A-Chloro aldehyde

The reaction of a-bromo (or a-chloro) aldehydes with higher... 

Additionally, it was found that the energy difference between the two transition states (3 and 4) is determined mainly by the difference in the conformational energy of the a-chloro aldehyde in the two transition states i.e., the energetic preference of transition state 3 over 4 is due to a more favorable conformation of the aldehyde rather than a more favorable interaction with the attacking nucleophile. In fact, interaction between lithium hydride and 2-chloropropanal stabilizes transition state 4, which yields the minor diastereomer. 

The synthetic application of the a-chloro aldehydes has been demonstrated by the preparation of a variety of important chiral building blocks (Scheme 2.35) [26b]. The a-chloro aldehydes could be reduced to the corresponding optically active a-chloro alcohols in more than 90% yield, maintaining the enantiomeric excess by using NaBFU. It was also shown that optically active 2-aminobutanol - a key intermediate in the synthesis of the tuberculostatic, ethambutol - could be obtained in high yields by standard transformations from 2-chlorobutanol. Furthermore, the synthesis of an optically active terminal epoxide was demonstrated. The 2-chloro aldehydes could also be oxidized to a-chloro carboxylic acids in high yields without loss of optical purity, and further transformations were also presented. 

Scheme 2.35 Various transformations of optically active a-chloro aldehydes.

A series of 1-substituted indolines such as 79 has been synthesized via aryl radieal cyclizations of acetophenone imines 80, providing an enantioselective route to indoline a-amino acids <03JA163>. Aluminum chloride-induced cyclization of imine precursors derived by condensation of p-anisidine and a-phosphorylated-a-chloro aldehydes provided 3-phosphorylated 5-methoxyindoles <03CHE1521>. 

Another interesting feature of MAPH is its capacity to stabilize reactive aldehydes by 1 1 Lewis acid-base complex formation. Thus, formaldehyde and a-chloro aldehydes can be successfully generated by treatment of readily available trioxane and a-chloro aldehyde trimers, respectively, with MAPH in CH2CI2. The resulting complexes can be utilized as a stable source of gaseous formaldehyde and reactive a-chloro aldehydes for the nucleophilic addition of different carbanions, as summarized in Sch. 124 [165]. 

Malone. G.R.. and Meyers. A.I., The chemistry of 2-chloromethyl-5,6-dihydro-l,3-oxazines. Grignard coupling metalation studies. A synthesis of a-chloro aldehydes and arylacetic acids, J. Org. Chem., 39. 618. 1974. 

In chlorination of aldehydes the nature of the product (a-chloro aldehyde or carboxylic acid) depends both on the concentration of the added acid and on the nature of its anion 628 In 0.5N-hydrochloric acid at 10-15° chlorination of propionaldehyde gives 98% of propionic acid but in 4.5-6.3N-hydrochloric acid gives 90-92% of 2-chloropropionaldehyde. The concentration of acid is held constant by addition of water during the chlorination. 

Scheme 7.82 NHC-catalyzed asymmetric formal Diels-Alder reaction of a-chloro-aldehydes with oxodiazenes reported by Huang and Zhong.

Thiazolidin-4-yl-l,3,4-oxadiazoles 59 are prepared through two sequential multicomponent reactions under mild conditions (14S1603). Reaction of a-chloro aldehyde 56 with ketone 57, aqueous ammonia, and sodium hydrosulfide leads to 3-thiazoline 58. Subsequent three-component reaction of 58 with an acid and (isocyanoimino)-triphenylphosphorane provides 1,3,4-oxadiazole derivative 59. 

Cornforth proposed a different explanation for the diastereoselective addition of Grignard reagents to a-chloro aldehydes and ketones. The underlying premise of this model is that electrostatic effects such as dipole-dipole interactions favor a reactant conformation in which the C=0 group and the C —Cl bonds are oriented anti-coplanar. The preferred path for approach of the nucleophile could then be predicted on the basis of the sizes of the other substituents on the a carbon (Figure 9.57). 

An examination of the stereoselectivities of the Lewis-acid-promoted Mukaiyama aldol and Sakurai allylations of aldehydes bearing polar a- and j8-substituents (under non-chelating conditions) indicates that many are predicted by current models. However, a-chloro-aldehydes are problematic, as are many Q ,j8-disubstituted cases. 

An apparently very simple synthesis of the bis-lactone avenadolide (75) (4, 119) involves a condensation between a suitable a-chloro-aldehyde and the half-ester of malonic acid in a two-phase system (C6H6-H2O) containing Bu"4NBr (Scheme 9). Presumably the first step proceeds via esterification of... 

A sequence reported recently for the preparation of dienone derivatives called for a-benzoyloxy-aldehydes as intermediates. These could be prepared satisfactorily in benzene-water from the a-chloro-aldehydes and sodium benzoate in the presence of a phase-transfer catalyst (Scheme 37). 

The route toward the chiral epoxide 107 and 108 starts from the synthesis of the enantiopure a-chloro aldehydes 101, 102 with (L)-proUnamide 100 as the chiral catalyst. The addition of the dialkyne 103,104 to the aldehydes 101, 102 afforded the chiral chlorohydrins 105,106, which were readily converted into the chiral epoxides 107 and 108 under basic conditions (Scheme 42.29). 

The aforementioned transformation also can be performed with simple and inexpensive iV-chloro succinimide (95a). In this case either Cj-symmetric pyrrolidine 98 or prolinamide 99 in 10 mol% could be successfully used with the reaction conditions being milder than in the previous case (methylene chloride at room temperature, Scheme 4.21). The obtained chiral a-chloro aldehydes 96 are configurationally stable to pH neutral silica purification, although they can be easily transformed into a wide variety of different compounds, such as epoxides (reduction with NaBH and... 

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