Synthesis of 4-membered ring alkaloid analogues via intramolecular [2+2] cycloaddition involving keteniminium salt intermediates

Straightforward Synthesis of 3‐Aminothiophenes Using Activated Amides

“…As shown in Scheme 6, this amide was applied for the synthesis of both 3-aminothiophene 13 and benzothiophene 11c in high yields (84 % and 74 %, respectively). Besides, like the diallyl derivatives, [36,[46][47][48] the main advantage of para-methoxybenzene is that it can be used as a protecting group and can be cleaved in a second step. It should be noted however that two equivalents of Tf 2 O were required to push the reaction to completion.…”

“…A density functional theory (DFT) study was performed in order to investigate the reactivity differences of the intramolecular competition reactions and rationalize the favorable formation of the thiophene in Scheme 7. All optimizations were performed with the widely used hybrid meta-GGA functional, at the M06-2X [51,52] /6-31 + G(d,p) level of theory, [36,38,[46][47][48] using the integral equation formalism-polarizable continuum (IEF-PCM) model [53,54] as implemented in Gaussian 16 (G16, Revision A.03). [55] 6 -311 + + G(3df,3pd) extra basis set was used for the sulfur atoms to attain more accurate results.…”

“…In the cycloaddition reaction of 8h, only the first transition state (TS1) results were presented, since previous studies disclosed that the rate-determining step of the stepwise [2 + 2] cycloaddition reaction is the initial addition of the central carbon atom of the keteniminium onto the π-system of pentenyl. [37,[46][47][48]62] In the competition reaction of 8e, due to the disruption of the aromaticity, the activation barrier for the formation of benzothiophene (ΔG � = 16.4 kcal/mol) is significantly higher than the barrier of the formation of thiophene (ΔG � = 8.3 kcal/ mol). The formation of thiophene is both kinetically and thermodynamically favored in line with the experimentally observed findings (100 %; Scheme 7 and Table 1).…”

Keteniminium Salts as Key Intermediates for the Efficient Synthesis of 3‐Amino‐Indoles and ‐Benzofurans

“…Of course, this methodology is not limited to the use of N ‐piperidylamide derivatives. Indeed, acyclic N ‐substituted amides can be used and, more importantly, mono‐ or di‐allyl substituents on the nitrogen are tolerated ( 2m and 2n ) which would allow further deprotection of this nitrogen …”

“…The conformational preferences of the R substituted keteniminium intermediates (R=H, CH 3 ) depicted in Scheme were computationally investigated in order to elucidate the R substituent's effect on the electrocyclization reaction. All optimizations were performed at the M06‐2X/6‐31+G(d,p) with IEF‐PCM in dichloromethane (CH 2 Cl 2 ) as implemented in Gaussian 16 (G16, Revision A.03) . Energy refinements were carried out using double hybrid B2PLYP functional in order to accurately evaluate the relative Gibbs free energies.…”