Additive-Free Pd-Catalyzed α-Allylation of Imine-Containing Heterocycles

An additive-free Pd-catalyzed α-allylation of different imino-group-ontaining heterocycles is reported. The activation of α-CH pronucleophiles (pKa (DMSO) > 25) occurs without the addition of strong bases or Lewis acids using only the Pd/Xantphos catalyst system. The reaction scope has been studied for various 5- and 6-membered nitrogen-containing heterocycles (yields up to 96%). Mechanistic investigations suggest an initial allylation of the imine-N followed by a Pd-catalyzed formal aza-Claisen rearrangement.

High Resolution Mass Spectrometry (HRMS) was performed on an Agilent Technologies 7890A (G3440A) GC system equipped with an Agilent Technologies J&W GC-column DB-5MS (length: 30 m; inner-diameter: 0.250 mm; film: 0.25 μm) at a constant helium flow. The GC was coupled to a Waters GCT Premier Micromass. For Direct Inlet (DI-EI) the Waters GCT Premier Micromass unit was used.
Melting points were measured on a Mel-Temp ® melting point apparatus (Electrothermal) with an integrated microscopical support in open capillary tubes and were not corrected. The temperature was measured with a mercury-in-glass thermometer.

Substrate Synthesis
General procedure for the synthesis of thiazolines: The synthesis of thiazolines was performed according to the work of C. Fuganti et al. [a] In a 80 mL Schlenk tube 1.01 g (44 mmol, 1.0 eqiv) sodium were carefully added to ice cooled abs. EtOH (20 mL). After complete dissolution of the sodium 5.00 g (44 mmol, 1.0 eqiv) cystamine hydrochloride were added portionwise at 0 °C to the NaOEt solution. Then the nitrile substrate and 2.00 g (26 mmol, 0.6 eqiv) NH 4 OAc were added slowly and heated under reflux for 17 h. The reaction mixture was concentrated under reduced pressure, diluted with 40 mL Et 2 O and washed with brine (1×20 mL) and water (1×20 mL). The organic phase was dried over Na 2 SO 4 and concentrated under reduced pressure to give the desired thiazolines. Further Purification was not necessary.

1-Benzyl-2-methyl-1H-benzo[d]imidazole
The synthesis of this compound was performed according to the work of Yamamoto. [d] To a solution of 1.19 g (9.00 mmol, 1.0 eqiv) 2-methyl-1H-benzo [d]imidazole in 15 mL methanol in a 50 mL round bottom flask were added 2.76 mL (23.98 mmol, 2.7 eqiv) benzyl chloride at rt. The reaction was heated under reflux for 24 h. After cooling to rt the reaction mixture was diluted with 70 mL chloroform and washed with sat. NaHCO 3 (1×100 mL). The organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude product (3.2 g) was taken up onto 3 g silica gel and purified via column chromatography (SiO 2 , ethyl acetate).

General procedure for the synthesis of dihydroisoquinolines:
In a 250 mL one neck round bottom flask 3.00 g (24.7 mmol, 1.00 eqiv.) phenylethylamine and 5.22 mL (37.1 mmol, 1.50 eqiv.) triethylamine were dissolved in 70 mL abs. dichloromethane. The reaction mixture was cooled in an ice bath to 0 °C and a solution of 24.7 mmol (1.00 eqiv.) of the corresponding acyl chloride in 40 mL dichloromethane were added dropwise via a dropping funnel within 30 min and stirred for 19 h at rt. The reaction mixture was washed with 1 M HCl (1x100 mL) and saturated NaHCO 3 solution (1x100 mL). The organic layer was dried over Na 2 SO 4 , filtered, washed with dichloromethane (1x20 mL), and the solvent was removed under reduced pressure to give a white solid in quantitative yield, which was used in the following step without further purification. 1.2 g (7.3 mmol, 1.00 eqiv.) of the crude product were weighed into a 100 mL one neck round bottom flask and an excess (5 g) polyphosphoric acid (PPA) was added. The suspension was heated to 180 °C under vigorous stirring. After stirring for 16 h the black suspension was cooled to rt and 25 mL water were added slowly. A pH of 10 was adjusted with 10 M NaOH. Subseqivuently, the reaction mixture was extracted with EtOAc (3x25 mL). The combined organic layers were washed with brine (1x100 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuum. The black residue was distilled under reduced pressure to give the desired product.

2-Phenyl-4,5-dihydrothiazole (42)
The synthesis of 2-phenyl-4,5-dihydrothiazole was performed according to the work of Trose. [e] 4.41g (38.79 mmol, 2.0 eqiv) cysteamine hydrochloride and 155 mg (3.88 mmol, 0.2 eqiv) NaOH were weighed into a 50 mL round bottom flask. 2.00 mL (19.39 mmol, 1.0 eqiv) benzonitrile were added and the reaction mixture was heated to 80 °C for 2 h. The reaction mixture was then cooled to rt, taken up in 40 mL ethyl acetate and washed with H 2 O (1×150 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic phase was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give product, which was used without further purification.