Design and diversity-oriented synthesis of benzo-and pyrido-annulated medium-sized N,S -heterocycles via thio-Michael and Friedel-Crafts approaches

Efficient and concise protocol for the synthesis of fused tetracyclic N,S -heterocycles in particular benzo-and pyrido-fused 1,4-thiazonines, 1,4-thiazecines and 1,4-thiazacycloundecanes is described. The process involves Lewis or Brønsted acids-promoted Friedel-Crafts cyclizations of heterocyclic esters. The required starting thiazepinones were obtained in moderate yields via intramolecular thio-Michael additions of mercapto-amides under mild conditions. The present study without stereochemical assignments illustrates the first example of straightforward access to promising pharmaceutical scaffolds in high yields


Introduction
For more than a century, syntheses of medium-sized benzofused N and S-heterocycles have garnered more attention of both synthetic and medicinal chemists due to their scaffolds constitutes a prominent framework in numerous bioactive natural alkaloids 1 and synthetic drugs 2 possessing interesting physiological properties. 3n the literature, a precise description of synthetic strategies in this area of research is so voluminous that it couldn't comprehend.5][6][7][8][9] In comparison with the regioisomeric thiazepines, a survey shows there are a limited number of published protocols accessing the thiazocines 10 and higher medium-sized N,S-heterocyclic systems.
The most general procedures to thiazocines implied, reactions of α,αˋ-dibromo-o-xylenes with 2aminothiophenols using NaHCO 3 in DMF, 11 the ring-closing metathesis (RCM) of sulfoxide and sulfone intermediates, 12 Pd-catalyzed carbonylations of 2-(2-iodobenzylthio)benzenamines, 13 intramolecular cyclization of thioethers substrates, 14 and LDA-induced cyclizations of 3-(2-bromophenylthio)propan-1amines. 15Unfortunately, the work in the literature towards the synthesis of highly valuable thiazonines or higher ring systems are limited to three restricted examples.These pioneering strategies to thiazonine regioisomers included ring expansion of ω-bromoalkyl benzothiazolium salts which derived from thiazoles substrates, 16 2,3-sigmatropic shifts of S-imides which originated from the reaction of chloramines-T with 2vinylthiacycloheptane 17 and arynic condensation of substituted S-lactam with NaIO 4 . 18In view of their enticing structural complexity, interesting pharmaceutical importance and the great structural diversity of such heterocyclic systems, synthetic chemists have sought to evaluate versatile methods for the synthesis of highly functionalized bioactive cores useful in the drug research field.With these importances in mind, we sought to design a facile protocol for the attempt of accessing medium-sized N&Sheterocycles focusing on achieving molecular diversity and efficiency.In continuation of our research interests in Friedel-Crafts reactions [19][20][21][22] regarding the development of concise methods for the construction carbo-and heterocycles, [23][24][25][26][27] herein, we wish to report the concise synthesis of condensed medium-sized N&Sheterocyclic scaffolds (e.g.tetracyclic benzo-and pyrido-fused 1,4-thiazoninones, 1,4-thiazecinones and 1,4-

Results and Discussion
We anticipated that the most commonly used synthetic procedures utilized to access medium-sized rings are the Friedel-Crafts reactions.Our synthetic route to the tetracyclic medium-sized rings containing N-or Sheterocycles 9a-f is summarized in Scheme 1.In the process, synthesis of heterocyclic ester precursors 8a-f was planned from the model 2-aminopyridine-3-sulfonic acid (1).Acylations of amino-sulfonic acid 1 with cinnamoyl chloride 2a or 3-(pyridin-2-yl)acryloyl chloride 2b 28 in benzene under reflux condition provides amides 3a,b.The latter amides were treated with PCl 5 and the resulting sulfonyl-chlorides were subjected to reduction with Zn/H 2 SO 4 /H 2 O following the standard procedures 29 to obtain thiols 4a,b in moderate yields.Cyclizations of the substituted mercapto-amides 4a,b were achieved via the thio-Michael 30 additions using Et 3 N as a catalyst in dry DCM to give the substituted pyrido [3,2-b] [1,4]thiazepinones 5a,b.The resulting bicyclic thiazepinones were reduced with LiAlH 4 in Et 2 O/THF to afford cyclic amines 6a,b followed by Nalkylation with ethyl α-or β-or γ-halo-alkanoate 7a-c in the presence of K 2 CO 3 in DMF to obtain the corresponding N-ester precursors 8a-f in good overall yields.The constitutions of the products without stereochemical assignments were appropriately characterized by the elemental analysis and spectroscopic analyses.1).
Cyclizations of ester precursors 8a-f have been performed by using AlCl 3 /CH 3 NO 2 or TfOH (trifluoromethanesulfonic acid)-catalysts under different reaction conditions to provide the fused tetracyclic skeletons 9a-f with different regiochemical outcomes (Table 1).After a search in the literature, it was found that this type of transformation is usually carried out by following the Thorpe-Ingold effect, and to test the possibility of cyclizations of suitable functionalized precursors, we decided to carry out a screening of various mild acidic catalysts and optimization of the reaction conditions.A closer look at the data cited in table 1, a few distinct observations that have a bearing on the work presented herein deserve further mention.Electrophilic inhibition problems are common with inter-and intramolecular Friedel-Crafts reactions in the preparation of heterocyclic systems. 31It was found that the ring closure of hetero-arenes is complicated by the continued presence of heteroatoms in the substrates and cyclization step occurs at a slower rate of reaction than that with carbocyclic substrates. 32This occurs due to the basic heteroatoms (sp 3 -hybridized) presented in substrates.This property inhibited acidic catalysts due to the binding properties of the catalyst which accumulates to a build-up of positive charge on the heteroatoms of the substrate.Such effects led to no reactions occurred with less than four equivalents of mild catalysts.The results depicted in Table 1 suggest that the selected acidic catalysts are poorly acidic and are unable to compete effectively complexation with the heteroatoms containing substrates.Hereby, in highly strained notoriously medium rings, the intramolecular cyclizations were carried out under more drastic conditions and the extent of interaction depends on the mildness of catalyst which could possibly allow the ring-closing processes to occur with expanding functional group congruity.
On the other hand, in order to achieve medium-sized carbocycles, these take place by minimizing the transannular severity at the expense of having the unfavorable eclipsed conformations of the cyclic congeners which would surmount or partially circumvented by using more drastic conditions.As a result, these difficulties could be overwhelmed by the use of poor electrophilic catalyst.Hence, we explored the cyclization of esters 8a-f by using more stoichiometric quantities of acidic promoters and the reactions were carried out at high temperatures for longer reaction times.At last, with our optimized reaction conditions in hand, we can ensure that the catalyst strength has proven to be a vital parameter in the cyclization process beside the activated functional group of substrate however, excellent results were obtained with poor electrophilic one.Further evidence for this result was confirmed from NMR spectroscopy.A closer look at the intermediates and cyclic structures, we observed that the benzylic-carbon (C-2) has different groups attached, and so is a chiral center.Because the methylene group is next to a chiral center, its protons are diastereotopic 33 nature.These protons are chemically inequivalent and will split each other resulted in the experience of complex overlapping signals and displayed different chemical shifts.Examples are illustrated in Figure 2. Interestingly, in this orientation, one of the methylene CHs is cis to the aromatic ring, and the other is trans, therefore, they experience different chemical environments with different chemical shifts as well as they cannot be interchanged by any symmetry operation.In addition to the presence of diastereotopic protons, another constitutionally non-equivalent set of conformations (pseudo-axial and equatorial hydrogens) appeared in both precursors 8a-f and products 9a-f.In general, the combination of the chirality with the different conformations in medium-rings, these would lead to that the protons of the methylene group become inequivalent and presenting as more complex signals.
Although the main aim of the research is exclusively directed towards the synthesis of polyheterocycles, herein we do our efforts to identify the configuration of intermediates and cyclic products by Interpretation of NMR spectra.For example, the direct inspection of the 1 H NMR spectrum of compounds 8b and 9b displayed complex signals for both for the protons of CH 2 -group adjacent to the stereogenic center and bridged pseudoaxial and equatorial protons.Moreover, the neighboring environment of the bridged N-CH 2 group is very unsymmetrical due to the ring conformations.The expected downfield shifting signal for pseudo-equatorial could be explained in terms of shielding effect exerted by the magnetic anisotropic effect generated by heteroatoms of both carbonyl group or N&S-heteroatoms of the tetracyclic structures.Thus, the 1 H NMR spectrum of 8b exhibited three triplet signals at δ 1.15, 2.51 and 3.41 ppm related to CH 3 , C  H 2 and C β H 2 groups and one quartet signal appeared at δ 4.10 ppm is assigned to the ester-CH 2 group.Two doublets of doublet doublets signals at 3.66 and 3.54 ppm were suggested to that one of these protons is pseudo-axial, while the other is pseudo-equatorial (C 4 Ha and C 4 Hb) respectively.The most downfield doublet of doublets signal appears at δ 4.20 ppm is assigned to the chiral-C 2 H group.The complex and shielded diastereotopic (C 3 Ha and C 3 Hb) protons of the CH 2 -group showed as a doublet of doublets of doublets of doublets (dddd) at upfield chemical shifts near δ 1.75 ppm with four higher vicinal coupling constants than the other proton.This was ascribed to the equatorial-H3a.While the other proton (axial-H3b) appeared as downfield chemical shifts near δ 2.02 ppm with the same multiplicity (dddd) and low vicinal couplings.
In comparison with the ester 8b, the 1 H NMR spectrum for compound 9b showed that the most upfield with a multiplicity of doublet of doublets of doublets of doublets at δ 2.62 ppm is assigned to the bridged axial-Ha.While the downfield bridged equatorial-Hb signals appeared at δ 2.66 ppm with the same multiplicity (dddd).Complex multiple signals appeared in the regions δ 2.89-3.10,3.69-3.59and 3.58-3.69ppm are assigned to C 7 H 2 CO, N-C 6 H 2 and bridged-NCH 2 groups, respectively.These upfield shifts could be explicated by shielding due to the magnetic anisotropic effect created by a heteroatom or the carbonyl group.The 13 C-NMR spectrum of compound 9b became rather simple showed the splitting patterns corresponding to four upfield signals at δ 31.6,35.2, 47.1 and 49.5 (2C) ppm represents C-7, ethano-bridged carbon C 13 CH 2 , C-13, ethanobridged carbon N 5 -CH 2 and C-6, respectively.
Based on literature precedents on Friedel-Crafts reactions, 19 the result highlights the utility of cyclization procedures lies in the mildness of selected catalysts, operated conditions and functional group compatibility in order to bring ring closure thoroughly.An insight into the carbocation-type mechanism 34 to account for the conversions of esters 8a-f into fused tetracyclic ketones 9a-f is realized on the creation of acyl-carbocation by loss of ethanol molecule upon treatment of ester with acidic catalysts.The resulting acyl-carbocation underwent intramolecular acylations into substituted tetracyclic ketones in overall good yields.][41][42]  Lately, the reactions have strong upsurge utilities for acylations and alkylations of highly reactive electronrich arenes (thiophene, indole, quinoline) constituting the main synthetic step in the synthesis of heterocycles of various ring sizes such as thiazocines, 43 pyrrolothienothiazocines 44 and benzodiazocines. 45In general, syntheses of medium-sized heterocycles via classical cyclization strategies are often entropically less favored by enthalpic and transannular barriers (Figure 3). 46The discovery of Friedel-Crafts processes have revolutionized in the area of medium-ring synthesis, in the main, the reaction was considered as one of the macrocyclization approaches (e.g.carbocyclizations, macrolactonizations and macrolactamizations) applied for the constructions of macromolecule frameworks.Literally, medium-ring rings have a large number of conformations with low energy barriers as well as commonly occurring transannular interactions (non-bonded repulsions).This leads to a considerable amount of Pitzer, Prelog and Baeyer strains. 47The significant cyclization progress in this direction is combined by a relatively small entropic strain in the transition state.To avoid these transannular interactions implied in the synthesis of medium-sized heterocycles, this takes place at the cost of minimized these penalties which could surmount or partially circumvented by using low strength catalysts. 48

Conclusions
In summary, we provided an efficient and concise approach to constructing functionalized benzo-and pyridofused 1,4-thiazonines, 1,4-thiazecines and 1,4-thiazacycloundecanes using AlCl 3 /CH 3 NO 2 and TfOH-mediated cyclizations of the heterocyclic carboxylic esters under a mild condition.Substituted pyrido[3,2b] [1,4]thiazepinone intermediates were synthesized in three linear steps with good yields.Our success with this reaction sequence demonstrating the versatility and the wide variability of Friedel-Crafts reactions in the synthesis of condensed heterocycles from readily available starting materials.

Experimental Section
General.Commercially available reagents were used without further purification unless otherwise stated; solvents were dried by standard procedures.Melting points were taken on a digital Gallenkamp capillary melting point apparatus and are uncorrected.Infrared (IR) spectra were obtained on a Perkin-Elmer 1600 FT-IR spectrophotometer using KBr wafer and thin-film techniques ( cm -1 ) and are in cm -1 .The 1 H NMR and 13 C NMR spectra were recorded on JEOL LA 400 MHz FT-NMR (400 MHz for 1 H NMR, 100 MHz for 13 C NMR) using CDCl 3 solvent with tetramethylsilane (Me 4 Si, TMS) as an internal standard.Chemical shifts are given in parts per million (δ), and the coupling constants (J) are given in Hertz (Hz), respectively.Elemental analyses were carried out by a GmbH Vario EL III, 2400, CHNOS-elemental analyzer.The progress of reactions was accomplished by thin-layer chromatography (TLC) analysis on precoated silica plates (Silufol, UV-254 TLC, aluminum sheets) and plates were visualized with UV light (at 254 and/or 360 nm).Flash column chromatography was performed on silica gel (230-400 mesh).Preparation of 3-(pyridin-2-yl)acryloyl chloride 2b was prepared by heating a mixture of 3-(pyridin-2-yl)acrylic acid, mp 225 °C, dec.(Lit. 16mp 233-236°C) 16 with PCl 5 in benzene for 2 h at a water bath.

General procedure for synthesis of arylamides 3a,b
A solution of acid chloride (cinnamoyl chloride 2a or 3-(pyridin-2-yl)acryloyl chloride 2b (35 mmol) in benzene (20 mL) was added dropwise with stirring to a solution of amino-acid 1 (30 mmol) in dry benzene (40 mL) containing a catalytic amount of pyridine (0.5 mL).The mixture was stirred at room temperature for 2 h and then refluxed in a steam bath for 4 h.The solvent was then concentrated in vacuo and the resulting deposit solid on standing was filtered to afford the crude amides.Purifications, yields and spectral data are given in the

General procedure for conversion of sulfonic acids 3a,b to mercapto-derivatives 4a,b
A mixture of compound 3a or 3b (25 mmol) and PCl 5 (50 mmol) was heated to reflux for 3 h in a water bath and then the sulfonyl chloride was decanted and used in the next step without further purification.To the resulted acid chloride, was added water (30 mL) and zinc dust (20 mmol) and the mixture was heated to 40-50 °C for 5 min.While keeping the temperature at 50-60 °C, zinc dust (40 mmol) added in one portion followed by gradually addition of H 2 SO 4 (80 mmol, 93%) during a period of one 30 min.After the addition was completed, the water-bath was removed and the mixture was stirred at room temperature for 3 h (monitored by TLC, AcOEt/hexane, 1:1).The reaction mixture was diluted with water (100 mL) and extracted with CHCl 3 (3×40 mL).The combined organic layer was separated, washed with water, dried over MgSO 4 , filtered and concentrated in vacuo.The residue was purified by flash column chromatography to provide the product 4a,b.Purifications, specified yields and spectral data are given in the following:

General procedure for the synthesis of thiazepinones via thiol-Michael reaction
To a stirred solution of 4a or 4b (20 mmol) in dry DCM (15 mL) was added dropwise Et 3 N (1 mL) during a period of 10 min while the temperature was kept between 40-50 °C.The mixture was stirred at the same temperature for 14-16h, while the progress of the reaction was monitored by TLC (hexane:EtOAc, 3:1).Upon completion of the reaction, the content was quenched by the addition of aq.HCl solution (10 mL, 20%) and the organic material was extracted with AcOEt (3×30 mL).The combined organic layer was washed with water, dried over Na 2 SO 4 , filtered and concentrated in vacuo.The residue was purified by flash chromatography (basic alumina, AcOEt/hexane, 2:1) to afford the bicyclic products.Purifications, yields and spectral data are given in the following:

Figure 1 .
Figure 1.Examples of medium-sized N and S-heterocycles containing pharmaceutical drugs.

Figure 2 .
Figure 2. Structural example of tetracyclic product 9b and its ester precursor 8b.