Aldehydes a-branched

Instead of a-halo esters, related reactants can be used e.g. the a-halo derivatives of ketones, nitriles, sulfones and A,A-disubstituted amides. The Darzens condensation is also of some importance as a synthetic method because a glycidic acid can be converted into the next higher homolog of the original aldehyde, or into a branched aldehyde (e.g. 5) if the original carbonyl substrate was a ketone ... 

The reactions are usually performed by stirring complex 2 with 1.5-2 equivalents of the aldehyde and 3-4 equivalents of methanol in dichloromethane at room temperature. As concluded from the examples published, it appears that a-branched aldehydes are not attacked at room temperature hy the reagents 2 and even sterically unhindered aldehydes react sluggishly. 

E Selective Wittig reagents. The reaction of 1 with lithium in THF provides LiDBP, which on reaction with an alkyl halide (2 equiv.) and NaNH2 in THF gives a salt-free ylide such as 2 or 3, formed by reaction with ethyl iodide or butyl iodide, respectively. These ylides react readily with aldehydes at —78°, but the intermediate oxaphosphetanes are unusually stable and require temperatures of 70-110° for conversion to the phosphine oxide and the alkene, which is obtained in E/Z ratios of 6-124 1. Highest (E)-selectivity is observed with a-branched aldehydes. 

With a branched aldehyde, such as isobutyraldehyde 78, the selectivity of the reaction is very high (76 72 > 100 1 Table 9.5), even with the less selective (but more reactive) boron enolate (5)-74a. 

In the presence of a primary amine (48) and chiral phosphoric acid R)-3o (5 mol%, R = a-branched aldehydes 50 undergo a quick racemiza-... 

Scheme 19 Reductive amination of a-branched aldehydes for the preparation of P-branched amines...

Three years later. List and coworkers extended their phosphoric acid-catalyzed dynamic kinetic resolution of enoUzable aldehydes (Schemes 18 and 19) to the Kabachnik-Fields reaction (Scheme 33) [56]. This transformation combines the differentiation of the enantiomers of a racemate (50) (control of the absolute configuration at the P-position of 88) with an enantiotopic face differentiation (creation of the stereogenic center at the a-position of 88). The introduction of a new steri-cally congested phosphoric acid led to success. BINOL phosphate (R)-3p (10 mol%, R = 2,6- Prj-4-(9-anthryl)-C H3) with anthryl-substituted diisopropylphenyl groups promoted the three-component reaction of a-branched aldehydes 50 with p-anisidine (89) and di-(3-pentyl) phosphite (85b). P-Branched a-amino phosphonates 88 were obtained in high yields (61-89%) and diastereoselectivities (7 1-28 1) along with good enantioselectivities (76-94% ee) and could be converted into... 

The reactions of phosphine with a-branched aldehydes follow a different pathway. They lead to the formation of stable, heterocyclic, secondary phosphines of the following type, J With suitable dialdehydes, spirocyclic phosphonium salts are obtained these are very difficult to prepare by... 

List later reported the asymmetric reductive amination of a wide spectrum of aromatic and aliphatic a-branched aldehydes via dynamic kinetic resolution (Scheme 5.27) [49]. The initial imine condensation product is believed to undergo fast racemization in the presence of the acid catalyst Ih through an imine/enamine tautomerization pathway. Preferential reductive amination of one of the imine enantiomers furnishes the optically pure P-branched amine. 

Since a-branched aldehydes gave rather higher asymmetric induction (Scheme 6.166), Nagasawa et al. extended the biphasic strategy to the diastereoselective Henry reaction of nitromethane with enantiomerically pure (S)-configured N,N -dibenzyl protected a-amino aldehydes and a-hydroxy aldehydes protected as silyl ethers. The screening reaction (Scheme 6.169) demonstrated a match/mismatch... 

While cyclohexanecarbaldehyde and pivaldehyde, being a-branched aldehydes, are excellent substrates for most ligands leading to nearly perfect enantioselec-tion, unbranched aldehydes still remain cumbersome substrates. 

The key observation was that L-proline would catalyze the addition of a-hetero aldehydes to a-branched aldehydes such as 2 to give the aldol product 3 with high cnantio- and diastereocontrol. Even more exciting, in the absence of other acceptors the a-hetero aldehydes dimerize with high relative and absolute stereocontrol. Both alkoxy and silyloxy aldehydes worked efficiently. 

Attempts have been made to apply the oxoreaction for the synthesis of fine chemicals. Hydroformylation of methyl acrylate to give an a-branched aldehyde is useful in providing chiral building blocks after enzymatic hydrogenation [Eq. (6)]. 

Although a retrosynthetic disconnection of an a-branched aldehyde to give an alkyl group and a mesomerically stabilised a-carbanion suggests a synthesis based on this strategy, in practice it is not feasible. This is because the a-... 

Simple straight-chain aliphatic aldehydes (C2 to Cj2 tested) and mono a-branched aldehydes. ... 

In direct nitroso aldol reactions of a-branched aldehydes, an L-prolinamide (50) catalyses to give a-hydroxyamino carbonyl compounds which are otherwise dis- favoured ees up to 64% were found.149 Another prolinamide derivative gives similar results in a nitrosobenzene reaction.150 For proline-catalysed cases involving highly substituted cyclohexanones, DFT calculations have highlighted the roles of electro- static and dipole-dipole interactions in the level of de achieved.151 (g)... 

The quantitative conversion of aldehydes into enolates with lithium amides hardly ever succeeds because an aldol reaction (cf. Section 13.1.2) occurs while the deprotonation with LDA is in progress. Aldol additions also occur upon conversion of a small fraction of the aldehyde into the enolate with a weak base (Section 13.3.1). Hence, it is generally impossible to alkylate an aldehyde without the simultaneous occurrence of an aldol addition. There is only one exception certain a-branched aldehydes can be deprotonated to their enolates in equilibrium reactions, and these enolates can be reacted with alkylating reagents to obtain tertiary aldehydes. 

As shown in Table 16, (i )-propargyl mesylate (ee > 95%) reacts with cyclohexanecarboxaldehyde in the presence of Ini and 5 mol% of a palladium catalyst to give, via an allenylindium intermediate, the adduct with high enantiomeric excess.55,56 The addition is most efficient in 3 1 THF-HMPA and 1 1 THF-DMPU solvents. The Anti syn ratios are excellent with a-branched aldehydes but only modest with unbranched and conjugated aldehydes. 

The best illustration of the high reactivity of the acyloxycarbenium ions 163 is a reaction which is not quite typical for other carboxonium ions. This is the retropinacol rearrangement of a-branched aldehydes and ketones 169 to the 1,2-dioles 173 which involves the unusual 1,2-shift of the migrating group R3 to the carbon atom attached to the oxygen atom of the acyloxycarbocation 17092-94 (equation 55). 

The previous examples are selected asymmetric reductive animations of ketones to give chiral, a-branched amines (Eq. 32) however, the corresponding reactions of aldehydes are unknown. We reasoned that such a process might be realized if enolizable, a-branched aldehydes are used. Their asymmetric reductive amination should give -branched amines via an enantiomer-differentiating kinetic resolution (Eq. 33). 

At the onset of this study, we hypothesized that under our reductive amination conditions an a-branched aldehyde substrate would undergo a fast racemization in the presence of the amine and acid catalyst via an imine/enamine tautomerization. The reductive amination of one of the two imine enantiomers would then have to be faster than that of the other, resulting in an enantiomerically enriched product via a dynamic kinetic resolution (Scheme 15 for reviews, see Noyori et al. 1995 Ward 1995 Caddick and Jenkins 1996 Stecher and Faber 1997 Huerta et al. 2001 Perllissier 2003). 

Indeed, when we studied various phosphoric acid catalysts for the reductive amination of hydratopicaldehyde (16) with p-anisidine (PMPNH2) in the presence of Hantzsch ester 11 to give amine 17, the observed enantioselectivities and conversions are consistent with a facile in situ racemization of the substrate and a resulting dynamic kinetic resolution (Scheme 16). TRIP (9) once again turned out to be the most effective and enantioselective catalyst for this transformation and provided the chiral amine products with different a-branched aldehydes and amines in high enantioselectivities (Hoffmann et al. 2006). 

For our first example we chose 2-methylpropanal as a model system for the aldol reaction with dioxanone and optimized the reaction conditions in terms of chemical yield, enantiomeric excess, and anti/syn ratio. The best reaction conditions so far call for (S )-proline as the catalyst, dimethylformamide (DMF) as the solvent, and a temperature of 2°C. The anti aldol product 7 was obtained diastereoselectively with an excellent yield of 97%, an anti/syn ratio of >98 2, and a high enantiomeric excess of 94% ee (Enders and Grondal 2005). Subsequently we were also able to show that the aldol reaction of 4 with the a-branched aldehydes proceeds with good to very good yields, excellent anti/syn ratios, and enantiomeric excesses in all cases (Scheme 3). When a linear aldehyde was used, the aldol product 7 was isolated in only moderate yield (40%), but still excellent stereoselectivity (anti/syn >98 2, 97% ee). 

To a solution of the geni-bis(triflate) (10 mmol) in CHjCU (100 niL) at O C was slowly added a solution of [Bu4N] [Ph3SnF2] (10 mmol) in CHjClj (50 mL). After 4 h (8 h for a-branched aldehydes) the mixture was filtered and the appropriate tetrabutylammonium halide (20 mmol) added. After stirring for 1 h at rt the solvent was evaporated at reduced pressure and the crude mixture filtered through a short (10 cm) column of silica gel. Pure products were obtained by column chromatography (silica gel. pentane). 

Under lower CO partial pressures a 16e RCo(CO)3 species will have a long enough lifetime to allow reverse P-Hydride Elimination (see Mechanisms of Reaction of Organometallic Complexes) and increase the possibility for alkene reinsertion to the branched alkyl species, which is slightly more favored thermodynamically. At this point, CO addition and insertion will yield a branched aldehyde, or another /3-hydride elimination can give alkene isomerization. This second mechanistic explanation is in line with more recent results from Rh/PPh3-catalyzed hydroformylation studies (see Section 2.4). 

Significantly higher diastereoselectivity was observed in reactions with a-branched aldehydes as illustrated in Eq. (34) [54]. Here the (5)-a-methyl-/3-OMOM aldehyde substrate is matched with the (f )-a-OMOM stannane in a Felkin-Ahn acyclic transition state to afford the syn, syn adduct almost exclusively. 

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