Friedel-Crafts chemistry. Part 50. Convergent and diversity-oriented constructions of polycyclic quinolines via Friedel-Crafts and Beckmann ring enlargement approaches

Condensed heterocyclic systems containing N-& S-medium-sized rings, in particular, thiazepine, thiazocine


Introduction
Condensed heterocycles containing N-and S-medium-sized rings, in particular thiazepine, thiazocine, and thiazonine systems, are receiving significant attention because of their presence in a wide range of natural products 1 , and are often incorporated into biologically-active drugs and pharmaceuticals. 2 Literature perusal of pharmacological studies of such moieties reveals that these compounds possess immense chemotherapeutic significance and are present as the core in a variety of drugs 3 (Fig. 1), such as Prothioconazole-thiazocine, Diltiazem, Clotiapine, Omapatrilat, Promazine, Mesoridazine and Quetiapine, and exhibit a wide spectrum of pharmacological activities such as anticoagulant, 4 antiarterisoclerotic, 5 antihypertensive, 6 antidepressant, 7 antihistaminic, 8 anticonvulsant, 9 antidopaminergic, 10 tranquilizer, 11 antidepressant, 12 antihypertensive, 13 calcium channel blocker, 14 blood-platelet-aggregation inhibitors 15 and antiallergic agents. 168][19][20][21][22][23] Formation of thiazonines and higher ring systems, however, remains unknown.Most of the reported strategies for the synthesis of 1,4-thiazocine and higher ring frameworks are presented in a few select publications.For example, Yale et al. 24 reported that dihydrodibenzo[b,f]1,4]thiazocine was obtained from derived α,αˋ-dibromo-o-xylenes and 2-aminothiophenol in the presence of NaHCO3 in DMF solution.In 2004, Bates et al. 25 reported a new strategy for the synthesis of several thiazocine-2-acetic acids from sulfoxide and sulfone analogues by ring-closing metathesis (RCM).They reported that a conjugate addition of allyl mercaptan to acrylate-containing olefinic intermediates, followed by RCM, provided the thiazocines in excellent yields.
Sashida et al. 26 , on the other hand, reported interesting examples for the synthesis of eight-, nine-, and tenmembered rings of tetrahydro-1,2-thiazocines, hexahydro-1,2-thiazonines and 1,2-thiazecines through the 2,3sigmatropic shifts of S-imides of (Z)-2-vinylthiacycloalkanes.They disclosed that the ten-membered ring is generated directly during the treatment of chloramine T with 2-vinylthiacycloheptane. Manhas et al. 27 synthesized several 6,7,8,9,10,11-hexahydro-10-methoxy-benzo[j][l,4]thiazonine-9,11-diones via enlargement (arynic condensation) by oxidation of the corresponding substituted S-lactam with NaIO4 in a water-isopropanol solution.Lu et al. 28 reported the formation of dibenzo[b,f] [1,4]thiazocin-11-ones via the Pd-catalyzed carbonylation reactions of 2-(2-iodobenzylthio)benzenamines in low overall yields.Another isomerization-RCM strategy was carried out by van Otterlo et al. 29 who reported that the synthesis of benzothiazocine dioxide from the corresponding sulfone was carried out in high yield.In an alternative strategy, Lilly et al. 30 reported a simple protocol for the synthesis of various benzo-1,4-thiazocines via intramolecular cyclization of acyclic-thioether substrates.Mukherjee et al. 31 have applied the same intramolecular cyclization methodology to the synthesis of 2,3,4,5-tetrahydro-2Hbenzo[b] [1,4]thiazocines by treatment of 3-(2-bromophenylthio)propan-1-amines (arenes) with lithium diisopropylamide (LDA).Federsel et al. 32 reported the formation of a N-formyl thiazocine series via the conversion of the thiazole and benzothiazole into the corresponding thiazolium salts, followed by ring expansion, which resulted in N-formyl thiazocine and benzothiazocine.Due to the wide range of biological, industrial and synthetic applications of these heterocyclic compounds, the development of a concise and efficient synthetic protocol for these moieties continues to challenge synthetic organic chemists.
In our previous works of this series, 33,34 we described a straightforward synthesis of a novel series of Ncarbocycles of various ring sizes via Friedel-Crafts 35 cycliacylation reactions.In a continuation of these studies, the present research addresses the synthesis and characterization of new heterocyclic skeletons, incorporating N-& S-medium-sized-rings nuclei fused to quinolines, to form the targeted tetracyclic 1,4-thiazocines, 1,4thiazonines and 1,4-thiazecines by applying the ring enlargement approaches of Friedel-Crafts and Beckmannrearrangement sequences.

Results and Discussion
Our synthetic route to the (N-aryl-N-tosylamino)quinolin-8-ylthio)carboxylic acids precursors 10a-i required for this work proceeded via consecutive steps starting from quinoline-8-thiol (1) as depicted in Scheme 1.Initial optimization studies were directed toward the ring-closure of acyclic precursors 4a-c, readily generated in a three-step sequence.

Conclusions
The development of a new, concise, and efficient protocol with broad applicability for the preparation of a range of tetracyclic, medium-sized N-& S-heterocyclic rings fused to quinoline scaffolds using Friedel-Crafts ring closures of synthesized heterocyclic acids in the presence of AlCl3/CH3NO2, P2O5 and PTSA catalysts, and Beckmann rearrangements has been achieved.The ambient conditions, short reaction times and easy work-up procedures make this synthetic strategy a better protocol for the synthesis of medium-sized heterocyclic rings bearing nitrogen and sulphur atoms.The results have demonstrated the significance of a Friedel-Crafts ringclosure approach in the synthesis of heteropolycycles.

General procedure for cyclization of propanoic acids (4a-c).
A mixture of acid 4a or b or c (5 mmol) and freshly prepared PPA (15 g) was heated on an oil bath and kept at temperature 100-110 °C for 5h.Afterwards, the flask was cooled to room temperature and basified by addition of NaHCO3 solution (25 mL, 30%).The residue was extracted with ether (3×20 mL) and the combined organic phases were washed with water, dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo to give the crude ketones 5a-c.

General Procedure for the synthesis of cyclic amides (7a-c).
The title compounds were obtained by applying Beckmann rearrangement of oximes 6a-c.Hence, these skeletons were obtained in a series of two steps.A summary of the steps is given in the following: Method (i) A solution of NH2OH.HCl (0.68 g, 10 mmol) in water (4 mL) was added dropwise with stirring to an ice-cold solution of ketones 5a or b or c (8 mmol) in ethanol (20 mL).Lastly, a solution of NaOH (4 mL, 4 N) was added gradually with efficient stirring during 5 min.The cooling bath was then removed and the reaction mixture was left to stir for 30 min at room temperature, and finally heated in a steam bath at 80-90 °C for 1 h.After cooling to room temperature, the reaction mixture was quenched by adding 50 mL of water.The resulting mixture was extracted with AcOEt (3×30 mL) and the combined organic layers were washed with HCl (2×30 mL, 5%) and water.The organic extracts were dried over anhydrous Na2SO4, filtered, and evaporated to afford the crude oxime.The residue was purified by flash column chromatography (basic alumina, EtOAc/n-hexane, 1/1) resulting in the pure oximes 6a-c.The yields and spectral data are given in the following: Thieno[3,2-h]quinolin-3(2H)-one oxime (6a

Method (ii)
A mixture of oximes 6a or b or c (10 mmol) and polyphosphoric acid (20.0 g) was stirred at 110-120 °C for 5 h.The reaction mixture was cooled to room temperature, diluted with water (50 mL), saturated with NaHCO3 solution (50 mL, 40%) and then left to stand overnight.The separated solid was filtered and washed with water to afford the respective cyclic amide.Recrystallization from ethanol gave the following:

General Procedure for hydrolysis of cyclic amides 7a-c to aminoacids (8a-c).
To a solution of cyclic amide 4a or b or c (20 mmol) in ethanol (30 mL) was added NaOH solution (10 N, 3.5 mL); the resulting mixture was stirred under reflux for 10 h.The excess alcohol was removed by distillation and the residue was diluted with water (50 mL).The resulting solution was filtered, and the filtrate was cooled to room temperature and adjusted to pH 6-7 with HCl solution (30 mL, 20 %).The solution was left to stand at 0 °C overnight.The precipitate was collected, washed and dried to give the crude acids.

Table 2 .
Friedel-Crafts ring closures of acids