Permethric acid

For the synthesis of permethric acid esters 16 from l,l-dichloro-4-methyl-l,3-pentadiene and of chrysanthemic acid esters from 2,5-dimethyl-2,4-hexadienes, it seems that the yields are less sensitive to the choice of the catalyst 72 77). It is evident, however, that Rh2(OOCCF3)4 is again less efficient than other rhodium acetates. The influence of the alkyl group of the diazoacetate on the yields is only marginal for the chrysanthemic acid esters, but the yield of permethric acid esters 16 varies in a catalyst-dependent non-predictable way when methyl, ethyl, n-butyl or f-butyl diazoacetate are used77). 

A striking example for the preferred formation of the thermodynamically less stable cyclopropane is furnished by the homoallylie halides 37, which are cyclopro-panated with high c/s-selectivity in the presence of copper chelate 3891 The cyclopropane can easily be converted into cw-permethric acid. In contrast, the direct synthesis of permethric esters by cyclopropanation of l,l-dichloro-4-methyl-l,3-pentadiene using the same catalyst produces the frans-permethric ester (trans-39) preferentially in a similar fashion, mainly trans-chrysanthemic ester (trans-40) was obtained when starting with 2,5-dimethyl-2,4-hexadiene 92). 

The search for catalysts which are able to reverse the ratio of cyclopropane diastereomers in favor of the thermodynamically less stable isomer has met with only moderate success to date. Rh(II) pivalate and some ring-substituted Rh(II) benzoates induce cw-selectivity in the production of permethric acid esters 77,98 99 contrary to rhodium(II) acetate, which gives a 1 1 mixture 74,77,98), and some copper catalysts 98) (Scheme 10). 

The change in selectivity is not credited to the catalyst alone In general, the bulkier the alkyl residue of the diazoacetate is, the more of the m-permethric acid ester results 77). Alternatively, cyclopropanation of 2,5-dimethyl-2,4-hexadiene instead of l,l-dichloro-4-methyl-l,3-pentadiene leads to a preference for the thermodynamically favored trans-chrysanthemic add ester for most eatalyst/alkyl diazoacetate combinations77 . The reasons for these discrepandes are not yet clear, the interplay between steric, electronic and lipophilic factors is considered to determine the stereochemical outcome of an individual reaction77 . This seems to be true also for the cyclopropanation of isoprene with different combinations of alkyl diazoacetates and rhodium catalysts77 . 

Preparation of chrysanthemic (208, R1=R2=Me) and permethric acid (208, R1 = r2 = C1) derivatives is a very useful testing ground for enantioselective (and... 

An analogous reaction applied to l,l-dichloro-4-methyl-l,3-pentadiene would lead to a selective synthesis of permethric acid, of which the cis isomer was more desirable. It is interesting that this seemingly simple structural change provided... 

Given the disadvantages mentioned before, the manufacture of chrysanthe-mic acid is economically less important than that of permethric acid. Scientifically, the syntheses of both compounds are ofinterest. The aim of (mostly industrial) research was to identify the simplest and cheapest way to access this structurally demanding class of substances. Nowadays, pyrethroid research is however largely a matter of the past, the insecticide market is dominated by... 

The process from the FMC company involves as the pivotal step an intramolecular stereoselective [2 + 1 [-cycloaddition. In a Prins reaction [94] of chloral and isobutene, followed by an isomerisation, a racemic, trichloromethyl-substituted aUyl alcohol is obtained. Reaction with the isocyanate from (R)-naphthylethyl-amine enables separation ofthe diastereomers by crystallisation. The carbamate is cleaved by trichlorosilane/triethylamine, thus permitting the recycling of the chiral auxiliary. The optically pure (R)-aUyl alcohol is reacted with diketene, to produce the / -keto-ester. After diazo transfer and basic cleavage, the diazoacetate is obtained catalysed by a copper salt, this is converted in a [2 + 1 ]-cyclo-addition into a bicyclic lactone. The Boord reaction (discovered by Cecil E. Boord in 1930) [95] finally gives (IR)-cis-permethric acid. [96]... 

Immediately after the discovery of the advantageous properties of permethric acid, many research laboratories initiated enhanced efforts to find the most convenient synthesis ofthis compound. The Japanese Sagami Research Institute developed a synthetic route based on a Claisen rearrangement and a 1,3-cyclo-elimination, for which FMC took out a licence. A few weeks later, two other firms, Sankyo and Kmaray, filed patent applications for similar syntheses. 

According to the Sagami synthesis, prenol is reacted with methyl orthoacetate. A Claisen rearrangement yields methyl 3,3-dimethylpent-4-enoate, which undergoes a radical addition to tetrachloromethane. The double elimination of hydrogen chloride gives finally permethric acid. In this transformation, the base and the solvent have a critical impact on the cis/trans-ratio. Under the most favourable conditions (t-BuONa, hexane, HMPT) the cis-proportion can reach up to 90%. [102-104]... 

The process for the industrial production of permethric acid by Roussel-Uclaf starts from racemic trons-chrysanthemic acid, which is in turn accessed by the Martel synthesis (cf. 1,3-cycloelimination). After separation of the enantiomers with an amino-alcohol, the (IR)-enantiomer is subjected to ozonolysis. Basic epimerisation gives (IR)-cis-caronaldehyde hemiacetal. Water is added to the (IS)-enantiomer in the presence of a catalytic amount of sulfuric acid then the carboxylic add function is epimerised with the formation of a lactone. Magnesium bromide-catalysed ring-opening leads to (lR)-c s-chrysanthemic acid, which is converted into (IR)-ds-caronaldehyde hemiacetal by an analogous route. [105]... 

Caronaldehyde hemiacetal can be transformed in a simple manner by the Corey-Fuchs reaction [107] into permethric acid, and as well its bromo-analogue deltamethric acid. Instead of triphenylphosphane, tris-(dimethylamino) phos-phane may also be used. 

A breakthrough in the use of pyrethroids as agricultural insecticides came with the discovery that esters of permethric acid are both highly potent and exhibit remarkable photostability. 

Substantial effort has been put into utilizing the optically active natural hydrocarbons (-h)"a-pinen and (-h)-A-3-caren for synthesis of chrysanthemic acid, permethric acid and other pyrethroid acids. These reactions are explained in Sect. I.3.6.5. 

Synthesis of permethric acid (also called DV-acid) 91 became one of the central items in the years of industrial pyrethroid research in the 1970 s. Many original proposals have been made. Only a very small number have appeared in the scientific hterature. But the wealth of findings as pubhshed in patent apphcations show, in a fascinating way, that modem synthetic organic chemistry can turn many diverse and simple chemicals into permethric acid for less and less money as shown in the following chapter, in which the vast majority of the pubhshed discoveries has been taken into account. 

More reactive is the monoolefine 94 in Reaction scheme 52. Intramolecular diazo reaction yields a precursor for the cis-permethric acid [138] (Reaction scheme 129). 

Mesityl oxide is the starting chemical for a synthesis (Reaction scheme 63) of permethric acid by subjecting it to the addition of the sulfur yhd 105 [168], forming the precursor acetyl-geminal-dimethylcyclopropanecarboxyhc ester 106 [169]. Effective synthesis of the sulfur yhd 105, chlorination of the side chain in 106 and removal of the oxygen constitute technical problems. Since sulfides do not react readily with... 

Acetic acid, on interaction with Mn-III-acetate [174] or other one-electron-oxidation agents of similar oxidation potential such as Cer-IV- [175] or Vanadium-V-salts, forms a radical, which in the presence of the diene 93 is trapped to form a butyrolactone 108 [176,177] (Reaction scheme 64). This lactone can be transformed into permethric acid as described in Sect. 1.3.2.2. 

In the chemistry of the permethric acids these butyrolacetones 108, 127, 128 play the role, which pyrozin 27 and isopyrocin 34 have in the chemistry of chrysanthemic acid. 

Therefore there are several strategies to obtain permethric acid by the synthesis of such butyrolactones. The Lehmann-Traube synthesis of the epoxide 129 and malonic ester (Reaction scheme 82) [214, 215] yields an product 128, isomeric to 102 in the preceding Reaction schemes 64, 79, 80, 81. 

In Reaction scheme 84 an isomeric cyclobutanone 133 is made from very different precursors, an a-chloroenamine 171 and the diene. But all these very different building blocks merge predominantly into the same trans permethric acid 91. 

A more classical sequence [220], involving no rearrangement, utiUzing diketene and isoprenol via the unsaturated acetic ester 134 produces the y-lactone 135 (Reaction scheme 85) for permethric acid. 

In search of different conditions to enforce this reaction, an interesting intramolecular rearrangement of the chlorine atoms in 139 across the 4-membered ring catalyzed by tertiary amines as well as by hydrochloric acid in alcohol (Reaction scheme 90) was discovered. The newly formed cis-isomeric diequatorial a-halo-cyclobutanone 141 is now again prone to the Faworski rearrangement under mild alkaline aqueous conditions, to give the cis-permethric acid [231] or analogously, the racemic deltamethric acid as a cis/trans 80 20 mixture (Reaction scheme 90) [224, 228, 230]. 

It was tempting to use the reaction in scheme 90 for a synthesis of optically active 1 R cis-permethric acid, because the cis-a-halocyclobutanone readily forms an adduct with sulfurous acid, an a-hydroxisulfonic acid 142, which could be resolved to the enantiomers using optically active amines like ephedrine and phenethylamine [228]. After hberation of the optically active a-halocyclobutanone 143 the Faworski reaction yielded 1 R cis-permethric acid in high optical yield (Reaction scheme 91). 

Other more recent approaches to permethric acid, utilizing the advantages of Faworski-type intermediates, use very cheap starting materials for refinement within a few steps as in Reaction scheme 92 (chloral + ketene) [229] or Reaction scheme 93 (isoprene + vinylchloride) [232]. 

While Reaction 95 yields a precursor of permethric acid, Reaction 96, starting with the alkoxyacrylester 153, ends up with permethric ester [239]. 

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