Alkylation of pyrazolones

Alkylation of pyrazolones via the Mitsunobu reaction

Table 1 Yields and product distributions


Pyrazolone       Alcohol        Solvent      5[a]   6[a]   5 : 6[b] 


                                          or 2[a]   3[a]   2 : 3[b] 




1                MeOH           THF                        1 : 3.5 


1                MeOH           CH₂Cl₂       10%    60%    1 : 6.3 


1                MeOH           benzene                    0 : 1   


1                Me₂CHOH        THF                        0 : 1   


1                Me₂CHOH        benzene             46%    0 : 1   
 

4a               MeOH           THF          traces 78%    1 : 50 


4a               MeOH           CH₂Cl₂                     1 : 4.7 


4a               MeOH           CHCl₃                      1 : 7.4 


4a               MeOH           CH₃CN                      1 : 2.8 


4a               MeOH           benzene       0%    93%    0 : 1 


4a               Me₂CHOH        benzene       0%    61%    0 : 1 


4a               Me₂CHOH        THF                        0 : 1 


4a               PhCH₂OH        THF           0%    90%    0 : 1 


4a               PhCH₂OH        CH₂Cl₂                     1 : 7.1 
 

4a               2,3-epoxy-     THF           0%    54%    0 : 1 


                 propanol 


4b               MeOH           THF           7%    75%    1 : 10.6 


4b               MeOH           CH₂Cl₂                     1 : 2.6 


4b               MeOH           benzene             50%    0 : 1  


4c               MeOH           THF          17%    48%    1 : 3.3 


4c               MeOH           CH₂Cl₂                     1 : 1.1 


4c               MeOH           benzene                    1 : 4.7 


4d               MeOH           THF          11%    62%    1 : 5.7 


4d               MeOH           CH₂Cl₂                     1 : 1.7 


4d               MeOH           benzene                    1 : 9.4

[a] Yield of purified product after chromatographic separation
[b] Ratio determined via ¹H NMR analysis of the crude reaction mixture

The reactions were performed on a 1 mmol scale according to the procedure given in ref. [4]. ¹H NMR analyses of the crude reaction mixtures afforded the product distributions 5 : 6 (2 : 3) (ratio N-R : O-R). Representative runs exhibiting higher selectivities were worked up completely and subjected to medium pressure liquid chromatography to yield the pure isomers 5 and 6 (2 and 3), respectively. Isolated new compounds were characterized by CHN-analysis and spectroscopic methods (¹H NMR, ¹³C NMR, IR, MS).