Enantioselective construction of C 2 -symmetric spiro skeleton through intramolecular copper-catalyzed N-arylation

Enantioselective construction of a C 2 -symmetric spirobi(1,2,3,4-tetrahydroquinoline) framework has been achieved through an intramolecular Cu-catalyzed C–N bond coupling of 1,3-propanediamide substrates possessing bromophenyl substituents. The use of N , N ’-dimethyl-1,2-diphenylethylenediamine as the chiral ligand was found to be essential in this asymmetric catalysis. Optically pure compound was shortly obtained by a single recrystallization of the enantioenriched product, which was successfully derivatised to a new chiral diphosphine ligand.


Introduction
Considerable attention has recently been paid to C 2 -symmetric spiro frameworks in organic synthesis owing to their potent asymmetric surroundings.A variety of functional molecules based on the rigid chiral backbone have therefore been developed for the fine chemical production.7][8] Since the seminal work of Tamao in which hydrosilylation catalyzed by a chiral Rh complex gave an optically active 5-silaspiro [4.4]nonane derivative, 9 enantioselective catalysis has been expected to be a straightforward method for the construction of C 2 -symmetric spiro skeletons.Other Rh-catalyzed intramolecular cyclizations via hydroacylation, 10,11 carbenoid insertion, 12 or [2+2+2] cycloaddition, 13 have likewise been applicable to asymmetric spirane synthesis.Spiroketal has been obtained enantioselectively through Ir-catalyzed asymmetric hydrogenation of α,α'-bis(2-hydroxyarylidene) ketones. 14,15Very recently, Gong et al. have established the use of a chiral iodine reagent as an organocatalyst, where oxidative C-H arylation has furnished enantioenriched spirooxindoles. 16We have also accomplished an enantioselective synthesis of spirobi(3,4-dihydro-2-quinolone) by using Pd-catalyzed N-arylation referred to as the Buchwald-Hartwig reaction. 17o further explore a practical synthetic route to the C 2 -symmetric spirane, we focused on the Cu-catalyzed Ullmann-Goldberg reaction recognized as a powerful C-N bond forming process between aryl halides and nitrogen nucleophiles. 18However, little interest has been directed to the development of its asymmetric catalysis because no stereogenic center is normally generated in this transformation.In 2012, Yu, Cai, and co-workers reported asymmetric desymmetrization based on the Cu-catalyzed C-N coupling leading to indoline derivatives with excellent enantiopurities. 19We envisioned that the intramolecular double N-arylation of N,N'-( 2

Results and Discussion
Ditosylamide 1 was able to be prepared without any difficulty from cheap and commercially available chemicals as shown in Scheme 1. Alkylation of malononitrile with 2-bromobenzyl bromide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF afforded 2,2bis(2-bromobenzyl)malononitrile (3) quantitatively. 20The nitrile functionalities of 3 were then reduced with an excess amount of BH 3 •SMe 2 in THF to give 2,2-bis(2-bromobenzyl)propane-1,3-diamine (4).Without purification of 4, the resulting amino groups were tosylated to produce 1 in 85% yield over 2 steps.To check whether the nitrogen-containing C 2 -symmetric spiro skeleton was indeed created, we conducted the Ullmann-Goldberg reaction of 1,3propanediamide 1 in a non-enantioselective manner.After surveying reaction conditions, we were pleased to find the nearly quantitative formation of desired spirobiquinoline 2 by employing a combination of CuI and N,N'-dimethylethylenediamine (DMEDA) as the catalyst system.Thus, treatment of 1 with CuI (5 mol % / Br) and DMEDA (10 mol % / Br) in the presence of K 3 PO 4 (2 equiv / Br) in DMF at 80 °C for 22 h gave racemic 2 in 93% yield.No special care such as high dilution was required for preventing possible intermolecular N-arylation.It is noteworthy that Pd catalysis, the Buchwald-Hartwig reaction, was not effective for the preparation of 2. Scheme 1. Preparation of substrate 1 and racemic product 2.
Various chiral ligands were next screened under slightly modified conditions (10 mol % of CuI and 40 mol % of ligand at 100 °C for 24 h) to achieve the enantioselective Ullmann-Goldberg reaction.Representative results are summarized in Table 1.Firstly, chiral diamine ligands L1-L4 analogous to DMEDA were applied to the Cu-catalyzed N-arylation of 1.The reaction using L1 and L2 led to a quantitative yield of 2, whose optical purity was determined to be 31% ee and 17% ee, respectively (entries 1 and 2).The chiral backbone was presumably important for the catalyst activity as well as the enantioselectivity.Spirane product 2 was obtained in 45% yield with 29% ee in the reaction with L3, whereas the chemical yield and the selectivity were decreased to 10% and 13% ee with L4 (entries 3 and 4).N,N'-Dimethyldiamine L5 derived from L-tartaric acid gave only a trace amount of 2 (entry 5).The nitrogen substituent of ligands also exerted an influence on the catalytic process.The reaction in the presence of primary amine ligand L6 afforded 2 in 95% yield with 20% ee (entry 6).Introduction of an ethyl group at the nitrogen atom (L7), however, significantly retarded the reaction (entry 7).When chiral amino alcohol L8 was employed as the ligand, the enantiopurity of 2 was as low as 8% ee (entry 8).The intramolecular N-arylation of 1 hardly proceeded with (-)-sparteine L9 bearing tertiary amine units (entry 9).1,1'-Binaphthalene-2,2'-diol L10, an effective ligand scaffold in the Cu-catalyzed asymmetric indoline synthesis, 19 did not exhibit any positive impacts in this 6membered ring formation (entry 10).From the screening study, L1 turned out to be a valuable chiral ligand for the enantioselective construction of C 2 -symmetric spirane 2. Unfortunately, no improvements on the enantioselectivity were observed even when other reaction parameters such as the base, solvent, and protecting group on the nitrogen atom were changed.Although the selectivity of this asymmetric Ullmann-Goldberg reaction was unsatisfactory, optically pure 2 was readily obtained by recrystallization of the enantioenriched product from CHCl 3 and MeOH due to the high crystallization ability of the racemate.X-ray crystallographic analysis of 2 unambiguously demonstrated its spiro structure and absolute configuration, the latter of which was definitely determined to be M based on the Flack parameter (Figure 1). a All reactions were performed in the presence of 10 mol % / Br of CuI, 40 mol % / Br of chiral ligand, and 2 equiv / Br of K 3 PO 4 at 100 °C for 24 h in DMF (0.1 M) under a nitrogen atmosphere.b NMR yields using 1,3,5-trimethoxybenzene as an internal standard.c Determined by HPLC equipped with a Chiralpak IA column.d The number in parentheses is the enantiopurity of the product after recrystallization.e The major enantiomer was opposite to that obtained in entry 1.With enantiopure 2 in hand, we carried out the development of a new chiral ligand based on the spirobiquinoline.The tosyl groups of (M)-2 were initially removed according to the reported procedure 21 to give spirobiquinoline (M)-5 22 (Scheme 2).Diphosphine (M)-6 was successfully synthesized by the treatment of secondary amine 5 with n-BuLi followed by the addition of Ph 2 PCl.A sharp singlet appeared at δ 49.7 in the 31 P NMR spectrum of (M)-6 and a peak at m/z 619.2423 in the HRMS spectrum indicated the smooth incorporation of two diphenylphosphino groups into the spiro framework.This aminophosphine was obtained as air-stable white solids, which was gradually oxidized in solution upon exposure to air.

Conclusions
We have developed an efficient protocol for the construction of a C 2 -symmetric spiro framework, where the Cu-catalyzed enantioselective N-arylation of 1,3-propanediamide 1 is involved as the key step.The desired optically pure product 2 was obtained from readily accessible chemicals without tedious chromatographic purification and optical resolution.Derivatizaton of spirobiquinoline 2 successfully led to new chiral diphosphine ligand 6, which proved to coordinate to Pd in a chelating fashion.Further study on the synthetic utility of the C 2symmetric spiranes is now in progress.

Experimental Section
General.All reactions were carried out with standard Schlenk techniques under a nitrogen atmosphere. 1 H and 13 C NMR spectra were recorded on JEOL JNM-ECS400 (400 MHz for 1 H and 100 MHz for 13 C).All signals in the 1 H NMR spectra were expressed as δ down field from Me 4 Si used as internal standard.Chemical shifts of the 13 C NMR signals are reported in δ referenced to CDCl 3 (δ 77.0). 31P NMR spectra were recorded on JEOL JNM-ECS600 (243 MHz) and the data are given relative to external 85% H 3 PO 4 .Optical rotations were measured with JASCO P-1030 polarimeter.HPLC analyses performed on JASCO HPLC system (JASCO PU 2080 pump and MD-2010 UV/Vis detector).Mass spectra were recorded on JEOL JMS-T100LC (ESI-HRMS or APCI-HRMS).Melting points were measured with Yanaco micro melting point apparatus model MP-S9 and were uncorrected.Anhydrous THF and toluene were purchased from Kanto Chemicals and further purified by passage through activated alumina using a GlassContour solvent purification system. 25Column chromatography was performed on Kishida Silica Gel 60 (63-200 µm).Merck silica gel 60 F 254 plates were used for TLC. 20To a solution of malononitrile (2.64 g, 40.0 mmol) and 2-bromobenzyl bromide (22.1 g, 88.4 mmol) in DMF (20 mL) was added DBU (13.4 g, 88.0 mmol) dropwise at 0 °C.The reaction mixture was allowed to stir at 80 °C for 3 h.After being cooled to room temperature, water was added to the reaction mixture, which was extracted with EtOAc.The organic phase was washed with water, 1 M aq.HCl and brine, and then dried over Na 2 SO 4 .The volatiles were removed by evaporation under reduced pressure.The resulting solid was triturated with a mixture of EtOH and hexane to give the titled compound (16.2 g, quant).

N,N'-(2,2-Bis(2-bromobenzyl)propane-1,3-diyl)bis(4-methylbenzenesulfonamide) (1).
To a flask containing 3 (808 mg, 2.00 mmol) was added a 2 M solution of BH 3 •SMe 2 in THF (6 mL, 12.0 mmol).The reaction mixture was refluxed for 18 h.To this solution was carefully added 6 M aq.HCl (3 mL) at 0 °C, which was again refluxed for 2 h.After being cooled to room temperature, the mixture was basified with 6 M aq.NaOH.The crude product was extracted with CH 2 Cl 2 and dried over Na 2 SO 4 .Evaporation of the volatiles under reduced pressure afforded diamine 4. Crude 4 was redissolved in CH 2 Cl 2 (10 mL), to which Et 3 N (607 mg, 6.00 mmol) and subsequently TsCl (915 mg, 4.80 mmol) were added at 0 °C.The reaction mixture was stirred at room temperature for 12 h.The reaction was then quenched by the addition of 1 M aq.HCl and extracted with CH 2 Cl 2 .The organic layer was washed with sat.aq.NaHCO 3 , dried over Na 2 SO 4 , and evaporated to dryness.The resulting solid was recrystallized from CHCl 3 /hexane to give the titled compound (1.22 g, 85% over 2 steps).White solid, mp 177 °C.A mixture of 1 (36.0 mg, 0.05 mmol), CuI (1.91 mg, 0.01 mmol), (1R,2R)-N,N'-dimethyl-1,2diphenyl-1,2-ethylenediamine L1 (9.61 mg, 0.04 mmol) and K 3 PO 4 (42.5 mg, 0.20 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 30 min, then at 100 o C for 24 h.The reaction mixture was quenched with 1 M aq.HCl, extracted with EtOAc, washed with water, dried over Na 2 SO 4 , and concentrated in vacuo.The residue was filtered through a short pad of silica gel, which was rinsed with CHCl 3 .The filtrate was evaporated to dryness to give 2 (27.7 mg, 99%).The enantiomeric excess was determined by HPLC analysis using a chiral stationary phase column (Daicel Chiralpak IA, hexane:CHCl 3 2:1, Flow rate 0.5 mL/min: t R (minor) 19.6 min, t R (major) 28.6 min) to be 31% ee.Optically pure 2 was obtained by a single recrystallization from CHCl  ). 21To a mixture of (M)-2 (55.9 mg, 0.100 mmol) and Mg powder (24.3 mg, 1.00 mmol) in THF (0.5 mL) were added Ti(O-i-Pr) 4 (56.8 mg, 0.200 mmol) and Me 3 SiCl (32.8 mg, 0.302 mmol).The reaction mixture was allowed to stir at 50 °C for 24 h.After being cooled to room temperature, to the mixture were added sat.aq.NaHCO 3 , THF, and anhydrous NaF sequentially, which was stirred for 30 min.The mixture was filtered through a pad of Celite and the filtrate was concentrated under  (0.91 mg, 2.5 µmol) was added degassed THF (0.2 mL) under a nitrogen atmosphere and the mixture was stirred for 1 h at room temperature.Then, a solution of 1,3-diphenylpropenyl acetate (9) (25.2 mg, 0.10 mmol) and KOAc (0.20 mg, 2.0 µmol) in THF was added into a catalyst solution.After addition of dimethyl malonate (10) (39.63 mg, 0.30 mmol) and BSA (63.03 mg, 0.30 mmol), the reaction mixture was stirred at room temperature for 24 h.The reaction mixture was filtered through a short pad of silica gel using EtOAc as an eluent and the resulting filtrate was concentrated.The product yield was determined by NMR analysis (1,3,5-trimethoxybenzene was used as an internal standard) to be 84% yield.The enantiomeric excess was determined by HPLC analysis using a chiral stationary phase column (Daicel Chiralcel OD-H, hexane:i-PrOH 99:1, Flow rate 0.2 mL/min: t R (major) 62.7 min, t R (minor) 67.4 min) to be 27% ee.

Figure 1 .
Figure 1.X-ray structure of C 2 -symmetric spiro compound 2 with thermal ellipsoids at the 50% probability level.All hydrogen atoms are omitted for clarity.One of the two independent molecules is shown.