Efficient Regio- and Stereoselective Formation of Azocan-2-ones via 8-Endo Cyclization of α-Carbamoyl Radicals

Abstract

The iodine-atom-transfer 8-endo cyclization of alpha-carbamoyl radicals was investigated experimentally and theoretically. With the aid of Mg(ClO(4))(2) and a bis(oxazoline) ligand, N-ethoxycarbonyl-substituted N-(pent-4-enyl)-2-iodoalkanamides underwent 8-endo cyclization leading to the formation of only the corresponding 3,5-trans-substituted azocan-2-ones in excellent yields. Similarly, the BF(3).OEt(2)/H(2)O-promoted reactions of N-ethoxycarbonyl-N-(2-allylaryl)-2-iodoalkanamides afforded exclusively the benzazocanone products with a 3,5-cis configuration in high yields. The bidentate chelation of substrate radicals not only significantly improved the efficiency of cyclization but also resulted in the change of stereochemistry of azocanone products from 3,8-trans to 3,8-cis. Theoretical calculations at the UB3LYP/6-31G* level revealed that the cyclization of N-carbonyl-substituted alpha-carbamoyl radicals occurs via the E-conformational transition states without the presence of a Lewis acid. On the other hand, the cyclization proceeds via the Z-conformational transition states when the substrates form the bidentate chelation with a Lewis acid. In both cases, the 8-endo cyclization is always fundamentally preferred over the corresponding 7-exo cyclization. The complexed radicals having the more rigid conformations also allow the better stereochemical control in the iodine-atom-abstraction step. To further understand the reactivity of alpha-carbamoyl radicals, the competition between the 8-endo and 5-exo cyclization was also studied. The results demonstrated that the 8-endo cyclization is of comparable rate to the corresponding 5-exo cyclization for alpha-carbamoyl radicals with fixed Z-conformational transition states. As a comparison, the 8-endo mode is fundamentally preferred over the 5-exo mode in the cyclization of NH-amide substrates because the latter requires the Z-conformational transition states, whereas the former proceeds via the more stable E-conformational transition states.

Synthesis of supramolecular precision polymers: Crystallization under conformational constraints

“…Dodec‐11‐enoic acid, dec‐9‐enoyl chloride, undec‐10‐enoyl chloride, and dodec‐11‐enoyl chloride were synthesized according to literatures …”

“…The synthesis was carried out analogous to literature . A two‐necked flask was filled with a NH 4 OH solution (250 mL, 25% in H 2 O) and cooled to 0 °C.…”

“…The synthesis was carried out according to the literature . A two‐necked flask was filled with undec‐10‐enamide (5.91 mmol, 1 g) dissolved in dry THF (30 mL).…”

“…Dodec-11-enoic acid, dec-9-enoyl chloride, undec-10-enoyl chloride, and dodec-11-enoyl chloride were synthesized according to literatures. 37,50 All chemicals were purchased from Sigma-Aldrich and used without further purification if not mentioned otherwise. All solvents were either distilled and/or dried using standard methods.…”

“…The synthesis was carried out according to the literature. 50 A two-necked flask was filled with undec-10-enamide (5.91 mmol, 1 g) dissolved in dry THF (30 mL). After cooling to 210 8C and careful addition of LiAlH 4 (8.86 mmol, 0.34 g), the mixture was allowed to stir overnight, followed by the addition of dry Et 2 O (20 mL).…”