Ultrasonics Sonochemistry 19 (2012) 264–269

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Ultrasonics Sonochemistry

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A facile and efficient ultrasound-assisted synthesis of novel dispiroheterocyclesthrough 1,3-dipolar cycloaddition reactions

Yu Hu a, Yi Zou a,b, Hui Wu b, Daqing Shi a,⇑a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR Chinab School of Chemistry and Chemical Engineering, Xuzhou Normal University, Xuzhou 221116, PR China

a r t i c l e i n f o a b s t r a c t

Article history:Received 21 March 2011Received in revised form 1 July 2011Accepted 21 July 2011Available online 26 July 2011

Keywords:Dispiroheterocyclic compound1,3-Dipolar cycloadditionAzomethine ylideUltrasound

1350-4177/$ - see front matter � 2011 Elsevier B.V. Adoi:10.1016/j.ultsonch.2011.07.006

⇑ Corresponding author.E-mail address: dqshi@suda.edu.cn (D. Shi).

A facile and efficient one-pot three-component procedure for synthesis of novel dispirooxindolecy-clo[pyrrolo[1,2-c]thiazole-6,50-thiazolidine] derivatives without any catalysts under ultrasonic conditionhas been developed. Combining with the advantages of sonochemistry, such as mild reaction conditions,good yield and short reaction times, we have made a progress on construction of novel disiproheterocy-clic compounds via the 1,3-dipolar cycloaddition of azomethine ylides. Several experiments were espe-cially carried out for investigating the acceleration mechanism of ultrasound on the cycloaddition.

� 2011 Elsevier B.V. All rights reserved.

1. Introduction

1,3-Dipolar cycloaddition reactions are efficient methods for theconstruction of heterocyclic units [1]. One of the most importantclasses for 1,3-dipolar cycloaddition involves azomethine ylide,which is a powerful method for the construction of biologicallyactive five-membered heterocycles especially substituted pyrroli-dine rings. The azomethine ylides were easily formed and readilytrapped by dipolarophiles, such reaction can be taken placed eitherinter- or intra-molecularly [2], and the corresponding pyrrolidinederivatives were achieved. Particularly, 1,3-dipolar cycloadditionof azomethine ylide for synthesizing the compounds with spiromoiety were usually in a highly regio- and stereo-selectivity.

Molecules with the thiazolidine nucleus have shown a wide spec-trum of bioactivities and drug activity [3]. In medicine, thiazolidinederivatives are well recognized for its anti-inflammatory and anti-hypertensive activities [4]; in pesticides, compounds with thiazoli-dine ring were treated as the research of novel pesticides for itslow toxicity to human being and excellent biological activity, suchas the goods of thifluzaminde, ethaboxam, benthiazole and clothi-anidim. The heterocyclic spiro-oxindole framework is an importantstructural motif in relevant compounds as natural products and alsoact as potent nonpeptide inhibitor of the p53-MDM2 interaction [5].Spiropyrrolidine oxindole ring systems are found in a number ofalkaloids such as horsifiline, spirotryprostatine A and B and elaco-

ll rights reserved.

mine [6]. Isatin derivatives are useful precursors in the synthesisof wide number of naturally occurring oxindole alkaloids [7].

Ultrasonic irradiation [8], as a powerful tool in modern chemis-try for the organic reactions, has attracted more attention of chem-ists. The ultrasonic irradiation with its advantages of convenientoperation, mild reaction conditions, short reaction time and highefficiency has become particularly popular in recent years, andnumerous examples under this condition for constructing hetero-cycles with interesting properties have been reported in theliterature [9].

To our knowledge, the synthesis of dispiroheterocycliccompounds by the 1,3-dipolar cycloaddition of azomethine ylidescarried out under ultrasound condition were seldom reported[10]. As part of our interest in the synthesis of spiro compoundvia the 1,3-dipolar cycloadditions of azomethine ylides [11] andin order to expand the application of ultrasound in the synthesisof heterocyclic compound [12], herein, we report the facile synthe-sis of novel dispirooxindolecyclo[pyrrolo[1,2-c]thiazole-6,50-thia-zolidine] derivatives having both thiazolone and spirooxindolemoieties via catalyst-free, one-pot, three-component 1,3-dipolarcycloaddition reaction of azomethine ylides promoted by ultra-sound at room temperature (Scheme 1).

2. Results and discussion

2.1. Solvent effect under classical refluxing and ultrasound irradiation

Azomethine ylides can be generated by several methods fromeasily available starting materials. Among them, the ‘decarboxyl-

HN

S

O

X Ar

S

NH

CO2H

32

NH

O

O

NH

N

HN

S

SO

OXAr

1 4

))), r.t.

Ethanol, 5 h

Scheme 1.

Table 2Effect of the ultrasonic temperature and the ultrasonic frequency.a

Entry Frequency (kHz) Temperature (�C) Time (h) Isolated yield (%)

1 25 25 5 932 40 25 5.5 883 25 40 5 904 25 50 5 89

a Reaction conditions: isatin 1 (0.5 mmol), thiazolidine-4-carboxylic acid 2(0.5 mmol), 5-benzylidene-2-thioxothiazolidin-4-one 3a (0.5 mmol) and ethanol(10 mL).

Table 3The synthesis of dispirooxindolecyclo[pyrrolo[1,2-c]thiazole-6,50-thiazolidine] deriv-atives 4 under sonication.a

Entry Compound X Ar Isolated yield (%) M.p. (�C)

1 4a S C6H5 93 167–1692 4b S 4-FC6H4 84 175–1773 4c S 4-BrC6H4 91 174–1764 4d S 4-NO2C6H4 95 168–1705 4e S 4-CH3C6H4 90 165–1676 4f O C6H5 93 136–1387 4g O 4-FC6H4 80 137–1388 4h O 4-ClC6H4 88 132–1349 4i O 4-BrC6H4 88 156–15810 4j O 3-CH3C6H4 86 148–150

a Reaction of isatin, thiazolidine-4-carboxylic acid, (Z)-5-benzylidene-2-thioxo-thiazolidin-4-one or (Z)-5-benzylidenethiazolidine-2,4-dione in ethanol at 25 �Cand the ultrasonic power 250 W, irradiation frequency 25 kHz.

Y. Hu et al. / Ultrasonics Sonochemistry 19 (2012) 264–269 265

ation route’ offers a general way for azomethine ylides prepared[13]. The in situ generated azomethine ylide is trapped by dipol-arophiles and cycloadducts were produced. Here we have chosenisatin 1, thiazolidine-4-carboxylic acid 2 and 5-benzylidene-2-thi-oxothiazolidin-4-one 3a as a simple model substrate under bothclassical refluxing (Method A) and ultrasound irradiation (MethodB) conditions. Different solvents such as methanol, ethanol, aceto-nitrile, 1,4-dioxane, tetrahydrofuran (THF), chloroform and waterwere explored. The results are summarized in Table 1. It can beseen from the Table 1 that the reaction performed under refluxcondition afforded comparatively lower yields at long reactiontime. While when water was chosen as the reaction medium thedesired product is not observed. Then, we have studied thesonochemical effect on model reaction. In all cases, the experimen-tal results show that the reaction times are strikingly shorter andthe yields of the products are higher under sonication. And theuse of ultrasound radiation in ethanol, especially, increased theyield of the reaction to 93% and decreased the reaction time to5 h (Table 1, Entry 2). It is apparent that the ultrasound canaccelerate the reaction significantly. Thus, ethanol is the solventof choice for this reaction under ultrasound irradiation.

2.2. Effect of the ultrasonic temperature and the ultrasonic frequency

We also observed the effect of frequency of ultrasound irradia-tion on the reaction. When the frequency was 25 kHz, the modelreaction gave the desired product 4a in 93% yield at 25 �C. Using40 kHz did not change reaction yield a considerable amount (88%in the similar time). Experiments performed at constant transmit-ted power but variable frequency (25 and 40 kHz) show the sametrend (Table 2, Entries 1 and 2). It is shown that there is an opti-mum frequency for effective synthesis of 4a in the frequency of25 kHz. In order to further improve the yield of the reaction, wetried to perform the reaction in higher temperature under ultra-sound irradiation. However, the yield did not increase. Conse-quently, it was indicated that there was no remarkable ultrasonictemperature effect on this reaction.

Table 1Optimization of solvent in the synthesis of 4a under classical refluxing and ultrasoundirradiation.a

Entry Solvent Method A (without USb) Method B (with USc)

Time(h)

Isolated yield(%)

Time(h)

Isolated yield(%)

1 Methanol 15 80 6 852 Ethanol 13 87 5 933 Acetonitrile 21 41 10 424 1,4-Dioxane 19 50 9 545 THF 13 60 7 666 Chloroform 16 65 9 707 Water 48 None 20 None

a Reaction conditions: isatin 1 (0.5 mmol), thiazolidine-4-carboxylic acid 2(0.5 mmol), 5-benzylidene-2-thioxothiazolidin-4-one 3a (0.5 mmol) and solvent(10 mL).

b Reaction under reflux condition.c Reaction under ultrasonic waves at room temperature and the ultrasonic power

250 W, irradiation frequency 25 kHz.

2.3. High efficiency synthesis of dispirooxindolecyclo[pyrrolo[1,2-c]thiazole-6,50-thiazolidine] derivatives 4 under ultrasound irradiation

After optimization of the conditions, to delineate this approach,particularly in regard to library construction, this methodologywas evaluated by using different dipolarophiles. A series of substi-tuted (Z)-5-benzylidene-2-thioxothiazolidin-4-one or (Z)-5-benzy-lidenethiazolidine-2,4-dione 3 were chosen for the libraryvalidation. Corresponding dispiroheterocyclic compounds 4 weresynthesized by the one-pot, three-component reaction of isatin 1,thiazolidine-4-carboxylic acid 2 and dipolarophiles 3 in good yieldsin ethanol at room temperature under ultrasound irradiation(Scheme 1). As in the case of the cycloaddition reactions describedin Scheme 1, we noticed that the reaction proceeded to give thebest yield of the products (80–95%). The results are summarizedin Table 3.

To the best of our knowledge, this new procedure provides thefirst example of an efficient and ultrasound-promoted approach forthe synthesis of dispirooxindolecyclo[pyrrolo[1,2-c]thiazole-6,50-thiazolidine] derivatives 4 under sonication. This method is themost simple and convenient. The structures of all the products 4were established by IR, 1H NMR, and HRMS spectroscopy and someof them were established by 13C NMR spectroscopy. The regio- andstereochemical outcome of the cycloaddition reaction was deter-mined unambiguously by single crystal X-ray analysis of cycload-duct 4h (Fig. 1).

2.4. The study of acceleration mechanism under irradiation ofultrasound

Through the experiments mentioned above, it was observedthat there was a great amount of solid in this system originally be-cause of the bad solubility of isatins and (Z)-5-benzylidene-2-thi-oxothiazolidin-4-one in ethanol at room temperature. As thereaction went on under sonication, the reactants were graduallydissolved in the reaction solvent and then disappeared after about

Fig. 1. ORTEP diagram of 4 h.

Fig. 2. Cavitation bubble in solubility behavior.

Fig. 3. Cavitation bubble in a homogeneous system.

266 Y. Hu et al. / Ultrasonics Sonochemistry 19 (2012) 264–269

15 min, while the classical condition needs 1 h. When the reactionwas over (monitored by TLC), more and more solids had appearedwhich color was different with that of isatins and (Z)-5-benzyli-dene-2-thioxothiazolidin-4-one. After separation and analysis suchas 1H NMR, it was surprising to find that the product is the desiredone. Then, we put two experiments to further study the accelera-tion mechanism under sonication. After dissolution of insolublesubstrates which were irradiated under sonication (pre-ultrasoni-cation as the physical aspect), we carry out the comparison be-tween with and without ultrasound. We found that the reactionwithout sonication for follow-up process took a long time andthe yields were relatively low. Therefore, in the present system,ultrasound was found to have beneficial effect on solubility behav-ior and the synthesis of 4a.

Ultrasound, when passing through a liquid medium, causesmechanical vibration of the liquid. In addition to this effect, ultra-sound also generates acoustic streaming within the liquid. If the li-quid medium contains dissolved gas nuclei, which will be the caseunder normal conditions, they can be grown and collapsed by theaction of the ultrasound. The phenomenon of growth and collapseof microbubbles under an ultrasonic field is known as ‘‘AcousticCavitation’’. Two important characteristics of acoustic cavitationshould be mentioned here. The first is that generally it is a non-lin-ear process in that the change in the radius of the bubble is notproportional to the sound pressure. The second is that the highcompressibility of the gas bubbles means that much potential en-ergy is obtained from the sound wave when the bubbles expandand that kinetic energy is concentrated when the bubbles collapse.In transient cavitation, this transformation of energy occurs be-cause of the non-linear behavior of bubbles. Because it concen-trates the energy into very small volumes, it can produce veryhigh pressures and temperatures which can erode solids and initi-ate chemical reactions. Therefore, once cavitation occurs near thesolid surface, cavity collapse is nonspherical and drives high-speedjets of liquid to the solid surface which leads to the acceleration ofdissolution and heat and mass transformations [14] (Fig. 2).

Localized ‘‘hot spots’’ generated from a violent collapse of thebubbles creates a transient high temperature and pressures, induc-ing molecular fragmentation, and highly reactive species are lo-cally produced (Fig. 3). From the Table 1, it is indicated that theobvious difference in the reaction efficiencies with or without son-ication suggests again that the reaction under ultrasound conditionproceeded in not the same, but in more efficient way than did thereaction under the heating conditions. The yield of the relatedreaction to synthesize 4a is up to 93% under ultrasound conditionat the temperature below 30 �C, whereas the yield of the reactionwithout sonication is only 87% at reflux temperature 80 �C, and

the reaction time under sonication is reduced from 13 to 5 h. Theimplosion of cavities reportedly established an unusual environ-ment for reactions. The gases and vapors inside the cavity are com-pressed, generating intense heat that raises the temperature of theliquid immediately surrounding the cavity and the high tempera-ture and pressure produced during cavitation break their chemicalbonds, short-lived chemical species are returned to the bulk liquidat room temperature, thus reacting with other species [15].

In sum, there were two main reasons for the acceleration inpresent system. One was the physical aspect of ultrasound whichleaded reactants to dissolve faster in ethanol; another was thechemical aspect of ultrasound which accelerated the reaction.Thus, we observed the significant decrease in the reaction timein comparison with conventional methods by our experiments.

2.5. Reaction mechanism

It is well known that 1,3-dipolar cycloadditions can occur byconcerted or diradical mechanism [16] and also by homogeneousreactions which are sensitive to the sonochemical effect and pro-ceeded via radical or radical-ion intermediates [17]. Therefore, itcan be suggested that pathway of this homogeneous reactionswitched from a concerted mechanism (Path A in Scheme 2) inthe conventional method to a diradical mechanism under sonica-tion (Path B in Scheme 2).

To support this idea, p-benzoquinone as a radical scavenger wasadded to the reaction mixture under sonication condition (Table 4).Interestingly, rate of reaction in presence of radical scavenger de-creased significantly. Furthermore, when radical scavenger wasadded to the reaction mixture in classical reaction, rate of reactiondecreased somewhat. We can see from Table 4 that the reactionsunder ultrasonic condition in absence of radical scavenger are fas-ter than the thermolytic reactions. The increase in reaction ratemight be due to an increase in rate of decarboxylation and forma-

HN

S

O

X Ar

S

NH

CO2H

32

NH

O

O

NH

N

HN

S

SO

OX

1

4

NH

O

N

S

NH

ON

O S

O

NH

O

N

S

Path A, Δ

Path B, )))

5

6

7

3

NH

O

N

SHN

S

Ar

X

O

Ar

3

1,3-dipolarCycloaddition

8

Scheme 2.

Table 4The results of the reactions in presence of or in absence of p-benzoquinone.

Entry Without US With US

Time (h) Isolated yield (%) Time (h) Isolated yield (%)

1a 13 82 10 322b 13 87 5 93

a Reactions in presence of p-benzoquinone.b Reactions in absence of p-benzoquinone.

Y. Hu et al. / Ultrasonics Sonochemistry 19 (2012) 264–269 267

tion of diradical ylide 7. This can cause the frequency of collisionsbetween ylide and the dipolarophiles of 3 to increase. Energy ofthese clashes and formation of diradical ylide 7 are provided byshort-lived and localized hot spots that generated during the cavi-tational collapse.

In order to corroborate mechanism, a hypothesis outlined inScheme 2. The reaction of isatin 1 with thiazolidine-4-carboxylicacid 2 in ethanol leads to the formation of an azomethine ylide 6and 7 after decarboxylation of 5. Regioselectivity of products inpathway B could be explained by high stability of diradicals 8which caused by resonance of each of the radicals with carbonylgroups.

3. Conclusion

In conclusion, we have succeeded in developing the 1,3-dipolarcycloaddition of azomethine ylides under ultrasonic condition, anda series of novel regioselective dispirooxindolecyclo[pyrrolo[1,2-c]thiazole-6,50-thiazolidine] derivatives were obtained. Because ofthe advantages of ultrasonic irradiation of mild reaction condi-tions, short reaction time and high efficiency, it is quite valuableto develop the 1,3-dipolar cycloaddition of azomethine ylides un-der this conditions.

4. Experimental

4.1. Apparatus and analysis

All reagents were purchased from commercial sources and usedwithout further purification. Melting points are uncorrected. IRspectra were recorded on a Varian F-1000 spectrometer in KBrwith absorptions in cm�1. 1H NMR were determined on a VarianInvoa-300/400 MHz spectrometer in DMSO-d6 solution. J valuesare in Hz. Chemical shifts are expressed in ppm downfield frominternal standard TMS. HRMS data were obtained using BrukermicrOTOF-Q instrument. Sonication was performed in aSY5200DH-T ultrasound cleaner with a frequency of 25 and40 kHz through manual adjustment and an output power of250 W. The reaction flask was located at the maximum energy area

in the cleaner, and the surface of the reactants was placed slightlylower than the level of the water. The addition or removal of watercontrolled the temperature of the water bath. The temperature ofthe water bath was controlled at 25–30 �C.

4.2. General procedure under conventional conditions (method A)

A stirred mixture of isatin 1 (0.5 mmol), thiazolidine-4-carbox-ylic acid 2 (0.5 mmol) and 5-benzylidene-2-thioxothiazolidin-4-one 3a (0.5 mmol) in solvent (10 ml) was heated under reflux con-dition for the specified period of time (see Table 1). After comple-tion of the reaction as indicated by TLC, the solvent was evaporatedunder reduced pressure and the residue was purified by columnchromatography using petroleum ether–ethyl acetate (3:1) as elu-ent. The corresponding products 4a were obtained.

4.3. General procedure under sonochemical conditions (method B)

A dry 50 ml flask was charged with isatins 1 (0.5 mmol), thia-zolidine-4-carboxylic acid 2 (0.5 mmol), (Z)-5-benzylidene-2-thi-oxothiazolidin-4-one or (Z)-5-benzylidenethiazolidine-2,4-dione3 (0.5 mmol) and ethanol (10 ml). The mixture was sonicated inthe water bath of an ultrasonic cleaner under air condition at25 �C for 5 h (monitored by TLC). After completion of the reaction,the solvent was removed under vacuum. The resulting crude prod-ucts were purified by column chromatography using petroleumether–ethyl acetate (3:1) as eluent. The corresponding products 4were obtained.

268 Y. Hu et al. / Ultrasonics Sonochemistry 19 (2012) 264–269

4.3.1. Compound 4aIR (KBr, m, cm�1): 3157, 3089, 2847, 1718, 1617, 1466, 1291,

1209, 1073, 1001, 759; 1H NMR (400 MHz, DMSO-d6) d: 2.75 (t,J = 8.4 Hz, 1H, CH–H), 2.96–2.99 (m, 1H, CH–H), 3.47 (d,J = 6.0 Hz, 1H, CH), 3.86 (d, J = 6.0 Hz, 1H, CH), 4.13 (d, J = 9.6 Hz,1H, CH–H), 4.83–4.89 (m, 1H, CH–H), 6.90 (d, J = 7.6 Hz, 1H, ArH),7.06 (t, J = 7.6 Hz, 1H, ArH), 7.33–7.40 (m, 7H, ArH), 11.02 (s, 1H,NH), 13.30 (s, 1H, NH); HRMS(m/z) calculated for C21H18N3O2S3

[M+H]: 440.0556, found: 440.0541.

4.3.2. Compound 4bIR (KBr, m, cm�1): 3191, 3084, 2927, 2863, 1706, 1618, 1513,

1459, 1289, 1204, 1067, 838, 753; 1H NMR (300 MHz, DMSO-d6)d: 2.71–2.77 (m, 1H, CH–H), 2.94–2.99 (m, 1H, CH–H), 3.44 (d,J = 6.0 Hz, 1H, CH), 3.83 (d, J = 6.3 Hz, 1H, CH), 4.13 (d, J = 9.3 Hz,1H, CH–H), 4.74–4.81 (m, 1H, CH–H), 6.88 (d, J = 7.8 Hz, 1H, ArH),7.04 (t, J = 7.2 Hz, 1H, ArH), 7.22 (t, J = 9.0 Hz, 2H, ArH), 7.33 (t,J = 7.5 Hz, 2H, ArH), 7.41–7.46 (m, 2H, ArH), 11.00 (s, 1H, NH),13.28 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) d: 32.40, 47.38,56.70, 70.87, 76.09, 80.71, 111.24, 116.25, 116.52, 122.98, 123.17,127.75, 131.75, 132.35, 132.45, 143.92, 176.48, 179.04, 200.50;HRMS(m/z) calculated for C21H17FN3O2S3 [M+H]: 458.0461, found:458.0484.

4.3.3. Compound 4cIR (KBr, m, cm�1): 3331, 3250, 2926, 2851, 1719, 1619, 1469,

1292, 1207, 1075, 1013, 754; 1H NMR (400 MHz, DMSO-d6) d:2.75 (t, J = 8.4 Hz, 1H, CH–H), 2.96–2.99 (m, 1H, CH–H), 3.45 (d,J = 6.0 Hz, 1H, CH), 3.85 (d, J = 6.0 Hz, 1H, CH), 4.13 (d, J = 8.0 Hz,1H, CH–H), 4.76–4.81 (m, 1H, CH–H), 6.93 (d, J = 8.0 Hz, 1H, ArH),7.05 (t, J = 8.0 Hz, 1H, ArH), 7.34 (t, J = 6.8 Hz, 3H, ArH), 7.42 (t,J = 8.4 Hz, 1H, ArH), 7.47 (d, J = 7.2 Hz, 1H, ArH), 7.60 (d,J = 8.0 Hz, 1H, ArH), 11.21 (s, 1H, NH), 13.37 (s, 1H, NH); 13CNMR (75 MHz, DMSO-d6) d: 32.33, 47.35, 56.75, 70.73, 76.04,80.53, 111.32, 122.92, 123.14, 127.70, 129.53, 131.74, 132.26,132.45, 132.59, 133.50, 136.01, 136.41, 144.02, 176.37, 179.15,200.51; HRMS(m/z) calculated for C21H17

79BrN3O2S3 [M+H]:517.9661, found: 517.9666.

4.3.4. Compound 4dIR (KBr, m, cm�1): 3365, 2927, 2853, 1720, 1617, 1520, 1468,

1346, 1206, 1074, 1016, 948, 855, 755; 1H NMR (400 MHz,DMSO-d6) d: 2.79 (t, J = 8.0 Hz, 1H, CH–H), 2.99 (t, J = 7.6 Hz, 1H,CH–H), 3.46 (d, J = 6.0 Hz, 1H, CH), 3.87 (d, J = 5.2 Hz, 1H, CH),4.31 (d, J = 9.2 Hz, 1H, CH–H), 4.83–4.89 (m, 1H, CH–H), 6.92 (d,J = 7.6 Hz, 1H, ArH), 7.08 (t, J = 7.6 Hz, 1H, ArH), 7.35 (t, J = 7.2 Hz,2H, ArH), 7.72 (t, J = 7.6 Hz, 2H, ArH), 8.27 (d, J = 7.2 Hz, 2H, ArH),11.15 (s, 1H, NH), 13.41 (s, 1H, NH); HRMS(m/z) calculated forC21H17N4O4S3 [M+H]: 485.0406, found: 485.0402.

4.3.5. Compound 4eIR (KBr, m, cm�1): 3246, 3025, 2920, 2855, 1722, 1618, 1595,

1515, 1471, 1414, 1327, 1286, 1203, 1073, 1020, 946, 754; 1HNMR (400 MHz, DMSO-d6) d: 2.29 (s, 3H, CH3), 2.71 (t, J = 8.4 Hz,1H, CH–H), 2.93–2.97 (m, 1H, CH–H), 3.46 (s, 1H, CH), 3.85 (d,J = 6.0 Hz, 1H, CH), 4.07 (d, J = 9.6 Hz, 1H, CH–H), 4.79–4.84 (m,1H, CH–H), 6.92 (d, J = 7.6 Hz, 1H, ArH), 7.05 (t, J = 7.6 Hz, 1H,ArH), 7.19 (t, J = 8.0 Hz, 2H, ArH), 7.25 (t, J = 8.0 Hz, 2H, ArH),7.34 (d, J = 8.0 Hz, 2H, ArH), 11.15 (s, 1H, NH), 13.31 (s, 1H, NH);HRMS(m/z) calculated for [M+Na] C22H19N3O2S3Na 476.0532,found: 476.0554.

4.3.6. Compound 4fIR (KBr, m, cm�1): 3235, 3024, 2928, 1700, 1619, 1468, 1385,

1320, 1162, 974, 765, 617; 1H NMR (400 MHz, DMSO-d6) d: 2.73(t, J = 8.4 Hz, 1H, CH–H), 2.95–2.98 (m, 1H, CH–H), 3.44 (t,

J = 5.6 Hz, 1H, CH), 3.83 (d, J = 5.6 Hz, 1H, CH), 4.15 (d, J = 7.2 Hz,1H, CH–H), 4.84–4.89 (m, 1H, CH–H), 6.90 (d, J = 8.0 Hz, 1H, ArH),7.04 (t, J = 7.6 Hz, 1H, ArH), 7.35 (t, J = 4.0 Hz, 3H, ArH), 7.39 (d,J = 5.6 Hz, 4H, ArH), 10.98 (s, 1H, NH), 12.21 (s, 1H, NH);HRMS(m/z) calculated for C21H18N3O3S2 [M+H]: 424.0784, found:424.0781.

4.3.7. Compound 4gIR (KBr, m, cm�1): 3437, 3253, 3068, 2925, 1702, 1617, 1512,

1470, 1320, 1224, 1017, 755; 1H NMR (400 MHz, DMSO-d6) d:2.74 (t, J = 8.4 Hz, 1H, CH–H), 2.95–2.99 (m, 1H, CH–H), 3.43 (d,J = 5.2 Hz, 1H, CH), 3.82 (d, J = 5.2 Hz, 1H, CH), 4.17 (d, J = 9.6 Hz,1H, CH–H), 4.77–4.82 (m, 1H, CH–H), 6.90 (d, J = 7.6 Hz, 1H, ArH),7.05 (t, J = 7.6 Hz, 1H, ArH), 7.24 (t, J = 7.6 Hz, 2H, ArH), 7.35 (t,J = 8.0 Hz, 2H, ArH), 7.45 (d, J = 5.6 Hz, 2H, ArH), 10.99 (s, 1H,NH), 12.24 (s, 1H, NH); HRMS(m/z) calculated for C21H17FN3O3S2

[M+H]: 442.0690, found: 442.0696.

4.3.8. Compound 4hIR (KBr, m, cm�1): 3413, 3233, 3003, 2931, 1702, 1618, 1486,

1339, 1321, 1207, 1015, 948, 754; 1H NMR (400 MHz, DMSO-d6)d: 2.73 (t, J = 8.4 Hz, 1H, CH–H), 2.94–2.98 (m, 1H, CH–H), 3.43 (s,1H, CH), 3.81 (d, J = 6.4 Hz, 1H, CH), 4.15 (d, J = 7.2 Hz, 1H, CH–H), 4.76–4.82 (m, 1H, CH–H), 6.92 (d, J = 7.6 Hz, 1H, ArH), 7.04 (t,J = 7.6 Hz, 1H, ArH), 7.31–7.36 (m, 2H, ArH), 7.41 (d, J = 8.4 Hz,2H, ArH), 7.46 (d, J = 7.6 Hz, 2H, ArH), 11.14 (s, 1H, NH), 12.33 (s,1H, NH); 13C NMR (75 MHz, DMSO-d6) d: 31.07, 45.88, 54.52,69.44, 74.88, 77.14, 109.93, 121.80, 121.85, 126.28, 128.21,130.44, 131.10, 132.17, 135.16, 142.78, 168.67, 175.29, 175.74;HRMS(m/z) calculated for C21H17

35ClN3O3S2 [M+H]: 458.0394,found: 458.0396.

4.3.9. Compound 4iIR (KBr, m, cm�1): 3415, 2927, 1701, 1620, 1472, 1387, 1322,

1205, 1011, 829, 753; 1H NMR (400 MHz, DMSO-d6) d: 2.73 (t,J = 8.8 Hz, 1H, CH–H), 2.94–2.98 (m, 1H, CH–H), 3.43 (s, 1H, CH),3.82 (d, J = 5.6 Hz, 1H, CH), 4.13 (d, J = 9.2 Hz, 1H, CH–H), 4.76–4.82 (m, 1H, CH–H), 6.93 (d, J = 7.6 Hz, 1H, ArH), 7.03 (t,J = 8.0 Hz, 1H, ArH), 7.34 (t, J = 8.4 Hz, 4H, ArH), 7.59 (d,J = 8.0 Hz, 1H, ArH), 11.13 (s, 1H, NH), 12.33 (s, 1H, NH); 13CNMR (75 MHz, DMSO-d6) d: 31.09, 45.89, 54.60, 69.39, 74.90,77.07, 109.94, 120.83, 121.80, 121.85, 126.30, 130.43, 131.14,131.43, 135.57, 142.79, 168.67, 175.29, 175.75; HRMS(m/z) calcu-lated for C21H17

79BrN3O3S2 [M+H]: 501.9889, found: 501.9890.

4.3.10. Compound 4jIR (KBr, m, cm�1): 3233, 3030, 2954, 1717, 1619, 1515, 1471,

1385, 1323, 1206, 1159, 1117, 1021, 943, 814, 787, 755; 1HNMR(400 MHz, DMSO-d6) d: 2.30 (t, 3H, CH3), 2.71 (t, J = 8.4 Hz,1H, CH–H), 2.93–2.97 (m, 1H, CH–H), 3.44 (d, J = 5.6 Hz, 1H, CH),3.82 (d, J = 6.0 Hz, 1H, CH), 4.10 (d, J = 9.6 Hz, 1H, CH–H), 4.80–4.86 (m, 1H, CH–H), 6.89 (d, J = 7.6 Hz, 1H, ArH), 7.02–7.06 (m,1H, ArH), 7.20 (t, J = 8.0 Hz, 2H, ArH), 7.25 (t, J = 8.0 Hz, 2H, ArH),7.34 (d, J = 8.0 Hz, 2H, ArH), 10.96 (s, 1H, NH), 12.18 (s, 1H, NH);HRMS(m/z) calculated for C22H19N3O3S2Na [M+Na]: 460.0760,found: 460.0778.

Acknowledgements

We acknowledge the financial support from the Foundation ofthe Natural Science Foundation of China (No. 21072144), the MajorBasic Research Project of the Natural Science Foundation of theJiangsu Higher Education Institutions (No. 10KJA150049), A projectFunded by the Priority Academic Project Development of JiangsuHigher Education Institutions and Key Laboratory of Organic Syn-thesis of Jiangsu Province (No. KJS0812). We are grateful to the

Y. Hu et al. / Ultrasonics Sonochemistry 19 (2012) 264–269 269

Analytical and Testing Center of Soochow University for supportsin IR, 1H NMR, 13C NMR and single crystal X-ray analyses, and weare also grateful to the Modern Analytical and Testing Center ofXuzhou Normal University for supports in HRMS analyses.

References

[1] (a) A. Padwa (Ed.), 1,3-Dipolar Cycloaddition Chemistry, vol. vols. 1-2, Wiley,New York, NY, 1984;(b) O. Tsuge, S. Kanemasa, Adv. Heterocycl. Chem., in: A.R. Katritzky (Ed.),Academic, San Diego, CA, 1989, p. 231;(c) R. Grigg, V. Sridharan, D.P. Curran (Eds.), Advance in Cycloaddition, JaiPress, London, 1993, p. 161.

[2] L. Coldham, R. Hufton, Chem. Rev. 105 (2005) 2765.[3] (a) L. Novák, G. Hornyánszky, J. Rohály, P. Kolonits, C. Szántay, Pestic. Sci. 49

(1997) 85;(b) P. Vicini, A. Geronikaki, M. Incerti, F. Zani, J. Deardenc, M. Hewittc, Bioorg.Med. Chem. 16 (2008) 3714;(c) D.K. Kim, J.H. Choi, Y.J. An, H.S. Lee, Bioorg. Med. Chem. Lett. 18 (2008)2122;(d) M.Q. Zheng, D.Z. Yin, J.P. Qiao, L. Zhang, Y.X. Wang, J. Fluorine Chem. 129(2008) 210.

[4] (a) T. Moulard, J.F. Lagorce, J.C. Thomes, C. Raby, J. Pharm. Pharmacol. 45(1993) 731;(b) I.F. Faermark, G. Shvarts, S.I. Grizik, V.G. Gravik, Khim. Farm. Zh. 24 (1990)35.

[5] (a) D. Basavaiah, R.K. Reddy, Org. Lett. 9 (2007) 57;(b) R.R. Kumar, S. Perumal, P. Senthilkumar, P. Yogeeswari, D. Sriram, Eur. J.Med. Chem. 44 (2009) 3821.

[6] S.T. Hilton, T.C.T. Ho, G. Pljevaljcic, K. Jones, Org. Lett. 2 (2000) 2639.[7] L. Wang, Y. Zhang, H.Y. Hu, H.K. Fun, J.H. Xu, J. Org. Chem. 70 (2005) 3850.[8] (a) G. Cravotto, P.J. Cintas, Chem. Soc. Rev. 35 (2006) 180;

(b) T.J. Mason, Chem. Soc. Rev. 26 (1997) 443;(c) E.A. Muravyova, S.M. Desenko, V.I. Musatov, I.V. Knyazeva, S.V. Shishkina,O.V. Shishkin, V.A. Chebanov, J. Comb. Chem. 9 (2007) 797;

(d) J.T. Li, S.X. Wang, G.F. Chen, T.S. Li, Curr. Org. Synth. 2 (2005) 415;(e) J.T. Li, Y. Yin, L. Li, M.X. Sun, Ultrason. Sonochem. 17 (2010) 11.

[9] R. Cella, H.A. Stefani, Tetrahedron 65 (2009) 2619.[10] S.Q. Ge, Y.Y. Hua, M. Xia, Ultrason. Sonochem. 16 (2009) 232.[11] (a) H. Liu, G.L. Dou, D.Q. Shi, J. Comb. Chem. 12 (2010) 292;

(b) H. Liu, G.L. Dou, D.Q. Shi, J. Comb. Chem. 12 (2010) 633.[12] Y. Zou, H. Wu, Y. Hu, H. Liu, X. Zhao, H.L. Ji, D.Q. Shi, Ultrason. Sonochem. 18

(2011) 708.[13] (a) M.W. Irvine, G.L. Patrick, J. Kewney, S.F. Hastings, S.J. MacKenzie, Bioorg.

Med. Chem. Lett. 18 (2008) 2032;(b) G. Bruno, L. Costantino, C. Curinga, R. Maccari, F. Monforte, F. Nicolò, R.Ottanà, M.G. Vigorita, Bioorg. Med. Chem. 10 (2002) 1077.

[14] (a) S. Koda, T. Kimurab, T. Kondoc, H. Mitomed, Ultrason. Sonochem. 13 (2003)149;(b) S. Koda, A. Suzuki, H. Nomura, Polym. J. 27 (1995) 1144;(c) G. Cravotto, P. Cintas, Chem. Soc. Rev. 35 (2006) 180;(d) T.S. Li, Q.G. Yin, Chaosheng Huaxue, Science Press, Beijing, 1995;(e) J.L. labored, C. Bouyer, J.P. Caltagirone, A. Gerard, Ultrasonics 36 (1998)589.

[15] (a) Y.Q. Jiang, X.L. Chen, L.B. Qu, J.L. Wang, J.W. Yuan, S.S. Chen, Ultrason.Sonochem. 18 (2011) 530;(b) E.B. Flint, K.S. Suslick, Science 253 (1991) 1397;(c) T.G. Leighton, The Acoustic Bubble, Academic Press, London, 1994;(d) K.S. Suslick, S.J. Doktycz, Adv. Sonochem. 1 (1990) 19.

[16] (a) K.N. Houk, J. Gonzalez, Acc. Chem. Res. 28 (1995) 81;(b) R. Huisgen, K.N. Houk, K. Yamaguchi, in: A. Padwa (Ed.), 1,3-DipolarCycloaddition Chemistry, Wiley Interscience, New York, 1984;(c) R. Huisgen, J. Org. Chem. 41 (1976) 1976;(d) R.A. Fireston, Tetrahedron 33 (1977) 3009;(e) K. Jadidi, R. Gharemanzadeh, M. Mehrdad, H.R. Darabi, H.R. Khavasi, D.Asgari, Ultrason. Sonochem. 15 (2008) 124;(f) S.J.T. Rezaei, M.R. Nabid, A. Yari, S.W. Ng, Ultrason. Sonochem. 18 (2011) 49.

[17] (a) J. Lindler, T.J. Mason, Chem. Soc. Rev. 16 (1987) 275;(b) J.P. Lorimer, T.J. Mason, Chem. Soc. Rev. 16 (1987) 275–311;(c) J.L. Luche, Synthetic Organic Sonochemistry, Plenum Press, New York,1998;(d) C. Einhorn, J.L. Einhorn, Synthesis 11 (1989) 787.