4-Toluenesulfonyl chloride → (4e)-n-Methyl-5-(5-methoxy-3-pyridinyl)-4-penten-2-ol p-toluensulfonate

HRID 1824734Notes

Reaction equation

HRID 1824734 reaction equation
[CH3:1][N:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4](/[CH:10]=[CH:11]/[CH2:12][CH:13]([OH:15])[CH3:14])[CH2:3]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:15][CH:13]([CH2:12]/[CH:11]=[CH:10]/[C:4]2[CH2:3][N:2]([CH3:1])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=2)[CH3:14])(=[O:24])=[O:23])=[CH:18][CH:17]=1

Participants

4

Reactant 2

HCID 73974-Toluenesulfonyl chlorideHCID 865851274E-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2ol

Product 1

HCID 131722240(4e)-n-Methyl-5-(5-methoxy-3-pyridinyl)-4-penten-2-ol p-toluensulfonate

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Procedure

The manner in which certain aryl substituted olefinic amine compounds possessing a branched side chain are provided can vary. Using one synthetic approach, a compound such as (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine can be synthesized by coupling a halo-substituted pyridine, 5-bromo-3-methoxypyridine with an olefin containing a secondary alcohol functionality, 4-penten-2-ol, under Heck reaction conditions; and the resulting pyridyl alcohol intermediate can be converted to its p-toluenesulfonate ester, followed by treatment with methylamine. Typically, the types of procedures set forth in W. C. Frank et al., J. Org. Chem. 43:2947 (1978) and N. J. Malek et al., J. Org. Chem. 47:5395 (1982) involving a palladium-catalyzed coupling of an olefin and an aromatic halide are used. The required halo-substituted pyridine, 5-bromo-3-methoxypyridine is synthesized using methodology similar to that described by H. J. den Hertog et al., Recl. Trav. Chim. Pays-Bas 74:1171 (1955), namely by heating 3,5-dibromopyridine with 2.5 molar equivalents of sodium methoxide in dry methanol in the presence of copper powder (5%, w/w of the 3,5-dibromopyridine) in a sealed glass tube at 150° C. for 14 hours to produce 5-bromo-3-methoxypyridine. The resulting 5-bromo-3-methoxypyridine, previously described by D. L. Comins, et al., J. Org. Chem. 55:69 (1990), can be coupled with 4-penten-2-ol in acetonitrile-triethylamine (1.1:1, v/v) using a catalyst consisting of 1 mole % palladium(II) acetate and 4 mole % tri-o-tolylphosphine. The reaction is carried out by heating the components in a sealed glass tube at 140° C. for 14 hours to yield (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2 -ol. The resulting alcohol is treated with 2 molar equivalents of p-toluenesulfonyl chloride in dry pyridine at 0° C. to produce (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-ol p-toluenesulfonate. The tosylate intermediate is treated with 120-molar equivalents of methylamine as a 40% aqueous solution, containing a small amount of ethanol as a co-solvent to produce (4E)-N-methyl-5-(5-methoxy-3-pyridyl)-4-penten-2-amine.

Sources & evidence

ORD record
ord-4c808b2c5bd74b55abd727b66493e909
Source dataset
uspto-grants-2006_05
Patent number
US07045538B2

Reaction notes

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