Asymmetric Cascade Aza-Henry/Lactamization Reaction in the Highly Enantioselective Organocatalytic Synthesis of 3-(Nitromethyl)isoindolin-1-ones from α-Amido Sulfones

The asymmetric synthesis of novel 3-substituted isoindolinones is herein reported. A new cascade reaction was developed that consisted of the asymmetric nitro-Mannich reaction of suitable α-amido sulfones designed from 2-formyl benzoates, followed by the in situ cyclization of the adducts. Very high enantioselectivities, up to 98% ee, and very good yields were obtained in the presence of the readily available neutral bifunctional organocatalyst derived from trans-1,2-diaminocyclohexane, which is known as Takemoto’s catalyst. The investigation of the reactivity of the obtained products allowed either the selective Boc-deprotection or reduction of the nitro group, leading to further functionalized 3-substituted isoindolinones without affecting the enantiomeric purity.

(0.25 mm) and visualized by fluorescence quenching at 254 nm. Flash chromatography was carried out using silica gel 60 (70-230 mesh, Merck, Darmstadt, Germany). Yields are given for isolated products showing one spot on a TLC plate and no impurities were detectable in the NMR spectrum. The NMR spectra were recorded on Bruker DRX 600, 400, and 300 MHz spectrometers (600 MHz, 1 H, 150 MHz, 13 C; 400 MHz, 1 H, 100 MHz; 13 C, 300 MHz, 1 H, 75 MHz, 13 C). Internal reference was set to the residual solvent signals (δ H 7.26 ppm, δ C 77 ppm for CDCl 3 and δ H 2.50 ppm, δ C 39 ppm for DMSO-d 6 ). The 13 C NMR spectra were recorded under broadband proton-decoupling. Spectra are reported only for unknown compounds. The following abbreviations are used to indicate the multiplicity in NMR spectra: s-singlet, d-doublet, t-triplet, q-quartet, dd-doublet of doublets, m-multiplet, brs-broad signal. Coupling constants (J) are quoted in Hertz. High resolution mass spectra (HRMS) were acquired using a Bruker SolariX XR Fourier transform ion cyclotron resonance mass spectrometer (Bruker Daltonik GmbH, Bremen, Germany) equipped with a 7T refrigerated actively-shielded superconducting magnet. For ionization of the samples electrospray ionization (ESI) or MALDI was applied.

Experimental procedures
Procedures for the synthesis of 6-iodophthalide

Synthesis of 6-iodophthalide:
In an ice bath a solution of NaNO 2 (610 mg, 1.2 eq., 6.5 mmol) in H 2 O (1.2 mL) was added dropwise to a suspension of 6-aminophthalide (800 mg, 1.0 eq., 5.4 mmol) in 37% HCl (3.5 mL) and the resulting mixture was stirred for 25 min at 0°C. Then, a solution of KI (4.5 g, 5.0 eq., 27.0 mmol) in H 2 O (4.6 mL) was added dropwise. The mixture was stirred at room temperature for 18 h. Then, the aqueous suspension was extracted with Ethyl acetate and the combined organic layers were washed with saturated aq. Na 2 S 2 O 3 and brine (14.0 mL), dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with CHCl 3 to obtain the product as white solid. (Yield= 900 mg, 65% To a solution of 3-methoxybenzoic acid (1.520 g, 1.0 eq., 10.0 mmol) in glacial acetic acid (5 mL), 37% HCl (7.5 mL) and 30% formaldehyde (3 mL, 4.0 eq., 40.0 mmol) were added, and the reaction mixture was stirred at 100°C for 1 h in an oil bath. After cooling, a saturated solution of NaHCO 3 was added until pH=7. The resulting mixture was extracted with CH 2 Cl 2 twice, the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Hexane/Ethyl acetate, 7:1) to afford 6-methoxyphthalide as a gum. (Yield= 700 mg, 43% A mixture of phthalide (1.0 eq., 2.5 mmol), N-bromosuccinimide (NBS, 1.1 eq., 2.75 mmol) and azobisisobutyronitrile (AIBN, 0.04 eq., 0.10 mmol) in 1,2-dichloroethane (15.0 mL) was refluxed for 1-6 h in an oil bath. The reaction mixture was kept in an ice bath for 2 h and then filtered. The solvent was removed under reduced pressure and the crude was suspended in water (7.0 mL) and the resulting mixture was refluxed for 1 h. The reaction mixture was cooled to room temperature and extracted with Ethyl acetate three times. The combined organic phases were dried and concentrated under reduced pressure to give 3hydroxyphthalide derivatives, which are known compounds. 3,5,6 5-bromo 3-hydroxy phthalide. 5  Procedure for the synthesis of 5-fluoro-3-hydroxyphthalide

Benzyl 2-formylbenzoate. (a) 7
Following the general procedure using 6.7 mmol of the respective of 3-hydroxyphthalide, the title compound was obtained as a colorless oil in 87% yield (1.4 g). Following the general procedure using 5.0 mmol of the respective of 3-hydroxyphthalide, the title compound was obtained as a colorless oil in 95% yield (780 mg). Following the general procedure using 2.2 mmol of the respective of 3-hydroxyphthalide, the title compound was obtained as a colorless oil in 80% yield (454 mg). Following the general procedure using 3.0 mmol of the respective of 3-hydroxyphthalide, the title compound was obtained as a colorless oil in 94% yield (772 mg).  Following the general procedure using 2.0 mmol of the respective of 3-hydroxyphthalide, the title compound was obtained as a colorless oil in 87% yield (555 mg). Following the general procedure using 3.0 mmol of the respective of 3-hydroxyphthalide, the title compound was obtained as a colorless oil in 35% yield (283 mg).

Crystallographic data
Crystals of compound 3e suitable for single crystal X-ray diffraction analysis were obtained dissolving 14 mg of the compound in a mixture of chloroform (0.3 mL) and hexane (0.1 mL) at room temperature. After the complete dissolution, the saturated solution was cooled down to -18°C. Crystals were obtained after few days. For the measurement, a colourless prismatic crystal of 0.34 mm x 0.21 mm x 0.07 mm was selected and mounted on a cryoloop with paratone oil.
Data collection was performed at room temperature with a Bruker D8 QUEST diffractometer equipped with a PHOTON II detector using CuKα radiation (λ= 1.54178 Å).
Data indexing, integration and reduction were performed using CrysAlisPro ver. 1.171.41.122a. 9 Empirical absorption correction was performed with CrysAlisPro ver. 1.171.41.122a using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. The structure was solved using SHELXS-97 10 and refined through full matrix least-squares based on F 10 using the program SHELXL. 11 Non-hydrogen atoms were refined anisotropically, hydrogen atoms were positioned geometrically and included in structure factors calculations but not refined.
The chirality on carbon atom C2 (R) was successfully assigned by anomalous-dispersion effects in diffraction measurements on the crystal (Flack parameter -0.025 (14)).
ORTEP diagrams ( Figure S1) was drawn using OLEX2. 12 In Table S1 are reported the crystallographic data.