Isopropanol → tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate

HRID 1508348Notes

Reaction equation

HRID 1508348 reaction equation
C(O)(C)C.N12CCCNC1CCCC=C2.[CH3:16][C:17]1([CH3:29])[C:21]([CH3:23])([CH3:22])[O:20][B:19]([C:24]2[CH:25]=[N:26][NH:27][CH:28]=2)[O:18]1.[C:30]([CH:32]=[C:33]1[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)#[N:31]>CCCCCCC>[C:30]([CH2:32][C:33]1([N:27]2[CH:28]=[C:24]([B:19]3[O:20][C:21]([CH3:22])([CH3:23])[C:17]([CH3:29])([CH3:16])[O:18]3)[CH:25]=[N:26]2)[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]1)#[N:31]

Participants

6

Reactant 4

HCID 3776IsopropanolHCID 27740104-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 98128211,8-Diazabicyclo[5.4.0]undec-2-eneHCID 457892161-(tert-Butoxycarbonyl)-3-(cyanomethylene)azetidine

Product 1

HCID 67457197tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylateYield 90.5%

Reagents, catalysts & solvents 1

HCID 8900HeptaneSolvent

Procedure

To a 1-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were sequentially added isopropanol (IPA, 200 mL), 1,8-diazabicyclo[5,4,0]undec-ene (DBU, 9.8 g, 64.4 mmol, 0.125 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 101 g, 520.51 mmol, 1.01 equiv) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (2, 100 g, 514.85 mmol) at ambient temperature to generate a reaction mixture as a suspension. The resulting reaction mixture was heated to reflux in 30 minutes to provide a homogenous solution and the mixture was maintained at reflux for an additional 2-3 hours. After the reaction was complete as monitored by HPLC, n-heptane (400 mL) was gradually added to the reaction mixture in 45 minutes while maintaining the mixture at reflux. Solids were precipitated out during the n-heptane addition. Once n-heptane addition was complete, the mixture was gradually cooled to ambient temperature and stirred at ambient temperature for an additional 1 hour. The solids were collected by filtration, washed with n-heptane (200 mL), and dried under vacuum at 50° C. with nitrogen sweeping to constant weight to afford tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (3, 181 g, 199.9 g theoretical, 90.5%) as a white to pale yellow solid. For 3: 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.74 (s, 1H), 4.45-4.23 (m, 2H), 4.23-4.03 (m, 2H), 3.56 (s, 2H), 1.38 (s, 9H), 1.25 (s, 12H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 155.34, 145.50, 135.88, 116.88, 107.08 (br), 83.15, 79.36, 158.74 (br), 56.28, 27.96, 26.59, 24.63 ppm; C19H29BN4O4 (MW 388.27), LCMS (EI) m/e 389 (M++H).

Workup

  1. customTo a 1-L flask equipped with a nitrogen inlet
  2. customat ambient temperature
  3. customThe resulting reaction mixture
  4. temperaturewas heated
  5. temperatureto reflux in 30 minutes
  6. customto provide a homogenous solution
  7. temperaturethe mixture was maintained
  8. temperatureat reflux for an additional 2-3 hours
  9. additionwas gradually added to the reaction mixture in 45 minutes
  10. temperaturewhile maintaining the mixture
  11. temperatureat reflux
  12. customSolids were precipitated out during the n-heptane addition
  13. additionOnce n-heptane addition
  14. filtrationThe solids were collected by filtration
  15. washwashed with n-heptane (200 mL)
  16. customdried under vacuum at 50° C. with nitrogen sweeping to constant weight

Sources & evidence

ORD record
ord-aa706a3b9f594f7faf5d8ff1a53ed448
Source dataset
uspto-grants-2015_12
Patent number
US09221845B2

Reaction notes

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