18-Crown-6 → (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amine

HRID 1472377Notes

Reaction equation

HRID 1472377 reaction equation
C1OCCOCCOCCOCCOCCOC1.[F-].[K+].C[Si](C)(C)[C:23]#[C:24][C:25]1([CH3:29])[CH2:28][O:27][CH2:26]1.Br[C:33]1[CH:34]=[C:35]2[C:46]3([N:51]=[C:50]([NH2:52])[CH2:49][O:48][CH2:47]3)[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([C:53]4[C:54]([F:59])=[N:55][CH:56]=[CH:57][CH:58]=4)[CH:44]=3)[O:39][C:36]2=[N:37][CH:38]=1>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.[Cu]I.CN(C=O)C>[F:59][C:54]1[C:53]([C:43]2[CH:44]=[C:45]3[C@:46]4([N:51]=[C:50]([NH2:52])[CH2:49][O:48][CH2:47]4)[C:35]4[C:36](=[N:37][CH:38]=[C:33]([C:23]#[C:24][C:25]5([CH3:29])[CH2:28][O:27][CH2:26]5)[CH:34]=4)[O:39][C:40]3=[CH:41][CH:42]=2)=[CH:58][CH:57]=[CH:56][N:55]=1

Participants

8

Reactant 4

HCID 2855718-Crown-6HCID 522689Potassium FluorideHCID 58547788Trimethyl((3-methyloxetan-3-yl)ethynyl)silaneHCID 674369573-Bromo-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amine

Product 1

HCID 58465992(S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-2',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,3'-[1,4]oxazin]-5'-amineYield 25.46%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418397HCID 178418397, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

A vial charged with 2-fluoropyridin-3-ylboronic acid (0.078 g, 0.556 mmol), PdCl2(dppf)-CH2Cl2 (0.022 g, 0.026 mmol), (S)-3-bromo-7-iodo-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine, and potassium carbonate (0.293 g, 2.118 mmol) was treated with 2.5 mL dioxane and 1 mL water. The vial was then flushed with argon, sealed and heated to 80° C. for 1 hr. The reaction mixture was diluted with EtOAc, dried over MgSO4 and concentrated under reduced pressure to yield 3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.309 g, 0.700 mmol, 132% yield). This material was used without further purification. Step 2: A vial charged with Pd(PPh3)4 (0.079 g, 0.068 mmol), copper(I) iodide (0.013 g, 0.068 mmol), 18-crown-6 (0.045 g, 0.170 mmol), potassium fluoride (0.118 g, 2.040 mmol), trimethyl((3-methyloxetan-3-yl)ethynyl)silane (0.229 g, 1.360 mmol), and 3-bromo-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.300 g, 0.680 mmol) was treated with 3 mL DMF, sealed under argon, and heated to 110° C. overnight. The reaction mixture was then poured onto water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification of the crude residue by column chromatography [0-50% (9:1 DCM/MeOH)/DCM] gave (S)-7-(2-fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-2′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.079 g, 0.094 mmol, 25.46% yield).

Workup

  1. customThis material was used without further purification
  2. customsealed under argon
  3. additionThe reaction mixture was then poured onto water (10 mL)
  4. extractionextracted with EtOAc (3×10 mL)
  5. dry with materialThe combined organic layers were dried over MgSO4
  6. concentrationconcentrated under reduced pressure
  7. customPurification of the crude residue by column chromatography [0-50% (9:1 DCM/MeOH)/DCM]

Sources & evidence

ORD record
ord-70cfee18dbc6408690b9ac25e8c3ff08
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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