Novel Convenient Approach to 6-, 7-, and 8-Numbered Nitrogen Heterocycles Incorporating Endocyclic Sulfonamide Fragment

Abstract

A new effective method for the construction of nitrogen heterocycles incorporating endocyclic pharmacophore sulfonamide fragment, based on the use of easy accessible N-(chlorosulfonyl)imidoyl chloride, CCl₃C(Cl)=NSO₂Cl (1), has been developed. Thus, a reaction of 1 as bielectrophilic 1,3-C–N–S reagent with benzylamines that act as 1,4-N–C–C-C binucleophiles, affords respective 1,2,4-benzothiadiazepine-1,1-dioxides. On the other hand, 1 reacts with alkenyl amines with the formation of respective N-alkenyl amidines undergoing Lewis acids initiated intramolecular cyclization to afford derivatives of 1,2,4-thiadiazines and 1,2,4-thiadiazocines bearing a halomethyl group able for further functionalization. The first examples of electrophilic heterocyclization of the chlorosulfonyl group onto an alkenyl or alkynyl group have been revealed.

1. Introduction

Nitrogen heterocycles are part of a huge number of marketed drugs. They are widely used in modern drugs design [1]. In particular, heterocyclic compounds of different size bearing an endocyclic pharmacophore sulfonamide fragment reveal a wide range of biological effects, including enzymes inhibition, antihypertensive [1,2,3,4], antimicrobial [5], and antiviral activity [6]. Benzothiadiazine-S,S-dioxides were used in the design of phosphodiesterase 7 inhibitors [7], HIV protease inhibitors [8], ATP-sensitive potassium channel openers exhibiting different tissue selectivity profiles [9], potent antiviral agents against HCMV, antagonists of the human CCR5 receptor [6], nonnucleoside human cytomegalovirus selective inhibitors [10], α₁-adrenoceptor antagonists [11], drugs for treatment of cancer and the early stages of Alzheimer disease [12], human herpes virus (HHV-6) and Varicella-Zoster virus [10], and ligands for complexation TACe inhibitors [13] and others. Bridged sultams (bridged sulfonamides) besides applications in medicinal chemistry have been used as a template in stereoselective synthesis enabled by the rapid scission of the N-SO₂ bond [14,15]. Some examples of biorelevant cyclic sulfonamides are shown in Figure 1.

Furthermore, cyclic N-sulfonylamides have been used as key building blocks in the synthesis of chiral auxiliaries, chiral ligands for the preparation of chiral ruthenium(II)-catalysts ([8] and references therein).

Many methods have been developed for the synthesis of fused six-membered cyclic sulfonamides, although each of them has some drawbacks and limitations (see e.g., [2,12] and references therein). The main method for the preparation of monocyclic 1,2,4-thiadiazine 1,1-dioxides is the condensation of 2-chloroethyl sulfonyl chloride with amidines [16]. The sulfa-Staudinger cycloaddition between methanesulfonyl sulfene and N-methyl imines produces mixtures of respective 1,2,4-thiadiazine 1,1-dioxides and 4-aza-δ-sultams in low yields [17]. The only example of the intramolecular addition of a sulfonyl chloride group to a cyanamide fragment producing monocyclic 1,2,4-thiadiazine dioxides derivative was also described [18]. On the other hand, the synthetic methods for medium sized heterocycles are less common as their formation is often hampered by enthalpic and entropic factors [19]. There existed only few approaches to 1,2,4-benzothiadiazepine-1,1-dioxides. In 1988, Palmisano et al. described electrochemical heterocyclization of o-tolenesulfonamides with nitriles, leading to 3-alkyl-4,5-dihydro-1,2,4-benzothiadiazepine dioxides [20]. The method requires special equipment and is limited to N-4 unsubstituted derivatives. Interesting route to benzodiazepines, based on carbodiimide insertion into saccharin via a two atom ring expansion, was reported recently [21]. A few benzothiadiazepines also were synthetized by cyclisation of 2-chlorosulfonylbenzoyl chloride with urea and thiourea [22]. These methods are limited by set of reagents, scope of reactions, and the use of column chromatography for purification of final products. Synthesis of medium sized N,S-heterocycles have been discussed in recent experimental and review papers [13,19,23]. It can be concluded that synthetic methods for the monocyclic thiadiazines and especially for seven- and eight numbered heterocycles with the endocyclic sulfonamide fragment are limited and rather specific for each particular type of compounds. To the best of our knowledge, 1,2,4-thiadiazocine ring system was not known so far.

Therefore, elaboration of new effective synthetic strategies for construction of mono- and polycyclic systems bearing pharmacophore sulfonamide moiety remains a challenging task.

Recently, we have developed a convenient method for the preparation of novel C-N-S-bielectrophilic reagent, N-chlorosulfonyltrichloroacetimidoyl chloride 1a, and demonstrated its utility for the synthesis of 1,2,4-benzothiadiazine 1,1-dioxides derivatives [24] (Scheme 1). The important advantage of C-N-S bielectrophilic reagent 1a is that the presence of strongly electron withdrawing trichloromethyl group at the C=N bond leads to a large difference between the electrophilicity of C- and S-electrophilic sites predetermining high regioselectivity in reactions with nucleophilic agents. Noterworthy, for analogous S,N-bielectrophilic N-chlorosulfonylchloroformamidine 1b (R = NMe₂) (Scheme 1) regioselectivity of reactions with nucleophiles depends on the nature of nucleophile ([24] and references therein).

In the present work, we describe the synthesis of monocyclic and fused six-, seven-, and eight membered heterocycles bearing sulfonamide moiety, based on the use of N-(chlorosulfonyl)acetimidoyl chloride 1a.

2. Results and Discussion

Electrophilic intramolecular cyclization of unsaturated compounds is a powerful tool for the construction of various heterocyclic systems. Much to our surprise, this methodology was never applied to unsaturated compounds with double or triple carbon-carbon bond as nucleophilic site and sulfonyl chloride as electrophile. Although intermolecular addition of sulfonyl chlorides to olefins under free-radical conditions (atom transfer radical addition) is well documented and widely used for the preparation of α-chloro sulfones and vinyl sulfones (see e.g., [25,26,27,28,29] and references therein), there is only one publication reporting small-scale homolytic intramolecular heterocyclization of pent-4-sulfonyl chloride proceeding at high temperature (AIBN-CuCl₂, MeCN, 170 °C) and resulting in 3-chlorotetrahydrothiopyran 1,1-dioxide in a low yield (17%) [30]. Obviously, this heterocyclization is of low preparative value and has rather theoretical meaning.

We believed that the reaction of N-chlorosulfonyl imidoyl chloride 1 with one equivalent of an unsaturated amine would result in regioselective substitution of the chlorine atom at the C=N bond and the formation of respective unsaturated amidine, in which the location and polarity of sulfonyl chloride and olefinic fragment are favorable for intramolecular electrophilic heterocyclization. Indeed, it was found that 1a reacted with N-methyl allyl amine 2a in the presence of triethylamine to form amidine 3a, bearing C=C bond and sulfonyl chloride moiety in the same molecule (Scheme 1). To our delight, addition of anhydrous aluminum chloride initiated clean intramolecular cyclization affording 1,2,4-thiadiazine 1,1-dioxide derivative 4a in 77% yield (Scheme 2, route a). Alternative direction involving cyclization on terminal carbon atom of the C=C bond (route b) was not observed. It is worth of noting that Cu catalyzed photoredox chlorosulfonation of terminal alkenes and alkynes proceeds in accordance with path b, i.e., the addition of the sulfonyl group occurs on the terminal carbon atom [30].

Next, we tested some other conditions for the intramolecular heterocyclization of 3a. In the absence of Lewis acid, 3a remains unchanged upon heating in dichloroethane (

Table 1. Intramolecular heterocyclization of 3a.

Entry	Reagent and Conditions	Conversion of 3a to 4a (%) a
1	ClCH2CH2Cl, reflux, 7 h	NR b
2	AlCl3, CH2Cl2, r.t, 24 h	100
3	TiCl4, CH2Cl2, r.t, 24 h	100
4	BF3·Et2O, CH2Cl2, r.t, 24 h	NR b
5	ZnCl2, CH2Cl2, r.t, 24 h	NR b

^a Determined by LCMS; ^b 4a not detected by LCMS.

, entry 1). Aluminum and titanium chlorides gave similar results, whereas boron trifluoride etherate or zinc chloride are non-effective for the heterocyclization (entries 2–5). From the preparative point of view, aluminum trichloride is the most convenient reagent for the heterocyclization.

The electrophilic heterocyclization found can be extended to other 2-alkenyl amines. As is seen from Scheme 3, the reaction proceeds by the same manner for primary and secondary amines 2 (R = H, Me). Noteworthy, 2-alkenylamines substituted at α- or β-position to nitrogen atom (R¹, R² = H, Me, Ph) can also be successfully used in this novel heterocyclization. Moreover, the preparation of hydrogenated 1,2,4-thiadiazine 1,1-dioxides 4a–e from dichloride 1a and respective alkenylamines 2 can be realized in “one-pot” procedure, without isolation of intermediate amidines of type 3a.

Molecular structure of compounds 4a,b,d was unambiguously proved by X-ray crystallographic analysis (Figure 2). Noteworthy, in compounds 4a,b,d C=N bond lengths (1.289–1.299 Å) are close to standard mean value (1.28 Å) for C=N double bond. Mean value for formally single C-N bonds (1.319 A) are only a little longer and typical for conjugated C-N bonds, indicating on strong delocalization of the electron density in N=C(CCl3)-N system for compounds 4.

Incorporation of the amino group or C=C bond into the cyclic structure allows the preparation of fused heterocycles bearing 1,2,4-thiadiazine fragment. Thus, the reaction of readily accessible 2-vinylpyperidine 6 with the dichloride 1a under the same conditions proceeds regioselectively to afford hydrogenated pyrido[1,2-d][1,2,4]thiadiazine 2,2-dioxide 7 in 75% yield (Scheme 4). The structure of novel pyrido[1,2-d][1,2,4]thiadiazine heterocyclic system 7 was unambiguously proved by X-ray crystallographic analysis (Figure 3). At the same time, the heterocyclization with isomeric cyclohexenylmethyl amine 8 proceeds by two competitive pathways to form regioisomeric spirocyclic thiadiazine 9 and fused thiadiazepine (10) in a ratio of about 3:1. The formation of a seven-numbered heterocycle 10 was confirmed by X-ray crystallographic analysis (Figure 4). The creation of six or seven membered heterocycles obviously resulted from involvement in the cyclization of C-1 or C-2 atom of the double bond. Compounds 9 and 10 were separated by chromatography and isolated in 32% and 10% yields, respectively.

Next, we elongated chain between the amino nitrogen atom and double bond. Surprisingly, the heterocyclization of imidoyl chloride 1a with acyclic 11, or cyclic alkenylamine 13 afforded, though in low yields, difficultly accessible thiadiazocine dioxides 12, 14, rather than expected seven-membered heterocyles, diazepines (Scheme 5). In contrast to Scheme 2 and Scheme 3, cyclization in this case proceeds on the terminal sp² C atom of the alkenylamines 11, 13. Formation of novel 1,2,4-thiadiazocine and pyrido[1,2-d][1,2,4]thiadiazocine heterocyclic systems 12, 14 in Scheme 5 was unambiguously proved by X-ray crystallographic analysis (Figure 5). Notably, cyclization of 1a with 13 proceeds diastereoselectively to form diastereomer 14 with (S*,S*)-relative stereochemistry of C-5 and C-6a stereogenic centers.

For the synthesis of benzothiadiazepines we developed another approach based on the use of benzylamines. It was found that N-alkyl benzylamines 15a,b regioselectively reacted with imidoyl chloride 1a to afford amidines 16a,b. In the presence of AlCl₃ the latter undergo intramolecular sulfonation of benzene ring with the formation of 4,5-dihydro-1,2,4-benzothiadiazepine-1,1-dioxides 17a,b (Scheme 6). The heterocyclization in this case requires more hard conditions (CH₂Cl₂, reflux) than for alkenyl amines (CH₂Cl₂, r.t.), due to less reactivity of the double bond, incorporated in the benzene ring in comparison with the C=C bond of alkenyl amines.

Reaction can be extended to primary benzylamines. In this case, it is more convenient to carry out the synthesis as “one-pot” procedure, without isolation of intermediate unstable NH-amidines. The use of chiral (S)-phenylethyl amine provides enantiomerically pure benzothiadiazepine 19 (Scheme 7).

Molecular structure of benzothiadiazepine-1,1-dioxides 17b, 18, and 19 was proved by X-ray crystallographic analysis (Figure 6).

Diversity of heterocyclic systems incorporating endocylic sulfonamide fragment, accessible from electrophilic heterocyclizations of imidoyl chloride 1 with alkenylamines, can be enlarged by the use of unsaturated amines with triple carbon-carbon bond. Thus, propargylamine reacts with imidoyl chloride 1a similarly to allylamine (Scheme 1) with the formation of comparatively stable ynamidine 20 (Scheme 8). Addition of AlCl₃ initiated clean regio- and stereoselective cyclization to 1,2,4-thiadizine 1,1-dioxides 21 bearing sterically less hindered exocyclic C=C bond of the E-configuration. It should be noted that, to the best of our knowledge, there has been no example of sulfonyl group addition to the non-terminal carbon atom of monosubstituted alkynes. Reported in the literature copper [30], iron [31], and iridium [32,33] catalyzed radical sulfonation of alkynes with sulfonyl chlorides takes place at the terminal carbon atom. Regiospecific intramolecular addition to the non-terminal atom of alkyne 20 in Scheme 7 results most likely from beneficial six-member ring formation. The structure of (E)-4-chloromethylene 1,2,4-thiadiazine-1,1-dioxide 21 was confirmed by X-ray crystallographic analysis (Figure 7).

The introduction of an additional group between C≡C bond and amine nitrogen atom allows preparation of larger sized heterocycles. Thus, the reaction of imidoyl chloride 1a with ynamine 22 leads to a mixture of pyridothiadiazocine-(23) and pyridothiadiazepine 1,1-oxides 24 in a ratio of 3:1 in 84% total yield (Scheme 9). Noteworthy, as in the case of analogous alkenylamines (Scheme 5), formation of eight-membered heterocycle is preferable over seven-membered. (E)-Configuration of exocyclic C=C bond in pyridothiadiazepine dioxide 24 was confirmed by NOE experiment: the signal of =CH proton did not show NOE effect with the two multiplets of the 5-CH₂ group. The similar NOE data were obtained for compound 21, (E)-configuration of which was proved by XRD analysis. Compounds 23 and 24 were separated by chromatography and isolated in 60% and 16% yields, respectively. The structure of the major isomer 23 was proved by X-ray crystallographic analysis (Figure 8).

Synthesized above heterocyclic systems can be further functionalized. Some examples are shown in Scheme 10. Thus, 1-chloromethyl derivative 7 in the presence of base affords methylene derivative 25. Mild dehydrochlorination is obviously associated with a high acidity of C-H proton in α-position to sulfonyl group. Reaction of 7 with Boc protected piperazine allows preparation of hybrid heterocyclic system 26 combining two potentially bioactive heterocyclic moieties in a single molecular platform. In this case, nucleophilic substitution is accompanied by dehydrochlorination and formation of 25 (30%). On the other hand, CCl₃C=N moiety of the thiadiazepine 1,1-dioxide 17a can be readily converted into amide group to afford benzothiadiazepinone-1,1-dioxide 27. Earlier we have reported the similar haloform cleavage of the benzothiadiazine 1,1-dioxides [24]. The molecular structure of benzothiadiazepinone 27 was unambiguously proven by X-ray crystallographic analysis (Figure 9).

All heterocyclic compounds synthesized are quite stable and can be stored for a long time.

3. Materials and Methods

3.1. General

¹H and ¹³C-NMR spectra were acquired on a Varian VXR 400 (Agilent Technologies, Santa Clara, CA, USA), Bruker Avance DRX 500 (Bruker, Ettlingen, Germany) and Agilent 600 (Agilent Technologies, Santa Clara, CA, USA) spectrometers. LCMS analyses were carried out on an Agilent 1200 LC (Agilent Technologies, Santa Clara, CA, USA) system equipped with a G6140 MSD detector (ESI mode). Zorbax C18 RR column (Agilent Technologies, Santa Clara, CA, USA) was used, and gradient elution with 0.1% HCOOH in H2O–MeCN was applied. Preparative HPLC was performed on a Shimadzu LC-8A (Shimadzu Corporation, Tokyo, Japan) equipped with a Phenomenex C18 column (30 × 150 mm) (Phenomenex, Torrance, CA, USA), compounds 23, 24, and 26, or Combiflash RF200 (Teledyne Isco, Lincoln, NE, USA) equipped with a RediSep column (Teledyne Isco, Lincoln, NE, USA),compounds 9 and 10. Elemental analysis was carried out in the analytical laboratory of Institute of organic chemistry, NAS of Ukraine. Melting points were determined by capillary method. All crystallographic measurements were performed on a Bruker Smart Apex II diffractometer (Bruker, Madison, WI, USA) operating in the ω scans mode. The structures were solved by direct methods and refined by the full-matrix least-squares technique in the anisotropic approximation for non-hydrogen atoms using the Bruker SHELXTL [34] and Crystals [35] program packages. The solvate CHCl₃ molecule of 4a could not be modeled satisfactorily thus SQEESE [36] routine in the PlLATON [37,38] software were applied for correction of the data (see Supplementary Materials).

3.2. Typical Procedure for the Synthesis of Compounds 3a, 16a,b, 20

A solution of the appropriate amine 2 (10 mmol) in anhydrous CH₂Cl₂ (50 mL) was added dropwise at 0–5 °C to a solution of 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a (2.8 g, 10 mmol) in anhydrous CH₂Cl₂ (50 mL) for 30 min. Subsequently, a solution of Et₃N (1.4 mL, 10 mmol) in anhydrous CH₂Cl₂ (20 mL) was added dropwise for 30 min and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum, the residue was treated with cold water (50 mL), the precipitate was filtered off, washed with water (4 × 30 mL), and air-dried. The crude material was recrystallized from hexane.

3.2.1. 1-(Allyl(methyl)amino)-2,2,2-trichloroethylidenesulfamoyl Chloride 3a

The title compound was prepared from N-methylallylamine 2a (1.37 g, 19.3 mmol), imidoyl chloride 1a (5.39 g, 19.3 mmol), and triethylamine (2.7 mL, 19.4 mmol). White solid; Yield 4.12 g (68%); mp 72–73 °C. ¹H-NMR (CDCl₃, 500 MHz) δ 3.51 (s, 3H, CH₃), 4.56 (d, 2H, J 5.5 Hz, CH₂), 5.46–5.51 (m, 2H, CH₂), 5.83–5.91 (m, 1H, CH). ¹³C-NMR (CDCl₃, 125 MHz) δ 42.8, 59.4, 92.4, 122.3, 128.6, 167.8. Anal. calcd for C₆H₈Cl₄N₂O₂S, %: C 22.95; H 2.57; Cl 45.16; S 10.21. Found, %: C 22.73; H 2.42; Cl 45.01; S 10.04.

3.2.2. 1-(Benzyl(methyl)amino)-2,2,2-trichloroethylidenesulfamoyl Chloride 16a

The title compound was prepared from N-methylbenzylamine (2.13 g, 17.6 mmol), imidoyl chloride 1a (4.92 g, 17.6 mmol), and triethylamine (2.5 mL, 17.9 mmol). White solid; Yield 4.87 g (76%); mp 71–72 °C; ¹H-NMR (CDCl₃, 500 MHz) δ 3.41 (s, 3H, CH₃), 5.17 (s, 2H, CH₂), 7.29–7.36 (m, 2H, Ph), 7.40–7.47 (m, 3H, Ph). ¹³C-NMR (CDCl₃, 125 MHz) δ 43.4, 61.2, 128.1, 129.3, 129.4, 132.4, 158.7. Anal. calcd for C₁₀H₁₀Cl₄N₂O₂S, %: C 32.99; H 2.77; Cl 38.95; S 8.81. Found, %: C 32.84; H 2.61; Cl 38.68; S 8.66.

3.2.3. 1-(Benzyl(isopropyl)amino)-2,2,2-trichloroethylidenesulfamoyl Chloride 16b

The title compound was prepared from N-isopropylbenzylamine (1.79 g, 12 mmol), imidoyl chloride 1a (3.35 g, 12 mmol), triethylamine (1.7 mL, 12.2 mmol). White solid; Yield 3.77 g (80%); mp 93–94 °C; ¹H-NMR (CDCl₃, 600 MHz) δ 1.27 (d, 6H, J 6.6 Hz, (CH₃)₂), 4.56 (br, 2H, CH₂), 4.95 (br, 1H, CH), 7.19–7.23 (m, 2H, arom.), 7.29–7.35 (m, 3H, arom.). Some signals of minor conformational isomer were also observed: 1.39 (d, J 6.7 Hz, (CH₃)₂), 3.66 (br, CH,), 4.90 (br, CH₂). ¹³C-NMR (CDCl₃+DMSO-d₆, 125 MHz); Major conformational isomer: δ 19.2, 48.2, 55.2, 87.8, 125.7, 127.7, 128.5, 131.8, 159.0; Minor conformational isomer: δ 19.7, 51.5, 51.7, 92.2, 125.8, 127.5, 128.4, 133.6, 151.7. Anal. calcd for C₁₂H₁₄Cl₄N₂O₂S, %: C 36.76; H 3.60; Cl 36.16; S 8.18. Found, %: C 36.68; H 3.54; Cl 35.85; S 8.06.

3.2.4. 1-(Propargyl(methyl)amino)-2,2,2-trichloroethylidenesulfamoyl Chloride 20

The title compound was prepared from N-methylpropargylamine (1.08 g, 15.7 mmol), imidoyl chloride 1a (4.39 g, 15.7 mmol), and triethylamine (2.2 mL, 15.8 mmol). White solid; Yield 3.14 g (64%); mp 85–86 °C; ¹H-NMR (CDCl₃, 400 MHz) δ 2.57 (t, 1H, J 2.4 Hz, CH), 3.66 (s, 3H, CH₃), 4.71 (d, 2H, J 2.4 Hz, CH₂), ¹³C-NMR (CDCl₃, 100 MHz) δ 43.5, 47.5, 74.9, 77.5, 93.6, 157.8. Anal. calcd for C₆H₆Cl₄N₂O₂S, %: C 23.10; H 1.91; Cl 45.45; S 10.28. Found, %: C 23.15; H 2.12; Cl 45.17; S 10.24.

3.3. 6-Chloromethyl-4-methyl-3-trichloromethyl-5,6-dihydro-4H-1,2,4-thiadiazine-1,1-dioxide 4a

Anhydrous AlCl₃ (0.99 g, 7.4 mmol) was slowly added to a solution of the amidine 3a (2.32 g, 7.4 mmol) in CH₂Cl₂ (50 mL), the mixture was stirred at room temperature for 24 h. The solvent was removed under vacuum, the residue was treated with cold water (50 mL), the precipitate was filtered off and dissolved in 10 mL of methanol, the obtained solution was poured into water (200 mL), the precipitate was filtered off, washed with 5% HCl (2 × 20 mL), water (3 × 20 mL) and air-dried. Yield 1.79 g (77%); mp 164–165°C (acetone-toluene 1:4); ¹H-NMR (acetone-d₆, 600 MHz) δ 3.68 (s, 3H, CH₃), 3.69 (dd, 1H, J 11.5 Hz, 9.8 Hz), 3.64–3.89 (m 1H), 4.10 (dd, 1H, J 11.5 Hz, 4.5 Hz), 4.15 (dd, 1H, J 15 Hz, 7.9 Hz), 4.33 (dd, 1H, J 15 Hz, 4.1 Hz), ¹³C-NMR (DMSO-d₆, 125 MHz) δ 38.6, 42.9, 52.4, 53.3, 92.5, 154.1. Anal. calcd for C₆H₈Cl₄N₂O₂S, %: C 22.95; H 2.57; Cl 45.16; S 10.21. Found, %: C 22.73; H 2.69; Cl 45.02; S 9.98.

3.4. Typical Procedure for One-Pot Synthesis of Compounds 4a–e, 7, 12, 14

A solution of the appropriate amine (5 mmol) in anhydrous CH₂Cl₂ (40 mL) was added dropwise at 0–5°C to a solution of imidoyl chloride 1a (1.4 g, 5 mmol) in anhydrous CH₂Cl₂ (20 mL) for 30 min. Subsequently, a solution of Et₃N (0.7 mL, 5 mmol) in anhydrous CH₂Cl₂ (10 mL) was added dropwise for 30 min, the mixture was stirred at room temperature for 1 h, then AlCl₃ (0.67 g, 5 mmol) was added and the obtained mixture was stirred for 24 h at room temperature. The solvent was removed under vacuum, the residue was treated with cold water (50 mL), the precipitate was filtered off and dissolved in 10 mL of methanol, the obtained solution was poured into water (200 mL), the precipitate was filtered off, washed with 5% HCl (2 × 20 mL), water (3 × 20 mL), and air-dried.

3.4.1. Compound 4a

The title compound was prepared from N-methylallylamine 2a (0.185 g, 2.6 mmol), 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a (0.73 g, 2.6 mmol), triethylamine (0.4 mL, 2.9 mmol) and AlCl₃ (0.35 g, 2.6 mmol). Yield 0.59 g (72%). Physico-chemical characteristics of the obtained compound are identical with the sample obtained from amidine 3a (Section 3.3).

3.4.2. 6-Chloromethyl-3-trichloromethyl-5,6-dihydro-4H-1,2,4-thiadiazine-1,1-dioxide 4b

The title compound was prepared from allylamine 2b (0.28 g, 5 mmol), 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a (1.4 g, 5 mmol), triethylamine (0.7 mL, 5 mmol) and AlCl₃ (0.67 g, 5 mmol). Colorless crystals (CH₃CN); Yield 1.26 g (84%); mp 200–202°C; ¹H-NMR (CD₃CN, 600 MHz) δ 3.62–3.67 (m, 1H), 3.95–3.98 (m, 1H), 4.06–4.10 (m, 2H), 8.14 (br, 1H, NH); ¹³C-NMR (DMSO-d₆, 125 MHz) δ 38.6, 41.9, 51.2, 91.9, 157.8. Anal. calcd for C₅H₆Cl₄N₂O₂S, %: C 20.02; H 2.02; Cl 47.27; S 10.69. Found, %: C 19.90; H 2.08; Cl 46.99; S 10.56.

3.4.3. 6-Chloromethyl-6-methyl-3-trichloromethyl-5,6-dihydro-4H-1,2,4-thiadiazine-1,1-dioxide 4c

The title compound was prepared from 2-methylprop-2-en-1-yl-amine 2c (0.41 g, 5.75 mmol), 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a, (1.61 g, 5.75 mmol), triethylamine (0.8 mL, 5.75 mmol) and AlCl₃ (0.77 g, 5.75 mmol). Colorless crystals (CHCl₃); Yield 1.41 g (78%); mp 184–185°C; ¹H-NMR (acetone-d₆, 600 MHz) δ 1.73 (s, 3H, CH₃), 3.51 (d, J 14.4 Hz, 1H), 3.68 (d, J 14.4 Hz, 1H), 3.94 (d, J 11.5 Hz, 1H), 4.16 (d, J 11.5 Hz, 1H), 8.74 (br, 1H, NH); ¹³C-NMR (DMSO-d₆, 125 MHz) δ 23.1, 47.9, 49.2, 57.8, 92.7, 156.6. Anal. calcd for C₆H₈Cl₄N₂O₂S, %: C 22.95; H 2.57; Cl 45.16; S 10.21. Found, %: C 22.88; H 2.49; Cl 45.13; S 10.09.

3.4.4. 6-Chloromethyl-6-phenyl-3-trichloromethyl-5,6-dihydro-4H-1,2,4-thiadiazine-1,1-dioxide 4d

The title compound was prepared from 2-phenylprop-2-en-1-yl-amine hydrochloride 2d (0.78 g, 4.6 mmol), 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a, (1.29 g, 4.6 mmol), triethylamine (1.3 mL, 9.3 mmol) and AlCl₃ (0.62 g, 4.6 mmol). Colorless crystals (CH₃CN); Yield 1.38 g (80%); mp 202–203 °C; ¹H-NMR (acetone-d₆, 600 MHz) δ 3.82 (d, J 14.7, 1H), 4.23 (d, J 14.7, 1H), 4.25 (d, J 12.3, 1H), 4.32 (d, J 12.3, 1H), 7.36–7.39 (m, 1H, Ph), 7.42–7.44 (m, 2H, Ph), 7.64–7.66 (m, 2H, Ph), 9.12 (br, 1H, NH); ¹³C-NMR (DMSO-d₆, 125 MHz) δ 48.8, 51.0, 64.0, 93.3, 126.3, 128.9, 129.1, 138.1, 157.3. Anal. calcd for C₁₁H₁₀Cl₄N₂O₂S, %: C 35.13; H 2.68; Cl 37.71; S 8.52. Found, %: C 35.05; H 2.57; Cl 37.59; S 8.34.

3.4.5. 6-Chloromethyl-5,5-dimethyl-3-trichloromethyl-5,6-dihydro-4H-1,2,4-thiadiazine-1,1-dioxide 4e

The title compound was prepared from 1,1-dimethylprop-2-en-1-yl-amine 2e (0.62 g, 7.3 mmol), imidoyl chloride 1a, (2.04 g, 7.3 mmol), triethylamine (1.1 mL, 7.9 mmol) and AlCl₃ (0.98 g, 7.3 mmol). Colorless crystals (i-PrOH); Yield 1.73 g (72%); mp 173–174 °C; ¹H-NMR (acetone-d₆, 600 MHz) δ 1.63 (s, 3H, CH₃), 1.77 (s, 3H, CH₃), 3.78 (dd, 1H, J 5.1 Hz, J 4.1 Hz CH), 4.13 (dd, 1H, J 12.8 Hz, J 4.1 Hz CH₂), 4.19 (dd, 1H, J 12.8 Hz, J 5.1 Hz CH₂), 8.57 (br, 1H, NH), ¹³C-NMR (DMSO-d₆, 125 MHz) δ 23.1, 28.2, 38.5, 58.9, 61.4, 93.1, 155.7. Anal. calcd for C₇H₁₀Cl₄N₂O₂S, %: C, 25.63; H, 3.07; Cl, 43.23; S, 9.77. Found, %: C, 25.49; H, 3.22; Cl, 43.08; S, 9.46.

3.4.6. 1-Chloromethyl-4-trichloromethyl-1,6,7,8,9,9a-hexahydropyrido[1,2-d][1,2,4]thiadiazine-2,2-dioxide 7

The title compound was prepared from 2-vinylpiperidine hydrochloride 6 (0.6 g, 4.1 mmol), 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a, (1.14 g, 4.1 mmol), triethylamine (1.15 mL, 8.25 mmol) and AlCl₃ (0.55 g, 4.1 mmol). Colorless crystals (benzene); Yield 1.09 g (75%); mp 172–173°C; ¹H-NMR (CDCl₃, 600 MHz) δ 1.69–1.77 (m, 1H), 1.78–1.84 (m, 1H), 1.87–1.89 (m, 2H), 2.04–2.07 (m, 1H), 2.48 (ddd, 1H, J 12.2 Hz, J 13.1 Hz, J 3.7 Hz), 3.24–3.29 (m, 1H), 3.32–3.34 (m, 1H), 3.47 (t, 1H, J 11.2 Hz), 4.10–4.14 (m, 2H), 4.92–4.96 (m, 1H). 29 (m, 1H), 3.32–3.34 (m, 1H), 3.47 (t, 1H, J 11.2 Hz), 4.10–4.14 (m, 2H), 4.92–4.96 (m, 1H). ¹³C-NMR (DMSO-d₆, 100 MHz) δ 25.1 (8-C), 27.0 (7-C), 32.7 (6-C), 41.3 (CH₂Cl), 55.1 (CH₂N), 58.2 (CHS), 63.4 (CHN), 93.7 (CCl₃), 154.9 (C=N). Anal. calcd for C₉H₁₂Cl₄N₂O₂S, %: C 30.53; H 3.42; Cl 40.05; S 9.06. Found, %: C 30.47; H 3.28; Cl 39.76; S 8.92.

3.4.7. 7-Chloro-4-methyl-3-trichloromethyl-5,6,7,8-tetrahydro-4H-1,2,4-thiadiazocine-1,1-dioxide 12

The title compound was prepared from N-methylbut-3-en-1-amine 11 (0.33 g, 3.9 mmol), 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a, (1.09 g, 3.9 mmol), triethylamine (0.55 mL, 3.9 mmol) and AlCl₃ (0.52 g, 3.9 mmol). Colorless crystals (benzene); Yield 0.26 g (20%); mp 174–175 °C; ¹H-NMR (CDCl₃, 600 MHz) δ 2.14–2.19 (m, 1H), 2.60–2.65 (m, 1H), 3.51 (s, 3H, CH₃), 3.66 (dd, 1H, J 11.5 Hz, 15.7 Hz), 3.73 (dd, 1H, J 8.9 Hz, 15.7 Hz), 4.01 (dt, 1H, J 2.3 Hz, 15.4 Hz), 4.18–4.22 (m, 1H), 4.51–4.57 (m, 1H); ¹³C-NMR (DMSO-d₆, 125 MHz) δ 35.7, 42.1, 53.2, 53.4, 60.6, 95.1, 152.8. Anal. calcd for C₇H₁₀Cl₄N₂O₂S, %: C, 25.63; H, 3.07; Cl, 43.23; S, 9.77. Found, %: C, 25.51; H, 3.15; Cl, 43.01; S, 9.54.

3.4.8. 5-Chloro-1-trichloromethyl-4,5,6,6a,7,8,9,10-octahydropyrido[1,2-d][1,2,4]thiadiazocine-3,3-dioxide 14

The title compound was prepared from 2-allylpiperidine hydrochloride 13 (0.81 g, 5 mmol), 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a (1.4 g, 5 mmol), triethylamine (1.4 mL, 10 mmol) and AlCl₃ (0.67 g, 5 mmol). Colorless crystals (benzene-cyclohexane 1:1); Yield 0.22 g (12%); mp 153–154 °C ¹H-NMR (CDCl₃, 600 MHz) δ 1.64–1.76 (m, 3H), 1.79–1.83 (m, 2H), 1.92–1.98 (m, 1H), 2.17 (ddd, 1H, J 14.6 Hz, J 11.3 Hz, J 4 Hz), 2.86–2.91 (m, 1H), 3.19–3.24 (m, 1H), 3.95 (dd, 1H, J 13.9 Hz, J 11 Hz), 4.16–4.24 (m, 2H), 4.58–4.62 (m, 1H), 5.36–5.40 (m, 1H), ¹³C-NMR (CDCl₃, 125 MHz) δ 17.8, 24.4, 29.5, 40.5, 47.1, 49.2, 54.3, 65.9, 94.3, 153.0. Anal. calcd for C₁₀H₁₄Cl₄N₂O₂S, %: C, 32.63; H, 3.83; Cl, 38.52; S, 8.71. Found, %: C, 32.54; H, 3.75; Cl, 38.41; S, 8.52.

3.5. 7-Chloro-3-trichloromethyl-1-thia-2,4-diazaspiro[5.5]undec-2-ene-1,1-dioxide 9 and 5a-Chloro-3-trichloromethyl-4,5,5a,6,7,8,9,9a-octahydro-1,2,4-benzothiadiazepine-1,1-dioxide 10

A suspension of cyclohex-1-en-1-ylmethylamine hydrochloride 8 (0.56 g, 3.8 mmol) in anhydrous CH₂Cl₂ (30 mL) was added at room temperature to a solution of 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a (1.06 g, 3.8 mmol) in anhydrous CH₂Cl₂ (30 mL). Subsequently, a solution of Et₃N (1.1 mL, 7.9 mmol) in anhydrous CH₂Cl₂ (20 mL) was added dropwise at 0–5 °C for 30 min, the reaction mixture was stirred at room temperature for 1.5 h, then AlCl₃ (0.51 g, 3.8 mmol) was added and the obtained mixture was stirred for 24 h at room temperature. The solvent was removed under vacuum, the residue was treated with cold water (50 mL), the precipitate was filtered off and dissolved in 5 mL of isopropanol, the solution was poured into cold water (150 mL), the precipitated solid was filtered off, washed with 5% HCl (2 × 20 mL), water (3 × 20 mL) and air-dried. Total yield of isomers 9 and 10 1.09 g (81%), 9/10 ~ 3:1. Compounds 9 and 10 were separated by preparative HPLC (hexane–i-PrOH) performing gradient elution from 3 to 20% of i-PrOH.

3.5.1. 7-Chloro-3-trichloromethyl-1-thia-2,4-diazaspiro[5.5]undec-2-ene-1,1-dioxide 9

Colorless needles (CH₃CN); Yield 0.43 g (32%); mp 203–204 °C. ¹H-NMR (CDCl₃, 600 MHz) δ 1.63–1.70 (m, 2H), 1.73–1.81 (m, 2H), 1.96–2.04 (m, 2H), 2.09–2.14 (m, 1H), 2.62–2.68 (m, 1H), 3.86 (dd, 1H, J 14.5 Hz, J 3.1 Hz), 4.00 (dd, 1H, J 14.5 Hz, J 3.8 Hz), 4.63–4.65 (m, 1H), 7.08 (br, 1H, NH). ¹³C-NMR (CDCl₃, 100 MHz) δ 18.9, 20.6, 25.0, 31.1, 50.5, 57.0, 58.6, 91.6, 157.9. Anal. calcd for C₉H₁₂Cl₄N₂O₂S, %: C, 30.53; H, 3.42; Cl, 40.05; S, 9.06. Found, %: C, 30.47; H, 3.31; Cl, 39.81; S, 9.01.

3.5.2. 5a-Chloro-3-trichloromethyl-4,5,5a,6,7,8,9,9a-octahydro-1,2,4-benzothiadiazepine-1,1-dioxide 10

Colorless prisms (CH₃CN); Yield 12 mg (9%); mp 223–224 °C; ¹H-NMR (CDCl₃, 600 MHz) δ 1.63–1.82 (m, 4H), 1.85–1.88 (m, 1H), 2.04–2.10 (m, 1H), 2.44–2.49 (m, 1H), 2.64–2.68 (m, 1H), 3.63 (dd, 1H, J 15.4 Hz, J 6.9 Hz), 3.74–3.76 (m, 1H), 4.63 (dd, 1H, J 15.4 Hz, J 5.1 Hz), 7.23 (br, 1H, NH). ¹³C-NMR (DMSO-d₆, 100 MHz) δ 20.0, 20.6, 22.3, 32.1, 56.5, 64.8, 75.0, 93.1, 158.8. Anal. calcd for C₉H₁₂Cl₄N₂O₂S, %: C, 30.53; H, 3.42; Cl, 40.05; S, 9.06. Found, %: C, 30.50; H, 3.47; Cl, 40.11; S, 8.89.

3.6. General Procedure for the Synthesis of Compounds 17a,b

A solution of the amidine 16 (5 mmol) in anhydrous CH₂Cl₂ (50 mL) was treated with AlCl₃ (0.67 g, 5 mmol) and heated under reflux for 16 h. The solvent was removed in vacuum, the residue was treated with cold water (200 mL), the precipitated solid was filtered off, washed with water (4 × 30 mL), and air-dried. The crude material was recrystallized from acetonitrile.

3.6.1. 4-Methyl-3-trichloromethyl-4,5-dihydro-1,2,4-benzothiadiazepine-1,1-dioxide 17a

The title compound was prepared from amidine 16a (2.33 g, 6.4 mmol), and AlCl₃ (0.86 g, 6.4 mmol). Colorless crystals (CH₃CN); Yield 1.14 g (54%); mp 202–203 °C (dec.); ¹H-NMR (CDCl₃, 500 MHz) δ 3.50 (s, 3H, CH₃), 4.93 (s, 2H, CH₂), 7.40 (d, 1H, J 7.3 Hz, arom.), 7.61 (dd, 1H, J 7.3 Hz, J 7.6 Hz, arom.), 7.67 (dd, 1H, J 7.3 Hz, J 7.6 Hz, arom.), 8.11 (d, 1H, J 7.6 Hz, arom.); ¹³C-NMR (DMSO-d₆, 150 MHz) δ 43.3, 55.7, 94.3, 127.2, 130.3, 130.7, 131.5, 134.7, 140.0, 151.9. Anal. calcd for C₁₀H₉Cl₃N₂O₂S, %: C 36.66; H 2.77; N 8.55; Cl 32.46. Found, %: C 36.58; H 2.82; N 8.43; Cl 32.51.

3.6.2. 4-Isopropyl-3-trichloromethyl-4,5-dihydro-1,2,4-benzothiadiazepine-1,1-dioxide 17b

The title compound was prepared from amidine 16b (1.78 g, 4.55 mmol) and AlCl₃ (0.61 g, 4.55 mmol). Colorless crystals (CH₃CN); Yield 0.76 g (47%); mp 209–210 °C (dec.); ¹H-NMR (CDCl₃, 600 MHz) δ 1.40 (d, 6H, J 6.6 Hz (CH₃)₂), 4.96 (s 2H, CH₂), 5.08 (sept, J 6.6 Hz, 1H, CH), 7.42 (d, 1H, J 7.5 Hz, arom.), 7.55 (dd, 1H, J 7.5 Hz, J 7.8 Hz, arom.), 7.63 (dd, 1H, J 7.5 Hz, J 7.8 Hz, arom.), 8.05 (d, 1H, J 7.8 Hz, arom.); ¹³C-NMR (DMSO-d₆, 125 MHz) δ 20.1, 46.3, 55.9, 95.0, 126.5, 130.4, 131.3, 131.9, 134.6, 141.3, 150.6. Anal. calcd for C₁₂H₁₃Cl₃N₂O₂S, %:C 40.52; H 3.68; N 7.88; Cl 29.90. Found, %: 40.48; H 3.64; N 7.76; Cl 29.84.

3.7. General Procedure for the Synthesis of Compounds 18, 19

A solution of benzylamine or (S)-1-phenylethylamine (5 mmol) in anhydrous CH₂Cl₂ (30 mL) was added dropwise at 0–5 °C to a solution of 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a (1.4 g, 5 mmol) in anhydrous CH₂Cl₂ (20 mL) for 30 min. Then a solution of Et₃N (0.7 mL, 5 mmol) in anhydrous CH₂Cl₂ (10 mL) was added dropwise for 10 min. The obtained mixture was treated with AlCl₃ (0.67 g, 5 mmol) and refluxed for 16 h. The solvent was removed in vacuum, the residue was treated with cold water (100 mL). Then, the precipitated solid was filtered off, washed with 5% HCl (2 × 20 mL), water (4 × 20 mL), and air-dried.

3.7.1. 3-Trichloromethyl-4,5-dihydro-1,2,4-benzothiadiazepine-1,1-dioxide 18

The title compound was prepared from benzylamine (0.6 g, 5.6 mmol), 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a (1.56 g, 5.6 mmol), triethylamine (0.8 mL, 5.75 mmol) and AlCl₃ (0.75 g, 5.6 mmol). Yield 0.88 g (50%); Colorless crystals (CH₃CN); mp 223–224 °C (dec.). ¹H-NMR (CDCl₃+DMSO-d₆, 500 MHz) δ 4.96 (br, 2H, CH₂), 7.36 (d, 1H, J 7.5 Hz, arom.), 7.50 (dd, 1H, J 7.5 Hz, J 7.8 Hz, arom.), 7.61 (dd, 1H, J 7.5 Hz, J 7.8 Hz, arom.), 7.92 (d, 1H, J 7.8 Hz, arom.), 9.49 (br, 1H, NH); ¹³C-NMR (DMSO-d₆, 125 MHz) δ 42.0, 94.4, 126.8, 130.2, 130.4, 131.3, 135.1, 140.8, 156.5. Anal. calcd for C₉H₇Cl₃N₂O₂S, %: C 34.47; H 2.25; N 8.93; Cl 33.92. Found, %: C 34.39; H 2.21; N 8.87; Cl 33.96.

3.7.2. (S)-5-Methyl-3-trichloromethyl-2,3,4,5-tetrahydro-1,2,4-benzothiadiazepine-1,1-dioxide 19

The title compound was prepared from (S)-1-phenylethylamine (0.86 g, 7.15 mmol), 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a (2 g, 7.15 mmol), triethylamine (1 mL, 7.2 mmol) and AlCl₃ (0.95 g, 7.15 mmol). Yield 0.85 g (36%); Colorless crystals (benzene-cyclohexane 4:1); mp 212–213 °C (dec.); [α]_D²⁵ –70.8 (c 1.5, CH₃CN). ¹H-NMR (CDCl₃, 600 MHz) δ 1.86 (d, 3H, J 6.9 Hz, CH₃), 6.14 (dq, J 6.9 Hz, J 3.9 Hz 1H, CH), 6.74 (br, 1H, NH), 7.47 (d, 1H, J 7.7 Hz, arom.), 7.58 (t, 1H, J 7.7 Hz, arom.), 7.72 (t, 1H, J 7.7 Hz, arom.), 8.11 (d, 1H, J 7.7 Hz, arom.). ¹³C-NMR (CDCl₃, 150 MHz) δ 17.1, 49.0, 94.0, 124.4, 128.2, 129.8, 134.3, 139.5, 155.0. Anal. calcd for C₁₀H₉Cl₃N₂O₂S, %: C 36.66; H 2.77; N 8.55; Cl 32.46. Found, %: C 36.55; H 2.85; N 8.47; Cl 32.42.

3.8. (E)-6-Chloromethylene-4-methyl-3-trichloromethyl-5,6-dihydro-4H-1,2,4-thiadiazine-1,1-dioxide 21

To a solution of amidine 20 (1.34 g, 4.3 mmol) in anhydrous CH₂Cl₂ (50 mL) was added AlCl₃ (0.58 g, 4.3 mmol) and the mixture was stirred for 24 h at room temperature. The solvent was removed in vacuum, the residue was treated with cold water (100 mL), the precipitate was filtered off and dissolved in 5 mL of methanol, the solution was poured into cold water (200 mL), the precipitated solid was filtered off, washed with water (3 × 30 mL) and air-dried. Yield 0.96 g (71%); Colorless crystals (benzene); mp 173–174 °C; ¹H-NMR (CDCl₃, 400 MHz) δ 3.61 (s, 3H, CH₃), 4.63 (d, 2H, J 1.3 Hz, CH₂), 7.33 (t, 1H, J 1.3 Hz, CH), ¹³C-NMR (DMSO-d₆, 100 MHz) δ 42.5, 51.8, 92.2, 129.4, 130.2, 154.7. Anal. calcd for C₆H₆Cl₄N₂O₂S, %: C 23.10; H 1.91; Cl 45.45; S 10.28. Found, %: C 23.12; H 1.84; Cl 45.36; S 10.19.

3.9. 5-Chloro-1-trichloromethyl-6,6a,7,8,9,10-hexahydropyrido[1,2-d][1,2,4]thiadiazocine 3,3-dioxide 23 and (E)-4-Chloromethylene-1-trichloromethyl-5,5a,6,7,8,9-hexahydro-4H-pyrido[1,2-d][1,2,4]thiadiazepine-3,3-dioxide 24

A solution of Et₃N (1.13 ml, 8.05 mmol) in anhydrous CH₂Cl₂ (40 mL) was added dropwise to a mixture of 2-prop-2-yn-1-ylpiperidine hydrochloride 22 (0.64 g, 4 mmol) and 2,2,2-trichloro-N-(chlorosulfonyl)acetimidoyl chloride 1a (1.12 g, 4 mmol) in anhydrous CH₂Cl₂ (60 mL) at 0–5 °C. After 1 h, AlCl₃ (0.54 g, 4 mmol) was added and the mixture was stirred for 24 h at room temperature. The solvent was removed under vacuum, the residue was treated with cold water (100 mL), the precipitate was filtered off and dissolved in 10 mL of isopropanol, the obtained solution was poured into water (200 mL), the precipitated solid was filtered off, washed with 5% HCl (2 × 20 mL), water (3 × 20 mL) and air-dried. Total yield of isomers 23 and 24 1.23 g (84%), 23/24 ~3:1. Individual compounds 23 and 24 were isolated by preparative HPLC (CH₃CN–H₂O) performing gradient elution from 50 to 100% of CH₃CN.

3.9.1. 5-Chloro-1-trichloromethyl-6,6a,7,8,9,10-hexahydropyrido[1,2-d][1,2,4]thiadiazocine 3,3-dioxide 23

White solid; Yield 0.88 g (60%); mp 152–153 °C. ¹H-NMR (CDCl₃, 600 MHz) δ 1.69–1.88 (m, 4H), 1.93–2.04 (m, 1H), 3.21–3.30 (m, 2H), 3.36–3.42 (m, 1H), 4.50–4.56 (m, 1H), 5.49–5.57 (m, 1H), 6.75 (d, 1H, J 2.4 Hz), ¹³C-NMR (CDCl₃, 100 MHz) δ 17.1, 24.5, 29.1, 39.8, 46.8, 56.6, 94.2, 128.2, 148.5, 157.5. Anal. calcd for C₁₀H₁₂Cl₄N₂O₂S, %: C, 32.81; H, 3.30; Cl, 38.74; S, 8.76. Found, %: C, 32.73; H, 3.37; Cl, 38.65; S, 8.62. Single crystals for XRD analysis were obtained by recrystallization from benzene.

3.9.2. (E)-4-Chloromethylene-1-(trichloromethyl)-5,5a,6,7,8,9-hexahydro-4H-pyrido[1,2-d][1,2,4]thiadiazepine-3,3-dioxide 24

White solid; Yield 0.23 g (16%); mp 124–125 °C. ¹H-NMR (CDCl₃, 600 MHz) δ 1.69–1.84 (m, 5H), 1.91–1.97 (m, 1H), 15.6 (ddd, 1H, J 15.6 Hz, J 4.4 Hz, J 2.6 Hz), 3.09–3.13 (m, 1H), 3.69 (dd, 1H, J 13.6 Hz, 15 Hz), 4.25–4.29 (m, 1H), 4.76–4.81 (m, 1H), 7.41 (d, 1H, J 2.6 Hz), ¹³C-NMR (CDCl₃, 100 MHz) δ 18.2, 24.3, 28.6, 31.7, 47.1, 55.6, 93.9, 132.2, 138.1, 159.2. Anal. calcd for C₁₀H₁₂Cl₄N₂O₂S, %: C, 32.81; H, 3.30; Cl, 38.74; S, 8.76. Found, %: C, 32.77; H, 3.39; Cl, 38.53; S, 8.60. Single crystals for XRD analysis were obtained by recrystallization from acetone-cyclohexane (1:2).

3.10. 1-Methylene-4-(trichloromethyl)-1,6,7,8,9,9a-hexahydropyrido[1,2-d][1,2,4]thiadiazine-2,2-dioxide 25

A solution of DABCO (47 mg, 0.42 mmol) in DMSO (2 mL) was added to a solution of 7 (142 mg, 0.4 mmol) in DMSO (3 mL) and the obtained mixture was stirred at room temperature overnight. The solution was poured into cold water (100 mL), the precipitated solid was filtered off, washed with water (4 × 10 mL) and air-dried. White solid; Yield 91 mg (71%); mp 173–174 °C. ¹H-NMR (CDCl₃, 600 MHz) δ 1.65–1.73 (m, 1H), 1.75–1.87 (m, 2H), 2.00–2.08 (m, 2H), 2.37 (ddd, 1H, J 25.7 Hz, J 12.7 Hz, J 3.6 Hz), 3.18–3.22 (m, 1H), 4.40 (d, 1H, J 12.1 Hz), 4.86–4.90 (m, 1H), 5.82 (s, 1H), 6.27 (s, 1H). ¹³C-NMR (CDCl₃, 100 MHz) δ 23.7, 25.5, 32.3, 53.6, 65.5, 93.3, 122.4, 140.0, 155.0. Anal. calcd for C₉H₁₁Cl₃N₂O₂S, %: C 34.03; H 3.49; N 8.82; Cl 33.49. Found, %: C 33.72; H 3.62; N 8.63; Cl 33.24.

3.11. 1-(4-N-Boc-piperazin-1-yl)methyl-4-trichloromethyl-1,6,7,8,9,9a-hexahydropyrido[1,2-d][1,2,4]thiadiazine-2,2-dioxide 26

N-Boc-piperazine (125 mg, 0.67 mmol) was added to a solution of the compound 7 (237 mg, 0.67 mmol) in DMSO (4 mL). Subsequently, a solution of DIPEA (86 mg, 0.67 mmol) in DMSO (2 mL) was added and the obtained mixture was stirred overnight at room temperature. The solution was poured into cold water (150 mL) the precipitated solid was filtered off, washed with water (5 × 10 mL) and air-dried to yield 315 mg of 26 containing 30% of dehydrochlorination product 25 (¹H-NMR). Compound 26 was isolated by preparative HPLC (CH₃CN–H₂O) performing gradient elution from 50 to 100% of CH₃CN. White solid; Yield 210 mg (62%); mp 112–113 °C. ¹H-NMR (CDCl₃, 600 MHz) δ 1.44 (s, 9H), 1.58–1.71 (br, 2H), 1.76–1.86 (m, 2H), 1.83–1.95 (br, 1H), 1.99–2.06 (m, 1H), 2.18–2.26 (m, 1H), 2.30–2.46 (br, 3H), 2.47–2.61 (br, 2H), 2.92–3.05 (br, 1H), 3.11–3.30 (br, 2H), 3.33–3.61 (br, 4H), 3.82–3.96 (br, 1H), 4.04–4.17 (br, 1H), 4.86–4.91 (m, 1H). ¹³C-NMR (CDCl₃, 100 MHz) δ 24.3 (8-C), 26.1 (7-C), 28.4 (Me), 31.8 (6-C), 43.5 (br, CH₂NCO), 53.4 (2CH₂N-piperazine), 54.0 (C-5), 54.4 (CH₂CHS), 55.8 (C-1), 63.3 (CHN), 80.0 (CMe3), 93.3 (CCl₃), 154.63, 154.7 (C=N, C=O) Some low intensity signals of minor conformational isomer, caused by restricted rotation around amide N-C bond, were also observed: 25.4, 26.3, 50.7, 52.2, 53.2, 63,4, 93.4, 153.9, 154.62 ppm. Anal. calcd for C₁₈H₂₉Cl₃N₄O₄S, %: C 42.91; H 5.80; N 11.12; Cl 21.11. Found, %: C 42.62; H 5.89; N 10.93; Cl 20.94.

3.12. 4-Methyl-4,5-dihydro-1,2,4-benzothiadiazepin-3(2H)-one-1,1-dioxide 27

The mixture of 0.65 g (2 mmol) of compound 17a and 30 mL of 30% aq. KOH solution was refluxed for 3 h until complete dissolution of the precipitate. Concentrated HCl (60 mL) was added to ice cooled solution, the precipitated solid was filtered off, washed with water (4 × 20 mL), and air-dried. Colorless crystals (CH₃CN); Yield 0.3 g (66%); mp 208–209 °C; ¹H-NMR (DMSO-d₆, 400 MHz) δ 3.00 (s, 3H, CH₃), 4.78 (s, 2H, CH₂), 7.60–7.63 (m, 2H, arom.), 7.67–7.71 (m, 1H, arom.), 7.82–7.84 (m, 1H, arom.), 11.31 (br, 1H, NH). ¹³C-NMR (DMSO-d₆, 125 MHz) δ 37.9, 52.2, 124.9, 129.6, 130.5, 133.6, 133.7, 140.2, 152.9. Anal. calcd for C₉H₁₀N₂O₃S, %: C 47.78; H 4.45; N 12.38; S 14.17. Found %: C 47.64; H 4.36; N 12.26; S 13.88.

4. Conclusions

In conclusion, a new type of intramolecular electrophilic heterocyclization involving sulfonyl chloride as electrophilic site and C=C or C≡C bond as a nucleophilic site was found. Aluminum chloride initiated electrophilic heterocyclization of unsaturated amidines generated from imidoyl chloride 1a and various amines bearing double or triple carbon-carbon bond allows preparation of six-, seven- and eight-numbered monocyclic and fused heterocycles with biorelevant endocyclic sulfonamide moiety. Four new heterocyclic ring systems were synthesized: derivatives of the pyrido[1,2-d][1,2,4]thiadiazine 7, 25, 26, 1,2,4-thiadiazocine 12, 14, 23, and pyrido[1,2-d][1,2,4]thiadiazepine 24. The structures of the heterocyles synthesized was unambigously proved by X-ray crystallographic analysis. The regularities found for the regiochemistry of the new heterocyclization may be used for the purposeful preparation of 6-, 7- and 8-numbered heterocycles with biorelevant sulfonamide fragment.