A simple copper-catalysed tandem cyclisation of ynamides leading to triazolo-1,2,4-benzothiadiazine-1,1-dioxides in PEG-400 medium

Abstract

An efficient one-pot approach for the synthesis of fused triazolo 1,2,4-benzothiadiazine-1,1-dioxide derivatives from functionalised ynamides and sodium azide in the presence of CuI using PEG-400 as the medium is described. The cyclisation process involves intermolecular C–N bond formation and subsequent cycloaddition between ynamide and azide. Thus three new C–N bonds are formed in a single step. It is also demonstrated that the triazole ring in triazolo-1,2,4-benzothiadiazine-1,1-dioxide can be readily decyclised in the presence of glacial acetic acid with the elimination of molecular nitrogen.

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Introduction

Alkynes have been extensively used in many organic transformations to synthesise important molecules and natural products.¹ Heteroatom substituted alkynes, especially ynamides (N-substituted alkynes) have drawn prominent attention from a synthetic perspective due to their high reactivity.² These precursors are utilized in both electrophilic and nucleophilic reactions.³ They also act as surrogates of allenes. Over the last few years, a rapid expansion in the cycloaddition reactions of ynamides has taken place.⁴ However, there is still enormous scope to explore reactions of functionalised ynamides in cycloaddition and cyclisation reactions.

Benzosultams display a significant role in drug discovery because of their diverse medicinal uses.^5,6 Recently, much interest has been directed towards sultams such as 1,2,4-benzothiadiazine-1,1-dioxides and triazolothiadiazepine 1,1-dioxides because of their wide range of biological activities.^7,8 Majumdar's group reported the synthesis of triazolothiadiazepine 1,1-dioxides by basic alumina supported azide–alkyne cycloaddition whereas Sun's group reported the synthesis of triazoloquinazolinones^9a via copper catalysed tandem click and intramolecular C–H amidation.^9b It should be noted that 1,2,3-triazole moiety is also important in synthetic, medicinal as well as materials chemistry.^10–12 In this context, we envisioned that compounds having both 1,2,3-triazole and sultam moieties will have utility in medicinal chemistry. Representative examples are shown in Fig. 1.¹³ To the best of our knowledge, formation of benzosultam fused triazoles directly from ynamide is not reported. In continuation to our studies on [Cu]-catalysed synthesis of fused triazoles,¹⁴ we report herein a simple route for benzosultam fused triazoles from ynamides using PEG-400 as a solvent in this work.

Fig. 1 Examples of pharmaceutically useful sultams and triazoles.

Results and discussion

The precursors used in the present study are N-alkynyl 2-halo-benzenesulfonamides. These were prepared using 2-halo-benzenesulfonamides 1a–i and the corresponding bromo-alkynes 2a–g following a literature method.¹⁵ However, all these compounds 3a–p (Fig. 2) are new. These substrates readily undergo hydrolysis at room temperature but can be stored at low temperature. Details of their synthesis are given in the ESI.†

Fig. 2 Ynamides used in the present study.

Initially, we performed the reaction between N-alkynyl-2-iodo-benzenesulfonamide 3a and sodium azide in the presence of CuI (10 mol%) and L-proline (20 mol%) in DMF solvent at 100 °C for 12 h. To our delight, we got the desired benzosultam fused 1,2,3-triazole product 4 in 64% isolated yield. This reaction proceeds via intermolecular C–N bond formation followed by cycloaddition between alkyne and azide. Our next step was directed towards screening various reaction parameters to improve the yield of the product and the details are given in Table 1.

Table 1 Optimization of the catalytic system for the synthesis of triazolo 1,2,4-benzothiadiazine 1,1-dioxide 4 (cf. Scheme 1)^a

Entry	CuX (mol%)	NaN3 (eq.)	Solvent	Temp. (°C)	Yield (%)^b
a Ynamide (0.24 mmol), CuI (x mol%), NaN3, solvent (1 mL) in the absence of L-proline for entries 1–15.b Yield of the isolated product.c Hydrolysed product 5 was isolated (36%).d Reaction was performed in an open air.e CuI (30 mol%), TMSN3 (2.5 eq.), DIPEA (3 eq.), DMF (1 mL) were used.
1	CuI (10)	1.2	DMF	100	64
2	CuI (10)	1.2	(EtO)2CO	100	0
3	CuI (10)	1.2	H2O	100	20^c
4	CuI (10)	1.2	PEG-400	100	65
5	CuI (5)	1.2	PEG-400	100	65
6	CuI (2)	1.2	PEG-400	100	58
7	CuI (5)	2.0	PEG-400	100	78
8	CuCl (5)	2.0	PEG-400	100	65
9	CuSO4·5H2O(5)	2.0	PEG-400	100	62
10	CuCl2·2H2O(5)	2.0	PEG-400	100	48
11	CuBr (5)	2.0	PEG-400	100	68
12	CuI (5)	2.0	PEG-400	100	56^d
13	CuI (5)	2.0	PEG-400	80	72^e
14	CuI (5)	2.0	PEG-400	60	38
15	CuI (5)	2.0	PEG-400	r.t.	52

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The absence of ligand (L-proline) did not affect the yield of the product (entry 1). Diethyl carbonate was ineffective and did not furnish the desired product (entry 2). Water as a solvent led to only 20% of 4 along with 36% of the hydrolysed product 5 (entry 3).¹⁶ Thus, hydrolysis was a major problem in water medium. Surprisingly, in PEG-400 as a solvent compound 4 was isolated in 65% yield (entry 4). Although all the solvents checked had oxygen donors, PEG-400 has a combination of ether and residual hydroxyl groups which may promote the reaction better.¹⁷ This might be responsible for the improved yield of the product. Later, we found that 5 mol% of CuI furnished similar yield (entry 5). Further decreasing catalyst loading to 2 mol% CuI, decreased the yield of the product (entry 6). The yield was increased to 78% by using 2 equiv. of NaN₃ instead of 1.2 equiv. of NaN₃ (entry 7). No reaction was observed in the absence of CuI. Utilization of other copper salts did not improve yield of the desired product. Decrease in the yield of the product was observed when the reaction was performed in open air (entry 12). Lowering the reaction temperature also decreased the yield of the product. The reaction proceeds at room temperature but the yield was only 52% even after longer reaction times (48 h) (entry 15). It is interesting to note that Yao's conditions^8a did give decent yields (ca. 70%) but in view of the use of simple NaN₃, the environmentally friendly solvent PEG-400, and lesser load of CuI, in this work we have chosen conditions shown in entry 7 as the best.

With the optimized conditions (entry 7) in hand, we examined the scope of this [Cu]-catalysed one-pot reaction by employing various N-alkynyl-2-iodo-benzenesulfonamides 3a–l with sodium azide. Gratifyingly, the triazolo 1,2,4-benzothiadiazine 1,1-dioxide derivatives (4, 6–15) were isolated in good to excellent yields (Table 2). The structure of compound 4 was confirmed by X-ray crystallography (Fig. 3). There was no significant effect on yields of the products by changing the substituent on the benzene ring of 2-iodo-benzenesulfonamides. While changing the substituent on the nitrogen of sulfonamide, we encountered a difficulty in the preparation of ynamide 3h; however we did not find any difficulty in the course of cyclisation process. The triisopropylsilyl substituted ynamide 3j afforded the desired product 14 in 80% yield with the removal of triisopropylsilyl group and the structure was confirmed by X-ray crystallography (Fig. 4). On the other hand the bulkier 1-bromo-2-biphenyl ethyne gave the corresponding ynamide 3k in excellent yield, but unfortunately the cyclisation reaction was not observed. This may be due to the steric effect caused by the biphenyl moiety. Both alkyl and aryl alkynyl ynamides were readily subjected to this one-pot protocol to obtain benzosultam fused triazoles. Overall the reaction involves the formation of three new C–N bonds.

Table 2 Synthesis of triazolo 1,2,4-benzothiadiazine 1,1-dioxides from N-alkynyl-2-iodo-benzene sulfonamides

Product		Yield (%)	Product		Yield (%)
	4	78		10	72
	6	84		11	48
	7	70		12	64
	8	78		13	62
	9	78		14	80
				15	72

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Fig. 3 ORTEP diagram for compound 4. Selected bond lengths [Å] with esds in parentheses: C(6)–N(1) 1.411(2), C(7)–N(1) 1.367(2), C(8)–N(3) 1.377(2), S(1)–O(1) 1.4229(13), S(1)–O(2) 1.4201(15), S(1)–N(4) 1.6487(15).

Fig. 4 ORTEP diagram for compound 14. Selected bond lengths [Å] with esds in parentheses: C(1)–N(1) 1.403(2), C(7)–N(1) 1.348(3), C(8)–N(3) 1.357(3), S(1)–O(1) 1.4188(18), S(1)–O(2) 1.4233(19), S(1)–N(4) 1.6491(18).

In a manner similar to above, N-alkynyl-2-bromo-benzenesulfonamides 3m–p were subjected to the tandem reaction following optimized conditions. This procedure afforded the desired cyclised products 16–18 and 4 in lower yields and required longer reaction time (Scheme 2). This shows that aryl bromides are less reactive than aryl iodides, which is in accordance with the literature reports.^14b

Scheme 1 One-pot [Cu]-catalysed reaction of ynamide 3a with sodium azide to afford compound 4.

Scheme 2 One-pot synthesis of fused triazoles 16–18 and 4 from ynamides 3m–p.

In continuation to above reactions, we made an attempt to synthesise seven membered benzosultam fused triazole. Following optimized reaction conditions, we employed the reaction between N-propargyl 2-iodo-benzenesulfonamide 19 and sodium azide (Scheme 3). Here, we were able to isolate the expected product 20 in 30% yield. There were also other byproducts that were not isolated. Thus it appears that for these systems, conditions available in the literature^8a were better.

Scheme 3 Synthesis of triazolothiadiazepine 1,1-dioxide 20.

To understand the reaction pathway, we performed the reaction between phenyl iodide and ynamide with NaN₃ in the presence of [Cu]-catalyst. We observed the formation of phenyl azide VI from phenyl iodide, but there was no reaction with ynamide VII (Scheme 4a and b). Thus the azide is formed first. The other possibility involving cycloaddition between alkyne and sodium azide followed by intramolecular C–N bond formation catalysed by [Cu]^8a,18 is not observed here. Thus, the plausible catalytic cycle for the synthesis of triazolo 1,2,4-benzothiadiazine 1,1-dioxide derivative is shown in Scheme 5. The intermediate VIII is not isolated. Later, the [3 + 2] cycloaddition between alkyne and azide affords the benzosultam fused triazole.

Scheme 4 Control experiments.

Scheme 5 Plausible pathway for the formation of benzothiadiazines.

Later, we made an attempt to utilize the 1,2,3-triazoles synthesised so far. We found that in the presence of glacial acetic acid 1,2,3-triazoles tend to undergo nitrogen elimination.¹⁹ We employed benzosultam fused triazoles under this condition. However, we isolated sulfonamides 21–24 in good yields (Scheme 6). These were formed by the cleavage of sulfonamide N–C bond along with nitrogen elimination from triazole moiety. The products may have considerable interest for chemists as they contain two functional groups amide and sulfonamide in a single molecule. The structure of compound 21 was confirmed by X-ray crystallography (Fig. 5). This type of cleavage followed by acetic acid–water addition was not reported earlier in the literature.

Fig. 5 ORTEP diagram for compound 21. Selected bond lengths [Å] with esds in parentheses: C(8)–O(3) 1.224(5), C(7)–O(4) 1.435(5), C(7)–C(8) 1.528(6), S(1)–O(1) 1.420(4), S(1)–O(2) 1.430(4), S(1)–N(1) 1.615(5).

Scheme 6 Utilization of the benzosultam fused triazoles.

Conclusions

In conclusion, we have described a sequential one-pot reaction to synthesise triazolo 1,2,4-benzothiadiazine 1,1-dioxide derivatives from functionalised ynamides and sodium azide using CuI as the catalyst using the solvent PEG-400. The reaction involves intermolecular C–N bond formation followed by cycloaddition between alkyne and azide. The main attractive feature of this methodology is using low catalyst loadings of air stable CuI and PEG-400, an eco-friendly solvent system.

Experimental section

The general experimental conditions and synthesis of the precursors are described in the ESI.†

Synthesis of triazolo 1,2,4-benzothiadiazine 1,1-dioxide derivatives (compounds 4–18) – representative procedure for compound 4

To an oven dried Schlenk tube was added 2-iodo-4,N-dimethyl-N-phenylethynyl-benzenesulfonamide 3a (0.24 mmol), CuI (10 mol%), NaN₃ (0.48 mmol) and PEG-400 (1 mL). The contents were sealed under nitrogen atmosphere and heated at 100 °C (oil bath temperature) overnight. After completion of the reaction as monitored by TLC, the crude reaction mixture was cooled to r.t. The mixture was diluted with ethyl acetate (20 mL) and washed with water. The aqueous layer was extracted twice with ethyl acetate (20 mL). The combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated in vacuum. The crude residue was then purified by using silica gel column chromatography using hexane–ethyl acetate (9 : 1) as the eluent to afford triazolo-1,2,4-benzothiadiazine 1,1-dioxide 4. Compounds 5–17 were prepared following same procedure and same molar quantities.

4,8-Dimethyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (4). White solid; yield 0.062 g (78%); Mp 196 °C; IR ν_max (KBr): 2992, 1605, 1468, 1353, 1178, 1123, 992, 849, 679 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 2.60 (s, 3H, Ar-CH₃), 3.15 (s, 3H, NCH₃), 7.44–7.47 (m, 2H, Ar-H), 7.53 (t, J = 7.2 Hz, 2H, Ar-H), 7.88 (d, J = 8.0 Hz, 1H, Ar-H), 8.03 (d, J = 7.2 Hz, 2H, Ar-H), 8.20 (s, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 22.0 (Ar-CH₃), 38.1 (NCH₃), 118.9, 121.2, 124.7, 126.4, 128.6, 129.1, 129.7, 131.6, 133.1, 138.0, 146.3; HRMS (ESI): calcd for C₁₆H₁₅N₄O₂S [M⁺ + H]: m/z 327.0915. Found: 327.0913. This compound was crystallized from ethyl acetate–hexane (2 : 1) mixture at room temperature. X-ray structure was determined for this compound.

N-((2-Iodo-4-methylphenyl)sulfonyl)-N-methyl-2-phenylacetamide (5). This compound was isolated when water was used as solvent (Table 1, entry 3) along with the triazole 4 (20%). White solid; yield 0.038 g (36%); Mp 106 °C; IR ν_max (KBr): 2942, 2909, 1704, 1578, 1457, 1336, 1161, 1073, 865, 766, 673 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 2.37 (s, 3H, Ar-CH₃), 3.39 (s, 3H, NCH₃), 3.96 (s, 2H, CH₂), 7.16 (d, J = 7.2 Hz, 1H, Ar-H), 7.27–7.34 (m, 4H, Ar-H), 7.88 (s, 1H, Ar-H), 8.17 (d, J = 8.0 Hz, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 20.9 (Ar-CH₃), 34.0 (NCH₃), 43.3 (CH₂), 91.4 (CI), 127.3, 128.7, 129.3, 129.4, 132.8, 138.6, 143.1, 145.7, 171.3; HRMS (ESI): calcd for C₁₆H₁₇INO₃S [M⁺ + H]: m/z 429.9974. Found: 429.9969.

8-(tert-Butyl)-4-methyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (6). White solid; yield 0.075 g (84%); Mp 152 °C; IR ν_max (KBr): 2970, 1600, 1458, 1364, 1189, 1129, 992, 833, 658, 641 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.45 (s, 9H, C(CH₃)₃), 3.16 (s, 3H, NCH₃), 7.44 (t, J = 7.6 Hz, 1H, Ar-H), 7.53 (t, J = 7.6 Hz, 2H, Ar-H), 7.68 (d, J = 8.4 Hz, 1H, Ar-H), 7.92 (d, J = 8.4 Hz, 1H, Ar-H), 8.04 (d, J = 8.4 Hz, 2H, Ar-H), 8.39 (s, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 31.0 (C(CH₃)₃), 36.0 (C(CH₃)₃), 38.1 (NCH₃), 115.7, 121.1, 124.6, 126.2, 126.5, 128.6, 129.1, 131.6, 133.1, 138.0, 159.5; HRMS (ESI): calcd for C₁₉H₂₀N₄O₂SNa [M⁺ + Na]: m/z 391.1205. Found: 391.1224.

8-Methoxy-4-methyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (7). White solid; yield 0.056 g (70%); Mp 192 °C; IR ν_max (KBr): 3003, 2937, 2844, 1605, 1595, 1458, 1353, 1178, 981, 844, 773 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.15 (s, 3H, NCH₃), 4.01 (s, 3H, Ar-OCH₃), 7.14 (dd, J = 8.8 and 2.4 Hz, 1H, Ar-H), 7.44 (t, J = 7.2 Hz, 1H, Ar-H), 7.53 (t, J = 7.2 Hz, 2H, Ar-H), 7.83 (d, J = 2.4 Hz, 1H, Ar-H), 7.90 (d, J = 8.8 Hz, 1H, Ar-H), 8.03 (d, J = 7.2 Hz, 2H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 38.1 (NCH₃), 56.4 (Ar-OCH₃), 102.9, 115.8, 115.9, 126.5, 126.7, 128.6, 129.1, 133.4, 138.2, 164.4; HRMS (ESI): calcd for C₁₆H₁₅N₄O₃S [M⁺ + H]: m/z 343.0865. Found: 343.0864.

4-Methyl-3,8-diphenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (8). White solid; yield 0.073 g (78%); Mp 180 °C; IR ν_max (KBr): 3058, 1605, 1468, 1392, 1370, 1178, 992, 827, 762 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.21 (s, 3H, NCH₃), 7.43–7.49 (m, 1H, Ar-H), 7.51–7.58 (m, 5H, Ar-H), 7.72 (d, J = 7.2 Hz, 2H, Ar-H), 7.86 (dd, J = 8.4 and 1.2 Hz, 1H, Ar-H), 8.04–8.07 (m, 3H, Ar-H), 8.59 (s, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 37.5 (NCH₃), 116.3, 121.7, 125.9, 126.8, 126.9, 127.9, 128.5, 128.8, 131.5, 132.5, 137.5, 147.5; HRMS (ESI): calcd for C₂₁H₁₇N₄O₂S [M⁺ + H]: m/z 389.1072. Found: 389.1071.

4,8-Dimethyl-3-(p-tolyl)-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (9). White solid; yield 0.064 g (78%); Mp 190 °C; IR ν_max (KBr): 2926, 1595, 1463, 1353, 1178, 1123, 986, 849, 822, 619 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 2.43 (s, 3H, Ar-CH₃), 2.59 (s, 3H, Ar-CH₃), 3.14 (s, 3H, NCH₃), 7.33 (d, J = 8.0 Hz, 2H, Ar-H), 7.45 (d, J = 8.0 Hz, 1H, Ar-H), 7.87 (d, J = 8.0 Hz, 1H, Ar-H), 7.91 (d, J = 8.0 Hz, 2H, Ar-H), 8.19 (s, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 21.4 (Ar-CH₃), 22.0 (Ar-CH₃), 38.0 (NCH₃), 118.9, 121.2, 124.7, 125.7, 126.4, 129.6, 129.8, 131.6, 132.7, 138.2, 139.1, 146.3; HRMS (ESI): calcd for C₁₇H₁₇N₄O₂S [M⁺ + H]: m/z 341.1072. Found: 341.1068.

3-Hexyl-4,8-dimethyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (10). Gummy liquid; yield 0.058 g (72%); IR ν_max(neat): 2926, 2860, 1605, 1468, 1364, 1184, 1123, 838, 679 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 0.90 (t, J = 6.8 Hz, 3H), 1.32–1.43 (m, 6H, 3 CH₂), 1.76–1.84 (m, 2H, CH₂), 2.56 (s, 3H, Ar-CH₃), 2.80 (t, J = 8.0 Hz, 2H, CH₂), 3.26 (s, 3H, NCH₃), 7.41 (d, J = 8.0 Hz, 1H, Ar-H), 7.83 (d, J = 8.0 Hz, 1H, Ar-H), 8.12 (s, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 14.1, 22.0 (Ar-CH₃), 22.6, 24.7, 28.8, 28.9, 31.5, 37.8 (NCH₃), 118.7, 121.6, 124.4, 129.3, 131.7, 133.6, 139.1, 146.1; HRMS (ESI): calcd for C₁₆H₂₃N₄O₂S [M⁺ + H]: m/z 335.1541. Found: 335.1544.

3-((Benzyloxy)methyl)-4,8-dimethyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (11). White solid; yield 0.043 g (48%); Mp 106 °C; IR ν_max (KBr): 3063, 2860, 1605, 1479, 1359, 1310, 1173, 1068, 877, 745 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 2.44 (s, 3H, Ar-CH₃), 3.38 (s, 3H, NCH₃), 4.47 (s, 2H, OCH₂), 4.58 (s, 2H, OCH₂), 6.54 (s, 1H, Ar-H), 7.30–7.32 (m, 1H, Ar-H), 7.34–7.38 (m, 4H, Ar-H), 7.43 (s, 1H, Ar-H), 7.84 (d, J = 8.0 Hz, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 21.9 (Ar-CH₃), 34.0 (NCH₃), 68.4 (OCH₂), 71.7 (OCH₂), 113.4, 122.1, 124.6, 127.9, 128.1, 128.2, 128.6, 133.1, 137.7, 142.8; HRMS (ESI): calcd for C₁₈H₁₉N₄O₃S [M⁺ + H]: m/z 371.1178. Found: 371.1178.

4-Isopropyl-8-methyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (12). White solid; yield 0.054 g (64%); Mp 154 °C; IR ν_max (KBr): 2981, 1605, 1468, 1370, 1348, 1184, 1118, 986, 778, 674 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 0.98 (d, J = 6.8 Hz, 6H, (CH(CH₃)₂)), 2.59 (s, 3H, Ar-CH₃), 4.19 (m, 1H, NCH), 7.44 (d, J = 7.2 Hz, 2H, Ar-H), 7.50 (t, J = 7.2 Hz, 2H, Ar-H), 7.86 (d, J = 8.0 Hz, 1H, Ar-H), 8.02 (d, J = 7.2 Hz, 2H, Ar-H), 8.16 (s, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 20.9 (CH(CH₃)₂), 22.0 (Ar-CH₃), 59.1 (NCH), 119.0, 124.2, 124.3, 127.3, 128.9, 129.1₉, 129.2₁, 129.6, 130.8, 131.8, 141.2, 146.0; HRMS (ESI): calcd for C₁₈H₁₉N₄O₂S [M⁺ + H]: m/z 355.1228. Found: 355.1229.

3-(3-Fluorophenyl)-4,8-dimethyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (13). White solid; yield 0.052 g (62%); Mp 206 °C; IR ν_max (KBr): 3079, 1600, 1463, 1364, 1178, 1123, 893, 789, 734, 674 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 2.60 (s, 3H, Ar-CH₃), 3.16 (s, 3H, NCH₃), 7.14 (dt, J = 8.4 and 2.4 Hz, 1H, Ar-H), 7.47–7.53 (m, 2H, Ar-H), 7.75–7.78 (m, 1H, Ar-H), 7.82 (d, J = 8.4 Hz, 1H, Ar-H), 7.89 (d, J = 8.0 Hz, 1H, Ar-H), 8.19 (s, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 22.0 (Ar-CH₃), 113.4 (d, J = 20 Hz), 116.0 (d, J = 20 Hz), 118.9, 121.2, 122.0, 124.9, 129.8, 130.6, 130.7, 130.8, 131.5, 133.5, 137.0, 146.4, 164.3 (d, J = 240 Hz); HRMS (ESI): calcd for C₁₆H₁₅N₄O₂S [M⁺ + H]: m/z 345.0821. Found: 345.0821.

4,8-Dimethyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (14). White solid; yield 0.048 g (80%); Mp 172 °C; IR ν_max (KBr): 3134, 1595, 1496, 1452, 1326, 1244, 1085, 975, 811, 685 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 2.58 (s, 3H, Ar-CH₃), 3.47 (s, 3H, NCH₃), 7.43–7.45 (m, 2H, Ar-H + triazole-CH), 7.90 (d, J = 8.0 Hz, 1H, Ar-H), 8.17 (s, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 22.0 (Ar-CH₃), 31.5 (NCH₃), 118.3, 119.5, 121.3, 123.4, 129.2, 131.5, 137.9, 146.4; HRMS (ESI): calcd for C₁₆H₁₅N₄O₂S [M⁺ + H]: m/z 251.0602. Found: 251.0601. This compound was crystallized from ethyl acetate–hexane (2 : 1) mixture at room temperature. X-ray structure was determined for this compound.

4-Methyl-3-phenyl-4H-naphtho[1,2-e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (15). White solid; yield 0.064 g (72%); Mp 184 °C; IR ν_max (KBr): 2921, 2855, 1595, 1447, 1353, 1178, 1118, 811, 690, 559 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.18 (s, 3H, NCH₃), 7.47 (d, J = 7.6 Hz, 1H, Ar-H), 7.56 (t, J = 7.6 Hz, 2H, Ar-H), 7.77–7.86 (m, 2H, Ar-H), 7.99–8.05 (m, 2H, Ar-H), 8.12 (d, J = 8.4 Hz, 1H, Ar-H), 9.66 (d, J = 8.4 Hz, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 37.9 (NCH₃), 119.3, 122.2, 124.0, 126.5, 127.4, 128.5, 128.6, 129.0, 129.1, 129.2, 129.6, 129.7, 130.3, 133.6, 136.7, 137.9; HRMS (ESI): calcd for C₁₉H₁₅N₄O₂S [M⁺ + H]: m/z 363.0915. Found: 363.0914.

4-Methyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (16). White solid; yield 0.042 g (56%); Mp 190 °C; IR ν_max (KBr): 2997, 2931, 1589, 1485, 1370, 1255, 1184, 986, 822, 778, 641 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 3.18 (s, 3H, NCH₃), 7.45 (t, J = 7.6 Hz, 1H, Ar-H), 7.53 (t, J = 7.6 Hz, 2H, Ar-H), 7.68 (t, J = 8.0 Hz, 1H, Ar-H), 7.89 (t, J = 8.0 Hz, 1H, Ar-H), 8.01–8.04 (m, 3H, Ar-H), 8.39 (d, J = 8.0 Hz, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 38.1 (NCH₃), 118.7, 124.0, 124.8, 126.5, 128.5, 128.9, 129.1, 129.2, 131.7, 132.9, 134.7, 138.0; HRMS (ESI): calcd for C₁₆H₁₅N₄O₂S [M⁺ + H]: m/z 313.0759. Found: 313.0757.

3-Hexyl-4-methyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (17). Gummy liquid; yield 0.040 g (52%); IR ν_max(neat): 2937, 2860, 1605, 1490, 1364, 1189, 1047, 849, 767 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 0.90 (t, J = 6.8 Hz, 3H, CH₃), 1.33–1.43 (m, 6H, 3 CH₂), 1.79–1.83 (m, 2H, CH₂), 2.81 (t, J = 7.8 Hz, 2H, CH₂), 3.29 (s, 3H, NCH₃), 7.63 (t, J = 7.6 Hz, 1H, Ar-H), 7.84 (t, J = 7.6 Hz, 1H, Ar-H), 7.97 (d, J = 7.2 Hz, 1H, Ar-H), 8.31 (d, J = 8.4 Hz, 1H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 14.1, 22.6, 24.7, 28.8, 28.9, 31.5, 37.8 (NCH₃), 118.6, 124.3, 124.5, 128.5, 131.8, 133.5, 134.5, 139.0; HRMS (ESI): calcd for C₁₅H₂₁N₄O₂S [M⁺ + H]: m/z 321.1385. Found: 321.1384.

4-Butyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (18). White solid; yield 0.052 g (60%); Mp 92 °C; IR ν_max (KBr): 2953, 2860, 1595, 1474, 1359, 1249, 1189, 1118, 981, 773, 636 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 0.60 (t, J = 7.4 Hz, 3H, CH₃), 0.90–1.16 (m, 4H, 2 CH₂), 3.66 (t, J = 8.0 Hz, 2H, CH₂), 7.43–7.54 (m, 3H, Ar-H), 7.66 (t, J = 7.6 Hz, 1H, Ar-H), 8.39 (d, J = 8.4 Hz, 1H, Ar-H), 7.87 (t, J = 8.0 Hz, 1H, Ar-H), 7.97–8.01 (m, 3H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 13.2, 19.4, 29.1, 51.3, 118.7, 123.9, 126.1, 126.9, 128.7, 128.9, 129.0, 129.2, 131.6, 131.7, 134.5, 138.2; HRMS (ESI): calcd for C₁₆H₁₅N₄O₂S [M⁺ + H]: m/z 355.1228. Found: 355.1228.

General procedure for the synthesis of esters 21–24

To an oven dried Schlenk vessel was added triazolo-1,2,4-benzothiadiazine 1,1-dioxide (4, 6, 8 or 14; 0.3 mmol) and glacial acetic acid (2 mL). Then the vessel was stoppered and heated under reflux for 3 days. After completion of reaction (tlc), the reaction mixture was quenched with saturated sodium bicarbonate solution (30 mL) and extracted twice with ethyl acetate (20 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by using silica gel column chromatography using hexane–ethyl acetate (4 : 1) as the eluent.

2-((5-Methyl-2-(N-methylsulfamoyl)phenyl)amino)-2-oxo-1-phenylethyl acetate (21). White solid; yield 0.090 g (80%); Mp 130 °C; IR ν_max (KBr): 3315, 2980, 1737, 1682, 1518, 1414, 1332, 1244, 1173, 1068, 756, 663 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 2.32 (s, 3H, COCH₃), 2.39 (s, 3H, Ar-CH₃), 2.51 (d, J = 5.2 Hz, 3H, NHCH₃), 4.67 (qrt, J = 5.2 Hz, 1H, SO₂NH), 5.99 (s, 1H, Ar-CH), 7.07 (d, J = 8.0 Hz, 1H, Ar-H), 7.44 (d, J = 6.8 Hz, 3H, Ar-H), 7.57 (d, J = 6.4 Hz, 2H, Ar-H), 7.76 (d, J = 8.0 Hz, 1H, Ar-H), 7.94 (s, 1H, Ar-H), 9.63 (s, 1H, CONH); ¹³C NMR (100 MHz, CDCl₃): δ 21.2 (COCH₃), 21.7 (Ar-CH₃), 29.1 (NCH₃), 76.7, 124.6, 124.8, 125.6, 127.4, 129.0, 129.4, 129.7, 134.3, 134.4, 145.2, 167.1, 171.4; HRMS (ESI): calcd for C₁₈H₂₀N₂O₅SNa [M⁺ + Na]: m/z 399.0991. Found: 399.1036. This compound was crystallized from methanol at 4 °C. X-ray structure was determined for this compound.

2-((5-(tert-Butyl)-2-(N-methylsulfamoyl)phenyl)amino)-2-oxo-1-phenylethyl acetate (22). Gummy liquid; yield 0.106 g (86%); IR ν_max(neat): 3310, 2964, 1759, 1704, 1567, 1529, 1403, 1326, 1222, 1167, 1052, 838 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 1.32 (s, 9H, C(CH₃)₃), 2.32 (s, 3H, COCH₃), 2.53 (d, J = 5.6 Hz, 3H, NHCH₃), 4.64 (qrt, J = 5.6 Hz, 1H, SO₂NH), 6.02 (s, 1H, Ar-CH), 7.27 (s, 1H, Ar-H), 7.44 (d, J = 7.6 Hz, 3H, Ar-H), 7.58 (d, J = 7.6 Hz, 2H, Ar-H), 7.78 (d, J = 8.4 Hz, 1H, Ar-H), 8.22 (s, 1H, Ar-H), 9.74 (s, 1H, CONH); ¹³C NMR (100 MHz, CDCl₃): δ 21.2 (COCH₃), 29.2 (NCH₃), 30.9 (C(CH₃)₃), 35.4 (C(CH₃)₃), 77.1, 121.4, 121.8, 124.3, 127.4, 129.0, 129.4, 129.5, 134.4, 134.6, 158.2, 167.1, 171.3; HRMS (ESI): calcd for C₂₁H₂₆N₂O₅SNa [M⁺ + Na]: m/z 441.1460. Found: 441.1465.

2-((4-(N-Methylsulfamoyl)-[1,1′-biphenyl]-3-yl)amino)-2-oxo-1-phenylethyl acetate (23). Gummy liquid; yield 0.102 g (78%); IR ν_max(neat): 3315, 2921, 1759, 1699, 1567, 1414, 1321, 1222, 1162, 1074, 701 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 2.33 (s, 3H, COCH₃), 2.56 (d, J = 5.2 Hz, 3H, NHCH₃), 4.87–4.88 (m, 1H, SO₂NH), 6.05 (s, 1H, Ar-CH), 7.37–7.48 (m, 7H, Ar-H), 7.58–7.61 (m, 4H, Ar-H), 7.93 (d, J = 8.0 Hz, 1H, Ar-H), 8.42 (s, 1H, Ar-H), 9.83 (s, 1H, CONH); ¹³C NMR (100 MHz, CDCl₃): δ 21.2 (COCH₃), 29.2 (NCH₃), 76.8, 122.8, 123.1, 125.9, 127.4, 128.7, 128.9₈, 129.0₃, 129.4, 130.2, 134.4, 134.9, 138.7, 147.0, 167.3, 171.4; HRMS (ESI): calcd for C₂₃H₂₂N₂O₅SNa [M⁺ + Na]: m/z 461.1147. Found: 461.1150.

2-((5-Methyl-2-(N-methylsulfamoyl)phenyl)amino)-2-oxoethyl acetate (24). White solid; yield 0.082 g (90%); Mp 110 °C; IR ν_max (KBr): 3271, 1753, 1688, 1589, 1419, 1321, 1244, 1140, 827, 767 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 2.29 (s, 3H, Ar-CH₃), 2.43 (s, 3H, COCH₃), 2.56 (d, J = 5.2 Hz, 3H, NHCH₃), 4.69 (s, 2H, COCH₂O), 4.82–4.83 (m, 1H, SO₂NH), 7.07 (d, J = 8.0 Hz, 1H, Ar-H), 7.75 (d, J = 8.0 Hz, 1H, Ar-H), 8.13 (s, 1H, Ar-H), 9.66 (s, 1H, CONH); ¹³C NMR (100 MHz, CDCl₃): δ 20.9 (COCH₃), 21.8 (Ar-CH₃), 29.1 (NCH₃), 63.4, 77.1, 123.9, 124.0, 125.4, 129.7, 134.3, 145.3, 165.9, 171.5; HRMS (ESI): calcd for C₁₂H₁₆N₂O₅SNa [M⁺ + Na]: m/z 323.0678. Found: 323.0677.

Single crystal X-ray data were collected on a Bruker AXS-SMART or OXFORD diffractometer using Mo-K_α (λ = 0.71073 Å) radiation. The structures were solved by direct methods and refined by full-matrix least squares method using standard procedures.²⁰ Absorption corrections were done using SADABS program, where applicable. In general, all non-hydrogen atoms were refined anisotropically; hydrogen atoms were fixed by geometry or located by a Difference Fourier map and refined isotropically.

Crystal data

4,8-Dimethyl-3-phenyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (4). C₁₆H₁₄N₄O₂S, M = 326.37, triclinic, space group P1̄, a = 7.1492(7), b = 7.7691(8), c = 14.105(2) Å, α = 97.012(10), β = 102.997(10), γ = 98.628(8)°, V = 744.79(15) ų, Z = 2, μ = 0.233 mm⁻¹, data/restraints/parameters: 3024/0/210, R indices (I > 2σ(I)): R₁ = 0.0405, wR₂ (all data) = 0.1171.†

4,8-Dimethyl-4H-benzo[e][1,2,3]triazolo[5,1-c][1,2,4]thiadiazine 5,5-dioxide (14). C₁₀H₁₀N₄O₂S, M = 250.28, monoclinic, space group P2₁/c, a = 8.0936(11), b = 21.469(3), c = 6.2322(8) Å, β = 95.001(11)°, V = 1078.8(2) ų, Z = 4, μ = 0.295 mm⁻¹, data/restraints/parameters: 2203/0/156, R indices (I > 2σ(I)): R₁ = 0.0442, wR₂ (all data) = 0.1167.†

2-((5-Methyl-2-(N-methylsulfamoyl)phenyl)amino)-2-oxo-1-phenylethyl acetate (21). C₁₈H₂₀N₂O₅S, M = 376.43, monoclinic, space group P2₁/c, a = 10.3978(17), b = 19.4530(4), c = 9.6211(19) Å, β = 97.179(16)°, V = 1930.7(6) ų, Z = 4, μ = 1.754 mm⁻¹, data/restraints/parameters: 3614/0/238, R indices (I > 2σ(I)): R₁ = 0.0622, wR₂ (all data) = 0.2664.†

Acknowledgements

We thank Department of Science and Technology (DST, New Delhi) for financial support and Single Crystal X-ray diffractometer facility, and the University Grants Commission (UGC, New Delhi) for equipment under UPE and CAS programs. ASR and MNR thank Council of Scientific and Industrial Research (CSIR, New Delhi) for fellowship. KCK thanks DST for the J. C. Bose fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Details on the synthesis of precursors 3a–p, ¹H and ¹³C NMR spectra and CIF files. CCDC 992617–992619. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra03503h

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