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An expedient synthesis of novel bis[thienopyridines] linked to arene or heteroarene core as novel hybrid molecules

A series of novel bis(thieno[2,3-b]pyridines) based arenes or heteroarenes have been synthesized from the appropriate bis-bromoacetyl derivatives upon treatment with the corresponding 2-mercaptonicotinonitrile derivatives in ethanolic sodium ethoxide at reflux. Attempts to synthesize these compounds via bis-alkylation of the appropriate phenol derivative with the corresponding dibromo compounds using a mild base were unsuccessful.


Introduction
Pyridine is one of the most interesting heterocyclic rings due to their wide range of pharmaceutical properties including anti-inflammatory, 1,2 antiasthmatic, 3 antidepressant, 4 acetylcholinesterase inhibitors (AChE), 5 HIV protease inhibitors. 6 They are also used for treating hypertension 7 or hypotension, 8 as well as for inducing or preventingapoptosis. 9 The pyridine structure is present in many natural compounds like nicotinic acid (vitamin B3) and pyridoxine (vitamin B6) and also in many drugs (Figure 1). Pyridines are also exploited in agrochemistry 10,11 as well as in materials science. 12 Different methodologies for construction and functionalization of pyridine derivatives have been recently reviewed. 13,14 Thienopyridines are considered as one of the important fused heterocyclic compounds for their usefulness therapeutic applications. 15,16 Moreover, several thienopyridine derivatives are known to possess antiviral, 17 anti-inflammatory, 18 antimicrobial, 19 antidiabetic, 20 antihypertensive 21 and osteogenic activities. 22 In particular, thieno [2,3-b]pyridines are reported to be useful as anticancer agents. [23][24][25] Due to the numerus applications of pyridine as well as thienopyridine systems, exploring novel structures and novel synthetic procedures for this class of compounds is still in need.

Results and Discussion
The new bis(thieno [2,3-b]pyridines) 5(a-d), in which the two thienopyridine moieties are linked via aromatic spacers, have been synthesized from the appropriate bis-bromoacetyl derivatives 2(a-b) upon treatment with the corresponding 2-mercaptonicotinonitrile derivatives 34 3a and 3b in ethanolic sodium ethoxide at reflux. Compounds 2(a-b) were obtained by bromination of the appropriate bis(acetyl) derivatives 1(a-b) 40 upon treatment with N-bromosuccinimide in acetonitrile at reflux. 40 The step-wise synthesis of 5(a-d) was also performed via initial formation of bis(sulfanediyl))bis(nicotinonitriles) 4(a-d) by the reaction of 2(a-b) with 2-mercaptonicotinonitriles 3a and 3b in ethanol containing few drops of piperidine at reflux. Cyclization of the latter compounds to the corresponding bis(thienopyridines) 5(a-d) was achieved in 65-77% yields, upon heating at reflux in ethanolic solution containing sodium ethoxide (Scheme 1).

Scheme 1. Synthesis of bis(thieno[2,3-b]pyridines) 5(a-d) linked via aromatic spacers.
The structures of compounds 5(a-d) were established based on their spectral data and elemental analyses. Thus, compound 5c showed in its IR spectra the presence of absorption bands at 3480, 3436 and 1593 cm -1 characteristic for the amino group and the carbonyl band, respectively. The successful ring closure of 4c is confirmed by the disappearance of absorption bands characteristic for the cyano group in compound 5c together with the presence of this band in compound 4c. Moreover, the 1 H NMR spectra provide a further confirmation for the ring closure of 4c to 5c Thus, compound 4c exhibited the presence of SCH 2 protons, resonated at δ 4.77 ppm as a singlet signal integrating four protons in compound 4c while that of compound 5c did not show this signal. Moreover, compounds 4c and 5c also featured the methylene ether linkage OCH 2 as a singlet signal at δ 5.2 ppm. All other protons were seen at the expected chemical shifts and integral values (See experimental section).
The free dicarboxylic acid, 3,4-bis((4-(3-amino-4,6diphenylthieno [2,3-b]pyridine-2-carbonyl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylic acid (16) was liberated upon neutralization of 15b with hydrochloric acid (Scheme 3). Compound 14a featured the ethyl ester protons as triplet and quartet signals at δ 1.27 and 4.33 in their 1 H NMR spectra. On the other hand, these signals disappeared in the 1 H NMR spectra of both of the di-sodium salts 15(a-b) as well as the free dicarboxylic acid 16. The latter compound showed the presence of broad signal at δ 3.40 characteristic for the COOH proton. The structure of 16 was further confirmed by IR spectra which showed absorption ban at 3430 cm -1 characteristic for the OH of the carboxylic acid COOH.
Our study included also the synthesis of novel sodium 3,4-bis((2-(3-aminothieno[2,3-b]pyridine-2carbonyl)phenoxy)methyl)thieno[2,3-b]thiophene-2,5-dicarboxylate 20(a-b) as outlined in Scheme 4. For this purpose, the bis-bromoacetyl derivative 18 41 was obtained from the corresponding bis(acetyl) derivative 17 41 upon treatment with N-bromosuccinimide in acetonitrile at reflux. 41   The formation of 21a and 21b proceeded via intramolecular cyclocondensation of the methylene groups at the 3-position of thienothiophene with the ketonic groups of compound 19a and 19b, respectively. Similar behavior of some related systems has been previously reported by us as well as by other groups. [42][43][44][45] The structures of compounds 21(a-b) were established based on their spectral data and elemental analyses. Thus compound 21a showed in its IR spectrum the presence of absorption bands at 3432 and 3330 cm -1 characteristic for the amino group. Moreover, its 1 H NMR spectrum provide a further confirmation for the ring closure of 19a to 21a Thus, compound 21a did not revealed the presence of characteristic signals for the methylene ether protons SCH 2 as well as the OCH 2 protons. On the other hand, its precursor 19a showed two singlet signals each integrating four protons resonated at δ 4.33 and 5.67 ppm characteristic for the SCH 2 and the OCH 2 protons, respectively. All other protons were seen at the expected chemical shifts and integral values (See experimental section).
Motivated by these results, we also attempted to synthesize the novel bis(thieno[2,3-b]pyridines) 22 and 23 ( Figure 2) which are linked to pyridine and quinoxaline, respectively, as spacers by the reaction of 2mercaptonicotinonitrile 3(a-b) with the appropriate bis(bromoacetyl) derivatives using a similar approach. To achieve this goal we studied the synthesis of bis(acetyl)pyridine 25 by the reaction of 2,6bis(bromomethyl)pyridine (7) with potassium 2-acetylphenolate in DMF at reflux. Likewise, bis(acetyl)quinoxaline 28 were also obtained by the reaction of 2,3-bis(bromomethyl)quinoxalines (27) with potassium 4-acetylphenolate in DMF at reflux. Attempted bromination of 25 and 28 to give the corresponding bis(bromoacetyl) derivatives 26 and 29, respectively, either by reaction with Br 2 in acetic acid or upon treatment with N-bromosuccinimide in acetonitrile at reflux were unsuccessful. In all trials, the reactions gave a mixture of products that were not easily handled and have not been characterized as yet (Scheme 5).

Scheme 5. Attempted Synthesis of bis(bromoacetyl) derivatives 26 and 29.
Aiming at synthesizing compounds 22 and 23, which could not prepared by the above method, we then turned to another strategy. For this purpose, (3- 46 have initially been synthesized by the reaction of 2-bromo-1-(4hydroxyphenyl)ethanone (30) with 3a. Compound 31 was then allowed to react with each of bis(bromomethylquinoxaline) 7 and 27 in the presence of ethanolic solution containing sodium ethoxide aiming at obtaining 22 and 23, respectively. Unfortunately, the 1 H-NMR of the reaction products indicated the presence of the target compounds 22 and 23 together with other non-isolable products which may be formed as a result of competing N-alkylation reaction (Scheme 6). It is worthy mentioned that repeated attempts to get the target products 22 or 23 by carrying out the alkylation reactions under different basic conditions were also unsuccessful.

Conclusions
We developed an efficient synthesis of previously unreported bis(thienopyridines) which are linked to arene or heteroarene via phenoxymethyl groups. The structures of the newly synthesized compounds were full characterized by both spectral data and elemental analyses. Trials to synthesize these compounds by alkylation of thieno[2,3-b]pyridin-2-yl)(4-hydroxyphenyl)methanone with the appropriate dibromocompounds were unsuccessful. The main advantages of these reactions include mild reaction conditions, good yields, easily accessible starting materials and straightforward product isolation. The newly synthesized compounds achieved the "hybrid molecules" concept which aims at combining two promising pharmacophores in one molecule.

Experimental Section
General. Melting points were determined in open glass capillaries with a Gallenkamp apparatus and were not corrected. Infrared spectra were recorded in potassium bromide disks on a PyeUnicam SP3-300 and Shimadzu FTIR 8101 PC infrared spectrophotometer. NMR spectra were recorded with a Varian Mercury VXR-300 NMR spectrometer operating at 300 MHz ( 1 H NMR) and 75 MHz ( 13 C NMR), a Varian VXR spectrometer operating at 400 MHz ( 1 H NMR) and 101 MHz ( 13 C NMR) and a Varian VXR spectrometer operating at 500 MHz ( 1 H NMR) and 126 MHz ( 13 C NMR) using TMS as an internal standard and DMSO-d6 as a solvent. Mass spectra were measured on a GC MS-QP1000 EX spectrometer at 70 eV. Elemental analyses were carried out at the Microanalytical Center of Cairo University, Giza, Egypt. The starting 1(a-b), 40 2(a-b), 40 3(a-b), 34 12, 41 13, 41 17, 41 18 41 and 31 46 were prepared following literature procedures.