Michael addition solvent effect

Similar additions may be performed with the enamine 13. However, with 3-buten-2-one or methyl 2-propenoate Lewis acid catalysis is needed to activate the Michael acceptor chloro-trimethylsilane proved to be best suited for this purpose. A remarkable solvent effect is seen in these reactions. A change from THF to HMPA/toluene (1 1) results in a reversal of the absolute configuration of the product 14, presumably due to a ligand effect of HMPA235. 

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). 

T. A Rhodes, K O Shea, G. Bennett, K. P. Johnston, M A Fox, Effect of Solvent-Solute and Solute-Solute Interactions on the Rate of a Michael Addition in Supercritical Fhioroform and Ethane , J. Phys. Chem 1995, 99, 9903-9908. 

There are only few examples of organic reactions catalysed effectively by Lewis acids which can be carried out in pure water without any organic co-solvent. While water can be used successfully for the uncatalysed Michael addition of 1,3-diketones (Table 4, entry D)22, the corresponding reaction of /i-kctocsters does not give satisfactory results. On the other hand, the Yb(OTf)3 catalysed Michael reaction of various /i-ketoesters (Table 21, entry A)257 and a-nitroesters (Table 21, entry B)258 takes place. 

The stereoselective Michael addition of the anion derived from diethyl acetyl-aminomalonate with chalcone has been found to be most effective under soliddiquid two-phase conditions in the absence of an added solvent [62]. For optimum overall conversion and enantiomeric excess (56% with 60% ee), A-benzyl-V-methyl-... 

Besides formaldehyde, Michael acceptors such as acrylonitrile and ethyl acrylate also serve as substrate to undergo the addition in the presence of various metal complexes [10-14]. Acrylonitrile affords P(CH2CH2CN)3 tcep (Scheme 3). The order of catalytic activity is reported to be Pt[P(CH2CH2CN)3]3>Pd[P(CH2CH2CN)3]3P IrCl[P(CH2CH2CN)3]3>Ni[P(C-H2CH2CN)3]3. The solvent effect on the rate is not significant. In acetonitrile, however, a small amount of a telomer is formed. 

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. 

Several other high inductions have been reported by using crown ethers as catalysts (Scheme 10.8). The Toke group has used a chiral crown 11 (Chart 10.2), which incorporates a glucose unit, for the addition of 2-nitropropane to a chalcone (Scheme 10.8) [38], Several other effective chiral crowns (12-17, Chart 10.2 and Scheme 10.8) are noted [24e,39-42,48b]. An interesting study of the Michael addition under both solvent-free (0% ee) and liquid-liquid conditions (up to 70% ee) was reported by Diez-Barra and co-workers, who also addressed the question of free -OH quats (28, 58% ee) verses O-benzyl quats (30, 46% ee) [43]. 

Kotsuki et al.909 have developed a method to effect the Michael addition of [3-ketoesters with ethyl acrylate in the presence of triflic acid under solvent-free conditions [Eq. (5.335)]. Nonactivated cyclohexanones as Michael donors and a,/3-unsaturated ketones as acceptors are also reactive. The use of menthyl acrylates did not result in any significant asymmetric induction. 

Michael addition of ketene sUyl acetals. TASF catalyzes the conjugate addition of ketene silyl acetals to enones in THF at room temperature. A similar addition can be effected without a catalyst in a polar solvent, acetonitrile at 55° (ref. 2) or CH,NO, at 25°, in the case of some less hindered ketene silyl acetals. The addition shows no dia-stcreoselection. The adducts can be alkylated to provide 2,3-disubstitutcd cycloalkanoncs as a 1 1 mixture of two diastereomers (both probably Irons). 

Among the fluoride ion promoted reactions which occur in dipolar non-HBD solvents are alkylations of alcohols and ketones, esterifications, Michael additions, aldol and Knoevenagel condensations as well as eliminations for a review, see reference [600]. In particular, ionic fluorides are useful in the dehydrohalogenation of haloalkanes and haloalkenes to give alkenes and alkynes (order of reactivity R4N F > K ([18]crown-6) F > Cs F K F ). For example, tetra-n-butylammonium fluoride in AjA-dimethylformamide is an effective base for the dehydrohalogenation of 2-bromo-and 2-iodobutane under mild conditions [641] cf Eq. (5-123). 

Tanaka, T. Kumanoto, T. Ishikawa, T. Solvent effects on stereoselectivity in 2,3-dimethyM- chromanone cyclization by quinine-catalyzed asymmetric intromolecular oxo-Michael addition. Tetrahedron-Asymmetry, 2000, 11 4633 637. 

In summary, D-limonene has been exploited with interesting results in polymer chemistry however, it remains to be seen whether its chirality can be used to induce similar effects in small molecule syntheses. Many of the benchmark reactions e.g. Diels-Alder, Michael addition) used in the alternative solvent field are reactions of olefinic substrates and therefore could not be performed successfully in a terpene solvent. 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

When MeNOa [233a] and DMSO [81] are used as solvents, Michael addition of KSA proceeds smoothly at room temperature without additional catalyst. Coordination of the solvent molecule to the silicon atom would enhance the nucleophilicity of KSA to effect the uncatalyzed reaction. 

Remu BC, Baneijee S, Jana R (2007) Ionic Uquid as catalyst and solvent the remarkable effect of a betsic ionic liquid, [bmim][OH] on Michael addition and alkylation of active methylene compounds. Tetiahedron 63 776-782... 

There are only few examples of organic reactions catalysed effectively by Lewis acids which can be carried out in pure water without any organic co-solvent. While water can be used successfully for the uncatalysed Michael addition of 1,3-diketones (Table 4, entry... 

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