Synthesis and crystal structures of new chiral 3-amino-2H-azirines and the Pd complex of one of them

Three new 3-amino-2H-azirine derivatives have been synthesized as racemates or mixtures of diastereoisomers. Comparison of their crystal structures with those of the 11 other 3-amino-2H-azirines in the literature reveal that the formal N—C single bond in the azirine ring is consistently long at around 1.57 Å.


Synthesis and crystallization
The 3-amino-2H-azirines 10-12 were prepared according to previously described syntheses. In the case of 10, sequential treatment of 1 g (3.19 mmol) of a diastereomeric mixture of the corresponding 2-methylbutyric acid amide, 13, bearing the chiral residue derived from (À )-trans-myrtanol, in dry THF (15 ml) with lithium diisopropylamide (LDA), diphenylphosphoryl chloride (DPPCl) and NaN 3 in DMF (Scheme 4; Villalgordo, 1992;cf. Villalgordo & Heimgartner, 1993) led to the desired product. Chromatographic work-up on SiO 2 (hexane-AcOEt, 9:1 v/v) gave 712 mg (72%) of 10 as a mixture of diastereoisomers as a slightly yellow oil. To a wellstirred suspension of 156 mg (0.654 mmol) PdCl 2 in dry acetonitrile (MeCN, 1.5 ml) at 273 K was added a solution of 200 mg (0.654 mmol) of azirine 10 in MeCN (0.5 ml). After stirring for 10 h, the solvent was partially evaporated and the residue was filtered through a short column of SiO 2 (hexaneethyl acetate, 9:1 v/v). Evaporation of the solvents gave 475 mg (92%) of the Pd complex, 14, as a red-orange solid. Recrystallization from MeCN by slow evaporation of the solvent yielded orange crystals of suitable quality for crystal structure analysis. The crystal structure of 14 revealed that one of each of the diastereoisomers of 10 were coordinated to the Pd centre to give a molecule with the absolute stereochemistry shown in Scheme 4.
Starting with the known (S)-pyrrolidine derivative 15 (Enders et al., 1988), the azirine 17 was prepared following procedures described earlier (Scheme 5; Bucher, 1996;cf. Bucher & Heimgartner, 1996). Whereas the precursor 16 was obtained in good yield (84%) as a mixture of diastereoisomers, the standard transformation to the aminoazirine led to a ca 2:1 mixture of the diastereomeric azirines 17 in only 10% yield. The electrolytical removal of the phenylsulfonyl group (-2.1 V, EtOH, Me 4 NCl, 278 K;cf. Bucher & Heimgartner, 1996) gave only a few crystals of the desired azirine 11, which were recrystallized from MeOH/Et 2 O, yielding crystals suitable for crystal structure determination.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 1. For each structure, the methyl H atoms were constrained to an ideal geometry (C-H = 0.98 Å ), with U iso (H) = 1.5U eq (C), but were allowed to rotate freely about the C-C bonds. All other H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms with C-H distances of 0.95 (aromatic), 0.99 (methylene) or 1.00 Å (methine) and with U iso (H) = 1.2U eq (C).
The molecule in the crystal structure of compound 11 is disordered in two regions. Atom C7 of the five-membered ring occupies two positions which represent alternate envelope conformations of the ring; the site-occupation factor of the major conformer refined to 0.619 (18). In addition, the azirine ring and its C2-ethyl and methyl substituents required three sets of positions to adequately model the arrangement. These positions indicate that the 2R and 2S diastereoisomers have crystallized at the same crystallographic site in the crystal and that the 2S diastereoisomer is further disordered over two conformations. The site occupation of the 2R configuration at atom C2 refined to 0.432 (3) (Flack & Bernardinelli, 1999 Absolute structure parameter À 1 (3) À 1.8 (10) À 0.02 (2) 0.305 (3) and 0.263 (3) for the conformations containing atoms with A and B suffixes, respectively, in their labels (Fig. 1). Target bond-length restraints were applied to the disordered atoms. In addition, similarity restraints were applied to the chemically equivalent bond lengths and angles involving all disordered atoms, while neighbouring atoms within and between each arrangement of the disordered groups were restrained to have similar atomic displacement parameters.
In the structure of 14, the chiral residue derived from (À )-trans-myrtanol in each ligand is conformationally disordered. Two sets of positions were defined for the atoms of each disordered residue and the site-occupation factors of the major conformations of these groups refined to 0.621 (11) and 0.675 (9) for the ligands containing atoms N1 and N21, respectively. Similarity restraints were applied to the chemically equivalent bond lengths involving all disordered C atoms, while neighbouring atoms within and between each conformation of the disordered groups were restrained to have similar atomic displacement parameters.

Results and discussion
The syntheses described in the Introduction include nonstereospecific reactions during the azirine ring formation to give 3-amino-2H-azirines. Therefore, the products are expected to be either racemic mixtures or, when another residue in the molecule contains one or more invariant stereogenic centres, mixtures of diastereoisomers. The three crystal structures described here are of crystals obtained from the products 11 ( Fig. 1), 12 (Fig. 2) and the PdCl 2 complex with 10 (14; Fig. 3). The chosen crystal in each case had crystallized in a chiral space group, which is a necessity for 11 and 14, because these molecules contain invariant chiral exocyclic amine residues derived from the known (S)-pyrrolidine derivative, 15, and (À )-trans-myrtanol {i.e. [(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]-heptan-2-yl]methanol}, respectively. The absolute structure chosen when refining the models for 11 and 14 was thus aligned to match the chirality of the known chiral residues. In the case of 14, the strong anomalous scattering power imparted by the Pd and Cl atoms allowed the absolute configuration of all stereogenic centres to be confirmed confidently from the diffraction experiment by refinement of the absolute structure parameter (Flack & Bernardinelli, 1999, which converged to a value of À 0.02 (2). The absolute structure of 11 could not be determined independently from the diffraction experiment on account of the weak anomalous scattering power of the compound with the available Mo K� X-ray radiation (the work was carried out in the early 1990s when it was not common to use Cu K� radiation routinely).
In contrast, compound 12 only contains a single stereogenic centre, which is at atom C2 of the azirine ring, so a racemic mixture could conceivably have crystallized in an achiral space group. Given that the synthesis of compound 12 most likely produced a racemic mixture of the product and not a single enantiomer, the fact that compound 12 crystallized in a chiral space group indicates that either a single enantiomer has crystallized in a spontaneous resolution process, or the crystal is an inversion twin and therefore a racemic mixture or another ratio (solid solution) of enantiomers. For the same reasons as given above for compound 11, the absolute structure of 12 could not be determined. Therefore, the presence of  Views and atom-labelling schemes of the individual disordered components in the molecular structure of 11, showing (a) the disorder component composed of the 2R diastereoisomer, and (b) the major and (c) the minor disordered conformations in the component composed of the 2S diastereoisomer. Displacement ellipsoids are drawn at the 50% probability level. H atoms have been omitted for clarity. An overlay of all three disorder components is presented in the supporting information (Fig. S1).

Table 2
Selected geometric parameters (Å , � ) around the Pd atom of 14. a specific enantiomer or even an inversion twin could not be established and the configuration of the molecule defined in the refinement model and depicted in Fig. 2 was chosen arbitrarily.
The unique molecule in the crystal structure of compound 11 is disordered in two regions (Fig. 1). The five-membered pyrrolidine ring has two distorted envelope conformations, while the azirine ring and its C2-ethyl and methyl substituents are disordered over three arrangements. The disorder model indicates that the 2R and 2S diastereoisomers are present in the crystal and are distributed randomly at the same crystallographic site. There is a slight excess of the 2S diastereoisomer, which is disordered additionally over two conformations (see Section 2.3 for more details).
The crystal structure of compound 14 reveals one symmetry-unique trans-PdCl 2 L 1 L 2 complex molecule, where L 1 and L 2 are diastereoisomers of product 10, which coordinate to the metal via their azirine ring N atom (Fig. 3). The diastereoisomers are the 2S and 2R species which result from interchange of the positions of the ethyl and methyl substituents at atom C2 of the azirine ring, while the configuration of the chiral residue derived from (À )-trans-myrtanol remains constant. It is perhaps remarkable that the Pd complex contains one of each of the pair of diastereoisomers, as conceivably the complex could consist of two of the same View of the molecule of 12, showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented by circles of arbitrary size.

Figure 3
Views of the (a) major and (b) minor disorder components of the molecule of 14, showing the atom-labelling schemes. Displacement ellipsoids are drawn at the 50% probability level. H atoms have been omitted for clarity. An overlay of the two disorder components is presented in the supporting information (Fig. S2). Table 3 Azirine ring geometry (Å , � ) in 3-amino-2H-azirines. diastereoisomer or a nonstoichiometric ratio of the two diastereoisomers, which would manifest itself in the same sort of disorder of the ethyl and methyl substitution site that was observed for 11, as described above. In the structure of 14, the chiral residue derived from (À )-trans-myrtanol in each ligand is conformationally disordered (Fig. 3), but this has no consequence for the unique absolute configuration of the residue. The coordination geometry around the Pd atom is square planar, as usual, and the coordination geometry is listed in Table 2.
Reports of crystal structures of 3-amino-2H-azirines are quite rare. The Cambridge Structural Database (CSD; Version 5.43 with November 2022 updates; Groom et al., 2016) lists only 11 structures, of which seven have been reported by the Heimgartner group (Villalgordo & Heimgartner, 1992;Bucher & Heimgartner, 1996;Brun et al., 2001) and the remaining four were reported by Galloy et al. (1974Galloy et al. ( , 1980, Piskunova et al. (1993) and Peters et al. (2000). The geometry of the azirine ring (Table 3) generally shows little variation across all of these structures. Possibly the most remarkable feature is the very long N-C single bond, which is, with one exception, always around 1.57 Å [mean 1.572 (5) Å for 10 structures], compared with N-C distances closer to 1.47 Å usually found for simple imines. This contrasts with the shorter formal C-C single bond with a mean length of 1.437 (7) Å . The short formal C-N single bond to the exocyclic N atom, with a mean value of 1.333 (12) Å , is likely a consequence of electron-pair delocalization between the exocyclic N atom and the ring N C bond; Galloy et al. (1974) described this as the consequence of a contribution from a polar mesomeric form. The biggest ring geometry outlier amongst the 11 structures mentioned above is in the structure of 3-dimethylamino-2-dimethylcarbamoyl-2-phenoxy-2H-azirine (3-phenoxy-3-dimethylcarbamoyldimethylamino-2-azirine) (Galloy et al., 1974), in which, in particular, the ring N-C single bond of 1.49 Å is significantly shorter than in the other structures. This might result from the inductive electron-withdrawal properties of the O atom in the phenoxy substituent at the azirine ring sp 3 -hybridized C atom, whereas all other structures have C atoms as the first atom of each substituent. The three new crystal structures reported here are no exception, notwithstanding the potential low accuracy for the disordered azirine ring in 11 because of the restraints applied while modelling the disorder; see Section 2.3. The coordination of the azirine rings via their N atom to the Pd atom in complex 14 also appears to influence very slightly the geometry of the azirine ring to give marginally shorter N-C and longer C-C single bonds, respectively (Table 3). This is perhaps unsurprising given the change in the electronic properties as a result of the coordination.

Conclusion
The 3-amino-2H-azirines 10-12 were synthesized with the aim of separating the stereoisomers after their direct crystallization or crystallization of their PdCl 2 complexes, as exemplified by complex 14, which incorporates compound 10 as ligands. Unfortunately, this objective was not achieved, as the crystal structures of 11 and 14 revealed the presence of a diastereoisomeric mixture of the azirines in the crystals, and the crystal structure of 12 was inconclusive as to whether the chosen crystal was enantiomerically pure or also a racemic mixture that had crystallized as an inversion twin. Nonetheless, the study has added to the small number of recorded crystal structures of aminoazirines with their unusually long formal ring N-C single bonds. TEXSAN PROCESS (Molecular Structure Corporation, 1989); program(s) used to solve structure: SHELXT2018 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2019 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009). Software used to prepare material for publication: publCIF (Westrip, 2010) for (11); publCIF (Westrip, 2010) and PLATON (Spek, 2020) for (12), (14). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.29 e Å −3 Δρ min = −0.27 e Å −3 Absolute structure: Absolute structure set to match the known S-configuration at atom C9 of the pyrrolidine residue Absolute structure parameter: −1 (3)

Special details
Experimental. Data collection and full structure determination done by Prof. Anthony Linden: anthony.linden@chem.uzh.ch Solvent used: MeOH / diethyl ether Crystal mount: on a glass fibre Client: C.b Bucher Sample code: CB P7 (HG9418) Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. The structure is disordered in two regions of the molecule. Atom C7 of the 5-membered ring occupies two positions which represent alternate envelope conformations of the ring; the site occupation factor of the major conformer refined to 0.619 (18). In addition, the azirine ring and its C2-ethyl and methyl substituents required three sets of positions to adequately model the arrangement. These positions indicate that the (2R)-and (2S)-diastereoisomers have crystallized at the same crystallographic site in the crystal and that the (2S)-diastereoisomer is further disordered over two conformations. The site occupation of the (2R)-configuration at atom C2 refined to 0.432 (3), while the site occupation factors for the two conformations of the (2S)-diastereoisomer refined to 0.305 (3) for atoms C4A and C5A, and 0.263 (3) for atoms C4B and C5B. Target bond length restraints were applied to the disordered atoms. In addition, similarity restraints were applied to the chemically equivalent bond lengths and angles involving all disordered atoms, while neighbouring atoms within and between each arrangement of the disordered groups were restrained to have similar atomic displacement parameters.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ.

phenylamino)-2H-azirine][(2S)-2-ethyl-2-methyl-3-(N-{[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2yl]methyl}-N-phenylamino)-2H-azirine]palladium(II) (14)
Crystal data [PdCl 2 (C 21 (Flack & Bernardinelli, 1999 Absolute structure parameter: −0.02 (2) Special details Experimental. Solvent used: MeCN Crystal mount: on a glass fibre Client: Jose Vollalgordo Sample code: HG9208 Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Both of the fused-ring substituents are disordered. Two sets of positions were defined for the atoms of each disordered group and the site occupation factors of the major conformations of these groups refined to 0.621 (11) and 0.675 (9). Similarity restraints were applied to the chemically equivalent bond lengths involving all disordered C-atoms, while neighbouring atoms within and between each conformation of the disordered groups were restrained to have similar atomic displacement parameters.