A Rearrangement Route to Fenvaleric Acid

Abstract

Esfenvalerate, (S,S)-α-cyano-3-phenoxybenzyl-2-(4-chlorophenyl)-3-methylbutyrate (1), one of the most widely-used pesticides in the synthetic pyrethrin analog class, holds a prominent place in the agrochemical world [1]. Designated by Several trade names such as Sumicidin ® , Sumi-alpha ® , Asana XL ® , Pydrin ® and fenvalerate ® [2], esfenvalerate is a broad-spectrum insecticide which exhibits limited mammalian toxicity and adequate stability in the environment [3]. Esfenvalerate has two chiral centers, thus allowing for the preparation of four possible stereoisomers, with the (S,S)-stereoisomer having the highest insecticidal activity [4]. Several routes have yielded racemic and stereochemically pure 1, both in isotopically-labeled and unlabeled form. A simple retrosynthetic analysis, formally an ester cleavage, transforms 1 to 2-(4-chlorophenyl)-3-methylbutyric acid (fenvaleric acid) (2) and (α-cyano-3-phenoxybenzyl alcohol (3). (Scheme 1). Therefore, the majority of previous routes for the preparation of 1 resides in the synthesis of fenvaleric acid (2). Examples of previously-reported syntheses of 2 include alkylation of 4-chlorophenylacetonitrile with isopropyl halides [5] followed by hydrolysis and optical resolution [6], rhodium-catalyzed asymmetric hydroformylation reactions of 2-methyl-1-(4-chlorophenyl)propene followed by oxidation [7], asymmetric reduction of 3-methyl-2-chlorophenyl-2-butenoic acid [8] and asymmetic alkylation of 4-chlorophenylacetic acid with a chiral auxiliary [9]. Our interest Abstract. (±)-Fenvaleric acid 2, the key intermediate for the preparation of the pesticide esfenvalerate 1, was prepared by a novel sequence which first involves the Henry reaction of 2-methyl-1-nitropropane and 4-chlorobenzaldehyde. The nitroaldol reaction provided nitroalcohol 5 which was then rein an alternative laboratory-scale synthesis of (±)-2 emerges from the standpoint of evaluating potential prepa-rative routes for isotopic labeling as well as probing the utility of the Henry reaction in preparing small molecules of commercial interest. This report addresses a novel preparation of racemic 2 which utilizes the nitroaldol (Henry) reaction [10] and the classical aminopinacol rearrangement [11] as the key steps. Our synthesis of (±)-2 (Scheme 2) commences with the reaction of 2-methyl-1-nitropropane 4, freshly-prepared by the method of Kornblum [12], and 4-chlorobenzaldehyde thereby furnishing nitroalcohol 5. The nitroaldol reaction required extended reaction times despite the usage of bases/reaction systems such as potassium fluoride/DMF, triethylamine/THF, sodium methoxide/methanol or the silyl nitronate of 4 [13]. Finally, the reaction of nitroalkane 4 and 4-chlorobenzaldehyde in the presence of a catalytic amount of 1,1,3,3-tetraduced to the corresponding aminoalcohol 6. Submission of 6 to an aminopinacol rearrangement promoted by nitrous acid deamination then afforded aldehyde 8 through a 1,2-aryl shift. The product fenvaleric aldehyde 8 was then converted to the title compound 2 by a modified Jone...

Rhodium‐Catalyzed Allylation of Aldehydes with Homoallylic Alcohols by Retroallylation and Isomerization to Saturated Ketones with Conventional or Microwave Heating

“…The spectra of compounds 1 f ,12 1 i ,13 2 a – e ,14 3 a ,15 3 b ,16 3 c ,17 3 d ,18 3 e ,18 3 g ,18 6 a ,19 6 b ,20 6 d ,14 6 e ,14 13 a ,19 13 b ,20 13 d ,21 13 e ,22 13 i ,23 13 j ,24 and 14 c 25 were identical to those reported in the literature.…”