Synthesis and Chemistry of 1,2,3-Benzothiadiazine 1,1-Dioxide Derivatives: A Comprehensive Overview

1,2,4-Benzothiadiazine 1,1-dioxide derivatives (e.g., chlorothiazide, hydrochlorothiazide) have been long used in the human therapy as diuretic and antihypertensive agents. Marketed drugs containing the structurally related phthalazinone scaffold are applied for the treatment of various diseases ranging from ovarian cancer to diabetes and allergy. 1,2,3-Benzothiadiazine 1,1-dioxides combine the structural features of these two compound families, which led to their more intensive research since the 1960s. In the present review, we summarize the literature of this period of more than half a century, including all scientific papers and patent applications dealing with the synthesis and reactions of this compound family, briefly hinting at their potential therapeutic application as well.

Nearly 20 years ago, our focus at Egis Pharmaceuticals (Hungary) turned to the chemistry of 2H-1,2,3-benzothiadiazine 1,1-dioxides (BTD, see parent compound 1a, Scheme 1) as relatively scarcely used potential building blocks in medicinal chemistry, which combine the structural features of the abovementioned therapeutically efficient compound families. In this review, we intend to summarize the synthetic strategies that have been employed in the literature to prepare BTDs, briefly mentioning the observed pharmacological activities as well. We seek to specify the reaction conditions and the yields of the discussed reactions in each case if the data are clearly present in the literature sources. Nearly 20 years ago, our focus at Egis Pharmaceuticals (Hungary) turned to the chemistry of 2H-1,2,3-benzothiadiazine 1,1-dioxides (BTD, see parent compound 1a, Scheme 1) as relatively scarcely used potential building blocks in medicinal chemistry, which combine the structural features of the abovementioned therapeutically efficient compound families. In this review, we intend to summarize the synthetic strategies that have been employed in the literature to prepare BTDs, briefly mentioning the observed pharmacological activities as well. We seek to specify the reaction conditions and the yields of the discussed reactions in each case if the data are clearly present in the literature sources. Scheme 1. The first described syntheses of 2H-1,2,3-benzothiadiazine 1,1-dioxide (BTD) parent compound 1a. (i) NH2NH2 (56%); (ii) PCl5, POCl3, NH2NH2 (5-80%); (iii) SOCl2, DMF; (iv) NH2NH2 (50%, two steps).

Synthesis of 4-Unsubstituted, 4-Aryl and 4-Alkyl Derivatives
The synthesis of the parent compound (1a) was first described by King et al. in 1969, starting from sodium 2-formylbenzenesulfonate (2) via hydrazone 3 with erratic reproducibility and low yields (Scheme 1). Better results were obtained by changing the order of the two steps, i.e., by transformation of the sulfonate salt 2 to 2-formylbenzenesulfonyl chloride 4a and cyclization of the latter with hydrazine [13,14].
It is obvious that the key issue regarding the construction of the heterocyclic ring is the availability of an ortho-disubstituted benzene derivative suitable for cyclization with hydrazine. The syntheses of the "commercially available" [14] key intermediate 2 were already described at the turn of the 20th century in German patents [15,16].
Simultaneously with the aforementioned work, Wright et al. published the synthesis of 4arylbenzothiadiazine dioxides 5 (Scheme 2) [17][18][19]. Diazotation of 2-aminobenzophenones 6 followed by reaction with sulfur dioxide in the presence of copper (II) chloride gave orthobenzoylbenzenesulfonyl chlorides 7, which were cyclized with hydrazine to give 4-aryl-substituted target compounds 5.  Nearly 20 years ago, our focus at Egis Pharmaceuticals (Hungary) turned to the chemistry of 2H-1,2,3-benzothiadiazine 1,1-dioxides (BTD, see parent compound 1a, Scheme 1) as relatively scarcely used potential building blocks in medicinal chemistry, which combine the structural features of the abovementioned therapeutically efficient compound families. In this review, we intend to summarize the synthetic strategies that have been employed in the literature to prepare BTDs, briefly mentioning the observed pharmacological activities as well. We seek to specify the reaction conditions and the yields of the discussed reactions in each case if the data are clearly present in the literature sources. Scheme 1. The first described syntheses of 2H-1,2,3-benzothiadiazine 1,1-dioxide (BTD) parent compound 1a. (i) NH2NH2 (56%); (ii) PCl5, POCl3, NH2NH2 (5-80%); (iii) SOCl2, DMF; (iv) NH2NH2 (50%, two steps).

Synthesis of 4-Unsubstituted, 4-Aryl and 4-Alkyl Derivatives
The synthesis of the parent compound (1a) was first described by King et al. in 1969, starting from sodium 2-formylbenzenesulfonate (2) via hydrazone 3 with erratic reproducibility and low yields (Scheme 1). Better results were obtained by changing the order of the two steps, i.e., by transformation of the sulfonate salt 2 to 2-formylbenzenesulfonyl chloride 4a and cyclization of the latter with hydrazine [13,14].
It is obvious that the key issue regarding the construction of the heterocyclic ring is the availability of an ortho-disubstituted benzene derivative suitable for cyclization with hydrazine. The syntheses of the "commercially available" [14] key intermediate 2 were already described at the turn of the 20th century in German patents [15,16].

Synthesis of 4-Unsubstituted, 4-Aryl and 4-Alkyl Derivatives
The synthesis of the parent compound (1a) was first described by King et al. in 1969, starting from sodium 2-formylbenzenesulfonate (2) via hydrazone 3 with erratic reproducibility and low yields (Scheme 1). Better results were obtained by changing the order of the two steps, i.e., by transformation of the sulfonate salt 2 to 2-formylbenzenesulfonyl chloride 4a and cyclization of the latter with hydrazine [13,14].
It is obvious that the key issue regarding the construction of the heterocyclic ring is the availability of an ortho-disubstituted benzene derivative suitable for cyclization with hydrazine. The syntheses of the "commercially available" [14] key intermediate 2 were already described at the turn of the 20th century in German patents [15,16].
Some representatives of the 4-aryl-BTD family (5) are useful as intermediates for the preparation of disinfectants, mothproofing agents, pickling inhibitors and herbicides [17]. Cyclization of the suitably substituted ortho-benzoylbenzenesulfonyl chloride 7a with hydrazine to give 5a, followed by reduction of the nitro group and subsequent N-benzylation, afforded aminobenzoic acid 8 (Scheme 3). However, it was devoid of the expected diuretic activity [20].
A new approach was disclosed by Kacem et al. for the synthesis of BTDs 5, 9 and 18 [28].    Chandra et al. elaborated a method for the N-acylation reactions of peptides by ketenes, generated from malonic acids in the presence of a coupling agent (HBTU, HATU, TATU, etc.) and bases (DIPEA, TEA) in DMF or DMSO at 0 • C [29]. When extending this procedure to the N-acetylation of sulfonylhydrazide 19 (Scheme 6), they concluded that under the reaction conditions applied for the acetylation (not specified in detail), intermediate 24 underwent immediate cyclization to BTD 9a. However, the attached spectroscopic data are not in accordance with structure 9a, which was previously convincingly characterized by Kacem et al. [28].
Chemistry 2020, 2, x 5 Chandra et al. elaborated a method for the N-acylation reactions of peptides by ketenes, generated from malonic acids in the presence of a coupling agent (HBTU, HATU, TATU, etc.) and bases (DIPEA, TEA) in DMF or DMSO at 0 °C [29]. When extending this procedure to the Nacetylation of sulfonylhydrazide 19 (Scheme 6), they concluded that under the reaction conditions applied for the acetylation (not specified in detail), intermediate 24 underwent immediate cyclization to BTD 9a. However, the attached spectroscopic data are not in accordance with structure 9a, which was previously convincingly characterized by Kacem et al. [28]. Scheme 6. Synthesis of 4,6-dimethyl-BTD (9a) by cyclization of para-toluenesulfonyl-acetohydrazide (24).
It is interesting to mention that two earlier Japanese patents dealt with the alkylation reactions of compound 1a (R 1 , R 2 = H, Scheme 7). Here, a large variety of alkylating agents were used (e.g., ωhalogen carboxylic acid esters); however, only N(2)-substituted derivatives were isolated, and no N(3)-alkylation was mentioned [32,33]. Some derivatives proved to be efficient fungicides preventing rice blast, one of the most destructive diseases of rice.

Alkylations
We found that alkylation of 2H-1,2,3-benzothiadiazine 1,1-dioxide and its derivatives substituted on the aromatic ring (1) with methyl and ethyl iodide occurred both at N(2) and N(3) atoms (25 and 26, Scheme 7) [30,31]. The N(3)-alkylated derivative (26) exhibited a unique mesoionic structure. When using t-BuOK as the base in DMF, compound 25 was the main product, while deprotonation with NaH in THF followed by alkylation preferred the formation of the N(3)-alkyl compound 26. The two products could be selectively isolated without chromatography.
Chandra et al. elaborated a method for the N-acylation reactions of peptides by ketenes, generated from malonic acids in the presence of a coupling agent (HBTU, HATU, TATU, etc.) and bases (DIPEA, TEA) in DMF or DMSO at 0 °C [29]. When extending this procedure to the Nacetylation of sulfonylhydrazide 19 (Scheme 6), they concluded that under the reaction conditions applied for the acetylation (not specified in detail), intermediate 24 underwent immediate cyclization to BTD 9a. However, the attached spectroscopic data are not in accordance with structure 9a, which was previously convincingly characterized by Kacem et al. [28]. Scheme 6. Synthesis of 4,6-dimethyl-BTD (9a) by cyclization of para-toluenesulfonyl-acetohydrazide (24).
It is interesting to mention that two earlier Japanese patents dealt with the alkylation reactions of compound 1a (R 1 , R 2 = H, Scheme 7). Here, a large variety of alkylating agents were used (e.g., ωhalogen carboxylic acid esters); however, only N(2)-substituted derivatives were isolated, and no N(3)-alkylation was mentioned [32,33]. Some derivatives proved to be efficient fungicides preventing rice blast, one of the most destructive diseases of rice.
It is interesting to mention that two earlier Japanese patents dealt with the alkylation reactions of compound 1a (R 1 , R 2 = H, Scheme 7). Here, a large variety of alkylating agents were used (e.g., ω-halogen carboxylic acid esters); however, only N(2)-substituted derivatives were isolated, and no N(3)-alkylation was mentioned [32,33]. Some derivatives proved to be efficient fungicides preventing rice blast, one of the most destructive diseases of rice.
Wright described the alkylations of variously substituted 4-aryl-BTDs 5 with alkyl iodides [17,18] and aminoalkyl bromides and chlorides [19] in the presence of sodium hydroxide (NaOH) in aqueous ethanol solution resulting in N(2)-alkyl derivatives 27 (Scheme 8, Method A). We carried out N(2)-methylation of compounds 5 at room temperature in DMF using either t-BuOK or NaH as the base (Method B). Similar alkylation with butyl iodide was conducted at an elevated temperature (60 • C) [27].
N(2)-Alkylations of 4-aryl derivatives 5 occurred more selectively than in the case of 4-unsubstituted congeners 1. For the sake of completeness, a detailed examination was carried out in one case: a small amount of mesoionic derivative 28 (Scheme 8) could be isolated. According to 1 H NMR measurements, the ratio of the N(2)and N(3)-alkylated compounds in the crude product mixture was 10:1 in this case [27]. N(2)-Alkylations of 4-aryl derivatives 5 occurred more selectively than in the case of 4unsubstituted congeners 1. For the sake of completeness, a detailed examination was carried out in one case: a small amount of mesoionic derivative 28 (Scheme 8) could be isolated. According to 1 H NMR measurements, the ratio of the N(2)-and N(3)-alkylated compounds in the crude product mixture was 10:1 in this case [27].
Alkylation of 4-methyl derivatives 9 with various alkylating agents (Scheme 9) in the presence of t-BuOK in DMF afforded the corresponding N(2)-alkylated derivatives 29 [24,30]. Carbapenem antibacterials, useful against Gram-positive microorganisms containing a BTD building block (33), were synthesized using Mitsunobu chemistry for N(2)-alkylation of BTDs (1,5,9) with hydroxymethyl-carbapenem derivative 34. Optionally, a R 1 substituent of compound 35 was further transformed before removal of the protecting groups (Scheme 11) [34]. Alkylation of 4-methyl derivatives 9 with various alkylating agents (Scheme 9) in the presence of t-BuOK in DMF afforded the corresponding N(2)-alkylated derivatives 29 [24,30]. N(2)-Alkylations of 4-aryl derivatives 5 occurred more selectively than in the case of 4unsubstituted congeners 1. For the sake of completeness, a detailed examination was carried out in one case: a small amount of mesoionic derivative 28 (Scheme 8) could be isolated. According to 1 H NMR measurements, the ratio of the N(2)-and N(3)-alkylated compounds in the crude product mixture was 10:1 in this case [27].

Reductions of the C=N Double Bond and Subsequent Alkylations and Acylations
There are two ways to perform the reduction of the C=N double bond of BTDs 1, 5 and 9. 3,4-Dihydro derivatives 38 were obtained either: (a) through catalytic reduction in the presence of platinum(IV) oxide or palladium on activated charcoal at 3.5 or 10-15 bar hydrogen pressure in acetic acid (Scheme 14, Method A), or (b) with NaBH4 in a mixture of trifluoroacetic acid (TFA) and dichloromethane (Method B) [19,24,26,27,30,38]. Compounds 38 were regioselectively alkylated at position N(3) by catalytic reductive alkylation using aldehydes or acetone to give derivatives 39 [24,30,38]. Scheme 11. Synthesis of antibacterials possessing a carbapenem core (33).

Reductions of the C=N Double Bond and Subsequent Alkylations and Acylations
There are two ways to perform the reduction of the C=N double bond of BTDs 1, 5 and 9. 3,4-Dihydro derivatives 38 were obtained either: (a) through catalytic reduction in the presence of platinum(IV) oxide or palladium on activated charcoal at 3.5 or 10-15 bar hydrogen pressure in acetic acid (Scheme 14, Method A), or (b) with NaBH4 in a mixture of trifluoroacetic acid (TFA) and dichloromethane (Method B) [19,24,26,27,30,38]. Compounds 38 were regioselectively alkylated at position N(3) by catalytic reductive alkylation using aldehydes or acetone to give derivatives 39 [24,30,38]. Wright published the acylation of 4-phenyl derivative 5c with some acyl chlorides in refluxing chloroform to afford N(2)-acyl derivative 37 (Scheme 13) [17,18]. In a Japanese patent, similar acetylation and propionylation of compound 1a are mentioned [33].

Reductions of the C=N Double Bond and Subsequent Alkylations and Acylations
There are two ways to perform the reduction of the C=N double bond of BTDs 1, 5 and 9. 3,4-Dihydro derivatives 38 were obtained either: (a) through catalytic reduction in the presence of platinum(IV) oxide or palladium on activated charcoal at 3.5 or 10-15 bar hydrogen pressure in acetic acid (Scheme 14, Method A), or (b) with NaBH4 in a mixture of trifluoroacetic acid (TFA) and dichloromethane (Method B) [19,24,26,27,30,38]. Compounds 38 were regioselectively alkylated at position N(3) by catalytic reductive alkylation using aldehydes or acetone to give derivatives 39 [24,30,38].
3-acetyl-2-methyl product 45 was obtained. It was planned to replace the 3-acetyl function by an alkyl group as well. However, attempts to remove the 3-acetyl function of 45 (R = Me) to give compound 40a even under drastic conditions were unsuccessful. Quenching of the lithium salt with dry ice gave 8-carboxy-7-chloro congener 1e in 60% yield. However, the lithiation of 8-chloro-7-methoxy derivative 1c under similar conditions followed by quenching with water afforded 7-methoxy target compound 1f only with poor yield (24%) and a substantial amount of the starting material was recovered. With the reaction temperature elevated to 0 °C, 4-butyl derivative 38a was formed as the main product, due to the addition of BuLi to the C=N double bond [21]. (1b, 1c). Quenching of the lithium salt with dry ice gave 8-carboxy-7-chloro congener 1e in 60% yield. However, the lithiation of 8-chloro-7-methoxy derivative 1c under similar conditions followed by quenching with water afforded 7-methoxy target compound 1f only with poor yield (24%) and a substantial amount of the starting material was recovered. With the reaction temperature elevated to 0 • C, 4-butyl derivative 38a was formed as the main product, due to the addition of BuLi to the C=N double bond [21].

Scheme 18. Lithiation of BTDs containing a 8-chloro substituent
Chemistry 2020, 2, x 9 3-acetyl-2-methyl product 45 was obtained. It was planned to replace the 3-acetyl function by an alkyl group as well. However, attempts to remove the 3-acetyl function of 45 (R = Me) to give compound 40a even under drastic conditions were unsuccessful. Quenching of the lithium salt with dry ice gave 8-carboxy-7-chloro congener 1e in 60% yield. However, the lithiation of 8-chloro-7-methoxy derivative 1c under similar conditions followed by quenching with water afforded 7-methoxy target compound 1f only with poor yield (24%) and a substantial amount of the starting material was recovered. With the reaction temperature elevated to 0 °C, 4-butyl derivative 38a was formed as the main product, due to the addition of BuLi to the C=N double bond [21]. (1b, 1c). Scheme 18. Lithiation of BTDs containing a 8-chloro substituent (1b, 1c).

Synthesis and Transformations of 4-Hydrazino-2H-1,2,3-benzothiadiazine 1,1-dioxides
The first published compound exhibiting a BTD skeleton was 4-hydrazino derivative 54a (R = H) disclosed by Schrader in 1917 (Scheme 21, Method A) [41]. It was obtained by treatment of 2cyanobenzenesulfonylchloride (55a) with hydrazine. More attention was paid to the compound family when two related compounds, the diuretic agent hydrochlorothiazide (Figure 1) and the antihypertensive compound hydralazine (Figure 2), successfully entered the pharmaceutical market in the 1950s [42][43][44][45]. In 1962, Schmidt et al. prepared the corresponding 7-chloro derivative 54b similarly (Method B), but with a much simpler work-up of the reaction mixture. When starting from 7-ethoxy derivative 55c, intermediate 56 was also isolated [46]. A detailed study on the hypotensive activity of 54a was published in 1965 [47].  [41]. A large variety of hydrazones 57 were synthesized starting from compound 54a using structurally diverse aldehydes and ketones. Some of them showed a significant antihypertensive activity [42]. As regards the stability of hydrazones 57, when refluxing a solution of 57c in the presence of air, the formation of dehydrogenated derivative 58 was observed, which was also prepared by reacting 54c with acetone in the presence of hydrogen peroxide [46]. The presence of the hydrazino group in the molecule enabled the synthesis of new types of derivatives. Schrader reported the formation of hydrazone 57 (R 1 = Ph, R 2 = H, R = H) in the reaction of 54a with benzaldehyde as a structure proof for the starting compound (Scheme 22) [41]. A large variety of hydrazones 57 were synthesized starting from compound 54a using structurally diverse aldehydes and ketones. Some of them showed a significant antihypertensive activity [42]. As regards the stability of hydrazones 57, when refluxing a solution of 57c in the presence of air, the formation of dehydrogenated derivative 58 was observed, which was also prepared by reacting 54c with acetone in the presence of hydrogen peroxide [46].

Synthesis and Transformations of 4-Hydrazino-2H-1,2,3-benzothiadiazine 1,1-dioxides
The first published compound exhibiting a BTD skeleton was 4-hydrazino derivative 54a (R = H) disclosed by Schrader in 1917 (Scheme 21, Method A) [41]. It was obtained by treatment of 2cyanobenzenesulfonylchloride (55a) with hydrazine. More attention was paid to the compound family when two related compounds, the diuretic agent hydrochlorothiazide (Figure 1) and the antihypertensive compound hydralazine (Figure 2), successfully entered the pharmaceutical market in the 1950s [42][43][44][45]. In 1962, Schmidt et al. prepared the corresponding 7-chloro derivative 54b similarly (Method B), but with a much simpler work-up of the reaction mixture. When starting from 7-ethoxy derivative 55c, intermediate 56 was also isolated [46]. A detailed study on the hypotensive activity of 54a was published in 1965 [47].  [41]. A large variety of hydrazones 57 were synthesized starting from compound 54a using structurally diverse aldehydes and ketones. Some of them showed a significant antihypertensive activity [42]. As regards the stability of hydrazones 57, when refluxing a solution of 57c in the presence of air, the formation of dehydrogenated derivative 58 was observed, which was also prepared by reacting 54c with acetone in the presence of hydrogen peroxide [46]. The 4-hydrazino group of compounds 54 retained the doubly nucleophilic character of hydrazine, as demonstrated by the synthesis of pyrazole derivative 59 by the treatment of 54c with acetylacetone (Scheme 23) [46]. Similar cyclization with ethoxymethylene-acetylacetone afforded 4-acetylpyrazole 60, which was further functionalized with paraformaldehyde and 4-fluorophenylpiperazine to give arylpiperazinyl derivative 61. This latter step represents a variant of N(2)-alkylation reactions of BTDs. Compound 61 did not show significant activity in antihypertensive and adrenolytic tests [48,49].

Conclusions
1,2,3-Benzothiadiazine 1,1-dioxides combine the structural features of two compound families, 1,2,4-benzothiadiazine 1,1-dioxides and phthalazinones, some of whose members are important medicines on the market. This structural similarity led to an intensive research of 1,2,3benzothiadiazine 1,1-dioxides, starting from the 1960s. This review summarizes the methods It was found that compound 79 behaved differently from its thio analogue 80 in the reaction with hydrazine, resulting in the formation of hydrazone 81 (Scheme 29) instead of ring expansion to 78 (Scheme 28). However, the reaction of 81 with substituted benzaldehydes in refluxing benzene and subsequent treatment with hydrazine afforded N(2)-alkyl-4-amino-BTDs 82, a compound family exhibiting a significant antibacterial activity [56,59].

Conclusions
1,2,3-Benzothiadiazine 1,1-dioxides combine the structural features of two compound families, 1,2,4-benzothiadiazine 1,1-dioxides and phthalazinones, some of whose members are important medicines on the market. This structural similarity led to an intensive research of 1,2,3-benzothiadiazine 1,1-dioxides, starting from the 1960s. This review summarizes the methods developed for the synthesis of 1,2,3-benzothiadiazine 1,1-dioxides substituted with various functional groups, allowing the attachment of new building blocks (among other pharmacophores) to the parent molecule. Efforts to use this compound family in drug development are also presented.