A-chloroaldehydes

Various compounds were obtained from the corresponding halomethyT ketones. Yields are generally better than in the case of a-chloroaldehydes... 

Further studies by Bode and co-workers have shown that enolate formation from a-chloroaldehydes and subsequent reaction with 4-oxo-enoates or unsaturated a-ketoesters 232 generates dihydropyranones 233 in excellent diastereo- and enantio-selectivities, and with impressively low catalyst loadings [90], This work has been extended to the generation of enolate equivalents from bisulfite adducts of a-haloaldehydes 234 under aqueous conditions (Scheme 12.50) [91]. 

When an a-chloroaldehyde or an a-chloroketone is condensed with a /3-ketoester, in the presence of aqueous base, a furan is produced bearing an ester substituent at the /3-position. It is thought that the reaction is of the aldol type intermediate dihydrofurans (256) have been isolated in certain cases (Scheme 70) (74BSF519). The condensation of ethyl bromopyru-vate and sodium oxaloacetate follows a similar mechanism (54JOC1671). The one-pot synthesis of 2,4,5-trisubstituted furans (257) from ketones and ethyl 3,4-dibromo-2-butenoate is a useful addition to a well known route (80S52). The analogous reaction of cyclic /3-diketones, i.e. cyclohexane-1,3-dione and 5,5-dimethylcyclohexane-l,3-dione, results in the formation of the condensed furans (258) and (259). These reactions are preformed either in ethanol with sodium ethoxide or in DMF with potassium carbonate. 

Alkoxyacetylenes are obtained by alcohol and hydrogen halide elimination from dialkylacetals of a-chloroaldehydes, induced by NaNH, in liquid ammonia (equation 81)108. 4-Pentyn-l-ol is obtained in similar fashion (equation 82) . 

Intermediates that undergo ring closures of type 93 are probably generated in the reactions of 6a-halopenicillanic acids with nucleophiles, and of p-mercaptoethylamines with either a-chloroaldehydes or 1,2-dibromoethenes. 

Thermal degradation of chloromethyl-1,3,5-trioxanes 127 (Scheme 29) in the presence of catalytic amounts of montmorillonite clay generated a-chloroaldehydes which could be treated in situ with thiourea to afford 2-aminothi-azoles 128, or with ethylene glycol to yield the corresponding 2-chloromethyl-l,3-dioxolanes 129 <1994CL2039>. The acidic sites in montmorillonite clays may act as acid catalysts, though the details of the mechanism were not provided. 

The imidazolidinone salt (5.110) has also been used as a catalyst in the asymmetric chlorination of aldehydes. For example, octanal (5.112) is converted into the a-chloroaldehyde with high ee using the antipode of (5.110) and quinone (5.113) as the chlorine source. Jorgensen and coworkers have achieved similar levels of enantioselectivity in this transformation using C2-symmetric diphenylpyrrolidine (5.114) as the organocatalyst in combination with NCS. ... 

In 2006, the Bode group documented NHC-catalyzed highly enantiose-lective 1-oxodiene Diels-Alder reactions of a broad range of enones with racemic a-chloroaldehydes as the dienophile precursors. This process affords a diverse set of highly enantioenriched 3,4,6-trisubstituted dihydro-pyran-2-ones from readily available starting materials under mild conditions (room temperature, 1.5 equiv. of NEtj, 6 h). The use of readily accessible racemic a-chloroaldehydes as enolate precursors greatly expands the scope of enantioselective NHC-catalyzed Diels-Alder reactions. It also makes possible, for the first time, asymmetric annulations with exceptional enantiose-lectivity under reliable eonditions with less than 1 mol% of a chiral NHC catalyst (Scheme 7.77). 

Scheme 7.77 NHC-catal3 ed asymmetric formal Diels-Alder reaction between a-chloroaldehydes and enones reported by Bode.

Scheme 7.78 NHC-catalyzed asymmetric formal Diels-Alder reaction of a-chloroaldehydes with a,p-disubstituted enones reported hy Kobayashi.

In 2014, Huang, Zhong, and co-workers delivered an NHC-catalyzed enan-tioselective aza-Diels-Alder reaction of oxodiazenes with a-chloroaldehydes... 

Seheme 7.83 NHC-catalyzed asymmetric a-amination of a-chloroaldehydes and oxodiazenes reported by Smith. 

In this cross-aldol reaction, formation of the enamine intermediate of an a-chloroaldehyde would be inhibited or significantly slowed down due to steric repulsion, and the formed enamine intermediate of a donor aldehyde reacts predominantly with the electronically activated a-chloroaldehyde (Scheme 17.7). The homo-aldol reaction of the donor aldehyde is suppressed probably due to the moderate nucleophilicity of (S)-4. 

Enantioselective organocatalytic a-chlorination of aldehydes, via enamine catalysis, was independently reported by the groups of MacMillan and Jprgensen in 2004 (Scheme 13.20) [46, 47]. MacMillan utilized his imidazolidinone catalyst and a perchlorinated quinone as the chlorine source, to obtain the S-enantiomer of the a-chloroaldehyde products. Jprgensen employed NCS as the chlorine source, and either a prolinamide catalyst to access the / -enantiomer of the a-chloroaldehyde products, or a Ci-symmetric amine catalyst to access the 5-enantiomer. A recyclable fluorous pyrrolidine-thiourea bifunctional organocatalyst was later employed as an enamine catalyst in this transformation [48]. 

In all cases, enantioenriched a-chloroaldehyde products were isolable and could be subsequently readily functionalized. Alternatively, the enantioenriched a-chloroaldehyde products could be functionalized in situ (Scheme 13.22). Using the conditions developed by Jprgensen for the a-chlorination of aldehydes, in situ reductive amination and base-catalyzed intramolecular S 2 reaction generated chiral terminal aziridines in one-pot from achiral saturated aldehydes [50]. Enantioenriched terminal epoxides could be produced in one-pot from achiral saturated aldehydes using SOMO catalysis for the a-chlorination of aldehydes, followed by an in situ reduction and base-catalyzed Sff2 reaction [49]. 

A rare chemo- and stereo-selective cross-aldol between aliphatic aldehydes, catalysed by proline and an axially chiral amino sulfonamide, links a simple aldehyde with an a-chloroaldehyde the chemoselectivity arises from the steric instability of 0 the enamine derived from the haloaldehyde. (g)... 

Bode demonstrated the effectiveness of A -heterocyclic carbenes as catalysts for inverse electron demand hetero Diels-Alder reactions involving both azadienes and oxodienes. In the oxodiene case, reaction of enones with a-chloroaldehydes affords substituted dihydropyranones. In one example, addition of catalyst 60 to chloroaldehyde 58 followed by elimination of HCl yields the electron-rich dienophile that readily combines with oxodiene 59 to selectively fiimish cycloadduct 61. ... 

A DFT study has examined the chemo-, diastereo- and enantio-selectivities in direct aldol reactions between two enolizable aldehydes with different electronic nature. " Self- and cross-aldols are considered for catalysis by proline and by Maruoka s axially chiral amino-sulfonamide. Potential energy profiles for the formation of the enamine confirm that both catalysts can distinguish between 3-methylbutanal as an enamine component and an a-chloroaldehyde as a carbonyl component. The calculations reproduce the anff-product preference of the proline, and syn- for Maruoka s catalyst, and the experimental ees. 

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