Vinylogous Michael addition

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

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). 

When the enamine is in conjugation with a carbonyl function, as in a-aminomethylene aldehydes (528,529), ketones (530), or esters (531), a Michael addition is found in vinylogous analogy to the reactions of amides. An application to syntheses in the vitamin A series employed a vinyl lithium compound (532). 

Vinylogous amides undergo reduction with lithium aluminum hydride, by Michael addition of hydride and formation of an enolate, which can resist further reduction. Thus -aminoketones are usually produced (309, 563,564). However, the alternative selective reduction of the carbonyl group has also been claimed (555). 

The Michael addition of nitromethane to vinylogous esters of / -protected amino acids proceeds with good yields and with good diastereoselectivity (Eq. 4.135).195... 

L2909>. An organocatalytic addition of 2-trimethylsilyloxyfuran to aldehydes using 10 mol% of l,3-bis(3-(trifluoromethyl)phenyl)urea provided adducts with modest threo selectivity <06TL8507>. A syn-selective, enantioselective, organocatalytic vinylogous Mukaiyama-Michael addition of 2-trimethylsilyloxyfuran to (E)-3-... 

Chen and co-workers utilized the chiral bifunctional catalysts to directly access vinylogous carbon-carbon bonds via the asymmetric Michael addition of a,a-dicy-ano-olefms to nitro-olefms [102]. The scope of the reaction was explored with a variety of substituted a,a-dicyano-olefins and P-substituted nitro-olefms (Scheme 50). The authors propose the catalysf s tertiary amine functionality depro-tonates the cyano-olefm, activating the nucleophile to add to the -face of the pre-coordinated nitro-olefm. 

The solid-state interaction of enamines (428, 333a) with trans-l,2-diben-zoylethene (87) provides quantitative yields of the pyrrole derivatives 445 or 446 [140]. These remarkable 5-cascades consist of initial vinylogous Michael addition, enol/keto tautomerism, imine/enamine tautomerism, cyclization, and elimination, all within the crystal without melting. A waste-free extraordinary atom economy is achieved that cannot nearly be obtained in solution. The milling times are unusually long here (3 h) but it s certainly worth the effort... 

The base-catalyzed Michael addition of oxazolin-5-ones to alkynic ketones produces 4-(3-oxopropenyl) derivatives (405) (79CB3221). The latter compounds are cleaved on warming with oxalic acid dihydrate in acetic acid to y-diketones (406). The mechanism of this transformation corresponds to a vinylogous Dakin-West reaction (Scheme 90). 

The first highly regio-, chemo-, diastereo-, and enantio-selective vinylogous Michael addition of oqa-dicyanoalkenes to oq/S-unsaturated aldehydes employs salts of a,a-diarylprolinol (103) (20 mol%) as organocatalysts. The reaction presumably involves the formation of an iminium species from the aldehyde as the first step of the cascade.153... 

Intermolecular Michael addition [4.1] Intermolecular aldol reaction [6.2.1] Intramolecular aldol reaction [6.2.2] Aldol-related reactions (e.g. vinylogous Mukaiyama-type aldol) [6.2.3]... 

The reaction between the perchlorate salt of 2,3,3-trimethylindolenine and crotonaldehyde involves Michael addition (at the 2-methyl group, not the N atom) and spontaneous cyclization to give 8.8,10-trimcthyl-l ()//-pyrido l,2-a indolium perchlorate (16) in 26% overall yield. This can be considered a vinylog of a Fischer s base salt (and also a 4-picolinium salt). This salt has been condensed with aromatic aldehydes to give styryl dyes, but there is no report of reaction with salicylaldehydes.26... 

Regioselective addition of 2-methoxyfuran and 2-trimethylsilyloxyfuran to chromium(O) alkynylcarbene complexes furnished interesting dienyne and dienediyne carboxylates <07AGE2610>. The reaction likely proceeded through a formal vinylogous Michael addition adduct, as illustrated in the following example. 

A ry -selective, organocatalytic, enantioselective vinylogous Mukaiyama-Michael addition of 2-trimethylsilyloxyfuran to a,/ -unsaturated aldehydes to produce 7-butenolides was achieved by using a chiral amine catalyst... 

Vinylogous Mukaiyama-Michael additions of 2-trimethylsilyloxyfuran to 3-alkenoyl-2-oxazolidinones to provide 7-butenolides were shown to be /7-selective. The reaction could be rendered enantioselective in the presence of a (T symmetric copper-bisoxazoline complex <1997T17015, 1997SL568> or a l,T-binaphthyl-2,2 -diamine-nickel(ii) complex as catalyst, as depicted in Equation (16) <2004CC1414>. 

In a related fashion, certain types of vinylogous amides can be prepared by a modification of this same method, as reported by Suzuki (equations 45 and 46). The triphenylsilyl moiety is essential for this transformation. The corresponding t-butyldimethylsilylacetylene gave the simple acylation product without subsequent Michael addition of the amine. In Ae ring expansion process the use of unmodified lithium acetylide (LiC uCH) lead to the formation of by-products. A similar ring expansion process was reported for a-lactams with formation of five-membered ring vinylogous amides. ... 

Sharpless bis-cinchona alkaloids such as [DHQD]2PYR (163a) have proved to serve as highly efficient catalysts for the asymmetric vinylogous Michael addition of the electron-deficient vinyl malonitriles 164 as the nucleophilic species to nitroole-fins 124 [50], This process exhibited exclusive y-regioselectivity and high diastereo-and enantioselectivity. Only the anti-products 165 were observed in all reactions (Scheme 9.57). Of note, 1-tetralone did not react with nitroolefins under these... 

A variety of a,a-dicyanoalkenes derived from aryl ketones have also been extensively explored under the same catalytic conditions, and in general the vinylogous Michael adducts were obtained due to the steric hindrance in the following enamine catalysis by primary amine lo [28]. Nevertheless, an interesting domino Michael-Michael-retro-Michael reaction was observed for a,a-dicyanoalkenes derived from acetophenone and propiophenone, giving a facile process to chiral 2-cyclohexen-l-one derivatives. It was noteworthy that a kinetic resolution was observed in the intramolecular Michael addition step (Scheme 10.22). 

Scheme 10.22 Vinylogous Michael addition and domino Michael-retro-Michael reaction.

The Mannich reaction is a very common process that occurs in many tandem reaction sequences. For example, the Overman Aza-Cope cascade sequence is terminated by a Mannich reaction (cf. Scheme 35). Several groups have used variants of the Mannich reaction to initiate cascades that lead to the formation of heterocyclic molecules. For example, the Lewis acid-catalyzed intermolecular vinylogous Mannich reaction (01T3221) of silyloxy furan 281 with nitrone 282 produced a diastereomeric mixture (49 3 42 6) of azabicycles 284a-d in 97% combined yield (Scheme 52) (96TA1059). These products arose from an intramolecular Michael addition of the initially formed oxonium ion 283. 

---