Modelling One-Pot Method for Synthesis of 2 , 3-Dihydro-1 H-pyrrolo [ 2 , 1-c ] [ 1 , 4 ] benzothiazine 5 , 5-Dioxides and Their Homologues

A facile method for synthesis of 2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzothiazines by interaction of methylenactive (2-fluorophenyl)sulfones with homologues of either 5-methoxy-3,4-dihydro-2H-pyrrole or 5-(methylthio)-3,4-dihydro2H-pyrrole has been developed.

The last synthetic approach for 1,1-dioxo-4H-1,4benzothiadiazines is the most convenient for the achievement of high range molecular diversity due to the variability of radicals in the aromatic ring (R 1 ) and the positions 2, 3, 4 of 1,4-benzothiadiazine moiety (A, R 3 , R 2 ).The most significant limitation of this method is mainly concerned with the leaving halogen (X) activity.For instance, the cyclization of orto-chloroderivatives (X = Cl) could be successfully carried out only in the presence of strong bases [20], silver nitrate [22,23], potassium carbonate-crown-ether [21] or requires the application of microwave technology [24,25].In the case of fluoroderivatives (Х = F), the cyclization proceeds readily [26].
Though the cyclization of 2-[(2-halogenophenyl)sulfonyl]ethylenamines is a versatile methodology for 1,1dioxo-4H-1,4-benzothiadiazines obtaining, the synthesis of the heterocyclic systems where R 2 and R 3 are the parts of the same cycle was not reported yet.
The heating of sulfones 1 with excess of lactims 2 (30% for sulfonylacetonitriles 1а, d-i and 50% for other compounds 1) at 90˚C has been chosen as the standard reaction conditions.The reaction for acetonitriles 1а, d-i was held in DMF media, for other compounds 1 was carried out solvent-free.The process was monitored by TLC and disappearance of starting sulfone 1 spot has been controlled.The results of experiment demonstrated that the interaction of sulfones 1 with 5-methoxy-3,4-dihydro-2H-pyrrole and its homologues 2a-c in chosen conditions did not produces solely products 3.In some cases the products of further cyclization 4 were also present in the reaction mixture.The lactims 2 having larger cycle required more reaction time.Experimental data (Table 1)   show that the compounds 3 with R 1 = CN are the most susceptible for cyclization.Thus, they were chosen as the model objects to study the influence of the substituent in benzene ring on the cyclization of compounds 3. It was established that electrondonating groups interdict formation of 1,4-benzothiadiazine ring, at the same time electronwithdrawing groups (halogens) promote cyclization of enamines 3.For example, the combination of О-methyllactim 2с with sulfonylacetonitriles 1h, i, where R 2 = Cl and F, only gave the product of cyclization 8,9, 10,11-tetrahydro-7H-azepino[2,1-c][1,4]benzothiazine-6carbonitrile 5,5-dioxides 4y, z.The reaction of sulfonylacetone 1b (R 1 = Ac) with О-methyllactim 2a resulted in selectively (1E)-1-[(2-fluorophenyl)sulfonyl]-1-(pyrrolidin-2-ylidene)acetone 3d, and its interaction with lactims 2b and 2c allowed us to isolate only 2-methyl-1,4-benzoxathiine 4,4-dioxide 5 (Figure 3).Probably in the case of sterically hindered lactims 2b, c, the competing reaction of intramolecular cyclization to 2-methyl-1,4-benzoxathiine-4,4-dioxide 5 became the preferable process.
To prove the formation of compound 5 in this reaction, we performed its alternative synthesis by heating of sulfonylacetone 1b in 1,4-dioxane at 90˚C in the presence of equimolar amount DBU for 4 hours.
The interaction of methyl [(2-fluorophenyl)sulfonyl]acetate 1с with O-methyllactim 2a requires more time than interaction with sulfones 1a and 1b and results in the mixture of E-and Z-isomers of enamine 3f.The reaction of sulfone 1с with larger O-methyllactims 2b, c is failed.
The According to the proposed "one-pot", procedure enamines 3 were not isolate.When the reaction of sulfones 1 with lactims 2 was complete, to the cool reaction mixture (20˚C) 1,4-dioxane and equimolar amount of DBU were added and the reaction mixture was heated at 60˚C for 2 -4 hours.After dilution of reaction mixture with 2-propanol, the precipitate formed was filtered and crystallized from DMF-2-propanol mixture.The yields and some properties of obtained compounds are given in Table 2.

Experimental Section
The melting points (˚C) were measured with a Buchi В-520 melting point apparatus and were not corrected.IR spectra were recorded on FT-IR Bruker Tensor-27 spectrometer in KBr.Thin-layer chromatography (TLC) was performed on aluminum sheets precoated with silica gel (Merck, Kieselgel 60 F-254).LC/MS spectra were recorded with PE SCIEX API 150EX liquid chromatograph equipped with a UV detector (λ max 215 and 254 nm) and using a C 18 column (100 × 4 mm).Elution started with water and ended with acetonitrile/water (95:5, v/v) and used a linear gradient at a flow rate of 0.15 mL/min and an analysis cycle time of 25 min. 1

[(2-Fluorophenyl)sulfonyl](pyrrolidin-2-ylidene) acetonitriles and their homologues 3a-c, i-z; typical procedure.
To the solution of [(2-fluorophenyl)sulfonyl]acetonetrile 1а,d-i (10 mmol) in DMF (4 mL) the correspondent O-methyllactim 2a-c (13 mmol) had been added and the mixture was additionally heated for to 8 hours (monitored by TLC, eluent-CHCl 3 ) at 90˚C.The reaction mixture was diluted with 2-propanol after cooling.The precipitate formed was filtered and used for further trans-formation without any additional purification.The compounds were isolated as the mixture of E and Z isomers.The compounds 3b, c, j, k, m, n, p, q, s, t, v, w, x contained a great amount of the correspondent cyclized products 4b, c, j, k, m, n, p, q, s, t, v, w, x as inseparable mixtures, and their analytical samples were not isolated.The compounds 3y, z were not isolated but only the products of their further cyclization 4y, z.
General procedure for synthesis of compounds 4a-z ("one-pot" method).
To the solution of 1 (10 mmol) in DMF (4 mL) the correspondent lactim 2 (13 mmol) had been added and the mixture was additionally heated for 4 to 8 hours (monitored by TLC, eluent-CHCl 3 ) at 90˚C.After the reaction mixture was cooled to room temperature, 1,4dioxane and equimolar amount of DBU were added and the reaction mixture was heated additionally at 60˚C for 2 -4 hours.The precipitate formed after dilution of reaction mixture with 2-propanol, was filtered and crystallized from DMF-2-propanol mixture.and crystallized from 2-propanol-DMF mixture.