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Synlett 2011(15): 2259-2261  
DOI: 10.1055/s-0030-1261186
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Solid-Phase Synthesis of 2,3,5,6-Tetrahydro-1H-imidazo[1,2-a]benzo[d]-[1,3]diazepines via Pd(OAc)2/Cu(OAc)2-Cocatalyzed Cyclization

Lili Oua, Zhanying Shaoa, Wenteng Chena, Marc A. Giulianottib, Richard A. Houghtenb, Yongping Yu*a,b
a College of Pharmaceutical Science, Zijin Campus, Zhejiang University, Hangzhou 310058, P. R. of China
Fax: +86(571)88208452; e-Mail: yyu@zju.edu.cn;
b Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
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Publikationsverlauf

Received 17 May 2011
Publikationsdatum:
12. August 2011 (online)

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Abstract

An efficient approach for the solid-phase synthesis of 2,3,5,6-tetrahydro-1H-imidazo[1,2-a]benzo[d][1,3]diazepines has been developed. It was realized by Pd(OAc)2/Cu(OAc)2-cocatalyzed intramolecular aryl guanidinylation.

Key words

solid-phase synthesis - 1,3-benzodiazepines - Pd(OAc)2/Cu(OAc)2 - cyclization - guanidinylation

12

Typical Procedure for the Synthesis of 7
MBHA resin (100 mg, loading: 1.1 mmol/g) was contained in a polypropylene mesh packet. The resin was washed with CH2Cl2 (2 × 5 mL) followed by neutralization with 5% DIEA in CH2Cl2 (3 × 5 mL) and washed with CH2Cl2 (2 × 5 mL). The first Boc-l-amino acid (6 equiv, 0.1 M in DMF) was coupled to MBHA resin using DIC (6 equiv) and HOBt (6 equiv) for 2 h at r.t., then the resin was washed with DMF (3 × 5 mL) and CH2Cl2 (3 × 5 mL). After that, the Boc group was removed with 55% TFA in CH2Cl2 (5 mL) for 30 min at r.t. Then the packet was washed with CH2Cl2 (2 × 5 mL), neutralized with 5% DIEA in CH2Cl2 (3 × 5 mL) and washed with CH2Cl2 (2 × 5 mL). The resin-bound amine was then acylated with a 2-bromo phenyl acetic acid derivative (10 equiv, 0.1 M in DMF) using DIC (10 equiv) and HOBt (10 equiv) as coupling reagents overnight. The resin was washed with DMF (3 × 5 mL), CH2Cl2 (3 × 5 mL), and MeOH (5 mL × 2) and lyophilized. The afforded resin was reduced with BH3-THF (40 equiv) at 65 ˚C for 4 d followed by decantation of the reaction solution and quenching with MeOH. After washing with DMF (5 mL) and MeOH (4 × 5 mL), the resin was treated with piperidine at 65 ˚C overnight to disproportionate the borane complex. Following decantation of the piperidine-borane solution, the resin packet was washed with DMF (4 × 5 mL), CH2Cl2 (4 × 5 mL), and MeOH (2 × 5 mL) and dried. The resulting resin-bound diamine was cyclized with cyanogen bromide (10 equiv, 0.1 M in CH2Cl2) at r.t. overnight. The resin was then washed with CH2Cl2 (3 × 5 mL), IPA (2 × 5 mL),CH2Cl2 (3 × 5 mL) and dried. To each tube was added the resin packet, Pd(OAc)2 (0.2 equiv), Cu(OAc)2 (1 equiv), and Cs2CO3 (5 equiv), followed by anhyd DMF (10 mL). The tube was sealed, and the mixture was heated at 100 ˚C for 48 h. Following washing with DMF (3 × 5 mL), CH2Cl2 (3 × 5 mL), and MeOH (2 × 5 mL), the resin was cleaved with HF at 0 ˚C for 1.5 h. The desired product was extracted with AcOH-H2O (95:5) and lyophilized. The product was characterized by electrospray LC-MS under ESI conditions, ¹H and ¹³C NMR.
Compound 7a: ESI-MS (m/z): 202.0 [M + H+]. ¹H NMR (500 MHz, DMSO-d 6): δ = 8.44 (s, 1 H), 7.23-7.18 (m, 2 H), 7.13-7.12 (m, 1 H), 7.02-7.00 (m, 1 H), 4.07-4.03 (m, 1 H), 3.76-3.72 (m, 1 H), 3.55-3.47 (m, 2 H), 3.17 (dd, J = 9.5, 6.5 Hz, 1 H), 3.07 (ddd, J = 15.0, 8.5, 3.0 Hz, 1 H), 2.99 (ddd, J = 15.0, 6.0, 2.5 Hz, 1 H), 1.25 (d, J = 6.0 Hz, 3 H). ¹³C NMR (125 MHz, DMSO-d 6): δ = 154.8, 137.8, 130.2, 130.1, 127.6, 123.4, 120.3, 58.9, 47.5, 46.3, 32.5, 17.9.