Diisopropylamine → 1-t-Butyldimethylsilyl-3-[hydroxy(5-isothiazolyl)methyl]-4-tritylthioazetidin-2-one

HRID 2291959Notes

Reaction equation

HRID 2291959 reaction equation
C([Li])CCC.C(NC(C)C)(C)C.[Si:13]([N:20]1[CH:23]([S:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][C:21]1=[O:44])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[CH:45]([C:47]1[S:51][N:50]=[CH:49][CH:48]=1)=[O:46].[Cl-].[NH4+].N1CCC1=O>O1CCCC1.C(OCC)(=O)C.C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Si:13]([N:20]1[CH:23]([S:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]([CH:45]([OH:46])[C:47]2[S:51][N:50]=[CH:49][CH:48]=2)[C:21]1=[O:44])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]

Participants

11

Reactant 6

HCID 7912DiisopropylamineHCID 25517Ammonium ChlorideHCID 1367212-Azetidinone2×HCID 1384425-IsothiazolecarboxaldehydeHCID 129287451-t-Butyldimethylsilyl-4-tritylthio-2-azetidinoneHCID 178418339Butyllithium

Product 1

HCID 212780061-t-Butyldimethylsilyl-3-[hydroxy(5-isothiazolyl)methyl]-4-tritylthioazetidin-2-one

Reagents, catalysts & solvents 4

HCID 6212ChloroformSolvent2×HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolventHCID 21226206Ethyl acetate hexaneSolvent

Conditions

Temperature
-30 °C

Procedure

A solution of n-butyl lithium (1.64M in hexane, 0.73 ml) was added to a solution of diisopropylamine (0.17 ml) in dry tetrahydrofuran (THF) (8 ml) at -30° C. under dry argon. After stirring at -30° C. for 10 minutes the mixture was cooled to -76° C. and treated with a solution of 1-t-butyldimethylsilyl-4-tritylthioazetidin-2-one (1) (459 mg) (Bristol-Myers Patent GB No. 2042515 A) in dry THF (4 ml). After a further 15 minutes at -76° C. the stirred mixture was treated with a solution of 5-formylisothiazole (135 mg) (M. P. L. Caton et. al., J. Chem. Soc., 1964, 446) in dry THF (1 ml). After 20 minutes at -76° C. the stirred mixture was treated with saturated ammonium chloride solution (5 ml) and allowed to attain 0° C. The mixture was diluted with ethyl acetate (25 ml) and washed with brine (5 ml), dilute scdium bisulphite solution (5 ml) and brine (3×5 ml). The dried (MgSO4) organic layer was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate/hexane mixtures to give two fractions. The less polar fraction contained a 3:1 mixture of a trans (Isomer A) and a cis-isomer (Isomer B) of the title azetidinone (2) (112 mg), a solid, νmax (CHCl3) 3600-3100, 1745 cm-1 ; δppm (CDCl3) 0.91 and 0.99 (9H, each s, ratio 3:1), 1.60-2.10 (1H, broad signal, exch. D2O), 3.35-3.56 (1.25H, m), 4.06 (0.75H, d, J3 Hz), 4.57 (0.75H, d, J2 Hz), 4.88 (0.25H, d, J5 Hz), 7.00-7.60 (16H, m), 8.29 (1H, d, J2 Hz), both Me3Si signals were obscured by the TMS signal. The more polar fraction contained a trans-isomer (Isomer C) of the title azetidinone (2) (144 mg), a solid, mp 183°-184° C. (prisms ex ethyl acetate/hexane); νmax (CHCl3) 3600-3100, 1735 cm-1 ; δppm (CDCl3) 0.81 (9H, s), 2.70-3.10 (1H, broad signal, exch. D2O), 3.70 (1H, dd, J7 and 2 Hz), 4.10 (1H, d, J2 Hz), 4.30-4.50br (1H, m, collapses to d, J7 Hz on exch. D2O), 6.81br (1H, s), 7.20-7.50 (15H, m), 8.22 (1H, d, J2 Hz), both Me3Si signals were obscured by the TMS signal. (Found: C, 67.1; H, 6.3; N, 4.9; S, 11.2. C32H36N2O2S2Si requires C, 67.1; H, 6.3; N, 4.9; S, 11.2%).

Workup

  1. temperaturewas cooled to -76° C.
  2. customto attain 0° C
  3. washwashed with brine (5 ml)
  4. additiondilute scdium bisulphite solution (5 ml) and brine (3×5 ml)
  5. dry with materialThe dried (MgSO4) organic layer
  6. customwas evaporated
  7. customthe residue chromatographed on silica gel eluting with ethyl acetate/hexane
  8. customto give two fractions

Sources & evidence

ORD record
ord-a605d8a743cc4c34b1b9cd42d230f368
Source dataset
uspto-grants-1989_01
Patent number
US04798828

Reaction notes

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