Diastereoselective synthesis of atropisomeric pyrazolyl pyrrolo[3,4-d]isoxazolidines via pyrazolyl nitrone cycloaddition to facially divergent maleimides: intensive NMR and DFT studies

A pyrazolyl nitrone (2) underwent 1,3-dipolar cycloadditions to afford some N-substituted maleimides (3a–o). An atropisomeric character was introduced into the formed cycloadducts by using maleimides that have a restricted rotation around the C–N bond. Also, facial selectivity of both endo and exo cycloaddition was observed where the major atropisomer was one that is formed by attacking the nitrone from the less hindered face of the dipolarophile. On the other hand, maleimides with free rotation around the C–N bond led to endo and exo cycloadducts without atropisomerism. The presence of atropisomerism in the formed cycloadducts was confirmed by extensive NMR studies and DFT calculations.


Introduction
Chemistry of nitrones has received signicant attention since its discovery, more than a century ago. 1 Most of the studies have focused on exploring the 1,3-dipole character of nitrones in [3 + 2] dipolar cycloadditions with dipolarophiles to construct functionalized ve-membered heterocycles which are important intermediates in organic synthesis. 2 The dipolarophiles include alkenes, 3 alkynes, 4 allenes 5 and other cumulated double bonds. 6 Isoxazolidines, formed from the [3 + 2] dipolar cycloadditions of nitrones and alkenes, exhibit good biological activities 7 and the possibility of their transformation via ring opening into open-chain derivatives 8 makes them valuable for the synthesis of natural and biologically important compounds such as amino sugars, amino alcohols, alkaloids, b-lactams, and amino acids. 9 Also, pyrazoles have received signicant attention because they are widely used as core motifs for a large number of compounds in various applications such as agrochemicals and medicine, due to their broad range of biological activities. 10 Several computational studies have been carried out to understand the origins of the regio-and stereoselectivities of cycloaddition reactions. 11 The stereochemical course of the 1,3dipolar cycloaddition reaction has been well explained in terms of secondary orbital interactions, steric factors, H-atom bonding and/or dipole-dipole electrostatic interactions.
Atropisomerism 12 is a well-known phenomenon resulting from hindered rotation about single bonds where the energy barrier to rotation is high enough to allow the isolation of the conformers. Atropisomeric compounds have several applications including in the design of bioactive molecules, and construction of molecular switches and motors. 13 To the best of our knowledge, little work has been reported about the effect of single bond restricted rotation on the route of cycloaddition reactions and the formation of atropisomeric cycloadducts. 14 In most of the reported cycloaddition reactions, the used reactants have no restricted rotation near the cycloaddition region of the molecules and the maximum number of cycloadducts was known to be two isomers, namely exo and endo isomers.
In this work, pyrazole-based nitrone 2 underwent 1,3-dipolar cycloaddition with a series of and N-substituted maleimides (3a-o) (as dipolarophiles) with different degrees of rotational restriction around the C-N single bond. The effect of restricted rotation around the C-N single bond on the route of cycloaddition has been studied.

Results and discussion
Nitrone 2 was prepared by reacting 1,3-diphenyl-1H-pyrazole-4carboxaldehyde (1) 15 with N-phenylhydroxylamine 16 (Scheme 1). Nitrone 2 was obtained in Z-form as was conrmed by spectral analysis and single-crystal crystallography. 17 Cycloadditions of 2 to N-substituted maleimides 3a-o (Scheme 2) were performed in toluene under reux and were monitored by TLC. A high-resolution 1 H-NMR spectrum (400 MHz) (ESI †) of the crude reaction products was measured to investigate the formed cycloadducts and estimate their ratio 18 (Table 1). Endo and exo isomers were afforded by maleimides 3a-j at a ratio of 3.5-24 : 1. The majority of endo isomers was interpreted by the presence of a stabilizing secondary orbital interaction in the transition state leading to the endo product.
This interaction is not present in the transition state of the exo product. 19 On the other hand, maleimides 3k-n gave, strikingly, four cycloadducts as a result of the steric hindrance between the ortho substituent of the phenyl group and the carbonyl group of the maleimide moiety ( Fig. 1) that forces phenyl and pyrrolidinedione rings to be tilted away (non-coplanar) to alleviate that steric hindrance. 20 So, when the nitrone attacks the dipolarophile, whether the attack is endo or exo, the nitrone will nd that the two faces are energetically different (divergent) and hence endo and exo atropisomers can be formed. The major endo or exo atropisomer is the product formed by attacking the nitrone through the dipolarophile face anti to the ortho substituent, where the transition state of the attack has lower energy (Fig. 2).
The above mentioned effect of single bond restricted rotation on the route of the cycloaddition was conrmed using 1 H-NMR and COSY spectra (ESI †). 1 H-NMR spectra of endo isomer 4 Scheme 1 Synthesis of nitrone 2.
Scheme 2 Cycloaddition reaction of nitrone 2 with dipolarophiles 3a-o.  formed from cycloaddition using any of dipolarophiles 3a-j showed only three signals in the region 3.8-6.2 ppm, a doublet, a doublet and a singlet corresponding to H3a, H6a and H3, respectively. On the other hand, 1 H-NMR spectra of the crude reaction products showed in that region, in addition to the signals corresponding to endo isomer 4, three other signals: a triplet, doublet and doublet corresponding to H3a, H3 and H6a, respectively. The new signals correspond to the exo isomer 5 as was conrmed by 1 H-NMR spectra of the separated exo isomers (ESI †). The yield and isomer ratio were determined from 1 H-NMR integrations; endo and exo isomers were formed in conversions of 69-95% and 3-20%, respectively ( Table 1). The unexpectedly higher d value of H3 than H6a for endo isomer was ascribed to the presence of H3 in the deshielding zone of the carbonyl group as is shown in the optimized structures of endo and exo isomers (Fig. 3). But H3 in exo isomer is far from this deshielding zone. On the other hand, 1 H-NMR spectra of endo atropisomers formed from the cycloaddition using any of the dipolarophiles 3k-n showed signals in the region 3.8-6.2 ppm corresponding to seven hydrogens. For example, the 1 H-NMR spectrum of endo atropisomers (4k, 4 0 k) formed using dipolarophile 3k (ESI †) showed two doublets at 4.06 ppm (J 7.32 Hz) and 4.09 ppm (J 7.32 Hz) corresponding to H3a of major and minor endo atropisomers (4k, 4 0 k), respectively; two doublets at 5.17 ppm (J 7.32 Hz) and 5.22 ppm (J 7.32 Hz) corresponding to H6a of major and minor endo atropisomers (4k, 4 0 k), respectively; two singlets at 5.71 ppm and 6.06 ppm corresponding to H3 of minor endo and major endo atropisomers (4 0 k, 4k), respectively; and a doublet at 5.68 ppm (J 8.08 Hz) with integration similar to that of any hydrogen of major endo isomer 4k, the origin of this signal being assigned to H6 0 . The lower d value of H6 0 for 4k was ascribed to shielding effect induced by the pyrazole ring as deduced from the optimized structure (Fig. 4).
Furthermore, 1 H-NMR spectra of the crude reaction product from the cycloaddition using any of dipolarophiles 3k-n were measured (ESI †) and showed signals in the region 3.8-6.2 ppm, in addition to the signals corresponding to seven hydrogens of two endo atropisomers (4, 4 0 ), corresponding to 6 hydrogens of two exo atropisomers (5, 5 0 ) as was conrmed from the 1 H-NMR of the separated exo atropisomers. The ratio of endo and exo isomers was determined from the 1 H-NMR integrations (Table 2).
Moreover, the effect of single bond restricted rotation on the route of the cycloaddition reaction was conrmed by using dipolarophile 3o, where the ortho substituent (o-uorine atom) does not cause steric hindrance between the N-maleimide moiety and the carbonyl groups of the pyrrolidine ring. Endo cycloadduct 4o gave only three signals in the region 3.8-6.2 ppm: two doublets and a singlet. At the same time, the 1 H-NMR spectrum of the crude reaction product showed, in the same region, only six signals corresponding to two cycloadducts.
Also, GC/mass chromatography (ESI †) conrmed the above mentioned results. The chromatogram obtained for the crude reaction products of the cycloaddition using dipolarophile 3f is simple (fewer peaks) than the chromatogram obtained for the crude reaction products of the cycloaddition using dipolarophile 3m (more peaks), and this conrms the formation of more products in the case of dipolarophile 3m than dipolarophile 3f conrming the occurrence of atropisomerism in the   formed cycloadducts obtained by cycloaddition using dipolarophiles with ortho substituent (such as 3m).
Ultimately, non-coplanarity in dipolarophiles 3k-n was conrmed by comparing their UV-visible spectra (Fig. 5). Dipolarophiles with ortho substituents have lower l max than the corresponding dipolarophiles having the substituent at meta or para position ( Table 3).
The formation of atropisomers, as a result of restricted rotation around single bonds, was conrmed by density functional theory (DFT) calculations, which were performed using the Gaussian 09 package. The geometrical optimization and (C6-N5-C1 0 -C6 0 ) dihedral angle scans of endo and exo cycloadducts, with methyl substitution at either ortho or para position, were performed using DFT at the B3LYP level. 21 The solvent effect has been considered based on the polarizable continuum model. 22 The solvent used in this calculation was toluene. The 6-311G(d,p) basis sets were employed for all atoms. Fig. 6 reveals the energy barriers for rotation around C-N bond of cycloadducts 4b, 5b, 4k and 5k. The presence of ortho substitution (4k, 5k) increases the energy barrier of rotation regardless of whether the cycloadduct is endo or exo. This conrms that the formation of separable atropisomeric cycloadducts of endo and exo cycloaddition duplicated the formed cycloadducts to be four rather two as in the cases of cycloaddition using dipolarophiles with free single bond rotation.

Conclusions
We have reported the signicant inuence of restricted rotation in dipolarophiles on the route of cycloaddition leading to the formation of atropisomeric cycloadducts. Furthermore, this restricted rotation could induce facial selectivity of the addition where the major cycloadduct(s) was the one formed by cycloaddition at the face with less steric hindrance.

Conflicts of interest
There are no conicts to declare. 1 a 4 and 4 0 are major and minor endo atropisomers, respectively, and 5 and 5 0 are major and minor exo atropisomers, respectively. b The isomer ratio was determined from 1 H-NMR integrations (400 MHz).   6 DFT calculation of the energy barrier for the C-N rotation in endo and exo isomers with either para or ortho methyl substitution.