Mild and efficient synthesis of benzothiazolopyrimidine derivatives via CuAAC/ring cleavage/cyclization reaction

Abstract

An operationally mild and efficient synthesis of benzothiazolopyrimidine is achieved by a three-component reaction of 2-aminebenzo[d]thiazoles, sulfonyl azides and terminal ynones. This cascade process involved a CuAAC/ring cleavage/cyclization reaction. Particularly, most of the benzothiazolopyrimidine derivatives could be isolated by filtration without further purification.

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Introduction

Benzothiazolopyrimidine derivatives are well established as privileged scaffolds which are commonly encountered in many pharmacologically active molecules that may be good drug candidates.^1–7 Most of the benzothiazolopyrimidines possess various biological activities like inhibition of SHP2 (Fig. 1, I),² anticancer agent (II),³ antitumor activity (III),⁴ analgesic (IV),⁵ and nucleoside transporter (V).⁶ Also, some benzothiazolopyrimidine derivatives are commercially available as chiral catalysts (VI).⁷ Therefore, the development of novel methods for the synthesis of these benzothiazolopyrimidine is important in the field of synthetic organic and pharmaceutical chemistry.

Fig. 1 Benzothiazolopyrimidines drug candidates and chiral catalyst.

Numerous synthetic methods for the preparation of benzothiazolopyrimidines reported in the literature involve three major strategies: (a) intramolecular cyclization reaction with amino alcohol substrates under reflux conditions (Scheme 1a);⁸ (b) [4 + 2] cycloaddition of 2-benzothiazolimines and alkenes or other unsaturated compounds (Scheme 1b);⁹ (c) a one-pot acylation–cyclization of 2-aminobenzothiazole with α,β-unsaturated acid chlorides (Scheme 1c).¹⁰ Each of these methods has considerable merit, including synthesis of stereoselective benzothiazolopyrimidine derivatives and polysubstituted products. However, there synthetic utility is impaired by the requirement of multistep synthesis, high temperatures and complex purification. Under this background, the development of operationally mild multicomponent one-pot synthetic strategies for the preparation of benzothiazolopyrimidines still remains highly desirable.

Scheme 1 Synthesis of benzothiazolopyrimidine derivatives by (a) intramolecular cyclization reaction, (b) [4+2] cycloaddition, (c) acylation−cyclization, (d) this work, CuAAC/ring cleavage/cyclization reaction.

Since reported by Chang's group,¹¹ copper-catalyzed sulfonyl azide–alkyne cycloaddition/ring cleavage (CuAAC/ring cleavage reaction) has been recognized as a mild multicomponent reaction and high efficient method for the synthesis of various N-heterocyclic compounds, which was applied to the structural modification of natural products, drugs or biological macromolecules.¹² Our group has also applied the CuAAC/ring cleavage reaction to the construction of pyridines, fused heterocycles, coumarins, indoles and other N-heterocyclic compounds.¹³ Accordingly, we here describe a mild and efficient synthesis of benzothiazolopyrimidine derivatives via CuAAC/ring cleavage reaction (Scheme 1d). This protocol encompasses stirring a three-component reaction of 2-aminebenzo[d]thiazoles, sulfonyl azides and terminal ynones.

Results and discussion

Our investigations began with an examination of the synthesis of (Z)-4-methyl-N-(2-methyl-4H-benzo[4,5]thiazolo [3,2-a]pyrimidin-4-ylidene)benzenesulfonamide 4a by using 2-aminobenzothiazole 1a, TsN₃ 2a and 3-butyn-2-one 3a (Table 1).

Table 1 Optimization of catalytic conditions^a

Entry	Cat.	Solvent	Yield^b (%) 4a
a Reaction conditions: 1a (0.5 mmol), cat. (10 mol%) in the solvent (3 mL) was added 2a (1.5 equiv.) and 3a (1.5 equiv.) stirring at room temperature for 12 h.b Isolated yields.c n.d. = not detected the target product.d The reaction temperature was 40 °C.e The temperature was 60 °C.f The temperature was 100 °C.
1	CuI	CHCl3	75
2	CuI	DCE	85
3	CuI	Toluene	70
4	CuI	MeCN	93
5	CuI	THF	60
6	CuI	1,4-Dioxane	51
7	CuI	DMSO	81
8	CuI	DMA	78
9	CuI	EtOH	93
10	CuI	Acetone	68
11	CuCl	EtOH	90
12	CuBr	EtOH	83
13	CuBr2	EtOH	80
14	Cu(OAc)2	EtOH	90
15	Cu(OTf)2	EtOH	80
16	Cu(acac)2	EtOH	85
17	AgTFA	EtOH	n.d.^c
18	CuI	EtOH	93^d
19	CuI	EtOH	90^e
20	CuI	EtOH	87^f

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The solvent screening revealed that by using CuI as the catalysts, EtOH and MeCN delivering product 4a in highest yield (93%) (Table 1, entries 1–10). Since EtOH is less toxic and cheaper than MeCN, the optimal solvent was determined to be EtOH. Encouraged by this promising result, variety of catalysts were screened. Among the copper catalysts used, both Cu^I or Cu^II catalysts exhibited high catalytic reactivity while AgTFA failed to produce the desired product (Table 1, entries 11–17). Lastly, the effect of temperature was evaluated (Table 1, entries 18–20). The results revealed room temperature is the best. Considering atomic economy, reaction rate and efficiency, the optimal reaction conditions have been defined to be Table 1, entry 9.

Under the optimized conditions (Table 1, entry 9), we performed a substrates screening using a series of 2-aminobenzothiazoles. Agreeably, as shown in Table 2, various 2-Aminobenzothiazoles with either electron-donating groups (–Me, –OMe, –OEt, –OH) or electron-withdrawing groups (–F, –Cl, –Br, –NO₂ –COOCH₂CH₃) exhibited good functional-group tolerance to produced the desired products (4a−4k). It is worth noting that the yield of 4c is relatively low due to the influence of steric effect, while the yield of 4g is the lowest with the influence of the strong pull electron effect. Gratifyingly, 2-aminothiazole proceeded smoothly in this transformation, which generated 4l in decent yield. However, 2-aminobenzothiazole bearing electron-withdrawing group (–CN) gave a complex reaction system and difficult to isolate the desired product.

Table 2 Substrate scope of the amines 1^a

a Reaction conditions: 1 (0.5 mmol), CuI (10 mol%) in EtOH (3 mL) was added 2a (1.5 equiv.) and 3a (1.5 equiv.) stirring at room temperature for 12 h.

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Next, the scope and limitation of substrates sulfonyl azides 2 were tested (Table 3). It is noteworthy that the substrates sulfonyl azides showed slight influence on this reaction. With R³ changed by aliphatic or aromatic substituents, such as phenyl, –(4-C₆H₅), –(4-ClC₆H₄), –(4-BrC₆H₄), –(4-OMeC₆H₄), –(4-NO₂C₆H₄), –Me, –Pr, etc., the reaction could smoothly give the anticipated products (4m–4x) in comparable yields of 76–97%.

Table 3 Substrate scope of the sulfonyl azides 2^a

a Reaction conditions: 1a (0.5 mmol), CuI (10 mol%) in the solvent (3 mL) was added 2 (1.5 equiv.) and 3 (1.5 equiv.) stirring at room temperature for 12 h.

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Products 4a–4z are stable towards purification under conventional conditions. Nevertheless, N-sulfonyl benzothiazolo-pyrimidine 4a could undergo hydrolysis and converted into imine 5a under forcing conditions (Scheme 2).

Scheme 2 Hydrolysis of N-sulfonyl benzothiazolopyrimidine 4a.

None of the product imidazo[1,2-a]pyridines 4a–4z have been reported previously, which were subject to full spectroscopic characterization in the experimental section and the derived data were in complete accord with the assigned structures. The structure of 4o was confirmed by single-crystal X-ray analysis (Fig. 2).

Fig. 2 Single-crystal X-ray analysis of 4o (CCDC 2270393).

A possible reaction pathway for the formation of benzothiazolopyrimidine (4a) from precursors 1a, 2a and 3a is shown in Scheme 3. As described in the literature,^12,13 the substrates 2a and 3a reacted in the presence of the copper(I) catalyst to form the metallated triazole A through the CuAAC pathway. Then, the complex A underwent a ring-cleavage rearrangement, leading to a highly active intermediate N-sulfonyl α-acylketenimine B. The species B was captured by 1a via nucleophilic addition to generate the intermediate C, which delivered the intermediate D by intramolecular cyclization, and generated the final product 4a after dehydration.

Scheme 3 Plausible reaction mechanism.

Conclusions

We have developed an operationally mild and high efficient reaction for preparing benzothiazolopyrimidines by a three-component reaction of 2-aminebenzo[d]thiazoles, sulfonyl azides and terminal ynones. From a mechanistic perspective, the cascade process involved a CuAAC/ring cleavage/cyclization reaction. This methodology appears quite flexible and offers a capacity to generate forms of the title products that will be particularly useful in drug development studies.

Experimental

General

¹H and ¹³C{¹H} NMR spectra were recorded at ambient temperatures on a 400 MHz Bruker spectrometer using CDCl₃ or DMSO-d₆ as solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts are presented as δ values relative to TMS and ¹H–¹H coupling constants (J values) are given in Hz. IR spectra were recorded on a BUCHI IRAffinity-1S spectrometer while HRMS measurements were carried out on a Bruker micrOTOF-Q II spectrometer. Melting points were determined on a BUCHI melting point M-565 apparatus and are uncorrected.

Preparation and characterizations of compounds 4a–4z

(Z)-4-Methyl-N-(2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin -4-ylidene)benzenesulfonamide (4a). To a solution of CuI (9.5 mg, 0.05 mmol) and 2-aminobenzothiazole (1a, 75.0 mg, 0.5 mmol) in EtOH (3 mL) was added TsN₃ (2a, 147.9 mg, 0.75 mmol), and 3-butyn-2-one (3a, 51.1 mg, 0.75 mmol). After stirring at room temperature for 12 h (TLC monitoring), the reaction mixture was directly centrifuged after the end of the reaction. The centrifuged solid was washed twice with EtOH : H₂O = 2 : 1 to obtain product 4a (171.6 mg, 93%) as a white solid, mp 252–254 °C (R_f = 0.37 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.26 (d, J = 10.4 Hz, 1H), 7.94 (d, J = 5.6 Hz, 2H), 7.70 (d, J = 10.0 Hz, 1H), 7.45–7.53 (m, 2H), 7.40 (s, 1H), 7.30 (d, J = 5.6 Hz, 2H), 2.44 (d, J = 14.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 163.1, 161.5, 156.2, 142.8, 140.0, 136.0, 129.5 (2C), 128.0, 127.4, 126.7 (2C), 124.6, 122.7, 122.0, 104.8, 24.2, 21.7; IR ν 2920, 1609, 1493, 1450, 1402, 1283, 1140, 1088, 984, 812, 793, 756, 692 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₈H₁₆N₃O₂S₂⁺, [M + H]⁺ 370.0679; found 370.0672.

The products 4b–4z were prepared by the similar procedure.

(Z)-N-(2,8-Dimethyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)-4-methylbenzenesulfonamide (4b). 172.4 mg (90%), yellow solid, mp 256–258 °C (R_f = 0.44 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.11 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 10.0 Hz, 2H), 7.49 (s, 1H), 7.39 (s, 1H), 7.29 (t, J = 11.4 Hz, 3H), 2.46 (d, J = 4.4 Hz, 6H), 2.43 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.9, 161.5, 156.0, 142.7, 140.1, 138.6, 133.9, 129.5 (2C), 128.5, 126.7 (2C), 124.7, 122.3, 122.0, 104.8, 24.2, 21.7, 21.5; IR ν 2924, 1599, 1493, 1277, 1142, 1086, 982, 822, 810, 789, 733, 700, 671 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₉H₁₈O₂N₃S₂⁺, [M + H]⁺ 384.0835; found 384.0827.

(Z)-N-(2,6-Dimethyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)-4-methylbenzenesulfonamide (4c). 63.2 mg (33%), white solid, mp 172–199 °C (R_f = 0.37 in 1 : 4 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 6.8 Hz, 1H), 7.37 (t, J = 6.4 Hz, 2H), 7.26 (d, J = 4.4 Hz, 3H), 2.49 (s, 3H), 2.41 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 162.5, 162.3, 157.0, 143.0, 139.6, 134.2, 132.8, 131.3, 129.4 (2C), 127.8, 126.9 (2C), 125.5, 119.4, 104.5 25.6, 23.8, 21.7; IR ν 2926, 1597, 1487, 1398, 1298, 1283, 1146, 1086, 978, 810, 787, 739, 706, 664 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₉H₁₈O₂N₃S₂⁺, [M + H]⁺ 384.0835; found 384.0828.

(Z)-N-(8-Fluoro-2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)-4-methylbenzenesulfonamide (4d). 137.4 mg (71%), white solid, mp 191–242 °C (R_f = 0.26 in 1 : 3 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.27 (t, J = 5.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 7.41 (s, 2H), 7.31 (d, J = 6.8 Hz, 2H), 7.18 (t, J = 9.2 Hz, 1H), 2.44 (d, J = 13.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 163.1, 161.20 (d, J = 250.1 Hz, 1C), 161.17, 155.9, 142.9, 139.9, 132.4 (d, J = 2.4 Hz, 1C), 129.6 (2C), 126.7 (2C), 126.4 (d, J = 10.3 Hz, 1C), 124.3 (d, J = 8.4 Hz, 1C), 115.1 (d, J = 22.9 Hz, 1C), 109.1 (d, J = 27.0 Hz, 1C), 105.0, 24.2, 21.7; IR ν 2920, 2851, 1595, 1491, 1460, 1400, 1148, 1088, 984, 854, 806, 789, 664 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₈H₁₅O₂N₃FS₂⁺, [M + H]⁺ 388.0584; found 388.0579.

(Z)-N-(8-Chloro-2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)-4-methylbenzenesulfonamide (4e). 173.3 mg (86%), yellow solid, mp 261–262 °C (R_f = 0.51 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.17 (d, J = 8.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.68 (s, 1H), 7.42 (d, J = 9.2 Hz, 2H), 7.31 (d, J = 8.8 Hz, 2H), 2.44 (d, J = 13.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 163.3, 161.0, 156.0, 143.0, 139.8, 134.5, 134.0, 129.6 (2C), 127.8, 126.7 (2C), 126.2, 123.5, 121.7, 105.0, 24.3, 21.7; IR ν 2924, 1597, 1495, 1395, 1312, 1150, 1092, 982, 824, 808, 791, 675, 664 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₈H₁₅O₂N₃ClS₂⁺, [M + H]⁺ 404.0289; found 404.0284.

(Z)-N-(8-Bromo-2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)-4-methylbenzenesulfonamide (4f). 131.9 mg (59%), white solid, mp 269–270 °C (R_f = 0.32 in 1 : 4 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.10 (d, J = 9.6 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.82 (s, 1H), 7.56 (d, J = 6.4 Hz, 1H), 7.42 (s, 1H), 7.31 (d, J = 5.6 Hz, 2H), 2.45 (d, J = 12.4 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 163.3, 160.9, 156.0, 143.0, 139.9, 134.9, 130.6, 129.6 (2C), 126.7 (2C), 126.5, 124.6, 123.7, 121.6, 105.1, 24.3, 21.7; IR ν 1597, 1487, 1474, 1391, 1362, 1302, 1287, 1144, 1086, 982, 814, 791, 664 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₈H₁₅O₂N₃BrS₂⁺, [M + H]⁺ 447.9784; found 447.9778.

(Z)-4-Methyl-N-(2-methyl-8-nitro-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)benzenesulfonamide (4g). 51.8 mg (25%), yellow solid, mp 253–255 °C (R_f = 0.46 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.39 (d, J = 9.6 Hz, 1H), 8.60 (s, 1H), 8.31 (d, J = 10.4 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.50 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 2.48 (d, J = 17.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 163.5, 161.3, 156.1, 146.2, 143.4, 139.7, 139.6, 129.8 (2C), 126.7 (2C), 126.2, 122.9, 122.7, 117.7, 105.4, 24.4, 21.7; IR ν 2920, 1694, 1597, 1539, 1504, 1458, 1337, 1315, 1152, 1090, 669 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₈H₁₅O₄N₄S₂⁺, [M + H]⁺ 415.0529; found 415.0522.

Ethyl(Z)-2-methyl-4-(tosylimino)-4H-benzo[4,5]thiazolo[3,2-a]pyrimidine-8-carboxylate (4h). 90.4 mg (41%), yellow solid, mp 135–209 °C (R_f = 0.35 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.27 (d, J = 9.2 Hz, 1H), 8.39 (s, 1H), 8.11 (d, J = 11.6 Hz, 1H), 7.94 (d, J = 10.8 Hz, 2H), 7.45 (s, 1H), 7.33 (d, J = 8.0 Hz, 2H), 4.40–4.46 (m, 2H), 2.46 (d, J = 13.6 Hz, 6H), 1.42 (t, J = 9.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 164.9, 163.3, 161.7, 156.2, 143.0, 139.9, 138.8, 130.0, 129.6 (2C), 128.6, 126.7 (2C), 125.0, 123.4, 122.3, 105.1, 62.0, 24.3, 21.7, 14.4; IR ν 2924, 1717, 1605, 1493, 1458, 1395, 1268, 1150, 1087, 984, 785, 762, 692 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₂₀O₄N₃S₂⁺, [M + H]⁺ 442.0890; found 442.0883.

(Z)-N-(8-Methoxy-2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)-4-methylbenzenesulfonamide (4i). 155.6 mg (78%), yellow solid, mp 248–250 °C (R_f = 0.25 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.18 (d, J = 9.6 Hz, 1H), 7.94 (d, J = 9.6 Hz, 2H), 7.37 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.16 (s, 1H), 6.99 (d, J = 9.2 Hz, 1H), 3.88 (s, 3H), 2.43 (d, J = 6.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 162.7, 161.1, 159.1, 155.8, 142.7, 140.2, 129.8, 129.5 (2C), 126.7 (2C), 126.3, 123.8, 114.3, 106.1, 104.8, 56.0, 24.2, 21.7; IR ν 2926, 1612, 1503, 1493, 1271, 1140, 1090, 1022, 984, 831, 737, 702, 673 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₉H₁₈O₃N₃S₂⁺ [M + H]⁺ 400.0784; found 400.0778.

(Z)-N-(8-Ethoxy-2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)-4-methylbenzenesulfonamide (4j). 107.4 mg (52%), white solid, mp 261–263 °C (R_f = 0.24 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.15 (d, J = 13.2 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.36 (s, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.14 (s, 1H), 6.97 (d, J = 11.2 Hz, 1H), 4.06–4.12 (m, 2H), 2.43 (d, J = 6.8 Hz, 6H), 1.45 (t, J = 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.6, 161.1, 158.5, 155.7, 142.7, 140.1, 129.6, 129.5 (2C), 126.7 (2C), 126.2, 123.7, 114.7, 106.6, 104.7, 64.4, 24.2, 21.7, 14.8; IR ν 1603, 1497, 1288, 1184, 1144, 1094, 982, 941, 829, 816, 665, cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₂₀H₂₀O₃N₃S₂⁺ [M + H]⁺ 414.0941; found 414.0933.

(Z)-N-(8-Hydroxy-2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)-4-methylbenzenesulfonamide (4k). 173.3 mg (90%), white solid, mp 255–257 °C (R_f = 0.31 in 2 : 1 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 10.50 (s, 1H), 8.98 (d, J = 9.6 Hz, 1H), 7.82 (d, J = 6.8 Hz, 2H),7.36 (d, J = 8.4 Hz, 3H), 7.11 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 2.35 (d, J = 10.0 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 162.8, 161.7, 157.2, 155.4, 142.7, 139.9, 129.8 (2C), 128.4, 126.7, 126.5 (2C), 122.8, 115.0, 108.8, 103.5, 23.8, 21.2; IR ν 3277, 2926, 1618, 1503, 1452, 1261, 1130, 1090, 1063, 988, 845, 835, 704, 687 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₈H₁₆O₃N₃S₂⁺ [M + H]⁺ 386.0628; found 386.0621.

(Z)-4-Methyl-N-(7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-ylidene)benzenesulfonamide (4l). 140.0 mg (84%), white solid, mp 93–122 °C (R_f = 0.22 in 1 : 1 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 8.29 (t, J = 4.2 Hz, 1H), 7.96 (d, J = 7.2 Hz, 2H), 7.35 (s, 3H), 7.26 (t, J = 4.0 Hz, 1H), 2.54 (s, 3H), 2.47 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 164.8, 162.0, 153.4, 142.7, 139.9, 129.4 (2C), 126.7 (2C), 123.3, 113.3, 102.4, 24.8, 21.6; IR ν 2920, 1587, 1456, 1412, 1279, 1140, 1083, 1045, 1003, 937, 822, 787, 706, 664 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₄H₁₄O₂N₃S₂⁺ [M + H]⁺ 320.0522; found 320.0516.

(E)-N-(2-Methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)benzenesulfonamide (4m). 156.2 mg (88%), white solid, mp 258–260 °C (R_f = 0.33 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.24 (d, J = 12.0 Hz, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.42–7.54 (m, 6H), 2.47 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.3, 161.6, 156.3, 142.9, 136.0, 132.2, 129.0 (2C), 128.0, 127.4, 126.7 (2C), 124.7, 122.7, 122.0, 104.9, 24.3; IR ν 2924, 1605, 1503, 1495, 1452, 1287, 1144, 1088, 984, 814, 758, 694 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₇H₁₄O₂N₃S₂⁺ [M + H]⁺ 356.0522; found 356.0517.

(E)-4-Chloro-N-(2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)benzenesulfonamide (4n). 175.1 mg (90%), yellow solid, mp 216–220 °C (R_f = 0.20 in 1 : 3 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.19 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 4.8 Hz, 2H), 7.72 (d, J = 10.8 Hz, 1H), 7.48–7.55 (m, 4H), 7.40 (s, 1H), 2.49 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.6, 161.6, 156.3, 141.5, 138.5, 136.0, 129.2 (2C), 128.2 (2C), 128.1, 127.5, 124.8, 122.6, 122.1, 104.9, 24.3; IR ν 1607, 1491, 1454, 1400, 1292, 1140, 1088, 984, 812, 756, 683 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₇H₁₃O₂N₃ClS₂⁺ [M + H]⁺ 390.0132; found 390.0126.

(E)-4-Bromo-N-(2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)benzenesulfonamide (4o). 210.0 mg (97%), yellow solid, mp 179–242 °C (R_f = 0.24 in 1 : 3 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.20 (d, J = 5.6 Hz, 1H), 7.92 (d, J = 9.2 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 9.2 Hz, 2H), 7.47–7.56 (m, 2H), 7.40 (s, 1H), 2.49 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.7, 161.7, 156.3, 142.0, 135.9, 132.2 (2C), 128.3 (2C), 128.2, 127.5, 127.0, 124.8, 122.6, 122.1, 104.9, 24.3; IR ν 3088, 1605, 1491, 1452, 1402, 1292, 1136, 1086, 982, 812, 756, 739, 677 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₇H₁₃O₂N₃BrS₂⁺ [M + H]⁺ 435.9607; found 435.9598.

(E)-4-Methoxy-N-(2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)benzenesulfonamide (4p). 186.8 mg (97%), white solid, mp 185–205 °C (R_f = 0.25 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.26 (d, J = 11.2 Hz, 1H), 7.99 (d, J = 10.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.46–7.54 (m, 2H), 7.41 (s, 1H), 6.98 (d, J = 10.4 Hz, 2H), 3.87 (s, 3H), 2.47 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.0, 162.6, 161.6, 156.2, 136.1, 134.9, 128.7 (2C), 128.0, 127.4, 124.7, 122.7, 122.0, 114.1 (2C), 104.8, 55.7, 24.3; IR ν 1595, 1487, 1443, 1406, 1285, 1250, 1140, 1086, 1026, 984, 812, 758, 669 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₈H₁₆O₃N₃S₂⁺ [M + H]⁺ 386.0628; found 386.0622.

(E)-N-(2-Methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)-4-nitrobenzenesulfonamide (4q). 184.0 mg (92%), yellow solid, mp 257–259 °C (R_f = 0.32 in 1 : 3 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.15 (d, J = 10.4 Hz, 1H), 8.37 (d, J = 9.6 Hz, 2H), 8.25 (d, J = 7.2 Hz, 2H), 7.75 (d, J = 5.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 8.6 Hz, 1H), 7.44 (s, 1H), 2.52 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 164.3, 161.8, 156.4, 149.9, 148.6, 135.8, 128.4, 128.0 (2C), 127.6, 124.9, 124.3 (2C), 122.5, 122.3, 104.9, 24.4; IR ν 2922, 1557, 1522, 1493, 1342, 1146, 1090, 984, 818, 764, 739, 685 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₇H₁₃O₄N₄S₂⁺ [M + H]⁺ 401.0373; found 401.0366.

(E)-N-(2-Methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)naphthalene-1-sulfonamide (4r). 188.4 mg (93%), white solid, mp 171–212 °C (R_f = 0.27 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.27 (d, J = 11.6 Hz, 1H), 8.63 (s, 1H), 8.05 (d, J = 11.6 Hz, 1H), 7.98 (t, J = 8.2 Hz, 2H), 7.90 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 11.2 Hz, 1H), 7.60 (s, 2H), 7.42–7.52 (s, 3H), 2.47 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.3, 161.6, 156.3, 139.8, 136.0, 134.8, 132.3, 129.4, 129.3, 128.5, 128.0 (2C), 127.4 (2C), 127.3, 124.7, 122.74, 122.68, 122.0, 104.9, 24.3; IR ν 1607, 1495, 1452, 1404, 1285, 1144, 1124, 1074, 986, 860, 806, 748, 691 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₁₆O₂N₃S₂⁺ [M + H]⁺ 406.0679; found 406.0671.

(E)-N-(2-Methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)methanesulfonamide (4s). 111.4 mg (76%), yellow solid, mp 133–223 °C (R_f = 0.14 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.29 (d, J = 5.2 Hz, 1H), 7.74 (d, J = 3.2 Hz, 1H), 7.55 (d, J = 3.6 Hz, 2H), 7.35 (s, 1H), 3.22 (s, 3H), 2.47 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.9, 161.5, 156.3, 136.0, 128.0, 127.2, 124.7, 122.3, 122.2, 105.1, 42.9, 24.2; IR ν 2922, 1605, 1503, 1493, 1454, 1277, 1252, 1115, 1063, 982, 953, 824, 761, 660 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₂H₁₂O₂N₃S₂⁺ [M + H]⁺ 294.0366; found 294.0359.

(E)-N-(2-Methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)propane-1-sulfonamide (4t). 133.2 mg (83%), white solid, mp 120–128 °C (R_f = 0.34 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.28 (d, J = 4.4 Hz, 1H), 7.73 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 3.6 Hz, 2H), 7.40 (s, 1H), 3.25 (t, J = 8.0 Hz, 2H), 2.46 (s, 3H), 2.00–2.07 (m, 2H), 1.14 (t, J = 9.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 162.6, 161.5, 156.5, 136.1, 127.9, 127.1, 124.7, 122.2 (2C), 105.3, 56.8, 24.2, 17.6, 13.3; IR ν 2967, 1603, 1493, 1452, 1406, 1275, 1250, 1115, 1059, 984, 820, 758, 669 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₄H₁₆O₂N₃S₂⁺ [M + H]⁺ 322.0679; found 322.0674.

(E)-2-Methyl-N-(2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)propane-1-sulfonamide (4u). 157.5 mg (94%), yellow solid, mp 127–145 °C (R_f = 0.43 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.29 (d, J = 6.8 Hz, 1H), 7.73 (d, J = 4.0 Hz, 1H), 7.55 (d, J = 4.0 Hz, 2H), 7.40 (s, 1H), 3.20 (s, 2H), 2.46 (s, 4H), 1.19 (d, J = 5.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 162.6, 161.5, 156.4, 136.1, 127.9, 127.1, 124.7, 122.3, 122.2, 105.2, 62.7, 25.1, 24.2, 23.0 (2C); IR ν 2922, 1605, 1495, 1450, 1402, 1369, 1283, 1113, 982, 835, 814, 758, 667 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₅H₁₈O₂N₃S₂⁺ [M + H]⁺ 336.0835; found 336.0828.

(E)-N-(2-Methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)-1-phenylmethanesulfonamide (4v). 149.5 mg (81%), white solid, mp 188–222 °C (R_f = 0.36 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 8.99 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.48 (d, J = 28.0 Hz, 5H), 7.30 (s, 3H), 4.46 (s, 2H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 163.0, 161.4, 156.9, 135.8, 134.5, 132.3, 131.0, 130.0, 129.1, 128.8, 128.0, 127.2, 124.6, 122.5, 122.1, 105.1, 60.6, 24.1; IR ν 2924, 1603, 1493, 1400, 1256, 1152, 1099, 982, 824, 756, 704, 677 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₈H₁₆O₂N₃S₂⁺ [M + H]⁺ 370.0679; found 370.0681.

(E)-3-Chloro-N-(2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)propane-1-sulfonamide (4w). 163.3 mg (92%), white solid, mp 107–120 °C (R_f = 0.25 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.28 (d, J = 4.8 Hz, 1H), 7.74 (t, J = 4.4 Hz, 1H), 7.56 (d, J = 5.2 Hz, 2H), 7.37 (s, 1H), 3.78 (t, J = 7.2 Hz, 2H), 3.46 (t, J = 6.0 Hz, 2H), 2.48 (s, 5H); ¹³C NMR (100 MHz, CDCl₃) δ 163.1, 161.6, 156.6, 136.0, 128.1, 127.4, 124.7, 122.3, 122.2, 105.3, 52.1, 43.4, 27.4, 24.2; IR ν 1601, 1491, 1452, 1445, 1406, 1281, 1250, 1111, 1061, 984, 820, 758, 669 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₁₄H₁₅O₂N₃ClS₂⁺, [M + H]⁺ 356.0289; found 356.0283.

1-((1R,4S)-7,7-Dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)-N-((E)-2-methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)methanesulfonamide (4x). 197.4 mg (92%), white solid, mp 202–240 °C (R_f = 0.29 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.37 (d, J = 10.8 Hz, 1H), 7.72 (d, J = 5.6 Hz, 1H), 7.56 (m, 2H), 7.47 (s, 1H), 3.90 (d, J = 14.8 Hz, 1H), 3.14 (d, J = 14.8 Hz, 1H), 2.76 (t, J = 14.8 Hz, 1H), 2.48 (s, 3H), 2.39 (d, J = 18.4 Hz, 1H), 2.02–2.11 (m, 2H), 1.92 (d, J = 18.8 Hz, 1H), 1.72–1.79 (m, 1H), 1.40 (t, J = 11.0 Hz, 1H), 1.18 (s, 3H), 0.91 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 215.6, 162.9, 161.5, 156.7, 136.0, 128.0, 127.4, 124.6, 122.8, 122.0, 105.3, 58.6, 50.4, 48.3, 42.9, 42.7, 27.2, 24.7, 24.2, 20.2, 20.0; IR ν 2953, 1740, 1611, 1503, 1456, 1398, 1281, 1121, 1053, 986, 818, 752, 683 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₂₁H₂₄O₃N₃S₂⁺, [M + H]⁺ 430.1254; found 430.1246.

(Z)-4-Methyl-N-(2-pentyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)benzenesulfonamide (4y). 180.7 mg (85%), white solid, mp 174–181 °C (R_f = 0.40 in 1 : 4 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.31 (d, J = 6.8 Hz, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.71 (d, J = 6.8 Hz, 1H), 7.50 (m, 2H), 7.37 (s, 1H), 7.30 (d, J = 7.6 Hz, 2H), 2.66 (t, J = 8.6 Hz, 2H), 2.42 (s, 3H), 1.71 (s, 2H), 1.34 (s, 4H), 0.91 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 167.0, 161.6, 156.5, 142.8, 140.0, 136.1, 129.5 (2C), 127.9, 127.4, 126.8 (2C), 124.7, 122.8, 122.0, 104.2, 37.8, 31.5, 28.0, 22.5, 21.7, 14.1; IR ν 2926, 1601, 1493, 1450, 1404, 1279, 1146, 1086, 1047, 810, 752, 669 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₂₂H₂₄O₂N₃S₂⁺, [M + H]⁺ 426.1305; found 426.1297.

(Z)-4-Methyl-N-(2-phenyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-ylidene)benzenesulfonamide (4z). 170.3 mg (79%), white solid, mp 258–259 °C (R_f = 0.24 in 1 : 6 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.36 (s, J = 3.6 Hz, 1H), 8.09 (s, 2H), 7.98 (s, 3H), 7.72 (s, 1H), 7.51 (s, 5H), 7.32 (d, J = 6.4 Hz, 2H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.9, 159.2, 156.8, 142.9, 140.1, 136.0, 135.1, 131.9, 129.6 (2C), 129.1 (2C), 128.0 (3C), 127.5, 126.8 (2C), 125.0, 122.8, 122.0, 101.0, 21.7; IR ν 2922, 1589, 1483, 1443, 1396, 1310, 1279, 1261, 1144, 1080, 818, 750, 660 cm⁻¹; HRMS (ESI-TOF) (m/z). Calcd for C₂₃H₁₈O₂N₃S₂⁺, [M + H]⁺ 432.0835; found 432.0830.

2-Methyl-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-imine (5a). 84.9 mg (79%), white solid, mp 141–178 °C (R_f = 0.31 in 1 : 2 v/v ethyl acetate/60–90 petroleum ether). ¹H NMR (400 MHz, CDCl₃) δ 9.41 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 6.4 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.38 (t, J = 8.6 Hz, 1H), 6.95 (s, 1H), 5.97 (s, 1H), 2.20 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 161.4, 159.3, 153.9, 137.3, 126.6, 126.0, 123.9, 121.4, 121.0, 107.7, 23.0; IR ν 2922, 2853, 2205, 1636, 1524, 1456, 1271, 1182, 976, 748, 698 cm⁻¹.

All NMR spectra please see ESI Section 3.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the Science and Technology Planning Program of Zhanjiang (2021A05247); Medical Scientific Research Foundation of Guangdong Province (A2021037); Key Discipline Construction Project of Guangdong Medical University (4SG23004G); Innovation and Entrepreneurship Team Leads the Pilot Program of Zhanjiang (2020LHJH005); Science and technology program of Guangdong Province (2019B090905011); Zhanjiang Ocean Young Talent Innovation Project (2022E05008) and Scientific Research Project of General Universities in Guangdong Province (2022KTSCX046) for support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2270393. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3ra04082h

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