Cyclobutanone → Tert-butyl 4-cyclobutyl-1,4-diazepane-1-carboxylate

HRID 1429602Notes

Reaction equation

HRID 1429602 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH:15]2[CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 14496CyclobutanoneHCID 14798Sodium HydroxideHCID 2756058Tert-butyl 1,4-diazepane-1-carboxylateHCID 5049666Sodium triacetoxyborohydride

Product 1

HCID 57425297Tert-butyl 4-cyclobutyl-1,4-diazepane-1-carboxylateYield 99.8%

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Procedure

A 3-L, 3-necked, round-bottomed flask under a positive pressure of nitrogen was equipped with a mechanical stirrer and charged with tert-butylhomopiperazine-1-carboxylate (1-BOC-homopiperazine) (73.0 g, 365.0 mmol) and anhydrous dichloroethane (800 mL). To this stirred solution was added cyclobutanone (25.5 g, 363.8 mmol). The pale yellow reaction was stirred at rt for 1 h, following which, sodium triacetoxyborohydride (92.5 g, 436.3 mmol) was added portion-wise over 1 h. The reaction mixture was stirred for 48 h. 1 N NaOH(aq) (225 mL) was added to the reaction mixture and stirred for 1 h. The phases were separated and the aqueous layer was extracted with dichloroethane (2×100 mL). The organic layers were pooled, washed with satd. aq. NaCl (1×250 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed by rotary evaporation under reduced pressure to afford the crude product as pale yellow semi-solid (92.4 g, 98%). 1H-NMR (400 MHz, CDCl3) δ ppm: 3.59-3.40 (m, 4H), 2.98-2.84 (m, 1H), 2.59-2.43 (m, 4H), 2.12-2.03 (m, 2H), 2.00-1.83 (m, 4H), 1.76-1.55 (m, 2H), 1.51-1.41 (s, 9H). MS m/z (ESI+): 255.2 (M+H+).

Workup

  1. customThe pale yellow reaction
  2. additionwas added portion-wise over 1 h
  3. stirringThe reaction mixture was stirred for 48 h
  4. stirringstirred for 1 h
  5. customThe phases were separated
  6. extractionthe aqueous layer was extracted with dichloroethane (2×100 mL)
  7. washwashed with satd
  8. dry with materialaq. NaCl (1×250 mL), dried over anhydrous Na2SO4
  9. filtrationfiltered
  10. customThe solvent was removed by rotary evaporation under reduced pressure

Sources & evidence

ORD record
ord-322c74143e53440a8cc66a3d72348617
Source dataset
uspto-grants-2015_01
Patent number
US08940731B2

Reaction notes

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