Carbonylative synthetic transformation methods

IBX is also tolerant of amine functionality, and therefore is used for the successful oxidation of amino alcohols to amino carbonyls. Frequently, this synthetic transformation requires the protection of the amino group, as a nonhasic derivative, prior to oxidation. IBX also provides an alternative method to oxidize alcohols selectively in the presence of primary, secondary, or tertiary amines, although the in situ protonation of the amine with acid is usually required (e.g., trifluoroacetic acid, 1-1.5 equiv) to avoid reduced yields. Oxidation of an aminocyclohexanol occurs selectively upon treatment with both IBX and TEA (1 1 ratio), without degradation of the amine functionality, to give cyclohexanone in 91% yield (eq 3). ... 

Although isatins having adjacent carbonyls of very different reactivity— amide vs. ketone—undergo a variety of chenucal reactions [86,87], the focus here is on synthetic transformations to indoles. Accordingly, isatins can be reduced directly to indoles (Scheme 11, equations 1-7) [16,89-93]. Given the availability of isatins from aromatic amines (e.g., Sandmeyer synthesis [86], Gassman synthesis [88]), the reduction of isatins to indoles can be an important alternative to other methods. 

As we are beginning to see, aldol additions and aldol condensations are important methods for carbon-carbon bond formation. They also result in j8-hydroxy and a,j8-unsaturated carbonyl compounds that are themselves useful for further synthetic transformations. Some representative reactions are shown below. 

The hydrosilylation of terminal alkynes disclosed by Trost can be applied to internal alkynes as well. i Remarkably, the (Z)-isomer is generated in this process, resulting from trans addition during hydrosilylation. The protodesilylation of these sily-lated products in the presence of copper(I) iodide and tetrabuty-lammonium fluoride (TBAF) or silver(I) fluoride (eq 15) leads to internal fraws-olefins. This two-step method is a useful synthetic transformation to access ( j-alkenes from internal alkynes. In contrast, the chemoselective reduction of alkynes to the corresponding ( -alkenes is conventionally accomplished readily with Lindlar s catalyst. The complementary process to afford ( )-olefins has proven much more difficult. Methods involving metal hydrides, dissolving metal reductions, low-valent chromium salts provide the desired chemical conversion, albeit with certain limitations. For example, functional substitution at the propargylic position (alcohols, amines, and carbonyl units) is often necessary to achieve selectivity in these transformations. Conversely, the hydrosilylation/protodesilyla-tion protocol is a mild method for the reduction of alkynes to ( )-alkenes. 

Nitro-compounds are also prepared by the replacement of benzylic hydroxyl by 2-nitropropyl groups," the replacement of activated bromine with silver nitrate in the presence of triphenylphosphine," and the Michael addition of nitroethane to a,/3-ethylenesulphoximines under phase-transfer conditions." The preparation and reactions of cyclic a-nitroketones have been reviewed." The conversion of primary and secondary nitroalkanes into the corresponding carbonyl compounds, i.e. the Nef reaction, is a useful synthetic transformation. Three new methods" " to effect this important reaction offer a variety of oxidative conditions, and thus enable the minimization of side reactions (Scheme 36). 

The enhanced reactivity of the silyl- and stannyl-substituted alkenes is also favorable to the synthetic utility of carbocation-alkene reactions. Silyl enol ethers also show enhanced reactivity. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCU. This reaction provides a method for introducing tertiary alkyl groups alpha to a carbonyl. This transformation cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

The thiation procedure described here is an example of a general synthetic method for the conversion of carbonyl to thiocarbonyl groups. Similar transformations have been carried out with ketones, carboxamides,esters,thioesters, 1 actones, " thiol actones, - imides, enaminones, and protected peptides. ... 

In this context the described methods for preparation of 2,5-dihydro-1,2-oxa-phosphole-2-oxide derivatives have to be considered as synthetic protocols for transformation of carbonyl compounds in to P-containing heterocycles. 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

Despite the rich chemistry of 288 that may be anticipated, " " synthetic methods for this type of compounds are limited to the one involving oxidation of the corresponding alcohols. In contrast, 288 is readily derived from 287 by a simple and one-pot operation. Since propargylic alcohols are readily accessible from ketones or aldehydes, the straightforward transformation from 70 to 288f provides a novel method for carbonyl olefination of ketones and aldehydes. For example, ethisterone, 301, is tolerable to this transformation (route 2, Scheme 16) without any protection of the functional groups to give 302 (Equation (51))." ... 

The chemical transformations of dialkyl dithioacetals have been reviewed in detail [47] and offer routes to a variety of useful carbohydrate derivatives. Dialkyl dithioacetal derivatives of sugars continue to play an important role in modem synthetic carbohydrate chemistry through reactions of die dithioacetal function and manipulation of the sugar hydroxyl groups. Dithioacetals also provide a convenient method for temporary protection of sugar carbonyl groups in the synthesis of noncarbohydrate natural products. 

Aldol reactions provide a valuable synthetic method for forming carbon-carbon bonds. They can be adapted to extend the length of a carbon chain, to form cyclic compounds, and to provide intermediates that can be transformed into more useful materials. An important feature of these intermediates is that functional groups useful for later reactions are located close to or on the carbons of the newly formed C-C bond. There is an almost bewildering number of variations on the aldol reaction and we shall not mention all of them. The main thing to recognize in all of these reactions is that the acceptor molecule always is a carbonyl compound, best an aldehyde, sometimes a ketone, even an ester (see Section 18-8E). The donor molecule is some type of carbanion usually, but not always, an enolate anion. However, any substance that has a... 

For this reason reactive groups are usually introduced before quinuclidine ring closure and various transformations are effected afterward. The carboxyl and carbonyl derivatives, e.g., quinuclidine-2-carboxylic acid, quinuclidin-3-one, and so on, are useful compounds containing such functional groups. Nearly all substituted quinuclidines were obtained from their carboxylic acids and carbonyl derivatives by common synthetic methods. 

The so-called crossed Cannizzaro reaction is synthetically more useful than the Cannizzaro reaction itself, as it can be applied for the preparation of alcohols in high yields, without loss of 50% of the product in the formation of the corresponding carboxylic acid. Typically, paraformaldehyde is used as a sacrificial reducing agent, together with the carbonyl compound which is to be transformed into the alcohol. The reaction thus serves as an alternative method to the use of complex hydrides for the reduction of aromatic aldehydes. 

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