Michael-type

Reagents with carbonyl type groupings exhibit a or (if n. S-unsaturated) a properties. In the presence of acidic or basic catalysts they may react as enol type electron donors (d or d reagents). This reactivity pattern is considered as normal . It allows, for example, syntheses of 1,3- and 1,5-difunctionaI systems via aldol type (a -H d or Michael type (a + d additions. 

Progress has been made toward enantioselective and highly regioselective Michael type alkylations of 2-cyclohexen-l -one using alkylcuprates with chiral auxiliary ligands, e. g., anions of either enantiomer of N-[2-(dimethylamino)ethyl]ephedrine (E. J. Corey, 1986), of (S)-2-(methoxymethyl)pyrrolidine (from L-proline R. K. EHeter, 1987) or of chiramt (= (R,R)-N-(l-phenylethyl)-7-[(l-phenylethyl)iinino]-l,3,5-cycloheptatrien-l-amine, a chiral aminotro-ponimine G. M. Villacorta, 1988). Enantioselectivities of up to 95% have been reported. 

Conventional synthetic schemes to produce 1,6-disubstituted products, e.g. reaction of a - with d -synthons, are largely unsuccessful. An exception is the following reaction, which provides a useful alternative when Michael type additions fail, e. g., at angular or other tertiary carbon atoms. In such cases the addition of allylsilanes catalyzed by titanium tetrachloride, the Sakurai reaction, is most appropriate (A. Hosomi, 1977). Isomerization of the double bond with bis(benzonitrile-N)dichloropalladium gives the y-double bond in excellent yield. Subsequent ozonolysis provides a pathway to 1,4-dicarbonyl compounds. Thus 1,6-, 1,5- and 1,4-difunctional compounds are accessible by this reaction. 

Difunctional target molecules are generally easily disconnected in a re/ro-Michael type transform. As an example we have chosen a simple symmetrical molecule, namely 4-(4-methoxyphenyl)-2,6-heptanedione. Only p-anisaldehyde and two acetone equivalents are needed as starting materials. The antithesis scheme given helow is self-explanatory. The aldol condensation product must be synthesized first and then be reacted under controlled conditions with a second enolate (e.g. a silyl enolate plus TiCl4 or a lithium enolate), enamine (M. Pfau, 1979), or best with acetoacetic ester anion as acetone equivalents. 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

In the reaction of Q,/3-unsaturated ketones and esters, sometimes simple Michael-type addition (insertion and hydrogenolysis, or hydroarylation, and hydroalkenylation) of alkenes is observed[53,54]. For example, a simple addition product 56 to methyl vinyl ketone was obtained by the reaction of the heteroaromatic iodide 55[S5]. The corresponding bromide affords the usual insertion-elimination product. Saturated ketones are obtained cleanly by hydroarylation of o,/3l-unsaturated ketones with aryl halides in the presence of sodium formate, which hydrogenolyses the R—Pd—I intermediate to R— Pd—H[56]. Intramolecular hydroarylation is a useful reaction. The diiodide 57 reacts smoothly with sodium formate to give a model compound for the afla-toxin 58. (see Section 1.1.6)[57]. Use of triethylammonium formate and BU4NCI gives better results. 

Other reactions that show preference for the acidic N-3—H group include Mannich aminomethylation by treatment with formaldehyde and an amine (38) to yield compound (8), reaction with ethyleneimine (39) to give (9), and Michael-type additions (40) such as the one with acrylonitrile to give (10) ... 

This Michael-type addition is catalyzed by lanthanum(3+) [16096-89-2] (80). Ethylene glycol [107-21-1] reacts with maleate under similar conditions (81). A wide range of nucleophilic reagents add to the maleate and fumarate frameworks including alcohols, ammonia, amines, sulfinic acids, thioureas, Grignard reagents, Michael reagents, and alkali cyanides (25). 

Methacryhc acid and its ester derivatives are Ctfjy -unsaturated carbonyl compounds and exhibit the reactivity typical of this class of compounds, ie, Michael and Michael-type conjugate addition reactions and a variety of cycloaddition and related reactions. Although less reactive than the corresponding acrylates as the result of the electron-donating effect and the steric hindrance of the a-methyl group, methacrylates readily undergo a wide variety of reactions and are valuable intermediates in many synthetic procedures. 

Addition Reactions. The addition of nucleophiles to quinones is often an acid-catalyzed, Michael-type reductive process (7,43,44). The addition of benzenethiol to 1,4-benzoquinone (2) was studied by A. Michael for a better understanding of valence in organic chemistry (45). The presence of the reduced product thiophenyUiydroquinone (52), the cross-oxidation product 2-thiophenyl-1,4-benzoquinone [18232-03-6] (53), and multiple-addition products such as 2,5-(bis(thiophenyl)-l,4-benzoquinone [17058-53-6] (54) and 2,6-bis(thiophenyl)-l,4-benzoquinone [121194-11-4] (55), is typical ofmany such transformations. 

Thiols can be prepared by a variety of methods. The most-utilised of these synthetic methods for tertiary and secondary thiols is acid-catalysed synthesis for normal and secondary thiols, the most-utilised methods are free-radical-initiated, alcohol substitution, or halide substitution for mercaptoalcohols, the most-utilised method is oxhane addition and for mercaptoacids and mercaptonitnles, the most-utilised methods are Michael-type additions. 

Michael-Type Additions. Michael additions are generally used to prepare methyl 3-mercaptopropionate (eq. 10) and mercaptopropionitrile (eq. 11) by the reaction of methyl acrylate or acrylonitrile and hydrogen sulfide using a basic catalyst. This reaction proceeds as shown ... 

Class (2) reactions are performed in the presence of dilute to concentrated aqueous sodium hydroxide, powdered potassium hydroxide, or, at elevated temperatures, soHd potassium carbonate, depending on the acidity of the substrate. Alkylations are possible in the presence of concentrated NaOH and a PT catalyst for substrates with conventional pX values up to - 23. This includes many C—H acidic compounds such as fiuorene, phenylacetylene, simple ketones, phenylacetonittile. Furthermore, alkylations of N—H, O—H, S—H, and P—H bonds, and ambident anions are weU known. Other basic phase-transfer reactions are hydrolyses, saponifications, isomerizations, H/D exchange, Michael-type additions, aldol, Darzens, and similar... 

The Michael-type addition of maleic hydrazide and other pyridazinones to activated alkenes, such as methyl acrylate, acrylonitrile, methyl vinyl ketone and other a,/3-unsatu-rated carbonyl compounds, results in the formation of mono-lV-substituted products. 

Michael-type addition, hydroxymethylation and Mannich reaction take place at nitrogen to give the corresponding 2-substituted 4-hydroxyphthalazin-l(2/f)-ones. 

The use of carbon nucleophiles in Michael-type addition reactions with pteridine and its derivatives leads to a quite complicated and divergent pattern. These reactions are strongly dependent on the nature of the carbon nucleophile and can be divided into various categories. 

The reactions of pyrroles with dienophiles generally follow two different pathways involving either a [4 + 2] cycloaddition or a Michael-type addition to a free a-position of the pyrrole ring. Pyrrole itself gives a complex mixture of products with maleic anhydride or maleic acid and with benzyne reacts to give 2-phenylpyrrole rather than a product of cycloaddition (Scheme 47). 

The reaction of a dibromochalcone with hydroxylamine hydrochloride in pyridine gave three products with the expected 2-isoxazoline product as the predominate compound. A ring bromination product and an isoxazole were also isolated (70UC796). The reaction of hydroxylamine with /S-thiosulfates of propiophenone at reflux produced 3-phenyl-2-isoxazo-line (455). At room temperature a bis-Michael product (456) was produced. The reaction with N -phenylhydroxylamine yielded a mono-Michael type product (457) (74CPB1990). 

Aziridines have been prepared stereospecifically by the nucleophilic addition of the nitrogen residue to alkenes <80T73). Introduction of the nitrene is accomplished readily via a Michael-type addition with free diphenylsulfilimine (Scheme 12), and where a chiral sulfilimine is used the chirality is transferred to the aziridine with optical yields in excess of 25%. 

Indolo[2,3-d][l,3]thiazine-2,4-dithione formation, 4, 299 Indolothiazines synthesis, 4, 519 Indoloyl azides Curtius rearrangement, 4, 288 Indolyl anions acylation, 4, 232 alkylation, 4, 235 Michael-type additions, 4, 236 Indomethacin... 

In contrast, tertiary amines do not possess a proton to transfer, and the reaction of the Michael-type addition adduct with ECA can only initiate polymerization to form high molecular weight adhesive polymer, as shown earlier in Scheme 1. 

D. Further Reactions of the Initial Michael-Type Zwitterions... 

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