Synthesis and Reduction of 10-Phthalimidocamphor Oxime

10-Phthalimidocamphor oxime was prepared from easily available 10-iodocamphor in two steps. Reduction of the oxime functionality resulted in the formation of two novel polycyclic isoindolinone heterocycles, the attempted preparation of the primary amine failed. The structures of novel heterocycles were unambiguously confirmed by single crystal X-ray diffraction as well as NMR techniques.

Instead of the desired diamine 5, isoindolinone heterocycles 6 and 7 were isolated. Isoindolinone/isoindole derivatives can be found in numerous natural and pharmaceutical compounds shoving multiple biological activities ( Figure 1). 25
Thus, the results of the reduction of oxime 4 are summarized in Scheme 2 and Table 1. Catalytic hydrogena-tion of 4 using Pd-C in MeOH with or without HCl yielded only the recovered starting material (Entries 1 and 2). On the other hand, reduction of 4 with Na in n-PrOH, as expected, gave a complex mixture of products (Entry 3). Catalytic hydrogenation using Raney-Ni gave the polycyclic secondary amine 6 in 37% isolated yield (Entry 4). Clearly, the reduction of oxime 4 was successful, though the reaction did not stop at the desired diamine level 5. Therefore, the reduction with Raney-Ni was repeated in the presence of AcOH (Entry 5) and aqueous formaldehyde (Entry 6) in order to obtain either the amine 5 or a tertiary dimethylamine derivative. The former reaction again delivered compound 6 in 20% yield, while the later  The formation of the products 6 and 7 could be rationalized by the initial formation of the primary amine 5, followed by the condensation with the proximal carbonyl group of the phthalimide functionality to give intermediate 8. Isomerization of 8 to imine 7 is explained by a simple imine-imine tautomerisation, while reduction (or isomerization/reduction) of 8 would lead to amine 6 (Scheme 3). The configuration of the newly formed stereogenic centers seems to be dictated by the reducing agent applied.

1. Crystal Structures of Compounds 6 and 7
The asymmetric units of compounds 6 and 7 are depicted in Figures 2 and 3, respectively. In both structures there is one molecule in the asymmetric unit. Bond lengths are given in Table 2. Most of bond lengths are very similar both in 6 and 7, with the exception of bonds including atoms N2 and C9. This is in accordance with their structural chemical formulas (as shown in Scheme 2) which differ only in the closeness of these two atoms. Bond N2-C9 in 6, 1.463(3) Å, is significantly longer than 1.265(2) Å in 7, which is in accordance with the fact that this is a single bond in 6 and a double bond in 7. The average C(sp 3  Compound 6 was tested as a potential covalent organocatalyst in the addition of 1-methylindole to cinnamaldehyde. 26 Amine 6 failed to catalyze the reaction (Scheme 4).
Molecules of 6 and 7 are asymmetric. In both structures, chiral carbon centres are C8, C10, and C14; in 6 C9 atom is also chiral. C10 and C14 from camphor part of the molecule have in both compounds absolute configuration (S) and (R), respectively. The absolute configuration of C8 atom from phthalimde ring is (R) in 6 and (S) in 7, respec-tively. Consequently, the conformation of molecules of 6 and 7 is different in a way how a camphor part is bonded to the remaining part of molecule which is shown in Figure  4. In accordance with their optical activity, both compounds crystalize in chiral space group. Com pound 6 crystalizes in orthorhombic crystal system in P2 1 2 1 2 1 and 7 in tetragonal P4 3 2 1 2, respectively. The pa c king of molecules is presented in Figures 5 and 6. In 6 molecules are connected via N2-H … O1 hydrogen bonds into chains parallel to b axis. Geometrical parameters of this H-bond are given in Table 3. The distance between the donor, N2, and acceptor, O1, is not short, which means that H-bond is weak. In 7 there are no N-H or O-H groups and consequently no classical intermolecular H-bonds. N and O atoms are acceptors of weak intermolecular H-bonds, donated by C-H moieties and presented in Table 3. In 6 and 7   there are no π … π or π … σ stacking interaction between aromatic rings.

Conclusion
The title 10-phthalimidocamphor oxime (4) was prepared as a precursor for the preparation of mono protected camphor derived 1,3-diamine building block 5. Reduction thereof under various reaction conditions could never be stopped at the diamine 5 level, instead polycyclic isoindolinone heterocycles 6 and 7 were iso lated. The structures of 6 and 7 were confirmed by X-ray analysis of the corresponding monocrystals.

Experimental Section
Solvents for extractions and chromatography were of technical grade and were distilled prior to use. Extracts were dried over technical grade Na 2 SO 4 . Melting points were determined on a Kofler micro hot stage and on SRS OptiMelt MPA100 -Automated Melting Point System (Stanford Research Systems, Sunnyvale, California, United States). The NMR spectra were obtained on a Bruker Ul-traShield 500 plus (Bruker, Billerica, Massachusetts, United States) at 500 MHz for 1 H and 126 MHz for 13 C nucleus, using DMSO-d 6 and CDCl 3 with TMS as the internal standard, as solvents. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, California, United States), IR spectra on a Perkin-Elmer Spectrum BX FTIR spec trophotometer (PerkinElmer, Waltham, Massachusetts, United States). Catalytic hydrogenation was performed on a Parr Pressure Reaction Hydrogenation Apparatus (Moline, IL, USA).    Column chromatography (CC) was performed on silica gel (Silica gel 60, particle size: 0.035-0.070 mm (Sigma-Aldrich, St. Louis, Missouri, United States)).
To a solution of 4 (113 mg, 0.362 mmol) in MeOH (10 mL) at room temperature HCl (aq. 12 M, 1 mL) was added. Next, at room temperature under vigorous stirring, Zn dust (100 mg, 1.53 mmol) was added. After the disappearance of the starting material (TLC analysis), the reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was suspended in H 2 O (10 mL), finely powdered NaOH was added till the pH ~ 10-12 followed by extraction with Et 2 O (3 × 30 mL). The combined organic phase was washed with H 2 O (10 mL) and NaCl (aq. sat., 10 mL), dried over anhydrous Na 2 SO 4 , filtered, and volatile components evaporated in vacuo.

1. Single Crystal X-ray Structure Analysis of Compounds 6 and 7
Single crystal X-ray diffraction data of compounds 6 and 7 have been collected on an Agilent SuperNova dual source diffractometer with an Atlas detector with CuKα radiation (1.54184 Å) at room temperature. The diffraction data were processed using CrysAlis PRO software. 30 Structure of both compounds was solved by direct methods, using SIR97. 31 A full-matrix least-squares refinement on F 2 was employed with anisotropic displacement parameters for all non-hydrogen atoms. H atoms were placed at calculated positions and treated as riding. For H atoms from methyl groups, torsion angles were calculated from electron density. Only H atom bonded to N2, was located from difference Fourier map and refined with isotropic displacement parameter. The absolute structure of both compounds was confirmed also by the refinement of Flack parameter. SHELXL97 software 32 was used for structure refinement and interpretation. Drawings of the structures were produced using ORTEP-3 28 and Mercury 29 . Structural and other crystallographic details on data collection and refinement have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 1539864-1539865, for 6 and 7, respectively. These data can be obtained free of charge via www.ccdc. cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: 44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).