-dioxo compounds to vinyl ketones. Potassium fluoride can act as weakly basic, non-nudeophilic catalyst in such Michael additions under essentially non-acidic and non-basic conditions (Y. Kitabara, 1964). 

For those substrates more susceptible to nucleophilic attack (e.g., polyhalo alkenes and alkenes of the type C=C—Z), it is better to carry out the reaction in basic solution, where the attacking species is RO . The reactions with C=C—Z are of the Michael type, and OR goes to the side away from the Z. Since triple bonds are more susceptible to nucleophilic attack than double bonds, it might be expected that bases would catalyze addition to triple bonds particularly well. This is the case, and enol ethers and acetals can be produced by this reaction. Because enol ethers are more susceptible than triple bonds to electrophilic attack, the addition of alcohols to enol ethers can also be catalyzed by acids. " One utilization of this reaction involves the compound dihydropyran... 

As we found that furan and thiophene substituted oximes can be used as substrates for the INOC reactions (Eq. 5) [29b] similarly, furan substituted nitro alkane 134 is also a good substrate for INOC reactions (Eq. 13) [40]. The furfuryl derivative 134, prepared via Michael addition of furfuryl alcohol to 4-methoxy- -nitrostyrene, was subsequently transformed without isolation of the intermediate nitrile oxide 135 to the triheterocyclic isoxazoline 136 as a 5 1 mixture of isomers in high yield. 

ISOC reaction was employed to synthesize substituted tetrahydrofurans 172 fused to isoxazolines (Scheme 21) [44b]. The silyl nitronates 170 resulted via the nitro ethers 169 from base-mediated Michael addition of allyl alcohols 168 to nitro olefins 167. Cycloaddition of 170 followed by elimination of silanol provided 172. Reactions were conducted in stepwise and one-pot tandem fashion (see Table 16). A terminal olefinic Me substituent increased the rate of cycloaddition (Entry 3), while an internal olefinic Me substituent decreased it (Entry 4). 

Balme and coworkers reported on a procedure for the preparation of highly functionalized furans of type 2-940 (Scheme 2.210) [480]. Their approach is based on a nucleophilic Michael addition of propargyl alcohols 2-937 to alkylidene or aryl-idenemalonates 2-938, followed by a palladium-catalyzed cydization via the carban-ion 2-939. The reactions with propargyl alcohol led to the formation of only one di-... 

Ono and Kamimura have found a very simple method for the stereo-control of the Michael addition of thiols, selenols, or alcohols. The Michael addition of thiolate anions to nitroalkenes followed by protonation at -78 °C gives anti-(J-nitro sulfides (Eq. 4.8).11 This procedure can be extended to the preparation of a/jti-(3-nitro selenides (Eq. 4.9)12 and a/jti-(3-nitro ethers (Eq. 4.10).13 The addition products of benzyl alcohol are converted into P-amino alcohols with the retention of the configuration, which is a useful method for anri-P-amino alcohols. This is an alternative method of stereoselective nitro-aldol reactions (Section 3.3). The anti selectivity of these reactions is explained on the basis of stereoselective protonation to nitronate anion intermediates. The high stereoselectivity requires heteroatom substituents on the P-position of the nitro group. The computational calculation exhibits that the heteroatom covers one site of the plane of the nitronate anion.14... 

The Michael addition of allyl alcohols to nitroalkenes followed by intramolecular silyl nitronate olefin cycloaddition (Section 8.2) leads to functionalized tetrahydrofurans (Eq. 4.15).20... 

Sequential Michael additions are versatile methods for the construction of cyclic compounds. Although a variety of these reactions have been developed, the use of alcohols as nucleophiles for the Michael addition to nitroalkenes has been little studied. Recently, Ikeda and coworkers have reported an elegant synthesis of octahydrobenzo[b]furans via the sequential Michael addition of 1-nitro-cyclohexene with methyl 4-hydroxy-2-butynoate in the presence of t-BuOK followed by radical denitration (Eq. 7.74).94... 

An intramolecular radical cyclization gives the cxo-cyclic compounds, which has been extensively used in the synthesis of cyclic compounds. Michael additions of allyl alcohols or propargy 1 alcohols to nitroalkenes and the subsequent treatment with tin radicals provide a useful method for the preparation of substituted furans (Eqs. 7.83 and 7.84).126... 

Ono and coworkers have extended the radical elimination of v/c-dinitro compounds to P-nitro sulfones151 and P-nitro sulfides.138,152 As P-nitro sulfides are readily prepared by the Michael addition of thiols to nitroalkenes, radical elimination of P-nitrosulfides provides a useful method for olefin synthesis. For example, cyclohexanone is converted into allyl alcohol by the reaction shown in Eq. 7.110. Treatment of cyclohexanone with a mixture of nitromethane, PhSH, 35%-HCHO, TMG (0.1 equiv) in acetonitrile gives ahydroxymethylated-P-nitro sulfide in 68% yield, which is converted into the corresponding allyl alcohol in 86% yield by the reaction with Bu3SnH.138 Nitro-aldol and the Michael addition reactions take place sequentially to give the required P-nitro sulfides in one pot. 

A diverse group of organic reactions catalyzed by montmorillonite has been described and some reviews on this subject have been published.19 Examples of those transformations include addition reactions, such as Michael addition of thiols to y./bunsatu rated carbonyl compounds 20 electrophilic aromatic substitutions,19c nucleophilic substitution of alcohols,21 acetal synthesis196 22 and deprotection,23 cyclizations,19b c isomerizations, and rearrangements.196 24... 

Although the selectivities are excellent, prolonged reaction times (2 1 days) are noted under these conditions. The addition of alcohols, particularly 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), was found to decrease reaction times (4 days to 36 h under identical conditions). In the presence of HFIP, Michael adducts are generated in comparable yields and selectivities suggesting that the principal role of the alcohol is catalyst turnover. 

Scheme 25. In situ IR spectroscopy of the Michael addition of enolsilane to fumaroylimide catalyzed by 271c observation of an intermediate and effect of alcohol on the reaction. [Adapted from (240).]...

Scheme 26. Effect of alcohol on the Michael addition of trimethylsiloxyfuran to crotonylimide catalyzed by 269c. [Adapted from (241, 242).]...

The base-catalysed Michael addition of a,/J-unsaturated nitro compounds 363 to electron-deficient olefins 364 (R4 = Ac, CC>2Me or CN) results in the formation of ally lie nitro compounds 365 aldehydes give alcohols 366 in this reaction409. 

Another structurally modified guanidine was reported by Ishikawa et al. as a chiral superbase for asymmetric silylation of secondary alcohols [122]. Soon after, Ishikawa discovered that the same catalyst promoted asymmetric Michael additions of glycine imines to acrylates [123]. The additions were promoted in good yield and great asymmetric induction under neat reaction conditions with guanidine catalyst 250 (Scheme 68). The authors deduced that the high conversion and selectivity were due to the relative configuration of the three chiral centers of the catalyst in... 

Two new types of optically active 1,3-oxazines (41) were synthesized by Rassat and Rey (74T265, 74T3315). The epimeric 1,3-amino alcohols 40, prepared from (-l-)-pulegone 39 by Michael addition of ammonia and subsequent reduction, were cyclized with acetone, cyclohexanone, and 4-tert-... 

A plausible mechanism for the ring expansion (Scheme 65) proceeds via an intermediate zwitterion A, resulting from Michael addition of the tertiary nitrogen to the alkyne. Cleavage of the C(l)-N bond occurs via formation of the six-membered transition state B in which a molecule of alcohol facilitates the Sn reaction. 

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