Aldehyde-derived carbon, nucleophile

Cyclization Exploiting the Aldehyde-Derived Carbon as Nucleophile... 

Fig. 13 Cyclization exploiting the aldehyde derived carbon as nucleophile...

Among all tandem hydroformylation sequences the ones involving additional C,C-bond formations are the most synthetically valuable tandem hydroformylation sequences. These C,C-bonds can be formed by adding nucleophiles, which attack the carbonyl carbon, or by adding electrophiles, which attack the a-position. Furthermore, tandem reactions in which the aldehyde or an aldehyde derivative is involved in sigmatropic rearrangement are described. 

A-Alkoxypyridinium salts can be nucleophilically dealkylated to give back the A-oxide. Hydroxide attack at the ring a-position can lead to ring opening of the carbinolamine derivative formed. Nucleophilic removal of a proton from the A-alkoxy side chain a-carbon results in elimination of the parent heterocycle and formation of an aldehyde, e.g. Scheme 112. 

The main strategies for the release of aldehydes or ketones from insoluble supports are sketched in Figure 3.34. These include the hydrolysis of acetals and related derivatives, the treatment of support-bound carboxylic acid derivatives with carbon nucleophiles, and the ozonolysis of resin-bound alkenes. 

They are, however, reactive carbon nucleophiles. Examples of enolates include anionic derivatives of aldehydes, ketones, acid derivatives, and dicarbonyl compounds. 

In all of the reactions with carboxylic acid derivatives, the carbonyl carbon is acting as the substrate in nucleophilic substitution. Rather than memorize all these reactions, you should remember that carboxylic acids and their derivatives undergo nucleophilic substitution aldehydes and ketones prefer nucleophilic addition. 

In chapter 10 we compared C-C disconnections with related two-group C-X disconnections, mainly at the alcohol oxidation level. In this chapter we deal more fully with carbonyl compounds, chiefly aldehydes and ketones, by two related disconnections. We start by comparing the acylation of heteroatoms by acid derivatives such as esters (a 1,1-diX disconnection 1 that can also be described as a one-group C-X disconnection) with the acylation of carbon nucleophiles and move on to compare the 1,2-diX disconnection 3 with the alkylation of enolates 6. Here we have reversed the polarity. We mention regioselectivity—a theme we shall develop in chapter 14. 

In chapters 19 (1,3-diCO) and 21 (1,5-diCO) we were able to use an enol(ate) as the carbon nucleophile when we made our disconnection of a bond between the two carbonyl groups. Now we have moved to the even-numbered relationship 1,2-diCO this is not possible. In the simple cases of a 1,2-diketone 1 or an a-hydroxy-ketone 4, there is only one C-C bond between the functionalised carbons so, while we can use an acid derivative 3 or an aldehyde 5 for one half of the molecule, we are forced to use a synthon of unnatural polarity, the acyl anion 2 for the other half. We shall start this chapter with a look at acyl anion equivalents (d1 reagents) and progress to alternative strategies that avoid rather than solve the problem. 

The preparative value of this compound lies in the surprising fact that bis(l,3-diphenylimidazolidinylidene-2) behaves in many reactions e.g., with aromatic aldehydes,2, and with carbon acids 2 7 °) as if it dissociated to form a nucleophilic carbene. The hydrolytic cleavage of these derived imidazolidine derivatives makes possible the preparation of formyl compounds, so that the amino olefin can be considered as a potential carbonyla-tion reagent. In many reactions it is not necessary to isolate the reagent, as it may be produced in situ.10 It should be pointed out, however, that the reaction of the amino olefin with aldehydes and carbon acids does not actually involve prior dissociation to... 

It was determined that carbon nucleophiles derived from carbon acids with p/fa > 22 or so are sufficiently reactive to combine with the diene ligand rapidly at —78°C to produce an anionic intermediate (Scheme 25). With a few exceptions, the regioselectivity favors formation of the homoallyl anionic complex from addition at C-2, by kinetic control. This intermediate can be quenched with protons to give the terminal alkene, or can react with excess CO to produce an acyl iron intermediate. Following the recipes of Collman s reaction, the acyl iron intermediate can lead to methyl ketones, aldehydes, or carboxylic acids. The processes are illustrated with the 1,3-cyclohexadiene complex (Scheme 25). ... 

Halogens (mainly chlorine) at position 4 of quinazolines 12 can be displaced by a variety of carbon nucleophiles, c.g. carbon nucleophiles derived from active methylene compounds, ketone enolates, aromatic aldehydes, organolithium reagents, alkylidenephosphorane, dimethyloxosulfonium methylide, alkynes, and cyanide. ... 

Moreover, aryl-oxazoles, -imidazoles [17], or-thiazoles [18], anhydrides [19], and imides [20] are accessible via intramolecular Heck-type carbonylations. In addition to typical acid derivatives, aldehydes [21], ketones [22], aroyl cyanides, aroyl acetylenes, and their derivatives [23] could be synthesized via nucleophilic attack of the acyl metal complex with the corresponding hydrogen or carbon nucleophiles. Even anionic metal complexes like [Co(CO)4] can act as nucleophiles and lead to aroylcobalt complexes as products [24]. 

Abramov nucleophilic addition of various phosphorus acid esters to nucleoside aldehyde derivatives yielded the phosphonate-based iso-polar, non-iso-steric 5 -nucleotide analogues (28) containing a geminal hydroxy phosphonate moiety on the 5 -carbon of the pentofuranose ring. The enantiomerically pure D- and l- 2, 3, 5 -trideoxy-4 -[(ethoxyphosphoryl) difluoromethyl] thymidine analogues(29) have been synthesized from (i 5)-( )-2-methyl-5-(4-methyl-phenyl-sulfinyl)pent-2-ene and ethyl 2-(diethoxyphosphoryl)-2,2-difluoro-acetate in 45% overall yield over seven steps. ... 

In 1982, Wynberg and coworkers discovered the cinchona alkaloid catalyzed enantioselective aldol lactonization of ketenes with chloral or trichloroacetone [35], in which the zwitterionic acyl ammonium enolate provides the carbon nucleophile. This work is probably one of the most important early contributions to enantioselective organocatalysis [36], One drawback associated with this process is the severe substrate limitations. The aldehydes should be highly reactive, presumably due to the relatively limited nudeophilicity of ammonium enolates. Nelson and coworkers first addressed the scope and reactivity problems associated with Wynberg s original protocol by combining a cinchona alkaloid derivative (O-trimethylsilylquinine (12) or O-trimethylsilylquinidine (13)) with a metal Lewis acid as a cocatalyst to... 

The various possibilities for the preparation of chiral allylic amines or a aryl substituted amines are outlined in Figure 1.9. Although the addition reaction of a carbon nucleophile to an imine derived from an aryl substituted aldehyde is very efficient (B), the related addition to an a,p unsaturated imine (A) can sometimes proceed via a 1,4 addition pathway. Similarly, the asymmetric C=N reduction reaction (C and D) is sometimes hampered by the possibility of either obtaining conjugate reduction (in the case of C) or low enantioselectivities (in D when R = aryl). The addition of sp hybridized carbanions to imines (E) is a particularly effective... 

In this chapter, the carbon nucleophiles discussed will include allyl, vinyl, ethynyl, propargyl and all-enyl silicon and tin systems, with most emphasis on the allyl, and the carbon electrophiles will be those at the oxidation level of aldehydes and ketones, including acetals, alkoxyalkyl halides and the corresponding sulfur derivatives. However, it does not include iminium ions, since these are covered in Chapter 4.3. 

The classical Vilsmeier-Haack reaction - involves electrophilic substitution of a suitable carbon nucleophile with a chloromethyleneiminium salt, for example salt (1). Suitable carbon nucleophiles are generally electron-rich aromatic compounds such as V,N-dimethylaniline (2), alkene derivatives such as styrene (3) or activated methyl or methylene compounds such as 2,4,6-trinitrotoluene (4 Scheme I). These compounds (2-4) react with salt (1) giving, after loss of hydrogen chloride, the corresponding im-inium salts (5-7). Hydrolysis of iminium salt (5) affords aldehyde derivative (8) and this transformation (Ar—H - Ar—CHO) is the well-known Vilsmeier-Haack formylation reaction. Hydrolysis of iminium... 

The Vilsmeier-Haack reaction, as depicted in Scheme 1, is an important method for synthesizing aldehyde derivatives. Numerous other transformations of iminium salts into products other than aldehydes have been achieved, and these additional transformations add considerable scope and versatility to the Vilsmeier-Haack reaction. The Vilsmeier-Haack reaction is not restricted to carbon nucleophiles oxygen and nitrogen nucleophiles also react with chloromethyleneiminium salts. 

The conjugate base of an alkyne is an alkyne anion (older literature refers to them as acetylides), and it is generated by reaction with a strong base and is a carbanion. It funetions as a nucleophile (a source of nucleophilic carbon) in Sn2 reactions with halides and sulfonate esters. Acetylides react with ketones, with aldehydes via nucleophilic acyl addition and with acid derivatives via nucleophilic acyl substitution. Acetylides are, therefore, important carbanion synthons for the creation of new carbon-carbon bonds. Some of the chemistry presented in this section will deal with the synthesis of alkynes and properly belongs in Chapter 2. It is presented here, however, to give some continuity to the discussion of acetylides. 

The key aldehyde 1151 is prepared from the malic acid-derived tosylate 59 as illustrated in Scheme 168. Attempted displacement of the tosyl function of 1145 with carbon nucleophiles fails due to base sensitivity caused by the ester group. Consequently, the ester is instead converted to a diisopropyl acetal, which alleviates the problem. Nucleophilic displacement of the tosylate with cyanide proceeds cleanly in this case to give nitrile 1147. Conversion of the nitrile to aldehyde 1148 followed by Wittig reaction with 1149 produces the protected (Z,Z)-diene 1150 with >95% (Z)-stereoselectivity. Hydrolysis of the acetal gives the dienal 1151 in 21% overall yield from dimethyl (5)-malate. 

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