Chem. Pharm. Bull. 67(11): 1248-1249 (2019)

1248 Chem. Pharm. Bull. 67, 1248–1249 (2019) Vol. 67, No. 11 Note

On the Nitrogen Inversion of Isoxazolidin-5-ones

Hidetoshi Noda* and Masakatsu Shibasaki* Institute of Microbial Chemistry, Tokyo; 3–14–23 Kamiosaki, Shinagawa-ku, Tokyo 141–0021, Japan. Received July 9, 2019; accepted August 15, 2019

The nitrogen inversion energies of a series of N-substituted isoxazolidin-5-ones were studied by density functional theory. The transition state energy was found to strongly correlate with the s-character of the lone pair of electrons on the nitrogen in the ground state. Although the activation energy trends for isxazolidin- 5-ones and isoxazolidines are similar, their conformational equilibria are slightly different and the isoxazolidin-5-one inversion energies are generally higher. Key words nitrogen inversion; isoxazolidine; conformational analysis; density functional theory

Introduction when choosing these substrates. The presence of the carbonyl Isoxazolidines, which are saturated ﬁve-membered het- group in the ring was expected to affect the energy difference erocycles that contain N–O bonds, have served as strategic between the pseudo-axial and -equatorial conformer in a dif- intermediates in synthetic organic chemistry.1) Although this ferent manner to that of the corresponding isoxazolidines. moiety itself is scarcely found in the structures of natural Table 1 summarizes the calculated relative energies of products, the labile N–O bond provides a facile way of install- each pair of conformers and the associated nitrogen inversion ing 1,3-aminoalcohol units in molecular frameworks.2) This transition state for systems with various substituents on the heterocycle has also received particular attention in physical nitrogen atom, which reveals a clear activation energy trend. organic chemistry because, as a unique property of an isoxa- Hydrogen and alkyl substituents imparted higher barriers than zolidine, its nitrogen inversion is slower than that of pyrro- C(sp2)-type substituents, such as phenyl and carbamate groups lidine.3,4) Consequently, a range of N-alkyl isoxazolidines has (entries 1–6), which is consistent with the trend observed been examined by NMR spectroscopy with the aim of deter- by NMR spectroscopy. The steric nature of the substituents mining the activation energies of these inversion processes.5,6) Isoxazolidin-5-ones are lactone derivatives of isoxazolidines,7) and have often been used as precursors for β-amino acids through reductive cleavage of their N–O bonds.8–16) We recently disclosed that unprotected isoxazolidin-5-ones armed with an aromatic ring undergo traceless electrophilic aminations in the presence of a rhodium catalyst, affording the benzo-fused cyclic β-amino acids.17) During the course of this study, a series of N-Boc and N-H isoxazolidin-5-ones Chart 1. Structures of Isoxazolidin-5-ones Studied in This Work were prepared. The 1H-NMR spectrum of an unprotected N-H derivative displays broad peaks, whereas that of an N-Boc Table 1. Relative Energies of Isoxazolidin-5-ones Conformers and As- derivative exhibits sharp peaks, which indicates that their sociated Transition Statesa) nitrogen inversion energies are signiﬁcantly different (see the Supplementary Materials for details). Since most studies on isoxazolidines have employed NMR line shape methods18) to determine the activation energies for nitrogen inversion, these studies have been limited to N-alkyl substrates that exhibit relatively slow inversion rates. The lack of data for isoxazolidin-5-ones bearing a range of substituents led us to examine Entry Compound R 1-ax TS 1-eq activation energies by computational means. 1 1a H 0.0 12.4 0.7 2 1b Me 1.2 13.6 0.0 Results and Discussion 3 1c tBu 1.5 12.6 0.0 Since the previous study noted that the nitrogen inver- 4 1d Ph 0.1 5.5 0.0 sion energy of substituted isoxazolidines was less sensitive 5 1e COOMe 0.0 2.3 0.3 18) to the polarity of solvents, in this study, all ground state 6 1f COOtBu 0.0 2.5 0.3 and transition state geometries were optimized in the gas 7 1g F 0.0 39.4 4.4 phase using density functional theory (DFT) methods at the 8 1h Hb) 0.0 12.7 1.0 ωB97X-D/6-311++G(2d,p) level of theory.19) The structures 9 1i Hc) 0.0 12.3 0.6 of the isoxazolidin-5-ones studied in this work are shown in a) All energies are reported in kcal/mol. b) Geminal dimethyl group at the 3-posi- Chart 1. Both electronic and steric factors were considered tion. c) Geminal dimethyl group at the 4-position.

Table 2. Bond Orders and s-Characters of the Lone Pairs of Electrons

1-ax 1-eq Entry Compound R N–O N–R N(spx) N–O N–R N(spx)

1 1a H 0.9542 0.8587 sp2.41 0.9466 0.8528 sp2.28 2 1b Me 0.9425 0.9859 sp3.12 0.9331 0.9870 sp3.01 3 1d Ph 0.9547 1.0155 sp4.07 0.9388 1.0329 sp4.41 4 1e COOMe 0.9694 0.9975 sp5.66 0.9623 1.0485 sp5.97 5 1g F 1.0328 0.8586 sp1.45 0.9800 0.9087 sp1.41

Table 3. Relative Energies for Selected Isoxazolidines and Associated 5-ones and isoxazolidines, but the positions of the conforma- Transition Statesa) tional equilibria are slightly different, and the isoxazolidin- 5-one inversion energies tend to be higher.

Acknowledgments This research was ﬁnancially sup- ported by JSPS KAKENHI Grant Number JP18K14878.

Entry Compound R 2-ax TS 2-eq Conflict of Interest The authors declare no conflict of 1 2a H 0.0 12.9 1.9 interest. 2 2b Me 0.8 13.1 0.0 3 2c tBu 2.1 11.8 0.0 Supplementary Materials The online version of this ar- 4 2d Ph 0.0 4.6 0.5 ticle contains supplementary materials. 5 2e COOMe 0.0 2.4 1.5 a) All energies are reported in kcal/mol. References 1) Berthet M., Cheviet T., Dujardin G., Parrot I., Martinez J., Chem. Rev., 116, 15235–15283 (2016). seems to be less influential (1b vs. 1c; 1e vs. 1f). The introduc- 2) Murahashi S.-I., Imada Y., Chem. Rev., 119, 4684–4716 (2019). tion of the strongly electron withdrawing fluorine atom on the 3) Griffith D. L., Olson B. L., J. Chem. Soc. Chem. Commun., 1968, nitrogen led to a significantly higher energy barrier such that 1682–1683 (1968). 4) Lehn J. M., Wagner J., Tetrahedron, 26, 4227–4240 (1970). two conformers would be expected to be separable at an ambi- 20) 5) Riddell F. G., Tetrahedron, 37, 849–858 (1981). ent temperature (entry 7). Geminally disubstituted methyl 6) Raban M., Jones F. B., Carlson E. H., Banucci E., LeBel N. A., J. groups at the periphery of the five membered ring appear to Org. Chem., 35, 1496–1499 (1970). have little effect with respect to the inversion energy (entries 7) Annibaletto J., Oudeyer S., Levacher V., Brière J.-F., Synthesis, 49, 8, 9). In addition, except for alkyl substituted compounds 1b 2117–2128 (2017). and 1c, each pseudo-axial isomer was found to be slightly 8) Baldwin J. E., Harwood L. M., Lombard M. J., Tetrahedron, 40, more stable than the corresponding pseudo-equatorial isomer. 4363–4370 (1984). Natural bond orbital analysis was used to calculate Wiberg 9) Shindo M., Itoh K., Tsuchiya C., Shishido K., Org. Lett., 4, 3119– bond indices21) for the N–O and N–R bonds, and the s-char- 3121 (2002). acter of the nitrogen lone pair for selected compounds (Table 10) Lee H.-S., Park J.-S., Kim B. M., Gellman S. H., J. Org. Chem., 68, 1575–1578 (2003). 2). The activation energy increases with increasing s-character 11) Tite T., Sabbah M., Levacher V., Brière J.-F., Chem. Commun., 49, of the lone pair of electrons because more energy is required 11569–11571 (2013). 22) for the ground state to reach the p-character transition state. 12) Berini C., Sebban M., Oulyadi H., Sanselme M., Levacher V., To provide a comparison, the calculated energies of several Brière J.-F., Org. Lett., 17, 5408–5411 (2015). isoxazolidines are listed in Table 3. Removing the carbonyl 13) Izumi S., Kobayashi Y., Takemoto Y., Org. Lett., 18, 696–699 group from the ring shifts the conformational equilibrium. (2016). The additional hydrogen atoms lead to larger 1,3-diaxial in- 14) Cadart T., Berthonneau C., Levacher V., Perrio S., Brière J.-F., teractions; hence, the pseudo-axial conformer of 2c is higher Chem. Eur. J., 22, 15261–15264 (2016). in energy relative to the equatorial conformer. In addition, 15) Yu J.-S., Noda H., Shibasaki M., Angew. Chem. Int. Ed., 57, 818– the activation energies of the N-substituted isoxazolidines are 822 (2018). 16) Yu J.-S., Noda H., Shibasaki M., Chem. Eur. J., 24, 15796–15800 similar to, or slightly lower than, those of the corresponding (2018). isoxazolidin-5-ones. 17) Yu J.-S., Espinosa M., Noda H., Shibasaki M., J. Am. Chem. Soc., 141, 10530–10537 (2019). Conclusion 18) Riddell F. G., Lehn J. M., Wagner J., J. Chem. Soc. Chem. Com- In summary, we have examined the nitrogen inversion pro- mun., 1968, 1403–1403 (1968). cess for a variety of isoxazolidin-5-ones using DFT methods. 19) Chai J.-D., Head-Gordon M., Phys. Chem. Chem. Phys., 10, 6615– The activation energy strongly correlates with the s-character 6620 (2008). of the lone pair of electrons on the nitrogen in the ground 20) Ghosh D. C., Jana J., Bhattacharyya S., Int. J. Quantum Chem., 87, state; consequently, C(sp2)-type substituents, such as Boc, 111–134 (2002). facilitate facile inversion. The general activation energy trend 21) Wiberg K. B., Tetrahedron, 24, 1083–1096 (1968). has been shown to be similar for substituted isxazolidin- 22) Kost D., Raban M., J. Org. Chem., 41, 1748–1751 (1976).