On the Nitrogen Inversion of Isoxazolidin-5-ones

Abstract

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.

Introduction

Isoxazolidines, which are saturated five-membered heterocycles that contain N–O bonds, have served as strategic intermediates in synthetic organic chemistry.¹⁾ Although this moiety itself is scarcely found in the structures of natural products, the labile N–O bond provides a facile way of installing 1,3-aminoalcohol units in molecular frameworks.²⁾ This heterocycle has also received particular attention in physical organic chemistry because, as a unique property of an isoxazolidine, its nitrogen inversion is slower than that of pyrrolidine.^3,4) Consequently, a range of N-alkyl isoxazolidines has been examined by NMR spectroscopy with the aim of determining 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 were prepared. The ¹H-NMR spectrum of an unprotected N-H derivative displays broad peaks, whereas that of an N-Boc derivative exhibits sharp peaks, which indicates that their 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 activation energies by computational means.

Results and Discussion

Since the previous study noted that the nitrogen inversion energy of substituted isoxazolidines was less sensitive to the polarity of solvents,¹⁸⁾ in this study, all ground state and transition state geometries were optimized in the gas phase using density functional theory (DFT) methods at the ωB97X-D/6-311++G(2d,p) level of theory.¹⁹⁾ The structures of the isoxazolidin-5-ones studied in this work are shown in Chart 1. Both electronic and steric factors were considered when choosing these substrates. The presence of the carbonyl group in the ring was expected to affect the energy difference between the pseudo-axial and -equatorial conformer in a different manner to that of the corresponding isoxazolidines.

Chart 1. Structures of Isoxazolidin-5-ones Studied in This Work

Table 1 summarizes the calculated relative energies of each pair of conformers and the associated nitrogen inversion transition state for systems with various substituents on the nitrogen atom, which reveals a clear activation energy trend. Hydrogen and alkyl substituents imparted higher barriers than C(sp²)-type substituents, such as phenyl and carbamate groups (entries 1–6), which is consistent with the trend observed by NMR spectroscopy. The steric nature of the substituents seems to be less influential (1b vs. 1c; 1e vs. 1f). The introduction of the strongly electron withdrawing fluorine atom on the nitrogen led to a significantly higher energy barrier such that two conformers would be expected to be separable at an ambient temperature (entry 7).²⁰⁾ Geminally disubstituted methyl groups at the periphery of the five membered ring appear to have little effect with respect to the inversion energy (entries 8, 9). In addition, except for alkyl substituted compounds 1b and 1c, each pseudo-axial isomer was found to be slightly more stable than the corresponding pseudo-equatorial isomer.

Table 1. Relative Energies of Isoxazolidin-5-ones Conformers and Associated Transition States^a)

Entry	Compound	R	1-ax	TS	1-eq
1	1a	H	0.0	12.4	0.7
2	1b	Me	1.2	13.6	0.0
3	1c	tBu	1.5	12.6	0.0
4	1d	Ph	0.1	5.5	0.0
5	1e	COOMe	0.0	2.3	0.3
6	1f	COOtBu	0.0	2.5	0.3
7	1g	F	0.0	39.4	4.4
8	1h	Hb)	0.0	12.7	1.0
9	1i	Hc)	0.0	12.3	0.6

a) All energies are reported in kcal/mol. b) Geminal dimethyl group at the 3-position. c) Geminal dimethyl group at the 4-position.

Natural bond orbital analysis was used to calculate Wiberg bond indices²¹⁾ for the N–O and N–R bonds, and the s-character of the nitrogen lone pair for selected compounds (Table 2). The activation energy increases with increasing s-character of the lone pair of electrons because more energy is required for the ground state to reach the p-character transition state.²²⁾

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

Entry	Compound	R	1-ax			1-eq
			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

To provide a comparison, the calculated energies of several isoxazolidines are listed in Table 3. Removing the carbonyl group from the ring shifts the conformational equilibrium. The additional hydrogen atoms lead to larger 1,3-diaxial interactions; hence, the pseudo-axial conformer of 2c is higher in energy relative to the equatorial conformer. In addition, the activation energies of the N-substituted isoxazolidines are similar to, or slightly lower than, those of the corresponding isoxazolidin-5-ones.

Table 3. Relative Energies for Selected Isoxazolidines and Associated Transition States^a)

Entry	Compound	R	2-ax	TS	2-eq
1	2a	H	0.0	12.9	1.9
2	2b	Me	0.8	13.1	0.0
3	2c	tBu	2.1	11.8	0.0
4	2d	Ph	0.0	4.6	0.5
5	2e	COOMe	0.0	2.4	1.5

a) All energies are reported in kcal/mol.

Conclusion

In summary, we have examined the nitrogen inversion process for a variety of isoxazolidin-5-ones using DFT methods. The activation energy strongly correlates with the s-character of the lone pair of electrons on the nitrogen in the ground state; consequently, C(sp²)-type substituents, such as Boc, facilitate facile inversion. The general activation energy trend has been shown to be similar for substituted isxazolidin-5-ones and isoxazolidines, but the positions of the conformational equilibria are slightly different, and the isoxazolidin-5-one inversion energies tend to be higher.

Acknowledgments

This research was financially supported by JSPS KAKENHI Grant Number JP18K14878.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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