Bromomethylcyclopropane → 3-Tert-butyl 6-cyano-6-(cyclopropylmethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

HRID 455287Notes

Reaction equation

HRID 455287 reaction equation
[C:1]([CH:3]1[CH:8]2[CH:4]1[CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7]2)#[N:2].[CH:16]1([CH2:19]Br)[CH2:18][CH2:17]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[C:1]([C:3]1([CH2:19][CH:16]2[CH2:18][CH2:17]2)[CH:4]2[CH:8]1[CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]2)#[N:2]

Participants

5

Reactant 3

HCID 81503BromomethylcyclopropaneHCID 3251421Potassium bis(trimethylsilyl)amideHCID 59529950Tert-butyl 6-cyano-3-azabicyclo[3.1.0]hexane-3-carboxylate

Product 1

HCID 595299433-Tert-butyl 6-cyano-6-(cyclopropylmethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a solution of 3 (1.68 g, 8.08 mmol) and cyclopropylmethyl bromide (1.31 g, 9.70 mmol) in toluene (25 mL) at 0° C. was added a solution of KHMDS (0.5 M in toluene, 17.8 mL, 8.89 mmol) and stirred for 18 h. The reaction was partially concentrated under vacuum and purified by column chromatography (silica gel) using 0 to 65% EtOAc in hexanes to 4a (minor diastereomer, 290 mg, 14%) and 4b (major diastereomer, 685 mg, 32%) as clear oils; 1H-nmr (400 MHz, CDCl3) δ (minor diastereomer) 3.60 (td, J=12.0, 4.0 Hz, 1H), 3.49 (d, J=12.0 Hz, 1H), 3.41 (d, J=12.0 Hz, 1H), 2.28-2.24 (m, 1H), 1.43 (s, 9H), 1.43-1.28 (m, 2H), 0.94-0.86 (m, 1H), 0.66-0.59 (m, 1H), 0.21 (q, J=6.0 Hz, 1H); LC-MS (214 nM) 3.18 min (>98%), m/z 207.1 [M-tBu]. 1H-nmr (400 MHz, CDCl3) δ (major diastereomer) 3.81 (d, J=12.0 Hz, 1H), 3.75 (d, J=12.0 Hz, 1H), 3.57 (td, J=12.0, 4.0 Hz, 1H), 1.83-1.78 (m, 2H), 1.43 (s, 9H), 1.46-1.40 (m, 2H), 0.92-0.84 (m, 1H), 0.61-0.52 (m, 2H), 0.22-0.16 (m, 2H); LC-MS (214 nM) 3.11 min (>98%), m/z 162.9 [M-Boc], 285.2 [M+Na].

Workup

  1. concentrationThe reaction was partially concentrated under vacuum
  2. custompurified by column chromatography (silica gel)
  3. customLC-MS (214 nM) 3.18 min (>98%), m/z 207.1 [M-tBu]
  4. customLC-MS (214 nM) 3.11 min (>98%), m/z 162.9 [M-Boc], 285.2 [M+Na]

Sources & evidence

ORD record
ord-ce3aa56376b14b46aa4514a0fe42e71d
Source dataset
uspto-grants-2013_07
Patent number
US08497289B2

Reaction notes

Loading…