Substitution carbonyl compounds

Once regiocontrol was achieved, donor-substituted allyl metallics found two synthetically important applications. The hetero-substituted vinyl compounds, obtained by alkylation of a substituted allyl carbanion in the 3-position ( ), can be hydrolyzed to carbonyl compounds substituted on the /1-carbon atom. Thus, the substituted allyl carbanion was used as an equivalent of the homoenolate synthon18 19. 

Moreover, INADEQUATE experiments for analysis of carbon-carbon connectivities require careful interpretation when the magnitudes of two-bond and one-bond carbon-carbon coupling constants approach each other. Large two-bond CC couplings, for example, are observed for alkynyl, cyclobutyl, cyclobutenyl substructures and for carbonyl compounds substituted by electronegative groups in an a position. 

These substitution products A and B need not be the final product of the reaction of nucleophiles with carboxyl species. Sometimes they may be formed only as intermediates and continue to react with the nucleophile. Being carbonyl compounds (substitution products A) or carboxylic acid derivatives (substitution products B), they can in principle undergo, another addition or substitution reaction (see above). Thus, carboxylic acid derivatives can react with as many as two equivalents of nucleophiles, and carbonic acid derivatives can react with as many as three. 

With a-bromo carbonyl compounds, substitution leads to two electrophilic groups on neighbouring carbon atoms. Each has a low-energy empty orbital, Jt from C=0 and a from C-Br (this is what makes them electrophilic), and these can combine to form a molecular LUMO (Jt + a ) lower in energy than either. Nucleophilic attack will occur easily where this new orbital has its largest coefficients, shown in orange on the diagram. 

Perhaps the most successful approach for promoting the 47r participation of 1-oxabutadiene systems in intermolecular Diels-Alder reactions employs a,/8-unsaturated carbonyl compounds substituted with an additional C-3 (a) electron-withdrawing group. The addition of the C-3 electron-withdrawing substituent increases the electron-deficient character of the oxabutadiene system, decreases the LUM0oxabutadiene, and as expected, enhances the observed [4 + 2] cycloaddition rate and regioselec-... 

A large number of carbonyl compounds substituted with ligands having Group VI donor atoms and, in particular, sulfur, have been reported. Elemental sulfur or sulfur atoms in thio compounds can assist in cluster formation by their capability of bridging between two or more metal atoms. 

Conjugate, Michael, or 1,4-addition to an a,p-unsaturated carbonyl compound results in a saturated carbonyl compound, substituted at the p-position. 

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. 

Synthetically useful stereoselective reductions have been possible with cyclic carbonyl compounds of rigid conformation. Reduction of substituted cyclohexanone and cyclopentan-one rings by hydrides of moderate activity, e.g. NaBH (J.-L. Luche, 1978), leads to alcohols via hydride addition to the less hindered side of the carbonyl group. Hydrides with bulky substituents 3IQ especially useful for such regio- and stereoselective reductions, e.g. lithium hydrotri-t-butoxyaluminate (C.H. Kuo, 1968) and lithium or potassium tri-sec-butylhydro-borates or hydrotri-sec-isoamylborates (=L-, K-, LS- and KS-Selectrides ) (H.C. Brown, 1972 B C.A. Brown, 1973 S. Krishnamurthy, 1976). 

Most syntheses of nitrogen heterocycles involve substitution and/or condensation reactions of nitrogen nucleophiles with difunctional halides or carbonyl compounds. Common nitrogen reagents are ... 

Other interesting regioselective reactions are carried out within the synthesis of nitrofurantoin. Benzaidehyde semicarbazone substitutes chlorine in chloroacetic ester with the most nucleophilic hydrazone nitrogen atom. Transamidation of the ester occurs with the di-protic outer nitrogen atom. Only one nucleophilic nitrogen atom remains in the cyclization product and reacts exclusively with carbonyl compounds. 

Cycloaddition of COj with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiocheraistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /3-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

Substitution of deuterium for hydrogen at the a carbon atom of an aldehyde or a ketone is a convenient way to introduce an isotopic label into a molecule and is readily carried out by treating the carbonyl compound with deuterium oxide (D2O) and base... 

Secondary amines are prepared by hydrogenation of a carbonyl compound m the presence of a primary amine An N substituted mine or Schijfs base is an intermediate... 

In general, the xanthenes are synthesized by the reaction of two moles of a nucleophilic / -substituted phenol (10) with an electrophilic carbonyl compound (11), the reaction occurring most readily with an acid catalyst at temperatures of 100—200°C. 

Oxidative cleavage of P-aminoacyl complexes can yield P-amino acid derivatives (320,321). The rhodium(I)-catalyzed carbonylation of substituted aziridines leads to P-lactams, presumably also via a P-aminoacyl—metal acycHc compound as intermediate. The substituent in the aziridine must have 7T or electrons for coordination with the rhodium (322,323). 

These reversible reactions are cataly2ed by bases or acids, such as 2iac chloride and aluminum isopropoxide, or by anion-exchange resias. Ultrasonic vibrations improve the reaction rate and yield. Reaction of aromatic aldehydes or ketones with nitroparaffins yields either the nitro alcohol or the nitro olefin, depending on the catalyst. Conjugated unsaturated aldehydes or ketones and nitroparaffins (Michael addition) yield nitro-substituted carbonyl compounds rather than nitro alcohols. Condensation with keto esters gives the substituted nitro alcohols (37) keto aldehydes react preferentially at the aldehyde function. 

The dipolar ion can react in several ways according to the solvent and the stmcture of the olefin. In inert solvents, if the carbonyl compound is highly reactive (eg, an aldehyde), the dipolar ion can be added to the carbonyl fragment to give the normal ozonide or 1,2,4-trioxolane (7) for example, 1,1-and 1,2-dialkylethylenes react in this manner. Tri- or tetraalkyl-substituted olefins produce a smaH, if any, yield of an ozonide when the ozonolysis is... 

Hydroxyall l Hydroperoxyall l Peroxides. There is evidence that hydroxyalkyl hydroperoxyalkyl peroxides (2, X = OH, Y = OOH) exist in equihbrium with their corresponding carbonyl compounds and other a-oxygen-substituted peroxides. For example, reaction with acyl haUdes yields diperoxyesters. Dilute acid hydrolysis yields the corresponding ketone (44). Reduction with phosphines yields di(hydroxyalkyl) peroxides and dehydration results in formation of cycHc diperoxides (4). 

Most ozonolysis reaction products are postulated to form by the reaction of the 1,3-zwitterion with the extmded carbonyl compound in a 1,3-dipolar cycloaddition reaction to produce stable 1,2,4-trioxanes (ozonides) (17) as shown with itself (dimerization) to form cycHc diperoxides (4) or with protic solvents, such as alcohols, carboxyUc acids, etc, to form a-substituted alkyl hydroperoxides. The latter can form other peroxidic products, depending on reactants, reaction conditions, and solvent. 

Hydroxypyrroles. Pyrroles with nitrogen-substituted side chains containing hydroxyl groups are best prepared by the Paal-Knorr cyclization. Pyrroles with hydroxyl groups on carbon side chains can be made by reduction of the appropriate carbonyl compound with hydrides, by Grignard synthesis, or by iasertion of ethylene oxide or formaldehyde. For example, pyrrole plus formaldehyde gives 2-hydroxymethylpyrrole [27472-36-2] (24). The hydroxymethylpyrroles do not act as normal primary alcohols because of resonance stabilization of carbonium ions formed by loss of water. 

A significant advance in the synthesis of monoorganotin trihaHdes was the preparation of P-substituted ethyl tin trihaHdes in good yield from the reaction of stannous chloride, hydrogen haHdes, and a,P-unsaturated carbonyl compounds, eg, acryHc esters, in common solvents at room temperature and atmospheric pressure (153,154). The reaction is beHeved to proceed through a solvated trichlorostannane intermediate (155) ... 

High yields of optically active cyanohydrins have been prepared from hydrogen cyanide and carbonyl compounds using an enzyme as catalyst. Reduction of these optically active cyanohydrins with lithium aluminum hydride in ether affords the corresponding substituted, optically active ethanolamine (5) (see Alkanolamines). 

The Michael-type addition of maleic hydrazide and other pyridazinones to activated alkenes, such as methyl acrylate, acrylonitrile, methyl vinyl ketone and other a,/3-unsatu-rated carbonyl compounds, results in the formation of mono-lV-substituted products. 

A-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloaddition reactions with carbonyl compounds to give oxetanes. This is illustrated by the addition of furan and benzophenone to give the oxetane (138). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 139). The intermediate oxetane undergoes rearrangement under the reaction conditions (79JOC2949). 

The comparatively ready accessibility of selenocarboxamides has encouraged the use of this procedure for the synthesis of selenazoles (1889LA(250)294). Reaction of the a-chloro-carbonyl compound (73) with the selenocarboxamide (74) provided a ready synthesis of a variety of substituted selenazoles (75). Useful variations of this general procedure are described in detail in Chapter 4.20, and particularly attractive is the reaction of hydrogen selenide with a mixture of a nitrile and the a-halogenoketone to afford the selenazole (48YZ191, 79S66). 

In the oxaziridines (1) ring positions 1, 2 and 3 are attributed to oxygen, nitrogen and carbon respectively. The latter almost always is in the oxidation state of a carbonyl compound and only in rare cases that of a carboxylic acid. Oxaziridinones are not known. The nitrogen can be substituted by aryl, alkyl, H or acyl the substituent causes large differences in chemical behavior. Fused derivatives (4), accessible from cyclic starting materials (Section 5.08.4.1), do not differ from monocyclic oxaziridines. 

Tetrazole, l-(p-substituted phenyl)-antimicrobial activity, 5, 835 Tetrazole, 5-thio-rearrangements, 5, 823 Tetrazole, 2-thioacyl-reactions, 5, 109 Tetrazole, 5-(o-tolyl)-tautomerism, 5, 804 Tetrazole, 5-(p-tolyl)-dipole moments, 5, 795 tautomerism, 5, 804 Tetrazole, 5-(trimethylsilylamino)-synthesis, 5, 832 Tefrazolecarbaldehydes reactions, 5, 820 Tetrazole-5-carbaldehydes reactions, 5, 820 Tetrazolecarbonitriles reactions, 5, 820 Tetrazole carbonyl compounds reactions, 5, 820 Tetrazolecarboxylic acid, 5-aryl-acidity, 5, 816... 

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