“…Over the last 26 years, the conditions reported by Aoyama, Shioiri, and co‐workers ( 4 , 5 M CH 3 OH in toluene or benzene)5a have been widely adopted as a safe and convenient alternative to the use of 1 for methyl esterification,3 especially by analytical chemists for acid derivatization prior to chromatographic analysis 6. Although it is known that methanol is not the methylating agent,7 the mechanism of the reaction has not been investigated in any detail 3b. 5a Herein we demonstrate, by way of isotopic labeling, that the methyl esterification of carboxylic acids by 4 /CH 3 OH proceeds through the in situ methanolytic liberation of diazomethane ( 1 ).…”
Despite being toxic, flammable, photosensitive, thermally unstable, and shock sensitive, diazomethane (CH 2 N 2 , 1) has had extensive application in synthesis, especially for the Omethylation (esterification) of carboxylic acids (2!3), Scheme 1.In 1968 Seyferth et al. reported [1] that the trimethylsilyl (TMS) derivative of diazomethane (TMS À CHN 2 , 4), [2,3] described by Lappert et al.[2a] reacts with acetic acid (2 a) in dry benzene to generate TMS-methyl acetate (5 a), Scheme 1. This reaction was proposed to arise from the protonation of 4 by 2 a and then nucleophilic substitution of N 2 by acetate in the resulting TMS-substituted methyl diazonium intermediate (6 a!5 a). [1,4] However, AcOTMS and methyl acetate (3 a) were also generated in 40-60 % yield. Seyferth et al. suggested that the intermolecular protodesilylation of intermediate 6 a by the acetic acid generates a methyl diazonium intermediate [AcO][CH 3 N 2 ] (7 a), thus yielding 3 a.[1] In 1981 Aoyama, Shioiri, and co-workers reported that a simple modification of the conditions reported by Seyferth et al. involving the addition of methanol as a cosolvent (20 % v/v, 4.94 m), increased the yields of methyl esters 3 to near quantitative (90-99 %).[5a,b] Unlike 1, which is a gas (b.p. À23 8C) and requires prior generation from toxic and irritant N-methyl N-nitroso species, TMS À CHN 2 (4) is a stable liquid (b.p. 96 8C) [1] that is easily handled and is commercially available.Over the last 26 years, the conditions reported by Aoyama, Shioiri, and co-workers (4, 5m CH 3 OH in toluene or benzene) [5a] have been widely adopted as a safe and convenient alternative to the use of 1 for methyl esterification, [3] especially by analytical chemists for acid derivatization prior to chromatographic analysis.[6] Although it is known that methanol is not the methylating agent, [7] the mechanism of the reaction has not been investigated in any detail.[3b, 5a] Herein we demonstrate, by way of isotopic labeling, that the methyl esterification of carboxylic acids by 4/CH 3 OH proceeds through the in situ methanolytic liberation of diazomethane (1).The key feature of the conditions reported by Aoyama, Shioiri, and co-workers [5a] is the high-yielding and rapid (< 5 min) generation of methyl esters 3, rather than TMSmethyl esters 5, through the presence of a large excess (> 50 equiv) of methanol in benzene, [5] or toluene. [3,6] 1 H NMR analysis demonstrates that, in the absence of added acid, 4 does not observably react with CD 3 OD (5 m) in [D 8 ]toluene over a period of hours, although very slow H/D exchange is detected over longer periods. To explore the key role of methanol, we have focused on the reaction of phenyl acetic acid (2 b) with 4, and correlated the partitioning between methyl ester 3 b and TMS-methyl ester 5 b as a function of methanol concentration and isotope effect (CL 3 OL; L = H/ D). To ensure that the partitioning (3 b/5 b) was not compromised by competing or subsequent processes, we conducted the methyl esterification of benzoic acid (2 c) in ...
“…Over the last 26 years, the conditions reported by Aoyama, Shioiri, and co‐workers ( 4 , 5 M CH 3 OH in toluene or benzene)5a have been widely adopted as a safe and convenient alternative to the use of 1 for methyl esterification,3 especially by analytical chemists for acid derivatization prior to chromatographic analysis 6. Although it is known that methanol is not the methylating agent,7 the mechanism of the reaction has not been investigated in any detail 3b. 5a Herein we demonstrate, by way of isotopic labeling, that the methyl esterification of carboxylic acids by 4 /CH 3 OH proceeds through the in situ methanolytic liberation of diazomethane ( 1 ).…”
Despite being toxic, flammable, photosensitive, thermally unstable, and shock sensitive, diazomethane (CH 2 N 2 , 1) has had extensive application in synthesis, especially for the Omethylation (esterification) of carboxylic acids (2!3), Scheme 1.In 1968 Seyferth et al. reported [1] that the trimethylsilyl (TMS) derivative of diazomethane (TMS À CHN 2 , 4), [2,3] described by Lappert et al.[2a] reacts with acetic acid (2 a) in dry benzene to generate TMS-methyl acetate (5 a), Scheme 1. This reaction was proposed to arise from the protonation of 4 by 2 a and then nucleophilic substitution of N 2 by acetate in the resulting TMS-substituted methyl diazonium intermediate (6 a!5 a). [1,4] However, AcOTMS and methyl acetate (3 a) were also generated in 40-60 % yield. Seyferth et al. suggested that the intermolecular protodesilylation of intermediate 6 a by the acetic acid generates a methyl diazonium intermediate [AcO][CH 3 N 2 ] (7 a), thus yielding 3 a.[1] In 1981 Aoyama, Shioiri, and co-workers reported that a simple modification of the conditions reported by Seyferth et al. involving the addition of methanol as a cosolvent (20 % v/v, 4.94 m), increased the yields of methyl esters 3 to near quantitative (90-99 %).[5a,b] Unlike 1, which is a gas (b.p. À23 8C) and requires prior generation from toxic and irritant N-methyl N-nitroso species, TMS À CHN 2 (4) is a stable liquid (b.p. 96 8C) [1] that is easily handled and is commercially available.Over the last 26 years, the conditions reported by Aoyama, Shioiri, and co-workers (4, 5m CH 3 OH in toluene or benzene) [5a] have been widely adopted as a safe and convenient alternative to the use of 1 for methyl esterification, [3] especially by analytical chemists for acid derivatization prior to chromatographic analysis.[6] Although it is known that methanol is not the methylating agent, [7] the mechanism of the reaction has not been investigated in any detail.[3b, 5a] Herein we demonstrate, by way of isotopic labeling, that the methyl esterification of carboxylic acids by 4/CH 3 OH proceeds through the in situ methanolytic liberation of diazomethane (1).The key feature of the conditions reported by Aoyama, Shioiri, and co-workers [5a] is the high-yielding and rapid (< 5 min) generation of methyl esters 3, rather than TMSmethyl esters 5, through the presence of a large excess (> 50 equiv) of methanol in benzene, [5] or toluene. [3,6] 1 H NMR analysis demonstrates that, in the absence of added acid, 4 does not observably react with CD 3 OD (5 m) in [D 8 ]toluene over a period of hours, although very slow H/D exchange is detected over longer periods. To explore the key role of methanol, we have focused on the reaction of phenyl acetic acid (2 b) with 4, and correlated the partitioning between methyl ester 3 b and TMS-methyl ester 5 b as a function of methanol concentration and isotope effect (CL 3 OL; L = H/ D). To ensure that the partitioning (3 b/5 b) was not compromised by competing or subsequent processes, we conducted the methyl esterification of benzoic acid (2 c) in ...
“…However, regardless of the absolute configuration of the tricyclic portion, the protons in this unit would experience the same type of shift effects due to the aromatic ring introduced by the formation of the 2-phenylbutyrate esters of 5 . The absolute stereochemistry for the bicyclo[3.1.1]heptane subunit common to 1 − 3 has not been reported for any member of this group, although the prior publications arbitrarily showed opposite configurations for 4 and 6 . ,, The corresponding subunits of compounds 1 − 6 are all depicted here in the same (arbitrarily chosen) absolute configuration. 1 Bisecting plane of the ( S )-2-phenylbutyrate ester of massarinolin B methyl ester and the observed chemical shift differences (Δδ = δ R − δ S ) for selected protons of the ( S )- and ( R )-2-phenylbutyrate esters.…”
mentioning
confidence: 85%
“…HMQC data were used to identify carbons bound to hydrogens. Although the COSY data for 2 defined two isolated spin systems, A ( 13 CH 3 C 10 CH 9 CH(OH) 8 CH 2 −) and B (− 14 CH 2 O−), a third spin system C (− 4 CH 2 5 CH 2 6 CH 2 CH 1 CH 2 − or − 4 CH 2 5 CH 2 6 CH 1 CH 2 2 CH−) could not be unambiguously assigned because of 1 H NMR signal overlap of a methine proton resonance (H-2) and one of the methylene proton resonances (H-1a) at δ 2.14. This ambiguity was removed by analysis of HMBC correlations (Table ).…”
Massarinolins A-C (1-3), three new bioactive sesquiterpenoids possessing rare ring systems, have been isolated from liquid cultures of the aquatic fungus Massarina tunicata Shearer & Fallah. The structures were determined primarily by analysis of NMR data. Metabolites 1-3 are the first compounds to be reported from any member of the genus Massarina.
“…Trimethylsilyldiazomethane is remarkably more stable than diazomethane and has led to investigations on its use in synthesis as a stable and safe substitute of diazomethane 7. Diazoesters are considered to be much safer than diazomethane due to the resonance stabilization of the ester functional group (although only estimated to be around 16 kJ/mol) (Scheme ) 8.…”
Diazo compounds are useful synthetic intermediates in organic synthesis but, due to their toxicity and unpredictable explosive behaviour, their unique reactivity has not been fully exploited and their use on large scale has been avoided. We have developed a reliable method that generates diazo compounds in situ. Our approach is based on the BamfordStevens reaction, which utilizes tosylhydrazone salts as diazo precursors. In the presence of phase-transfer-catalysts (PTC), we found that tosylhydrazone salts can be cleanly converted to diazo compounds under mild reaction conditions and in a wide range of solvents. These diazo compounds can then be
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