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Synlett 2006(16): 2609-2612  
DOI: 10.1055/s-2006-951482
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Polymer-Assisted Solution-Phase Strategy for the Synthesis of Fused [2,1-b]Quinazolinones and the Preparation of Optically Active Vasicinone

Ahmed Kamal*, V. Devaiah, N. Shankaraiah, K. Laxma Reddy
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax: +91(40)27193189; e-Mail: ahmedkamal@iict.res.in;
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Publication History

Received 21 June 2006
Publication Date:
22 September 2006 (online)

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Abstract

An efficient preparation of fused [2,1-b]quinazolinones has been developed utilizing polymer-supported reagents. (±)-Vasicinone was converted into its dione by oxidation with poly (4-vinylpyridiniumdichromate). An efficient method has been developed for the synthesis of (d)- and (l)-vasicinone via asymmetric reduction of pyrrolo[2,1-b]quinazoline-3,9-dione by employing NaBH4/Me3SiCl as the reducing agent and polymer-supported chiral sulfonamide as catalyst.

Key words

polymer-supported reagents - fused [2,1-b]quinazolinones - oxidations - vasicinone

9

Typical Procedure: Preparation of Compound 3a. N-Cyclohexylcarbodiimide N-methyl polystyrene A (1.32 mmol, 1.30 mmol/g) was added to a dry reaction vessel. Compound 1a (163 mg, 1.0 mmol) in CH2Cl2 (10 mL) was added to the dry resin and the resulting mixture was stirred at r.t. for 5 min before the corresponding lactam 2 (56 mg, 0.66 mmol) in CH2Cl2 (2 mL) was added and the stirring continued at r.t. for 10 h. The resin was removed by filtration and washed with CH2Cl2. Evaporation of the filtrate provided 3a in 97% yield. Mp 81-83 °C; IR (KBr): 2150, 1750, 1680 cm-1; 1H NMR (200 MHz, CDCl3): δ = 2.19 (q, J = 6.8 Hz, 2 H), 2.62 (t, J = 7.5 Hz, 2 H), 4.0 (t, J = 7.5 Hz, 2 H), 7.2 (m, 3 H), 7.5 (t, J = 7.5 Hz, 1 H); MS (EI): m/z = 230 [M+].

10

Typical Procedure: Preparation of Compound 6a. Triphenylphosphine-impregnated polystyrene B (3.2 mmol, 3 mmol/g) was suspended in anhydrous CH2Cl2 (10 mL) and the 2-azidobenzoyl lactam 3a (150 mg, 0.65 mmol) was added and the suspension was stirred for 5 h at r.t. The resin was removed by filtration and washed with CH2Cl2 and evaporation of the filtrate afforded 6a in 98% yield. Mp 104-106 °C; IR (KBr): 1675 cm-1; 1H NMR (200 MHz, CDCl3): δ = 2.32 (q, J = 7.5 and 8.0 Hz, 2 H), 3.22 (t, J = 8.0 Hz, 2 H), 4.19 (t, J = 7.5 Hz, 2 H), 7.5 (t, J = 7.4 Hz, 1 H), 7.6-7.8 (m, 2 H), 8.31 (d, J = 8.0 Hz, 1 H); MS (EI): m/z = 186 [M+].

11

Typical Procedure: Preparation of Compound 9a. To a stirred solution of compound 6a (115 mg, 0.61 mmol) in dry THF was added the Br3 - form of Amberlyst A-26 C (515 mg, 0.65 mmol, 1.26 mmol/g). The mixture was allowed to stir at r.t. for 18-20 h. After completion of the reaction as indicated by TLC the reaction was filtered and the resin washed with CH2Cl2 and EtOH. The filtrate was concentrated under reduced pressure to afford 9a in >99% yield. Mp 141-142 °C; IR (KBr): 1684, 776 cm-1; 1H NMR (200 MHz, CDCl3): δ = 2.50-2.90 (m, 2 H), 4.10-4.30 (m, 1 H), 4.30-4.50 (m, 1 H), 5.20 (dd, J = 4.6, 1.8 Hz, 1 H), 7.40-7.60 (m, 2 H), 7.60-7.80 (m, 1 H), 8.30 (d, J = 8.0 Hz, 1 H); MS (EI): m/z = 264 [M+].

12

Typical Procedure: Preparation of Compound 10a. To a stirred solution of 3-bromo-3-deoxyvasicinone 9 (134 mg, 0.50 mmol) in MeOH (5 mL) was added Amberlyst A-26 in the AcO- form D (275 mg, 1.00 mmol, 3.65 mmol/g). The mixture was stirred at r. t. for 1 h then a MeOH (5 mL) solution of Pd(OAc)2 (56 mg, 0.25 mmol) and boron hydride exchange resin E (500 mg, 1.5 mmol) was added to the reaction flask under a nitrogen atmosphere and the mixture was held at reflux for 1 h. After completion of the reaction as indicated by TLC the reaction was filtered the resin was washed with CH2Cl2 and EtOH. The filtrate was concen-trated under reduced pressure to afford 10a in 95% yield. Mp 203-204 °C; 1H NMR (200 MHz, CDCl3): δ = 2.30-2.50 (m, 1 H), 2.60-2.80 (m, 1 H), 4.00-4.20 (m, 1 H), 4.30-4.50 (m, 1 H), 5.10-5.30 (m, 2 H), 7.50-7.60 (m, 1 H), 7.70-7.80 (m, 2 H), 8.40 (d, J = 8.1 Hz, 1 H). MS (EI): m/z = 202 [M+].

13

Typical Procedure: Preparation of Compound 11. To a stirred solution of compound 10a (75 mg, 0.036 mmol) in DMF (5 mL) was added poly(vinylpyridinium dichromate) F (190 mg, 0.14 mmol). The reaction mixture was stirred at 70 °C until the completion of the reaction. The resin was removed by filtration and washed with CH2Cl2. Evaporation of the filtrate provided 11a in 92% yield. Mp 165-170 °C; IR (KBr): 1744, 1656, 1600 cm-1; 1H NMR (200 MHz, CDC13): δ = 3.05 (t, J = 6.7 Hz, 2 H), 4.41 (t, J = 6.7 Hz, 2 H) 7.63 (ddd, J = 7.8, 7.6, 1.5 Hz, l H), 7.85 (d, J = 7.8, 1.5 Hz, 1 H), 7.98 (ddd, J = 8.3, 7.6, 1.5 Hz, 1 H), 8.37 (dd, J = 8.3, 1.5 Hz, lH); MS (EI): m/z = 200 [M+].

14

Typical Procedures: Preparations of (d)-Vasicinone (10R)a and (l)-Vasicinone (10S)a. A solution of Me3SiCl (132 mg, 1.2 mmol) was added to a suspension of NaBH4 (45 mg, 1.2 mmol) in THF (10 mL) and the resulting suspension held at reflux for 1 h. The polymer-supported chiral sulfonamide G (50 mg, 0.12 mmol) was added and the suspension was treated with a solution of compound 11a (100 mg, 0.5 mmol) in THF (10 mL) at rate of 3 mL h-1. After completion of the reaction, the mixture was treated with water and filtered. The resulting aqueous solution was extracted with CH2Cl2. The organic phase was dried (Na2SO4) and evaporated to afford the (10R)a in 93% yield and 94% ee (as determined by chiral HPLC [15] ). Mp 202-203 °C; [α]D 22 +102 (c 1, CHCl3), Lit. [16a] [α]D 22 +148 (c 1.35, EtOH); IR (KBr): 3140, 1668 cm-1; 1H NMR (200 MHz, CDCl3): δ = 2.21-2.42 (m, 1 H), 2.63-2.79 (m, 1 H), 3.92-4.11 (m, 1 H), 4.30-4.49 (m, 1 H), 4.82 (s, 1 H), 5.19 (t, J = 7.35 Hz, 1 H), 7.43-7.62 (m, 1 H), 7.68-7.77 (m, 2 H), 8.33 (d, J = 7.35 Hz, 1 H); MS (EI): m/z = 202 [M+]. Alternatively, polymer-supported chiral sulfonamide H (98 mg, 0.25 mmol) suspension was treated with compound 11a (200 mg, 1.0 mmol) to give (10 S )a in 95% yield and 94% ee (as determined by chiral HPLC [15] ). Mp 200-202 °C; [α]D 22 -85 (c 0.5, CHCl3), Lit. [16b] [α]D 22 -90 (c 0.5, CHCl3); IR (KBr): 3135, 1648 cm-1; 1H NMR (200 MHz, CDCl3): δ = 2.21-2.39 (m 1 H), 2.62-2.83 (m, 1 H), 4.0-4.1 (m, 1 H), 4.32-4.53 (m, 1 H), 4.75 (s, 1 H), 5.19 (t, J = 7.15 Hz, 1 H), 7.39-7.58, (m, 1 H), 7.71-7.82 (m, 2 H), 8.29 (d, J = 7.15 Hz, 1 H); MS (EI): m/z = 202 [M+].

15

Conditions: Chiracel OD column employing hexane-2-propanol (85:15) as the mobile phase at 0.7 mL/min flow rate and monitored at 254 nm wavelength.