Diastereoselective synthesis and cytotoxic evaluation of new isoxazoles and pyrazoles with monoterpenic skeleton

Unveiling the Different Chemical Reactivity of Diphenyl Nitrilimine and Phenyl Nitrile Oxide in [3+2] Cycloaddition Reactions with (R)-Carvone through the Molecular Electron Density Theory

“…82.5%, computed as the separation between S3-NI and S5-NI relative to TS-1-NI in the IRC, suggests a two-stage one-step mechanism [37] (see Figure 5); (v) formation of the first C3−C4 single bond involves the most nucleophilic centre of diphenyl NI 2a, which corresponds to the carbenoid C1 carbon, and the most electrophilic of (R)-carvone 1, the β-conjugated position (see section S2 in Supplementary Material) [23]. This behaviour makes it possible to explain the chemo-and regioselectivity found experimentally in this 32CA reaction [16]; and finally, (vi) the present bond formation patterns for C−C and N−C single bonds agree with those previously reported in cb-type 32CA reactions [21]. reaction between diphenyl NI 2a and(R)-carvone 1, 12.4 kcal•mol −1 , can mainly be related to the depopulation of the N2−C3 bonding region of the diphenyl NI fragment, which leads to the formation of non-bonding electron density at the N2 nitrogen.…”

“…Thus, in view of the different chemical reactivity experienced by diaryl-NIs 2a-d and aryl-NOs 4a-d towards the two different C−C double bonds of (R)-carvone 1, experimentally studied by Ait Itto et al [16], an MEDT study of the 32CA reactions of diphenyl NI 2a and with phenyl-NO 4a towards (R)-carvone 1 is herein carried out in order to shed light on the experimental outcomes, i.e., the opposite chemoselectivity of the 32CA reactions of these TACs with (R)-carvone 1.…”

“…Only four reaction paths were considered: the attack to the C4−C5 or C8−C9 double bonds of (R)-carvone 1, and the two regioisomeric approach modes of diphenyl NI 2a to these C−C double bonds (see Scheme 2). Facial selectivity was not considered [16]. Analysis of the mentioned reaction paths allowed locating and characterising four TSs and the corresponding pyrazoles, indicating that this 32CA reaction takes place through a one-step mechanism (see Scheme 2).…”

“…The total and relative energies in the gas phase and in DCM and the thermodynamic data are given in Tables S5 and S7 considered: the attack to the C4−C5 or C8−C9 double bonds of (R)-carvone 1, and the regioisomeric approach modes of phenyl NO 4a to these C−C double bonds (see Scheme 3). Facial selectivity was not considered [16]. Analysis of the stationary points involved in the four reaction paths indicates that this 32CA reaction takes place also through a one-step mechanism.…”

“…Very recently, Ait Itto et al reported the 32CA reactions of (R)-carvone 1 with diaryl nitrilimines (NIs) 2a-d and arylnitrile oxides (NOs) 4a-d in dichloromethane (DCM), yielding pyrazoles 3a-d and isoxazoles 5a-r, respectively (see Scheme 1) [16]. These 32CA reactions presented total regioand chemoselectivity, resulting in a mixture of a pair of diastereoisomers resulting from the attack of Thus, in view of the different chemical reactivity experienced by diaryl-NIs 2a-d and aryl-NOs 4a-d towards the two different C−C double bonds of (R)-carvone 1, experimentally studied by Ait Itto et al [16], an MEDT study of the 32CA reactions of diphenyl NI 2a and with phenyl-NO 4a towards (R)-carvone 1 is herein carried out in order to shed light on the experimental outcomes, i.e., the opposite chemoselectivity of the 32CA reactions of these TACs with (R)-carvone 1.…”