From a,-Unsaturated Carbonyls

in The Chemistry of Heterocyclic Compounds (A. Weissberger, ed.). Wiley (Interscience), New York, 1962. 

In a second example, Ruhemann145 found that the reaction of benzamidine with benzilideneacetylacetone at 100°C results in the loss of an acetyl group with formation of 6-methyl-2,4-diphenyldihydropyrimidine (MDHP) (20) [see Eq. (31)]. 

Further improvements that facilitated each step of this reaction (using molecular sieves, DMSO, and air) led to a new one-pot synthesis of 

Substances R1 R2 R3 R4 Yield (%) 86 Melting point fC) Yield (%) 88 Melting point (°C) 

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In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

As already mentioned, besides multistage reactions there are also synthetic methods for obtaining aziridinyl ketones from unsaturated carbonyl compounds without the need for initial modification. Among such methods, the Southwick reaction consisting of the interaction of unsaturated ketones... 

Cheap and readily available L-proline has been used numerous times for the intermediate and reversible generation of chiral iminium ions from a,/ -unsaturated carbonyl compounds. For example, Yamaguchi et al. reported in 1993 that the rubidium salt of L-proline catalyzes the addition of di-iso-propyl malonate to the acyclic Michael acceptors 40a-c (Scheme 4.13), with enantiomeric excesses as high as 77% [22], With 2-cycloheptenone and 2-cyclohexenone as substrates ca 90% yield and ee of 59% and 49% were obtained. Later the enantioselectivity of this process was increased to a maximum of 88% ee in the addition of di-tert-butyl malonate to the E-pentenone 40a in the presence of 20 mol% Rb-L-prolinate and 20 mol% CsF [23], Taguchi and Kawara employed the L-proline-derived ammonium salts 41a and... 

Radical Anions. Radical anions are common intermediates in organic reactions they are easily prepared from compounds with low-enough LUMOs by the addition of an electron (from a dissolving metal or from a cathode, or the solvated electron itself). Those derived from carbonyl groups (421) dimerize at carbon 339 those derived from a,/ -unsaturated carbonyl compounds (422) dimerize at the /1-position,340 and pyridines dimerize predominantly at the 4-position.341 In each case, the odd electron has been fed into the orbital which was the LUMO of the starting material the site of coupling therefore should, and does, correlate with the site at which nucleophiles attack the neutral compounds. 

As was mentioned in Section 13.2, the [27t + 27i] photocycloaddition of alkenes is an allowed reaction according to orbital symmetry considerations. Among the most useful reactions in this categoty, from a synthetic point of view, are intramolecular [27t + 2ti] cycloadditions of dienes and intermolecular [2ti + 2ti] cycloadditions of alkenes with cyclic a, -unsaturated carbonyl compounds. These reactions will be discussed in more detail in Section 6.4 of Part B. 

Table VII gives a survey of alkaloids that exhibit the hasubanonine-type cleavage. The characteristic fragmentation pattern of this group, possessing an a,/ -unsaturated carbonyl group in ring C, is significantly different from other groups. In the case of hasubanonine (5) (3), the most abundant and nitrogen-free ion peak was observed at m/z 315, which is important for structure elucidation of this group (2,73).

Aldehyde dimer may undergo dehydration to give an a, -unsaturated carbonyl. From butanal, the conjugated carbonyl is ethylpropylacrolein (Equation 2.10). The conjugated system of this material competes for coordination sites on the rhodium catalyst so that hydroformylation inhibition is observed.[8] The formation of 2-ethylhex-2-enal can be limited by minimizing the concentration of dimers. Dimers are removed along with the product in a liquid recycle separation system. 

Condensation of benzotriazole with 2-carboxybenzaldehyde gives 3-(benzotriazol-l-yl)phthalide 795 (Scheme 127). The anion derived from phthalide 795 adds to the ft-carbon atom of a,( -unsaturated carbonyl compounds E to produce anion 796 that by intramolecular nucleophilic attack on the phthalide carbonyl group is converted to anion 797. Spontaneous expulsion of benzotriazole from molecules 797 followed by aromatization leads to 1,4-dihydroxy-naphthalenes 798 <1997SC3951>. 

Elimination of phenyltellurol from the telluroesters intermediate explains the formation of a, -unsaturated carbonyl compounds. 

These a,/l-unsaturated ketones and aldehydes are used as reactants in Michael additions (Section 1.10) and Robinson annulations (Section 2.1.4), as well as in a number of other reactions that we will encounter later. Entries 8 and 9 in Scheme 2.11 illustrate Michael reactions carried out by in situ generation of a,/ -unsaturated carbonyl compounds from Mannich bases. 

In general, the mechanisms of nucleophilic additions to double bonds have not been as much studied or systemized as those of electrophilic addition. Reactions 7.51 and 7.52 are examples of the very useful Michael condensation, in which a carbanion adds to an a,/ -unsaturated carbonyl or nitrile compound. The usefulness of these reactions arises from the fact that the number of ways of building longer carbon chains from smaller ones is limited. 

The rate-determining step in nucleophilic additions is usually nucleophilic attack on the multiple bond.127 For example, the entropy of activation of a Michael condensation is always a large, negative quantity. This arises from the fact that in the transition state the five atoms, 0=C—C—C=0 of the anion and the four atoms, C=C-—C=0 (or C=C—C=N) of the a,/ -unsaturated carbonyl (or nitrile) system are all restricted to one plane to allow maximum... 

The semi-stabilized telluronium ylides, generated in situ from the corresponding telluronium salts (156 R1 = CH=CHSiMe3, CH=CH2, CH=CHMe, CH=CHPh, Ph), have been reported to react with a,/(-unsaturated carbonyl compounds (157 R2 = Ph, OR, NR)) to afford 2-vmylcyclopropyl derivatives (158) with high... 

In a reaction which is mechanistically related to the Skraup reaction an a,/ -unsaturated carbonyl compound, generated by way of an acid-catalysed aldol condensation, reacts with a primary aromatic amine in the presence of acid to yield a quinoline derivative (Doebner-Miller reaction). For example, when aniline is heated with paraldehyde (which depolymerises to acetaldehyde during the reaction) in the presence of hydrochloric acid the final product is 2-methyl-quinoline (101) (quinaldine, Expt 8.40). Retrosynthetic analysis for the 1,2-dihydroquinoline reveals crotonaldedhyde as the unsaturated carbonyl component which is in turn formed from acetaldehyde (see Section 5.18.2, p. 799). 

The fluorines of a CF2= group of an a,/ -unsaturated carbonyl system are considerably deshielded, and the geminal and vicinal coupling constants dramatically diminished, as seen from the examples given in Scheme 4.62. 

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

The bicyclic ketone 13 was made from the simpler enone 14 that also had to be made. Aldol (a, -unsaturated carbonyl compound—still our first choice) disconnection reveals the keto-aldehyde 15. 

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