Potassium Carbonate → 4-Methoxy-5''-methyl-6'-[2-(prop-1-yn-1-yl)pyridin-4-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amine

HRID 1965099Notes

Reaction equation

HRID 1965099 reaction equation
Br[C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].Br[C:54]1[CH:59]=[CH:58][N:57]=[C:56]([C:60]#[C:61][CH3:62])[CH:55]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:14][O:13][CH:10]1[CH2:11][CH2:12][C:7]2([C:15]3([N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]3)[C:22]3[C:5](=[CH:4][CH:3]=[C:2]([C:54]4[CH:59]=[CH:58][N:57]=[C:56]([C:60]#[C:61][CH3:62])[CH:55]=4)[CH:23]=3)[CH2:6]2)[CH2:8][CH2:9]1

Participants

10

Reactant 5

HCID 11430Potassium CarbonateHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 573851176'-Bromo-4-methoxy-5''-methyl-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amineHCID 679795284-Bromo-2-(prop-1-yn-1-yl)pyridine2×

Product 1

HCID 679796114-Methoxy-5''-methyl-6'-[2-(prop-1-yn-1-yl)pyridin-4-yl]-3'H-dispiro[cyclohexane-1,2'-indene-1',2''-imidazol]-4''-amineYield 9%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
110 °C

Procedure

(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2″-indene-1′,2″-imidazol]-4″-amine (Example 19, 75 mg, 0.20 mmol), potassium acetate (39.1 mg, 0.40 mmol), bis(pinacolato)diboron (55.7 mg, 0.22 mmol) and PdCl2(dppf)-CH2Cl2 adduct (8.14 mg, 9.97 μmol) were taken up in dioxane (2 mL) in a microwave vial. The reaction vessel was sealed and heated at 110° C. for 30 min and then at 120° C. for 15 min in a Biotage Initiator. After cooling, K2CO3 (55 mg, 0.40 mmol), Pd(Ph3P)4 (11.5 mg, 9.97 μmol), and water (0.3 mL) were added followed by 4-bromo-2-(prop-1-ynyl)pyridine (Intermediate 33, 39 mg, 0.20 mmol) in dioxane (1 mL). The reaction vessel was sealed and heated at 110° C. for 30 min in a Biotage Initiator. After cooling, the mixture was filtered and concentrated in vacuo. The product was purified by flash chromatography using a gradient of EtOAc in heptane (0-100%), then EtOAc:MeOH (9:1) followed by preparative chromatography to give the title compound (7 mg, 9% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 0.96 (m, 1 H), 1.12-1.29 (m, 2 H), 1.39-1.50 (m, 3 H), 1.83 (m, 2 H), 2.08 (s, 3 H), 2.18 (s, 3 H), 2.90-3.13 (m, 3 H), 3.20 (s, 3 H), 6.56 (s, 2 H), 6.89 (d, 1 H), 7.42 (d, 1 H), 7.50 (dd, 1 H), 7.58 (d, 1 H), 7.62 (dd, 1 H), 8.49 (d, 1 H); MS (MM−ES+APCI)+m/z 413 [M+H]+.

Workup

  1. customThe reaction vessel was sealed
  2. temperatureAfter cooling
  3. customThe reaction vessel was sealed
  4. temperatureheated at 110° C. for 30 min in a Biotage Initiator
  5. temperatureAfter cooling
  6. filtrationthe mixture was filtered
  7. concentrationconcentrated in vacuo
  8. customThe product was purified by flash chromatography

Sources & evidence

ORD record
ord-325dcf7b054047b9857e9960264b38db
Source dataset
uspto-grants-2013_04
Patent number
US08415483B2

Reaction notes

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