Diastereoselective synthesis of highly functionalized polycyclic benzosultams via tandem cyclisations of cyclic N-sulfonylimines with in situ generated Huisgen 1,4-dipoles

Abstract

Under mild reaction conditions, the tandem cycloadditions of cyclic N-sulfonylimines with in situ generated Huisgen 1,4-dipoles from dialkyl acetylenedicarboxylates and pyridines underwent readily, and delivered highly functionalized polycyclic 1,2,3,4-tetrahydropyrimidine-fused benzosultams in low to excellent chemical yields with excellent diastereoselectivities.

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1. Introduction

The polycyclic benzosultams constitute a class of biologically and medicinally important molecules, and exhibit a wide range of biological activities as shown in Fig. 1.¹ Due to the biological importance of these molecules, some elegant and robust synthetic methodologies have been developed for their racemic² and enantioselective³ construction. Noticeably, the transition-metal- and organo-catalyzed cyclisation reactions serve as the main tools for the synthesis of majority of polycyclic benzosultams.⁴ Despite these advances, the development of novel and efficient methodologies remains highly desirable for the synthesis of polycyclic benzosultams bearing structural and stereochemical diversity and complexity.

Fig. 1 Bioactive polycyclic benzosultams.

Cyclic N-sulfonylimines represent a family of valuable and versatile building blocks, and have been widely applied in the synthesis of structurally diverse polycyclic benzosultams. For examples, Nishimura et al. prepared polycyclic benzosultams diastereoselectively via the Ir-catalyzed [3 + 2] annulation of cyclic N-sulfonylimines with 1,3-dienes.⁵ The Chen's group developed the formal [3 + 3] cycloaddition of ketones with cyclic N-sulfonylimines for the enantioselective synthesis of polycyclic benzosultams.⁶ Bode and co-workers reported the synthesis of polycyclic benzosultams through the diastereoselective NHC-catalyzed annulation of enals with cyclic N-sulfonylimines.⁷ Recently, the Zhang's group designed the organocatalytic stereoselective cascade reaction of enals with cyclic N-sulfonylimines for the construction of polycyclic benzosultams in excellent diastereo- and enantioselectivity.⁸ However, the tandem cyclisations of cyclic N-sulfonylimines with in situ generated Huisgen 1,4-dipoles from dialkyl acetylenedicarboxylates and pyridines has not been explored in the literature to date.

Herein, encouraged by previous work, we envisioned the first tandem cycloadditions of cyclic N-sulfonylimines with synthetically versatile Huisgen 1,4-dipoles in situ derived from dialkyl acetylenedicarboxylates and pyridines.⁹ Satisfyingly, our works indicated that the designed tandem cyclisations of N-sulfonylimines with in situ formed Huisgen 1,4-dipoles proceeded smoothly, and delivered highly functionalized polycyclic 1,2,3,4-tetrahydropyrimidine-fused benzosultams in 19–98% chemical yields with >99 : 1 dr. To the best of our knowledge, no such a work has been reported in the literature so far.

2. Results and discussion

Initially, we screened the solvent effects on the tandem cyclisation of 1a, 2a and 3b as shown in Table 1. In all the tested solvents, the tandem cyclisation furnished product 4aab in >99 : 1 dr. By comparison, the chemical yield of the tandem cyclisation was significantly affected by the solvents used. For example, the use of MeOH gave 4aab in a trace amount after 4 h (Table 1, entry 1). However, the replacement of MeOH with Et₂O furnished 28% chemical yield (Table 1, entries 1 vs. 6). When toluene, CH₂Cl₂ and DMF were chosen as solvents, product 4aab was achieved in 44–65% chemical yields (Table 1, entries 2, 3 & 5). The best chemical yield of 4aab was obtained when the tandem cyclisation was carried out in THF (Table 1, entry 4).

Table 1 Screening of solvents^a

Entry	Solvent	Time (h)	Yield^b (%)	dr^c
a Unless otherwise noted, reactions were carried out with 1a (0.15 mmol), 2a (0.15 mmol) and 3b (0.10 mmol) in the used solvent (0.5 mL) at room temperature.b Isolated yield.c Determined by ^1H NMR.
1	MeOH	4	Trace	>99 : 1
2	Toluene	4	44	>99 : 1
3	CH2Cl2	4	62	>99 : 1
4	THF	4	79	>99 : 1
5	DMF	2	65	>99 : 1
6	Et2O	4	28	>99 : 1

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Then, we investigated the additive effects of Lewis acid, Brønsted acid and Lewis base on the tandem cyclisation of 1a, 2a and 3b as outlined in Table 2. Disappointedly, it was disclosed that the use of Cu(OTf)₂ and PhCO₂H as additives significantly decreased the chemical yield of the tandem cyclisation (Table 2, entries 1 vs. 2 and 3). Moreover, the chemical yield of the tandem cyclisation slightly lowered when DIPEA and Et₃N were attempted as additives (Table 2, entries 1 vs. 4 and 5). Therefore, the use of the additives tended to decrease the chemical yield of the tandem cyclisation. Moreover, it was noted that, in all cases above, the starting materials remained left after the indicated reaction times.

Table 2 Screening of additives^a

Entry	Additive	Time (h)	Yield^b (%)	dr^c
a Unless otherwise noted, reactions were carried out with 1a (0.15 mmol), 2a (0.15 mmol) and 3b (0.10 mmol) in the presence of 10 mol% additive in THF (0.5 mL) at room temperature.b Isolated yield.c Determined by ^1H NMR.
1	—	4	79	>99 : 1
2	Cu(OTf)2	24	24	>99 : 1
3	PhCO2H	24	19	>99 : 1
4	DIPEA	4	71	>99 : 1
5	Et3N	4	70	>99 : 1

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Next, we examined the temperature effects on the tandem cyclisation of 1a, 2a and 3b where the substrate ratio of 1a, 2a and 3b was kept at 1.5 : 1.5 : 1 as shown in Table 3 (entries 1–3). Product 4aab was achieved in 69% chemical yield at 0 °C. In contrast, the chemical yield dramatically lowered at 60 °C (Table 3 entries 1 vs. 2). Moreover, product 4aab was obtained in 79% chemical yield at room temperature (Table 3, entry 3). Simultaneously, at room temperature, we optimized the substrate ratio of 1a, 2a and 3b as shown in Table 3 (entries 4–6). The chemical yields changed from 34% to 95% when the substrate ratio ranged from 1 : 1 : 0.5 to 1 : 1 : 1.5. To our delight, the tandem cycloaddition proceeded readily at room temperature, and furnished product 4aab in the highest chemical yield when the substrate ratio was equal to 1 : 1 : 0.5 (Table 4, entry 4).

Table 3 Screening of substrate ratio and temperature^a

Entry	Ratio (1a : 2a : 3b)	Temp (°C)	Time (h)	Yield^b (%)	dr^c
a Unless otherwise noted, reactions were carried out with the use of the indicated substrate ratios and temperatures in THF (0.5 mL).b Isolated yield.c Determined by ^1H NMR.
1	1.5 : 1.5 : 1	0	5	69	>99 : 1
2	1.5 : 1.5 : 1	60	8	39	>99 : 1
3	1.5 : 1.5 : 1	rt	4	79	>99 : 1
4	1 : 1 : 0.5	rt	2	95	>99 : 1
5	1 : 1 : 1	rt	4	43	>99 : 1
6	1 : 1 : 1.5	rt	4	34	>99 : 1

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Table 4 Extension of the reaction scope^a

Entry	1 (R1)	2 (R2)	3 (R3, R4)	4	Time (h)	Yield^b (%)	dr^c
a Unless otherwise noted, reactions were carried out with 1 (0.20 mmol), 2 (0.20 mmol) and 3 (0.10 mmol) in THF (0.5 mL) at room temperature.b Isolated yield.c Determined by ^1H NMR spectroscopy.d No reaction.
1	1a (H)	2a (Me)	3a (Me, H)	4aaa	2	19	>99 : 1
2	1a (H)	2a (Me)	3b (Ph, H)	4aab	4	95	>99 : 1
3	1a (H)	2a (Me)	3c (4-MeC6H4, H)	4aac	2	90	>99 : 1
4	1a (H)	2a (Me)	3d (4-ClC6H4, H)	4aad	2	95	>99 : 1
5	1a (H)	2a (Me)	3e (Ph, Me)	4aae	2	88	>99 : 1
6	1a (H)	2a (Me)	3f (Ph, Cl)	4aaf	2	98	>99 : 1
7	1a (H)	2b (Et)	3b (Ph, H)	4abb	3	83	>99 : 1
8	1a (H)	2c (^isoPr)	3b (Ph, H)	4acb	7	23	>99 : 1
9	1a (H)	2b (Et)	3c (4-MeC6H4, H)	4abc	5	75	>99 : 1
10	1a (H)	2b (Et)	3d (4-ClC6H4, H)	4abd	2	97	>99 : 1
11	1b (2-Me)	2b (Et)	3b (Ph, H)	4bbb	48	nr^d	—
12	1c (3-Me)	2b (Et)	3b (Ph, H)	4cbb	2	84	>99 : 1
13	1d (4-Me)	2b (Et)	3b (Ph, H)	4dbb	2	88	>99 : 1
14	1e (4-CO2Me)	2b (Et)	3b (Ph, H)	4ebb	48	Trace	—
15	1f (4-CO2Et)	2b (Et)	3b (Ph, H)	4fbb	48	Trace	—
16	1g (4-CN)	2b (Et)	3b (Ph, H)	4gbb	48	nr^d	—
17	1d (4-Me)	2a (Me)	3e (Ph, Me)	4dae	2	79	>99 : 1
18	1d (4-Me)	2a (Me)	3f (Ph, Cl)	4daf	2	93	>99 : 1
19	1d (4-Me)	2b (Me)	3c (4-MeC6H4, H)	4dbc	2	95	>99 :  1
20	1d (4-Me)	2b (Et)	3d (4-ClC6H4, H)	4dbd	2	95	>99 : 1
21	1d (4-Me)	2c (^isoPr)	3e (Ph, Me)	4dce	2	45	>99 : 1
22	1d (4-Me)	2c (^isoPr)	3f (Ph, Cl)	4dcf	2	59	>99 : 1
23	1c (3-Me)	2a (Me)	3c (4-MeC6H4, H)	4cac	2	93	>99 : 1
24	1c (3-Me)	2a (Me)	3d (4-ClC6H4, H)	4cad	2	97	>99 : 1
25	1c (3-Me)	2a (Me)	3b (Ph, H)	4cab	4	94	>99 : 1
26	1c (3-Me)	2c (^isoPr)	3c (4-MeC6H4, H)	4ccc	7	58	>99 : 1
27	1c (3-Me)	2c (^isoPr)	3d (4-ClC6H4, H)	4ccd	7	76	>99 : 1
28	1c (3-Me)	2b (Et)	3f (Ph, Cl)	4cbf	2	92	>99 : 1
29	1g (4-CN)	2a (Me)	3f (Ph, Cl)	4gaf	48	34	>99 : 1
30	1e (4-CO2Me)	2a (Me)	3f (Ph, Cl)	4eaf	30	72	>99 : 1

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Finally, under the optimized reaction conditions (1a : 2a : 3b = 1 : 1 : 0.5, THF, r.t.), we extended the reaction scope of the tandem cyclisation by diversifying substrates 1, 2 and 3 as summarized in Table 4. In most cases, the tandem cyclisation produced products 4 in excellent diastereoselectivities (Table 4, entries 1–10, 12–13 & 17–30). However, the chemical yield was significantly changed with the used substrates 1, 2 and 3. For example, when 1b, 2b and 3b were chosen as substrates, the tandem cyclisation did not take place at all (Table 4, entry 11). The same result was observed with the tandem cyclisation of 1g, 2b and 3b (Table 4, entry 16). Moreover, products 4ebb and 4fbb were formed in a trace amount in 48 h, respectively (Table 4, entries 14 and 15). In the case of other tandem cyclisations, the chemical yield varied in the wide range from 19% to 98% (Table 4, entries 1–10, 12–13 & 17–30). Interestingly, we found that the position variation of R₁ group of substrate 1 affected the chemical yield of the tandem cyclisation (Table 4, entries 11–13). Moreover, it was noted that the substrate 1 with an electron-donating R₁ group preferred to furnish product 4 in higher chemical yield than that bearing an electron-withdrawing R₁ group (Table 4, entries 13 vs. 14–16). In addition, the substrate 3 with an electron-withdrawing R₄ group favorably produced product 4 in higher chemical yield than that having electron-donating R₄ group (Table 4, 5 vs. 6, 17 vs. 18, 21 vs. 22). Simultaneously, the substrate 3d with an electron-withdrawing substituent on the benzene ring of R₃ group preferentially gave product 4 in higher chemical yield than the substrate 3c bearing with an electron-donating substituent (Table 4, entries 3 vs. 4, 9 vs. 10, 19 vs. 20, 23 vs. 24, 26 vs. 27). The relative configuration of 4aaf was determined by single crystal X-ray analysis as depicted in Fig. 2.¹⁰ On the basis of the relative stereochemistry of 4aaf, we similarly assigned the relative configuration of other products 4 as shown in Table 4. Moreover, we proposed the reaction mechanism for the diastereoselective formation of products 4 as shown in Scheme 1 on the basis of previously published works.¹¹ Initially, pyridine 1a condenses with dimethyl acetylenedicarboxylate 2a to furnish Huisgen 1,4-dipole 5. Then, the formed intermediate 5 react with 3f through the transition state TS to produce the final compound 4aaf diastereoselectively.

Fig. 2 X-ray single crystal structure of 4aaf (with thermal ellipsoids shown at the 50% probability level).

Scheme 1 Proposed mechanism for the diastereoselective formation of 4aaf.

3. Conclusions

In conclusion, we first developed the tandem cyclisations of cyclic N-sulfonylimines with in situ produced Huisgen 1,4-dipoles from dialkyl acetylenedicarboxylates and pyridines. Under mild reaction conditions, the tandem cyclisations underwent readily, and furnished the highly functionalized polycyclic 1,2,3,4-tetrahydropyrimidine-fused benzosultams in 19–98% chemical yields with excellent diastereoselectivities. The further exploration of novel tandem cyclisations of cyclic N-sulfonylimines with other dipoles is ongoing in our organic lab and will be reported in due course.

4. Experimental section

4.1 General procedure

Proton (¹H) and carbon (¹³C) NMR spectra were recorded on 400 MHz instrument (400 MHz for ¹H NMR, 100 MHz for ¹³C NMR) and calibrated using tetramethylsilane (TMS) as internal reference. High resolution mass spectra (HRMS) were recorded under electrospray ionization (ESI) conditions. The melting point of compounds was determined by a melting point instrument. Flash column chromatography was performed on silica gel (0.035–0.070 mm) using compressed air. Thin layer chromatography (TLC) was carried out on 0.25 mm SDS silica gel coated glass plates (60F254). Eluted plates were visualized using a 254 nm UV lamp. Unless otherwise indicated, all reagents were commercially available and used without further purification. All solvents were distilled from the appropriate drying agents immediately before using. N-sulfonylimines (3a–3f) were prepared according to literature procedures.¹²

4.2 Procedure for the synthesis of products 4

A mixture of pyridines 1 (0.2 mmol), dialkyl acetylenedicarboxylates 2 (0.2 mmol) and N-sulfonylimines 3 (0.1 mmol) in 0.5 mL of anhydrous THF was stirred at room temperature for 2–48 hours. After the reaction was completed as indicated by TLC plate, the solvent was removed by evaporation and the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4 : 1) to afford the pure products 4 as yellow solid (19–98% yields; >99 : 1 dr).

Dimethyl-7a-methyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4aaa). Yellow solid, yield: 7.6 mg, 19%; M.P. = 140.5–141.7 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.11 (d, J = 8.0 Hz, 1H), 7.82–7.75 (m, 2H), 7.69–7.65 (m, 1H), 6.42 (s, 1H), 6.27 (d, J = 7.6 Hz, 2H), 5.76–5.73 (m, 1H), 5.22 (t, J = 6.8 Hz, 1H), 3.77 (s, 3H), 3.66 (s, 3H), 2.01 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.9, 163.7, 144.8, 138.9, 134.0, 132.4, 131.0, 128.3, 127.1, 125.9, 121.1, 115.9, 107.1, 101.6, 65.3, 63.9, 53.6, 52.2, 29.6 ppm; HRMS (ESI) calculated for C₁₉H₁₉N₂O₆S [M + H]⁺: 403.09583, found 403.09506.

Dimethyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4aab). Yellow solid, yield: 44.1 mg, 95%; M.P. = 165.6–167.1 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.93 (d, J = 8.0 Hz, 1H), 7.76–7.70 (m, 2H), 7.61 (d, J = 6.8 Hz, 1H), 7.42–7.36 (m, 3H), 7.13 (d, J = 7.2 Hz, 2H), 6.33 (d, J = 7.6 Hz, 1H), 6.20 (t, J = 7.2 Hz, 1H), 5.80 (s, 1H), 5.48 (d, J = 10 Hz, 1H), 5.24 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H), 3.55 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.7, 163.6, 146.3, 142.9, 138.7, 133.8, 133.2, 131.5, 130.4, 129.2, 128.8, 128.7, 127.0, 126.1, 121.0, 115.4, 102.8, 102.2, 70.1, 63.6, 55.4, 53.8, 52.1 ppm; HRMS (ESI) calculated for C₂₄H₂₁N₂O₆S [M + H]⁺: 465.11148, found 465.11111.

Dimethyl-7a-(p-tolyl)-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]-pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4aac). Yellow solid, yield: 43.0 mg, 90%; M.P. = 174.3–175.4 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.92 (d, J = 6.4 Hz, 1H), 7.75–7.69 (m, 2H), 7.59 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 7.6 Hz, 2H), 7.0 (d, J = 8 Hz, 2H), 6.31 (d, J = 7.6 Hz, 1H), 6.19 (t, J = 6.8 Hz, 1H), 5.79 (s, 1H), 5.48 (d, J = 9.6 Hz, 1H), 5.23 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H), 3.54 (s, 3H), 2.30 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.8, 163.6, 146.2, 140.2, 138.8, 138.3, 133.6, 133.3, 131.4, 130.5, 129.3, 129.2, 127.0, 126.0, 120.9, 115.4, 103.0, 102.2, 70.0, 63.6, 53.8, 52.1, 21.1 ppm; HRMS (ESI) calculated for C₂₅H₂₃N₂O₆S [M + H]⁺: 479.12713, found 479.12646.

Dimethyl-7a-(4-chlorophenyl)-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4aad). Yellow solid, yield: 47.3 mg, 95%; M.P. = 151.7–152.8 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.95 (d, J = 6 Hz, 1H), 7.75–7.73 (m, 2H), 7.61 (d, J = 6.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 6.33 (d, J = 7.6 Hz, 1H), 6.21 (t, J = 7.2 Hz, 1H), 5.84 (s, 1H), 5.51 (d, J = 10 Hz, 1H), 5.25 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H), 3.56 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.6, 163.5, 146.5, 141.9, 138.4, 134.0, 133.6, 133.1, 131.7, 131.2, 130.1, 128.8, 126.9, 126.0, 121.1, 115.7, 102.4, 102.2, 69.6, 63.7, 53.8, 52.2 ppm; HRMS (ESI) calculated for C₂₄H₂₀ClN₂O₆S [M + H]⁺: 499.07251, found 499.07153.

Dimethyl-9-methyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4aae). Yellow solid, yield: 42 mg, 88%; M.P. = 167.9–168.5 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.81 (d, J = 8 Hz, 1H), 7.54 (d, J = 8 Hz, 1H), 7.42–7.35 (m, 4H), 7.14 (d, J = 7.6 Hz, 2H), 6.32 (d, J = 7.6 Hz, 1H), 6.19 (t, J = 7.2 Hz, 1H), 5.77 (s, 1H), 5.47 (d, J = 9.6 Hz, 1H), 5.23 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H), 3.56 (s, 3H), 2.36 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.8, 163.6, 146.3, 144.2, 143.0, 138.9, 132.3, 130.7, 130.2, 129.3, 128.7, 126.9, 126.0, 120.1, 115.4, 102.9, 102.2, 70.0, 63.6, 53.8, 52.1, 21.9 ppm; HRMS (ESI) calculated for C₂₅H₂₃N₂O₆S [M + H]⁺: 479.12713, found 479.12485.

Dimethyl-9-chloro-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4aaf). Yellow solid, yield: 48.8 mg, 98%; M.P. = 168.9–170.2 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.03 (d, J = 8.4 Hz, 1H), 7.82 (dd, J₁ = 8.4 Hz, J₂ = 0.8 Hz, 1H), 7.62 (s, 1H), 7.43–7.37 (m, 3H), 7.15 (d, J = 7.2 Hz, 2H), 6.35 (d, J = 7.6 Hz, 1H), 6.21 (t, J = 7.2 Hz, 1H), 5.80 (s, 1H), 5.49 (d, J = 9.6 Hz, 1H), 5.26 (t, J = 6.8 Hz, 1H), 3.86 (s, 3H), 3.58 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.7, 163.4, 146.8, 142.3, 140.8, 138.3, 132.1, 132.0, 130.2, 129.1, 129.0, 128.9, 127.0, 126.2, 123.1, 115.4, 102.5, 102.2, 69.9, 63.7, 53.9, 52.3 ppm; HRMS (ESI) calculated for C₂₄H₂₀ClN₂O₆S [M + H]⁺: 499.07251, found 499.07022.

Diethyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4abb). Yellow solid, yield: 40.8 mg, 83%; M.P. = 164.7–165.9 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.95–7.93 (m, 1H), 7.74–7.72 (m, 2H), 7.65–7.64 (m, 1H), 7.42–7.36 (m, 3H), 7.13 (d, J = 7.2 Hz, 2H), 6.31 (d, J = 7.6 Hz, 1H), 6.20 (t, J = 7.2 Hz, 1H), 5.81 (s, 1H), 5.48 (d, J = 9.6 Hz, 1H), 5.25 (t, J = 6.8 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.03 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 6.8 Hz, 3H), 1.06 (t, J = 6.8 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.3, 163.1, 146.2, 143.1, 138.7, 133.7, 133.3, 131.5, 130.5, 129.2, 128.8, 128.7, 126.8, 126.1, 120.9, 115.4, 103.2, 102.1, 70.2, 63.6, 63.0, 61.0, 14.2, 14.1 ppm; HRMS (ESI) calculated for C₂₆H₂₅N₂O₆S [M + H]⁺: 493.14278, found 493.14203.

Diisopropyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4acb). Yellow solid, yield: 12.0 mg, 23%; M.P. = 172.6–174.3 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.95–7.94 (m, 1H), 7.74 (t, J = 4 Hz, 2H), 7.66–7.64 (m, 1H), 7.42–7.36 (m, 3H), 7.12 (d, J = 7.2 Hz, 2H), 6.25–6.19 (m, 2H), 5.80 (s, 1H), 5.47 (d, J = 10 Hz, 1H), 5.26 (d, J = 6.8 Hz, 1H), 5.17–5.11 (m, 1H), 4.92–4.85 (m, 1H), 1.30 (dd, J₁ = 17.6 Hz, J₂ = 6.4 Hz, 6H), 1.12 (d, J = 6.0 Hz, 3H), 1.01 (d, J = 6.0 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.0, 162.5, 146.3, 143.1, 138.7, 133.6, 133.3, 131.5, 130.7, 129.2, 128.8, 128.6, 126.7, 126.1, 121.0, 115.4, 103.5, 102.0, 71.0, 70.3, 69.1, 63.5, 21.8, 21.7, 21.5, 21.4 ppm; HRMS (ESI) calculated for C₂₈H₂₉N₂O₆S [M + H]⁺: 521.17408, found 521.17200.

Diethyl-7a-(p-tolyl)-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4abc). Yellow solid, yield: 38.0 mg, 75%; M.P. = 154.2–155.3 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.92–7.91 (m, 1H), 7.72–7.71 (m, 2H), 7.64 (s, 1H), 7.20 (d, J = 7.2 Hz, 2H), 7.00 (d, J = 7.6 Hz, 2H), 6.29 (d, J = 7.6 Hz, 1H), 6.20 (s, 1H), 5.80 (s, 1H), 5.47 (d, J = 9.6 Hz, 1H), 5.25 (d, J = 5.6 Hz, 1H), 4.32 (d, J = 7.2 Hz, 2H), 4.03 (t, J = 3.6 Hz, 2H), 2.30 (s, 3H), 1.29–1.27 (m, 3H), 1.09–1.05 (m, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.3, 163.1, 146.0, 140.3, 138.8, 138.2, 133.5, 133.3, 131.4, 130.6, 129.2, 129.1, 126.8, 126.1, 120.9, 115.4, 103.5, 102.0, 70.1, 63.6, 62.9, 61.0, 21.1, 14.2, 14.1 ppm; HRMS (ESI) calculated for C₂₇H₂₇N₂O₆S [M + H]⁺: 507.15843, found 507.15793.

Diethyl-7a-(4-chlorophenyl)-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyramidine-6,7-dicarboxylate-12,12-dioxide (4abd). Yellow solid, yield: 51.0 mg, 97%; M.P. = 137.4–138.9 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.96–7.94 (m, 1H), 7.75–7.73 (m, 2H), 7.65 (d, J = 4.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.31 (d, J = 7.6 Hz, 1H), 6.21 (t, J = 6.8 Hz, 1H), 5.84 (s, 1H), 5.51 (d, J = 9.6 Hz, 1H), 5.26 (t, J = 6.8 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.2, 163.0, 146.4, 142.0, 138.4, 133.9, 133.6, 133.2, 131.7, 131.1, 130.3, 128.7, 126.7, 126.0, 121.1, 115.6, 102.5, 102.3, 69.6, 63.7, 63.0, 61.1, 14.2, 14.1 ppm; HRMS (ESI) calculated for C₂₆H₂₄ClN₂O₆S [M + H]⁺: 527.10381, found 527.10181.

Diethyl-3-methyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyramidine-6,7-dicarboxylate-12,12-dioxide (4cbb). Yellow solid, yield: 42.5 mg, 84%; M.P. = 150.9–152.3 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.92–7.90 (m, 1H), 7.72–7.65 (m, 3H), 7.42–7.35 (m, 3H), 7.14 (d, J = 7.2 Hz, 2H), 6.23 (d, J = 7.6 Hz, 1H), 5.99 (d, J = 5.6 Hz, 1H), 5.51 (s, 1H), 5.23 (t, J = 6.8 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.08–4.01 (m, 2H), 1.51 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.5, 163.3, 146.5, 143.3, 138.9, 133.5, 131.4, 131.0, 129.1, 128.7, 128.6, 124.7, 123.6, 122.6, 120.9, 104.0, 102.5, 70.8, 66.5, 62.9, 61.1, 19.1, 14.2, 14.1 ppm; HRMS (ESI) calculated for C₂₇H₂₇N₂O₆S [M + H]⁺: 507.15843, found 507.15799.

Diethyl-2-methyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4dbb). Yellow solid, yield: 44.5 mg, 88%; M.P. = 152.7–153.5 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.92–7.90 (m, 1H), 7.73–7.63 (m, 3H), 7.39–7.35 (m, 3H), 7.11 (d, J = 6.8 Hz, 2H), 6.29 (d, J = 7.6 Hz, 1H), 5.70 (s, 1H), 5.21 (s, 1H), 5.12 (t, J = 7.6 Hz, 1H), 4.33 (q, J = 6.8 Hz, 2H), 4.03 (q, J = 6.8 Hz, 2H), 1.73 (s, 3H), 1.27 (t, J = 6.8 Hz, 3H), 1.06 (t, J = 6.8 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.3, 163.1, 146.0, 143.1, 138.7, 134.3, 133.6, 133.5, 131.4, 130.5, 129.1, 128.7, 128.6, 126.3, 120.9, 110.5, 105.6, 103.0, 70.1, 63.9, 62.9, 61.0, 21.1, 14.2, 14.1 ppm; HRMS (ESI) calculated for C₂₇H₂₇N₂O₆S [M + H]⁺: 507.15843, found 507.15802.

Dimethyl-2,9-dimethyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4dae). Yellow solid, yield: 38.9 mg, 79%; M.P. = 137.3–138.7 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.79 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.40–7.35 (m, 4H), 7.13 (d, J = 7.2 Hz, 2H), 6.30 (d, J = 7.6 Hz, 1H), 5.66 (s, 1H), 5.21 (s, 1H), 5.11 (d, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.56 (s, 3H), 2.36 (s, 3H), 1.73 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.8, 163.6, 146.1, 144.1, 143.0, 138.9, 134.2, 132.2, 130.9, 130.2, 129.2, 128.7, 126.5, 120.7, 110.5, 105.7, 102.7, 69.9, 63.9, 53.8, 52.1, 21.9, 21.1 ppm; HRMS (ESI) calculated for C₂₆H₂₅N₂O₆S [M + H]⁺: 493.14278, found 493.14035.

Dimethyl-9-chloro-2-methyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4daf). Yellow solid, yield: 47.6 mg, 93%; M.P. = 120.1–121.8 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.99 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.43–7.36 (m, 3H), 7.14 (d, J = 7.2 Hz, 2H), 6.32 (d, J = 7.6 Hz, 1H), 5.70 (s, 1H), 5.23 (s, 1H), 5.14 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.58 (s, 3H), 1.74 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.7, 163.4, 146.6, 142.3, 140.8, 138.2, 134.4, 132.3, 132.0, 130.2, 129.1, 129.0, 128.9, 126.5, 123.0, 110.5, 106.1, 102.1, 69.7, 64.0, 53.8, 52.3, 21.1 ppm; HRMS (ESI) calculated for C₂₅H₂₂ClN₂O₆S [M + H]⁺: 513.08816, found 513.08594.

Diethyl-2-methyl-7a-(p-tolyl)-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4dbc). Yellow solid, yield: 49.4 mg, 95%; M.P. = 142.1–143.2 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.88 (d, J = 6.8 Hz, 1H), 7.71–7.69 (m, 2H), 7.62 (d, J = 6.8 Hz, 1H), 7.18 (d, J = 8 Hz, 2H), 6.98 (d, J = 7.6 Hz, 2H), 6.27 (d, J = 7.6 Hz, 1H), 5.66 (s, 1H), 5.19 (s, 1H), 5.11 (d, J = 8 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 4.04–4.01 (m, 2H), 2.30 (s, 3H), 1.73 (s, 3H), 1.27 (t, J = 6.8 Hz, 3H), 1.07 (t, J = 6.8 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.3, 163.1, 145.9, 140.3, 138.9, 138.2, 134.2, 133.5, 131.4, 130.6, 129.2, 129.1, 126.3, 120.8, 110.5, 105.6, 103.3, 69.9, 63.8, 62.9, 61.0, 21.1, 21.0, 14.2, 14.1 ppm; HRMS (ESI) calculated for C₂₈H₂₉N₂O₆S [M + H]⁺: 521.17408, found 521.17352.

Diethyl-7a-(4-chlorophenyl)-2-methyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4dbd). Yellow solid, yield: 51.3 mg, 95%; M.P. = 130.3–131.2 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.91 (d, J = 4.8 Hz, 1H), 7.73 (t, J = 3.6 Hz, 2H), 7.64 (d, J = 4.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.28 (d, J = 7.6 Hz, 1H), 5.74 (s, 1H), 5.24 (s, 1H), 5.14 (d, J = 7.6 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.04 (q, J = 7.2 Hz, 2H), 1.74 (s, 3H), 1.27 (t, J = 6.8 Hz, 3H), 1.07 (t, J = 6.8 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.2, 163.0, 146.2, 142.0, 138.4, 134.2, 133.8, 133.5, 133.4, 131.6, 131.1, 130.3, 128.7, 126.2, 121.0, 110.6, 105.8, 102.4, 69.5, 63.9, 62.9, 61.1, 21.1, 14.2, 14.1 ppm; HRMS (ESI) calculated for C₂₇H₂₆ClN₂O₆S [M + H]⁺: 541.11946, found 541.11896.

Diisopropyl-2,9-dimethyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4dce). Yellow solid, yield: 24.7 mg, 45%; M.P. = 147.3–148.1 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.79 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.41–7.35 (m, 4H), 7.12 (d, J = 7.2 Hz, 2H), 6.21 (d, J = 8.0 Hz, 1H), 5.66 (s, 1H), 5.20–5.12 (m, 3H), 4.93–4.87 (m, 1H), 2.35 (s, 3H), 1.73 (s, 3H), 1.30 (dd, J₁ = 15.2 Hz, J₂ = 6.0 Hz, 6H), 1.12 (d, J = 6.0 Hz, 3H), 1.01 (d, J = 6.0 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.1, 162.6, 146.2, 143.7, 143.2, 139.1, 134.2, 132.2, 131.0, 130.3, 129.2, 128.7, 128.5, 125.9, 120.8, 110.5, 105.5, 103.4, 70.9, 70.0, 68.9, 63.8, 21.9, 21.7, 21.6, 21.1 ppm; HRMS (ESI) calculated for C₃₀H₃₃N₂O₆S [M + H]⁺: 549.20538, found 549.20282.

Diisopropyl-9-chloro-2-methyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4dcf). Yellow solid, yield: 33.5 mg, 59%; M.P. = 141.3–142.7 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.00 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.42–7.38 (m, 3H), 7.14 (d, J = 7.2 Hz, 2H), 6.22 (d, J = 7.6 Hz, 1H), 5.69 (s, 1H), 5.22–5.12 (m, 3H), 4.96–4.89 (m, 1H), 1.74 (s, 3H), 1.30 (dd, J₁ = 16.0 Hz, J₂ = 6.0 Hz, 6H), 1.13 (d, J = 6.0 Hz, 3H), 1.02 (d, J = 6.0 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 167.4, 164.0, 162.4, 146.8, 142.4, 141.0, 138.0, 134.4, 132.4, 132.2, 131.9, 130.2, 129.2, 129.1, 129.0, 128.8, 125.8, 123.2, 110.5, 105.9, 102.5, 71.1, 69.8, 69.1, 65.5, 64.0, 30.5, 21.9, 21.7, 21.5, 21.1, 19.1, 14.0 ppm; HRMS (ESI) calculated for C₂₉H₃₀ClN₂O₆S [M + H]⁺: 569.15076, found 569.14819.

Dimethyl-3-methyl-7a-(p-tolyl)-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyramiddine-6,7-dicarboxylate-12,12-dioxide (4cac). Yellow solid, yield: 45.8 mg, 93%; M.P. = 174.3–175.7 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.88 (d, J = 6.4 Hz, 1H), 7.72–7.66 (m, 2H), 7.58 (d, J = 7.2 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.23 (d, J = 7.6 Hz, 1H), 5.99 (d, J = 6.0 Hz, 1H), 5.50 (s, 1H), 5.21 (d, J = 7.2 Hz, 1H), 3.83 (s, 3H), 3.57 (s, 3H), 2.31 (s, 3H), 1.52 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.9, 163.8, 146.5, 140.4, 139.0, 138.1, 133.5, 133.4, 131.3, 130.9, 130.4, 130.3, 129.2, 129.1, 124.9, 123.7, 122.5, 120.8, 103.9, 102.5, 70.7, 66.4, 52.7, 52.1, 21.1, 19.2 ppm; HRMS (ESI) calculated for C₂₆H₂₅N₂O₆S [M + H]⁺: 493.14278, found 493.14096.

Dimethyl-7a-(4-chlorophenyl)-3-methyl-7a,13a-dihydrobenzo [4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4cad). Yellow solid, yield: 49.7 mg, 97%; M.P. = 151.4–152.3 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.92–7.90 (m, 1H), 7.73–7.71 (m, 2H), 7.61 (d, J = 7.2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.25 (d, J = 7.6 Hz, 1H), 6.00 (d, J = 5.6 Hz, 1H), 5.55 (s, 1H), 5.23 (t, J = 6.8 Hz, 1H), 3.83 (s, 3H), 3.59 (s, 3H), 1.54 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.8, 163.7, 146.8, 142.1, 138.6, 133.8, 133.5, 133.3, 131.6, 131.1, 130.5, 128.7, 124.7, 123.9, 122.5, 121.0, 102.9, 102.8, 70.3, 66.5, 53.8, 52.2, 19.1 ppm; HRMS (ESI) calculated for C₂₅H₂₂ClN₂O₆S [M + H]⁺: 513.08816, found 513.08777.

Dimethyl-3-methyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4cab). Yellow solid, yield: 44.9 mg, 94%; M.P. = 160.5–161.1 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.89 (d, J = 6.4 Hz, 1H), 7.71–7.61 (m, 3H), 7.39 (d, J = 7.2 Hz, 3H), 7.14 (d, J = 6.4 Hz, 2H), 6.24 (d, J = 7.2 Hz, 1H), 5.99 (d, J = 4.4 Hz, 1H), 5.51 (s, 1H), 5.22 (t, J = 6.8 Hz, 1H), 3.84 (s, 3H), 3.59 (s, 3H), 1.51 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.9, 163.8, 146.6, 143.2, 138.9, 133.6, 133.4, 131.4, 130.8, 129.2, 128.8, 128.7, 124.9, 123.7, 122.5, 120.9, 103.6, 102.6, 70.8, 66.5, 53.8, 52.1, 19.1 ppm; HRMS (ESI) calculated for C₂₅H₂₃N₂O₆S [M + H]⁺: 479.12713, found 479.12653.

Diisopropyl-3-methyl-7a-(p-tolyl)-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4ccc). Yellow solid, yield: 31.8 mg, 58%; M.P. = 110.6–111.3 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.89–7.87 (m, 1H), 7.71–7.59 (m, 3H), 7.20 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.14 (d, J = 7.6 Hz, 1H), 5.98 (d, J = 5.2 Hz, 1H), 5.48 (s, 1H), 5.23 (t, J = 6.8 Hz, 1H), 5.13 (q, J = 6.4 Hz, 1H), 4.91 (q, J = 6.4 Hz, 1H), 2.30 (s, 3H), 1.52 (s, 3H), 1.32 (d, J = 6.0 Hz, 3H), 1.26 (d, J = 6.0 Hz, 3H), 1.14 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.3, 162.7, 146.4, 140.5, 139.1, 138.1, 133.5, 133.2, 131.3, 131.2, 129.1, 124.3, 123.6, 122.5, 120.8, 104.7, 102.4, 70.9, 70.7, 66.4, 21.8, 21.7, 21.5, 21.1, 19.2 ppm; HRMS (ESI) calculated for C₃₀H₃₃N₂O₆S [M + H]⁺: 549.20538, found 549.20331.

Diisopropyl-7a-(4-chlorophenyl)-3-methyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4ccd). Yellow solid, yield: 43.2 mg, 76%; M.P. = 127.5–128.2 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 7.92–7.90 (m, 1H), 7.74–7.72 (m, 2H), 7.65–7.62 (m, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 6.16 (d, J = 7.6 Hz, 1H), 5.99 (d, J = 5.2 Hz, 1H), 5.53 (s, 1H), 5.26 (t, J = 7.2 Hz, 1H), 5.14 (q, J = 6.4 Hz, 1H), 4.96–4.90 (m, 1H), 1.54 (s, 3H), 1.32 (d, J = 6.4 Hz, 3H), 1.27 (d, J = 6.0 Hz, 3H), 1.14 (d, J = 6.0 Hz, 3H), 1.07 (d, J = 6.0 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.0, 162.6, 146.8, 142.3, 138.6, 133.6, 133.5, 133.4, 131.6, 131.1, 130.9, 128.6, 124.2, 123.9, 122.5, 121.0, 103.6, 102.7, 71.0, 70.3, 69.2, 66.5, 21.8, 21.7, 21.5, 19.1 ppm; HRMS (ESI) calculated for C₂₉H₃₀ClN₂O₆S [M + H]⁺: 569.15076, found 569.14874.

Diethyl-9-chloro-3-methyl-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4cbf). Yellow solid, yield: 49.7 mg, 92%; M.P. = 116.5–117.3 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.00 (d, J = 8.4 Hz, 1H), 7.81–7.79 (m, 1H), 7.63 (s, 1H), 7.44–7.38 (m, 3H), 7.15 (d, J = 7.2 Hz, 2H), 6.23 (d, J = 7.6 Hz, 1H), 6.00 (d, J = 6.0 Hz, 1H), 5.51 (s, 1H), 5.25 (t, J = 7.2 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 4.15–4.02 (m, 2H), 1.51 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.6, 163.1, 147.0, 142.6, 141.1, 138.1, 132.3, 131.9, 130.7, 129.1, 129.0, 128.8, 124.7, 123.6, 123.1, 122.6, 103.2, 102.9, 70.5, 66.6, 63.0, 61.3, 19.1, 14.2, 14.1 ppm; HRMS (ESI) calculated for C₂₇H₂₆ClN₂O₆S [M + H]⁺: 541.11946, found 541.11719.

Dimethyl-9-chloro-2-cyano-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-6,7-dicarboxylate-12,12-dioxide (4gaf). Yellow solid, yield: 17.8 mg, 34%; M.P. = 122.4–123.1 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.09 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.42 (d, J = 7.6 Hz, 3H), 7.15 (d, J = 6.8 Hz, 2H), 6.62 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 2.8 Hz, 1H), 6.11 (d, J = 4.0 Hz, 1H), 5.37 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 3.60 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.5, 162.9, 145.7, 141.7, 140.4, 138.7, 132.3, 131.4, 130.3, 129.7, 129.3, 129.1, 129.0, 127.4, 123.3, 116.9, 112.3, 105.2, 98.7, 70.1, 63.1, 54.1, 52.7 ppm; HRMS (ESI) calculated for C₂₅H₁₉ClN₃O₆S [M + H]⁺: 524.06776, found 524.06561.

Trimethyl-9-chloro-7a-phenyl-7a,13a-dihydrobenzo[4,5]isothiazolo[2,3-c]pyrido[1,2-a]pyrimidine-2,6,7-tricarboxylate-12,12-dioxide (4eaf). Yellow solid, yield: 40.0 mg, 72%; M.P. = 174.8–176.4 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 8.03 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.42 (d, J = 7.6 Hz, 3H), 7.15 (d, J = 6.8 Hz, 2H), 6.51 (d, J = 7.6 Hz, 1H), 6.30 (s, 1H), 6.05 (d, J = 3.6 Hz, 1H), 5.57 (d, J = 7.6 Hz, 1H), 3.87 (s, 3H), 3.73 (s, 3H), 3.60 (s, 3H) ppm; ¹³C NMR (100 MHz, DMSO-d₆): δ 164.6, 164.1, 163.1, 146.1, 141.9, 140.7, 138.6, 132.2, 131.5, 130.3, 129.2, 129.1, 129.0, 128.4, 123.2, 122.2, 103.4, 99.3, 70.0, 63.5, 54.1, 52.9, 52.5 ppm; HRMS (ESI) calculated for C₂₆H₂₂ClN₂O₈S [M + H]⁺: 557.07799, found 557.07568.

Acknowledgements

We thank Beijing Municipal Commission of Education (No. JC015001200902), Beijing Municipal Natural Science Foundation (No. 7102010, No. 2122008), Basic Research Foundation of Beijing University of Technology (X4015001201101), Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (No. PHR201008025), Doctoral Scientific Research Start-up Foundation of Beijing University of Technology (No. 52015001200701) for financial supports.

Notes and references

1. (a) J. Wrobe, A. Dietrich, S. A. Woolson, J. Millen, M. McCaleb, M. C. Harrison, T. C. Hohman, J. Sredy and D. Sullivan, J. Med. Chem., 1992, 35, 4613; (b) Z. Jakopin, E. Corsini, M. Gobec, I. Mlinaric-Rascan and M. S. Dolenc, Eur. J. Med. Chem., 2011, 46, 3762; (c) Z. Jakopin, M. Gobec, I. Mlinaric-Rascan and M. Sollner Dolenc, J. Med. Chem., 2012, 55, 6478; (d) B. Qiao, Y. J. Huang, J. Nie and J. A. Ma, Org. Lett., 2015, 17, 4608; (e) S. Zhang, L. Li, Y. Hu, Z. Zha, Z. Wang and T. P. Loh, Org. Lett., 2015, 17, 1050; (f) P. C. Zheng, J. Cheng, S. Su, Z. Jin, Y. H. Wang, S. Yang, L. H. Jin, B. A. Song and Y. R. Chi, Chemistry, 2015, 21, 9984.
2. (a) M. Rommel, T. Fukuzumi and J. W. Bode, J. Am. Chem. Soc., 2008, 130, 17266; (b) P.-C. Chiang, M. Rommel and J. W. Bode, J. Am. Chem. Soc., 2009, 131, 8714; (c) B. H. Zhu, J. C. Zheng, C. B. Yu, X. L. Sun, Y. G. Zhou, Q. Shen and Y. Tang, Org. Lett., 2010, 12, 504; (d) X. Y. Chen, R. C. Lin and S. Ye, Chem. Commun., 2012, 48, 1317; (e) X.-Y. Chen and S. Ye, Eur. J. Org. Chem., 2012, 2012, 5723; (f) L. Dong, C. H. Qu, J. R. Huang, W. Zhang, Q. R. Zhang and J. G. Deng, Chemistry, 2013, 19, 16537; (g) J. R. Huang, Q. Song, Y. Q. Zhu, L. Qin, Z. Y. Qian and L. Dong, Chemistry, 2014, 20, 16882; (h) S. T. Mei, H. W. Liang, B. Teng, N. J. Wang, L. Shuai, Y. Yuan, Y. C. Chen and Y. Wei, Org. Lett., 2016, 18, 1088.
3. For selected examples, see: (a) X. Feng, Z. Zhou, C. Ma, X. Yin, R. Li, L. Dong and Y. C. Chen, Angew. Chem., Int. Ed. Engl., 2013, 52, 14173; (b) Q. An, J. Shen, N. Butt, D. Liu, Y. Liu and W. Zhang, Adv. Synth. Catal., 2015, 357, 3627; (c) M. Hatano and T. Nishimura, Angew. Chem., Int. Ed. Engl., 2015, 54, 10949; (d) F. Wei, H. Y. Huang, N. J. Zhong, C. L. Gu, D. Wang and L. Liu, Org. Lett., 2015, 17, 1688.
4. For selected examples, see: (a) B. M. Trost and S. M. Silverman, J. Am. Chem. Soc., 2012, 134, 4941; (b) X. Y. Chen, Z. H. Gao, C. Y. Song, C. L. Zhang, Z. X. Wang and S. Ye, Angew. Chem., Int. Ed. Engl., 2014, 53, 11611; (c) J. Gu, C. Ma, Q. Z. Li, W. Du and Y. C. Chen, Org. Lett., 2014, 16, 3986; (d) Q. An, J. Li, J. Shen, N. Butt, D. Liu, Y. Liu and W. Zhang, Chem. Commun., 2015, 51, 885; (e) X. Chen, J. Q. Zhang, S. J. Yin, H. Y. Li, W. Q. Zhou and X. W. Wang, Org. Lett., 2015, 17, 4188; (f) B. S. Li, Y. Wang, Z. Jin, P. Zheng, R. Ganguly and Y. R. Chi, Nat. Commun., 2015, 6, 6207.
5. T. Nishimura, Y. Ebe and T. Hayashi, J. Am. Chem. Soc., 2013, 135, 2092.
6. X. L. He, Y. C. Xiao, W. Du and Y. C. Chen, Chem.–Eur. J., 2015, 21, 3443.
7. A. G. Kravina, J. Mahatthananchai and J. W. Bode, Angew. Chem., Int. Ed. Engl., 2012, 51, 9433.
8. Q. An, J. Shen, N. Butt, D. Liu, Y. Liu and W. Zhang, Org. Lett., 2014, 16, 4496.
9. For selected examples, see: (a) C.-Q. Li and M. Shi, Org. Lett., 2003, 5, 4273; (b) M. T. Maghsoodlou, S. M. Habibi-Khorassani, A. Moradi, N. Hazeri, A. Davodi and S. S. Sajadikhah, Tetrahedron, 2011, 67, 8492; (c) H.-B. Yang, X.-Y. Guan, Y. Wei and M. Shi, Eur. J. Org. Chem., 2012, 2012, 2792; (d) J. Sun, H. Gong and C.-G. Yan, Tetrahedron, 2013, 69, 10235; (e) J. Sun, F. Wang, H. Hu, X. Wang, H. Wu and Y. Liu, J. Org. Chem., 2014, 79, 3992.
10. CCDC 1477146 contains the supplementary crystallographic data for compound 4aaf.†.
11. For selected examples, see: (a) M. Adib, H. Yavari and M. Mollahosseini, Tetrahedron Lett., 2004, 45, 1803; (b) V. Nair, S. Devipriya and E. Suresh, Tetrahedron, 2008, 64, 3567; (c) A. Shaabani, A. H. Rezayan, A. Sarvary and H. R. Khavasi, Tetrahedron Lett., 2008, 49, 1469; (d) M. B. Teimouri, T. Abbasi, S. Ahmadian, M. R. Poor Heravi and R. Bazhrang, Tetrahedron, 2009, 65, 8120; (e) A. A. Esmaeili, H. Vesalipoor, R. Hosseinabadi, A. F. Zavareh, M. A. Naseri and E. Ghiamati, Tetrahedron Lett., 2011, 52, 4865; (f) J. Sun, Y. Sun, H. Gong, Y.-J. Xie and C.-G. Yan, Org. Lett., 2012, 14, 5172.
12. For selected examples, see: (a) T. Nishimura, A. Noishiki, G. C. Tsui and T. Hayashi, J. Am. Chem. Soc., 2012, 134, 5056; (b) C. M. Tan, G. S. Chen, C. S. Chen, P. T. Chang and J. W. Chern, Bioorg. Med. Chem., 2011, 19, 6316; (c) Q. R. Zhang, J. R. Huang, W. Zhang and L. Dong, Org. Lett., 2014, 16, 1684.

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Footnote

† Electronic supplementary information (ESI) available: Copies of NMR spectra for all products related to this article; X-ray single crystal structure analysis data for 4aaf. CCDC 1477146. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra12771a

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