Microwave irradiation: A facile, scalable and convenient method for synthesis of N-phthaloylamino acids

1 Introduction

Phthalimide derivatives are used as anesthetics (Settimo et al., 1989), DNA cleaving agents (Brana and Ramos, 2001; Brana et al., 2003), tumericidals (Kirhenbaum et al., 1994), optical brighteners (Schellhammer and Schroeder, 1975; Stewart, 1981) and as dyes (Wurthner et al., 2004; Ramachandram and Samanta, 1997). They are used as fluoroprobes (Barros et al., 1997) and have interesting photophysical properties (Arhens et al., 2004; Yan et al., 2005). Pyromellitic dianhydride is an analogous compound, which undergoes facile polymerization reaction with diamines to give amide or imides containing polymers. It also has relevance to nanomaterials (Holman et al., 2003). Compounds analogous to phthalimides self assemble to form nano-tube like structures (Kimizuka et al., 1995; Kishikawa et al., 1999; Barooah et al., 2003). The N-phthaloyl derivatives have vast host–guest chemistry (Davies et al., 1984; Jaber et al., 1995; Sandhu and Sandhu, 1995; El-Asmy et al., 1994). The N-phthaloylglycine is a simple N-protected amino acid and has interesting supramolecular structural features on formation of metal complexes (Abdel-Rahman, 2001). Because of the great importance of amino acids in physiological and pharmacological events, and because biological interactions (Juaristi, 1997) and the important of the N-protecting amino in peptide synthesis, it is worthwhile to find a simple, moderate, clean and convenient method for preparation of N-phthaloyl amino acid derivatives which are usually prepared by conventional method (Bedair et al., 2006). The present work represented the synthesis of N-phthaloyl amino acids under solventless mild conditions using microwave irradiation as a rapid, convenient method which give excellent yields and high purity of the products than conventional method.

2 Experimental

Melting points are determined on an electrothermal’s IA9000 series digital capillary melting point apparatus. IR spectra were run (KBr discs) on Perkin Elmer FT spectrophotometer 1000. ¹H and ¹³C NMR spectra were recorded on a JEOL ECP 400 NMR spectrometer operating at 400 MHz in CDCl₃ unless otherwise stated with TMS as internal standard. DEPT and HETCOR experiments were recorded on 500 MHz instrument (Brucker, J.F.B. 288) at King Saud University. Chemical shifts are given in δ ppm and coupling constants (J) are given in Hz. The used Microwave oven is Model No. NN-CD997s/NN-CD987W. Solid structure of 3b was determined by single-crystal X-ray diffraction spectroscopy.

3 Result and discussion

Several parameters have been used to deal with protecting group during peptide-coupling reactions. A key issue is the use of appropriate N-protecting groups, such as the carbamate [tert-butyloxycarbonyl (Boc, 4)] (Mckay and Albertson, 1957), benzyloxycarbonyl (Cbz, Z, 5), (Bergmann and Zervas, 1932), 9-fluorenylmethy-loxcarbonyl (Fmoc, 6) (Carpino, 1987), or the recent type of base-sensitive amino protecting groups 1,1-dioxobenzo[b]thiophene-2-ylmethyloxycarbonyl (Bsmoc,7) (Carpino and Philbin, 1999), 2-(tert-butylsulfonyl)-2-propyloxycarbonyl (Bspoc, 8a) (Carpino et al., 1999), and 2-methylsulfonyl-3-phenyl-1-prop-2-enyloxycarbonyl (Mspoc, 8b) (Carpino and Mansour, 1999), (Fig. 1). It rarely mentioned about the N-Phthaloyl group in peptide synthesis, but it is very useful for other application and synthesis (Burger et al., 1998), because it could be easily removed by aqueous HBr (Hughes and Griffiths, 1997) or hydrazine in ethanol (Chen et al., 1998) and this might not be a suitable condition for longer peptide synthesis.

Close

Figure 1

Structure of protecting group.

Export to PPT

Although the wide application of microwave-mediated synthesis of organic compounds, only very little work appeared about N-phthaloylamino acids. Inspection in the literature cites two works where phthalic anhydride couples with amino acids under microwave-mediated conditions. So, in 1995 Bose et al. (1990) reported that N-phthaloylamino acids could be synthesized within few minutes in good yields using microwave irradiation in DMF. Vidal et al. (2000) reported examination of the latter technique for synthesis of phthalimides, among them phthaloylglycine which was obtained in 90 and 81% yields in xylenes and DMF, respectively. However, at the end of irradiation of these syntheses, the products usually extracted with acetone. Here we re-examined this non-thermal methodology in acetic acid for the preparation of N-phthaloylglycine and other ten representatives. Therefore, we have applied this procedure for the synthesis of target compounds which proved to give excellent yields and in short time reactions (15–20 min), while using conventional method takes 10–14 h reflux in acetic acid or DMF. The synthetic pathway depicted in Scheme 1 outlines the chemistry of the present study. Full characterization of the synthesized compounds was based on the spectral data, particularly ¹H and ¹³C NMR. The assignments of various protons and carbons were achieved by running DEPT-135 and HETCOR Experiments. Thus, IR spectra of 3a–l exhibited two stretching bands in the regions 1658–1670 cm⁻¹ and 1705–1740 cm⁻¹, attributed to the amidic carbonyl and acidic one, respectively.

Close

Scheme 1

Export to PPT

¹H and ¹³C NMR of 3a–l confirmed their structures, and the assignments of all protons and carbons (see experimental) were done by the help of HETCOR experiments while the assignment of the aliphatic protons in 3a–h was further confirmed by DEPT-135. The used method proved to be safe in term of racemization. This was confirmed by the synthesis of authentic sample from N-phthaloyl-(l)-valine and N-phthaloyl-(dl)-valine. The ¹H NMR not detected any of the d-valine in the pure sample of l-isomer (l-at δ 1.05 & 1.07 ppm and d-at δ 0.81 & 0.82 ppm). The structures of the prepared phthalimides were unambiguously verified by single X-ray crystallography of N-phthaloyl-β-alanine (3b) (Fig. 2). The N-phthaloyl glycine generally crystallizes in a monomeric form with a molecule of water and it has an extended hydrogen bonded structure. Recently the dimeric structure was confirmed by X-ray crystallography (Barooah et al., 2006). From the X-ray crystallography of N-phthaloyl-β-alanine (3b) it was observed that (3b) exist as a dimer due to the H-bond between the OH of the carboxyl group and the carbonyl group of the second phthaloyl group (–CO–O4-H–O1⚌C–, Fig. 2A) (Tables 1–4). The dimeric step-like structure with two phthaloyl units disposed in a trans manner should be able to accommodate planar molecules to form guest-host compound (Fig. 2B).

Close

Figure 2

X-ray structure of N-phthaloyl-β-alanine (3b).

Export to PPT

4 Conclusion

Microwave irradiation is safe in term of racemization, fast and rapid technique for preparation of N-phthaloyl amino acids. The X-ray crystallography established the structure of the prepared N-protected amino acids and most of the N-phthaloyl amino acids exist as a dimer. Further investigation for the x-ray crystallography and the biological activity of the prepared compounds are under investigation in our laboratory.