Rearrangement of o-(pivaloylaminomethyl)benzaldehydes: an experimental and computational study

Abstract

Treatment of alkoxy-substituted o-(pivaloylaminomethyl)benzaldehydes under acidic conditions resulted in the formation of the regioisomeric aldehydes and/or dimer-like products. Detailed NMR studies and single-crystal X-ray measurements supported the structure elucidation of the compounds. DFT calculations were also carried out to clarify the reaction mechanism, and to explain the observed product distributions and structural variances in the dimer-like products. Studies on the transformation of unsubstituted o-(pivaloylaminomethyl)benzaldehyde under similar conditions were presented as well.

Experimental and computational study of BF3-catalyzed transformations of ortho-(pivaloylaminomethyl)benzaldehydes: an unexpected difference from TFA catalysis

“…After separation, compound 14 was crystallized by stirring in heptane, while derivative 15 in hexane. There is a noteworthy difference between the results of the TFA-catalyzed (Scheme 2) 3 and BF 3catalyzed (Scheme 4) transformation also in the case of aldehyde 5. During the monitoring of the TFA-catalyzed reaction of 5 by HPLC, the appearance of products 14 and 15 was not observed.…”

“…The calculations were carried out with the (1S,1′R) diastereomer (and these obviously relate to its enantiomer, as well), which proved to be energetically favored in our previous study. 3 The isomerization of salts 11 to salts 17 is considered as a two-step process through aromatic intermediate 16. First, the conjugate base of the catalyst deprotonates 11A and 11B, leading to 16 through TS1A and TS1B, respectively.…”

“…In our previous publications [1][2][3] we disclosed that alkoxy-substituted ortho-( pivaloylaminomethyl)benzaldehydes (1a-d), when kept in dichloromethane (DCM) or tetrahydrofuran (THF) in the presence of a catalytic amount of trifluoroacetic acid (TFA) at room temperature, gave isomeric aldehydes 2a-d and/or dimer-like racemic products 3a, b or 4c, d (Scheme 1). According to the reaction mechanism discussed in our earlier paper, 3 it is important to mention that theoretically the formation of four dimer-like regioisomers can be expected from aldehydes 1a-d, each of them as the mixture of two diastereomeric racemates. Although the presence of isomeric dimers was indeed detected in the crude product mixtures, only one major isomer (3a, 3b, 4c or 4d) was isolated in each case as a racemate.…”

“…Compound 6a was isolated in 58% yield, while minor product 6b was also isolated and identified after a multistep purification process. 3 The formation of dimer-like products 6a and 6b was explained by protonation of ring tautomer 7 to 8A (trifluoroacetate salts are designated with "A" after the compound number), followed by water elimination resulting in cation 9A, which was deprotonated to afford isoindole 10. Similar reactivity of isoindoles is well demonstrated in the literature.…”

“…The mechanism proposed for the formation of the products (Scheme 2) has been supported by DFT calculations. 3 It is to be noted that in the case of derivatives substituted at the aromatic ring (1a-d), coupling of "monomers" (analogous to 9A and 10) leads to the formation of 4 regioisomers, depending on which position of the cation ( position 1 or 3) and the isoindole ( position 1 or 3) are affected in the reaction.…”