Aldehydes functionalised

Note The imidazolium salts and the palladium(II) complexes can be reversibly hydrolysed to the corresponding aldehyde functionalised compounds (see Figure 3.65). 

Figure 3.65 Acetalisation and hydrolysis of acetate/aldehyde functionalised imidazolium salts and their palladium(ll) complexes.

While the synthesis of fnnctionalised secondary alcohols and amines can be achieved withont catalyst by the addition of organolithium and organomagnesium reagents to C=N and C=0 gronps, these methods lack a significant functional group tolerance. In order to overcome this limitation and access to more functionalised compounds, the catalytic arylation of aldehydes and imines has been extensively studied [2]. 

A range of a-functionalised aldehydes have been used to generate acylazolium species via the corresponding enol intermediate. For example, addition of an NHC to an a-halo aldehyde 84 presumably generates the Breslow species 86, with elimination of HX to afford the enol 87. Subsequent in situ tautomerisation generates... 

The reduction of nitrobenzene to aniline is a major industrial process at the heart of the production of polyurethanes, and it is also often used as a marker reaction to compare activities of catalysts [1,2], It can be performed over a variety of catalysts and in a variety of solvents. As well as its main use in polymethanes, aniline is used in a wide range of industries such as dyes, agrochemicals, by further reaction and functionalisation. Reductive alkylation is one such way of functionalising aromatic amines [3, 4], The reaction usually takes place between an amine and a ketone, aldehyde or alcohol. However it is possible to reductively alkylate direct from the nitro precursor to the amine and in this way remove a processing step. In this study we examined the reductive alkylation of nitrobenzene and aniline by 1-hexanol. 

Dipolar cycloaddition of azomethine ylides, generated by the condensation of an a-amino acid and an aldehyde, is an efficient method for covalent sidewall functionalisation and has been successfully used to solubilise CNTs in most organic solvents (Tasis et al., 2003 Holzinger et al., 2003). This particular technique has also been utilised to obtain the first example of a bioactive peptide covalently linked to CNTs by the prospect for the potential applications in immunology (Bianco and Prato, 2003 Pantarotto et al., 2003a, b Bianco et al., 2005b). 

The formation of unsaturated cyanohydrins (from a, -unsaturated aldehydes) is of further advantage as these products possess an additional synthetic potential. As in the saturated cyanohydrins (above in Scheme 6) they possess the same opportunities for elaboration of the hydroxyl or nitrile moiety, although the presence of the carbon-carbon double bond offers the possibility for additional transformations to be performed such as additions [108], oxidative cleavage [117,118] and epoxidation [119] (Scheme 7). Thus, these highly functionalised chiral units can be of greater importance to an organic chemist. 

Simultaneous publication of the iminium ion catalysed hydrophosphination of a,p-unsaturated aldehydes by Melchiorre and Cordova showed diarylprolinol silyl ether 55 was effective in the conjugate addition of diphenylphosphine 74 [117, 118], Direct transformation of the products allowed for one-pot methods for the preparation of P-phosphine alcohols 75 (72-85% yield 90-98% ee), P-phosphine oxide acids 76 (65% yield 92% ee) and 3-amino phosphines 77 (71% yield 87% ee) (Scheme 34). These reports represent the first examples of the addition of P-centred nucleophiles and the resulting highly functionalised products may well have further use in asymmetric catalysis. 

Cordova has also shown hydrogen peroxide to be an effective oxidant in the epoxidation of a,P-unsatnrated aldehydes using diarylprolinol ether 30 as the catalyst (Fig. 9) [146, 147], Within these reports it was also shown that the resulting epoxy aldehydes could be used directly in either Wittig or Mannich reactions, providing synthetically useful one-pot protocols to prepare densely functionalised building blocks for further elaboration. 

More recent reports from Cordova [155] and Wang [156] have described the cyclopropanation of a, P-unsaturated aldehydes 99 with diethyl bromomalonates 100 and 2-bromo ethyl acetoacetate catalysed by a series of diaryIprolinol derivatives. Both describe 30 as being the most efficient catalyst in many cases and optimal reaction conditions are similar. Some representative examples of this cyclopropanation are shown in Scheme 40. The transformation results in the formation of two new C-C bonds, a new quaternary carbon centre and a densely functionalised product ripe for further synthetic manipulation. Triethylamine or 2,6-lutidine are required as a stoichiometric additive in order to remove the HBr produced during the reaction sequence. The use of sodium acetate (4.0 equivalents) as an additive led to subsequent stereoselective ring opening of the cyclopropane to give a,P-unsaturated aldehydes 101. It can be envisioned that these highly functionalised materials may prove useful substrates in a variety of imin-ium ion or metal catalysed transformations. 

Wang identified a series of Michael/Michael and Michael/aldol sequences catalysed by diarylprolinol ethers that led directly to densely functionalised five-mem-bered rings [172-174]. For example, highly diastereoselective and enantioselective double Michael addition reactions were achieved by treatment of a,p-unsaturated aldehydes with triester 113 catalysed by 30 (Scheme 45). Initial conjugate addition... 

An interesting alternative intramolecular cyclisation was discovered by Jprgensen and co-workers [187]. Although not strictly exploiting an enamine intermediate, the transformation represents a secondary amine catalysed Morita-Baylis-Hillman reaction leading to a series of highly functionalised cyclohexene products. Reaction of the Nazarov reagent 137 with a,P-unsaturated aldehydes in the presence of the diarylprolinol ether 30 led to the cyclohexene products 138 (49-68% yield 86-96% ee) via a tandem Michael/Morita-Baylis-Hillman reaction (Scheme 54). 

They produced an 18-member library of a-acylamino amides, in acceptable to high yields and purity, from a variety of isocyanides, aldehydes and carboxylic acids by using an amino-functionalised TentaGel resin (TentaGel S RAM). The developed procedure represents a rapid and efficient way of synthesising a-acylamino amides, simplifying the tedious purifications, which can usually accompany multi-component reactions. 

The desired spiroacetal 36 was converted to the TBS ether and the terminal alkene moiety was elaborated to the corresponding ethyl ketone in four steps, to provide the fully-functionalised CD-spiroacetal ketone 5, now ready for aldol union with the AB-spiroacetal aldehyde 4. This route was found to be highly scalable, enabling production of multi-gram quantities of the desired C16-C28 fragment 5 with little need to repeat the synthetic sequence. 

Since its discovery in 1953, the reaction has been extensively studied with respect to structural variation in the phosphonium ylide, in the range of functionalised aldehydes and ketones, in the nature of the bases and the polarity of the solvents that may be used, and in the mechanism of the reaction and the factors which influence the ( /Z) ratio. Many thousands of simple and complex syntheses have been effected and the method is widely exploited in research laboratories and in the industrial processes for syntheses in the steroid and carotenoid field. 

Figure 5-17. The reaction of an aldehyde with a co-ordinated amino acid provides a useful method for functionalisation of the ligand. The precipitation of copper sulfide in the final step is a convenient way of obtaining the free ligand.

The amines 3 reported by Morao and Cossio also constitute neutral dendritic catalysts without metal sites they consist of a simple amine core functionalised with Frechet dendrons (Fig. 6.44) [74]. Such amines can catalyse the nitroaldol or Henry reaction [75] between aromatic aldehydes and nitroalkanes. Whereas neither the yield nor the stereoselectivity (syn/anti 1 1) of the reaction of p-nitro-benzaldehyde with nitroethane was found to change on use of different generations of dendritic catalysts, a distinctly negative dendritic effect was observed in the reaction of benzaldehyde with 3-nitro-l-propanol. Catalysts 3 a and 3 b gave... 

This chapter deals with target molecules of two main types hydroxyketones 1 and 1,3- or P-diketones 4. Both have a 1,3-relationship between the two functionalised carbons. Both can be disconnected at one of the C-C bonds between the functional groups to reveal the enolate 2 of one carbonyl compound reacting with either an aldehyde 3 or acid derivative 5 such as an ester. 

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. 

Metaproterenol 64 is an adrenaline analogue used as a bronchodilator.11 The amine might be inserted by reductive amination on the aldehyde 65 and this might be made by a-functionalisation of the available ketone 66. 

The phenols need to be protected as their methyl ethers 67 and functionalisation by SeC>2, as described earlier in this chapter, gives the keto-aldehyde 68. To get 65 we should have to reduce the ketone in the presence of the aldehyde but the workers at Boehringer discovered a shortcut reductive amination using hydrogenation reduced both the imine (from i-PrNH2 and the aldehyde) and the ketone to give 69 and hence, by deprotection, metaproterenol 64. Notice that the aldehyde in 68 is more electrophilic than the conjugated ketone so it forms the imine needed for reductive amination. 

Barluenga and Yus showed that reductive lithation with naphthalene was nonetheless an effective way of making functionalised organolithiums. The (3-oxygenated species such as 11 are stable below -78 °C provided the lithium is at a primary centre (above this temperature they decompose with elimination of Li20) and can be formed by reductive lithiation of the lithium alkoxide 10.22 25 The amide 12 behaves similarly,26 and protected aldehyde 14 yields homoenolate equivalent 15.27... 

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