Microwave assisted synthesis of symmetrically and asymmetrically substituted acyclic enediynes

A convenient method for the synthesis of symmetrically and asymmetrically substituted acyclic enediynes has been developed using microwave irradiation. The reaction completes in 3-5 minutes, while same reaction takes 14-18 h to complete under conventional heating method


Introduction
5][6][7] Although enediynes possess potent anti-tumor activity but their clinical use has been limited because of their modest selectivity for cancer cells.Apart from anti-cancer activity, these compounds exhibit cytotoxicity against various cell lines, 8,9 protein degradation activity, 10 topoisomerase inhibitory activity 11 and natural product enediynes are known to exhibit potent antibacterial activity against both grampositive and gram-negative strains. 124][25] Microwave assisted synthesis has gained popularity in recent years, as it not only reduces the reaction time from hours to minutes, but also increases the yields. 26To the best of our knowledge there is no report of enediyne synthesis under microwave irradiation conditions.To this end, herein we report microwave assisted synthesis of symmetrically and asymmetrically substituted acyclic enediynes.

Results and Discussion
The starting alkynes (1-8) used in the synthesis of acyclic enediynes, were prepared by literature or modified literature methods.Commercially available alcohols/phenols/thiophenol were treated with propargyl bromide in the presence of anhydrous K 2 CO 3 in dry DMF or NaH in dry THF.The reaction was stirred at room temperature and progress of the reaction was monitored by TLC.The reaction takes 8-10 h to complete.After usual work up of the reaction mixture, the crude product was purified over silica gel column (scheme 1).The yield of the substituted alkynes ranged from 65-85%.These alkynes (1-8) were used in the preparation of symmetrical or asymmetrical enediynes.
Compounds 9 and 11 were earlier prepared in 70% and 40% yield respectively using copper acetylides and chloro-iodo-ethylene as starting materials.No analytical data was given for these compounds. 27When 0.5 equivalent of cis-dichloroethylene was reacted with 1.0 equivalent of substituted alkynes under identical reaction conditions as discussed above, 61-65% of the symmetrical enediynes (11, 12) were obtained along with 6-8% of the chloro-en-yne precursor (9, 10).Enediyne 12 was earlier prepared in 59% yield using conventional methodology and reaction completed in 16 h. 28Asymmetrical enediynes were synthesized in good yields as the procedure described above and shown in scheme 3.For example, coupling of chloro-pent-4-en-2-ynyloxy-tetrahydro-pyran (10) 29 with prop-2ynyloxy-pyran (8) under microwave irradiations as discussed above, leads to the formation of the enediyne 14 in 62% yield in 3 minutes (scheme 3, table 1).Reaction of 2,3dibromothiophene (25) with 2-methyl-5-prop-2-ynyloxy-pyridine (5) or 2-prop-2-ynyloxytetrahydropyran (8) in the presence of catalytic amount of Pd(PPh 3 ) 4 , CuI and n-BuNH 2 in benzene under microwave irradiations, gave the desired enediynes (26, 27) in 52-54% yield in 3-5 minutes (scheme 4).While under conventional heating conditions this reaction takes 16-18 h to complete at 80 o C.This reaction further confirms the utility of microwave irradiation in the enediyne synthesis.Microwave irradiation of (13, 14) in presence of 100 equivalent of cyclohexadiene in benzene at 850 W for 30 minutes, results no cyclization of the enediynes.This clearly indicates that these compounds are stable under experimental conditions.Thermal cyclization temperature of these enediyes were measured on a neat materials by Differential scanning calorimetry (DSC).DSC clearly indicates an irreversible exothermic peaks at elevated temperatures, and results are given in the experimental section.
In summary, we have successfully developed a simple and efficient methodology for the synthesis of asymmetrically and symmetrically substituted acyclic enediynes using microwave irradiations.These reaction conditions provide an efficient method for the rapid access of medicinally important class of organic compounds.

Experimental Section
General Procedures.All of the chemicals used in the synthesis were purchased from Sigma-Aldrich and were used as such.Thin layer chromatography was used to monitor the progress of the reactions.All of the compounds were purified over silica gel column.Solvents were distilled before using for purification purposes.Melting points were determined on a melting point apparatus and are uncorrected.IR(KBr) spectra were recorded using Perkin-Elmer FT-IR spectrophotometer and the values are expressed as ν max cm −1 .Mass spectral data were recorded on a Jeol (Japan) JMS-DX303 and micromass LCT, Mass Spectrometer/Data system.The 1 H NMR and 13 C NMR spectra were recorded on Bruker Spectrospin spectrometer at 300 MHz and 75.5 MHz, respectively using TMS as an internal standard.The chemical shift values are recorded on δ scale and the coupling constants (J) are in Hz.Elemental analysis for all compounds were performed on a Carlo Erba Model EA-1108 elemental analyzer and data of C, H and N is within ±0.4% of calculated values.Microwave reactions were performed in a domestic microwave oven of 850W (Kenstar model no: OM2ODGQX).Differential scanning calorimetry (DSC) traces were recorded on a Pyris 6 Differential scanning calorimeter of Perkin Elmer Corporation at a heating rate of 10 o C min -1 .