Chiral phosphoric acid-catalyzed enantioselective construction of structurally diverse benzothiazolopyrimidines

Chiral phosphoric acid catalyzed the formal [4+2]-cycloaddition of 2-benzothiazolimines with enecarbamates to provide benzothiazolopyrimidines with up to 99% yield and >99% ee.

VI. Post-transformation : Synthesis of compound 5 and 10 S103 VII. Computational models of cis and trans diastereoisomers of cycloadduct 4g S109 VIII. X-Ray data of compounds 4k and 10 S113 S2

II. General Procedures General procedure A: Synthesis of enecarbamates 3 from acyl chlorides
A solution of the corresponding acyl chloride (1.0 equiv) in toluene (4 M) was added dropwise to a solution of NaN3 (1.5 equiv) and tetrabutylammonium iodide (TBAI, 0.05 equiv) in H2O (3 M) at 0 °C. After stirring the reaction for 15 h at 0 °C, the organic layer was separated and washed with 10% aqueous solution of Na2CO3 and water. The organic solution was dried over MgSO4 before use in the following step. Then, the toluene solution of acyl azide was added dropwise to a stirred mixture of hydroquinone (0.05 equiv), pyridine (0.05 equiv), and the corresponding alcohol (1.2 equiv) at 95 °C. The mixture was then stirred at 100 °C until the gas evolution stops. The resulting solution was evaporated under reduced pressure and the crude product was purified by flash chromatography on silica gel employing mixtures of heptane and ethyl acetate as eluents to afford the desired product 3.

General procedure B: Synthesis of enecarbamates 3 from carboxylic acids
To a solution of the corresponding carboxylic acid (1 equiv) in toluene (0.15 M), was added Et3N (4.0 equiv) and diphenylphosphoryl azide (DPPA, 4.0 equiv). The mixture was stirred at room temperature overnight. Then the reaction was diluted in CH2Cl2 and washed with brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude acyl azide was purified by column chromatography on silica gel (Heptane/EtOAc). Then, the solution of the acyl azide in toluene (1 M) was added dropwise to a stirred mixture of hydroquinone (0.05 equiv), pyridine (0.05 equiv), and corresponding alcohol (1.2 equiv) at 95 °C. The resulting solution was evaporated under reduced pressure and the crude product was purified by flash chromatography on silica gel employing mixtures of heptane and ethyl acetate as eluents to afford the desired product 3.

General procedure C: Synthesis of 2-benzothiazolimines 2
To solution of 2-benzothiazolamine (1 equiv) and para-toluenesulphonic acid (20 mol%) in benzene (0.1 M), was added the appropriate arylaldehyde (1.2 equiv). The mixture was stirred under reflux for a minimum of 24 h while water was removed in a Dean-Stark trap. After completion (monitored by TLC), the solvent was removed under reduced pressure and the crude product was directly purified by flash chromatography on silica gel employing mixtures of heptane and ethyl acetate as eluents to afford the desired product 2. Imines 2a, 2g, 2h and 2l were already described in the literature. 3

General procedure D: Enantioselective synthesis of homobenzotetramizoles 4
To a solution of imine 2 (1 equiv) and catalyst 1c (10 mol%) in dry 1.2-DCE (0.1 M), was added the enecarbamate 3 (3 equiv) in one portion. The reaction mixture was stirred for 24 h at 50 °C. After completion (monitored by TLC), the solvent was removed under reduced pressure and the crude product was directly purified by flash chromatography on silica gel employing mixtures of heptane and ethyl acetate as eluents to afford the desired product 4.

General procedure E: Racemic synthesis of homobenzotetramizoles 4
To a solution of imine 2 (1 equiv) and racemic phosphoric acid catalyst (20 mol%) in dry 1.2-DCE (0.1 M), was added the enecarbamate 3 (3 equiv) in one portion. The reaction mixture was stirred for 24 h at 50 °C. After completion (monitored by TLC), the solvent was removed under reduced pressure and the crude product was directly purified by flash chromatography on silica gel employing mixtures of heptane and ethyl acetate as eluents to afford the racemic compound 4.

General procedure F: Enantioselective synthesis of homobenzotetramizoles 4
To a solution of imine 2 (1 equiv) and catalyst 1c (10 mol%) in dry 1.2-DCE (0.1 M), was added the enecarbamate 3 (3 equiv) in one portion. The reaction mixture was stirred for 24 h at 50 °C. After completion (monitored by TLC), the solvent was removed under reduced pressure and the crude product S4 was directly purified by flash chromatography on silica gel employing mixtures of heptane and ethyl acetate as eluents to afford the desired product 4.

General procedure G: Racemic synthesis of homobenzotetramizoles 4
To a solution of imine 2 (1 equiv) and racemic phosphoric acid catalyst (20 mol%) in dry 1.2-DCE (0.1 M), was added the enecarbamate 3 (3 equiv) in one portion. The reaction mixture was stirred for 24 h at 50 °C. After completion (monitored by TLC), the solvent was removed under reduced pressure and the crude product was directly purified by flash chromatography on silica gel employing mixtures of heptane and ethyl acetate as eluents to afford the racemic compound 4.

General procedure H: Enantioselective synthesis of homobenzotetramizoles 4w and 5
To a solution of imine 2k (1 equiv) and catalyst 1c (10 mol%) in dry 1.2-DCE (0.1 M), was added the enecarbamate 3e (3 equiv) in one portion. The reaction mixture was stirred for 24 h at 50 °C. After completion (monitored by TLC), the solvent was removed under reduced pressure and the crude product was directly purified by flash chromatography on silica gel employing mixtures of heptane and ethyl acetate as eluents to afford the desired products 4w and 5.

General procedure I: Racemic synthesis of homobenzotetramizoles 4w and 5
To a solution of imine 2k (1 equiv) and racemic phosphoric acid catalyst (20 mol%) in dry 1.2-DCE (0.1 M), was added the enecarbamate 3e (3 equiv) in one portion. The reaction mixture was stirred for 24 h at 50 °C. After completion (monitored by TLC), the solvent was removed under reduced pressure and the crude product was directly purified by flash chromatography on silica gel employing mixtures of heptane and ethyl acetate as eluents to afford the racemic compounds 4w and 5.

Aspect
Colorless oil

VII. Computational models of cis and trans diastereoisomers of cycloadduct 4g
Computational method: Low energy conformations of cis and trans-4g were firstly identified using MMFF94 4 force field as implemented in the Tinker v8.4.4 5 software package. Geometries were then further optimised at the B3LYP/6-31G(d) 6 level using the Gaussian 09 revD.01 7 software package and characterized by vibrational analysis within the harmonic approximation at the same level of theory.