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Synlett 2014; 25(16): 2323-2326
DOI: 10.1055/s-0034-1378558
letter
© Georg Thieme Verlag Stuttgart · New York

Atom-Economical Construction of a Rare 6,7-Dihydropyrido[3′,2′:4,5]imidazo[1,2-d][1,4]benzodiazepine Scaffold

Prashant Mujumdar
a   Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
,
Mikhail Korsakov
b   The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000, Russian Federation
,
Mikhail Dorogov
b   The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl, 150000, Russian Federation
,
Mikhail Krasavin*
a   Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia
c   Department of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt, Peterhof 198504, Russian Federation   Fax: +7(812)4286939   Email: m.krasavin@hotmail.com
› Author Affiliations
Further Information

Publication History

Received: 25 May 2014

Accepted after revision: 29 June 2014

Publication Date:
26 August 2014 (online)

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Abstract

We have developed a route towards novel 6,7-dihydropyrido[3′,2′:4,5]imidazo[1,2-d][1,4]benzodiazepines, in five straightforward steps from commercially available 2-bromobenzaldehydes and 3-(2-aminoethyl)imidazo[4,5-b]pyridines we have described previously, with full control over the three elements of diversity. The route appears to be suitable for systematic exploration of structure–activity relationships around this medicinally relevant tetracyclic scaffold.

Key words

scaffold-oriented synthesis - Buchwald arylation - Bechamp reduction
 

  • References and Notes

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  • 15 General Procedure for the Intramolecular Buchwald Arylation (0.1–0.4 mmol Scale) A thick-glassed, screw-capped pressure tube (50 mL) was charged with a suspension of the requisite 2-aminoethyl-substituted imidazo[4,5-b]pyridine intermediate 17 (1.0 equiv) and Cs2CO3 (1.1 equiv) in toluene (3 mL/mmol), along with a stir bar. Meanwhile, Pd(OAc)2 (0.05 equiv) and BINAP (0.1 equiv) were weighed into a vial, suspended in toluene (2–3 mL), and shaken while immersed in a 100 °C oil bath for 2 min. The resulting clear, purple, or light-brown catalyst solution was added in one portion to the vigorously stirred reaction mixture. The tube was filled with argon, capped and stirred at 100 °C for 16 h (48 h for 3). The mixture was allowed to cool to ambient temperature, filtered through a plug of Celite, and the latter was additionally washed with EtOAc. The filtrate was concentrated under reduced pressure, and the crude material was purified by column chromatography on silica gel using a 0–5% gradient of MeOH in CH2Cl2 to furnish target compounds 3 and 18a–m.
  • 16 Crystallographic data (excluding structure factors) for compound 3 have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 1004050. Copies of the data can be obtained free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].
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  • 18 General Procedure for the Reductive Alkylation of 16 (0.5 mmol Scale) Equimolar amounts of 16 and the requisite aldehyde were combined in CH2Cl2 (5 mL). Anhydrous MgSO4 (500 mg) was added, and the mixture was stirred at r.t. overnight. The MgSO4 was filtered off, washed with CH2Cl2 (50 mL), and the combined filtrate and washings were concentrated in vacuo. The residue was dissolved in MeOH (5 mL), treated with NaBH4 (0.3 mmol), and the mixture stirred at r.t. for 1 h, at which point the reaction was complete according to TLC analysis. The mixture was partitioned between EtOAc (50 mL) and sat. aq NaHCO3 (25 mL), the organic layer separated, dried over anhydrous MgSO4, filtered, and concentrated. The crude product was analyzed by 1H NMR spectroscopy and used in the next step without further purification.
  • 19 Characterization Data for Selected Compounds Compound 18d: white solid; mp 131–133 °C. 1H NMR (500 MHz, CDCl3): δ = 8.71 (dd, J = 7.9, 1.45 Hz, 1 H), 8.34 (dd, J = 4.75, 1.25 Hz, 1 H), 8.11 (dd, J = 7.95, 1.25 Hz, 1 H), 7.34–7.37 (m, 1 H), 7.26 (dd, J = 7.95, 4.75 Hz, 1 H), 7.21 (d, J = 8.55 Hz, 2 H), 7.06 (t, J = 7.85 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 4.58 (s, 2 H), 4.43–4.45 (m, 2 H), 3.80 (s, 3 H), 3.64–3.66 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 159.3, 153.3, 149.8, 148.7, 143.4, 134.2, 132.1, 131.9, 129.3, 129.0, 126.4, 120.7, 119.1, 118.0, 117.9, 114.4, 56.9, 55.5, 51.7, 45.5. LC–MS (ESI): m/z = 357.40 [M + H]+. Anal. Calcd for C22H20N4O: C, 74.14; H, 5.66; N, 15.72. Found: C, 73.98; H, 5.57; N, 15.84. Compound 18g: white solid; mp 170–172 °C. 1H NMR (500 MHz, CDCl3): δ = 8.67 (dd, J = 8.05, 1.5 Hz, 1 H), 8.34 (dd, J = 4.8, 1.25 Hz, 1 H), 8.11 (dd, J = 7.75, 1.4 Hz, 1 H), 7.26–7.36 (m, 4 H), 7.21 (d, J = 8.3 Hz, 2 H), 7.07 (t, J = 7.9 Hz, 1 H), 6.98 (d, J = 8.3 Hz, 1 H), 4.60 (s, 2 H), 4.47–4.49 (m, 2 H), 3.65–3.67 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 153.2, 149.2, 148.6, 143.6, 136.1, 134.3, 133.5, 132.1, 132.0, 129.2, 129.0, 126.6, 121.1, 119.2, 118.5, 118.1, 57.1, 52.5, 45.0. LC–MS (ESI): m/z = 361.31 [M + H]+. Anal. Calcd for C21H17ClN4: C, 69.90; H, 4.75; N, 15.53. Found: C, 70.02; H, 4.67; N, 15.64. Compound 18k: beige solid, mp 134–136 °C. 1H NMR (500 MHz, CDCl3): δ = 7.83–7.99 (m, 2 H), 7.77 (dd, J = 8.2, 1.7 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 1 H), 7.46 (d, J = 1.7 Hz, 1 H), 4.33–4.38 (m, 2 H), 3.85–3.33 (m, 2 H), 3.33–3.47 (m, 2 H), 2.83 (s, 3 H), 1.38–1.53 (m, 9 H), 1.12–1.28 (m, 3 H). 13C NMR (125 MHz, CDCl3): δ = 154.8, 149.6, 147.7, 143.1, 132.3, 130.1, 128.6, 128.5, 126.3, 119.2, 118.7, 114.3, 60.1, 53.4, 40.5, 40.4, 30.1, 27.1, 26.5, 22.8. LC–MS (ESI): m/z = 381.92 [M + H]+. Anal. Calcd for C22H25ClN4: C, 69.16; H, 6.86; N, 14.64. Found: C, 69.07; H, 6.79; N, 14.72.
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