Synthesis And Antibacterial Activity Of New Chiral Nitrogen-containing Heterocycles From (＋)-2-hydroxy-3-pinanone

A large number of nitrogen-containing heterocycles have been increasing proportion in theorganic compounds because of their unique structures and properties, and have a wide range ofapplications in the fields of pharmaceuticals, pesticides, dyes, materials, and food.A new series of α,β-unsaturated ketones were synthesized from （－）-α-pinene afterselective oxidation, aldol condensation reaction, which then reacted with guanidinehydrochloride, hydroxylamine hydrochloride or hydrazine hydrate, synthetizing new chiralpinanyl-2-aminopyrimidines, isoxazolines and pyrazolines. The structures of the targetcompounds were identified by means of FT-IR, GC-MS,¹H NMR,¹³C NMR techniques andelemental analysis, and their antibacterial activity were tested. This research will lay a goodfoundation for developing the utilization field of α-pinene and exploiting new types ofnitrogen-containing heterocycles with good bioactivity.（＋）-2-hydroxy-3-pinanone was prepared by selective oxidation of （－）-α-pinene withpotassium permanganate in the acetone－water mixed solvent, and the yield and purity of（＋）-2-hydroxy-3-pinanone were75.6%and98.3%（GC）, respectively. Its melting point andspecific rotation were38.1～39.0℃and[α]_D²⁵＋37.5（c0.5, CHCl3）.4-arylidene-2-hydroxy-3-pinanones （1-a）～（1-g） were prepared by condensation of （＋）-2-hydroxy-3-pinanone with aromactic aldehydes including benzaldehyde, p-chlorobenzaldehyde,p-methylbenzaldehyde, p-nitrobenzaldehyde, p-methoxybenzaldehyde, p-hydroxybenzaldehyde,and furfural using NaOH, sodium ethoxide or potassium tert-butoxide as catalyst. Effects ofcatalytic system, aldehyde/ketone molar ratio, and reaction temperature on the aldolcondensation reaction were examined, and the optimum preparation conditions weredetermined. The products were all solids with the yields varied in the range of42.3%～83.3%,the purity was more than99.0%（GC）, and all had optical activity. The ultraviolet absorptioncharacteristics and light stability of the4-arylidene-2-hydroxy-3-pinanones were investigated,and the results showed that the compounds （1-a）,（1-b）,（1-c） exhibited good absorbency as theUV-B-type absorbents, and compounds （1-d）,（1-e）,（1-f） and （1-g） had both functions oflong-wave ultraviolet （UVA） and medium-wave ultraviolet （UVB） absorbents. The lightstability sequence of these compounds was （1-f）＞（1-e）＞（1-b）＞（1-d）＞（1-c）＞（1-a）＞（1-g）.Pinanyl-2-aminopyrimidines （2-a）～（2-f） were prepared by cyclization reaction of4-arylidene-2-hydroxy-3-pinanones with guanidine hydrochloride using30%NaOH solution orpotassium tert-butoxide as catalyst, absolute alcohol or tert-butyl alcohol as solvent, and thesuitable reaction conditions were also determined as follows: guanidine hydrochloride/4-arylidene-2-hydroxy-3-pinanones molar ratio3.0～4.0times, reaction temperature60～70℃, and reaction time12～16h. The products, having optical activity, were all solids, the yields varies in the range of75.7%～84.8%, and the purity was more than99.5%（GC）.Pinanyl isoxazolines （3-a）～（3-d） were prepared by cyclization reaction of4-arylidene-2-hydroxy-3-pinanones and hydroxylamine hydrochloride using20%NaOH solution as catalyst,absolute alcohol as solvent, and the suitable reaction conditions were also determined asfollows: hydroxylamine hydrochloride/4-arylidene-2-hydroxy-3-pinanones molar ratio1.5～5.0times, reaction temperature60～70℃, and reaction time1～3h. The products were all solidswith the yields varied in the range of56.4%～74.6%, the purity was more than99.2%（GC）,and all had optical activity.Pinanyl pyrazolines （4-a） and （4-b） were prepared by cyclization reaction of4-arylidene-2-hydroxy-3-pinanones with80%hydrazine hydrate in absolute alcohol, and the suitablereaction conditions were also determined as follows: hydrazine hydrate/4-arylidene-2-hydroxy-3-pinanones molar ratio1.2～1.5times, reflux temperature, and reaction time3～5h.The products were all solids with the yields varied in the range of72.4%～75.6%, the puritywas more than98.6%（GC）, and all had optical activity.Minimum inhibitory concentrations （MIC） of the synthesized compounds includingpinanyl-2-aminopyrimidines, isoxazolines, and pyrazolines were tested with double dilutionmethod, and the test results showed that the three kinds of nitrogen-containing heterocycles hadalmost the same inhibitory effects against fungi. The strength sequence of against bacteria was2-aminopyrimidines＞isoxazolines＞pyrazolines. In the same kind of derivatives, thecompounds containing different substituting in aromatic cycles have different antibacterialactivities, and the sequence was4-Cl＞4-NO2＞4-OCH3＞4-H＞4-CH3. Among the testedcompounds,（2-b） and （2-d） had strong antibacterial effects to E. coli and B. subtilis,（2-a）,（2-e）,（3-b） and （3-d） had strong antibacterial effects to E. coli,（2-b） and （3-b） had relatively strongantibacterial effects to S. aureus.