Mechanistic Pathways in CF₃COOH-Mediated Deacetalization Reactions

Abstract

It has been widely accepted that both the protection of carbonyls and the deprotection of acetals and ketals involve the participation of a water molecule: formation of acetals and ketals is a dehydration process, whereas the deprotection is often referred to as hydrolysis, which, as implied by its name, always requires the presence of water. Herein, we report experimental evidence and mechanistic investigations that provide an alternative view to this process. We have demonstrated that water is not required to convert acetals and ketals to the corresponding carbonyls. The (1)H NMR experimental results revealed that the TFA-mediated transformation of acetal to aldehyde occurs via a hemiacetal TFA ester intermediate, which differentiates itself from the classic acid-catalyzed hydrolysis, where the hemiacetal is the putative intermediate responsible for the formation of the aldehyde. More interestingly, alcohols are not the final byproducts as they are in the classical hydrolysis, rather, the two alcohol molecules are converted to two TFA esters under the reaction conditions. On the basis of the NMR evidence, we have proposed that the two TFA esters are formed in two separate steps via a different mechanism along the reaction pathway. Formation of the TFA esters renders the reaction irreversible. To the best of our knowledge, the cascade reaction pathway presented by the TFA-mediated conversion of acetals and ketals to carbonyls has never been previously postulated.

Monitoring organic reactions by UF‐NMR spectroscopy

“…The combined application of tandem homonuclear and heteronuclear UF sequences provides new mechanistic insights in the reaction of ketones with nitriles in the presence of triflic anhydride. Thus, a new and unexpected iminic intermediate (26) was detected for the first time, which explains the low reactivity of alicyclic ketones.…”

“…Other applications for extending UF methodology to further systems can be reported. One of these is related to the chemistry of acetals, which are useful synthetic intermediates in the synthesis and protection of carbonyl compounds . Normally, acetal hydrolysis leading to the unprotected carbonyl compound is carried out in aqueous acid .…”

“…These signals, whose intensities rise and fall with the time, apparently represent an intermediate. To explain the olefinic nature of the cross-peaks observed, an imine intermediate (26) formed from cyclohexanone (23) was proposed. Predicted chemical shifts from modeling (obtained at the GIAO-PCM(acetonitrile)-B3LYP/6-31 + G* level) [19][20][21] are in good agreement with the proposed structure for an iminic intermediate (26) (Fig.…”

“…One of these is related to the chemistry of acetals, which are useful synthetic intermediates in the synthesis and protection of carbonyl compounds. [26] Normally, acetal hydrolysis leading to the unprotected carbonyl compound is carried out in aqueous acid. [27] However, identifying the intermediates in these hydrolysis is problematical because of their short lifetimes.…”

Enantioselective Total Syntheses of (−)‐Rhazinilam, (−)‐Leucomidine B, and (+)‐Leuconodine F

“…We noted that imine 9 was sufficiently stable to be purified by flash column chromatography.While condensation of 1-alkyl-3,4-dihydroisoquinolines with a-halo ketones has been exploited for the synthesis of pyrrolo[2,1-a]isoquinolines, [16] heteroannulation of imines with bromoacetaldehyde has,t ot he best of our knowledge,n ever been examined. After much experimentation, we were pleased to find that simply stirring an acetonitrile solution of 9 and bromoacetaldehyde (10) [17] at 70 8 8Cinthe presence of aweak base (NaHCO 3 )a fforded tetrahydroindolizine 6 in excellent yield. Mechanistically,t he reaction might be initiated by Nalkylation to give enamine aldehyde A,w hich undergoes cyclization to give B.Dehydration of B followed by tautomerization would afford tetrahydroindolizine 6.W es ubsequently found that the Staudinger reduction/Aza-Wittig and heteroannulation can be integrated into aone-pot reaction to allow the direct conversion of 20 into 6 in 76 %yield.…”