Toluene → tert-butyl (1'-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidine]-4-yl)methylcarbamate

HRID 2190081Notes

Reaction equation

HRID 2190081 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1.Cl[C:87]1[C:88]2[CH:95]([CH2:96][CH3:97])[CH2:94][CH2:93][C:89]=2[N:90]=[CH:91][N:92]=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[N:15]([C:87]3[C:88]4[CH:95]([CH2:96][CH3:97])[CH2:94][CH2:93][C:89]=4[N:90]=[CH:91][N:92]=3)[CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 5

HCID 1140TolueneHCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86651806Tert-butyl (1'-benzylspiro[indoline-3,4'-piperidine]-4-yl)methylcarbamateHCID 866518114-chloro-5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

Product 1

HCID 86651812tert-butyl (1'-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidine]-4-yl)methylcarbamateYield 70%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
95 °C

Procedure

A 3-neck round bottom flask was charged with tert-butyl (1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (446 mg, 1.09 mmol; see Example 27, Step 3), Pd(OAc)2 (24.6 mg, 0.109 mmol), Xantphos (95 mg, 0.164 mmol) and Cs2CO3 (536 mg, 1.64 mmol) and purged with N2. Toluene (6 mL, 0.547 mmol; sparged with N2 for 30 minutes) and 4-chloro-5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 1.09 mmol) were injected into the reaction, and the reaction was heated to 95° C. for 24 hours. LCMS showed most of the starting material had been consumed. The reaction was cooled, mixed with EtOAc and filtered through glass filter paper. The filtrate was concentrated to a residue and purified by silica gel chromatography (gradient: 5-50% (80 DCM: 19 MeOH: 1 NH4OH)/DCM). Purification provided tert-butyl (1′-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (422 mg, 0.762 mmol, 70% yield). 1H NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H), 7.29-7.35 (m, 5H), 7.25 (m, 1H), 7.16 (t, 1H), 6.91 (d, 1H), 4.54 (br.s, 1H), 4.20-4.30 (m, 3H), 3.97 (m, 2H), 3.53 (s, 2H), 3.27 (m, 1H), 2.85-2.97 (m, 4H), 2.51 (m, 1H), 2.26 (m, 1H), 2.11 (d, 2H), 2.04 (t, 1H), 1.85 (m, 1H), 1.75 (d, 1H), 1.59 (d, 1H), 1.46 (s, 9H), 1.18 (m, 1H), 0.77 (t, 311). MS (APCI+) [M+H]: 554.2.

Workup

  1. custompurged with N2
  2. customhad been consumed
  3. temperatureThe reaction was cooled
  4. additionmixed with EtOAc
  5. filtrationfiltered through glass
  6. filtrationfilter paper
  7. concentrationThe filtrate was concentrated to a residue
  8. custompurified by silica gel chromatography (gradient: 5-50% (80 DCM: 19 MeOH: 1 NH4OH)/DCM)
  9. customPurification

Sources & evidence

ORD record
ord-f176fb8ca2ea4383806889e536f5793a
Source dataset
uspto-grants-2012_12
Patent number
US08324221B2

Reaction notes

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