Efficient and convenient synthesis of pyrido [2,1-b]benzothiazole, pyrimidopyrido[2,1-b]benzothiazole and benzothiazolo[3,2-a][1,8]naphthyridine derivatives

Introduction

Benzothiazole derivatives have been important heterocycles for many years because of their broad bioactivities, including antimicrobial [1–5], anticancer [6–11], anthelmintic [12], anticonvulsant [13], and antidiabetic [14] activities. They also serve as intermediates for dyes [15]. In addition, some fused pyridopyrimidine derivatives are biologically active [16–18].

In a similar way, 1,8-naphthyridine derivatives have received attention recently, primarily because this ring system is present in many compounds isolated from natural sources. They exhibit various biological activities [19], such as antibacterial [20, 21], antitumor [22], and antiplatelet [23, 24] activities. Furthermore, various substituted benzothiazoles such as 2-aryl benzothiazoles have received much attention because of their unique structures and uses as radioactive amyloid imagining agents [25] and anticancer agents [26]. In continuation of our interest in the synthesis of heterocycles containing a benzothiazole moiety [27–30], we report herein a facile route to several new benzothiazole-fused heterocyclic systems. We present efficient synthesis of novel pyrido[2,1-b][1,3]benzothiazole, pyrimidopyrido[2,1-b][1,3]benzothiazole, and benzothiazolo[3,2-a][1,8] naphthyridine derivatives.

Results and discussion

As shown in Scheme 1, condensation of compound 1 with benzaldehyde, furfural, 5-bromo-1H-indole-3-carbaldehyde, piperonal, or 4-hydroxy-2-methoxybenzaldehyde in refluxing THF containing a catalytic amount of TEA furnished the corresponding 1-amino-3-aryl-2-(2-benzothiazolyl)-3H-pyrido[2,1-b][1,3]benzothiazole-4-carbonitrile derivatives 2a–e. The assignments of structures 2a–e were supported by their elemental analyses and spectral data. The ¹H NMR spectra of structures 2a–e show two singlets at δ 4.60–4.82 and 8.10–8.90 ppm for C₃-H and NH₂ protons, respectively. In addition, the ¹H-NMR spectrum of compound 2c shows a singlet at δ 10.95 ppm assignable to the NH proton of the indole group. Also, compound 2d showed a signal at δ 6.10 ppm assignable to the methylene group. Compound 2e exhibits singlets at δ 3.80 and 10.10 assignable to the OMe and OH protons, respectively. Mass spectra of 2a–e contain the molecular ion peak for each compound.

Scheme 1

In contrast to the above-mentioned reaction, the treatment of compound 1 with 1,5-diphenyl-1H-pyrazole-3-carbaldehyde (3) in THF in the presence of a catalytic amount of TEA furnished 2-(benzo[d]thiazol-2-yl)- 3-(1,5-diphenyl-1H-pyrazol-3-yl)acrylonitrile (4) rather than the expected product 5 (Scheme 2). The IR spectrum of 4 shows the absence of NH₂ absorption band, but the absorption band at 2198 cm^-1 corresponding to a CN group is seen clearly. The structure of 4 is consistent with the ¹H NMR spectrum, which shows the absence of any D₂O exchangeable signal. There is a precedence in the literature for this outcome, in which the condensation between 1 and isonicotinaldehyde in boiling THF containing a catalytic amount of TEA afforded the (E)-2-(benzo[d]thiazol-2-yl)-3-(pyridin-4-yl)acrylonitrile (6) [31] (Scheme 3). Heating under reflux of compound 6 with malononitrile in ethanol in the presence of a catalytic amount of TEA afforded 1-amino-3-(pyridin-4-yl)-3H-pyrido[2,1-b][1,3]benzothiazole-2,4-dicarbonitrile (7) [32] (Scheme 4). The IR spectrum of 7 displays stretching vibration bands at 3363, 3243, 2208, and 2191 cm^-1 corresponding to NH₂ and two CN groups, respectively. Its ¹H NMR spectrum reveals the presence of signals at δ 4.71 and 6.52 ppm assignable to the C₃-H and NH₂ protons, respectively. The mass spectrum shows the molecular ion peak at m/z 329 (M⁺, 49%), corresponding to the molecular formula C₁₈H₁₁N₅S.

Scheme 2

Scheme 3

Scheme 4

Compound 7 was utilized as a starting material for preparation of a wide variety of fused heterocyclic compounds. Thus, heating of compound 7 with formamide afforded 4-amino-5-(pyridin-4-yl)-5H-pyrimido[5′,4′:5,6]pyrido[2,1-b][1,3]benzothiazole-6-carbonitrile (8). Similarly, a cyclocondensation of compound 7 with hot formic acid afforded 4-oxo-5-(pyridin-4-yl)-3,5-dihydropyrimido[5′,4′:5,6]pyrido[2,1-b][1,3]benzothiazole-6-carbonitrile (9) (Scheme 5). The IR spectrum of compound 9 displays stretching vibration bands at 3284, 2195, and 1645 cm^-1 corresponding to NH, CN, and C=O groups, respectively. Its ¹H NMR spectrum reveals the presence of three singlet signals at δ 4.71, 8.68, and 11.23 ppm assignable to the respective protons C₅-H, C₂-H, and NH protons. The mass spectrum shows the molecular ion peak at m/z 357 (M⁺, 25%) corresponding to the molecular formula C₁₉H₁₁N₅OS. Compound 9 is apparently formed by partial nitrile hydrolysis, amine formylation, and cyclodehydration.

Scheme 5

Compound 7 can be transformed into a number of derivatives. For example, heating compound 7 with malononitrile in DMF and a catalytic amount of TEA under reflux conditions afforded 2,4-diamino-5-(pyridin-4-yl)-5H-[1,3]benzothiazolo[3,2-a][1,8]naphthyridine-3,6-dicarbonitrile (10) rather than the analog 11, in line with the reported results [33] (Scheme 6). The IR spectrum of compound 10 shows the presence of signals for two NH₂ groups around 3405–3313 cm^-1 and two cyano groups at 2205 and 2199 cm^-1. The ¹H NMR spectrum of compound 10 shows a singlet at δ 4.73 assignable to C₅-H, two singlets (D₂O exchangeable) at 6.52 and 8.25 ppm assignable to two NH₂ groups and no signal in the region of 3–4 ppm for a methylene group. Also, ¹³C NMR spectrum reveals only one signal in the region of 20–60 ppm because of C₅, which is consistent with the given structure 10.

Scheme 6

By contrast, the treatment of 7 with ethyl cyanoacetate in boiling DMF containing a catalytic amount of TEA afforded the dicarbonitrile 15 rather than its analog 13 (Scheme 7).

Scheme 7

The structure of 15 was confirmed on the basis of IR, ¹H NMR, ¹³C NMR, and MS data. The mass spectrum shows the molecular ion peak at m/z 396 (M⁺, 100%), which is consistent with the proposed structure, whereas the absence of a triplet-quartet pattern in the ¹H NMR spectrum confirms elimination of the ethoxy group during the reaction.

Conclusions

A convenient and efficient one-pot synthesis of substituted pyrido[2,1-b][1,3]benzothiazoles based on reaction of benzothiazoleacetonitrile with different aromatic aldehydes has been developed. Pyrido[2,1-b]benzothiazole derivative 7 was used as a key precursor for synthesis of novel pyrimidopyrido[2,1-b][1,3]benzothiazole and [1,3]benzothiazolo [3,2-a][1,8]naphthyridine derivatives.

Experimental

Melting points were measured with a Gallenkamp apparatus and are uncorrected. IR spectra were recorded in KBr discs on a Mattson 5000 FTIR spectrophotometer at Microanalytical Unit, Faculty of Science, Mansoura University. ¹H NMR (300 MHz) and ¹³C NMR (75 MHz) spectra were measured on Bruker WP AC 300 instrument in DMSO-d₆. Electron-impact mass spectra were determined on Finnigan Incos 500 at 70 eV. Elemental analyses were carried out at the Microanalytical Centre, Faculty of Science, Cairo University.