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

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

• 1a Clark RL. Pessolano AA. Shen T.-Y. Jacobus DP. Jones H. Lotti VJ. Flataker LM. J. Med. Chem.  1978,  21:  965 
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• 1d Lesher GY, Brundage RP, Opalka CJ, and Page DF. inventors; FP  2478637.  ; Chem. Abstr. 1982, 96, 85551k
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• 1g Vaughn JR. inventors; US Patent  2637731. 
• 1h Rochling HFW, Buchel K.-H, and Korte FWAGK. inventors; US Patent  3459759. 
• 2 Meanwell NA. Sit SY. Gao J. Wong HS. Gao Q. St. Laurent DR. Balasubramanian N. J. Org. Chem.  1995,  60:  1565 
• 3 Kuethe JT. Wong A. Davies IW. J. Org. Chem.  2004,  69:  7752 
• 4 An aryl bromide example with an ortho-ethylcarbamate, presumably by way of an S_NAr mechanism, has been reported: Blanksma JJ. Verberg G. Recl. Trav. Chim. Pays-Bas  1934,  53:  988 
• 5 Huang X. Anderson KW. Zim D. Jiang L. Klapars A. Buchwald SL. J. Am. Chem. Soc.  2003,  125:  6653 
• 6a Horino H. Ishiyama T. Tatematsu T. Makino C. Ochiai Y. Kito K. Kanaya N. Hishida K. Chem. Abstr.  2001,  135:  166835 
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• 7 Kelly TA. McNeil DW. Tetrahedron Lett.  1994,  35:  9003 
• 10 First reported by van Leeuwen: Kranenberg M. van der Burgt YEM. Kamer PCJ. van Leeuwen PWNM. Organometallics  1995,  14:  3081 
• 12 The addition of Et₃N has been shown to provide rate enhancement in Pd-catalysed aryl iodide aminations when Cs₂CO₃ is employed as base. See: Ali MH. Buchwald SL. J. Org. Chem.  2001,  66:  2560 
• 18 Use of a Josiphos ligand for amination of 2-chloropyridine with primary alkylamines has been recently reported: Shen Q. Shekhar S. Stambuli JP. Hartwig JF. Angew. Chem. Int. Ed.  2005,  44:  1371 

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.