Abstract
The catalytic synthesis of nitrogen-containing heterocycles is of great importance to medicinal and synthetic chemists, and also a challenge for modern chemical methodology. In this paper, we report the synthesis of pyrazolidine derivatives through a domino aza-Michael/hemiacetal sequence with chiral or achiral secondary amines as organocatalysts. Thus, a series of achiral pyrazolidine derivatives were obtained with good yields (up to 90%) and high diastereoselectivities (>20:1) with pyrrolidine as an organocatalyst, and enantioenriched pyrazolidines are also achieved with good results (up to 86% yield, >10/1 regioselectivity, >20:1 dr, 99% ee) in the presence of (S)-diphenylprolinol trimethylsilyl ether catalyst.
Highlights
Pyrazolidines are privileged and valuable heterocyclic compounds, which are of great importance in biological and medicinal chemistry (Figure 1) [1-5]
We present a convenient access to racemic and enantioenriched 5-hydroxypyrazolidines through a domino aza-Michael/hemiacetal organocatalytic sequence of disubstituted hydrazines to α,β-unsaturated aldehydes
When di-tert-butyl hydrazine-1,2-dicarboxylate (2c) was used as the donor and 20 mol % pyrrolidine (1c) as the catalyst, 5-hydroxypyrazolidine 4a could be obtained in 68% yield with over 20:1 dr after five days (Table 1, entry 1)
Summary
Pyrazolidines are privileged and valuable heterocyclic compounds, which are of great importance in biological and medicinal chemistry (Figure 1) [1-5]. When increasing the amount of di-tert-butyl hydrazine1,2-dicarboxylate (2c) to 2 equiv, the desired product 4a was obtained in 81% yield without any additive (Table 1, entry 16).
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