Carbonyl compounds Ester Ketones

The introduction of tritium into molecules is most commonly achieved by reductive methods, including catalytic reduction by tritium gas, PH2], of olefins, catalytic reductive replacement of halogen (Cl, Br, or I) by H2, and metal pH] hydride reduction of carbonyl compounds, eg, ketones (qv) and some esters, to tritium-labeled alcohols (5). The use of tritium-labeled building blocks, eg, pH] methyl iodide and pH]-acetic anhydride, is an alternative route to the preparation of high specific activity, tritium-labeled compounds. The use of these techniques for the synthesis of radiolabeled receptor ligands, ie, dmgs and dmg analogues, has been described ia detail ia the Hterature (6,7). 

Alcohols are among the most versatile of all organic compounds. They occur widely in nature, are important industrial 7, and have an unusually rich chemistry. The most widely used methods of alcohol synthesis start with carbonyl compounds. Aldehydes, ketones, esters, and carboxylic acids are reduced by reaction with LiAlH4. Aldehydes, esters, and carboxylic acids yield primary alcohols (RCH2OH) on reduction ketones yield secondary alcohols (R2CHOH). 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Only scare data is available in the literature on the application of rhenium containing mono- or bimetallic catalysts in the hydrogenolysis of esters to alcohols. Decades ago Broadbent and co-workers studied the hydrogenation of organic carbonyl compounds (aldehydes, ketones, esters, anhydrides, acids,... 

The initial carbon-carbon bond formation (— 84) is often reversible, and a subsequent step—such as dehydration—may be necessary to displace the equilibrium. The many different (often named) reactions really differ from each other only in the nature of the particular carbonyl compound (aldehyde, ketone, ester, etc.), and in the type of carbanion, employed. 

Dialkylboron trifluoromethanesulfonates (Inflates) are particularly useful reagents for the preparation of boron enolates from carbonyl compounds, including ketones, thioesters and acyloxazoiidinones. Recentiy, the combination of dicylohexyiboron trifluoromethanesulfonate and triethyiamine was found to effect the enolization of carboxyiic esters. The boron-mediated asymmetric aldoi reaction of carboxyiic esters is particuiariy usefui for the construction of anti p-hydroxy-a-melhyl carbonyl units. The present procedure is a siight modification of that reported by Brown, et ai. ... 

To address limitations in the use of glyceraldehyde acetonide (43) as a three-carbon chiral building block, butane-2,3-diacetal-protected glyceraldehyde (44, R1 = R2 = H) has been prepared. It undergoes diastereoselective aldol reactions with a range of carbonyl compounds esters, thioesters, and ketones. The work has been extended (g) to other derivatives such as the a-substituted aldehyde (44, R1 = Me, allyl) and the methyl ketone (44, R2 = Me).122a,b... 

Attempts were made to observe a curvature of the Bronsted plots for ketone ionisation. Cohen and Marcus (1968) and Bell (1973) (see also J. R. Jones, 1973 Kresge, 1975b) collected data for the reaction of carbonyl compounds (including ketones, esters and keto-esters) with bases and have observed a slight curvature. The data fit the Marcus equation with AG% = 10 kcal mol-1 and Wr = 4 kcal mol-1 (Hupe and Wu, 1977). 

A range of nucleophiles will undergo conjugate additions with a, 3-unsaturated carbonyl compounds, and six examples are shownbelow. Note the range of nucleophiles, and also the range of carbonyl compounds esters, aldehydes, acids, and ketones. 

Lithium diisopropylamide (LDA), LiN(i-Pr)2 Reacts with carbonyl compounds (aldehydes, ketones, esters) to yield enolate ions (Sections 22.5 and 22.7). 

A selection of A//p gp values has already been given in Table 2-4 in Section 2.2.6. This new Lewis basicity scale is more comprehensive and seems to be more reliable than the donor number scale. Analogously, a Lewis basicity scale for 88 carbonyl compounds (esters, carbonates, aldehydes, ketones, amides, ureas, carbamates) has been derived from their standard molar enthalpies of complexation with gaseous boron trifluoride in dichloromethane solution [143]. The corresponding Aff Q gp values range from 33 kJ mol for di-t-butyl ketone to 135 kJ mol for 3-diethylamino-5,5-dimethyl-cyclohexen-2-one. 

Chapters 20 through 24 of this text discuss carbonyl compounds—aldehydes, ketones, acid halides, esters, amides, and carboxylic acids. The carbonyl group is perhaps the most important Functional group in organic chemistry, because its electron-deficient carbon and easily broken 7t bond make it susceptible to a wide variety of useful reactions. 

As olefinic substrates a,j -unsaturated carbonyl compounds (esters, anhydrides, ketones, quinones), nitriles and nitro compounds can be used. The rate of addition of the diazo compounds is dependent upon the nature of the diazo compound and generally the following order of reactivity can be observed diazomethane > diphenyldiazomethane > methyl diazoacetate > diazoketones. 

The reaction sequence is called the Regitz diazo transfer and requires active methylene compounds as substrates/ Hence it is common to use formic esters to create P-carbonyl compounds from ketones or aldehydes in an aldol reaction. These are used as substrates for deformy-lative diazo transfer reactions in which the diazo group is transferred and the formyl group is removed in one concerted step. The mechanism of the deformylative diazo transfer is shown below. In this case the bulky base NaHMDS ensures deprotonation at the less-hindered a-position of 3, forming the so-called kinetic enolate 13. This enolate is formylated by ethyl formate yielding the P-formyl ketone 14, which is used as substrate in the deformylative diazo transfer. 

The predominant conformation of a,P-unsaturated carbonyl compounds (aldehydes, ketones, esters) can vary when Lewis adds are coordinated to the carbonyl group, ft has been experimentally shown that the s-trans conformer of acrolein is more stable than the s-ds conformer, in the absence of any Lewis add. The two conformers are of almost equal stability in the case of acrylic acid or methyl acrylate 83] (Figure L21). The barriers between these conformers are low (4-9 kcal mol ). Interconversion is rapid, and the Curtin-Hammett principle ( 1.3) can be applied. 

Many types of reactive molecules are well known to medicinal chemists acyl halides, aldehydes, aliphatic esters, aliphatic ketones, alkyl halides, anhydrides, alpha-halocarbonyl compounds, aziridines, 1,2-dicarbonyl compounds, epoxides, halopyrimidines, heteroatom-heteroatom single bonds, imines, Michael acceptors and (l-heterosubstituted carbonyl compounds, perhalo ketones, phosphonate esters, thioesters, sulfonate esters, and sulfonyl halides, to name a few [14]. This is not to say that these functionalities are not useful - some even appear in approved drugs -but all of these can react covalently with proteins, and thus should be regarded with suspicion. However, molecules can react covalently with proteins even if they do not contain functionalities that raise alarm. Jonathan Baell has referred to these as pan assay interference compounds, or PAINS, and has published a list of moieties to watch out for, as well as strategies to detect them [15, 16]. 

Lithium aluminium hydride is a more powerful reducing agent than sodium borohydride and reduces most of the commonly encountered organic functional groups (see Table 7.3). It reacts readily with water and other compounds that contain active hydrogen atoms and must be used under anhydrous conditions in a non-hydroxylic solvent diethyl ether and THF are commonly employed. Lithium aluminium hydride has found widespread use for the reduction of carbonyl compounds. Aldehydes, ketones, esters, carboxylic acids and lactones can all be reduced smoothly to the corresponding alcohols under mild conditions. Carboxylic amides are converted into amines or aldehydes, depending on the conditions and on the... 

Conjugate addition of organocuprates to , -unsaturated carbonyl compounds, including ketones, esters, and amides, are accelerated by addition of TMSCl to provide good yields of the 1,4-addition products (eq 31). The effect of additives such as HMPA, DMAP, and TMEDA have also been examined. The role of the TMSCl on 1,2- and 1,4-addition has been explored by several groups, and a recent report has been published by Lipshutz." His results appear to provide evidence that there is an interaction between the cuprate and TMSCl which influences the stereochemical outcome of these reactions. 

Several examples of solvent-free reactions of hypervalent iodine reagents under microwave irradiation conditions have been reported [2, 68-72], A solvent-less oxidation of 1,4-dihydropyridines to the respective pyridines can be performed using [bis(trifluoroacetoxy)iodo]benzene at room temperature under microwave irradiation conditions [68], Carbonyl compounds (aldehydes, ketones and esters) can be converted into the respective a-[(2,4-dinitrobenzene)sulfonyl]oxy carbonyl compounds by the reaction of the neat carbonyl compounds with [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]benzene (HDNIB) under microwave irradiation in less than 40 s [69], Likewise, a-halocarbonyl compounds 55 can be conveniently prepared by sequential treatment of carbonyl compounds 54 with [hydroxy(tosyloxy)iodo]benzene followed by magnesium halides under solvent-free microwave irradiation (MWI) conditions (Scheme 6.21) [70],... 

Michael reactions take place with a wide variety of a,j8-unsaturated carbonyl compounds (aldehydes, ketones, esters, and amides) as well as a,)8-unsaturated nitro and nitrile compounds. 

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