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2-Methyl-3-butyn-2-ol → 10-(3-Hydroxy-3-methylbut-1-yn-1-yl)-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

HRID 575249
Notes
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Reaction equation

HRID 575249 reaction equation
BrC1C=CC2OCCN3C=C(I)N=C3C=2C=1.C=O.O.N1CCCC1.C[Si](N[Si](C)(C)C)(C)C.Br[C:35]1[CH:36]=[CH:37][C:38]2[O:44][CH2:43][CH2:42][N:41]3[C:45]([CH2:51][N:52]4[CH2:56][CH2:55][CH2:54][CH2:53]4)=[C:46]([C:48]([NH2:50])=[O:49])[N:47]=[C:40]3[C:39]=2[CH:57]=1.[CH3:58][C:59]([OH:63])([C:61]#[CH:62])[CH3:60]>C(O)(=O)C.ClCCl.CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:63][C:59]([CH3:60])([CH3:58])[C:61]#[C:62][C:35]1[CH:36]=[CH:37][C:38]2[O:44][CH2:43][CH2:42][N:41]3[C:45]([CH2:51][N:52]4[CH2:56][CH2:55][CH2:54][CH2:53]4)=[C:46]([C:48]([NH2:50])=[O:49])[N:47]=[C:40]3[C:39]=2[CH:57]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

11

Reactant 6

HCID 82582-Methyl-3-butyn-2-olHCID 13838HexamethyldisilazaneHCID 31268PyrrolidineHCID 22136924Formaldehyde--water (1/1)HCID 5820440710-Bromo-2-iodo-5,6-dihydrobenzo[F]imidazo[1,2-D][1,4]oxazepineHCID 8669325310-Bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

Product 1

HCID 8669325210-(3-Hydroxy-3-methylbut-1-yn-1-yl)-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamideYield 18%

Reagents, catalysts & solvents 4

HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 176Acetic AcidSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

10-bromo-2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.77 mmol, 1.00 equiv), HCHO/H2O (312 mg, 4.00 equiv), pyrrolidine (332 mg, 4.67 mmol, 6.00 equiv) in acetic acid (4 mL) was stirred overnight at 55° C. The resulting solution was diluted with dichloromethane, washed with saturated aqueous NaHCO3 solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/MeOH (10/1). This resulted in 200 mg of 10-bromo-2-iodo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineas yellow oil that was used without further purification or characterization. Similar to as described in Example 10 (carbonylative amidation), a solution of this intermediate (200 mg, 0.42 mmol, 1.00 equiv), HMDS (135 mg, 0.84 mmol, 2.00 equiv), Pd(dppf)Cl2(34 mg, 0.05 mmol, 0.10 equiv) in N,N-dimethylformamide (2 mL) was stirred overnight at 70° C. under an atmosphere of CO (g). The resulting solution was diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (1:10). This resulted in 80 mg (48%) of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide as a yellow solid. Similar to as described in General Procedure G, 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a yellow solid (14 mg, 18%).

Workup

  1. washwashed with saturated aqueous NaHCO3 solution
  2. dry with materialdried over anhydrous sodium sulfate
  3. concentrationconcentrated under vacuum
  4. customThis resulted in 200 mg of 10-bromo-2-iodo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepineas yellow oil that
  5. customwas used without further purification or characterization
  6. washwashed with brine
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationconcentrated under vacuum
  9. customThis resulted in 80 mg (48%) of 10-bromo-3-(pyrrolidin-1-ylmethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide as a yellow solid

Sources & evidence

ORD record
ord-0ef1a7b03ed64e8eab92cd9dc8db772b
Source dataset
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09034866B2

Reaction notes

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