Acetic Acid → tert-Butyl 4-(4-cyanophenoxy)piperidine-1-carboxylate

HRID 529976

Reaction equation

[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.CC(O)=O>CN(C=O)C.CC(O)(C)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]

Participants

Conditions

Temperature: 60 °C

Procedure

Step-1: To a stirred solution of N—BOC 4-hydroxypiperidine (7.50 g, 0.0373 mol) in dry DMF (50 mL) was added 95% NaH solid (1.12 g, 0.047 mol) in small portions over 5-10 min. After the evolution of gas had subsided, 4-chlorobenzonitrile (5.18 g, 0.0376 mol) was added in one portion, and the mixture heated to 60° C. overnite. The mixture was diluted with tBuOH (about 5 mL) and neutralized to pH 7 using glacial AcOH. The DMF was concentrated in vacuo, and the crude product chromatographed over a 120 g Isco column using 20% DCM/hexanes to DCM as an eluent to get step-1 product, 4-(4-cyanophenoxy)piperidine-1-carboxylic acid tert-butyl ester, as a white solid (10.33 g, 92%): LC Rt=3.40; 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 1.74-1.80 (m, 2H), 1.89-1.97 (m, 2H), 3.40 (ddd, J=10.3, 7.6, 4.0 Hz, 2H), 3.68 (ddd, J=10.3, 8.7, 4.0 Hz, 2H), 4.55 (septet, J=3.6 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 7.58 (d, J=9.0 Hz, 2H).

Workup

concentrationThe DMF was concentrated in vacuo
customthe crude product chromatographed over a 120 g Isco column

Sources & evidence

ORD record: ord-7dda535dfd1d4e7a9ac4e094c1d50c55
Source dataset: uspto-grants-2016_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09351964B2

Linked notes

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