(S)-morpholin-2-ylmethanol → 4-(4-chlorophenyl)-2-[2-(hydroxymethyl)morpholin-4-yl]-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one

HRID 1615572Notes

Reaction equation

HRID 1615572 reaction equation
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:47][CH2:46][NH:45][C:44](=[O:48])[C:43]3[S:49][C:50](I)=[CH:51][C:42]2=3)=[CH:37][CH:36]=1.[NH:53]1[CH2:58][CH2:57][O:56][C@H:55]([CH2:59][OH:60])[CH2:54]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:47][CH2:46][NH:45][C:44](=[O:48])[C:43]3[S:49][C:50]([N:53]4[CH2:58][CH2:57][O:56][CH:55]([CH2:59][OH:60])[CH2:54]4)=[CH:51][C:42]2=3)=[CH:37][CH:36]=1

Participants

6

Reactant 4

HCID 1512575(S)-morpholin-2-ylmethanolHCID 2733832Lithium HexamethyldisilazideHCID 162179852-Dicyclohexylphosphino-2',6'-diisopropoxybiphenylHCID 681830544-(4-chlorophenyl)-2-iodo-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one

Product 1

HCID 681829774-(4-chlorophenyl)-2-[2-(hydroxymethyl)morpholin-4-yl]-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-oneYield 16%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

RuPhospalladium(II)phenethylaminechloride (2.83 mg, 0.00388 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (1.81 mg, 0.00388 mmol), 4-(4-chlorophenyl)-2-iodo-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one (31.3 mg, 0.0776 mmol), (2S)-morpholin-2-ylmethanol (16.0 mg, 0.137 mmol), and tetrahydrofuran (0.63 mL) were combined in a rbf equipped with a stirbar. The flask was sealed with a septum then evacuated and refilled with argon three times. To this solution was added a solution of lithium bis(trimethylsilyl)amide) in tetrahydrofuran (1.0 M, 0.31 mL, 0.31 mmol). The sealed r×n was vigorously stirred @ 40° C. for 19 hr. The reaction was cooled to rt, quenched into saline, extracted into EA, washed with saline, dried over Na2SO4, filtered, and concentrated in vacuo. The crude oil was purified using column chromatography on silica gel (24 g ISCO column, gradient 100% DCM to 100% EA over 50 minutes; after unreacted starting material and dehalogenated starting material eluted, the eluant was switched to 5% MeOH in EA) to give the title compound (4.8 mg, 16%) as a mixture of diastereomers. LCMS: (FA) ES+ 393, 395. 1H NMR (400 MHz, DMSO) δ 7.78 (t, J=4.6 Hz, 1H), 7.38-7.35 (m, 2H), 7.15-7.11 (m, 2H), 5.59 (s, 1H), 4.80-4.75 (m, 1H), 4.34-4.31 (m, 1H), 3.91-3.79 (m, 1H), 3.61-3.35 (m, 6H), 3.24 (d, J=11.9 Hz, 1H), 3.11-3.07 (m, 2H), 2.81-2.69 (m, 1H), 2.22-2.14 (m, 1H), 2.02-1.88 (m, 1H).

Workup

  1. customequipped with a stirbar
  2. customThe flask was sealed with a septum
  3. customthen evacuated
  4. additionrefilled with argon three times
  5. customquenched into saline
  6. extractionextracted into EA
  7. washwashed with saline
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe crude oil was purified
  12. customover 50 minutes
  13. washeluted

Sources & evidence

ORD record
ord-65c534c905f345a9b48f6f6e0161b23b
Source dataset
uspto-grants-2014_07
Patent number
US08765746B2

Reaction notes

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