ChemInform Abstract: Fluorine‐Containing Organozinc Reagents. Part 5. The Reformatskii‐Claisen Reaction of Chlorodifluoroacetic Acid Derivatives.

Greuter, Hans; Lang, R. W.; Romann, Andres J.

doi:10.1002/chin.198850084

Cited by 3 publications

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“…The preliminary reaction of allyl chlorodifluoroacetate with chlorotrimethylsilane was essential to ensure the formation of the ketene acetal intermediate, as proposed by Greuter et al for the mechanism of this reaction (18).…”

Section: Resultsmentioning

confidence: 99%

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Fluorinated Analogs as Mechanistic Probes in Valproic Acid Hepatotoxicity: Hepatic Microvesicular Steatosis and Glutathione Status

Tang¹,

Borel²,

Fujimiya³

et al. 1995

Chem. Res. Toxicol.

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It is postulated that the hepatotoxicity of valproic acid (VPA) results from the mitochondrial beta-oxidation of its cytochrome P450 metabolite, 2-propyl-4-pentenoic acid (4-ene VPA), to 2-propyl-(E)-2,4-pentadienoic acid ((E)-2,4-diene VPA) which, in the CoA thioester form, either depletes GSH or produces a putative inhibitor of beta-oxidation enzymes. In order to test this hypothesis, 2-fluoro-2-propyl-4-pentenoic acid (alpha-fluoro-4-ene VPA) which was expected to be inert to beta-oxidative metabolism was synthesized and its effect on rat liver studied in comparison with that of 4-ene VPA. Similarly, the known hepatotoxicant 4-pentenoic acid (4-PA) and 2,2-difluoro-4-pentenoic acid (F2-4-PA) were compared. Male Sprague-Dawley rats (150-180 g, 4 rats per group) were dosed ip with 4-ene VPA (0.7 mmol/kg per day), 4-PA (1.0 mmol/kg per day), or equivalent amounts of their alpha-fluorinated analogues for 5 days. Both 4-ene VPA and 4-PA induced severe hepatic microvesicular steatosis ( > 85% affected hepatocytes), and 4-ene VPA produced mitochondrial alterations. By contrast, alpha-fluoro-4-ene VPA and F2-4-PA were not observed to cause morphological changes in the liver. The major metabolite of 4-ene VPA in the rat urine and serum was the beta-oxidation product (E)-2,4-diene VPA. The N-acetylcysteine (NAC) conjugate of (E)-2,4-diene VPA was also found in the urine. Neither (E)-2,4-diene VPA nor the NAC conjugate could be detected in the rats administered alpha-fluoro-4-ene VPA. In a second set of rats (3 rats per group), total liver GSH levels were determined to be depleted to 56% and 72% of control following doses of 4-ene VPA (1.4 mmol/kg) and equivalent alpha-fluoro-4-ene VPA, respectively. Mitochondrial GSH remained unchanged in the alpha-fluoro-4-ene VPA treated group but was reduced to 68% of control in the rats administered 4-ene VPA. These results strongly support the theory that hepatotoxicity of 4-ene VPA, and possibly VPA itself, is mediated largely through beta-oxidation of 4-ene VPA to reactive intermediates that are capable of depleting mitochondrial GSH.

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Section: Resultsmentioning

confidence: 99%

“…Synthesis of 2,2-Difluoro-4-pentenoic Acid (F2-4-PA). F2-4-PA was synthesized with modifications to a procedure described by Greuter et al (18). To allyl alcohol (0.1 mol, 6.0 g) and triethylamine (0.1 mol, 10.1 g) in ether was added chlorodifluoroacetic anhydride (0.1 mol, 25 g) at 0 °C.…”

Section: Methodsmentioning

confidence: 99%

Fluorinated Analogs as Mechanistic Probes in Valproic Acid Hepatotoxicity: Hepatic Microvesicular Steatosis and Glutathione Status

Tang¹,

Borel²,

Fujimiya³

et al. 1995

Chem. Res. Toxicol.

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“…One of the earliest applications of Reformatsky-Claisen rearrangement of fluorinated substrates, reported by Lang and co-workers, was the conversion of allyl chlorodifluoroacetate 14 to difluoroacid 15 ( Scheme 5 ). Various allyl chlorodifluoroacetates can undergo a Reformatsky-Claisen protocol to give 2,2-difluoro-4-pentenoic acid derivatives [ 18 ].…”

Section: Pioneering Work Of the Reformatsky-claisen Rearrangementmentioning

confidence: 99%

Recent Developments in the Reformatsky-Claisen Rearrangement

Ishihara

Hatakeyama

2012

Molecules

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The rearrangement of allyl α-bromoacetates with Zn dust is known as the Reformatsky-Claisen rearrangement. Whereas the Ireland-Claisen rearrangement has been widely used in the synthesis of a diverse range of natural products, the Zn-mediated Reformatsky-Claisen rearrangement has not been utilized so often. In this article, we will provide an overview of recent advances in the Reformatsky-Claisen rearrangement field, including the In-mediated Reformatsky-Claisen rearrangement we have recently developed.

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“…Ireland–Claisen rearrangements of propargyl esters are not very common, but the addition/rearrangement of propargyl ester 4 (Scheme ) proceeded smoothly to afford a satisfying 82% yield of the allene product 5 on a 1 mmol scale.…”

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Tandem Insertion/[3,3]-Sigmatropic Rearrangement Involving the Formation of Silyl Ketene Acetals by Insertion of Rhodium Carbenes into S–Si Bonds

2021

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Allyl 2-diazo-2-phenylacetates are shown to react with trimethylsilyl thioethers in the presence of rhodium(II) catalysts to generate α-allyl-α-thio silyl esters. The transformation involves a tandem process involving formal rhodium-catalyzed insertion of the carbene group into the S–Si bond to generate a silyl ketene acetal, followed by a spontaneous Ireland–Claisen rearrangement. The silyl ester products were isolated as the corresponding carboxylic acids after aqueous workup. Intramolecular cyclopropanation of the allyl fragment generally competes with addition of the heteroatom to the carbene center. The reaction occurs under mild conditions and in high yield, allowing for rapid entry into rearrangement tetrasubstituted products. Propargyl esters were shown to generate the corresponding α-allenyl products.

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ChemInform Abstract: Fluorine‐Containing Organozinc Reagents. Part 5. The Reformatskii‐Claisen Reaction of Chlorodifluoroacetic Acid Derivatives.

Abstract: The allylic chlorodifluoroacetates (I) and (IX) rearrange upon heating in the presence of zinc and chlorotrimethylsilane, yielding the α,α‐difluoro‐4‐pentenoic acids (II) or (X) after work‐up with SiO2/water.

Cited by 3 publications

References 1 publication

Fluorinated Analogs as Mechanistic Probes in Valproic Acid Hepatotoxicity: Hepatic Microvesicular Steatosis and Glutathione Status

Fluorinated Analogs as Mechanistic Probes in Valproic Acid Hepatotoxicity: Hepatic Microvesicular Steatosis and Glutathione Status

Recent Developments in the Reformatsky-Claisen Rearrangement

Tandem Insertion/[3,3]-Sigmatropic Rearrangement Involving the Formation of Silyl Ketene Acetals by Insertion of Rhodium Carbenes into S–Si Bonds

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