Addition of a-Carbonyl Compounds

A significant acceleration of Michael addition was reported by Lubineau in the reaction of nitroalkanes with buten-2-one when the reaction media was changed from nonpolar organic solvents to water 

The Michael reaction of benzylidene acetophenone and benzylidene acetone with ethyl acetoacetate, nitromethane, and acetylacetone was studied by Musaliar and co-workers in the presence of a cetyltrimethy-lammonium bromide-containing aqueous micellar medium. The Michael reaction of various nitro alkanes with electrophilic alkenes is performed in NaOH (0.025-0.1 M) in the presence of cetyltrimethylam-monium chloride (CTACI) without any organic solvent (Eq. 10.23).  

Jenner investigated the kinetic pressure effect on some specific Michael and Henry reactions and found that the observed activation volumes of the Michael reaction between nitromethane and methyl vinyl ketone are largely dependent on the magnitude of the electrostriction effect, which is highest in the lanthanide-catalyzed reaction and lowest in the base-catalyzed version. In the latter case, the reverse reaction is insensitive to pressure.Recently, Kobayashi and co-workers reported a highly efficient Lewis-acid-catalyzed asymmetric Michael addition in water. A variety of unsaturated carbonyl derivatives gave selective Michael additions with a-nitrocycloalkanones in water, at room temperature without any added catalyst or in a very dilute aqueous solution of potassium carbonate (Eq. 10.24).  

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The photochemical addition of a carbonyl compound to an olefin to form an oxetane is called the Paterno-Buchi reaction (Equation 13.52) and is one of... 

The addition of a carbonyl compound to methyl 2-siloxycyclopropanecarboxylate (113 equation 47) in the presence of a stoichiometric amount of TiCU affords a mixture of hyctoxyalkylation products (114) and (115), which are versatile starting materials for highly substituted tetrahydrofurans, dihydrofu-rans, and y-butyrolactones. ... 

Deprotonadon of thioanisole and addition of a carbonyl compound affords an isolable hydroxy sulfide which can then be alkylated (Scheme 7). Treatment with base generates the same betaine that would have been formed using the sulfur ylide approach, and effects the intramolecular displacement reaction. The addition of methylthiomethyllithium to 2-cyclohexenone exclusively provides the 1,2-addition prod-uct the dianions derived from phenylmethanethiol or allylthiol react in a similar manner. In one case a 6-keto steroidal substrate was found to undergo smooth methylenation using this procedure. 

If you want to do a conjugate addition of a carbonyl compound without having a second anion-stabilizing group, you need some stable and relatively unreactive enol equivalent. In Chapters 27 and 28 you saw how enamines are useful in alkylation reactions. These neutral species are also perfect for conjugate addition as they are soft nucleophiles but are more reactive than ends and can be prepared quantitatively in advance. The reactivity of enamines is such that heating the reactants together, sometimes neat, is all that is required. Protic or Lewis acid catalysis can also be used to catalyse the reaction at lower temperature. 

Typical examples for the reaction of RX with a 1 -lithiocyclopropene giving cyclopropenes and for the addition of a carbonyl compound to a 1-lithiocyclopropene giving 1-(1-hydroxyalkyl)cyclopropene are given. Examples of this type of reaction are collected in Table 1. For related reactions see Section 4.2.1.4. 

Vinyl sulfides, selenides, and tellurides are prepared in a one-pot procedure by treating mixtures of the chloromethyl phenyl chalcogenide and triphenylphosphine in THF with /-BuOK (to form the ylide), followed by the addition of a carbonyl compound (eq 95). The yields are good to poor and the Z isomer is usually favored. 

Addition of a carbonyl compound results in the almost immediate formation of a phos-phonates chlorohydrin. After a few hours, only the signals for the corresponding epoxyalkanephosphonates can be detected in the NMR spectra. This procedure has led to almost quantitative yields of the epoxyalkanephosphonate (see Appendix). This method is applicable to (i) a wide range of ahphatic and aromatic aldehydes and ketones, (ii) to the preparation of 1-substituted 1,2-epoxyalkanephosphonates. 

As noted for amino acids, the addition of a carbonyl compound to a primary amino group at an appropriate pH can trigger the formation of the corresponding imine, which greatly enhances the acidity of the a-carbon, thus stabilizing the enolate and favoring racemization. In this context, studies of the racemization of amino esters in the presence of various aldehydes have been performed [43], and this phenomenon has been exploited by coupling the racemization with enzymatic hydrolysis to initiate resolution under DKR conditions (Scheme 8.5) [44]. 

Addition of SO2 bleaches anthocyanins. The flavylium cation reacts to form a carbinol base corresponding to compounds XII or XIII (Formula 18.27). The color is restored by acidification to pH 1 or by addition of a carbonyl compound (e. g. ethanal). Since compounds of type XIV (R = CH3, C2H5) are not affected by SO2, it appears that compound XIII is involved in such bleaching reactions. 

The TiCl3-H20-promoted cross-coupling reaction has been extended to the addition of a carbonyl compound to a,P-unsaturated aldehydes [80c]. The addition occurs selectively to the carbon atom of the carbonyl group, and highly functionalized allylic pinacols are obtained with good yields. 

The conversion of a carbonyl compound by ammonium polysulphide solution into an amide with the same number of carbon atoms is known as the Willgerodt reaction. The procedure has been improved by the addition of about 40 per cent, of dioxan or of pyridine to increase the mutual solubility of the ketone and aqueous ammonium polysulphide the requisite temperature is lowered to about and the yield is generally better. 

When two moles of a carbonyl compound are used instead of formalin, the mechanism is different (Scheme 58) (70BSF3147). In one example (80CCC2417) the product of the nucleophilic addition of the hydrazine to the pyrazolinium salt (635 R = = Ph, R = R" =... 

To a solution of the lithium dialkylamide (1.1 mmol) in THF (2 ml) cooled to -78°C was added a solution to TMSC1 (5-10mmoI) in THF (2ml), also cooled to -78 °C. This was followed by dropwise addition of the carbonyl compound (lmmol) in THF (2ml). After lmin, triethylamine (2ml) was added, followed by quenching with saturated sodium hydrogen carbonate solution. The product was extracted into pentane, and these extracts were... 

The reactivity of a carbonyl compound RjCOR2 is correlated with its rate constant with eh against (<3j + o ). The result was a fairly good straight line, with a slope of-0.74. The active center of reaction is known to be the carbonyl oxygen. 

The Peterson olefination reaction involves the addition of an a-silyl substituted anion to an aldehyde or a ketone followed by the elimination of silylcarbinol either under acidic (awP -elimination) or basic (syn-elimination) conditions to furnish olefins178. Thus, Peterson olefination, just like Wittig and related reactions, is a method for regioselective conversion of a carbonyl compound to an olefin. Dienes and polyenes can be generated when the Peterson reaction is conducted using either an ,/l-unsaturated carbonyl compound or unsaturated silyl derivatives as reaction partners (Table 20)179. 

The apparently quite broad structural requirements for anticonvulsant activity, noted earlier in this chapter, extend to yet another class of five-membered heterocycles that include an imide function. Imidazo-2,4-diones, better known as hydan-toins, have comprised some of the most widely used drugs for treating severe motor and psychomotor epileptic seizures. The general reaction used to prepare this heterocyclic system involves the treatment of a carbonyl compound with ammonium carbonate and potassium cyanide. The first step in the complex sequence can be visualized as the addition of the elements of ammonia and hydrogen cyanide to give an a-aminonitrile (88-2). Addition of ammonia to the cyano group would then lead to an amidine (88-3). Carbon dioxide or carbonate ion present in the reaction... 

Similar changes take place in the acidification of the enol salt of a carbonyl compound, the principal difference being the much longer life of the acf-nitro compound compared to that of an enol of a simple ketone (see Section 17-IB), Primary and secondary nitro compounds undergo aldol additions and Michael additions with suitable carbonyl compounds and basic catalysts ... 

Another common umpolung synthon is a homoenolate. Normally the ft position of a carbonyl compound is an electrophilic center (by Michael addition to an 0, /3-unsaturated carbonyl derivative). To make it a nucleophilic center, an organometallic is needed since it is unactivated and nonconjugated. A common way to do this is to use a /3-bromo acetal. 

Another fundamental reaction of >C=0 involves its reactivity as a base. In the Brpnsted sense, >C=0 - may react with a proton donor to produce a neutral ketyl radical (>C(.)OH, Figure 2, reaction 2). This is an important process when the reduction of a carbonyl compound is carried out under acidic conditions or in a protic media (e.g. elec-trochemically, with less reactive reducing reagents such as Mg or Zn, or when >C=0"-is produced via PIET and R3N"+ has available a-protons). The follow-up chemistry of >C(.)OH is that of a neutral free radical (dimerization to form pinacols, addition to unsaturated compounds, fragmentations/ring-openings, etc.), and thus beyond the scope of this chapter. 

Tamaru and Kimura have recently developed a three-component coupling reaction of carbonyl compounds, 1,3-dienes, and dimethylzinc leading to homoallylic alcohols 30 via Ni-catalyzed conjugate addition of the carbonyl compound to the 1,3-diene in a 1,4-fashion (Scheme 8.11) [44], They later showed that 1,3-dienes... 

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