An expendient method for the synthesis of bis(acylhydrazones) under microwave irradiation in solvent-free medium

BIOPROCESS ENGINEERING

An expendient method for the synthesis of bis(acylhydrazones) under microwave irradiation in solvent-free medium

J. P. Li^*; P. Z. Zheng; J. G. Zhu; R.J. Liu; G. R. Qu

College of Chemical and Environmental Science, Key Laboratory Pollution Control Technology Henan Province, Henan Normal University, Xinxiang, 453007, China. E-mail: [e-mail]

ABSTRACT

A simple, efficient and eco-friendly method for the synthesis of bis(acylhydrazones) from hexanediohydrazide aldehydes under microwave irradiation without use solvent catalyst is reported. technique solvent-free condition proved to be quite valuable in organic synthesis.

Keywords: Bis(acylhydrazones); Hexanediohydrazide; Adehydes; Microwave; Solvent-free.

INTRODUCTION

Acylhydrazones have been extensively investigated in recent years as they were found to be associated with various biological activities promising analytical properties and can used catalysts (Patrica et al. 2006, Silva 2004 Holla 2000). Their metal complexes usually more active pharmacological properties, described by Carcelli (1995), Paolo (1999) Baldini (2003). The cyclic products of are an important class heterocyclic compounds a wide range pharmaceutical activities, depicted Hamid (2004) Kidwai (2000). Bis(acylhydrazones), category them also (Alessia 2006).

Usually, the synthetic method to produce acylhydrazones involves a reaction between acylhydrazides and aldehydes in ethanol at reflux temperature for about 2-3 hours. Then solvent is concentrated solid filtered recrystallized, giving yields of 70-80%.

Microwave-assisted heating has been shown to be an invaluable technology in synthesis, since it can often dramatically reduce reaction times, typically from days or hours minutes even seconds. also provide pure products quantitative yield and selectivity. Some reports describe the synthesis of acylhydrazones their derivcatives under microwave irradiation, as described by Rostamizadeh Housaini (2004), Bose et al. (2000), Xia Pan (2004); however, this was carried out either on solid supports using solvent a teflon vessel. Though time shortened (10-20min), procedure more tedious when support. is used, condition must carefully controlled special apparatus should due danger organic solvents irradiation because low boiling points high vapor pressure. are partially soluble aldehyde absorbed onto surface with occurring at interphase, principle performed without additional solvent. presence could deleterious dilution reactant.

Solvent-free reaction techniques were successfully coupled with microwave (Loupy et al., 1998) synthesis because they avoid the use of low boiling points and high vapor pressure solvents, which may produce potentially dangerous conditions, such as an explosion. Additionally, a process is less expensive environmentally friendly. rapid development combinatorial libraries, in systematic system initial screening potential activities compounds possible, fast method could be very attractive.

RESULTS AND DISCUSSION

In this paper, we introduce a microwave-assisted solvent-free method for the synthesis of bis(acylhydrazones), which allows more rapid and easier procedure. Self-made hexanediohydrazide reacted with twelve aldehydes to produce corresponding bis(acylhydrazones) (see Figure 1). 4f is new compound. Several experiments were carried out at various reaction times, power levels and different reactant ratios to establish the optimum reaction conditions. The inside temperature of the MW reaction was also studied. The products were analyzed using IR, ¹H NMR and elemental analysis. The ¹H NMR spectra of most compounds display two sets of methylene, imine and amide proton signals, indicating that both cis and trans amide conformers were formed. It is known from conventional synthesis that the cis isomer is formed in excess (Palla et al., 1986). It is expected that the cis isomers of 4a should be due to the formation of an intramolecular hydrogen bond (Cordier et al., 2004).

It was found that there no inevitable relationship between the yields and electron-withdrawing -donating groups in substrates of benzene ring aldehydes. However, containing can make reaction time shorter.

All products were obtained in excellent yields (85-93%) and within minutes (between 2 5 minutes). The optimum conditions, inside temperature of MW reaction are presented Table 1.

EXPERIMENTAL

Melting points were determined with an XRC-1 micromelting point apparatus and uncorrected. Infrared spectra recorded on a FTS-40 spectrophotometer using KBr pellets. ¹H NMR spectra were measured on a Bruker DPX-400 spectrometer at 400 MHz using TMS as internal standard and DMSO-d₆ as solvent. Chemical shifts (d) were expressed in ppm downfield from internal standard TMS and coupling constants J were given in Hz. Elemental analyses were performed on a PE-2400 elemental analyzer. The experiment was carried out in a domestic microwave oven (Galanz Cambi-Grill 750W).

Synthesis of Hexanediohydrazide (2)

One-tenth mol of hexanedioic acid (1) was dissolved in 0.8mol 85% hydrazine hydrate and the mixture was heated at 90ºC for 4h; upon cooling, a white crystal was separated out and recrystallized with ethanol-DMF to get the pure hexanediohydrazide (2).

Synthesis of Bis(acylhydrazones)(4a-4l)

a) Thermal Conditions: General Procedure

Hexanediohydrazide and aldehydes at a ratio of 2:1 were mixed in ethanol refluxed for about 2-4h; then the solvent was concentrated solid filtered recrystallized with ethanol-DMF to get pure product.

b) Microwave Conditons

General procedure for 4a-4g: 1 mmol of hexanediohydrazide (2) was put in a test tube and then 2.4 mmol liquid aldehydes (3a-3g) were added, The test tube was subjected to mechanical vibration to ensure maximum dissolution of the solid in the aldehydes. The reaction tubes were then subjected to microwave irradiation (300W) for the specified time. After the reaction had been completed, the solid was filtered and washed with cool ethanol to get pure products. No further purification was required.

General procedure for 4h-4l: 1 mmol of hexanediohydrazide (2) and 2 mmol of solid aldehydes (3h-3l) were mixed thoroughly in an agate mortar and then the mixture was put into the microwave oven (495W) and irradiated for a specified time to produce the crude solid, which recrystallized with ethanol-DMF to give pure products.

Hexanedioic Acid, Bis[[(2-hydroxyphenyl)methylene]hydrazide] (4a)

White solid; m.p.: 294-296ºC; IR(KBr) u (cm^-1): 3440(OH), 3203(NH), 3069(=CH), 1681(C=O), 1491(C=N); ¹H NMR(400MHz,DMSO-d₆): d 11.57,11.16(2s, 2H, NH), 10.08(s, 2H, OH), 8.32,8.23(2s, 2H, CH=N), 7.60-6.80(m, 8H, Ar-H), 2.60-1.60(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₂₀H₂₂N₄O₄(382.4): C 62.82, H 5.80, N 14.65; Found: C 62.78, H 5.63, N 14.69.

Hexanedioic Acid, Bis[(phenylmethylene)hydrazide] (4b)

White solid; m.p.: 216-218 ºC; IR(KBr) u (cm^-1): 3185(NH), 3094(=CH), 1670(C=O), 1486(C=N); ¹H NMR(400MHz,DMSO-d₆): d 11.31,11.18(2s, 2H, NH), 8.14,7.95(2s, 2H, CH=N), 7.90-7.34(m, 10H, Ar-H), 2.65-1.59(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₂₀H₂₂N₄O₂(350.4): C 68.55, H 6.33, N 15.99; Found: C 68.68, H 6.42, N 15.85.

Hexanedioic Acid, Bis[(2-furanylmethylene)hydrazide] (4c)

White solid; m.p.: 250-252 ºC; IR(KBr) u (cm^-1): 3180(NH), 3093(H-C=N), 1662(C=O), 1473(C=N); ¹H NMR(400MHz,DMSO-d₆): d 11.24,11.12(2s, 2H, NH), 8.03,7.83(2s, 2H, CH=N), 7.78-6.55(m, 6H, Ar-H), 2.55-1.56(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₁₆H₁₈N₄O₄(330.3): C 58.17, H 5.49, N 16.96; Found: C 58.08, H 5.60, N 16.85.

Hexanedioic Acid, Bis[(3-phenyl-2-propenylidene)hydrazide] (4d)

White solid; m.p.: 262-264 ºC; IR(KBr) u (cm^-1): 3238(NH), 3063(=CH), 1666(C=O), 1448(C=N); ¹H NMR(400MHz,DMSO-d₆): d 11.19,11.08(2s, 2H, NH), 7.90,7.77(2d, 2H, CH=N, J=5.6Hz), 7.57-6.92(m, 10H, Ar-H), 2.54-1.56(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₂₄H₂₆N₄O₂(402.5): C 71.62, H 6.51,, N 13.92; Found: C 71.78, H 6.60, N 13.85.

Hexanedioic Acid, Bis[[(4-fluorophenyl)methylene]hydrazide] (4e)

White solid; m.p.: 236-238 ºC; IR(KBr) u (cm^-1): 3235(NH), 3057(=CH), 1661(C=O), 1461(C=N); ¹H NMR(400MHz,DMSO-d₆): d 11.32,11.19(2s, 2H, NH), 8.13,7.94(2s, 2H, CH=N), 7.71-7.16(m, 8H, Ar-H), 2.63-1.57(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₂₀H₂₀F₂N₄O₂(386.4): C 62.17, H 5.22, N 14.50; Found: C 62.38, H 5.15, N 14.41.

Hexanedioic acid, bis[[(2-bromophenyl)methylene]hydrazide] (4f)

White solid; m.p.: 272-274 ºC; IR(KBr) u (cm^-1): 3191(NH), 3052(=CH), 1674(C=O), 1463(C=N); ¹H NMR(400MHz,DMSO-d₆): d 11.58,11.41(2s, 2H, NH), 8.48,8.29(2d, 2H, CH=N, J=2.8), 7.90-7.27(m, 8H, Ar-H), 2.65-1.62(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₂₀H₂₀Br₂N₄O₂(508.2): C 47.27, H 3.97, N 11.02; Found: C 47.08, H 3.80, N 11.11.

Hexanedioic Acid, Bis[[(4-methylphenyl)methylene]hydrazide] (4g)

White solid; m.p.: 244-246 ºC; IR(KBr) u (cm^-1): 3247(NH), 3055(=CH), 1666(C=O), 1462(C=N); ¹H NMR(400MHz,DMSO-d₆): d 11.23,11.10(2s, 2H, NH), 8.09,7.91(2s, 2H, CH=N), 7.54-7.14(m, 8H, Ar-H), 2.63-1.57(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₂₂H₂₆N₄O₂(378.5): C 69.82, H 6.92, N 14.80; Found: C 69.78, H 6.80, N 14.97.

Hexanedioic Acid, Bis[[(3-methoxy-4-hydroxyphenyl)methylene]

hydrazide] (4h)

White solid; m.p.: 213-216 ºC; IR(KBr) u (cm^-1): 3489(OH), 3240(NH), 3059(=CH), 1662(C=O), 1461(C=N); ¹H NMR(400MHz,DMSO-d₆): d 11.11,11.00(2s, 2H, NH), 9.43,9.39(s, 2H, OH), 8.01,8.00(2s, 2H, CH=N), 7.21-6.74(m, 6H, Ar-H), 3.76(s, 6H, CH₃), 2.62-1.56(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₂₂H₂₆N₄O₆(442.5): C 59.72, H 5.92, N 12.66; Found: C 59.78, H 5.70, N 12.51.

Hexanedioic Acid, Bis[[(3-nitrophenyl)methylene]hydrazide] (4i)

White solid; m.p.: 256-258 ºC; IR(KBr) u (cm^-1): 3194(NH), 3086(=CH), 1667(C=O), 1454(C=N); ¹H NMR(400MHz,DMSO-d₆): d 11.57,11.43(2s, 2H, NH), 8.45,8.38(2s, 2H, CH=N), 8.25-7.62(m, 8H, Ar-H), 2.70-1.60(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₂₀H₂₀N₆O₆(440.4): C 54.54, H 4.58, N 19.08; Found: C 54.71, H 4.60, N 18.95.

Hexanedioic Acid, Bis[[(4-chlorophenyl)methylene]hydrazide] (4j)

White solid; m.p.: 265-268 ºC; IR(KBr) u (cm^-1): 3207(NH), 3066(=CH), 1666(C=O), 1489(C=N); ¹H NMR(400MHz,DMSO-d₆): d 11.38,11.25(2s, 2H, NH), 8.12,7.93(2s, 2H, CH=N), 7.67-7.39(m, 8H, Ar-H), 2.63-1.61(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₂₀H₂₀Cl₂N₄O₂(419.3): C 57.29, H 4.81, N 13.36; Found: C 57.38, H 4.71, N 13.25.

Hexanedioic Acid, Bis[[[4-(dimethylamino)phenyl]methylene] hydrazide] (4k)

Yellow solid; m.p.: 302-304ºC; IR(KBr) u (cm^-1): 3188(NH), 3078(=CH), 1671(C=O), 1463(C=N); ¹H NMR(400MHz,DMSO-d₆): d 10.99,11.88(2s, 2H, NH), 7.98,7.81(2s, 2H, CH=N), 7.45-6.63(m, 8H, Ar-H), 2.93-2.88(m, 12H, CH₃), 2.60-1.55(m, 8H, CH₂); Elemental analysis: Calcd.(%) for C₂₄H₃₂N₆O₂(436.6): C 66.03, H 7.39, N 19.25; Found: C 66.17, H 7.51, N 19.21.

Hexanedioic Acid, Bis[[[4-(diethylamino)phenyl]methylene] hydrazide] (4l)

Yellow solid; m.p.: 224-225 ºC; IR(KBr) u (cm^-1): 3193(NH), 3091(=CH), 1668(C=O), 1471(C=N); ¹H NMR(400MHz,DMSO-d₆): d 10.95,10.84(2s, 2H, NH), 7.95,7.79(2s, 2H, CH=N), 7.42-6.57(m, 8H, Ar-H), 3.37-3.32(m, 8H, N-CH₂), 2.62-1.55(m, 8H, CH₂), 1.09-1.02(m, 12H, CH₃); Elemental analysis: Calcd.(%) for C₂₈H₄₀N₆O₂(496.7): C 68.26, H 8.18, N 17.06; Found: C 68.13, H 8.11, N 17.23.

ACKNOWLEDGEMENTS

We gratefully acknowledge the financial support of this work received from Natural Science Foundation China (Project No. 20372018).

(Received: April 24, 2006 ; Accepted: August 6, 2007)

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To whom correspondence should be addressed

Publication Dates

• Publication in this collection
  11 Feb 2008
• Date of issue
  Dec 2007

History

• Accepted
  06 Aug 2007
• Received
  24 Apr 2006