Diastereoselective synthesis of novel tetra-and pentacyclic annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine derivatives via intramolecular 1,3-dipolar cycloadditions

Abstract

A facile and efficient strategy towards the novel tetra- and pentacyclic annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine via intramolecular 1,3-dipolar cycloadditions of nitrones or azomethine ylides is described. These highly functionalized polycyclic scaffolds were obtained with high diastereoselectivity in high yields via condensation of the initially prepared coumarin-based bifunctional starting materials with sarcosine or N-phenylglycine, L-proline or L-4-thiazolidinecarboxylic acid, and methyl or benzylhydroxylamine. The proof of the structures relies on analytical investigation and X-ray crystallography.

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Introduction

In the domain of cycloaddition,¹ intramolecular 1,3-dipolar cycloaddition of azomethine ylides² and nitrones³ with alkenes on carbo- and heterocyclic systems is one of the most efficient and reliable strategies for the construction of functionalized and stereoisomerically pure five-membered pyrrolidines, pyrrolizidines, pyrrolothiazoles and isoxazolidines. As valuable building blocks, the functionalized derivatives of pyrrolidines,⁴ pyrrolizidines⁵ and pyrrolothiazoles⁶ have outstanding application in the synthesis of natural compounds and pharmaceuticals. On the other hand, the isoxazolidines are valuable precursors, owing to the labile nature of the N–O bond which can be easily modified to biologically active β-amino acids, β-lactams, amino sugars, and alkaloids.⁷ Thus, it is not surprising that development of synthetic routes to pyrrolidine-, pyrrolizidine-, pyrrolothiazole-, and isoxazolidine-containing heterocycles is an interesting challenge in organic synthesis.

Whereas intermolecular 1,3-dipolar cycloadditions employing azomethine ylides⁸ or nitrones⁹ lead to substituted pyrrolidines/pyrrolizines/pyrrolothiazoles and isoxazolidines, respectively, in contrast, intramolecular 1,3-dipolar cycloadditions give annulated polycyclic ring analogs.^2,3 To access this goal, attention has been dedicated toward synthesis of systems in which both reacting components are tethered to the starting material so that polycyclic molecular architecture can be constructed via intramolecular addition of the in situ generated azomethine ylide or nitrone to the dipolarophile partner. So, design and synthesis of a wide variety of polycyclic scaffolds has been carried out by changing the length or position of the tether between the two reaction centers.

Sulfonamides have a rich chemical and biological history and are an important class of compounds in drug discovery due to their extensive chemical and biological activities.¹⁰ Significant interest has been directed toward cyclic sulfonamides, also known as sultams. Although not found in nature,¹¹ sultams are known as privileged structures in drug discovery due to their diverse biological properties.¹² Examples include the ampiroxicam (COX-2) anti-inflammatory agent,¹³ calpain inhibitor 1,¹⁴ benzodithiazine dioxides displaying anti-HIV-1 activity,¹⁵ antiepileptic agent sulthiame,¹⁶ brinzolamide for the treatment of glaucoma,¹⁷ and MMP-2 inhibitor.¹⁸ Sultams with promising bioactivities such as antiviral,¹⁹ anticancer,²⁰ antimicrobial,²¹ antimalarial,²² and antileukemic,²³ are also known. As chemically important materials, sultams have been utilized as efficient chiral auxiliaries and reagents.²⁴

On the other hand, coumarin derivatives have been the subject of recent excellent reviews^25a,b due to the presence of this core structure in many pharmaceuticals and biologically active natural compounds with a wide spectrum of considerable biological activities such as anti-inflammatory,^25c,d anticancer,^25e–g antioxidant,^25h and antituberculosis.²⁵ⁱ

Given that the synthesis of fused triheterocycles encompassing bioactive coumarin, δ-sultam and five-membered pyrrolidine, pyrrolizidine, pyrrolothiazole or isoxazolidine motifs seemed to be interesting due to their individual widespread known biological activities and uses, we undertook a study of the synthesis of heterocyclic scaffolds containing three motifs into one molecule. In continuation of our previous research based on the cyclization reactions,²⁶ as well as sultam scaffold,²⁷ herein, we report an efficient protocol for the synthesis of novel tetra and pentacyclic coumarin-based δ-sultam annulated pyrrolidine, pyrrolizine, pyrrolothiazole and isoxazolidine scaffolds through in situ formation of nitrones or azomethine ylides followed by an intramolecular 1,3-dipolar cycloaddition reaction sequence using coumarin-based biofunctional starting materials. It is noticeable that two/three new rings and three/four contiguous stereocenters with high regio- and stereoselectivity are efficiently created in a single step in this procedure.

Results and discussion

Initially, 4-chloro-3-formyl coumarin (2)²⁸ and (E)-N-alkyl-2-phenylethenesulfonamide 6a–d²⁹ were prepared using the previously reported procedure (Scheme 1a). In the next step, four derivatives of (E)-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-alkylethenesulfonamides 7a–d were synthesized using the method depicted in Scheme 1b.

Scheme 1 Preparation of (a) aldehyde 2 and (E)-N-alkyl-2-phenylethenesulfonamide 6a–d, and (b) (E)-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-alkylethenesulfonamides 7a–d.

(E)-N-(3-Formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-propylethenesulfonamide (7a) served for our early exploration of 1,3-dipolar cycloaddition reaction. Indeed, 9a was isolated as the sole reaction product in 72% upon treatment of 7a with an equimolar amount of sarcosine 8a in EtOH within 10 h (entry 1, Table 1). Whereas reaction in MeOH and toluene occurred more efficiently (entries 2 and 3, Table 1), it was sluggish in DCE and DCM (entries 4 and 5, Table 1). It was discovered that reaction proceeded to completion within 5 h in MeCN, affording 9a in 96% yield (entry 6, Table 1).

Table 1 Optimization conditions of the 1,3-dipolar cycloaddition reaction of azomethine ylide^a

Entry	Solvent	Time (h)	Yield^b (%)
a Reaction conditions: all reactions were carried out using aldehyde (1 mmol), sarcosine (1.1 mmol) with 4 Å MS and 15 mL of solvent at reflux.b Isolated yields.
1	EtOH	10	72
2	MeOH	10	75
3	Toluene	7	88
4	DCE	96	82
5	DCM	96	85
6	MeCN	5	96

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This new method was then applied to a range of 7a–d, sarcosine or N-phenylglycine 8a,b in MeCN at reflux for 5 h. Tetracyclic coumarino-δ-sultam annulated pyrrolidines 9a–h were obtained in excellent yields (Table 2).

Table 2 Synthesis of tetracyclic annulated coumarino-δ-sultam pyrrolidines 9a–h^a,b

a Reaction conditions: aldehyde (1 mmol), cyclic secondary amino acid (1.1 mmol) with 4 Å MS in MeCN (15 mL) at reflux for 5 h.b Isolated yields.c Structure of the molecule was further obtained by single crystal X-ray-diffraction analysis.

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To explore the generality and the substrate scope of the developed condensation, sarcosine and N-phenylglycine 8a,b were replaced with L-proline or L-4-thiazolidinecarboxylic acid 10a,b. The corresponding pyrrolizine and thiopyrrolizine products 11a–h were obtained in satisfactory yields (Table 3).

Table 3 Synthesis of pentacyclic annulated coumarino-δ-sultam pyrrolizines or pyrrolothiazoles 11a–h^a,b

a Reaction conditions: aldehyde (1 mmol), cyclic secondary amino acid (1.1 mmol) with 4 Å MS in MeCN (15 mL) at reflux for 5 h.b Isolated yields.c Structure of the molecule was further obtained by single crystal X-ray-diffraction analysis.

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Inspired by these results, we decided to study the 1,3-dipolar cycloaddition reaction of (E)-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-alkylethenesulfonamides 7a–d with N-methyl or N-benzylhydroxylamine hydrochlorides 12a,b. To prepare 13a, (E)-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-propylethene sulfonamide (7a) was treated with N-methylhydroxylamine hydrochloride 12a and potassium carbonate in methanol at reflux. The isoxazolidine 13a was obtained in 54% yield within 15 h (entry 1, Table 4). When the reaction was repeated in ethanol and acetonitrile, isoxazolidine 13a was obtained in 56% and 73% during 15 h and 10 h, respectively (entries 2 and 3, Table 4). Changing the base to cesium carbonate showed comparable result in acetonitrile and lesser yield in toluene (entries 4 and 5, Table 4). It was shown that reaction with sodium methoxide is sluggish in acetonitrile (entry 6, Table 4). Triethylamine proved to be an excellent base especially in acetonitrile on the basis of the obtained results (entries 7 to 10, Table 4). Encouraged by this result, aldehydes 7a–d were then treated with N-methyl or N-benzylhydroxylamine hydrochlorides 12a,b, which successfully yielded desired derivatives 13a–h (Table 5).

Table 4 Optimization conditions of the 1,3-dipolar cycloaddition reaction of nitrone ylide^a

Entry	Solvent	Base	Time (h)	Yield^b (%)
a Reaction conditions: all reactions were carried out using aldehyde (1 mmol), N-methyl hydroxylamine hydrochloride (1.1 mmol), and base (1.1 mmol) with 4 Å MS and 15 mL of solvent at reflux.b Isolated yields.
1	MeOH	K2CO3	15	54
2	EtOH	K2CO3	15	56
3	MeCN	K2CO3	10	73
4	MeCN	Cs2CO3	10	71
5	Toluene	Cs2CO3	10	68
6	MeCN	NaOMe	15	52
7	EtOH	Et3N	10	68
8	MeOH	Et3N	10	70
9	Toluene	Et3N	7	81
10	MeCN	Et3N	5	92

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Table 5 Synthesis of tetracyclic annulated coumarino-δ-sultam isoxazolidines 13a–h^a,b

a Reaction conditions: aldehyde (1 mmol), N-substituted hydroxylamine hydrochloride (1.1 mmol) with 4 Å MS in the presence of Et₃N (1.1 mmol) in MeCN (15 mL) at reflux for 5 h.b Isolated yields.c Structure of the molecule was further obtained by single crystal X-ray-diffraction analysis.

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Compounds 9a–h, 11a–h and 13a–h were characterized by elemental analysis, MS, IR, and ¹H and ¹³C NMR spectroscopy. Unambiguous evidence for the proposed structures of 9h,³⁰ 11a³¹ and 13h³² was finally obtained by single crystal X-ray-diffraction analysis and the ORTEP diagrams are shown in Fig. 1–3.

Fig. 1 ORTEP diagram of compound 9h with 50% probability displacement ellipsoids (CCDC 1433802†).

Fig. 2 ORTEP diagram of compound 11a 50% probability displacement ellipsoids (CCDC 998125†).

Fig. 3 ORTEP diagram of compound 13h 50% probability displacement ellipsoids (CCDC 1429726†).

Although the precise mechanism is not known, a mechanistic postulate as shown in Scheme 2 may be invoked to rationalize the diastereoselective formation of cis–trans 9a–h, 11a–h and 13a–h, respectively. The dipolar cycloaddition of an azomethine ylide or nitrone generated from sarcosine, methyl or benzylhydroxylamine and an aldehyde with a dipolarophile could lead to a mixture of stereoisomers. Based on the crystal structures of compounds 9h, 11a and 13h, the relative stereochemistry of the Ph group and the adjacent H atom is in the anti orientation, presumably due to the initial E geometry of the double bond present in compounds 7a–d. Since the trans stereochemistry of the alkene dipolarophiles 7a–d has been maintained in pyrrolidines 9a–h, pyrrolizidines 11a–d, thiopyrrolizines 11e–h and isoxazolidines 13a–h (see Table 2, 3 and 5), the cycloadditions have proceeded concerted with both carbon–carbon σ-bonds being formed at the same time, although not necessarily to the same extent. It seems justified that the cis–trans and trans–trans annealated products are expected to be formed via endo-E-ylide I or endo-Z-nitrone I′ transition states and exo-Z-ylide II or exo-E-nitrone II′ transition states, respectively (Scheme 2a and b). The highly diastereoselective formation of cis–trans pyrrolidines 9a–h and isoxazolidines 13a–h reveals the implication of the endo-E-ylide I or endo-Z-nitrone I′ transition states, perhaps due to the more favorable π-interactions in the 1,3-dipolar cycloaddition reaction. Since both endo-E-ylide I or endo-Z-nitrone I′ transition states correspond to an endo-orientation of the substituent Ph and exo-orientation of the rather bulkier coumarin substituent on the dipolarophile, reactions in these cases proceed faster in comparison to those passing respectively through exo-Z-ylide II or exo-E-nitrone II′ transition states.

Scheme 2 Suggested mechanism for the formation of (a) pyrrolidines 9a–h, (b) isoxazolidines 13a–h and (c) pyrrolizidines and thiopyrrolizines 11a–h.

Notably, the dipolar cycloaddition reaction of an azomethine ylide generated from L-proline or L-4-thiazolidinecarboxylic acid and an aldehyde with a dienophile could lead to a mixture of endo-S-shaped III or exo-W-shaped III′ ylides, respectively (Scheme 2c). Inspection of other reported examples together with highly diastereoselective formation of cis–trans pyrrolizidines 11a–d and thiopyrrolizines 11e–h in this presentation perhaps shows some general preference for cycloaddition through an endo-S-shaped ylide III (Scheme 2c).

Overall, novel tetra-and pentacyclic annulated coumarino-δ-sultam pyrrolidine, pyrrolizidine, pyrrolothiazole and isoxazolidine derivatives were obtained via highly diastereoselective processes. These reactions have presumably been proceeded intramolecularly via the in situ generated azomethine or nitrone ylides, affording the desired products in excellent yields (Table 2, 3 and 5). As such, it can be concluded that azomethine and nitrone ylide intermediates react with dipolarophile with the least decomposition of the ylides under the reaction conditions. It implies in turn that both azomethine and nitrone ylides are rather stable although the nature of the tethered RN–SO₂–CH=CHPh group as a good dipolarophile may not be overlooked.

Conclusions

In conclusion, a number of bifunctional (E)-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-alkylethenesulfonamides 7a–d were initially prepared from 4-chloro-3-formyl coumarin (2) and (E)-N-alkyl-2-phenylethenesulfonamide 6a–d. These starting materials underwent reactions with secondary amino acids or N-substituted methyl or benzylhydroxylamines in acetonitrile at reflux within 5 h. A variety of pyrrolidines 9a–h, pyrrolizidines 11a–h and isoxazolidines 13a–h were obtained in excellent yields. These reactions were designed to initially generate in situ an azomethine or nitrone ylides to accomplish an intramolecular 1,3-dipolar cycloadditions. These new structures broaden the scaffolds that are accessible through 1,3-dipolar cycloadditions reactions and many of them may represent interesting pharmacophores.

Experimental

General information

All commercially available chemicals and reagents were purchased from Merck Chemical Company and used without further purification. Melting points were determined with an Electrothermal model 9100 apparatus and are uncorrected. IR spectra were recorded on a Shimadzu 4300 spectrophotometer, in cm⁻¹. ¹H and ¹³C NMR spectra were recorded on a Bruker DRX-500-AVANCE spectrometer at 300 (¹H) and 75 MHz (¹³C) using CDCl₃ as solvent. Mass spectra of the products were obtained with an HP (Agilent technologies) 5937 Mass Selective Detector. Elemental analyses were carried out by a CHN-Rapid Heraeus elemental analyzer (Wellesley, MA).

General procedure for the synthesis of compounds 6a–d

To a stirring solution of (E)-2-phenylethenesulfonyl chloride 4 (10 mmol) in CH₃CN (30 mL) were added primary amines 5a–d (10 mmol) and K₂CO₃ (1.38 g, 10 mmol) and the reaction mixture was stirred at room temperature (25 °C) for 24 h. After completion of the reaction as indicated by TLC, the solid was filtered, and the filtrate was concentrated under reduced pressure to afford products 6a–d as yellowish oil or white solid.

General procedure for the synthesis of compounds 7a–d

To an ice-cooled solution of (E)-N-alkyl-2-phenylethenesulfonamide derivatives 6a–d (10 mmol) in DMF (20 mL) was added 60% sodium hydride in mineral oil (0.88 g, 22 mmol), and the mixture was stirred for 30 min at room temperature. Subsequently, 4-chloro-3-formyl coumarin 2 (2.08 g, 10 mmol) was added, and the mixture was stirred for 2 h at room temperature. After completion of the reaction as indicated by TLC, the reaction mixture was poured into ice-water with constant stirring. The mixture was then extracted with methylene chloride for three times, and the organic phase was washed with water and brine solution, and finally dried over Na₂SO₄. The solvent was then evaporated under reduced pressure, and the crude product was purified by column chromatography (SiO₂, eluent: 5 : 1, n-hexane/EtOAc) to afford products 7a–d as yellow solids.

(E)-N-(3-Formyl-2-oxo-2H-chromen-4-yl)-2-phenyl-N-propylethenesulfonamide (7a). Yellow solid (103 mg, 26%); mp 166–168 °C; IR (KBr) ν_max 1705 (C=O), 1343 (–SO₂), 1142 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.47; ¹H NMR (300 MHz, CDCl₃) δ 0.85 (t, J = 7.4 Hz, 3H, MeCH₂CH₂N), 1.46–1.55 (m, 1H, MeCHHCH₂N), 1.69–1.79 (m, 1H, MeCHHCH₂N), 3.38 (ddd, J = 14.6, 11.0, 5.3 Hz, 1H, MeCH₂CHHN), 3.73 (ddd, J = 14.5, 11.3, 5.4 Hz, 1H, MeCH₂CHHN), 6.93 (d, J = 15.3 Hz, 1H, SO₂CH), 7.39–7.62 (8H, m, Ar and PhCH), 7.73 (td, J = 8.5, 1.4 Hz, 1H, Ar), 8.21 (dd, J = 8.1, 1.3 Hz, 1H, Ar), 10.35 (s, 1H, CHO) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 11.1, 22.8, 54.1, 116.9, 118.6, 120.7, 124.8, 125.2, 128.5 (2C), 129.1 (2C), 129.3, 131.1, 132.2, 135.3, 143.3, 154.0, 154.3, 161.1, 188.0 ppm; m/z (EI, 70 eV) 398 (19, M⁺ + 1), 333 (25), 304 (74), 230 (100), 212 (32), 200 (15), 186 (25), 175 (8), 167 (14), 161 (30), 146 (8), 119 (25), 103 (89), 91 (26), 77 (46%); anal. calcd for C₂₁H₁₉NO₅S: C, 63.46; H, 4.82; N, 3.52. Found: C, 63.23; H, 4.91; N, 3.34%.

(E)-N-Butyl-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-phenylethenesulfonamide (7b). Yellow solid (103 mg, 25%); mp 139–141 °C; IR (KBr) ν_max 1705 (C=O), 1347 (–SO₂), 1139 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.52; ¹H NMR (300 MHz, CDCl₃) δ 0.83 (t, J = 7.3 Hz, 3H, MeCH₂CH₂CH₂N), 1.19–1.28 (m, 2H, MeCHHCH₂CH₂N), 1.40–1.45 (m, 1H, MeCH₂CHHCH₂N), 1.65–1.69 (m, 1H, MeCH₂CHHCH₂N), 3.40 (ddd, J = 14.6, 11.0, 5.2 Hz, 1H, MeCH₂CH₂CHHN), 3.71–3.79 (ddd, J = 14.5, 11.0, 5.5 Hz, 1H, MeCH₂CH₂CHHN), 6.91 (d, J = 15.3 Hz, 1H, SO₂CH), 7.38–7.60 (8H, m, Ar and PhCH), 7.72 (td, J = 8.5, 1.3 Hz, 1H, Ar), 8.19 (dd, J = 8.1, 1.2 Hz, 1H, Ar), 10.33 (s, 1H, CHO) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 13.5, 19.9, 31.5, 52.3, 117.0, 118.6, 120.9, 124.9, 125.3, 128.5 (2C), 129.1 (2C), 129.4, 131.2, 132.3, 135.3, 143.4, 154.1, 154.4, 161.2, 188.1 ppm; m/z (EI, 70 eV) 412 (11, M⁺ + 1), 347 (21), 318 (54), 244 (100), 226 (45), 214 (15), 200 (12), 186 (36), 175 (16), 167 (14), 161 (4), 146 (11), 119 (19), 103 (90), 77 (51%); anal. calcd for C₂₂H₂₁NO₅S: C, 64.22; H, 5.14; N, 3.40. Found: C, 64.25; H, 5.14; N, 3.51%.

(E)-N-Benzyl-N-(3-formyl-2-oxo-2H-chromen-4-yl)-2-phenylethenesulfonamide (7c). Yellow solid (129 mg, 29%); mp 155–157 °C; IR (KBr) ν_max 1706 (C=O), 1336 (–SO₂), 1142 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.38; ¹H NMR (300 MHz, CDCl₃) δ 4.60 (d, J = 14.3 Hz, PhCHHN), 4.97 (d, J = 14.3 Hz, PhCHHN), 7.01 (d, J = 15.4 Hz, 1H, SO₂CH), 7.17–7.65 (14H, m, Ar and PhCH), 7.87 (d, J = 8.0 Hz, 1H, Ar), 10.22 (s, 1H, CHO) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 55.4, 116.7, 119.1, 120.3, 124.9, 125.1, 128.6 (4C), 128.7, 129.2 (2C), 129.6 (2C), 131.3, 132.2, 133.8, 135.1, 143.7, 153.4, 154.2, 161.0, 188.2 ppm; m/z (EI, 70 eV) 446 (3, M⁺ + 1), 381 (8), 352 (9), 278 (92), 262 (5), 248 (6), 220 (4), 167 (4), 103 (31), 91 (100%); anal. calcd for C₂₅H₁₉NO₅S: C, 67.40; H, 4.30; N, 3.14. Found: C, 67.65; H, 4.37; N, 3.03%.

(E)-N-(3-Formyl-2-oxo-2H-chromen-4-yl)-N-(4-methylbenzyl)-2-phenylethenesulfonamide (7d). Yellow solid (124 mg, 27%); mp 166–167 °C; IR (KBr) ν_max 1704 (C=O), 1347 (–SO₂), 1139 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.45; ¹H NMR (300 MHz, CDCl₃) δ 2.22 (s, 3H, Me), 4.60 (d, J = 14.2 Hz, PhCHHN), 4.90 (d, J = 14.2 Hz, PhCHHN), 6.98–7.04 (5H, m, Ar and SO₂CH), 7.26–7.65 (9H, m, Ar and PhCH), 7.92 (dd, J = 8.3, 1.4 Hz, 1H, Ar), 10.18 (s, 1H, CHO) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 21.1, 55.1, 116.8, 119.3, 120.3, 124.96, 125.03, 128.6 (2C), 129.2 (2C), 129.3 (2C), 129.5 (3C), 130.7, 131.3, 132.3, 135.1, 138.6, 143.7, 153.5, 154.2, 160.9, 188.2 ppm; m/z (EI, 70 eV) 460 (3, M⁺ + 1), 395 (2), 354 (1), 292 (90), 276 (3), 263 (7), 248 (4), 235 (3), 207 (4), 167 (6), 146 (3), 120 (5), 105 (100), 77 (31%); anal. calcd for C₂₆H₂₁NO₅S: C, 67.96; H, 4.61; N, 3.05. Found: C, 67.78; H, 5.68; N, 2.90%.

General procedure for the synthesis of compounds 9a–d and 11a–h

A mixture of aldehyde derivatives 7a–d (1 mmol) and acyclic secondary amino acids 8a,b or cyclic secondary amino acids 10a,b (1.1 mmol) in MeCN (15 mL) containing molecular sieves (500 mg, 4 Å) was heated at reflux with stirring for 5 h. After completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure and the residue was recrystallized from 30% EtOAc in hexane to afford the products 9a–h and 11a–h.

3-Methyl-1-phenyl-10-propyl-1,2,3,3a,10,11a-hexahydro-4H-chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one-11,11-dioxide (9a). White crystal (408 mg, 96%); mp 197–198 °C; IR (KBr) ν_max 1693 (C=O), 1350 (–SO₂), 1145 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.47; ¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, 3H, J = 7.4 Hz, MeCH₂CH₂N), 1.85–2.01 (m, 2H, MeCHHCH₂N), 2.38 (s, 3H, MeN), 2.61 (dd, J = 10.1, 9.0 Hz, 1H, MeNCHH), 3.55–3.70 {[2H, consisting dd, J = 8.3, 7.9 Hz, 1H (3.58), SO₂CH]; and ddd, J = 14.2, 10.9, 5.5 Hz, 1H (3.65), MeCH₂CHHN}, 3.97–4.10 {[ddd, J = 14.2, 10.9, 6.0 Hz, 1H (4.02), MeCH₂CHHN]; and dd, J = 9.0, 6.5 Hz, 1H (4.08), MeNCHH}, 4.16–4.29 {[2H, consisting ddd, J = 10.1, 7.9, 7.9 Hz, 1H (4.20), PhCH]; and d, J = 8.3 Hz, 1H (4.27), CHN}, 7.28–7.41 (m, 7H, Ar), 7.63 (td, J = 8.5, 1.4 Hz, 1H, Ar), 7.81 (dd, J = 8.0, 1.1 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 11.4, 23.8, 39.4, 47.6, 56.5, 63.0, 63.5, 72.4, 117.2, 118.0, 119.0, 124.5, 124.8, 127.5, 127.7 (2C), 129.0 (2C), 133.2, 140.0, 153.8, 155.6, 161.5 ppm; m/z (EI, 70 eV) 425 (12, M⁺), 360 (9), 345 (17), 331 (14), 317 (41), 302 (8), 288 (28), 274 (16), 256 (100), 240 (20), 226 (53), 214 (41), 198 (29), 133 (61), 115 (19), 104 (14), 91 (25%); anal. calcd for C₂₃H₂₄N₂O₄S: C, 65.07; H, 5.70; N, 6.60. Found: C, 64.98; H, 5.72; N, 6.61%.

10-Butyl-3-methyl-1-phenyl-1,2,3,3a,10,11a-hexahydro-4H-chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one-11,11-dioxide (9b). White crystal (413 mg, 94%); mp 166–167 °C; IR (KBr) ν_max 1693 (C=O), 1351 (–SO₂), 1144 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.50; ¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, 3H, J = 7.3 Hz, MeCH₂CH₂CH₂N), 1.27–1.48 (m, 2H, MeCHHCH₂CH₂N), 1.78–1.99 (m, 2H, MeCH₂CHHCH₂N), 2.38 (s, 3H, MeN), 2.61 (dd, J = 10.1, 9.0 Hz, 1H, MeNCHH), 3.57 (dd, J = 8.6, 7.5 Hz, 1H, SO₂CH), 3.70 (ddd, J = 14.2, 11.1, 5.1 Hz, 1H, MeCH₂CH₂CHHN), 4.02–4.12 {[2H, consisting m, MeCH₂CH₂CHHN]; and dd, J = 9.0, 6.4 Hz, 1H (4.08), MeNCHH}, 4.17–4.29 {[2H, consisting ddd, J = 10.1, 7.5, 7.5 Hz, 1H (4.20), PhCH]; and d, J = 8.6 (4.28) Hz, 1H, CHN}, 7.28–7.41 (m, 7H, Ar), 7.63 (td, J = 8.5, 1.4 Hz, 1H, Ar), 7.81 (dd, J = 8.0, 1.1 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 13.7, 20.2, 32.4, 39.4, 47.7, 54.7, 62.9, 63.5, 72.4, 117.2, 118.1, 119.0, 124.5, 124.8, 127.5, 127.7 (2C), 129.0 (2C), 133.2, 140.0, 153.8, 155.7, 161.4 ppm; m/z (EI, 70 eV) 439 (12, M⁺), 374 (6), 359 (18), 331 (29), 317 (15), 302 (14), 288 (25), 270 (100), 254 (16), 240 (65), 228 (70), 214 (29), 198 (47), 170 (10), 158 (14), 143 (12), 133 (69), 115 (37), 104 (30), 91 (49%); anal. calcd for C₂₄H₂₆N₂O₄S: C, 65.73; H, 5.98; N, 6.39. Found: C, 65.62; H, 5.95; N, 6.40%.

10-Benzyl-3-methyl-1-phenyl-1,2,3,3a,10,11a-hexahydro-4H-chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one-11,11-dioxide (9c). White crystal (449 mg, 95%); mp 142–144 °C; IR (KBr) ν_max 1691 (C=O), 1361 (–SO₂), 1143 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.41; ¹H NMR (300 MHz, CDCl₃) δ 2.40 (s, 3H, MeN), 2.59 (dd, J = 9.6, 8.5 Hz, 1H, MeNCHH), 3.51 (dd, J = 8.4, 7.6 Hz, 1H, SO₂CH), 4.06 (dd, J = 8.5, 6.2 Hz, 1H, MeNCHH), 4.17 (ddd, J = 9.6, 7.6, 7.6 Hz, 1H, PhCH), 4.31 (d, J = 8.4 Hz, 1H, CHN), 4.73 (d, J = 14.9 Hz, 1H, PhCHHN), 5.45 (d, J = 14.9 Hz, 1H, PhCHHN), 6.97 (t, J = 7.6 Hz, 1H, Ar), 7.16 (t, J = 7.8 Hz, 1H, Ar), 7.27–7.37 (m, 11H, Ar), 7.48 (t, J = 7.7 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 39.4, 47.5, 58.9, 63.2, 63.5, 72.0, 116.7, 117.8, 119.0, 124.3, 125.4, 127.5, 127.7 (2C), 128.4, 128.6 (2C), 129.0 (2C), 129.4 (2C), 133.0, 135.9, 140.0, 153.6, 156.1, 161.6 ppm; m/z (EI, 70 eV) 473 (0.8, M⁺), 408 (3), 393 (16), 381 (23), 365 (22), 317 (19), 304 (92), 288 (8), 274 (53), 261 (19), 230 (13), 213 (58), 158 (8), 133 (38), 115 (21), 104 (12), 91 (100%); anal. calcd for C₂₇H₂₄N₂O₄S: C, 68.62; H, 5.12; N, 5.93. Found: C, 68.61; H, 5.08; N, 5.95%.

3-Methyl-10-(4-methylbenzyl)-1-phenyl-1,2,3,3a,10,11a-hexahydro-4H-chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one 11,11-dioxide (9d). White crystal (467 mg, 96%); mp 131–133 °C; IR (KBr) ν_max 1623 (C=O), 1352 (–SO₂), 1144 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.45; ¹H NMR (300 MHz, CDCl₃) δ 2.35 (s, 3H, Me), 2.40 (s, 3H, MeN), 2.56–2.62 (m, 1H, MeNCHH), 3.48–3.53 (m, 1H, SO₂CH), 4.03 (br s, 1H, MeNCHH), 4.13–4.19 (m, 1H, PhCH), 4.30 (d, J = 8.1 Hz, 1H, CHN), 4.70 (d, J = 14.8 Hz, 1H, PhCHHN), 5.40 (d, J = 14.8 Hz, 1H, PhCHHN), 7.00 (t, J = 7.1 Hz, 1H, Ar), 7.11–7.36 (m, 9H, Ar), 7.49 (t, J = 7.3 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 21.2, 39.4, 47.4, 58.7, 63.2, 63.5, 71.9, 116.6, 117.8, 118.9, 124.3, 125.5, 1257.5, 127.7 (2C), 129.0 (2C), 129.2 (2C), 129.3 (2C), 132.9, 132.9, 138.2, 140.0, 153.6, 156.1, 161.6 ppm; m/z (EI, 70 eV) 487 (7, M⁺), 422 (4), 407 (17), 381 (31), 318 (76), 302 (4), 288 (32), 275 (22), 213 (31), 133 (26), 105 (100%); anal. calcd for C₂₈H₂₆N₂O₄S: C, 69.11; H, 5.39; N, 5.76. Found: C, 69.10; H, 5.39; N, 5.81%.

1,3-Diphenyl-10-propyl-1,2,3,3a,10,11a-hexahydro-4H-chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one-11,11-dioxide (9e). Yellow crystal (452 mg, 93%); mp 225–226 °C; IR (KBr) ν_max 1712 (C=O), 1328 (–SO₂), 1139 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.52; ¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J = 7.3 Hz, 3H, MeCH₂CH₂N), 1.74–1.97 (m, 2H, MeCHHCH₂N), 3.47 (ddd, J = 14.0, 11.8, 4.9 Hz, 1H, MeCH₂CHHN), 3.40 (d, J = 8.5 Hz, 1H, PhNCHH), 3.95–4.05 (ddd, J = 14.0, 11.4, 5.7 Hz, 1H, MeCH₂CHHN), 4.18 (d, J = 5.8 Hz, 1H, SO₂CH), 4.36–4.44 (m, 2H, PhCH and PhNCHH), 5.48 (d, J = 5.8 Hz, 1H, CHN), 6.92 (t, J = 7.2 Hz, 2H, Ar), 7.02 (d, J = 7.9 Hz, 2H, Ar), 7.21 (d, J = 6.8 Hz, 1H, Ar), 7.28–7.38 (m, 7H, Ar), 7.60 (t, J = 7.7 Hz, 1H, Ar), 7.78 (d, J = 8.0 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 11.3, 23.7, 45.1, 54.8, 54.9, 57.5, 74.7, 116.6 (2C), 117.2, 118.1, 120.1, 120.5, 124.4, 124.9, 127.2 (2C), 127.8, 129.3 (2C), 129.6 (2C), 133.3, 139.8, 145.9, 153.7, 154.7, 161.3 ppm; m/z (EI, 70 eV) 486 (9, M⁺), 443 (4), 318 (100), 289 (32), 276 (48), 260 (12), 240 (13), 226 (42), 213 (13), 195 (30), 115 (28), 106 (58), 91 (42), 77 (74%); anal. calcd for C₂₈H₂₆N₂O₄S: C, 69.11; H, 5.39; N, 5.76. Found: C, 68.96; H, 5.45; N, 5.62%.

10-Butyl-1,3-diphenyl-1,2,3,3a,10,11a-hexahydro-4H-chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one-11,11-dioxide (9f). Yellow crystal (475 mg, 95%); mp 226–228 °C; IR (KBr) ν_max 1710 (C=O), 1324 (–SO₂), 1138 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.53; ¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J = 7.3 Hz, 3H, MeCH₂CH₂CH₂N), 1.25–1.46 (m, 2H, MeCHHCH₂CH₂N), 1.64–1.91 (m, 2H, MeCH₂CHHCH₂N), 3.54 (ddd, 1H, J = 14.0, 11.9, 4.8 Hz, 1H, MeCH₂CH₂CHHN), 3.70 (d, J = 9.2 Hz, 1H, PhNCHH), 4.02 (ddd, 1H, J = 14.0, 11.4, 5.6 Hz, 1H, MeCH₂CH₂CHHN), 4.18 (d, J = 5.8 Hz, 1H, SO₂CH), 4.33–4.43 {[2H, consisting m, 1H, PhCH]; and dd, J = 9.5, 6.8 Hz, 1H (4.41), PhNCHH}, 5.47 (d, J = 5.8 Hz, 1H, CHN), 6.90 (t, J = 7.3 Hz, 1H, Ar), 6.99 (d, J = 8.0 Hz, 2H, Ar), 7.20 (d, J = 6.8 Hz, 2H, Ar), 7.27–7.38 (m, 7H, Ar), 7.60 (t, J = 7.3 Hz, 1H, Ar), 7.76 (d, J = 8.0 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 13.6, 20.2, 32.1, 45.1, 53.0, 54.7, 57.4, 74.9, 116.4 (2C), 117.3, 118.1, 120.1, 120.3, 124.3, 124.9, 127.2 (2C), 127.8, 129.3 (2C), 129.6 (2C), 133.3, 139.8, 145.9, 153.7, 154.6, 161.3 ppm; m/z (EI, 70 eV) 500 (20, M⁺), 443 (3), 332 (100), 318 (27), 289 (69), 276 (28), 260 (10), 240 (36), 227 (13), 195 (27), 116 (16), 106 (42), 91 (24), 77 (41%); anal. calcd for C₂₉H₂₈N₂O₄S: C, 69.58; H, 5.64; N, 5.60. Found: C, 69.61; H, 5.58; N, 5.61%.

10-Benzyl-1,3-diphenyl-1,2,3,3a,10,11a-hexahydro-4H-chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one-11,11-dioxide (9g). Yellow crystal (486 mg, 91%); mp 225–227 °C; IR (KBr) ν_max 1701 (C=O), 1353 (–SO₂), 1141 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.43; ¹H NMR (300 MHz, CDCl₃) δ 3.73 (dd, J = 9.7, 1.7 Hz, 1H, PhNCHH), 4.13–4.30 {[2H, consisting d, J = 6.0 Hz, 1H (4.23), SO₂CH]; and d, J = 15.3 Hz, 1H (4.28), PhCHHN}, 4.39–4.41 (m, 1H, PhCH), 5.47 (dd, J = 9.7, 7.4 Hz, 1H, PhNCHH), 5.52–5.57 {[2H, consisting d, J = 15.3 Hz, 1H (5.544), PhCHHN]; and d, J = 6.0 Hz, 1H (5.540), CHN}, 6.89 (t, J = 7.6 Hz, 1H, Ar), 6.95–7.48 (m, 18H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 45.0, 55.1, 57.0, 57.6, 74.3, 116.7 (3C), 117.8, 120.1, 120.6, 124.4, 125.5, 127.3 (2C), 127.9, 128.4, 128.8 (2C), 128.9 (2C), 129.4 (2C), 129.7 (2C), 133.2, 136.5, 139.7, 146.0, 153.6, 155.5, 161.3 ppm; m/z (EI, 70 eV) 534 (11, M⁺), 443 (15), 366 (100), 275 (68), 261 (14), 230 (8), 195 (17), 116 (11), 106 (25), 91 (100%); anal. calcd for C₃₂H₂₆N₂O₄S: C, 71.89; H, 4.90; N, 5.24. Found: C, 71.78; H, 4.94; N, 5.31%.

10-(4-Methylbenzyl)-1,3-diphenyl-1,2,3,3a,10,11a-hexahydro-4H-chromeno[4,3-c]pyrrolo[2,3-e][1,2]thiazin-4-one-11,11-dioxide (9h). Yellow crystal (515 mg, 94%); mp 198–200 °C; IR (KBr) ν_max 1698 (C=O), 1340 (–SO₂), 1139 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.52; ¹H NMR (300 MHz, CDCl₃) δ 2.38 (s, 3H, Me), 3.70 (dd, J = 9.7, 2.3 Hz, 1H, PhNCHH), 4.21 (dd, J = 6.0, 1.5 Hz, 1H, SO₂CH), 4.26 (d, J = 15.5 Hz, 1H, PhCHHN), 4.36–4.38 (m, 1H, PhCH), 4.45 (dd, J = 9.7, 7.2 Hz, 1H, PhNCHH), 5.47–5.52 (m, 2H, PhCHHN and CHN), 6.90–7.40 (m, 17H, Ar), 7.46 (t, J = 7.2 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 21.2, 45.0, 55.2, 56.7, 57.5, 74.2, 116.6 (2C), 116.7, 117.8, 120.0, 120.5, 124.3, 125.6, 127.3 (2C), 127.83, 128.78 (2C), 129.3 (2C), 129.6 (2C), 129.6 (2C), 133.2, 133.4, 138.3, 139.7, 146.0, 153.6, 155.4, 161.2 ppm; m/z (EI, 70 eV) 548 (7, M⁺), 443 (20), 380 (62), 288 (41), 275 (80), 260 (8), 195 (10), 116 (9), 105 (100), 77 (42%); anal. calcd for C₃₃H₂₈N₂O₄S: C, 72.24; H, 5.14; N, 5.11. Found: C, 72.21; H, 5.18; N, 4.97%.

7-Phenyl-5-propyl-5,6a,7,7a,8,9,10,11a-octahydro-12H-chromeno[4′,3′:3,4][1,2]thiazino[6,5-b]pyrrolizin-12-one-6,6-dioxide (11a). White crystal (388 mg, 86%); mp 156–158 °C; IR (KBr) ν_max 1721 (C=O), 1354 (–SO₂), 1159 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.17; ¹H NMR (300 MHz, CDCl₃) δ 0.86 (t, J = 7.4 Hz, 3H, MeCH₂CH₂N), 1.18–1.31 (m, 1H, CHHCH₂CH₂N), 1.37–1.47 (m, 1H, CHHCH₂CH₂N), 1.65–1.95 (m, 4H, CH₂CHHCH₂N and MeCHHCH₂N), 3.08–3.17 (m, 1H, CH₂CH₂CHHN), 3.31–3.39 (m, 1H, CH₂CH₂CHHN), 3.64 (ddd, J = 14.6, 11.0, 5.7 Hz, 1H, MeCH₂CHHN), 3.88 (ddd, J = 14.6, 11.2, 5.8 Hz, 1H, MeCH₂CHHN), 4.08 (td, J = 8.6, 7.4 Hz, 1H, NCHCPh), 4.27 (dd, J = 7.4, 6.1 Hz, 1H, PhCH), 4.39 (dd, J = 8.3, 6.1 Hz, 1H, SO₂CH), 4.78 (d, J = 8.3 Hz, 1H, CHN), 7.22–7.39 (m, 7H, Ar), 7.56 (t, J = 8.3 Hz, 1H, Ar), 7.73 (d, J = 8.0 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 11.3, 23.2, 26.4, 27.5, 48.1, 55.0, 56.1, 63.6, 66.4, 70.0, 117.0, 117.2, 119.1, 124.4, 124.6, 127.3, 127.9 (2C), 128.8 (2C), 132.6, 138.1, 149.8, 153.1, 161.1 ppm; m/z (EI, 70 eV) 451 (8, M⁺), 357 (4), 343 (6), 317 (100), 288 (46), 274 (40), 260 (19), 240 (90), 226 (19), 212 (24), 198 (49), 159 (19), 115 (33), 91 (39%); anal. calcd for C₂₅H₂₆N₂O₄S: C, 66.64; H, 5.82; N, 6.22. Found: C, 66.61; H, 5.78; N, 6.22%.

5-Butyl-7-phenyl-5,6a,7,7a,8,9,10,11a-octahydro-12H-chromeno[4′,3′:3,4][1,2]thiazino[6,5-b]pyrrolizin-12-one-6,6-dioxide (11b). White crystal (395 mg, 85%); mp 162–164 °C; IR (KBr) ν_max 1722 (C=O), 1353 (–SO₂), 1157 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.19; ¹H NMR (300 MHz, CDCl₃) δ 0.86 (t, J = 7.4 Hz, 3H, MeCH₂CH₂CH₂N), 1.18–1.35 (m, 3H, CH̲HCH₂CH₂N and MeCH̲₂CH₂CH₂N), 1.38–1.49 (m, 1H, CHHCH₂CH₂N), 1.70–1.93 (m, 4H, CH₂CHHCH₂N and MeCH₂CHHCH₂N), 3.09–3.18 (m, 1H, CH₂CH₂CHHN), 3.32–3.40 (m, 1H, CH₂CH₂CHHN), 3.70 (ddd, J = 14.5, 11.2, 5.3 Hz, 1H, MeCH₂CH₂CHHN), 3.93 (ddd, J = 14.5, 11.2, 5.3 Hz, 1H, MeCH₂CH₂CHHN), 4.08 (td, J = 9.0, 7.4 Hz, 1H, NCHCPh), 4.27 (dd, J = 7.4, 6.0 Hz, 1H, PhCH), 4.39 (dd, J = 8.3, 6.0 Hz, 1H, SO₂CH), 4.79 (d, J = 8.3 Hz, 1H, CHN), 7.22–7.42 (m, 7H, Ar), 7.59 (td, J = 8.5, 1.4 Hz, 1H, Ar), 7.75 (dd, J = 8.0, 1.2 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 13.5, 20.0, 26.5, 27.6, 31.7, 48.1, 53.3, 56.2, 63.6, 66.4, 70.0, 117.0, 117.2, 119.2, 124.5, 124.5, 127.3, 127.9 (2C), 128.8 (2C), 132.5, 138.1, 149.8, 153.1, 161.2 ppm; m/z (EI, 70 eV) 465 (47, M⁺), 400 (3), 357 (5), 343 (6), 331 (100), 303 (28), 288 (31), 274 (34), 254 (81), 240 (25), 227 (23), 198 (38), 159 (19), 115 (17), 91 (25%); anal. calcd for C₂₆H₂₈N₂O₄S: C, 67.22; H, 6.07; N, 6.03. Found: C, 67.20; H, 6.12; N, 6.06%.

5-Benzyl-7-phenyl-5,6a,7,7a,8,9,10,11a-octahydro-12H-chromeno[4′,3′:3,4][1,2]thiazino[6,5-b]pyrrolizin-12-one-6,6-dioxide (11c). White crystal (449 mg, 90%); mp 183–184 °C; IR (KBr) ν_max 1712 (C=O), 1355 (–SO₂), 1159 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.13; ¹H NMR (300 MHz, CDCl₃) δ 1.13–1.18 (m, 1H, CHHCH₂CH₂N), 1.43–1.46 (m, 1H, CHHCH₂CH₂N), 1.65–1.67 (m, 2H, CH₂CHHCH₂N), 2.91–3.00 (m, 1H, CH₂CH₂CHHN), 3.33–3.40 (m, 1H, CH₂CH₂CHHN), 3.71 (br s, 1H, NCHCPh), 4.09 (s, 2H, PhCH and SO₂CH), 4.49 (d, J = 7.9 Hz, 1H, CHN), 4.78 (d, J = 15.3 Hz, 1H, PhCHHN), 5.24 (d, J = 15.3 Hz, 1H, PhCHHN), 6.93–6.95 (m, 2H, Ar), 7.19–7.39 (m, 10H, Ar), 7.53–7.62 (m, 2H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 26.8, 27.5, 47.1, 56.4, 56.7, 64.3, 67.0, 69.8, 116.3, 117.1, 120.0, 124.6, 125.1, 127.1, 127.8 (2C), 128.7 (2C), 128.8, 128.9 (2C), 129.1 (2C), 132.6, 134.3, 138.3, 148.8, 153.1, 160.8 ppm; m/z (EI, 70 eV) 499 (0.8, M⁺), 365 (89), 337 (6), 288 (12), 274 (40), 261 (11), 246 (4), 230 (13), 217 (4), 202 (5), 159 (6), 128 (8), 115 (10), 91 (100%); anal. calcd for C₂₉H₂₆N₂O₄S: C, 69.86; H, 5.26; N, 5.62. Found: C, 69.81; H, 5.31; N, 5.61%.

5-(4-Methylbenzyl)-7-phenyl-5,6a,7,7a,8,9,10,11a-octahydro-12H-chromeno[4′,3′:3,4][1,2]thiazino[6,5-b]pyrrolizin-12-one-6,6-dioxide (11d). White crystal (451 mg, 88%); mp 207–208 °C; IR (KBr) ν_max 1716 (C=O), 1356 (–SO₂), 1161 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.17; ¹H NMR (300 MHz, CDCl₃) δ 1.07–1.20 (m, 1H, CHHCH₂CH₂N), 1.44–1.52 (m, 1H, CHHCH₂CH₂N), 1.60–1.76 (m, 2H, CH₂CHHCH₂N), 2.32 (s, 3H, Me), 2.88–2.96 (m, 1H, CH₂CH₂CHHN), 3.36–3.43 (m, 1H, CH₂CH₂CHHN), 3.49 (br s, 1H, NCHCPh), 4.01–4.03 (m, 1H, CHPh), 4.10–4.17 (m, 1H, SO₂CH), 4.44 (d, J = 7.8 Hz, 1H, CHN), 4.72 (d, J = 15.1 Hz, 1H, PhCHHN), 5.17 (d, J = 15.1 Hz, 1H, PhCHHN), 6.87–6.89 (m, 2H, Ar), 7.06 (s, 4H, Ar), 7.37 (d, J = 8.2 Hz, 1H, Ar), 7.56 (t, J = 7.6 Hz, 1H, Ar), 7.67 (d, J = 7.7 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 21.1, 27.1, 27.5, 46.7, 56.2, 57.1, 64.6, 67.1, 69.7, 116.2, 117.1, 120.1, 124.6, 125.1, 127.1, 127.8 (2C), 128.6 (2C), 129.3 (2C), 129.4 (2C), 130.9, 132.6, 138.6, 138.9, 148.4, 153.1, 160.7 ppm; m/z (EI, 70 eV) 512 (0.8, M⁺), 407 (2), 379 (67), 343 (8), 302 (4), 288 (8), 274 (29), 230 (10), 202 (5), 173 (8), 128 (8), 115 (10), 105 (100), 91 (19%); anal. calcd for C₃₀H₂₈N₂O₄S: C, 70.29; H, 5.51; N, 5.46. Found: C, 70.33; H, 5.47; N, 5.33%.

7-Phenyl-5-propyl-5,6a,7,7a,8,11a-hexahydro-10H,12H-chromeno[4,3-c]thiazolo[3′,4′:1,5]pyrrolo[2,3-e][1,2]thiazin-12-one 6,6-dioxide (11e). White crystal (421 mg, 90%); mp 2.68–270 °C; IR (KBr) ν_max 1715 (C=O), 1345 (–SO₂), 1141 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.38; ¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J = 7.4 Hz, 3H, MeCH₂CH₂N), 1.85–1.98 (m, 2H, MeCHHCH₂N), 2.51–2.64 (m, 2H, SCH₂C), 3.79–3.90 (m, 1H, MeCH₂CHHN), 3.94–4.10 (m, 2H, MeCH₂CHHN and NCHCPh), 4.27 (d, J = 10.3 Hz, 1H, NCHHS), 4.53 (d, J = 10.3 Hz, 1H, NCHHS), 4.58–4.73 (m, 2H, PhCH and SO₂CH), 4.89 (d, J = 9.5 Hz, 1H, CHN), 7.32–7.43 (m, 7H, Ar), 7.63 (td, J = 8.4, 1.4 Hz, 1H, Ar), 7.78 (dd, J = 8.0, 1.2 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 11.3, 23.7, 32.6, 49.2, 55.1, 56.7, 57.6, 65.7, 74.5, 117.3, 117.6, 118.9, 124.4, 124.8, 127.6 (2C), 127.8, 129.0 (2C), 133.3, 136.3, 153.6, 154.1, 161.8 ppm; m/z (EI, 70 eV) 468 (0.8, M⁺), 357 (11), 318 (100), 288 (36), 274 (31), 260 (14), 240 (68), 228 (25), 214 (19), 198 (50), 177 (58), 156 (16), 130 (63), 115 (69), 103 (25), 91 (69%); anal. calcd for C₂₄H₂₄N₂O₄S₂: C, 61.52; H, 5.16; N, 5.98. Found: C, 61.50; H, 5.16; N, 6.01%.

5-Butyl-7-phenyl-5,6a,7,7a,8,11a-hexahydro-10H,12H-chromeno[4,3-c]thiazolo[3′,4′:1,5]pyrrolo[2,3-e][1,2]thiazin-12-one 6,6-dioxide (11f). White crystal (429 mg, 89%); mp 210–213 °C; IR (KBr) ν_max 1716 (C=O), 1345 (–SO₂), 1141 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.41; ¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, J = 7.3 Hz, 1H, MeCH₂CH₂CH₂N), 1.26–1.45 (m, 2H, MeCHHCH₂CH₂N), 1.82–1.92 (m, 2H, MeCH₂CHHCH₂N), 2.51–2.63 (m, 2H, SCH₂C), 3.75–3.93 (m, 1H, MeCH₂CH₂CHHN), 3.98–4.10 (m, 2H, MeCH₂CH₂CHHN and NCHCPh), 4.26 (d, J = 10.3 Hz, 1H, NCHHS), 4.54 (d, J = 10.3 Hz, 1H, NCHHS), 4.58–4.73 (m, 2H, PhCH and SO₂CH), 4.89 (d, J = 9.5 Hz, 1H, CHN), 7.27–7.42 (m, 7H, Ar), 7.62 (td, J = 8.6, 1.5 Hz, 1H, Ar), 7.77 (dd, J = 8.0, 1.2 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 13.7, 20.1, 32.2, 32.6, 49.2, 53.4, 56.8, 57.7, 65.6, 74.5, 117.3, 117.6, 118.9, 124.4, 124.8, 127.6 (2C), 127.8, 129.0 (2C), 133.2, 136.3, 153.6, 154.1, 161.8 ppm; m/z (EI, 70 eV) 482 (5, M⁺), 371 (16), 361 (14), 332 (100), 315 (8), 302 (16), 288 (25), 274 (30), 254 (58), 240 (36), 228 (23), 198 (51), 177 (68), 156 (13), 130 (46), 115 (48), 103 (19), 91 (53%); anal. calcd for C₂₅H₂₆N₂O₄S₂: C, 62.22; H, 5.43; N, 5.80. Found: C, 62.23; H, 5.40; N, 5.73%.

5-Benzyl-7-phenyl-5,6a,7,7a,8,11a-hexahydro-10H,12H-chromeno[4,3-c]thiazolo[3′,4′:1,5]pyrrolo[2,3-e][1,2]thiazin-12-one-6,6-dioxide (11g). White crystal (475 mg, 92%); mp 230–231 °C; IR (KBr) ν_max 1703 (C=O), 1346 (–SO₂), 1143 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.34; ¹H NMR (300 MHz, CDCl₃) δ 2.48 (d, J = 8.3 Hz, 1H, SCH₂C), 3.73 (td, J = 8.3, 7.1 Hz, NCHCPh), 4.17 (d, J = 10.2 Hz, 1H, NCHHS), 2.35 (dd, J = 8.5, 7.1 Hz, 1H, PhCH), 4.47–4.53 {[2H, consisting dd, J = 9.3, 8.5 Hz, 1H (4.50), SO₂CH]; and d, 1H (4.30), J = 10.2 Hz, NCHHS}, 4.84 (d, J = 9.5 Hz, 1H, CHN), 4.95 (d, J = 14.9 Hz, 1H, PhCHHN), 5.35 (d, J = 14.9 Hz, 1H, PhCHHN), 7.10 (td, J = 8.1, 0.9 Hz, 1H, Ar), 7.20 (d, J = 8.1 Hz, 2H, Ar), 7.30–7.40 (m, 10H, Ar), 7.54 (td, J = 7.4, 1.4 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 32.6, 48.5, 56.7, 56.8, 57.5, 65.5, 74.4, 117.0, 117.1, 118.7, 124.5, 125.2, 127.5 (2C), 127.7, 128.6 (3C), 128.9 (2C), 129.6 (2C), 133.1, 135.6, 136.2, 153.6, 154.2, 161.8 ppm; m/z (EI, 70 eV) 516 (1, M⁺), 455 (2), 425 (39), 405 (8), 366 (64), 331 (10), 313 (9), 288 (18), 274 (83), 262 (19), 246 (8), 230 (23), 217 (9), 202 (14), 177 (39), 147 (9), 130 (42), 115 (36), 103 (13), 91 (100%); anal. calcd for C₂₈H₂₄N₂O₄S₂: C, 65.09; H, 4.68; N, 5.42. Found: C, 65.17; H, 4.65; N, 5.38%.

5-(4-Methylbenzyl)-7-phenyl-5,6a,7,7a,8,11a-hexahydro-10H,12H-chromeno[4,3-c]thiazolo[3′,4′:1,5]pyrrolo[2,3-e][1,2]thiazin-12-one-6,6-dioxide (11h). White crystal (482 mg, 91%); mp 175–177 °C; IR (KBr) ν_max 1706 (C=O), 1334 (–SO₂), 1135 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.38; ¹H NMR (300 MHz, CDCl₃) δ 2.37 (Me), 2.49 (d, J = 8.2 Hz, 1H, SCH₂C), 3.75 (td, J = 8.2, 7.0 Hz, NCHCPh), 4.17 (d, J = 10.2 Hz, 1H, NCHHS), 4.36 (dd, J = 8.5, 7.0 Hz, 1H, PhCH), 4.45 (dd, J = 9.1, 8.5 Hz, 1H, SO₂CH), 4.53 (d, J = 10.2 Hz, 1H, NCHHS), 4.82 (d, J = 9.1 Hz, 1H, CHN), 4.90 (d, J = 14.9 Hz, 1H, PhCHHN), 5.30 (d, J = 14.9 Hz, 1H, PhCHHN), 7.10–7.43 (m, 12H, Ar), 7.55 (td, J = 8.4, 1.4 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 21.2, 32.6, 48.3, 56.7, 56.8, 57.5, 65.3, 74.3, 116.99, 117.04, 118.6, 124.4, 125.3, 127.5 (2C), 127.7, 128.9 (2C), 129.2 (2C), 129.5 (2C), 132.4, 133.1, 136.3, 138.5, 153.6, 154.1, 161.8 ppm; m/z (EI, 70 eV) 530 (2, M⁺), 425 (52), 400 (4), 380 (27), 333 (12), 313 (7), 295 (69), 274 (19), 253 (6), 239 (22), 177 (12), 130 (16), 115 (19), 105 (100%); anal. calcd for C₂₉H₂₆N₂O₄S₂: C, 65.64; H, 4.94; N, 5.28. Found: C, 65.43; H, 5.03; N, 5.18%.

General procedure for the synthesis of compounds 13a–h

A mixture of aldehyde derivatives 7a–d (1 mmol), N-methyl or benzylhydroxylamines hydrochloride 12a,b (1.1 mmol) and Et₃N (1.1 mmol) in MeCN (15 mL) containing molecular sieves 4 Å was heated at reflux with stirring for 5 h. After completion of the reaction as indicated by TLC, the solvent was removed under reduced pressure, and then H₂O (10 mL) was added and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phase was dried over Na₂SO₄, filtered, and evaporated in vacuo and the residue was recrystallized from 30% EtOAc in hexane to afford the products 13a–h.

3-Methyl-1-phenyl-10-propyl-1,3a,10,11a-tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one-11,11-dioxide (13a). White crystal (392 mg, 92%); mp 182–183 °C; IR (KBr) ν_max 1697 (C=O), 1328 (–SO₂), 1144 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.45; ¹H NMR (300 MHz, CDCl₃) δ 0.99 (t, J = 7.4 Hz, 3H, MeCH₂CH₂N), 1.95–2.05 (m, 2H, MeCHHCH₂N), 2.85 (s, 3H, MeN), 3.69 (ddd, J = 14.3, 10.2, 6.4 Hz, 1H, MeCH₂CHHN), 4.11 (ddd, J = 14.3, 10.2, 6.6 Hz, 1H, MeCH₂CHHN), 4.25 (dd, J = 9.1, 6.7 Hz, 1H, SO₂CH), 4.55 (d, J = 9.1 Hz, 1H, CHN), 5.71 (d, J = 6.7 Hz, 1H, PhCHO), 7.37–7.46 (m, 5H, Ar), 7.52–7.54 (m, 2H, Ar), 7.65 (td, J = 8.4, 1.2 Hz, 1H, Ar), 7.81 (d, J = 8.1 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 11.3, 23.8, 43.2, 56.8, 66.0, 74.4, 82.0, 115.1, 117.4, 117.6, 124.5, 125.0, 126.7 (2C), 128.9 (2C), 129.1, 133.7, 136.7, 153.9, 156.2, 160.9 ppm; m/z (EI, 70 eV) 426 (49, M⁺), 380 (19), 338 (31), 316 (100), 304 (13), 288 (21), 274 (80), 255 (36), 240 (22), 227 (80), 214 (94), 198 (51), 185 (18), 134 (70), 115 (25), 105 (35), 91 (35%); anal. calcd for C₂₂H₂₂N₂O₅S: C, 61.96; H, 5.20; N, 6.57. Found: C, 61.97; H, 5.17; N, 6.61%.

10-Butyl-3-methyl-1-phenyl-1,3a,10,11a-tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one-11,11-dioxide (13b). White crystal (405 mg, 92%); mp 151–153 °C; IR (KBr) ν_max 1701 (C=O), 1352 (–SO₂), 1144 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.50; ¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J = 7.4 Hz, 3H, MeCH₂CH₂CH₂N), 1.30–1.50 (m, 2H, MeCHHCH₂CH₂N), 1.85–2.04 (m, 2H, MeCH₂CHHCH₂N), 2.85 (s, 3H, MeN), 3.72 (ddd, J = 14.3, 11.0, 5.5 Hz, 1H, MeCH₂CH₂CHHN), 4.17 (ddd, J = 14.3, 11.0, 5.7 Hz, 1H, MeCH₂CH₂CHHN), 4.25 (dd, J = 9.0, 6.7 Hz, 1H, SO₂CH), 4.55 (d, J = 9.0 Hz, 1H, CHN), 5.71 (d, J = 6.7 Hz, 1H, PhCHO), 7.37–7.45 (m, 5H, Ar), 7.52–7.54 (m, 2H, Ar), 7.66 (td, J = 8.5, 1.3 Hz, 1H, Ar), 7.81 (d, J = 8.1 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 13.7, 20.1, 32.4, 43.2, 55.2, 66.0, 74.4, 82.1, 115.2, 117.4, 117.6, 124.5, 125.0, 126.7 (2C), 128.9 (2C), 129.1, 133.7, 136.8, 153.9, 156.2, 160.9 ppm; m/z (EI, 70 eV) 440 (20, M⁺), 394 (12), 359 (9), 338 (31), 330 (100), 288 (19), 274 (69), 240 (18), 227 (88), 214 (49), 198 (46), 185 (14), 134 (63), 115 (28), 105 (34), 115 (30), 105 (36), 91 (38), 77 (74%); anal. calcd for C₂₃H₂₄N₂O₅S: C, 62.71; H, 5.49; N, 6.36. Found: C, 62.74; H, 5.50; N, 5.54%.

10-Benzyl-3-methyl-1-phenyl-1,3a,10,11a-tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one-11,11-dioxide (13c). White crystal (431 mg, 91%); mp 175–176 °C; IR (KBr) ν_max 1705 (C=O), 1346 (–SO₂), 1141 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.45; ¹H NMR (300 MHz, CDCl₃) δ 2.89 (s, 3H, MeN), 4.23 (br s, 1H, SO₂CH), 4.59 (d, J = 8.9 Hz, 1H, CHN), 4.68 (d, J = 15.2 Hz, 1H, PhCHHN), 5.60 (d, J = 15.2 Hz, 1H, PhCHHN), 5.72 (d, J = 6.5 Hz, 1H, PhCHO), 6.97 (t, J = 7.4 Hz, 1H, Ar), 7.13 (d, J = 7.6 Hz, 1H, Ar), 7.30–7.52 (m, 12H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 43.2, 59.6, 66.3, 74.1, 82.2, 115.2, 116.8, 117.4, 124.5, 125.6, 126.7 (2C), 128.6, 128.8 (2C), 129.0 (2C), 129.1 (3C), 133.5, 135.8, 136.7, 153.7, 157.0, 161.0 ppm; m/z (EI, 70 eV) 474 (39, M⁺), 364 (72), 319 (8), 303 (43), 286 (8), 274 (49), 246 (10), 230 (24), 213 (52), 202 (14), 136 (88), 105 (25), 91 (100%); anal. calcd for C₂₆H₂₂N₂O₅S: C, 65.81; H, 4.67; N, 5.90. Found: C, 62.80; H, 5.71; N, 5.79%.

3-Methyl-10-(4-methylbenzyl)-1-phenyl-1,3a,10,11a-tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one-11,11-dioxide (13d). White crystal (464 mg, 95%); mp 150–152 °C; IR (KBr) ν_max 1705 (C=O), 1346 (–SO₂), 1141 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.50; ¹H NMR (300 MHz, CDCl₃) δ 2.36 (s, 3H, Me), 2.88 (s, 3H, MeN), 4.20 (br s, 1H, SO₂CH), 4.57 (d, J = 8.9 Hz, 1H, CHN), 4.65 (d, J = 15.2 Hz, 1H, PhCHHN), 5.55 (d, J = 15.2 Hz, 1H, PhCHHN), 5.72 (d, J = 6.5 Hz, 1H, PhCHO), 7.02 (t, J = 7.5 Hz, 1H, Ar), 7.14–7.54 (m, 12H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 21.2, 43.2, 59.4, 66.3, 74.0, 82.1, 115.1, 116.8, 117.5, 124.4, 125.7, 126.7 (2C), 129.0 (2C), 129.1 (3C), 129.4 (2C), 132.7, 133.5, 136.8, 138.4, 153.7, 157.1, 161.0 ppm; m/z (EI, 70 eV) 488 (9, M⁺), 378 (39), 317 (14), 289 (14), 274 (30), 246 (8), 230 (19), 213 (18), 202 (13), 136 (51), 105 (100), 91 (21), 77 (78%); anal. calcd for C₂₇H₂₄N₂O₅S: C, 66.38; H, 4.95; N, 5.73. Found: C, 66.40; H, 4.96; N, 5.71%.

3-Benzyl-1-phenyl-10-propyl-1,3a,10,11a-tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one-11,11-dioxide (13e). White crystal (452 mg, 90%); mp 158–159 °C; IR (KBr) ν_max 1696 (C=O), 1357 (–SO₂), 1147 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.43; ¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J = 7.3 Hz, 1H, MeCH₂CH₂N), 1.98–2.10 (m, 2H, MeCHHCH₂N), 3.80 (ddd, J = 14.2, 10.8, 6.5 Hz, 1H, MeCH₂CHHN), 4.12–4.31 {[4H, consisting s, 2H (4.17), PhCH₂N]; [m, 1H, MeCH₂CHHN]; and dd, 1H, J = 8.8, 6.5 Hz, 1H (4.28), SO₂CH}, 4.85 (d, J = 8.8 Hz, 1H, CHN), 5.74 (d, J = 6.4 Hz, 1H, PhCHO), 7.22–7.54 (m, 12H, Ar), 7.66 (t, J = 7.6 Hz, 1H, Ar), 7.83 (d, J = 7.8 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 11.3, 23.9, 56.9, 60.1, 64.6, 74.3, 82.1, 115.3, 117.3, 117.7, 124.6, 125.0, 126.7 (2C), 127.4, 128.2 (2C), 128.4 (2C), 128.9 (2C), 129.0, 133.8, 136.8, 136.9, 153.9, 156.3, 161.2 ppm; m/z (EI, 70 eV) 502 (17, M⁺), 411 (42), 380 (8), 369 (7), 331 (15), 316 (70), 303 (8), 288 (16), 274 (31), 249 (21), 227 (26), 212 (12), 198 (42), 105 (36), 91 (100%); anal. calcd for C₂₈H₂₆N₂O₅S: C, 66.91; H, 5.21; N, 5.57. Found: C, 66.90; H, 5.25; N, 5.68%.

3-Benzyl-10-butyl-1-phenyl-1,3a,10,11a-tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one-11,11-dioxide (13f). White crystal (480 mg, 93%); mp 199–200 °C; IR (KBr) ν_max 1711 (C=O), 1346 (–SO₂), 1140 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.45; ¹H NMR (300 MHz, CDCl₃) δ 0.98 (t, J = 7.3 Hz, 1H, MeCH₂CH₂CH₂N), 1.35–1.49 (m, 2H, MeCHHCH₂CH₂N), 1.94–2.05 (m, 2H, MeCH₂CHHCH₂N), 3.87 (ddd, J = 14.0, 11.4, 5.6 Hz, 1H, MeCH₂CH₂CHHN), 4.12–4.32 {[4H, consisting AB-q, J = 14.9 Hz, 2H (4.17), PhCH₂N]; [m, 1H, MeCH₂CH₂CHHN]; and dd, 1H, J = 8.9, 6.8 Hz, 1H (4.29), SO₂CH}, 4.84 (d, J = 9.0 Hz, 1H, CHN), 5.73 (d, J = 6.8 Hz, 1H, PhCHO), 7.22–7.54 (m, 12H, Ar), 7.66 (t, 1H, J = 7.6 Hz, Ar), 7.82 (d, J = 7.8 Hz, 1H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 13.7, 20.2, 32.5, 55.0, 60.1, 64.6, 74.4, 82.1, 115.3, 117.4117.7, 124.5, 125.0, 126.7 (2C), 127.3, 128.2 (2C), 128.4 (2C), 128.9 (2C), 129.0, 133.8, 136.8, 136.9, 153.9, 156.2, 161.2 ppm; m/z (EI, 70 eV) 516 (5, M⁺), 425 (36), 394 (7), 369 (8), 345 (14), 330 (95), 303 (22), 288 (17), 274 (44), 249 (28), 220 (29), 198 (65), 105 (58), 91 (100%); anal. calcd for C₂₉H₂₈N₂O₅S: C, 67.42; H, 5.46; N, 5.42. Found: C, 67.50; H, 5.46; N, 5.48%.

3,10-Dibenzyl-1-phenyl-1,3a,10,11a-tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one-11,11-dioxide (13g). White crystal (517 mg, 94%); mp 195–197 °C; IR (KBr) ν_max 1721 (C=O), 1385 (–SO₂), 1148 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.41; ¹H NMR (300 MHz, CDCl₃) δ 4.19–4.31 {[3H, consisting AB-q, J = 14.7 Hz, 2H (4.25) PhCH₂N]; and br s, 1H (4.31), SO₂CH}, 4.74 (d, J = 15.1 Hz, 1H, PhCHHNSO₂), 4.92 (d, J = 8.8 Hz, 1H, CHN), 5.70 (d, J = 15.1 Hz, 1H, PhCHHNSO₂), 5.77 (d, J = 6.4 Hz, 1H, PhCHO), 6.92 (t, J = 7.5 Hz, 1H, Ar), 7.05 (d, J = 7.7 Hz, 1H, Ar), 7.27–7.55 (m, 17H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 60.0, 60.1, 65.1, 73.9, 82.4, 115.2, 116.7, 117.6, 124.4, 125.6, 126.7 (2C), 127.5, 128.3 (2C), 128.5 (2C), 128.6, 128.88 (2C), 128.94 (2C), 129.1, 129.2 (2C), 133.6, 135.9, 136.7, 136.8, 153.7, 157.4, 161.3 ppm; m/z (EI, 70 eV) 550 (7, M⁺), 459 (11), 364 (44), 289 (20), 275 (75), 230 (22), 220 (26), 202 (12), 106 (38), 91 (100%); anal. calcd for C₃₂H₂₆N₂O₅S: C, 69.80; H, 4.76; N, 5.09. Found: C, 69.82; H, 4.71; N, 4.95%.

3-Benzyl-10-(4-methylbenzyl)-1-phenyl-1,3a,10,11a-tetrahydrochromeno[4,3-c]isoxazolo[3,4-e][1,2]thiazin-4(3H)-one-11,11-dioxide (13h). White crystal (519 mg, 92%); mp 210–212 °C; IR (KBr) ν_max 1712 (C=O), 1345 (–SO₂), 1148 (–SO₂) cm⁻¹; R_f (33% EtOAc/hexane) 0.46; ¹H NMR (300 MHz, CDCl₃) δ 2.38 (s, 3H, Me), 4.23–4.29 {[3H, consisting s, 2H (4.24) PhCH₂N]; and br s, 1H (4.30), SO₂CH}, 4.70 (d, J = 15.1 Hz, 1H, PhCHHNSO₂), 4.90 (d, J = 8.8 Hz, 1H, CHN), 5.65 (d, J = 15.1 Hz, 1H, PhCHHNSO₂), 5.76 (d, J = 6.5 Hz, 1H, PhCHO), 6.96 (t, J = 7.6 Hz, 1H, Ar), 7.14–7.53 (m, 17H, Ar) ppm; ¹³C NMR (75 MHz, CDCl₃) δ 21.2, 60.0, 60.1, 65.0, 73.9, 82.3, 115.1, 116.7, 117.6, 124.4, 125.7, 126.7 (2C), 127.4, 128.3 (2C), 128.4 (2C), 128.9 (2C), 129.0, 129.1 (2C), 129.5 (2C), 132.8, 133.5, 136.7, 136.9, 138.4, 153.7, 157.4, 161.3 ppm; m/z (EI, 70 eV) 564 (5, M⁺), 378 (25), 289 (34), 274 (12), 220 (8), 105 (100), 91 (83%); anal. calcd for C₃₃H₂₈N₂O₅S: C, 70.19; H, 5.00; N, 4.96. Found: C, 70.23; H, 5.06; N, 5.01%.

Acknowledgements

We acknowledge the University of Tehran for financial support of this research.

Notes and references

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27. (a) M. Ghandi, S. H. Nazari, A. Hasani Bozcheloei, M. Sadeghzadeh and R. Kia, Tetrahedron Lett., 2011, 52, 6613; (b) M. Ghandi, S. Feizi, F. Ziaie and B. Notash, Tetrahedron, 2014, 70, 2563; (c) M. Ghandi, M. Asle Kia, M. Sadeghzadegh, A. Hasani Bozcheloei and M. Kubicki, J. Heterocycl. Chem., 2015, 52, 1646.
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30. The CCDC deposition number for compound 9h is 1433802. Formula: C₃₃H₂₈N₂O₄S. Unit cell parameters: a = 13.148(3) Å, b = 16.285(3) Å, c = 17.991(6) Å, α = 90.00°, β = 133.170(18)°, γ = 90.00°, space group P2₁/c.†.
31. The CCDC deposition number for compound 11a is 998125. Formula: C₂₅H₂₆N₂O₄S. Unit cell parameters: a = 8.790(2) Å, b = 15.553(2) Å, c = 16.313(2) Å, α = 90.00°, β = 90.00°, γ = 90.00°, space group P2₁2₁2₁.†.
32. The CCDC deposition number for compound 13h is 1429726. Formula: C₃₃H₂₈N₂O₅S. Unit cell parameters: a = 14.898(3) Å, b = 11.159(2) Å, c = 17.179(3) Å, α = 90.00°, β = 108.33(3)°, γ = 90.00°, space group P2₁/n.†.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H NMR, ¹³C NMR, MS and IR of all the compounds, and crystallographic data for 9h, 11a and 13h. CCDC 1433802, 998125 and 1429726. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra14169b

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