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Sodium Carbonate → 5-(2-Chloro-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine

HRID 579339
Notes
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Reaction equation

HRID 579339 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[S:17][C:16]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[N:15][N:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]1[S:17][C:16]([N:18]([CH3:29])[CH:19]2[CH2:24][C:23]([CH3:25])([CH3:26])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[N:15][N:14]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 177502292-Chloro-4-fluorobenzeneboronic acidHCID 867271295-Bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine2×

Product 1

HCID 867271615-(2-Chloro-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amineYield 68%

Reagents, catalysts & solvents 4

HCID 178418397
HCID 178418397, compound
Catalyst
HCID 962WaterSolvent
HCID 6344DichloromethaneSolvent
HCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

To a stirred suspension of (2-chloro-4-fluorophenyl)boronic acid (251 mg, 1.44 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (400 mg, 1.2 mmol) in dioxane (10 mL) under nitrogen was added Pd(PPh3)4 (69 mg, 0.06 mmol) followed by a solution of Na2CO3 (382 mg, 3.6 mmol) in water (2.5 mL). The reaction mixture was sealed and heated at 120° C. under microwave irradiation for 1 hour. The reaction mixture was diluted with DCM (100 mL) and washed with saturated NaHCO3(aq) (40 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was diluted with MeOH (10 mL) and SiliaMetS-DMT (0.61 mmol/g, 0.984 mg, 0.6 mmol) was added. The resulting suspension was stirred at room temperature for ˜18 hours then filtered. The filtrate was concentrated in vacuo to afford the crude product as a yellow/orange oil. The crude material was purified by flash chromatography using a 24 g silica cartridge running a gradient from 2-10% [2M NH3 in MeOH]/DCM to afford the title compound as a pale yellow solid (312 mg, 68% yield). LC-MS: Rt 0.97 min; MS m/z 383.4 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (dd, J=8.84, 6.32 Hz, 1H), 7.65 (dd, J=9.09, 2.53 Hz, 1H), 7.36-7.43 (m, 1H), 4.34 (tt, J=12.38, 3.28 Hz, 1H), 3.00 (s, 3H), 1.62 (dd, J=12.13, 3.03 Hz, 2H), 1.43 (t, J=12.38 Hz, 2H), 1.28 (br. s., 1H), 1.20 (s, 6H), 1.08 (s, 6H).

Workup

  1. customThe reaction mixture was sealed
  2. washwashed with saturated NaHCO3(aq) (40 mL)
  3. customThe organic phase was separated
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. additionThe filtrate was diluted with MeOH (10 mL) and SiliaMetS-DMT (0.61 mmol/g, 0.984 mg, 0.6 mmol)
  7. additionwas added
  8. filtrationthen filtered
  9. concentrationThe filtrate was concentrated in vacuo
  10. customto afford the crude product as a yellow/orange oil
  11. customThe crude material was purified by flash chromatography

Sources & evidence

ORD record
ord-6b1179de73cc4fd8920827e6b180819d
Source dataset
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09040712B2

Reaction notes

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