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This article was downloaded by: [Lulea University of Technology]On: 05 August 2013, At: 05:04Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registeredoffice: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: AnInternational Journal for RapidCommunication of Synthetic OrganicChemistryPublication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/lsyc20
NaCl as a Novel and Green Catalystfor the Synthesis of Biodynamic SpiroHeterocycles in Water Under SonicationAnshu Dandia a , Anuj Kumar Jain a & Dharmendra Singh Bhati aa Department of Chemistry, University of Rajasthan, Jaipur, IndiaPublished online: 29 Jun 2011.
To cite this article: Anshu Dandia , Anuj Kumar Jain & Dharmendra Singh Bhati (2011) NaCl as a Noveland Green Catalyst for the Synthesis of Biodynamic Spiro Heterocycles in Water Under Sonication,Synthetic Communications: An International Journal for Rapid Communication of Synthetic OrganicChemistry, 41:19, 2905-2919, DOI: 10.1080/00397911.2010.515365
To link to this article: http://dx.doi.org/10.1080/00397911.2010.515365
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NaCl AS A NOVEL AND GREEN CATALYST FOR THESYNTHESIS OF BIODYNAMIC SPIRO HETEROCYCLESIN WATER UNDER SONICATION
Anshu Dandia, Anuj Kumar Jain, and Dharmendra Singh BhatiDepartment of Chemistry, University of Rajasthan, Jaipur, India
GRAPHICAL ABSTRACT
Abstract An efficient and novel green catalytic protocol for the synthesis of biologically
important spirooxindole derivatives is developed in a one-pot, three-component approach
involving substituted isatin, activated methylene reagent, and 3-methyl-1-phenyl-
2-pyrazolin-5-one in water under sonication. This report describes the use of sodium chlor-
ide as a nonacidic and green catalyst for a variety of substrates. The advantageous features
of this methodology are the environmentally benign character, operational simplicity, high
yield processing, easy handling, and the fact that the products do not need to be purified.
Keywords Green chemistry; multicomponent reaction; ring-closing metathesis; sodium
chloride; sonication
INTRODUCTION
Within the past few years, green chemistry has become a major interest of thechemistry community.[1–3] The investigations and applications of green chemistryprinciples have led to the development of cleaner and more benign chemicalprocesses, with many new technologies being developed each year.
In most chemical processes, major adverse effects on the environment aremainly a result of the consumption of energy for heating. To overcome this problem,it is highly desirable to develop efficient methods that use alternative energy sources,such as ultrasonic irradiation, to facilitate chemical reactions.[4,5] At the same time,water can undoubtedly be considered as the cleanest solvent available for chemists.[6]
The spirooxindole unit is a privileged heterocyclic motif that forms the core ofa large family of alkaloid and natural products with strong bioactivity profiles and
Received May 26, 2010.
Address correspondence to Anshu Dandia, Department of Chemistry, University of Rajasthan,
Jaipur 302004, India. E-mail: [email protected]
Synthetic Communications1, 41: 2905–2919, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515365
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interesting structural properties.[7–9] Significant recent advances in the synthesis ofthis fused heterocyclic system have led to an intense interest in the development ofrelated compounds as potential medicinal agents or biological probes. For example,Alstonisine, a natural alkaloid, was first isolated from Alstonia muelleriana[10] andhas been identified for its biomimetic transformations.[11] Further, Strychnofolinehas been found to inhibit mitosis in a number of cell lines including mouse mela-noma B16, Ehrlich, and Hepatom HW165.[12] Chitosenine is another structurallyinteresting natural product that exhibits short-lived inhibitory activity of ganglionictransmission ‘‘in vivo’’ in rats and rabbits.[13] The unique structural array and thehighly pronounced pharmacological activities displayed by the class of spirooxindolecompounds have made them attractive synthetic targets.
On the basis of biological studies that show the existence of two or more dif-ferent heterocyclic moieties in a single molecule often remarkably enhances the bio-cidal profile we intended the synthesis of a series of spirooxindoles with fusedpyrano[2,3-c]pyrazoles through a three-component reaction of isatin, active methyl-ene reagent, and 3-methyl-1-phenyl-2-pyrazolin-5-one in the presence of green cata-lyst sodium chloride in water under sonication. Fused pyrano[2,3-c]pyrazoles havealso received considerable attention because of their wide range of useful biologicalproperties, which include molluscicidal,[14] antimicrobial,[15] analgesic, andanti-inflammatory[16] activities.
Development of novel synthetic methodologies to facilitate the preparation ofcompound libraries based on privileged structures is an intense area of research. Oneapproach to address this challenge involves the development of multicomponentreactions (MCRs), in which three or more reactants are combined together in a sin-gle reaction flask to generate a product incorporating most of the atoms contained inthe starting materials. In addition to the intrinsic atom economy and selectivityunderlying such reactions, simpler procedures, equipment, time, and energy savings,as well as environmental friendliness have all led to a sizable effort to design andimplement MCRs in both academia and industry.[17,18]
In the context of this program, we have previously reported the synthesis of spir-ooxindole derivatives by a multistep process catalyzed by Et3N in ethanol underreflux.[19–21] Recently, two articles,[22,23] describing three-component syntheses ofpyran 5 in aqueous medium with surfactants or solvent free reaction catalyzed byInCl3 with microwave assistance, appeared in the literature. These methods displayimportant disadvantages in generating of mixtures of pyrans and unsaturated nitriles.Microwave assistance is not necessary in pyran synthesis because the reactions areslightly exothermic. Moreover, this method requires relatively expensive InCl3 in com-parison with more convenient and cheap sodium chloride and a complicated workup,requiring large amounts of organic solvents (chromatographic column). Pyrans werealso prepared by electrochemical methods that suffer from technical intricacy.[24,25]
Thus, we tried to utilize a more appropriate and more accessible green catalyst,sodium chloride, and water for these transformations. This method is very expedientand would be useful for the syntheses of different types of spirooxindoles.
In continuation of our aim to develop new and ecofriendly synthetic method-ologies,[26,27] herein, we report a novel, green, nonacidic, and effective sodiumchloride–catalyzed one-pot method for the synthesis of spirooxindole derivativesin water under sonication.
2906 A. DANDIA, A. K. JAIN, AND D. S. BHATI
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To the best of our knowledge, there is no report available in the literaturedescribing the use of sodium chloride as nonacidic catalyst in aqueous media forthe synthesis of spiro-indoline derivatives.
In our method, 24 compounds were obtained in excellent yield (purity not less95%) without using complex catalysis and organic solvents and without additionalpurification.
RESULTS AND DISCUSSION
In this article, we describe a versatile synthetic approach based on a three-component sodium chloride–catalyzed reaction under sonication, as the most simpleand convenient methodology, which would be applicable to the syntheses of differenttypes of spirooxindole derivatives.
Initially, evaluation of various catalysts was carried out for the synthesis ofspirooxindole derivatives in water under ultrasonic irradiation in the absence andpresence of various catalysts. After some preliminary experiments, we found thata mixture of isatin, ethylcynoacetate, and 3-methyl-1-phenyl-2-pyrazolin-5-one inthe presence of catalytic sodium chloride affored ethyl 60-amino-30-methyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carboxylate (5a) in excellentyield (94%). With other catalysts, the product formed with yields ranging between 54and 76%. In the absence of catalyst, the yield of the product was found to be verypoor (Table 1).
To find an effective catalyst for the synthesis of spirooxindole derivatives undersonication, we emphasized the amount of catalyst to be used in this condensationreaction in the presence of several type of catalysts. While using the catalyst sodiumchloride, the results seemed to be better. Adding 2.5mol% of sodium chloride to thesystem under similar reaction conditions resulted in obvious acceleration, but theyield was not improved. While increasing the amount of sodium chloride from2.5mol% to 5 or 10mol% the reaction resulted in the formation of 5a in 80–86%and 94% respectively. Thus, the best results were obtained when 10mol% of sodiumchloride was used.
Table 1. Optimization of reaction conditiona
Entry Catalystb Time (min) Yieldc (%)
1 — 84 18
2 K2 CO3 55 58
3 NaHCO3 52 61
4 TBAB 60 63
5 CTAC 68 54
6 PTSA 50 68
7 L-proline 42 76
8 NaCl 20 94
aThe reaction was carried out with isatin, ethylcynoacetate, and 3-methyl-1-
phenyl-2-pyrazolin-5-one under sonication.bThe amount of each additive was 10mol%.cIsolated yield.
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To verify the specific effect of ultrasound irradiation, we also performed theexperiments under silent conditions. The syntheses of 5a and 5b were carried outby stirring for 1.5 and 2 h at 80 �C, resulting in 68% and 66% yields, respectively.While under ultrasound irradiation for 20min, 5a and 5b were obtained in 94%and 92% yields (Table 2). It showed that ultrasound irradiation was found to havea beneficial effect on the synthesis of spiro[indoline-3,40-pyrano[2,3-c]pyrazolederivatives.
Encouraged by these results, we have extended this reaction to various substi-tuted isatins under similar conditions to furnish the respective spirooxindole deriva-tives in excellent yields (Scheme 1, Table 2) without the formation of any sideproducts.
The plausible mechanism for the formation of spiro derivatives 5 is described inScheme 2. The process represents a typical cascade reaction in which the isatin 1 firstcondenses with malononotrile 2 to afford isatylidene malononitrile derivative 4. Thisstep is regarded as fast Knoevenagel condensation. The second step involves the 4C-alkylation of 3-methyl-1-phenyl-2-pyrazoline-5-one by the reaction withelectrophilic C=C double bond of 4 and the nucleophilic addition of the -OH groupon the cyano moiety to form the desired product 5.
Table 2. Synthesis of spiro[indoline-3,40-pyrano[2,3-c]pyrazole]derivatives
Mp (�C)
Entry R X Time (min) Yielda (%) Found Reported[Ref.]
5a H COOEt 20 94 238–240
5b 5-CH3 COOEt 20 92 230–232
5c 5-Cl COOEt 18 92 246–248
5d 5-Br COOEt 20 91 252–254
5e 5-NO2 COOEt 20 92 268–270
5f 5,7-diCH3 COOEt 18 91 260–262
5g H CN 10 95 237–238 236–23724
5h 5-CH3 CN 10 98 288–290 288–28924
5i 5-Cl CN 10 92 232–234 230–23219
5j 5-Br CN 12 92 242–244
5k 5-NO2 CN 14 91 226–228 226–22819
5l 5,7-diCH3 CN 12 94 218–220 218–22119
aIsolated yield.
Scheme 1. Preparation of spirooxindoles from 3-methyl-1-phenyl-2-pyrazolin-5-one.
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To further explore the potential of this protocol for heterocyclic synthesis, weinvestigated one-pot reactions involving 5,5-dimethylcyclohexane-1,3-dione 6
instead of 3-methyl-1-phenyl-2-pyrazoline-5-one (Scheme 3). To our delight, under
Scheme 2. Plausible mechanism for the reaction of isatin and malononitrile with 3-methyl-1-phenyl-
2-pyrazolin-5-one.
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these optimized conditions, the reactions proceeded smoothly, and a variety of thedesired spirooxindole derivatives 7 were obtained in excellent yields (Table 3).
EXPERIMENTAL
The melting points of all compounds were determined on a Toshniwal appar-atus. The purity of compounds was checked on thin layers of silica gelG–coated glassplates with n-hexane ethyl acetate (7:3) as eluent. Infrared (IR) spectra were recordedon a Shimadzu Fourier transform (FT)–IR 8400S spectrophotometer using KBr pel-lets. 1H and 13C NMR spectra were recorded in dimethylsulfoxide (DMSO)-d6 usingtetramethylsilane (TMS) as an internal standard on a Bruker spectrophotometer at300 and 75MHz respectively. Mass spectrum of representative compound wasrecorded on a Jeol SX-102 spectrometer at 70 eV. Elemental microanalyses werecarried out on a Carlo-Erba 1108 CHN analyzer.
Sonication was carried out with the help of a standard ultrasonic irradiationinstrument Sonapros PR-1000MP (Oscar Ultrasonics Pvt. Ltd.) oprating at 750Wand a generating 23- KHz output frequency. It has the following characteristics:standard titanium horn with a diameter of 6mmn12mm, adjustable power out,replaceable flat stainless steel tip, and digital thermometer to determine temperature.The glass reactor was designed and made from borosil glass.
Table 3. Synthesis of spiro[chromene-4-30 indoline] derivatives
Mp (�C)
Entry R X Time (min) Yielda (%) Found Reported[Ref]
7a H COOEt 18 95 278–280
7b 5-CH3 COOEt 16 95 282–284
7c 5-Cl COOEt 16 96 292–294
7d 5-Br COOEt 18 92 296–298
7e 5-NO2 COOEt 20 92 276–278
7f 5,7-diCH3 COOEt 18 95 280–282
7g H CN 10 98 290–292 289–290[22]
7h 5-CH3 CN 10 97 278–280 279–280[22]
7i 5-Cl CN 11 98 294–296
7j 5-Br CN 11 93 306–308 305–307[25]
7k 5-NO2 CN 12 92 302–304
7l 5,7-diCH3 CN 10 96 >360
aIsolated yield.
Scheme 3. Preparation of spirooxindoles from 5,5-dimethylcyclohexane-1,3-dione.
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General Procedure
An equimolar mixture of isatin (1mmol, 0.147 g), ethyl cycnoacetate (1mmol,0.113 g), 3-methyl-1-phenyl-2-pyrazolin-5-one (1mmol, 0.174 g) and 10mol%sodium chloride in 5ml water was introduced in a 20-mL, heavy-walled,pear-shaped, two-necked flask with nonstandard taper outer joint. The flask wasattached to a 12-mm-tip-diameter probe, and the reaction mixture was sonicatedat ambient temperature for the specified period at 50% power of the processorand 230W output in a 4-s pulse mode. At the end of the reaction period, thin-layerchromatography (TLC) was checked, and the flask was detached from the probe.The contents were transferred to a beaker. The formed solid was filtered off, washedthoroughly with warm water (2� 20ml), and then dried to obtain pure products 5(TLC), giving satisfactory spectral and elemental analysis.
Selected Data
Compound 5a. Ethyl 60-amino-30-methyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano [2,3-c]pyrazole]-50-carboxylate. White crystalline solid (yield: 94%); mp:238–240 �C.
nmax (KBr): 3392, 3230, 3172, 1716, 1652, 1600, 1554, 1160 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.71 (t, 3H, CH3), 1.55 (s, 3H, CH3), 3.72 (q, J¼ 6.80Hz,2H, CH2), 6.84–6.93 (m, 3H), 7.18 (t, J¼ 5.40Hz, 1H), 7.32 (t, J¼ 07.5Hz, 1H), 7.49(t, J¼ 8.4Hz, 2H), 7.75 (d, J¼ 7.5Hz, 2H), 8.14 (br s, 2H, NH2, D2O exchangeable),10.53 (s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-d6, 75MHz): d 12.0, 13.4,48.0, 59.6, 75.1, 98.7, 109.4, 120.5, 122.3, 123.5, 126.9, 128.3, 129.9, 136.1, 137.9,142.4, 144.7, 161.7, 168.3, 179.9. MS (m=z): 416 (Mþ). Anal. calcd. forC23H20N4O4: C, 66.34; H, 4.84; N, 13.45. Found: C, 66.30; H, 4.81; N, 13.38.
Compound 5b. Ethyl 60-amino-30,5-dimethyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carboxylate. White crystalline solid (yield:92%); mp: 230–232 �C.
nmax (KBr): 3400, 3236, 3168, 1710, 1652, 1612, 1546, 1158 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.76 (t, 3H, CH3), 1.59 (s, 3H, CH3), 2.16 (s, 3H, CH3),3.74 (q, J¼ 6.90Hz, 2H, CH2), 6.73–6.77 (m, 2H), 6.97 (d, J¼ 7.8Hz, 1H), 7.32(t, J¼ 7.5Hz, 1H), 7.50 (t, J¼ 7.5Hz, 2H), 7.80 (d, J¼ 8.1Hz, 2H), 8.19 (br s,2H, NH2, D2O exchangeable), 10.42 (s, 1H, NH, D2O exchangeable). 13C NMR(DMSO-d6, 75MHz): d 11.8, 13.2, 20.7, 47.6, 59.2, 74.8, 98.4, 108.7, 120.0, 123.8,126.4, 128.1, 129.5, 130.7, 135.9, 137.4, 139.8, 144.0, 144.4, 161.4, 168.0, 179.4.MS (m=z): 430 (Mþ). Anal. calcd. for C24H22N4O4: C, 66.97; H, 5.15; N, 13.02.Found: C, 66.92; H, 5.11; N, 13.05.
Compound 5c. Ethyl 60-amino-5-chloro-30-methyl-2-oxo-10-phenyl-10H-spiro-[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carboxylate. White crystalline solid (yield:92%); mp: 246–248 �C.
nmax (KBr): 3396, 3228, 3172, 1698, 1644, 1608, 1566, 1160 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.77 (t, 3H, CH3), 1.61 (s, 3H, CH3), 3.75 (q, J¼ 6.6Hz,2H, CH2), 6.89 (d, J¼ 8.4Hz, 1H), 7.08 (s, 1H), 7.23 (d, J¼ 8.1Hz, 1H), 7.33 (t,J¼ 7.2Hz, 1H), 7.50 (t, J¼ 7.8Hz, 2H), 7.80 (d, J¼ 8.1Hz, 2H), 8.25 (br s, 2H,
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NH2, D2O exchangeable), 10.68 (s, 1H, NH, D2O exchangeable). 13C NMR(DMSO-d6, 75MHz): d 11.8, 13.2, 47.8 59.2, 74.1, 97.6, 110.4, 120.2, 123.5, 125.9,126.5, 127.7, 129.5, 137.3, 137.9, 141.1, 144.1, 161.5, 167.8, 179.2. MS (m=z): 450(Mþ). Anal. calcd. for C23H19 ClN4O4: C, 61.27; H, 4.25; N, 12.43. Found: C,61.30; H, 4.31; N, 12.42.
Compound 5d. Ethyl 60-amino-5-bromo-30-methyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carboxylate. White crystalline solid(yield: 91%); mp: 252–254 �C.
nmax (KBr): 3408, 3232, 3168, 1702, 1652, 1610, 1546, 1156 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.78 (t, 3H, CH3), 1.62 (s, 3H, CH3), 3.74 (q, J¼ 6.6Hz,2H, CH2), 6.85 (d, J¼ 7.8Hz, 1H), 7.20 (s, 1H), 7.36 (d, J¼ 6.3Hz, 1H), 7.50 (d,J¼ 6.9Hz, 1H), 7.64 (t, J¼ 7.8Hz, 2H), 7.80 (d, J¼ 7.20Hz, 2H), 8.25 (br s, 2H,NH2, D2O exchangeable), 10.69 (s, 1H, NH, D2O exchangeable). 13C NMR(DMSO-d6, 75MHz): d 11.8, 13.2, 47.8, 59.2, 74.2, 97.6, 111.0, 113.6, 120.2, 126.2,126.5, 129.0, 129.5, 130.6, 137.3, 138.3, 141.5, 144.1, 161.5, 167.8, 179.1. MS(m=z): 495 (Mþ). Anal. calcd. for C23H19 BrN4O4: C, 55.77; H, 3.87; N, 11.31.Found: C, 55.71; H, 3.88; N, 11.29.
Compound 5e. Ethyl 60-amino-30-methyl-5-nitro-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carboxylate. White crystalline solid(yield: 92%); mp: 268–270 �C.
nmax (KBr): 3424, 3236, 3173, 1700, 1652, 1608, 1586, 1170 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.76 (t, 3H, CH3), 1.62 (s, 3H, CH3), 3.75 (q, J¼ 6.9Hz,2H, CH2), 7.76–7.84 (m, 3H), 7.86 (t, J¼ 7.8Hz, 1H), 7.94 (t, J¼ 7.6Hz, 2H),8.18 (d, J¼ 7.8Hz, 2H), 8.26 (br s, 2H, NH2, D2O exchangeable), 11.49 (s, 1H,NH, D2O exchangeable). 13C NMR (DMSO-d6, 75MHz): d 12.1, 13.5, 48.9, 60.1,75.9, 98.7, 110.2, 120.5, 122.9, 124.5, 126.9, 129.8, 129.95, 139.5, 144.5, 144.7,144.9, 147.2, 162.8, 169.7, 180.2. MS (m=z): 461 (Mþ). Anal. calcd. forC23H19N5O6: C, 59.87; H, 4.15; N, 15.18. Found: C, 59.78; H, 4.11; N, 15.21.
Compound 5f. Ethyl 60-amino-30,5,7-trimethyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carboxylate. White crystalline solid (yield:91%); mp: 260–262 �C.
kmax (KBr): 3398, 3228, 3170, 1702, 1648, 1611, 1570, 1168 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.75 (t, 3H, CH3), 1.58 (s, 3H, CH3), 2.12 (s, 3H, CH3),2.19 (s, 3H, CH3), 3.73 (q, J¼ 6.90Hz, 2H, CH2), 6.57 (s, 1H), 6.78 (s, 1H), 7.32(t, J¼ 7.2Hz, 1H), 7.50 (t, J¼ 7.8Hz, 2H), 7.80 (d, J¼ 7.8Hz, 2H), 8.17 (br s,2H, NH2, D2O exchangeable), 10.47 (s, 1H, NH, D2O exchangeable). 13C NMR(DMSO-d6, 75MHz): d 11.8, 12.9, 16.3, 18.6, 20.6, 47.8, 56.2, 59.2, 75.0, 98.6,117.9, 120.0, 121.2, 126.4, 129.4, 129.5, 130.6, 135.5, 137.4, 138.3, 144.0, 144.4,161.3, 168.1, 179.9. MS (m=z): 444 (Mþ). Anal. calcd. for C25H24N4O4: C, 67.55;H, 5.44; N, 12.60. Found: C, 67.49; H, 5.39; N, 12.63.
Compound 5g. 60-Amino-30-methyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carbonitrile. White crystalline solid (yield: 95%); mp:237–238 �C.
nmax (KBr): 3412, 3280, 3174, 2200, 1692, 1650, 1526, 1132 cm�1. 1H NMR(DMSO-d6, 300MHz): d 1.55 (s, 3H, CH3), 6.94 (d, J¼ 7.4Hz, 1H), 7.03 (t,
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J¼ 7.6Hz, 1H), 7.18 (d, J¼ 7.2Hz, 1H), 7.28 (t, J¼ 7.5Hz,1H), 7.36 (t, J¼ 7.6Hz,1H), 7.52 (t, J¼ 7.8Hz, 2H), 7.58 (br s, 2H, NH2, D2O exchangeable), 7.79(d, J¼ 7.9Hz, 2H), 10.76 (s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-d6,75MHz): d 12.3, 48.3, 56.6, 96.9, 110.4, 118.6, 120.7, 123.2, 125.4, 127.1, 129.8,130.8, 132.6, 138.2, 142.1, 144.5, 145.5, 162.3, 178.8. MS (m=z): 369 (Mþ). Anal.calcd. for C21H15N5O2: C, 68.28; H, 4.09; N, 18.96. Found: C, 68.26; H, 4.04; N,18.88.
Compound 5h. 60-Amino-30,5-dimethyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c] pyrazole]-50-carbonitrile. White crystalline solid (yield: 98%);mp: 288–290 �C.
nmax (KBr): 3426, 3269, 3178, 2192, 1696, 1650, 1576, 1174 cm�1. 1H NMR(DMSO-d6, 300MHz): d 1.56 (s, 3H, CH3), 2.26 (s, 3H, CH3), 6.84 (d, J¼ 7.8Hz,1H), 7.08 (s, 1H), 7.12 (d, J¼ 7.6Hz, 1H), 7.35 (t, J¼ 8Hz, 1H), 7.52 (t, J¼ 8.4Hz,2H), 7.55 (br s, 2H, NH2, D2O exchangeable), 7.78 (d, J¼ 8.3Hz, 2H), 10.64 (s, 1H,NH, D2O exchangeable). 13C NMR (DMSO-d6, 75MHz): d 11.9, 20.4, 48.2, 56.7,96.6, 110.1, 118.4, 119.9, 125.3, 126.8, 129.9, 130.5, 131.9, 132.6, 137.4, 139.8,144.3, 145.7, 161.2, 177. MS (m=z): 383 (Mþ). Anal. calcd. for C22H17N5O2: C,68.92; H, 4.47; N, 18.27. Found: C, 68.82; H, 4.51; N, 18.11.
Compound 5i. 60-Amino-5-chloro-30-methyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carbonitrile. White crystalline solid (yield:92%); mp: 232–234 �C.
nmax (KBr): 3440, 3264, 3172, 2196, 1698, 1652, 1576, 1174 cm�1. 1H NMR(DMSO-d6, 300MHz): d 1.58 (s, 3H, CH3), 6.96 (d, J¼ 8.4Hz, 1H), 7.34–7.42(3H, m), 7.52 (t, J¼ 8.2Hz, 2H), 7.63 (br s, 2H, NH2, D2O exchangeable), 7.78(d, J¼ 8Hz, 2H), 10.89 (s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-d6,75MHz): d 11.8, 47.9, 56.4, 96.5, 109.6, 118.1, 120.2, 125.4, 126.6, 129.5, 129.6,131.7, 132.3, 137.3, 139.2, 144.1, 145.0, 161.0, 177.5. MS (m=z): 403 (Mþ). Anal.calcd. for C21H14ClN5O2: C, 62.46; H, 3.49; N, 17.34, Found: C, 62.48; H, 3.47;N, 17.35.
Compound 5j. 60-Amino-5-bromo-30-methyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carbonitrile. White crystalline solid (yield:92%); mp: 242–244 �C.
nmax (KBr): 3436, 3269, 3168, 2198, 1706, 1650, 1576, 1168 cm�1. 1H NMR(DMSO-d6, 300MHz): d 1.58 (s, 3H, CH3), 6.91 (d, J¼ 7.6Hz, 1H), 7.42–7.54(4H, m), 7.28 (t, J¼ 7.9Hz, 1H), 7.64 (br s, 2H, NH2, D2O exchangeable), 7.79 (d,J¼ 7.8Hz, 2H), 10.90 (s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-d6,75MHz): d 12.1, 47.9, 56.4, 96.7, 110.6, 118.2, 120.9, 125.8, 126.6, 129.5, 129.6,131.7, 132.3, 137.3, 139.2, 144.1, 145.0, 161.0, 178. MS (m=z): 447 (Mþ). Anal. calcd.for C21H14BrN5O2: C, 56.27; H, 3.15; N, 15.62. Found: C, 56.17; H, 3.21; N, 15.60.
Compound 5k. 60-Amino-30-methyl-5-nitro-2-oxo-10-phenyl-10H-spiro-[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carbonitrile. White crystalline solid (yield:91%); mp: 226–228 �C.
nmax(KBr): 3446, 3269, 3176, 2208, 1710, 1650, 1576, 1178 cm�1. 1H NMR(DMSO-d6, 300MHz): d 1.59 (s, 3H, CH3), 7.12 (d, J¼ 8.4Hz, 1H), 7.38–7.55(m, 3H), 7.68 (br s, 2H, NH2, D2O exchangeable), 7.78 (m, 2H), 7.98 (d, J¼ 6.8Hz,
BIODYNAMIC SPIROHETEROCYCLES 2913
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2H), 11.44 (s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-d6, 75MHz): d 12.3,47.9, 56.4, 96.5, 109.6, 118.1, 120.2, 125.4, 126.6, 132.0, 132.6, 131.7, 134.3, 137.3,139.2, 144.9, 145.0, 161.2, 178.8. MS (m=z): 414 (Mþ). Anal. calcd. forC21H14N6O4: C, 60.87; H, 3.41; N, 20.28. Found: C, 60.76; H, 3.47; N, 20.29.
Compound 5l. 60-Amino-30,5,7-trimethyl-2-oxo-10-phenyl-10H-spiro[indoline-3,40-pyrano[2,3-c]pyrazole]-50-carbonitrile. White crystalline solid (yield 94%);218–220 �C
nmax (KBr): 3428, 3264, 3171, 2198, 1700, 1652, 1564, 1155 cm�1. 1H NMR(DMSO-d6, 300MHz): d 1.57 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.33 (s, 3H, CH3),6.84 (s, 1H), 7.02 (s, 1H), 7.39 (t, J¼ 7.6Hz, 1H), 7.48 (t, J¼ 8.0Hz, 2H), 7.58 (brs, 2H, NH2, D2O exchangeable), 7.64 (d, J¼ 7.6Hz, 2H), 10.68 (s, 1H, NH, D2Oexchangeable). 13C NMR (DMSO-d6, 75MHz): d 11.9, 19.2, 20.6, 47.9, 56.8, 96.3,109.6, 118.4, 120.2, 125.4, 126.6, 129.5, 129.8, 131.6, 132.3, 137.3, 139.7, 143.9,145.0, 161.0, 177. MS (m=z): 397(Mþ). Anal. calcd. for C23H19N5O2: C, 69.51; H,4.82; N, 17.62, Found: C, 69.47; H, 4.80; N, 17.56.
Compound 7a. Ethyl 2-amino-7,7-dimethyl-20,5-dioxo-5,6,7, 8-tetrahydrospiro[chromene-4,30indoline]-3-carboxylate. White crystalline solid (yield: 95%); mp:278–280 �C.
nmax (KBr): 3398, 3276, 3212, 2925, 1698, 1652, 1610, 1221 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.82 (t, J¼ 7.2Hz, 3H, CH3), 0.98 (s, 3H, CH3), 1.01 (s,3H, CH3), 2.04 (d, J¼ 16.2Hz, 1H, CH), 2.18 (d, J¼ 16.2Hz, 1H, CH), 2.55 (d,J¼ 6.2Hz, 2H, CH2), 3.69 (q, J¼ 7.2Hz, 2H, CH2), 6.65 (d, J¼ 7.5Hz, 1H), 6.76(t, J¼ 7.5Hz, 1H), 6.84 (d, J¼ 6.9Hz, 1H), 7.09 (t, J¼ 7.5Hz, 1H), 7.72 (br s,2H, NH2, D2O exchangeable), 10.19 (s, 1H, NH, D2O exchangeable). 13C NMR(DMSO-d6, 75MHz): d 13.5, 27.1, 28.2, 32.3, 47.1, 51.1, 59.3, 76.7, 108.6, 113.5,120.9, 122.6, 127.5, 136.7, 144.3, 159.1, 160.8, 162.8, 168.1, 180.4, 195.3. MS(m=z): 382 (Mþ). Anal. calcd. for C21H22N2O5: C, 65.96; H, 5.80; N, 7.33. Found:C, 65.72; H, 6.01; N, 7.47.
Compound 7b. Ethyl 2-amino-50,7, 7-trimethyl-20,5-dioxo-5,6,7,8-tetra-hydrospiro[chromene-4,30indoline]-3-carboxylate. White crystalline solid (yield:95%); mp: 282–284 �C.
nmax (KBr): 3402, 3280, 3209, 2930, 1696, 1652, 1614, 1220 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.82 (t, J¼ 7.2Hz, 3H, CH3), 0.99 (s, 3H, CH3), 1.02 (s,3H, CH3), 2.04 (d, J¼ 16.2Hz, 1H, CH), 2.19 (d, J¼ 16.2Hz, 1H, CH), 2.2 (s,3H, CH3), 2.56 (d, J¼ 6.2Hz, 2H, CH2), 3.68 (q, J¼ 7.2Hz, 2H, CH2), 6.66 (d,J¼ 7.6Hz, 1H), 6.75 (s, 1H), 6.84 (d, 1H, J¼ 6.9Hz), 7.74 (br s, 2H, NH2, D2Oexchangeable), 10.21 (s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-d6,75MHz): d 13.5, 27.2, 21.1, 28.5, 32.3, 47.2, 51.4, 59.2, 76.8, 108.6, 113.7, 121.1,122.6, 127.5, 136.7, 144.4, 159.2, 160.8, 162.8, 168.8, 180.5, 195.4. MS (m=z): 396(Mþ). Anal. calcd. for C22H24N2O5: C, 66.65; H, 6.10; N, 7.07. Found: C, 66.82;H, 6.01; N, 7.27.
Compound 7c. Ethyl 2-amino-50-chloro-7,7-trimethyl-20,5-dioxo-5,6,7, 8-tetrahydrospiro[chromene-4,30-indoline]-3-carboxylate. White crystalline solid(yield: 96%); mp: 292–294 �C.
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nmax (KBr): 3401, 3284, 3218, 2935, 1698, 1658, 1610, 1226 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.82 (t, J¼ 7.2Hz, 3H, CH3), 0.98 (s, 3H, CH3), 1.01 (s,3H, CH3), 2.07 (d, J¼ 16.4Hz, 1H, CH), 2.2 (d, J¼ 16.4Hz, 1H, CH), 2.56 (d,J¼ 6.2Hz, 2H, CH2), 3.67 (q, J¼ 7.4Hz, 2H, CH2), 6.68 (d, J¼ 7.4Hz, 1H), 6.76(s, 1H), 6.85 (d, J¼ 7.2Hz, 1H), 7.74 (br s, 2H, NH2, D2O exchangeable), 10.19(s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-d6, 75MHz): d 13.6, 27.2,28.5, 32.3, 47.2, 51.4, 59.2, 76.8, 108.6, 113.7, 116.9, 121.9, 128.4, 136.9, 145.8,159.2, 160.4, 162.8, 168.7, 180.6, 195.3. MS (m=z): 416 (Mþ). Anal. calcd. forC21H21Cl N2O5: C, 60.51; H, 5.08; N, 6.72. Found: C, 60.72; H, 5.01; N, 6.55.
Compound 7d. Ethyl 2-amino-50-bromo-7,7-dimethyl-20,5-dioxo-5,6,7,8-tetrahydrospiro [chromene-4,30 indoline]-3-carboxylate. White crystalline solid(yield: 92%); mp: 296–298 �C.
nmax (KBr): 3398, 3282, 3209, 2934, 1700, 1662, 1612, 1223 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.82 (t, J¼ 7.2Hz, 3H, CH3), 0.99 (s, 3H, CH3), 1.01 (s,3H, CH3), 2.06 (d, J¼ 16.4Hz, 1H, CH), 2.2 (d, J¼ 16.4Hz, 1H, CH), 2.54 (d,J¼ 6.2Hz, 2H, CH2), 3.68 (q, J¼ 7.2Hz, 2H, CH2), 6.67 (d, J¼ 7.2Hz, 1H), 6.76(s, 1H), 6.86 (d, J¼ 7.4Hz, 1H), 7.72 (br s, 2H, NH2, D2O exchangeable), 10.20(s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-d6, 75MHz): d 13.3, 27.4,28.5, 32.6, 47.2, 51.5, 59.2, 76.3, 108.6, 111.7, 118.9, 121.9, 128.5, 136.9, 145.8,159.7, 161.4, 161.9, 168.7, 181.1, 195.6. MS (m=z): 461 (Mþ). Anal. calcd. forC21H21Br N2O5: C, 54.68; H, 4.59; N, 6.07. Found: C, 54.85; H, 4.48; N, 5.92.
Compound 7e. Ethyl 2-amino-7,7-dimethyl-50-nitro-20,5-dioxo-5,6,7,8-tetrahydrospiro [chromene-4,30 indoline]-3-carboxylate. White crystalline solid(yield: 92%); mp: 276–278 �C.
nmax (KBr): 3406, 3288, 3212, 2935, 1702, 1662, 1618, 1225 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.83 (t, J¼ 7.4Hz, 3H, CH3), 0.99 (s, 3H, CH3), 1.02 (s,3H, CH3), 2.07 (d, J¼ 16.2Hz, 1H, CH), 2.2 (d, J¼ 16.2Hz, 1H, CH), 2.58 (d,J¼ 6.8Hz, 2H, CH2), 3.71 (q, J¼ 7.6, 2H, CH2), 6.86 (d, J¼ 7.6Hz, 1H), 6.98 (s,1H), 7.27 (d, J¼ 7.6Hz, 1H), 7.78 (br s, 2H, NH2, D2O exchangeable), 11.39 (s,1H, NH, D2O exchangeable). 13C NMR (DMSO-d6, 75MHz): d 13.5, 27.8, 28.6,32.4, 47.6, 51.9, 59.2, 76.3, 108.6, 112.8, 121.9, 123.9, 132.5, 138.9, 148.8, 159.9,163.4, 164.1, 168.7, 181.4, 195.7. MS (m=z): 427 (Mþ). Anal. calcd. for C21H21
N3O7: C, 59.01; H, 4.95; N, 9.83. Found: C, 58.85; H, 4.82; N, 9.92.
Compound 7f. Ethyl 2-amino-50,70,7,7-tetramethyl-20,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,30-indoline]-3-carboxylate. White crystalline solid(yield: 95%); mp: 280–282 �C.
nmax (KBr): 3398, 3282, 3210, 2934, 1698, 1652, 1615, 1223 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.82 (t, J¼ 7.2Hz, 3H, CH3), 0.99 (s, 3H, CH3), 1.02 (s,3H, CH3), 2.03 (d, J¼ 16.2Hz, 1H, CH), 2.18 (d, J¼ 16.2Hz, 1H, CH), 2.24 (s,3H, CH3), 2.32 (s, 3H, CH3), 2.57 (d, J¼ 6.2Hz, 2H, CH2), 3.69 (q, J¼ 7.4Hz,2H, CH2), 6.64 (s, 1H), 6.72 (s, 1H), 7.74 (br s, 2H, NH2, D2O exchangeable),10.20 (s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-d6, 75MHz): d 13.4,21.2, 22.7, 27.2, 28.5, 32.4, 47.5, 51.5, 59.2, 76.6, 108.6, 113.7, 121.4, 122.7, 127.3,136.9, 144.8, 159.7, 160.8, 162.8, 168.6, 180.7, 195.4. MS (m=z): 410 (Mþ). Anal.calcd. for C23H26N2O5: C, 67.30; H, 6.38; N, 6.82. Found: C, 67.52; H, 6.31; N, 7.07.
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Compound 7g. 2-Amino-7,7-dimethyl-20,5-dioxo-5,6,7,8-tetrahydrospiro-[chromene-4,30-indoline]-3-carbonitrile. White crystalline solid (yield: 98%); mp:290–292 �C.
nmax (KBr): 3412, 3280, 3114, 2200, 1692, 1650, 1526, 1132 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.97 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.08 (d, J¼ 16.2Hz,1H, CH) 2.17 (d, J¼ 16.2Hz, 1H, CH) 2.47 (d, J¼ 6.2Hz, 2H, CH2) 6.75 (d,J¼ 7.5Hz, 1H), 6.84 (t, J¼ 7.5Hz, 1H), 6.94 (d, J¼ 6.9Hz, 1H), 7.09 (t, J¼ 7.5Hz,Hz, 1H), 7.22 (br s, 2H, NH2, D2O exchangeable), 10.39 (s, 1H, NH, D2O exchange-able). 13C NMR (DMSO-d6, 75MHz): d 27.3, 27.9, 32.3, 47.1, 50.3, 57.7, 109.6,111.1, 117.7, 122.1, 123.4, 128.5, 134.7, 142.3, 159.1, 164.5, 178.4, 195.3. MS (m=z): 335 (Mþ). Anal. calcd. for C19H17N3O3: C, 68.05; H, 5.11; N, 12.53. Found:C, 68.24; H, 5.21; N, 12.64.
Compound 7h. 2-Amino-50,7,7-trimethyl-20,5-dioxo-5,6,7,8-tetrahydrospiro-[chromene-4,30-indoline]-3-carbonitrile. White crystalline solid (yield: 97%); mp:278–280 �C.
nmax (KBr): 3410, 3286, 3122, 2195, 1692, 1648, 1526, 1128 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.98 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.11 (s, 2H, CH2),2.17 (s, 3H, CH3), 2.48 (d, J¼ 14.70Hz, 2H, CH2) 6.63 (d, J¼ 7.80Hz, 1H), 6.75(s, 1H), 6.90 (d, J¼ 7.80Hz, 1H), 7.21 (br s, 2H, NH2, D2O exchangeable), 10.29(s, 1H, NH, D2O exchangeable). 13C NMR (DMSO-d6, 75MHz): d 21.0, 27.5,27.8, 32.3, 47.3, 50.3, 57.8, 109.3, 111.1, 117.8, 123.9, 128.8, 130.8, 134.8, 139.9,159.0, 164.4, 178.4, 195.3. MS (m=z): 349 (Mþ). Anal. calcd. for C20H19N3O3: C,68.75; H, 5.48; N, 12.03. Found: C, 68.91; H, 5.56; N, 12.10.
Compound 7i. 2-Amino-50-chloro-7,7-dimethyl-20,5-dioxo-5,6,7,8-tetra-hydrospiro[chromene-4,30-indoline]-3-carbonitrile. White crystalline solid (yield:98%); mp: 294–296 �C.
nmax (KBr): 3416, 3268, 3118, 2202, 1692, 1650, 1528, 1132 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.97 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.12–2.18 (m, 2H,CH2) 2.48–2.60 (m, 2H, CH2), 6.80 (d, J¼ 8.40Hz, 1H), 7.10 (s, 1H), 7.18 (d,J¼ 8.40Hz, 1H), 7.30 (br s, 2H, NH2, D2O exchangeable), 10.52 (s, 1H, NH, D2Oexchangeable). 13C NMR (DMSO-d6, 75MHz): d 27.7, 27.9, 32.4, 47.5, 50.4, 57.2,110.3, 111.1, 117.6, 123.7, 126.2, 128.6, 137.1, 141.6, 141.9, 159.3, 165.4, 178.3,195.5. MS (m=z): 369 (Mþ). Anal. calcd. for C19H16ClN3O3: C, 61.71; H, 4.36; N,11.36. Found: C, 61.84; H, 4.50; N, 11.58.
Compound 7j. 2-Amino-50-bromo-7,7-dimethyl-20,5-dioxo-5,6,7,8-tetra-hydrospiro[chromene-4,30-indoline]-3-carbonitrile. White crystalline solid (yield:93%); mp: 306–308 �C.
nmax (KBr): 3408, 3280, 3133, 2206, 1690, 1658, 1520, 1128 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.97 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.09-2.16 (m, 2H,CH2) 2.41–2.55 (m, 2H, CH2), 6.76 (d, J¼ 8.40Hz, 1H), 7.16 (s, 1H), 7.29 (d,J¼ 8.40Hz, 1H), 7.30 (br s, 2H, NH2, D2O exchangeable), 10.53 (s, 1H, NH, D2Oexchangeable). 13C NMR (DMSO-d6, 75MHz): d 27.7, 27.9, 32.4, 47.5, 50.4, 57.2,110.3, 111.1, 117.6, 123.7, 126.2, 128.6, 137.1, 141.6, 141.9, 159.3, 165.4, 178.3,195.5. MS (m=z): 413 (Mþ). Anal. calcd. for C19H16BrN3O3: C, 55.09; H, 3.89; N,10.14. Found: C, 55.32; H, 3.97; N, 10.22.
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Compound 7k. 2-Amino-7,7-dimethyl-50-nitro-20,5-dioxo-5,6,7,8-tetrahydro-spiro[chromene-4,30-indoline]-3-carbonitrile. White crystalline solid (yield: 92%);mp: 302–304 �C.
nmax (KBr): 3422, 3290, 3139, 2202, 1698, 1660, 1520, 1132 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.99 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.23–2.35 (m, 2H,CH2) 2.68–2.81 (m, 2H, CH2), 7.30 (d, J¼ 8.60Hz, 1H), 8.20–8.29 (m, 1H),8.34–8.42 (m, 1H), 7.78 (br s, 2H, NH2, D2O exchangeable), 11.32 (s, 1H, NH,D2O exchangeable). 13C NMR (DMSO-d6, 75MHz): d 27.9, 28.4, 33.4, 48.8, 50.9,58.8, 112.3, 113.8, 118.6, 124.7, 126.9, 129.4, 138.6, 142.4, 143.2, 160.8, 167.2,179.3, 196.1. MS (m=z): 380 (Mþ). Anal. calcd. for C19H16N4O5: C, 60.0; H, 4.24;N, 14.73. Found: C, 60.26; H, 4.35; N, 14.64.
Compound 7l. 2-Amino-50,70,7,7-tetramethyl-20,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,30-indoline]-3-carbonitrile. White crystalline solid (yield: 96%);mp: >360 �C.
nmax (KBr): 3412, 3286, 3116, 2195, 1692, 1648, 1526, 1128 cm�1. 1H NMR(DMSO-d6, 300MHz): d 0.98 (s, 3H, CH3), 1.01 (s, 3H, CH3), 2.12 (s, 2H, CH2)2.17 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.47 (d, J¼ 14.8Hz, 2H, CH2), 6.61 (s, 1H),6.78 (s, 1H), 7.18 (br s, 2H, NH2, D2O exchangeable), 10.26 (s, 1H, NH, D2Oexchangeable). 13C NMR (DMSO-d6, 75MHz): d 21.2, 22.7, 27.5, 27.8, 32.3, 47.3,50.3, 57.8, 109.3, 111.1, 117.8, 123.9, 128.8, 130.8, 134.8, 139.9, 159.0, 164.4,178.4, 195.4. MS (m=z): 363 (Mþ). Anal. calcd. for C21H21N3O3: C, 69.41; H,5.82; N, 11.56. Found: C, 69.60; H, 5.66; N, 11.40.
CONCLUSION
In conclusion, we have demonstrated a novel and highly efficient methodologyfor the synthesis of spirooxindole derivatives through sodium chloride catalyzedprocess under sonication. The method provides many obvious advantages such asthe avoidance of harmful organic solvents, simplicity of work up, good yields,environmental friendliness and use of the safer green technique. The results showedthat ultrasonic irradiation can be used as a valuable means for synthesis of organiccompounds.
ACKNOWLEDGMENTS
Financial assistance from the University Grants Commission (34-349=08=SR)and Council for scientific and Industrial Research (01=2248=08=EMR-II), NewDelhi, is gratefully acknowledged. We are also thankful to the Central DrugResearch Institute (CDRI), Lucknow, for the elemental and spectral analyses.
REFERENCES
1. Anastas, P. T.; Warner, J. C. Green chemistry: Theory and practice; Oxford UniversityPress: New York, 1988.
2. Matlack, A. S. Introduction to Green Chemistry; Marcel Dekker: New York, 2001.
BIODYNAMIC SPIROHETEROCYCLES 2917
Dow
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ded
by [
Lul
ea U
nive
rsity
of
Tec
hnol
ogy]
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5:04
05
Aug
ust 2
013
3. Lancester, M. Green Chemistry: An Introductory Text; Royal Society of Chemistry:Cambridge, 2002.
4. Khosropour, A. R. Ultrasound-promoted greener synthesis of 2,4,5-trisubstituted imida-zoles catalyzed by Zr(acac)4 under ambient conditions. Ultrason. Sonochem. 2008, 15,659–664.
5. Wang, S. X.; Li, Z. Y.; Zhang, J. C.; Li, J. T. The solvent-free synthesis of 1,4-dihydro-pyridines under ultrasound irradiation without catalyst. Ultrason. Sonochem. 2008, 15,677–680.
6. Chandra, A.; Fokin, V. V. Organic synthesis ‘‘on water.’’ Chem. Rev. 2009, 109, 725–748.7. Trost, B. M.; Brennan, M. K. Asymmetric syntheses of oxindole and indole spirocyclic
alkaloid natural products. Synthesis 2009, 18, 3003–3025.8. Galliford, C. V.; Scheidt, K. A. Pyrrolidinyl-spirooxindole natural products as inspira-
tions for the development of potential therapeutic agents. Angew. Chem. Int. Ed. 2007,46, 8748–8758.
9. Marti, C.; Carreira, E. M. Construction of spiro[pyrrolidine-3,30-oxindoles]—Recentapplications to the synthesis of oxindole alkaloids. Eur. J. Org. Chem. 2003, 63, 2209–2219.
10. Wong, W. H.; Lim, P. B.; Chuah, C. H. Oxindole alkaloids from Alstonia Macrophylla.Phytochemistry 1996, 41, 313–315.
11. Garnick, R. L.; Lequesne, P. W. Biomimetic transformations among monomericmacroline-related indole alkaloids. J. Am. Chem. Soc. 1978, 100, 4213–4219.
12. Dideberg, O.; Brasseur, J. L.; Dupont, L.; Campsteyn, H.; Vermeire, M.; Angenot, L.Structure cristalline et moleculaire d’un nouvel alcaloide bisindolique: Complexe molecu-laire 1:2 strychnofoline-ethanol (C30H34N4O2 � 2C2H6O). Acta Crystallogr. Sect. B 1977,33, 1796–1801.
13. Sakai, S.; Aimi, N.; Yamaguchi, K.; Yamanaka, E.; Haginiwa, J. Gardneria Alkaloids,part 13: Structure of gardmultine and demethoxygardmultine; bis- type indole alkaloidsof Gardneria multiflora Makino. J. Chem. Soc., Perkin Trans. 1 1982, 1257–1262.
14. Abdelrazek, F. M.; Metz, P.; Kataeva, O.; Jager, A.; El-Mahrouky, S. F. Synthesis andmolluscicidal activity of new chromene and pyrano[2,3-c]pyrazole derivatives. Arch.Pharm. Chem. Life Sci. 2007, 340, 543–548.
15. Patel, H. D.; Mistry, B. D.; Desai, K. R. Synthesis and antimicrobial activity of pyra-no[2,3-c]pyrazole derivatives. Oriental. J. Chem. 2003, 19, 497–498.
16. Abdallah, N. A.; Zaki, M. E. A. Synthesis and pharmacological evaluation of some pyr-ano[2,3-c]pyrazole derivatives of analgesic and antiinflamatory profiles. Acta Pharm. 1999,49, 159–170.
17. Gerencser, J.; Dorman, G.; Darvas, F. Meldrum’s acid in multicomponent reactions:Applications to combinatorial and diversity-oriented synthesis. QSAR Comb. Sci. 2006,439–448.
18. Ramon, D. J.; Yus, M. Asymmetric multicomponent reactions (AMCRs): The new fron-tier. Angew. Chem. Int. Ed. 2005, 44, 1602–1634.
19. Dandia, A.; Arya, K.; Sati, M.; Sharma, R. Facile microwave-assisted one-potSolid-phase synthesis of spiro[3H-indole-3,40-pyrazolo[3,4-b]pyridines]. Heterocycl.Commun. 2003, 9, 415–420.
20. Dandia, A.; Singh, R.; Sachdeva, H.; Gupta, R.; Paul, S. Microwave-promoted andimproved thermal synthesis of spiro-[indole pyranobenzopyrans] and spiro[indole-pyranoimidazoles]. J. Chin. Chem. Soc. 2003, 50, 273–278.
21. Joshi, K. C.; Dandia, A.; Baweja, S.; Joshi, A. Studies in spiroheterocycles, part XVII:Synthesis of novel fluorine containing spiro[indole pyranobenzopyran] and spiro-[indenopyran-indole]derivatives. J. Heterocycl. Chem. 1989, 26, 1097–1099.
2918 A. DANDIA, A. K. JAIN, AND D. S. BHATI
Dow
nloa
ded
by [
Lul
ea U
nive
rsity
of
Tec
hnol
ogy]
at 0
5:04
05
Aug
ust 2
013
22. Zhu, S. L.; Ji, S. J.; Zhang, Y. A simple and clean procedure for three-component syn-thesis of spirooxindoles in aqueous medium. Tetrahedron 2007, 63, 9365–9372.
23. Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. A new InCl3-catalyzed, facile, and efficientmethod for the synthesis of spirooxindoles under conventional and solvent-free micro-wave conditions. Tetrahedron 2007, 63, 2057–2063.
24. Elinson, M. N.; Dorofeev, A. S.; Miloserdov, F. M.; Nikishin, G. I. Electrocatalytic multi-component assembling of isatins,3-methyl-2-pyrazolin-5-ones and malononitrile: Facileand convenient way to functionalized spirocyclic [indole-3,40-pyrano[2,3-c]pyrazole]system. Mol. Divers. 2009, 13, 47–52.
25. Elinson, M. N.; Ilovaisky, A. L.; Dorofeev, A. S.; Merkulova, V. M.; Stepanov, N. O.;Miloserdov, F. M.; Ogibin, Y. N.; Nikishin, G. I. Electrocatalytic multicomponent trans-formation of cyclic 1, 3-diketones, isatins, and malononitrile: Facile and convenient wayto functionalized spirocyclic (5,6,7,8-tetrahydro-4H-chromene)-4,30-oxindole system.Tetrahedron 2007, 63, 10543–10548.
26. Dandia, A.; Singh, R.; Bhaskaran, S. Ultrasound-promoted greener synthesis ofspiro[indole-3,50-[1,3]oxathiolanes in water. Ultrason. Sonochem. 2010, 17, 399–402.
27. Dandia, A.; Arya, K. The expedient synthesis of 1,5-benzothiazepines as a family ofcytotoxic drugs. Bioorg. Med. Chem. Lett. 2008, 18, 114–119.
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by [
Lul
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