Cyclization-Carbonylation-Cyclization Coupling Reaction of Propargyl Ureas with Palladium(II)-Bisoxazoline Catalyst

The cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of propargyl ureas catalyzed by PdII(box) complexes afforded symmetrical ketones bearing two 2-amino-2-oxazoline groups in good to moderate yields.

In these transformations, the triple bond of the substrate coordinates to palladium(II) and undergoes nucleophilic attack by the intramolecular nucleophile X, followed by CO insertion to produce the acyl palladium intermediate A (Scheme 2). Coordination of the triple bond of a second molecule induces the second cyclization. Reductive elimination then leads to formation of a ketone bearing two heterocyclic groups. We believe that the box ligand enhances the -electrophilicity of palladium(II) [14][15][16][17][18][19], and thus promotes coordination of the second triple bond to the acyl palladium intermediate A, leading to dimerization. Previously, Bacchi et al. reported that the PdI 2 -KI catalyzed cyclization-alkoxycarbonylation of propargyl urea 1a afforded 2-amino-2-oxazoline derivative 2a in 70% yield along with imidazoline derivative 3a in 23% yield (Scheme 3) [20,21]. To extend our concept of the CCC-coupling reaction, we investigated the Pd II (box) catalyzed carbonylation reaction of propargyl ureas 1 (Scheme 1).

Substrate Scope and Limitations
Having optimized the reaction conditions, we examined the reaction of various propargyl ureas 1b-j with the box complex [Pd(L)(tfa) 2 ] ( Table 2). The reactions proceeded well for substrates 1a-g bearing two methyl groups in the propargylic position (R 1 = Me) ( Table 2, entries 1-5). The bulky cyclohexyl group in the propargylic position (R 1 = -(CH 2 ) 5 -) did not affect the yields of 4f and 4g (Table 2, entries 6 and 7). The alkyl substituent of the terminal nitrogen (R 2 ) was found to be important for promoting the cyclization, lower yields were obtained for 1h (R 2 = Ph) ( Table 2, entry 8). The reaction of unsubstituted 1i (R 2 = H) did not proceed ( Table 2, entry 9). In addition, the gem-dialkyl effect [23] plays a fundamental role for the success of the reaction; the reaction of substrate 1j having no substituent on the propargylic position did not proceed ( Table 2, entry 10).

General
All melting points were measured on a Yanaco MP-3S micro melting point apparatus and are uncorrected. 1 H-, 13 C-NMR and HMBC spectra were recorded on JEOL AL 400 and JEOL Lambda 500 spectrometer spectrometers in CDCl 3 with Me 4 Si as an internal reference. 13 C-NMR spectra were recorded at 100 MHz. In the case of CD 2 Cl 2 , solvent peaks were used as a reference (5.32 ppm for 1 H, and 53.8 ppm for 13 C). High-resolution mass spectra (HR-MS) were obtained with JEOL GC Mate II, JMS-SX102 and JEOL JMS 600H spectrometer. IR spectra were recorded with JASCO FT/IR-300 spectrometer. All reagents were purchased from commercial sources and used without purification. All evaporations were performed under reduced pressure. For column chromatography, silica gel (Kieselgel 60) was employed.

General Procedure for the CCC-Coupling Reaction of 1
A 50-mL two-neck round-bottom flask containing a magnetic stirring bar, substrate 1 (0.5 mmol), p-benzoquinone (1.5 mmol) and MeOH (7 mL) was fitted with a rubber septum and a three-way stopcock connected to a balloon filled with carbon monoxide. The apparatus was purged with carbon monoxide by pump-filling via the three-way stopcock. A MeOH (1 mL) suspension of [Pd(L)(tfa) 2 ] (0.025 mmol) was added to the stirred solution at an appropriate temperature using a syringe. The remaining [Pd(L)(tfa) 2 ] was washed in MeOH (1 mL) twice. After stirring at the appropriate temperature for a period of time, the mixture was diluted with CH 2 Cl 2 (50 mL) and washed with 3% NaOH (40 mL). The aqueous layer was extracted with CH 2 Cl 2 (50 mL) twice and the combined organic layers were dried over MgSO 4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel. The fraction eluted with hexane-AcOEt (30/1-1/1) afforded the monomeric ester 2 and the dimeric ketone 4. 4 was then precipitated from the reaction mixture and the resulting precipitate was collected by filtration and washed with cold MeOH (1 mL × 2). The filtrate was reprocessed via the above procedure to provide additional products after chromatography.

Preparation of L and L′
To a mixture of dimethylmalononitrile (681 mg, 7.23 mmol) and (±)-phenylglycinol (2.00 g, 14.5 mmol) in anhydrous toluene (160 mL) under Ar was added zinc triflate (2.63 g, 7.23 mmol), and the mixture was refluxed for 3 days. The mixture was allowed to cool, and was then diluted with a saturated NaHCO 3 aqueous solution (200 mL) and CHCl 3 (300 mL). After vigorously stirring for 1 h, the layers were separated. The aqueous layer was extracted with CHCl 3 (50 mL) twice. The combined organic layers were dried with MgSO 4 and concentrated in vacuo. The crude products were purified by column chromatography on silica-gel (70 g). The fraction eluted with hexane/ethyl acetate (7/1) (containing 0.5% Et 3 N) afforded L′ (914 mg, 38%) [10] and L (818 mg, 34%) as pale yellow oils.

Conclusions
In conclusion, we have presented a cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of propargyl ureas 1 catalyzed by Pd II (box) complexes. Symmetrical ketones possessing two 2-amino-2-oxazoline groups were obtained in moderate to good yields. We believe that the box ligand enhances the -electrophilicity of palladium(II), and thus promotes coordination of the triple bond (second molecule) to the acyl palladium intermediate A, leading to the dimerization reaction. We are currently investigating additional cascade reactions based on the cyclizationcarbonylation-cyclization strategy for the synthesis of other types of ketones containing two heterocyclic groups.