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aDepartment of Chemistry, K. L. University,

Pradesh, IndiabDr. Reddy's Institute of Life Sciences, Unive

Hyderabad 500046, India. E-mail: manojitpcDepartment of Chemistry, Krishna Univ

Pradesh, India

† Electronic supplementary information (and copies of NMR for all new compound

Cite this: RSC Adv., 2013, 3, 24863

Received 28th August 2013Accepted 10th October 2013

DOI: 10.1039/c3ra44703k

www.rsc.org/advances

This journal is ª The Royal Society of

Catalysis by Amberlyst-15 under ultrasound in water: agreen synthesis of 1,2,4-benzothiadiazine-1,1-dioxidesand their spiro derivatives†

S. Kiran Kumar,a D. Rambabu,b C. H. Vijay Kumar,b B. Yogi Sreenivas,b K. R. S. Prasad,a

M. V. Basaveswara Rao*c and Manojit Pal*b

A green and general synthesis of 1,2,4-benzothiadiazine-1,1-dioxides

possessing a spiro group or a substituent at C-3 has been achieved

first time via an Amberlyst-15mediated reaction under ultrasound in

water. The reaction is operationally simple and can be performed at

room temperature in an open flask to give a range of products that

do not require any chromatographic purification. The catalyst is

recyclable.

The benzothidiazine-1,1-dioxide class of heterocycles haveattracted particular attention in the area of medicinal/pharma-ceutical chemistry because of their broad range of biologicalproperties,1 such as antihypertensive,2 antimicrobial,3 antiviral,4

respiratory syncytial virus (RSV) inhibitory activities,5 along withsedative and hypotensive activities.6 A literature search revealedthat the 1,2,4-benzothiadiazine-1,1-dioxides are generally synthe-sized either via condensation of 2-aminobenzenesulfonamideswith urea at elevated temperature7 or with isocyanates in DMFunder reux.8 While various approaches9 are known for thepreparation of 1,2,4-benzothiadiazine-1,1-dioxides includingnon-catalytic10 or metal catalyzed reactions,11 many of thesemethods however, suffer from drawbacks, such as low yieldsof products, moisture sensitivity, environmental toxicity, therequirement of longer reaction time and high temperaturealong with the use of non-recyclable catalysts. Moreover,the preparation of required catalysts is cumbersome in somecases. Thus, development of a facile, atom efficient and eco-friendly method is desirable.

In recent years, heterogeneous catalysis have been exploredwidely in various organic transformations.12 For example,

Vaddeswaram, Guntur 522 502, Andhra

rsity of Hyderabad Campus, Gachibowli,

al@rediffmail.com

ersity, Machlipatnam 521001, Andhra

ESI) available: Experimental proceduress. See DOI: 10.1039/c3ra44703k

Chemistry 2013

inexpensive and commercially available Amberlyst-15 has beenutilized to catalyze a number of useful chemical reactions andattracted our attention13 due to its non-hazardous nature andeasy removal from the reaction mixture e.g. via simple ltration.The ultrasound mediated reactions on the other hand oenoffer several advantages over the traditional methods. Forexample, these reactions are known to be faster, convenient andhigh yielding process and therefore have found wide applica-tions in organic synthesis.14 Due to our continuing interest inspiro heterocycles13c we now report an Amberlyst-15 mediatedfaster and practical synthesis of 1,2,4-benzothiadiazine-1,1-dioxides 3 possessing a spiro group or a substituent at C-3 viathe reaction of 2-aminobenzenesulfonamide 1 with carbonylcompounds 2 under ultrasound irradiation in water (Scheme 1).To the best of our knowledge this is the rst example of usingthe combination of Amberlyst-15/ultrasound/water for thesynthesis of 3.

Initially, the reaction of commercially available 2-amino-benzenesulfonamide (1) with cyclopentanone (2a) in the pres-ence of Amberlyst-15 under ultrasound irradiation (SONOREXSUPER RK 510H model producing irradiation 35 KHz) wasselected as a model reaction and was carried out under variousconditions (Table 1). Though the reaction proceeded well indichloromethane (DCM), MeOH, toluene and CH3CN (Table 1,entry 1–4) affording good yield of expected product 3a thereaction was found to be faster in MeOH. This prompted us toexamine the reaction in PEG and more importantly in water. Toour satisfaction the reaction proceeded well in these solvents

Scheme 1 Amberlyst-15 mediated synthesis of 1,2,4-benzothiadiazine-1,1-dioxides 3 via the reaction of 1 and 2.

RSC Adv., 2013, 3, 24863–24867 | 24863

Table 1 Amberlyst-15 catalyzed reaction of 1a with 2a under variousconditionsa

Entry Solvent Time (min) %Yieldb

1 CH2Cl2 90 882 MeOH 60 863 Toluene 120 804 CH3CN 90 925 PEG 50 926 H2O 30 92 (90, 88, 86)c

7 H2O 90 40d

8 H2O 90 50e

9 H2O 180 60 f

a All the reactions were carried out using 2-aminobenzenesulfonamide1a (1.0 mmol), ketone 2a (1.2 mmol) and Amberlyst-15 (10%, w/w)under ultrasound irradiation (35 KHz) at room temperature. b Isolatedyield. c Catalyst was reused for additional three runs and gureswithin parentheses indicate the corresponding yield for each run.d The reaction was carried out in the absence of Amberlyst-15 andultrasound. e The reaction was carried out in the absence ofAmberlyst-15. f The reaction was carried out without ultrasound(using a stirrer).

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affording high yield of 3a (Table 1, entry 5 and 6). The reactionwas completed within 30 min in case of water. Notably, thereaction was found to be not sensitive to the presence of air oratmospheric moisture and therefore was performed in an openask. The role of catalyst and ultrasound was assessed by per-forming the reaction in the absence of both (Table 1, entry 7) oronly catalyst (Table 1, entry 8) or only ultrasound (Table 1,entry 9). The poor yield of 3a in all these cases conrmed the keyrole of Amberlyst-15 in enhancing the reaction rate and thecombination of Amberlyst-15, ultrasound and water was foundto be optimum for the faster synthesis of 3a in high yield atroom temperature.

This observation encouraged us to extend the scope andgenerality of this methodology. A variety of cyclic ketones or alde-hydes (2) therefore were reacted with 2-aminobenzenesulfonamide(1) in the presence of Amberlyst-15 under the conditions ofentry 6 of Table 1. The reactions were carried out in round-bottom asks attached with a condenser with the help of astandard ultrasonic bath producing irradiation at 35 kHz. Theresults are summarized in Table 2. The reaction proceededsmoothly in all these cases to give the corresponding products(3) in excellent yields. Generally, the product was separated asa solid from the reactionmixture and was isolated by ltration.The solid was puried by treating with EtOAc followed byltration (to remove the insoluble catalyst present) andconcentrating the ltrate. The residue was triturated in diethylether (to remove any unreacted reactants present), ltered anddried to give the pure product. Thus, the methodology is freefrom any chromatographic purication. Like the reaction of 1a

24864 | RSC Adv., 2013, 3, 24863–24867

with 2a (Table 1), all these reactions were performed in asksthat were open to air as the methodology does not require thepresence of either inert or anhydrous atmosphere highlightingthe simplicity of the process. The aliphatic ketones containing5 or 6 or 7-menbered ring participated well in the reactionaffording the corresponding products in high yields (Table 2,entries 1–3). The use of cyclic ketones containing aromaticring also afforded the desired products in excellent yields(Table 2, entries 5–8). Aldehydes containing various substituentssuch as electron donating Cl, Br, OH and OMe and electronwithdrawing NO2 were well tolerated and did not affect theproduct yields (Table 2, entries 9–17). The presence of substit-uent on the 2-aminobenzenesulfonamide ring was also welltolerated. For example 2-amino-5-iodobenzenesulfonamide (1a)was reacted with cyclic ketone to afford the correspondingproducts smoothly (Table 2, entry 18). Structure elaboration of arepresentative compound 3r was performed via Sonogashiratype reaction to afford the corresponding alkyne 4 (Scheme 2).All the compounds synthesized were characterized by NMR, IRand MS spectra and their purity was determined by HPLCmethod. All the cyclic ketones (2) used in the present reactionare commercially available except 2g, 2h and 2i that wereprepared from 2e according to the known procedure.13c

Based on the fact that the reaction of a ketone with anamine is greatly facilitated by Amberlyst-15,15 a plausablemechanism15–17 for the present Amberlyst-15 mediated reac-tion of 1 with the carbonyl compound 2 under ultrasound isshown in Scheme 3. Thus, the reaction proceeds via (i) in situgeneration of an iminium intermediate E which subsequentlyundergoes (ii) intramolecular cyclization involving the nucle-ophilic attack by the –SO2NH2 moiety on the activated –C]N–affording the spiro derivative 3. It is likely that ultrasoundperhaps activated the solid state structure of Amberlyst-15which in turn catalyzed the reaction. To test this, an experi-ment was performed where Amberlyst-15 was stirred underultrasound irradiation in water for 30 min. Upon addition ofthe reactants 1a and 2a, the reaction was then stirred in theabsence of ultrasound. While the reaction proceeded well inthis case affording 3a in 81% yield, the duration of the reactionwas longer (i.e. 90 min) than that observed in the presence ofultrasound. Also only 50% conversion was observed aer 30min. Thus in addition to activating the catalyst ultrasoundperhaps was also involved in inuencing the dispersion orparticle size of the reactants in water.18

In conclusion, Amberlyst-15 has been identied as a greenand reusable catalyst in the practical and general synthesis of1,2,4-benzothiadiazine-1,1-dioxides possessing a spiro groupor a substituent at C-3 under ultrasound irradiation atroom temperature. The methodology involved the reaction of2-aminobenzenesulfonamide with cyclic ketones or aldehydesin water to give the corresponding products that do not requireany chromatographic purication. The reaction is high yielding,operationally simple and can be performed in an open askwithin a short period of time. The methodology therefore isamenable for the rapid synthesis of a library of structurallydiverse and novel small molecules useful for medicinal/phar-maceutical chemistry and drug discovery.

This journal is ª The Royal Society of Chemistry 2013

Table 2 Synthesis of spiro 2,3-dihydroquinazolin-4(1H)-ones (3) via the reactionof 2-amino benzamides (1) and cyclic ketones (2)a (Scheme 1)

EntryCarbonylcompound (2) Product (3)

t (min);% yieldb

1 30; 92

2 40; 90

3 50; 91

4 60; 83

5 120; 85

6 120; 83

7 90; 87

8 190; 84

Table 2 (Contd. )

EntryCarbonylcompound (2) Product (3)

t (min);% yieldb

9 30; 80

10 30; 91

11 45; 82

12 30; 92

13 30; 94

14 60; 93

15 90; 83

16 150; 86

This journal is ª The Royal Society of Chemistry 2013 RSC Adv., 2013, 3, 24863–24867 | 24865

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Table 2 (Contd. )

EntryCarbonylcompound (2) Product (3)

t (min);% yieldb

17 150; 88

18 2b 90; 87c

a Reaction conditions: all the reactions were carried out using 1 (1.0mmol), an appropriate cyclic ketone or aldehyde 2 (1.2 mmol) andAmberlyst-15 (10%, w/w) in water under ultrasound irradiation (35KHz) at room temperature. b Isolated yield. c 2-Amino-5-iodobenzenesulfonamide (1a) was used in place of 1.

Scheme 2 Structure elaboration of a representative compound 3r.

Scheme 3 Proposed mechanism for the Amberlyst-15 mediated reaction of 1with the carbonyl compound 2 under ultrasound.

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The authors thank the management of Dr Reddy's Insti-tute of Life Sciences, Hyderabad for continuous support andencouragement.

Notes and references

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F. Somers, P. Chiap, P. Lebrun and B. Pirotte, J. Med.Chem., 2011, 54, 8353; (c) P. Francotte, E. Goffin,P. Fraikin, P. Lestage, J.-C. van Heugen, F. Gillotin,L. Danober, J.-Y. Thomas, P. Chiap, D.-H. Caignard,B. Pirotte and P. de Tullio, J. Med. Chem., 2010, 53, 1700;(d) B. Pirotte, P. de Tullio, Q.-A. Nguyen, F. Somers,P. Fraikin, X. Florence, P. Wahl, J. B. Hansen andP. Lebrun, J. Med. Chem., 2010, 53, 147.

2 A. Tait, A. Luppi, S. Franchini, E. Preziosi, C. Parenti,M. Buccioni, G. Marucci, A. Leonardi, E. Poggessi andL. Brasili, Bioorg. Med. Chem. Lett., 2005, 15, 1185.

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18 We thank one of the reviewers for pointing out this.

RSC Adv., 2013, 3, 24863–24867 | 24867