Synthesis and characterization of novel substituted N-benzothiazole-2-yl-acetamides

1 Introduction

Various substituted benzothiazoles are known to cover a large domain of pharmacological activities serving as antitumor (Beneteau et al., 1999), anti-microbial (Kabeer et al., 2001; Hassan et al., 1978), anthelmintic (Nadkarni et al., 2000), analgesic (Mruthyunjayasawmy and Shanthaveerappa, 2000), anti-inflammatory (Pontiki and Hadjipavoulou-Litina, 2007; Miyamatsu et al., 1974; Bhusari et al., 2001, 2000a,b) and anticonvulsive (Hays et al., 1994) agents. Moreover, it was reported that the Schiff bases (Hadjipavlou-Litina and Geronikaki, 1998) of thiazole and benzothiazole act as inhibitors of the lipoxygenase affecting inflammation and/or psoriasis. Lipoxygenase is an enzyme which catalyzes the rate-limiting step in the biosynthesis of leukotrienes from arachidonic acid (Brain and Williams, 1990; Muller, 1994). The effective role of azomethine linkage in some biological reactions was also studied (Geronikaki, 1990). Similarly, substituted N-benzothiazol-2-yl-amides are an important class of heterocyclic compounds that exhibit a wide range of biological properties such as ubiquitin ligase inhibitors (Parlati et al., 2005), antitumor (Yoshida et al., 2005), antirotavirus infections (Bailey and Pevear, 2004), the adenosine receptor (Alanine et al., 2001; Kerwin et al., 1997) and the nuclear hormone receptor (Kerwin et al., 1997). In particular, some benzothiazoles substituted at the 2-position with a benzoylamino moiety showed antibacterial, antifungal and antitubercular activities (Brade et al., 1998) and it is therefore of interest to consider the synthesis of novel Schiff bases of benzothiazole and amides except 2b–e and 3d. The compounds were described in the literature (Rathod et al., 2000; Li et al., 1998; Subramanian et al., 2009; Ojha et al., 2001; Shimidzu and Uno, 1973).

In our previous study, some novel benzothiazole Schiff bases and their reduced amine compounds were determined by UV–vis spectroscopic technique and their acidity constants and pK_a values were evaluated in structure elucidation and protonation – deprotonation mechanisms for 2b, 2d, 3b, 3d (Öğretir et al., 2009). In the present work, we report on (i) the synthesis of a novel benzothiazole Schiff base (ii) reduction of the obtained imines (iii) synthesis of the corresponding amide (iv) spectroscopic characterization of the obtained compounds.

2 Experimental

Melting points (mp) were determined on Gallenkamp apparatus, Infrared (FT-IR) spectra were recorded as pressed KBr disc, using Perkin Elmer Precisely Spectrum 100 FT-IR Spectrophotometer, ¹H NMR and ¹³C NMR spectra were recorded Bruker DPX FT NMR (500 MHz) and (125 MHz) spectrometer instrument at 298 K. Chemical shifts are given in δ (ppm) relative to TMS (DMSO-d₆) as the internal standard. Electron impact mass spectra (EI) were obtained using a (LS/MS-APCl) AGILENT 1100 MSD spectrometer at 100 eV. Elemental analyses were obtained on Elementar Analsensysteme GmbH varioMICRO CHNS (Turkish Technical and Scientific Research Council Laboratories, Ankara, Turkey). TLC was performed on pre-coated silica gel plates (Merk 60, F₂₅₄, 0.25 mm). Organic solvents used were of HPLC grade or were purified by the standard procedure. All reagents were of commercial quality or were purified before use.

3 Results and discussion

The title compounds, 2a–4e have been synthesized according to the described process in Scheme 1. The structures of all the compounds 2a–4e were established on the basis of elemental analyses, IR, ¹H NMR, ¹³C NMR and Mass spectral data.

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Scheme 1

Reaction pathways for synthesis of 2a–4e.

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The novel Schiff base 2a was synthesized according to Scheme 1. The products 2b and 2e compounds which were formed through the condensation of aldehyde with amines and 3d were literature compounds (Rathod et al., 2000; Li et al., 1998; Subramanian et al., 2009; Ojha et al., 2001; Shimidzu and Uno, 1973). Compounds 2a, 2c and 2d were formed through the condensation of aldehyde with amines in good yields (76, 72 and 85%). The IR spectra of benzothiazole Schiff base 2a–e exhibit one characteristic band within the range of 1605–1615 cm⁻¹, which can be assigned as (–CH⚌N–). The existence of the aromatic rings is proved by the following bands: aromatic carbon-H stretching υC–H (3045–3040 cm⁻¹), phenyl ring stretching υC–C (1597, 1530, 1505 cm⁻¹).

In the ¹H NMR spectra of benzothiazole Schiff bases, the chemical shift of the aromatic protons is observed within the 7.01–8.06 ppm region of spectrum. The hydroxyl protons for 2a, 2b and 2d appear as a broad signal within the 9.90–11.80 ppm. A sharp singlet is observed within the 9.05–9.14 ppm region of spectrum, which corresponds to the azomethine proton.

Furthermore, in the ¹³C NMR spectrum, a down field shift in peak positions is observed at δ 167.54 ppm due to the presence of carbon atom which is double bonded to nitrogen atoms. The EI-MS of 2a, 2b and 2d show strong molecular ion peaks (m/z 269.1, 15.5%), (m/z 269.1, 10.5%), (m/z 254.1, 10%), respectively. This suggests that the reaction of substituted 2-aminobenzothiazole with different substituted benzaldehydes produces exclusively the Schiff bases. These data confirm the proposed stoichiometry and the structure.

The reduction of benzothiazole Schiff bases 2a–e by NaBH₄ in methanol afforded the corresponding amine compounds 3a–e in good yields 73–93% (Scheme 1). IR studies of each amine compound confirm the formation of –NH– groups, which are observed in the range of 3350–3437 cm⁻¹. The spectra of compounds 3a and 3b having free OH groups display somewhat broadened bands within the 3420–3425 cm⁻¹ region. The integral intensities of each signal in the ¹H NMR spectra of the amine compounds are found to agree with the number of different types of protons present. The ¹H NMR spectra of the compounds 3a–e revealed a fine triplet at δ 8.31–8.45 ppm for the –NH– group. The signals of the methylene protons for the –CH₂–NH– group were detected in the region expected in the range of δ 4.50–4.52 ppm as a doublet. The spectra of 3a and 3b show a singlet at δ 9.4 and δ 10.0 ppm due to the hydrogen of the hydroxyl group. In the ¹H NMR spectra of compound 3a, the peaks at 6.65 ppm (d, 1H), 6.79 ppm (s, d, 2H), 7.02 ppm (d, 1H), 7.14 ppm (t, 1H), 7.28 ppm (d, 1H) and 7.46 ppm (s, 1H) are assigned to be H15, H11, H13, H5, H14, H4, H17, respectively, as aromatic protons. Aromatic protons of compounds 3b–e show similar characteristics as those discussed in compound 3a. In the mass spectral pattern of compound 3a and 3d, the base peak is the M⁺+1 (m/z 271.1, 100%), M⁺+1 (m/z 257.1, 100%), respectively.

The substituted amine compounds 3a–e were reacted with chloroacetyl chloride in dichloromethane to provide the corresponding amide 4c, 4e and esters in good yield 4a, 4b and 4d 60–80% (Scheme 1). The IR spectra of the ester products depict ν(–N–C⚌O) bands within the range of 1672–1699 cm⁻¹ and ν(OC⚌O) bands at 1715–1780 cm⁻¹, which support the assigned structure 4a, 4b and 4d. In the IR spectra of the obtained amides 4c and 4e, carbonyl amide absorption bands appeared to be at 1689–1701 cm⁻¹. Spectral studies reveal that the amide possesses mono carbonyl group. In the ¹H NMR spectra of the ester compound 4a the three different methylene protons of the newly synthesized esters were detected to appear as three separate singlets at 4.65, 4.75 and 5.51 ppm as expected for ester compounds. The seven aromatic protons of the ester compound 4a appear as four doublets, two singlets and a triplet. These doublets appear at chemical shift values of 7.12–7.21 ppm corresponding to H4 and H13, and 7.27–7.68 ppm for H5 and H15. Two singlets are observed within the 7.10–7.83 ppm region of spectrum, which corresponds to H7 and H11. A triplet appears at 7.48 ppm, which is assigned as H14. In the ¹H NMR spectra of the amide compound 4c the two different methylene protons appear as two separate singlets at 4.75 and 5.55 ppm. Aromatic protons of compound 4c show similar characteristics as those discussed in compound 4a. In the ¹³C NMR spectrum of 4c, peak at 167.72 corresponds to carbonyl carbon and peaks at 21.10, 21.50, 43.96 and 50.16 indicate the presence of methyl and methylene carbons, respectively, in the structure. The EI-MS of 4b registered a molecular ion peak at (m/z 424, 10%) (M⁺+1) and fragment ions at (m/z 347, 60.9%), (m/z 105, 3.9%) and the base peak at (m/z 241, 100%) well attests our assignment. The mass spectrum of 4c showed a molecular ion peak at (m/z 346.1, 15%) (M⁺+1). The base peak observed at m/z 345.1 and other fragmentations confirmed our assignment. Along with the above spectral methods, the interesting mass fragmentation study has also helped to confirm the structure of the compounds 2a–4e.

As a result we can conclude that the suggested formulae were confirmed by spectroscopy.

4 Conclusion

Unlike other studies in the literature (Vicini et al., 2003; Billman and Diesing, 1957; Davion et al., 2004), the compounds of 2a and 4e were synthesized according to the references given but by realising some modifications such as in reaction time, solvent type and atmospheric pressure a decrease in reaction time was obtained and an increase in reaction yield. Additionally the solvent used is not greately hazardous for the environment and this also means an important benefit of our method. All spectroscopic analyses confirmed the proposed structures of these compounds.