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Tetrabutylammonium Fluoride Trihydrate → 2-Fluoropyridin 3-((3-methyloxetan-3-yl)ethynyl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine

HRID 455704
Notes
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Reaction equation

HRID 455704 reaction equation
O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[Si](C)(C)[C:24]#[C:25][C:26]1([CH3:30])[CH2:29][O:28][CH2:27]1.Br[C:34]1[CH:35]=[C:36]2[C@:47]3([CH2:52][CH2:51][O:50][C:49]([NH2:53])=[N:48]3)[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:54]4[C:55]([F:60])=[N:56][CH:57]=[CH:58][CH:59]=4)[CH:45]=3)[O:40][C:37]2=[N:38][CH:39]=1>C1COCC1.CO.CCOC(C)=O.[Cu]I.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>[F:60][C:55]1[CH:54]=[CH:59][CH:58]=[CH:57][N:56]=1.[CH3:30][C:26]1([C:25]#[C:24][C:34]2[CH:35]=[C:36]3[C:47]4([CH2:52][CH2:51][O:50][C:49]([NH2:53])=[N:48]4)[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[O:40][C:37]3=[N:38][CH:39]=2)[CH2:29][O:28][CH2:27]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 3

HCID 11726816Tetrabutylammonium Fluoride TrihydrateHCID 58465877(S)-3-bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amineHCID 58547788Trimethyl((3-methyloxetan-3-yl)ethynyl)silane

Product 1

HCID 866583882-Fluoropyridin 3-((3-methyloxetan-3-yl)ethynyl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amineYield 72%

Reagents, catalysts & solvents

4
HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 21584119Ethylacetate methanolSolvent

Conditions

Temperature
80 °C

Procedure

In a microwave vial, tetrabutylammonium fluoride trihydrate (0.059 g, 0.187 mmol), trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.031 g, 0.187 mmol), copper(I) iodide (2.374 mg, 0.012 mmol), Pd(PPh3)4 (0.014 g, 0.012 mmol), and (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (0.055 g, 0.125 mmol) were suspended in THF (1.25 mL). Argon gas was blown through the vessel, which was sealed and heated in an 80° C. oil bath for 1.5 h. The mixture was taken up in 10% MeOH-EtOAc (60 mL) and the organic layer was extracted with dilute brine (8 mL) then with saturated brine (8 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (5% MeOH/DCM), to afford (S)-7-(2-fluoropyridin-3-((3-methyloxetan-3-yl)ethynyl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (41 mg, 0.09 mmol). MS (m/z) 457 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm: 8.32 (d, 1H, J=2.0 Hz), 8.20 (d, 1H, J=4.9 Hz), 7.90 (m, 1H), 7.78 (s, 1H), 7.53 (m, 2H), 7.38 (d, 1H, J=8.4 Hz), 7.27 (m, 1H), 4.94 (d, 2H, J=5.3 Hz), 4.50 (d, 2H, J=5.5 Hz), 4.44 (br, 2H), 4.28 (m, 2H), 1.95 (m, 1H), 1.85 (m, 1H), 1.74 (s, 3H).

Workup

  1. customwas sealed
  2. extractionthe organic layer was extracted with dilute brine (8 mL)
  3. dry with materialwith saturated brine (8 mL), dried over sodium sulfate
  4. concentrationconcentrated
  5. customThe residue was purified by chromatography (5% MeOH/DCM)

Sources & evidence

ORD record
ord-549e18b94e5c4184bed5256fc5ff10f4
Source dataset
uspto-grants-2013_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08497264B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes