General Papers ARKIVOC 2006 (xiv) 1-9
dimethylpiperazine. By the route of Dolitzky,3 the piperazine was made from N- (2-chloroethyl)N- methyl-ß-chloro-ß-phenylethylamine and this method afforded by product 1-methyl-2phenylpiperazine. This may be because of the non-selectivity in the reaction of starting material preparation. The method described by Guo,5 involves the use of excess of lithium aluminum hydride,7 for the unsubstituted amide reduction. We wish to report herein an improved procedure using new intermediates, which circumvents these problems. Different 1-alkyl-3phenylpiperazines were prepared in two methods by simply changing the sequence of reduction and deprotection of the phenylpiperazine derivatives. First method involves the reduction of 3a-e followed by the deprotection of 4a-e to get 1-alkyl-3-phenylpiperazine 5a-e (Scheme 1).
P
P
H
N
N C6H5 N C6H5 C6H5
iii
i
ii
NO
NO NO
HH
R
3a P=CH2C6H5; R=CH3
2a P=CH2C6H5
1
3b P=CH2C6H5; R=CH2CH3
2b P=OCOC(CH3)3
3c P=OCOC(CH3)3; R=CH2CH=CH2 3d P=CH2C6H5; R=CH2CH=CH2 3e P=OCOC(CH3)3; R=CH2C6H5
P
H
N C6H5 N C6H5
iv
NN RR
4a P=CH2C6H5; R=CH3 5a R=CH34b P=CH2C6H5; R=CH2CH3 5b R=CH2CH34c P=OCOC(CH3)3; R=CH2CH=CH2 5c R=CH2CH=CH24d P=CH2C6H5; R=CH2CH=CH2 5d R=CH2CH2CH34e P=OCOC(CH3)3; R=CH2C6H5 5e R=CH2C6H5
Scheme 1. i. Protection: for benzyl; C6H5CH2Cl, NaHCO3, DMF, 100 °C; for Boc. di-tert-butyl dicarbonate, (C2H5)3N, CH2Cl2, rt. ii. RI, NaH, DMF, 25 °C. iii. LiAlH4, THF, reflux. iv. deprotection: for benzyl; H2, Pd-C, CH3OH, CH3COOH, rt; for Boc; 6N HCl, rt.
Second method involves the deprotection of 3a-c, e followed by reduction of 1-alkyl-2oxo- 3-phenylpiperazines 6a-d giving the 1-alkyl-3-phenylpiperazines 5a-c, e (Scheme 2).
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