Cesium carbonate → (R)-tert-butyl 2-(1'-benzyl-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidine]-4-yl)pyrrolidine-1-carboxylate

HRID 529138Notes

Reaction equation

HRID 529138 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[C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:15][CH2:14]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:35]1[C:36]2[C@H:43]([CH3:44])[CH2:42][CH2:41][C:37]=2[N:38]=[CH:39][N:40]=1.C([O-])([O-])=O.[Cs+].[Cs+].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>C1(C)C=CC=CC=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[C@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[N:15]([C:35]3[C:36]4[C@H:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=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 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 59670769(R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidineHCID 68760890(R)-tert-butyl 2-(1'-benzylspiro[indoline-3,4'-piperidine]-4-yl)pyrrolidine-1-carboxylate

Product 1

HCID 69813454(R)-tert-butyl 2-(1'-benzyl-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4'-piperidine]-4-yl)pyrrolidine-1-carboxylateYield 23.5%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of (R)-tert-butyl 2-(1′-benzylspiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (50 mg, 0.11 mmol), (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (19 mg, 0.11 mmol), Cs2CO3 (40 mg, 0.12 mmol), Pd(OAc)2 (3.0 mg, 0.01 mmol), Xantphos (7.0 mg, 0.01 mmol) in toluene (5 mL) was degassed by a nitrogen balloon, and the mixture was heated to 90° C. for 12 hours. The reaction mixture was filtered by a pad of celite and eluted with EtOAc. The filtrate was concentrated, and the residue was purified by flash chromatography to afford the product (R)-tert-butyl 2-(1′-benzyl-1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)pyrrolidine-1-carboxylate (15 mg, 23%) as a solid. 1H NMR (CDCl3, 400 MHz) δ 8.68 (s, 1H), 7.20-7.40 (m, 5H), 7.09-7.12 (m, 1H), 6.84-6.90 (m, 1H), 6.70-6.74 (m, 1H), 5.25-5.32 (m, 1H), 4.10-4.20 (m, 1H), 3.80-3.90 (m, 1H), 3.70-3.80 (m, 1H), 3.50-3.60 (m, 2H), 3.30-3.40 (m, 1H), 2.95-3.00 (m, 2H), 2.85-2.95 (m, 2H), 2.20-2.60 (m, 4H), 1.95-2.05 (m, 2H), 1.80-1.95 (m, 2H), 1.60-1.80 (m, 4H), 1.30 (s, 4H), 1.20 (s, 5H), 0.80-0.90 (m, 3H). MS (APCI+) [M+H]+ 580.

Workup

  1. customwas degassed by a nitrogen balloon
  2. filtrationThe reaction mixture was filtered by a pad of celite
  3. washeluted with EtOAc
  4. concentrationThe filtrate was concentrated
  5. customthe residue was purified by flash chromatography

Sources & evidence

ORD record
ord-9b645a7c02e4435f86597a312c85b62c
Source dataset
uspto-grants-2016_05
Patent number
US09346805B2

Reaction notes

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