Tri-o-tolylphosphine → (1R,2S)-2-(3-((E)-2-(6-methylpyridin-3-yl)vinyl)-1H-indazol-6-yl)spiro [cyclopropane-1,3'-indolin]-2'-one

HRID 447415Notes

Reaction equation

HRID 447415 reaction equation
[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C@H:12]3[C@@:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13]3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[CH2:2].Br[C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:31][C:26]1[N:27]=[CH:28][C:29](/[CH:2]=[CH:1]/[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C@H:12]4[C@@:14]5([C:22]6[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=6)[NH:16][C:15]5=[O:23])[CH2:13]4)=[CH:9][CH:10]=3)[NH:5][N:4]=2)=[CH:30][CH:25]=1

Participants

7

Reactant 4

HCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 12010033-Bromo-2-methylpyridineHCID 68760231(1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-one

Product 1

HCID 58486240(1R,2S)-2-(3-((E)-2-(6-methylpyridin-3-yl)vinyl)-1H-indazol-6-yl)spiro [cyclopropane-1,3'-indolin]-2'-oneYield 31.9%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Procedure

To a mixture of (1R*,2S*)-2-(3-vinyl-1H-indazol-6-yl)spiro[cyclopropane-1,3′-indolin]-2′-one (60.2 mg, 0.2 mmol) and 3-bromo-2-methylpyridine (34.4 mg, 0.2 mmol) in DMF (1.5 mL) was added iPr2NEt (0.07 mL), followed by Pd(OAc)2 (2.2 mg, 0.01 mmol) and P(o-tol)3 (6.7 mg, 0.022 mmol). The resulting mixture was purged with argon, and then microwaved 2 h at 125° C. Purification by prep-HPLC gave the title compound as a light yellow solid (25 mg, 25%). NMR indicated 6% of the branched isomer. 1H NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 7.74 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.78 (d, J=16.8 Hz, 1H), 7.55 (d, J=16.8 Hz, 1H), 7.49 (s, 1H), 7.07-7.00 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 6.55 (t, J=7.6 Hz, 1H), 5.97 (d, J=7.6 Hz, 1H), 3.34 (t, J=8.4 Hz, 1H, partially overlapping with MeOH residue), 2.78 (s, 3H), 2.23 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 2.18 (dd, J=8.8 Hz, J=4.8 Hz, 1H); MS ESI 393.1 [M+H]+, calcd for [C25H20N4O+H]+ 393.2.

Workup

  1. customThe resulting mixture was purged with argon
  2. custommicrowaved 2 h at 125° C
  3. customPurification

Sources & evidence

ORD record
ord-0d20eba1846f44cb85c78f5f0e4ab41a
Source dataset
uspto-grants-2013_07
Patent number
US08481533B2

Reaction notes

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