3-phenoxybenzaldehyde cyanohydrin

Synthesis of Chiral Phenoxybenzaldehyde Cyanohydrin Intermediate for the Synthesis of Pyrethroid Insecticides... 

Scheme 7.22 Synthesis of pyrethroid insecticides via (S)-phenoxybenzaldehyde cyanohydrin.

A large number of the most important modem insecticides are derived from cyanohydrins. Especially some esters formed from enantiopure cyanohydrins and chrysanthemum acid derivatives are known to be very potent [201]. Nowadays, the formation of 3-phenoxybenzaldehyde cyanohydrin is performed in a biocatalytic industrial process using Me HNL or 7/bHNL isolated from mbber trees (Hevea... 

A further important asymmetric biocatalytic synthesis represents the hydrocyanation of aldehydes [116] for the production of cyanohydrins which are intermediates for a broad variety of life science molecules. For example, (/ )-mandelonitrile is a versatile intermediate for the synthesis of ( )-mandelic acid, and (S)-m-phenoxybenzaldehyde cyanohydrin is a building block for the preparation of pyrethroids. 

For the production of (5)-m-phenoxybenzaldehyde cyanohydrin (47) DSM established an enzymatic hydrocyanation process on an industrial scale (Scheme 31). An efficient (S)-oxynitrilase biocatalyst has been developed. This enzyme is derived from the plant Hevea brasiliensis, and has been cloned and overexpressed in a microbial host organism [117]. In the presence of this biocatalyst the desired product 47 has been obtained with high enantioselec-tivity. 

PTC condensation of 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride with m-phenoxybenzaldehyde cyanohydrin PTC Benzyltriethylammonium chloride (TEBAC)... 

Preparation of meta-phenoxybenzaldehyde cyanohydrine 299 in substance can be avoided. Generated in situ from the aldehyde 280 and potassium cyanide [793] it is trapped by the acid chloride to give the desired esters 373 exemplified for fenvalerate 373 in Scheme 252. 

Cyanohydrins are bifunctional molecules and therefore constitute a particularly useful class of compounds for synthetic purposes. A hydroxyl and a nitrile functional group are available for chemical and enzymatic follow-up reactions (Scheme 25.2 [7, 93-95]), resulting in hydroxy carboxylic acids [96-99], carbamates [KXl], hydroxy-amides [101], primary and secondary hydroxyamines [46,102-104], aziridines [105, 106], aminonitriles [107, 108], diamines [108], azidonitriles [108], a-fluoronitriles [109], hydroxy ketones [110], and many more. The (S)-selective H HNL and the (R)-selective PaHNL, in particular are used on large scale either for the s)mthesis of (S)-3-phenoxybenzaldehyde cyanohydrin, a precursor for p5U ethroids, a class of insecticides (R)- and (S)-mandelonitrile, which can be further converted to man-delic acids (R)-chloromandelonitrile, a precursor for an anticoagulant (R)-2-hydroxy-4-phenylbutyronitrile, which serves as intermediate for the production of angiotensin-converting enzyme inhibitors (ACEi) or (R)-2-amino-l-(2-furyl)ethanol [94]. Several HNLs are commercially available as free or immobilized enzymes. 

Lipase-Catalyzed Hydrolysis of Cyanohydrin Acetates. Hydrolytic enzymes, especially lipases, are widely used for enantioselective transformations, and have been used to prepare optically active cyanohydrins. For example, the lipase-catalyzed kinetic resolution of racemic w-phenoxybenzaldehyde cyanohydrin acetate was an essential step in the synthesis of (li ,ci5,aiS)-cypermethrine 19). Another recent report described the lipase-catalyzed kinetic resolution of pentafluorobenzaldehyde cyanohydrin acetate 20). To examine this approach, 2- and 6-fluoro-3,4-dibenzyloxybenzaldehyde cyanohydrin acetates (12b,d) were prepared from the aldehydes 10b,d. Preliminary attempts to carry out lipase-catalyzed kinetic resolutions of Aese cyanohydrin acetates were unsuccessfiil (unpublished results). 

The situation is further complicated by chiral autoinduction, first reported by Danda et al. for the hydrocyanation of 3-phenoxybenzaldehyde [39]. It was found that the enantiomeric excess of the product increases with reaction time, and that addition of small amounts of optically pure cyanohydrin at the beginning of the reaction led to high ee of the bulk product, irrespective of catalyst ee. It was concluded that the active catalyst is not the diketopiperazine alone but a 1 1 aggregate with the product cyanohydrin of the opposite configuration (e.g. (R,R)-1 plus S-mandelonitrile) [39]. Lipton et al. later developed a mathematical model for this effect and exploited it to improve the enantioselectivity of the hydrocyanation of... 

The search for other amino acid-based catalysts for asymmetric hydrocyanation identified the imidazolidinedione (hydantoin) 3 [49] and the e-caprolactam 4 [21]. Ten different substituents on the imide nitrogen atom of 3 were examined in the preparation, from 3-phenoxybenzaldehyde, of (S)-2-hydroxy-2-(3-phenoxy-phenyl)acetonitrile, an important building block for optically active pyrethroid insecticides. The N-benzyl imide 3 finally proved best, affording the desired cyanohydrin almost quantitatively, albeit with only 37% enantiomeric excess [49]. Interestingly, the catalyst 3 is active only when dissolved homogeneously in the reaction medium (as opposed to the heterogeneous catalyst 1) [49]. With the lysine derivative 4 the cyanohydrin of cyclohexane carbaldehyde was obtained with an enantiomeric excess of 65% by use of acetone cyanohydrin as the cyanide source [21]. 

Asymmetric synthesis by means of a cyandiydrin is an imprvtant process in organic synthesis, because the cyanohydrin can be easily converted into a variety of valuable synthetic intermediates, such as a-hy-droxy ketones, a-hydroxy acids, y-diketones, p-amino alcohols, 4-oxocarboxylic esters, 4 xonitriles, a-amino acids and acyl cyanides. More specifically, the (S)-cyanohydrin of m-phenoxybenzaldehyde is a building block for the synthesis of the insecticide deltamethrin, or (IR)-cis-pyrethroids. ... 

Another important derivative of m-cresol used in the manufacture of plant protection agents is m-phenoxytoluene, which can be produced from m-cresol and chloro- or bromobenzene at temperatures of 200 °C, with copper catalysts. m-Phenoxytoluene is converted into m-phenoxybenzoic acid methyl ester by oxidation with a cobalt acetate/KBr catalyst and subsequent esterification m-phenoxybenzoic add methyl ester serves as an intermediate in the production of m-phenoxybenzaldehyde, which is used as the raw material in the production of the synthetic pyrethroid insecticide, fenvalerate (see Chapter 6.3.2). The cyanohydrin is formed in-situ, then made to react with 2-isopropyl-(4-chlorophenyl) acetic acid chloride to yield fenvalerate, which was developed by Sumitomo Chemical in 1972. Pyrethroid insecticides are distinguished by their low toxicity and high activity. 

Of particular interest is the industrial-scale synthesis of the (5)-conligured cyanohydrin from wi-phenoxybenzaldehyde (Table 2.8), which is an important intermediate for synthetic pyrethroids. 

The approved way of preparing the cyanohydrine 299 by the addition of prussic acid is no problem in the case of 3-phenoxybenzaldehyde 280, The use of acetone cyanhydrine as a source of prussic acid [629] seems to be advantageous. In order to circumvent the aldehyde 280, an alternative route from the trimethyl-3-phenoxy benzylammonium salt 296 and the corresponding 3-phenoxybenzyl nitrile 297 [630] was proposed, in which oxalic ester condensation and subsequent brominative degradation of this whole group was applied (Reaction scheme 211). This procedure supposedly yields a particularly pure a-bromobenzyl cyanide 298 [631]. 

Several attempts were also made to increase the substrate scope of (S)-selective HNLs. The active sites of HfcHNL from R brasiliensis and MeHNL from M. esculenta are accessible via a narrow hydrophobic tunnel harboring a tryptophan residue (W128), which hampers the passage of large substrates. Replacement of W128 by smaller residues led to improved conversions of sterically hindered substrates [154] like the industrially interesting 3-phenoxybenzaldehyde, whose (S)-cyanohydrin is a pyrethroid precursor (Scheme 25.7). 

For comparison in Table 2 the results of (i )-PaHNL-catalyzed preparation of (R)-cyanohydrins in water-ethanol as well as in diisopropyl ether are summarized. In contrast to most other enzymes, PaHNL combines low substrate specificity with high enantiose-lectivity. It accepts aromatic as well as aliphatic aldehydes. Even with sterically demanding substrates such as isopentyl aldehyde relatively high e.e. values (83%) are obtained. The reaction of 3-phenoxybenzaldehyde strikingly illustrates the advantage of the organic solvent. Even after 192 h reaction time, the corresponding cyanohydrin is obtained with 98% e.e. whereas in water-ethanol after 5 h only 11% e.e. is obtained (Table 2). 

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