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Synlett 2006(13): 2083-2086  
DOI: 10.1055/s-2006-947355
LETTER
© Georg Thieme Verlag Stuttgart · New York

Two-Step Synthesis of 3-Aryl-1,3-Dihydro-2H-imidazo[4,5-b]pyridin-2-ones

Jeremy P. Scott*
Department of Process Research, Merck Sharp & Dohme, Hertford Road, Hoddesdon, EN11 9BU, UK
Fax: +44(1992)452581; e-Mail: jeremy_scott@merck.com;
Further Information

Publication History

Received 5 May 2006
Publication Date:
12 July 2006 (online)

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Abstract

One-pot tandem palladium-catalysed amination and ­intramolecular amidation of tert-butyl (2-chloropyridin-3-yl)carb­amate with substituted primary anilines allows for the preparation of 3-arylated-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones (49-90% yield) in two steps from commercially available materials.

Key words

palladium - amination - tandem reaction - ring closure

    References and Notes

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8

Preparation of tert -Butyl (2-Chloropyridin-3-yl)carbamate ( 4).
To a stirred solution of NaHMDS (1 M in THF, 700 mL, 700 mmol) at -10 °C under N2 was added a solution of 2-chloro-3-aminopyridine (40.9 g, 318 mmol) in THF (80 mL) over 10 min. The mixture was aged 10 min and then Boc2O (72.9 g, 334 mmol) as a solution in THF (56 mL) was added over 10 min maintaining the internal temperature <8 °C. After aging 0.5 h, 2 M HCl (600 mL) and isopropyl acetate (400 mL) were added. The organic layer was washed with H2O (200 mL) and concentrated in vacuo. The residue was crystallised from i-PrOH (250 mL) and H2O (300 mL) to afford 58.9 g (81%) of 4 as an off-white solid. 1H NMR (400 MHz, CDCl3): δ = 8.49 (1 H, d, J = 8.0 Hz), 8.02 (1 H, d, J = 4.4 Hz), 7.21 (1 H, dd, J = 8.4, 4.8 Hz), 7.01 (1 H, br s), 1.53 (9 H, s). 13C NMR (100 MHz, CDCl3): δ = 152.1, 142.5, 139.1, 132.6, 127.0, 123.2, 81.8, 28.2. Mp 84-85 °C. MS (ES): m/z = 229 [M + H]+.

9

BINAP and dppf were found to be inferior for the formation of 2a than XantPhos.

11

XantPhos = 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene.

13

The THF used in our study had a water content between 60 mg/mL and 110 mg/mL as determined by Karl-Fischer titration.

14

Representative Procedure for the Preparation of 3-Phenyl-1,3-dihydro-2 H -imidazo[4,5- b ]pyridin-2-one ( 2a).
A mixture of XantPhos (61 mg, 0.11 mmol, 6 mol%), Pd2(dba)3 (48 mg, 0.05 mmol, 3 mol%, 6 mol% Pd), tert-butyl (2-chloropyridin-3-yl)carbamate (4, 0.40 g, 1.75 mmol), aniline (0.24 g, 2.63 mmol, 150 mol%) and t-BuONa (0.24 g, 2.45 mmol, 140 mol%) in THF (6.0 mL, 15 mL/g) was degassed with N2 and then heated at reflux for 18 h. After cooling to ambient, the reaction mixture was diluted with CH2Cl2 and filtered through a silica plug. Evaporation in vacuo and flash chromatography (EtOAc-heptane) afforded 2a as a white solid (0.30 g, 82%). 1H NMR (400 MHz, DMSO-d 6): δ = 11.40 (1 H, s), 7.94 (1 H, d, J = 4.8 Hz), 7.72-7.63 (2 H, m), 7.57-7.49 (2 H, m), 7.43-7.36 (2 H, m), 7.11-7.05 (1 H, m). 13C NMR (100 MHz, DMSO-d 6): δ = 153.1, 144.3, 140.2, 134.0, 129.2, 127.6, 126.6, 123.3, 118.5, 115.8. Mp 240-241 °C; Lit. [1a] 240-241 °C. MS (ES): m/z = 212 [M + H]+.

15

The approach used in Scheme [2] for the construction of 3-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one has not been previously reported and given the diversity of commercially available isocyanates, may constitute another general entry to compounds in this class.

16

All new compounds gave satisfactory spectroscopic characterisation data.

17

Alkylamines screened were cyclopropylamine, sec-butyl-amine, (R)-1-phenylethylamine and 1-(2-aminoethyl)-piperidine. In all instances <20A% of desired imidazo-pyridin-2-one was identified by LCMS using either THF or toluene-i-PrOH (4:1) as reaction solvent.

19

No examples of the preparation of 3-alkyl-substituted 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones are documented in ref. 3 which employs Pd2(dba)3/BINAP as catalyst system for amination.