Dimethylformamide → Tert-butyl 6-cyano-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylate

HRID 1405344Notes

Reaction equation

HRID 1405344 reaction equation
ClS([N:5]=[C:6]=O)(=O)=O.[CH3:8][N:9]1[C:17]2([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[C:13]2=[CH:14][CH:15]=[CH:16][N:12]2[CH2:11][CH2:10]1.CN(C)C=O>O1CCCC1>[C:6]([C:16]1[N:12]2[CH2:11][CH2:10][N:9]([CH3:8])[C:17]3([CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[C:13]2=[CH:14][CH:15]=1)#[N:5]

Participants

5

Reactant 3

HCID 6228DimethylformamideHCID 70918Chlorosulfonyl isocyanateHCID 68153652tert-Butyl 2'-methyl-3',4'-dihydro-2'H-spiro[piperidine-4,1'-pyrrolo[1,2-a]pyrazine]-1-carboxylate

Product 1

HCID 68153526Tert-butyl 6-cyano-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylateYield 25.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

A solution of chlorosulfonyl isocyanate (590.9 mg, 363.4 μL, 4.175 mmol) in tetrahydrofuran (2 mL) was slowly added to a solution of tert-butyl 2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (1020 mg, 3.340 mmol) in tetrahydrofuran (9 mL) held at −78° C. (bath temperature) under an atmosphere of argon. The reaction mixture was allowed to stir for 1 hour at −78° C. N,N-dimethylformamide (732.4 mg, 775.8 μL, 10.02 mmol) was then slowly added to the cold reaction mixture. The reaction mixture was then allowed to slowly warm to room temperature. After stirring for 3 hours at room temperature the crude material was diluted with 25 mL of tetrahydrofuran, washed with a 1M solution of sodium hydroxide, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified on 80 g of silica gel utilizing a gradient of 0-70% ethyl acetate in hexanes to yield tert-butyl 6-cyano-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (280 mg, 25%) as a white solid. ESI-MS m/z calc. 330.2, found 331.1 (M+1)+; Retention time: 0.94 minutes. 1H NMR (400 MHz, CDCl3) δ 6.76 (d, J=4.0 Hz, 1H), 5.97 (d, J=4.0 Hz, 1H), 4.01 (t, J=6.0 Hz, 2H), 3.98-3.76 (m, 2H), 3.36 (t, J=6.0 Hz, 2H), 3.30-3.08 (m, 2H), 2.36 (s, 3H), 2.09-1.98 (m, 2H), 1.84-1.66 (m, 2H), 1.47 (s, 9H).

Workup

  1. customheld at −78° C.
  2. temperatureto slowly warm to room temperature
  3. washwashed with a 1M solution of sodium hydroxide
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. filtrationfiltered
  6. customevaporated to dryness
  7. customto yield the crude product
  8. customThe crude material was purified on 80 g of silica gel utilizing a gradient of 0-70% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-cd37b023c0bc4b008228ba01b84629d8
Source dataset
uspto-grants-2014_12
Patent number
US08916565B2

Reaction notes

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