Nitrogen → HCID 59560534, compound

HRID 1176184Notes

Reaction equation

HRID 1176184 reaction equation
Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@@:9]3([CH2:15][N:14]4[CH2:16][CH2:17][CH:11]3[CH2:12][CH2:13]4)[O:8][C:5]2=[N:6][CH:7]=1.[CH:18]([C:20]1[S:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].N#N>COCCOC.O.CCO.Cl[Pd](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:23]3[S:24][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)[CH:3]=[C:4]2[CH2:10][C@:9]21[CH2:15][N:14]1[CH2:16][CH2:17][CH:11]2[CH2:12][CH2:13]1

Participants

7

Reactant 4

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 27734305-Formyl-2-thiopheneboronic acidHCID 54506690(2R)-5'-bromo-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridine]

Product 1

HCID 59560534HCID 59560534, compoundYield 99.3%

Reagents, catalysts & solvents 2

HCID 178479802HCID 178479802, compoundCatalystHCID 86587095Dimethoxyethane ethanol waterSolvent

Conditions

Temperature
70 °C

Procedure

To a stirred solution of (2R)-5′-bromo-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine] (Scheme 1, 3.2 g, 10.8 mmol) and (5-formyl-2-thienyl)boronic acid (3.37 g, 21.6 mmol) in 150 mL DME/H2O/EtOH (7:3:2), powdered Na2CO3 (4.58 g, 43.2 mmol) was added. The resulting mixture was purged with N2 at rt for 15 min, before the addition of dichloro[bis(triphenylphosphoranyl)]palladium (380 mg, 0.54 mmol). The reaction mixture was purged with N2 for another 15 min, before being heated in a 70° C. oil bath under N2 for 3-4 h. The reaction mixture was cooled and then concentrated under reduced pressure. The solid residue was treated with 150 mL CHCl3, and the resulting suspension was filtered through a short pad of diatomaceous earth (the filter cake was washed with ˜100 mL CHCl3). The combined filtrate was concentrated under reduced pressure. The blackish solid was taken into 0.5 M HCl (100-150 mL) and EtOAc (˜100 mL). The acidic aqueous layer was separated and the blackish organic layer was washed further with 0.5 M HCl (2×50 mL). The combined aqueous layers were then basified with 1 M NaOH to pH ˜12, and extracted with CHCl3 (100 mL, then 2×50 mL). The CHCl3 extracts were dried over MgSO4, filtered, and concentrated to give 3.5 g (99%) of 5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]thiophene-2-carbaldehyde. 1H NMR (500 MHz, CDCl3) δ 1.50 (dddd, J=12.8, 10.7, 6.7, 2.3 Hz, 1H), 1.68-1.72 (m, 2H), 2.03 (t, J=2.9 Hz, 1H), 2.22-2.26 (m, 1H), 2.78-2.95 (m, 3H), 2.97 (dd, J=14.7, 2.1 Hz, 1H), 3.01-3.05 (m, 1H), 3.08 (d, J=16.5 Hz, 1H), 3.40 (dd, J=14.7, 1.6 Hz, 1H), 3.48 (d, J=16.5 Hz, 1H), 7.29 (d, J=4.0 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.72 (d, J=4.0 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 9.88 (s, 1H); MS ES+ m/z=327 (M+H+).

Workup

  1. customThe reaction mixture was purged with N2 for another 15 min
  2. temperatureThe reaction mixture was cooled
  3. concentrationconcentrated under reduced pressure
  4. additionThe solid residue was treated with 150 mL CHCl3
  5. filtrationthe resulting suspension was filtered through a short pad of diatomaceous earth (the filter cake
  6. washwas washed with ˜100 mL CHCl3)
  7. concentrationThe combined filtrate was concentrated under reduced pressure
  8. customThe acidic aqueous layer was separated
  9. washthe blackish organic layer was washed further with 0.5 M HCl (2×50 mL)
  10. extractionextracted with CHCl3 (100 mL
  11. dry with materialThe CHCl3 extracts were dried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-e56fd4f48991425e861cab7a7e68893b
Source dataset
uspto-grants-2010_11
Patent number
US07842803B2

Reaction notes

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