Carbonyl compounds components

The usual base or acid catalyzed aldol addition or ester condensation reactions can only be applied as a useful synthetic reaction, if both carbonyl components are identical. Otherwise complicated mixtures of products are formed. If two different aldehydes or esters are to be combined, it is essential that one of the components is transformed quantitatively into an enol whereas the other component remains as a carbonyl compound in the reaction mixture. 

A classical reaction leading to 1,4-difunctional compounds is the nucleophilic substitution of the bromine of cf-bromo carbonyl compounds (a -synthons) with enolate type anions (d -synthons). Regio- and stereoselectivities, which can be achieved by an appropiate choice of the enol component, are similar to those described in the previous section. Just one example of a highly functionalized product (W.L. Meyer, 1963) is given. 

Some catalysts are ha2ardous materials, or they react to form ha2ardous substances. For example, catalysts used for hydrogenation of carbon monoxide form volatile metal carbonyl compounds such as nickel carbonyl, which are highly toxic. Many catalysts contain heavy metals and other ha2ardous components, and environmentally safe disposal has become an increasing concern and expense. 

The photochemistry of carbonyl compounds has been extensively studied, both in solution and in the gas phase. It is not surprising that there are major differences between the photochemical reactions in the two phases. In the gas phase, the energy transferred by excitation cannot be lost rapidly by collision, whereas in the liquid phase the excess energy is rapidly transferred to the solvent or to other components of the solution. Solution photochemistry will be emphasized here, since both mechanistic study and preparative applications of organic reactions usually involve solution processes. 

Especially with the ordinary aldol reaction a number of side reactions can be observed, as a result of the high reactivity of starting materials and products. For instance, the a ,/3-unsaturated carbonyl compounds 4 can undergo further aldol reactions by reacting as vinylogous components. In addition compounds 4 are potential substrates for the Michael reaction. 

As a catalyst sulfuric acid is most often used phosphoric acid, boron trifluoride or an acidic ion exchange resin have also found application. 1,1-disubstituted alkenes are especially suitable substrates, since these are converted to relatively stable tertiary carbenium ion species upon protonation. o ,/3-unsaturated carbonyl compounds do not react as olefinic component. 

The Michael reaction occurs with a variety of a,/3-unsaturated carbonyl compounds, not just conjugated ketones. Unsaturated aldehydes, esters, thio-esters, nitriles, amides, and nitro compounds can all act as the electrophilic acceptor component in Michael reactions (Table 23.1). Similarly, a variety of different donors can be used, including /3-diketones, /3-keto esters, malonic esters, /3-keto nitriles, and nitro compounds. 

A new route to 2//-thiopyrans has been found in the cyclocondensation of thioenolates with a./J-unsaturated carbonyl compounds. The starting sulfur component can be methyl thiol-thione-ethanoate (90BSF446) or a /3-thienol-aldehyde (90ZC247) as shown by Eqs. (1) and (2), respectively. 

The addition of the dianion of /j-sulfmylcarboxylic acids to carbonyl compounds leads to the formation of the corresponding hydroxy derivatives which undergo spontaneous eyclization to give y-lactones. It was found that when optically active ( + )-(/ )-3-(4-methylphenylsulfinyl)pro-panoic acid is used for the reaction, the corresponding diastereomeric /i-sulfinyl-y-lactones are formed in a ratio which is dependent on the substituents of the carbonyl component. However, the diastereoselectivity was always moderate. 

C-coupling is of outstanding importance in the azo coupling reaction for the synthesis of azo dyes and pigments. An aromatic or heteroaromatic diazonium ion reacts with the so-called coupling component, which can be an aromatic primary, secondary, or tertiary amine, a phenol, an enol of an open-chain, aromatic, or heteroaromatic carbonyl compound, or an activated methylene compound. These reactions at an sp2-hybridized carbon atom will be discussed in Chapter 12. In the... 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

TABLE 16.1 Base Catalyzed Condensations Showing the Active Components and the Carbonyl Compounds... 

The Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde, and a primary or secondary amine. The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions to give mixtures of isomeric 3-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone, and the more highly branched (3-amino ketone usually predominates. 

Both unsymmetrical alkenes and diols can be prepared by applying these methods to mixtures of two different carbonyl compounds. An excess of one component can be used to achieve a high conversion of the more valuable reactant. A mixed reductive... 

Various other Lewis acids have been explored as catalysts, and the combination InCl3-(CH3)3SiCl has been found to be effective.88 The catalysis requires both components and is attributed to assistance from O-silylation of the carbonyl compound. 

Especially reactive carbonyl compounds such as methyl pyruvate can trap the carbonyl oxide component. For example, ozonolysis of cyclooctene in the presence of methyl pyruvate leads to 5 when treated with triethylamine 5 is converted to 6, in which the two carbons of the original double bond have been converted to different functionalities.205... 

In synthetic applications, Li et al. examined the propargylation-allenylation of carbonyl compounds by using a variety of metals including Sn, Zn, Bi, Cd, and In.203 By using the indium-mediated allenylation reaction, Li and co-workers developed the synthesis of the antiviral, antitumor compound (+)-goniofufurone (Scheme 8.22),204 a key component isolated from the Asian trees of the genus Goniothalamus,205 and other styryl lactone derivatives (Eq. 8.80). 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

Modern MCRs that involve isocyanides as starting materials are by far the most versatile reactions in terms of available scaffolds and numbers of accessible compounds. The oldest among these, the three-component Passerini MCR (P-3CR), involves the reaction between an aldehyde 9-1, an acid 9-2, and an isocyanide 9-3 to yield a-acyloxycarboxamides 9-6 in one step [8], The reaction mechanism has long been a point of debate, but a present-day generally accepted rational assumption for the observed products and byproducts is presented in Scheme 9.1. The reaction starts with the formation of adduct 9-4 by interaction of the carbonyl compound 9-1 and the acid 9-2. This is immediately followed by an addition of the oxygen of the carboxylic acid moiety to the carbon of the isocyanide 9-3 and addition of this carbon to the aldehyde group, as depicted in TS 9-5 to give 9-5. The final product 9-6 is... 

Perhaps the best-known MCR is the Ugi four-(or higher) component condensation (U-4CR) [29]. First reported in 1959, the Ugi-4CR describes the conversion of carbonyl compounds 9-16, amines 9-17, various types of acids 9-19 and isocyanides 9-21, the final product being peptide-like structures 9-24. A rather simplified mechanism of the Ugi-4CR is depicted in Scheme 9.4. 

A one pot samarium-catalyzed three-component reaction of aldehydes, amines, and nitroal-kanes leads to pyrroles. The reaction proceeds via imines, generated from the amine and carbonyl compound, followed by the Michael addition of the nitro compound (Eq. 10.10).12a In... 

The use of enol- and phenol-esters in cross-coupling reactions is a valuable protocol, as it gives an indirect way to involve readily available phenols and carbonyl compounds as the electrophilic components of cross-couplings (Equation (22)) ... 

Reagents and methods for the synthesis of 1,5-benzodiazepine derivatives from o-phenylenediamine and carbonyl compounds have attracted an unusually high degree of interest in 2006. Illustrative of this, the condensation of two mol equivalents of acetone with o-phenylenediamine 97 was reported <06TL3135> on simple grinding of the components in the presence of an organic acid catalyst at room temperature resulting in 98. The yields of 98 were... 

Oxygenates were recovered from the Fischer-Tropsch aqueous product, employing a separation strategy similar to that in the Sasol 1 refinery. The main difference was in volume, and this made further separation of the different alcohols and carbonyl compounds worthwhile. Some of the ethanol served as a blending component in motor gasoline, with the final blend containing around 10% ethanol.38 Most of the alcohols and carbonyl compounds were sold as chemicals. In addition to the oxygenates, the C2 hydrocarbons were also recovered and sold. 

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