JACS: fatty acid decarboxyxanthate initiated by hydrogen capture of amide radical

Since Barton's decarboxylation, carboxylic acid free radical decarboxylation has made great progress In recent years, the photocatalytic decarboxylation of fatty acids and active esters has attracted much attention due to its mild conditions and wide substrate tolerance However, the formation of carboxyl radicals by these methods still needs to go through redox pathway, so it is inevitable to need oxidant or reductant The formation of carboxyl radicals by hydrogen transfer (HAT) is a neutral method of redox, which can solve the problem that the substrate sensitive to redox conditions is not suitable However, compared with the bond dissociation energy of alkane C-H bond (BDE, 96-101 kcal / mol), the carboxyl O-H bond has a higher BDE (~ 112 kcal / mol), which makes it difficult for the carboxyl O-H bond to split Recently, Erik J Alexanian, Professor of Chapel Hill University of North Carolina, has developed a new reaction (Figure 1) in which n-xanthoyl-pentafluorobenzamide radicals selectively react with O-H bond of carboxyl group to form carboxyl radicals, then decarboxylate and recombine to form xanthate This reaction is suitable for a variety of fatty acids including complex biomolecules Through the mechanism research experiment and theoretical calculation, the author found that the N-H bond of benzamide has higher BDE than that of benzenesulfonamide, which makes the hat of O-H bond of benzamide and carboxylic acid happen smoothly It was published in J am Chem SOC (DOI: 10.1021 / JACS 9b10825) (photo source: J am Chem SOC.) the author first explored the reaction conditions by transforming hexanoic acid into model reaction (Table 1) Under 440 nm blue light excitation, the decarboxylation product can be obtained with 59% yield by using amide 1 as hat reagent; the yield is reduced by using lauroyl peroxide as free radical initiator; under blue light excitation, the efficiency is greatly increased by replacing hat reagent with n-xanthoyl pentafluorobenzamide 2, with 2 to 1.2 additives The aging rate of lauroyl peroxide is a little lower than that under the condition of equivalence Through the control experiment, the author found that there was no reaction under the condition of carboxylate as the substrate or no free radical initiation (photo source: J am Chem SOC.) established the reaction conditions, the author studied the substrate applicability of the developed decarboxyxanthate (Figure 2) The results showed that the primary, secondary and tertiary carboxylic acids showed good tolerance to the reaction Among them, bromine, ester group and alkenyl group in primary carboxylic acid, N-Boc indole are compatible with the reaction; in secondary carboxylic acid, internal norbornene carboxylic acid only produces external xanthate 12, while 1, 4-cyclohexanedicarboxylic acid produced a pair of enantiomers 13, and tertiary carboxylic acid was also converted into corresponding xanthate in high yield Among them, the challenging keto pinic acid can generate product 21 through bridgehead free radical The method can also be used for the later modification of natural products and drug molecules A pair of diastereomers 22 can be produced by coagulation acid in 90% yield Because of the stability of benzyl radicals, the transfer process of xanthate was reversible and the yield was reduced Terpenes and steroids can also react In the process of transformation, the function groups of hydroxyl and ketene are not affected Acetylated gibberellin can produce single isomer 30 with high yield Amino acids can also react, and the xanthate of glutamic acid can be used as a platform molecule for amino acid post modification and unnatural amino acid synthesis The author also tried decarboxyxanthate of tripeptide and obtained xanthate with excellent recovery yield Cysteine, as a representative, has many functions in peptide chemistry, including natural chemical linkage (NCL), so decarboxyxanthate can provide a new method for protein chemistry (photo source: J am Chem SOC.) xanthate can undergo further transformation Xanthate 26 derived from cholelithic acid was hydrolyzed by amination to obtain mercaptan in excellent yield, followed by thiol ene reaction with gluconallyl glycoside to obtain coupling product (EQ 1); xanthate derived from gibberellin can generate hydroxyl derivative 35 (EQ 2) by N-O bond breaking of alkoxyamine intermediate under zinc powder reduction condition (photo source: J am Chem SOC.) the author evaluated the hat process of O-H bond by comparing the reactivity of n-xanthoyl amide and n-xanthoyl sulfonamide (Figure 3) Because the N-H bond BDE of sulfonamide is weaker than that of carboxyl O-H bond BDE (104 vs 112 kcal / mol), in the presence of n-hexanoic acid and cyclohexane, when n-xanthoylsulfonamide is used as hat reagent, only the C-H functional product of cyclohexane is generated, while the C-H of cyclohexane is also initiated by n-xanthoylsulfonamide The free radical decarboxylation of activated and n-hexanoic acid showed that they had different reaction activities As expected, n-xanthoyl amide initiated decarboxyxanthate, while n-xanthoyl sulfonamide initiated C-H xanthate (photo source: J am Chem SOC.) the author finally studied the mechanism In the part of condition optimization, the process of oxidative free radical decarboxylation has been eliminated by the reaction of carboxylate, and the free radical process has been proved by the experiment of no free radical initiator in the dark The author further verified the irreversible O-H bond hat process (EQ 3, KIE = 5.4) in the presence of relatively weak C-H bond through the kinetic isotope effect experiment The author believed that the chemical selectivity may be due to the kinetic advantage of hat between heteroatoms (photo source: J am Chem SOC.) the author also verified their proposed mechanism through theoretical calculation In the O-H bond HAT process of n-propionic acid, when the free radicals of five fluorobenzamide are used as HAT reagents, the process Δ G is -1.68 kcal/mol, which is carried out spontaneously in thermodynamics; while in the HAT process of sulfonamide, the process Δ G becomes +5.90 kcal/mol, which is unable to be carried out spontaneously At the same time, compared with the hat process of pentafluorobenzamide, sulfonamide radicals need to face a larger activation energy barrier (+ 20.04 vs + 25.39 kcal / mol) Therefore, whether in thermodynamics or kinetics, the hat of pentafluorobenzamide radical is more favorable In this paper, Erik J Alexanian, Professor of Chapel Hill University of North Carolina, has developed a kind of fatty acid decarboxyxanthate reaction based on the free radical hat of pentafluorobenzamide The reaction is suitable for a variety of carboxylic acids including natural products and drug molecules The xanthate group in the product can be further transformed into complex bioactive molecules with later modification By means of comparative experiments and theoretical calculation, the author proves that the free radicals of pentafluorobenzamide are beneficial to the hat process of carboxyl O-H bond, both in thermodynamics and kinetics, which lays a foundation for the further development of carboxyl radical decarboxylation.