research article hydrolysis and hydrazinolysis of isatin...

Research ArticleHydrolysis and Hydrazinolysis of Isatin-BasedAld- and Ketazines

Hany S Ibrahim1 Soha R Abdelhadi1 and Hatem A Abdel-Aziz23

1Department of Pharmaceutical Chemistry Faculty of Pharmacy Egyptian Russian University Badr City Cairo 11829 Egypt2Department of Pharmaceutical Chemistry College of Pharmacy King Saud University PO Box 2457 Riyadh 11451 Saudi Arabia3Department of Applied Organic Chemistry National Research Centre Dokki Cairo 12622 Egypt

Correspondence should be addressed to Hatem A Abdel-Aziz hatem 741yahoocom

Received 14 January 2015 Revised 10 April 2015 Accepted 17 April 2015

Academic Editor Tanaji Talele

Copyright copy 2015 Hany S Ibrahim et alThis is an open access article distributed under theCreativeCommonsAttributionLicensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

The hydrolysis of isatin aldazine 4andashd afforded the unexpected 331015840-(hydrazine-12-diylidene)bis(indolin-2-one) (5) and 12-di(arylidene)hydrazines 6andashd through dual hydrolysis of 4andashd Amechanism to explain the formation of 5 and 6andashdwas proposedIn addition the hydrazinolysis of 4andashd yielded 3-hydrazonoindolin-2-one (2) and 12-di(arylidene)hydrazines 6andashd instead ofhydrazones 17andashd while hydrazinolysis of isatin ketazine 5 gave the expected 3-hydrazonoindolin-2-one (2)These results indicatedthe ability of the title compounds for unusual hydrolysis and hydrazinolysis reactions

1 Introduction

Isatin imines including Schiff bases 1b and isatin hydrazones2 which are the product of condensation of amines orhydrazines with isatins 1a respectively are considered as apharmacophore for diverse spectrum of biological activities[1ndash5] (Figure 1) They have been reported as anticanceragents where they were found to be inhibitors of tyrosinephosphatase Shp2 [6] Furthermore they have been identifiedas kinase inhibitors and they also have been reported as cyto-toxic agents towards U937 lymphoma cells [7] In additionhydrazones 2 (R = ndashCOAr) revealed a good cytotoxic activityagainst K562 MDA-MB-468 and HT-29 cell lines [8]

Isatin-based azines 4 are usually prepared by the con-densation of isatin hydrazones 2 (R1 = H) with aldehydes orketones 3 to construct the connectivitygtC=NndashN=CR2R3 andthen the formation of isatin aldazines (4 R2 or R3 = H) orisatin ketazines (4 R2 and R3 = H) respectively (Figure 1)Isatin aldazines 4 showed a significant anticancer activityagainst human breast cell line MCF-7 [9] whereas a seriesof symmetrical and asymmetrical isatin ketazines 5 showed aselective activity against multidrug-resistant cancer cells [10]Moreover bis-Schiff bases of isatins 4 represent significantantiglycation activity [11]

On the other hand azines undergo hydrolysis to regen-erate the hydrazine and aldehydes or ketones Howeverketazines are important intermediates in the production ofhydrazine hydrate when subjected to hydrolysis processes[12] In addition the reaction of azines with hydrazine(hydrazinolysis) regenerates the hydrazones [13] In lightof the latter results and in continuation of our interestin the chemistry of isatin-based azines 4 and 5 we hopeto report herein the unexpected results of hydrolysis andhydrazinolysis of isatin aldazines 4andashd and isatin ketazines5

2 Experimental

21 General Melting points were measured with a Stuartmelting point apparatus and were uncorrected IR spectra(KBr disks) were recorded with a Pye Unicam SP 1000 IRspectrophotometer The NMR spectra were recorded by Var-ianGemini-300BB 300MHzFT-NMR spectrometers (VarianInc Palo Alto CA) 1H and 13C spectra were run at 300and 75MHz respectively in deuterated dimethyl sulfoxide(DMSO-119889

6) Chemical shifts (120575H) are reported relative to

TMS as internal standard All coupling constant (119869) values aregiven in Hertz Chemical shifts (120575C) are reported relative to

Hindawi Publishing CorporationJournal of ChemistryVolume 2015 Article ID 826489 6 pageshttpdxdoiorg1011552015826489

2 Journal of Chemistry

NH

NH

NN

N

N

R3

R3

OO

O

OX

OHN

NH

5

R2

R2

1a X = O1b X = =N-R2 X = =N-NH-R

3 4

Figure 1 General structure of 1ndash5

DMSO-1198896as internal standardsThe abbreviations used are as

follows s singlet d doublet and m multiplet Mass spectrawere recorded on Helwett Packard 5988 spectrometer at70 eV Reaction courses and product mixtures were routinelymonitored by thin layer chromatography (TLC) on silicagel precoated F

254Merck plates Unless otherwise noted all

solvents and reagents were commercially available and wereused without further purification

22 Synthesis of Isatin Aldazines 4andashd A mixture of 3-hydrazonoindolin-2-one (2) (0161 g 1mmol) and aldehydefrom 3andashc (1mmol) in acetic acid (25mL)was stirred at roomtemperature for 12 h The resulted precipitate was filtereddried and finally crystallized from EtOHDMF to affordhydrazones 4andashc respectively Aldazines 4andashd were alsoprepared by the reaction of 2 with 3andashd in refluxing ethanolin the presence of catalytic amount of glacial acetic acid for6 h [10]

221 3-((Benzylidene)hydrazono)indolin-2-one (4a) Yield(62) mp gt 300∘C (lit mp 300∘C [14]) IR (KBr) v 3280(NH) 1722 (C=O) 1614 (C=N) cmminus1 1H NMR (DMSO-d6) 120575 690 (d 1H J = 78Hz H4 of isatin) 704 (t 1H J =75Hz H5 of isatin) 742 (t 1H J = 75Hz H6 of isatin) 751(d 1H J = 78Hz H7 of isatin) 757ndash799 (m 5H ArndashH)861 (s 1H N=CH) 1097 (s D

2O exchangeable 1H NH)

13C NMR (DMSO-d6) 120575 11095 11119 11573 12239 1226312803 12825 13426 13447 14470 14516 16336 (C=O)MSmz () 249 (M+ 3002) 221 (1703) 145 (3541)

222 3-((4-Nitrobenzylidene)hydrazono)indolin-2-one (4b)[11] Yield (66) mp 254ndash256∘C IR (KBr) v 3161 (NH) 1734(C=O) 1616 (C=N) cmminus1 1HNMR(DMSO-d6) 120575 690 (d 1HJ = 78Hz H4 of isatin) 701 (t 1H J = 75Hz H5 of isatin)741 (t 1H J = 75Hz H6 of isatin) 773 (d 1H J = 78HzH7 of isatin) 820 (d 2H J = 87Hz ArndashH) 837 (d 2H J =87 ArndashH) 866 (s 1H N=CH) 1086 (s D

2O exchangeable

1HNH) 13CNMR (DMSO-d6) 120575 11085 11108 11601 1222912253 12423 12859 12878 12964 13398 13419 1390614527 14897 14967 15621 15635 16410 (C=O)MSmz ()294 (M+ 1049) 266 (100)

223 3-((4-Chlorobenzylidene)hydrazono)indolin-2-one (4c)Yield (78) mp = 270ndash272∘C (lit mp = 200∘C [14]) IR(KBr) v 3248 (NH) 1734 (C=O) 1604 (C=N) cmminus1 1HNMR

(DMSO-d6) 120575 690 (d 1H J = 75Hz H4 of isatin) 702 (t 1HJ = 78Hz H5 of isatin) 741 (t 1H J = 78Hz H6 of isatin)763 (d 2H J = 84Hz ArndashH) 785 (d 1H J = 75Hz H7of isatin) 798 (d 2H J = 84 ArndashH) 861 (s 1H N=CH)1086 (s D

2O exchangeable 1H NH) 13C NMR (DMSO-d6)

120575 11073 11098 11626 12882 12923 13037 13045 1322413392 13665 14172 14507 15029 15875 16435 (C=O) MSmz () 285 (M+ + 2 678) 283 (M+ 2010) 255 (8986) 145(1696) 138 (5466) 111 (9501)

224 3-((4-Methoxybenzylidene)hydrazono)indolin-2-one(4d) Yield (69) mp = 182-183∘C (lit mp = 182∘C [14]) IR(KBr) v 3194 (NH) 1732 (C=O) 1606 (C=N) cmminus1 1H NMR(DMSO-d6) 120575 387 (s 6H 2OCH

3) 689 (d 1H J = 75Hz

H4 of isatin) 704 (t 1H J = 78Hz H5 of isatin) 712 (d 2HJ = 84 ArndashH) 739 (t 1H J = 75Hz H6 of isatin) 794 (d2H J = 84Hz ArndashH) 802 (d 1H J = 78Hz H7 of isatin)861 (s 1H N=CH) 1076 (s D


13C NMR (DMSO-d6) 120575 5555 (OCH3) 11058 11081 11462

11487 11659 12213 12236 12632 12879 12886 1309113103 13329 13352 14480 14515 15065 16181 1619316258 16336 16469 (C=O) MS mz () 279 (M+ 3031)251 (100) 134 (1779)

23 Hydrolysis of Isatin Aldazines 4andashd

Method A A solution of isatin aldazines 4andashd (1mmol) inH2OAcOH (1 3 v v 25mL) was refluxed for 4 hThe given

331015840-(hydrazine-12-diylidene)bis(indolin-2-one) (5) was fil-tered while hot and crystallized from EtOHDMFThe filtrateof the latter reaction was concentrated The solid formedwas washed with 50 ethanol dried and crystallized fromEtOH to give 12-di(arylidene)hydrazines 6andashd The physicalconstants of 5 and 6andashd were identical with that reported

Method B A mixture of 3-hydrazonoindolin-2-one (2)(0161 g 1mmol) and the appropriate aldehyde from 3andashc(1mmol) in H

2OAcOH (1 3 v v 25mL) was refluxed for

4 h Ketazine 5 was filtered while hot and crystallized fromEtOHDMF while aldazines 6andashd were isolated from thefiltrate after evaporation of the solvent

231 331015840-(Hydrazine-12-diylidene)diindolin-2-one (5) [8]Yield (46) mp gt 300∘C IR (KBr) v 3276 (2NH) 1722(2C=O) 1615 (2C=N) cmminus1 1H NMR (DMSO-d6) 120575 682 (d

Journal of Chemistry 3

NN

N

NN

N N

NH

HNHN

HN

HN

O

OO

O

O

OAr

Ar

ArH2OAcOH

reflux

H2OAcOHreflux

AcOH rt

ArPh4-Cl-C6H4

4-MeO-C6H4

4-NO2-C6H4

3 4 6abcd

1a 2 5

2 + 3

+

NH2

3andashd

4andashd

3andashd

6andashd

andashd

H2NndashNH2

ArndashCHO

ArndashCHO

Scheme 1 The reaction of 3-hydrazonoindolin-2-one (2) with aldehydes 3andashd

2H 119869 = 78Hz H5 of isatin) 696 (t 2H 119869 = 75Hz H6of isatin) 714 (t 2H 119869 = 75Hz H7 of isatin) 734 (d 2H119869 = 78Hz H4 of isatin) 1055 (s D

2O exchangeable 2H

2NH) 13C NMR (DMSO-d6) 120575 11159 11626 12303 1286613489 14522 14568 16389 (2C=O)

232 12-Di(benzylidene)hydrazine (6a) Yield (70) mp =95ndash97∘C (Litmp=92ndash93∘C [15]) IR 1615ndash1620 (2C=N) cmminus11HNMR (DMSO-d6) 120575 757ndash799 (m 10H ArndashH) 861 (s 2HN=CH)MSmz () 209 (M+ + 1 1168) 208 (M+ 7943) 207(100) 138 (100)

233 12-Bis(-4-chlorobenzylidene)hydrazine (6b) Yield(82) mp = 211ndash213∘C (Lit mp = 207-208∘C [15]) IR 1617ndash1625 (2C=N) cmminus1 1H NMR (DMSO-d6) 120575 756 (d 4HJ = 84 Hz ArndashH) 788 (d 4H J = 84Hz ArndashH) 861 (s2H N=CH) 13C NMR (DMSO-d6) 120575 12893 12989 13256135791 16044 (2C=N) MS mz () 279 (M+ + 2 968) 277(M+ 3114) 165 (100) 138 (2301) 111 (3485)

234 12-Bis(4-methoxybenzylidene)hydrazine (6c) Yield(77) mp = 170ndash172∘C (Lit mp = 175∘C [15]) IR 1615ndash1622(2C=N) cmminus1 1H NMR (DMSO-d6) 120575 383 (s 6H OCH

3)

704 (d 4H J = 84Hz ArndashH) 779 (d 4H J = 84Hz ArndashH)861 (s 2H N=CH) 13CNMR (DMSO-d6) 120575 5527 (2OCH

3)

11423 12653 12983 16035 16162 (2C=N) MSmz () 268(M+ 1837) 161 (3172) 134 (2680) 107 (1607)

235 12-Bis(4-nitrobenzylidene)hydrazine (6d) Yield (74)mp = 223ndash225∘C (Lit mp = 2233-2234∘C [16]) IR 1610ndash1617(2C=N) cmminus1 1HNMR(DMSO-d6) 120575 755 (d 4H 119869 = 84HzArndashH) 788 (d 4H 119869 = 84Hz ArndashH) 860 (s 2H N=CH)MSmz 272 () 298 (M+ 1003) 252 (100) 176 (5055)

24 Hydrazinolysis of 4andashd To a solution of hydrazones 4andashd (1mmol) in ethanol (25mL) hydrazine hydrate (006 g012mmol) was added The reaction was refluxed for 5 h

The formed precipitate was filtered washed with ethanoldried and finally crystallized from EtOHDMF to give 3-hydrazonoindolin-2-one (2) with mp = 217ndash219∘C (Lit mp= 219ndash220∘C [16]) IR (KBr) V 3361ndash3215 (NH NH

2) 1687

(C=O) 1608 (C=N) cmminus1 1HNMR(DMSO-d6) 120575 687 (d 1HJ = 75 Hz H5 of isatin) 697 (t 1H J = 78Hz H6 of isatin)715 (t 1H J = 78Hz H7 of isatin) 737 (d 1H J = 75HzH4 isatin) 955 (d 1H J = 140Hz D

2O exch amino H)

1056 (d 1H J = 140Hz D2O exch amino H) 1072 (s D

2O

exch 1H NH isatin) MSmz () 1611 (M+) The filtrate wasevaporated under vacuumThe obtained residue was filteredwashed with 50 ethanol dried and crystallized from EtOHto yield 12-di(arylidene)hydrazines 6andashd

25 Hydrazinolysis of 5 To a solution of 5 (029 g 1mmol)in ethanol (25mL) hydrazine hydrate (006 g 012mmol) wasadded The reaction was refluxed for 5 h The formed pre-cipitate was filtered washed with ethanol dried and finallycrystallized from EtOHDMF to give hydrazonoindolin-2-one (2)

3 Results and Discussion

In the reaction of 3-hydrazonoindolin-2-one (2) (R = H)with aldehydes 3andashd in glacial acetic acid for 12 h at ambienttemperature isatin aldazines 4andashd were isolated extensivelyThe targeted aldazines 4andashd were also prepared by thereaction of 3-hydrazonoindolin-2-one (2) with aldehydes 3andashd in refluxing ethanol in the presence of catalytic amount ofglacial acetic acid for 6 h (Scheme 1) [9]

Hydrolysis of hydrazones 4andashd by their refluxing inH2OAcOH afforded reddish precipitates during reflux in

each case These precipitates showed identical physical andchemical properties and they are not matched with theexpected hydrazone 2 (R = H) (Scheme 1)

The 1H NMR spectrum of the isolated precipitate didnot show the characteristic signal of NH

2of 2 and its mass


N

NNN

N

N

NN

N

NN

N

N

N

N N

N

N

H

H

H H

H HH

HH

H H

H

H

H

H

H

H

H

HN

HN

O

O O

OO

O

O

OO

O

O

O

OO

O

O

O

O

O

O

HN

HN

HN

HN

OH

OH

HN

HN

HN

HN

HNHN

Ar

Ar

Ar

Ar

Ar

ArAr

Ar

Ar

Ar

H2O

H2O

H2O

H2O

H2O

H2O

OH2

16

NH2

NH2

HOH2

HOH2

2

2

5

H2O

H2O

H3O+

+

H3O+

H3O+

NN+

++

+

+

+

+

+

+

+

NH2NH2 +

+

++

+

1a

1a

1a

3a d + NH2NH2

Ar + H2O

Ar + H3O+

∙∙ ∙∙∙∙

∙∙

∙∙

12andashd

14andashd

13andashd

15andashd

10andashd

11andashd

17andashd

17andashd

+ +

+

4andashd

3andashd

6andashd3andashd

7andashd 8andashd

9andashd

Figure 2 The proposed mechanism for the hydrolysis of isatin aldazines 4andashd in refluxing H2OAcOH

spectrum exhibited molecular ion peak atmz = 290The lat-ter data proposed the assigned structure 331015840-(hydrazine-12-diylidene)bis(indolin-2-one) (5) for the isolated compoundAn authentic sample of compound 5 is prepared [10] and itwas identical in all respects with the isolated compound inour hands

After evaporation of the filtrates of the latter reactionsthey gave in each case a compound with melting points97∘C (Ar = Ph) 213∘C (Ar = 4-Cl-C

6H4) 172∘C (Ar =

4-MeO-C6H4) and 225∘C (Ar = 4-NO

2-C6H4) respec-

tively These values do not match this reported for 2 217ndash219∘C Our attempts to explore these unknown compoundsguided us to assign structure 12-di(arylidene)hydrazines 6andashd for the isolated compounds We found that the analyticaldata of authentic samples of isolated compounds is iden-tical with those of 6andashd [17ndash20] Interestingly refluxing

2 with aldehydes 3andashd in H2OAcOH 331015840-(hydrazine-12-

diylidene)bis(indolin-2-one) (5) and aldazines 6andashd werealso isolated

Keeping in mind the reported data about the mech-anism of hydrolysis of ndashC=Nndash imines [21] we are inter-ested in proposing a mechanism to explain the formationof 331015840-(hydrazine-12-diylidene)bis(indolin-2-one) (5) and12-di(arylidene)hydrazines 6andashd In this mechanism dualacidic hydrolysis of aldazines 4andashd took place in their twonucleophilic centers which are accessible to attack by twoprotons from the acidicmedium (Figure 2)The first pathwayin which acidic proton attack took place by the nitrogenof ndashN=CndashAr followed by hydrolysis to give intermediates7(andashd)ndash10(andashd) respectively yielded aldehydes 3andashd and3-hydrazonoindolin-2-ones (2) which would not undergofurther hydrolysis The second pathway in which the other


N N

N N

NN

N

N

NN N

N N NN

NN

H

H

H

H

HH

HN N

N

N N

NH

NH2

NH2

NH2

NH2

HN

HN

HN

O

O

O

O

OO

O

O

2

HN

HN

HN HN

HN

Ar

Ar

Ar Ar Ar Ar

Ar

Ar

Ar

Ar Ar

H2N

NH2ndashNH2

NH2ndashNH2

∙∙

∙∙∙∙

NH2ndashNH2

∙∙

+

+

+2

2

4andashd

4andashd

6andashd

4andashd

6andashd

18andashd 19andashd

17andashd

20andashd

Scheme 2 Hydrazinolysis of aldazines 4andashd

HN

N N

NH NHNH2NH2

H

H

NNN

N

21

O

O

O

O

O

25

HN

HN

∙∙

∙∙

NH2ndashNH2

Scheme 3 Hydrazinolysis of 331015840-(hydrazine-12-diylidene)bis(indolin-2-one) (5)

nitrogen of hydrazone function attacked the acidic protonfollowed by hydrolysis to give intermediates 12(andashd)ndash15(andashd) respectively yielded indoline-23-dione (1) and the cor-responding hydrazones 17andashd without further hydrolysisFinally the reaction of 1a with 2 (R = H) and 3andashd with 17andashd led to the formation of final products 331015840-(hydrazine-12-diylidene)bis(indolin-2-one) (5) and aldazines 6andashd respec-tivelyThe expected last step is hydrolysis of 2 (R = H) andor17andashd

According to the previous results and in light of behaviorof hydrazine hydrate towards certain ndashN=Nndash containingcompounds [12] we stimulated to explore the reactivity ofhydrazine hydrate towards ndashN=Cndash function in aldazines 4andashd Thus the reaction of 4andashd with hydrazine hydrate inrefluxing ethanol afforded 3-hydrazonoindolin-2-one (2) and12-di(arylidene)hydrazines 6andashd respectively instead of 2and 17andashd (Scheme 2)

Hydrazine as a nucleophile attacked the carbon ofndashN=Cndash function of two molecules of hydrazones 4andashdto form the nonisolable intermediates 18andashd and 19andashdrespectively (Scheme 3) Finally the nonisolable intermedi-ate 19andashd afforded 3-hydrazonoindolin-2-one (2) and 12-di(arylidene)hydrazines 6andashd as final isolated compounds

Consequently the reaction of hydrazine hydrate withC-3 of 331015840-(hydrazine-12-diylidene)bis(indolin-2-one) (5)yielded the corresponding 3-hydrazonoindolin-2-one (2) as

hydrazinolysis product (Scheme 3) The previous reactionproceeded through the attack of nucleophilic nitrogen ofhydrazine on ketazine 5 to form the nonisolable intermediate21 and then the formation of 3-hydrazonoindolin-2-one (2)

4 Conclusion

In conclusion we reported herein the hydrolysis of isatinaldazines 4andashd which gave unusual product 331015840-(hydrazine-12-diylidene)bis(indolin-2-one) (5) and aldazines 6andashdwereformed through dual acidic hydrolysis The hydrazinolysisof isatin aldazines 4andashd yielded 3-hydrazonoindolin-2-one(2) and 6andashd instead of 17andashd These results established theability of the title compounds for unusual hydrolysis andhydrazinolysis reactions

Conflict of Interests

Theauthors have declared that there is no conflict of interests

Acknowledgments

The authors would like to extend their sincere appreciation tothe Deanship of Scientific Research at King Saud Universityfor its funding of this research through the Research GroupProject no RGP-VPP-321 Department of Pharmaceutical


Chemistry Faculty of Pharmacy Egyptian Russian Univer-sity Cairo Egypt is highly appreciated for supporting thisresearch

References

[1] S K Sridhar M Saravanan and A Ramesh ldquoSynthesis andantibacterial screening of hydrazones Schiff andMannich basesof isatin derivativesrdquo European Journal of Medicinal Chemistryvol 36 no 7-8 pp 615ndash625 2001

[2] A Jarrahpour J Sheikh I E Mounsi H Juneja and T BHadda ldquoComputational evaluation and experimental in vitroantibacterial antifungal and antiviral activity of bis-Schiff basesof isatin and its derivativesrdquoMedicinal Chemistry Research vol22 no 3 pp 1203ndash1211 2013

[3] T N Akhaja and J P Raval ldquo13-dihydro-2H-indol-2-onesderivatives design Synthesis in vitro antibacterial antifungaland antitubercular studyrdquo European Journal of Medicinal Chem-istry vol 46 no 11 pp 5573ndash5579 2011

[4] M Verma S N Pandeya K N Singh and J P StablesldquoAnticonvulsant activity of Schiff bases of isatin derivativesrdquoActa Pharmaceutica vol 54 no 1 pp 49ndash56 2004

[5] S K Sridhar S N Pandeya J P Stables and A RameshldquoAnticonvulsant activity of hydrazones Schiff and Mannichbases of isatin derivativesrdquo European Journal of PharmaceuticalSciences vol 16 no 3 pp 129ndash132 2002

[6] H R Lawrence R Pireddu L Chen et al ldquoInhibitors of Srchomology-2 domain containing protein tyrosine phosphatase-2 (Shp2) based on oxindole scaffoldsrdquo Journal of MedicinalChemistry vol 51 no 16 pp 4948ndash4956 2008

[7] A H Abadi SM Abou-Seri D E Abdel-Rahman C Klein OLozach and L Meijer ldquoSynthesis of 3-substituted-2-oxoindoleanalogues and their evaluation as kinase inhibitors anticancerand antiangiogenic agentsrdquo European Journal of MedicinalChemistry vol 41 no 3 pp 296ndash305 2006

[8] H A Abdel-Aziz T Elsaman A Al-Dhfyan M I Attia K AAl-Rashood and A-R M Al-Obaid ldquoSynthesis and anticancerpotential of certain novel 2-oxo-N1015840-(2-oxoindolin- 3-ylidene)-2H-chromene-3-carbohydrazidesrdquo European Journal of Medic-inal Chemistry vol 70 pp 358ndash363 2013

[9] H E Dweedar H Mahrous H S Ibrahim and H A Abdel-Aziz ldquoAnalogue-based design synthesis and biological evalu-ation of 3-substituted-(methylenehydrazono)indolin-2-ones asanticancer agentsrdquo European Journal of Medicinal Chemistryvol 78 pp 275ndash280 2014

[10] T A F M Hassan A A Kadi and H A K Abdel-AzizldquoNovel N N1015840-Hydrazino-bis-isatin Derivatives with SelectiveActivity against Multidrug-Resistant Cancer Cellsrdquo US PatentsUS20120252860 2012

[11] K M Khan M Khan M Ali et al ldquoSynthesis of bis-Schiffbases of isatins and their antiglycation activityrdquo Bioorganic ampMedicinal Chemistry vol 17 no 22 pp 7795ndash7801 2009

[12] E C Gilbert ldquoStudies on hydrazine the hydrolysis of dimeth-ylketazine and the equilibriumbetween hydrazine and acetonerdquoJournal of the American Chemical Society vol 51 no 11 pp3394ndash3409 1929

[13] A C Day and M C Whiting ldquoAcetone hydrazonerdquo OrganicSyntheses vol 50 p 3 1970

[14] V K Sharma S Srivastava and A Srivastava ldquoNovel coordina-tion complexes of the trivalent ruthenium rhodium and irid-iumwith hydrazones derived from isatin hydrazide and various

aldehydes with spectral and biological characterizationrdquo PolishJournal of Chemistry vol 80 no 3 pp 387ndash396 2006

[15] H Eshghi and M Hosseini ldquoSelective and convenient pro-tection of aldehydes as azines under solvent-free conditionsrdquoJournal of the Chinese Chemical Society vol 55 no 3 pp 636ndash638 2008

[16] S Okumura C-H Lin Y Takeda and S Minakata ldquoOxidativedimerization of (hetero)aromatic amines utilizing t-BuOI lead-ing to (hetero)aromatic azo compounds scope andmechanisticstudiesrdquo The Journal of Organic Chemistry vol 78 no 23 pp12090ndash12105 2013

[17] K M Khan W Jamil N Ambreen M Taha S Perveen andG A Morales ldquoAn expeditious synthetic approach towardsthe synthesis of Bis-Schiff bases (aldazines) using ultrasoundrdquoUltrasonics Sonochemistry vol 21 no 3 pp 1200ndash1205 2014

[18] A-F E Mourad ldquoCharge-transfer complexes of heterocyclicazines with Π-acceptorsrdquo Spectrochimica Acta Part A vol 41no 1-2 pp 347ndash350 1985

[19] K Saito and H Ishihara ldquoThermolysis of sodium salts oftosylhydrazones of some heterocyclic aldehydes in the presenceof silver chromate 13 NrarrCmigration of tosyl grouprdquoHetero-cycles vol 26 no 7 pp 1891ndash1898 1987

[20] L Yang X Shan Q Chen Z Wang and J S Ma ldquoThefirst silver(I) side-on 1205782-coordination network formed byself-assembly of bis(pyrrol-2-ylmethylene)hydrazinerdquo Euro-pean Journal of Inorganic Chemistry no 7 pp 1474ndash1477 2004

[21] E H Cordes and W P Jencks ldquoThe mechanism of hydrolysisof Schiff bases derived from aliphatic aminesrdquo Journal of theAmerican Chemical Society vol 85 no 18 pp 2843ndash2848 1963

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Chromatography Research International


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Analytical ChemistryInternational Journal of


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Organic Chemistry International

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NH

NH

NN

N

N

R3

R3

OO

O

OX

OHN

NH

5

R2

R2

1a X = O1b X = =N-R2 X = =N-NH-R

3 4

Figure 1 General structure of 1ndash5

DMSO-1198896as internal standardsThe abbreviations used are as

follows s singlet d doublet and m multiplet Mass spectrawere recorded on Helwett Packard 5988 spectrometer at70 eV Reaction courses and product mixtures were routinelymonitored by thin layer chromatography (TLC) on silicagel precoated F

254Merck plates Unless otherwise noted all

solvents and reagents were commercially available and wereused without further purification

22 Synthesis of Isatin Aldazines 4andashd A mixture of 3-hydrazonoindolin-2-one (2) (0161 g 1mmol) and aldehydefrom 3andashc (1mmol) in acetic acid (25mL)was stirred at roomtemperature for 12 h The resulted precipitate was filtereddried and finally crystallized from EtOHDMF to affordhydrazones 4andashc respectively Aldazines 4andashd were alsoprepared by the reaction of 2 with 3andashd in refluxing ethanolin the presence of catalytic amount of glacial acetic acid for6 h [10]

221 3-((Benzylidene)hydrazono)indolin-2-one (4a) Yield(62) mp gt 300∘C (lit mp 300∘C [14]) IR (KBr) v 3280(NH) 1722 (C=O) 1614 (C=N) cmminus1 1H NMR (DMSO-d6) 120575 690 (d 1H J = 78Hz H4 of isatin) 704 (t 1H J =75Hz H5 of isatin) 742 (t 1H J = 75Hz H6 of isatin) 751(d 1H J = 78Hz H7 of isatin) 757ndash799 (m 5H ArndashH)861 (s 1H N=CH) 1097 (s D


13C NMR (DMSO-d6) 120575 11095 11119 11573 12239 1226312803 12825 13426 13447 14470 14516 16336 (C=O)MSmz () 249 (M+ 3002) 221 (1703) 145 (3541)

222 3-((4-Nitrobenzylidene)hydrazono)indolin-2-one (4b)[11] Yield (66) mp 254ndash256∘C IR (KBr) v 3161 (NH) 1734(C=O) 1616 (C=N) cmminus1 1HNMR(DMSO-d6) 120575 690 (d 1HJ = 78Hz H4 of isatin) 701 (t 1H J = 75Hz H5 of isatin)741 (t 1H J = 75Hz H6 of isatin) 773 (d 1H J = 78HzH7 of isatin) 820 (d 2H J = 87Hz ArndashH) 837 (d 2H J =87 ArndashH) 866 (s 1H N=CH) 1086 (s D

2O exchangeable

1HNH) 13CNMR (DMSO-d6) 120575 11085 11108 11601 1222912253 12423 12859 12878 12964 13398 13419 1390614527 14897 14967 15621 15635 16410 (C=O)MSmz ()294 (M+ 1049) 266 (100)

223 3-((4-Chlorobenzylidene)hydrazono)indolin-2-one (4c)Yield (78) mp = 270ndash272∘C (lit mp = 200∘C [14]) IR(KBr) v 3248 (NH) 1734 (C=O) 1604 (C=N) cmminus1 1HNMR

(DMSO-d6) 120575 690 (d 1H J = 75Hz H4 of isatin) 702 (t 1HJ = 78Hz H5 of isatin) 741 (t 1H J = 78Hz H6 of isatin)763 (d 2H J = 84Hz ArndashH) 785 (d 1H J = 75Hz H7of isatin) 798 (d 2H J = 84 ArndashH) 861 (s 1H N=CH)1086 (s D

2O exchangeable 1H NH) 13C NMR (DMSO-d6)

120575 11073 11098 11626 12882 12923 13037 13045 1322413392 13665 14172 14507 15029 15875 16435 (C=O) MSmz () 285 (M+ + 2 678) 283 (M+ 2010) 255 (8986) 145(1696) 138 (5466) 111 (9501)

224 3-((4-Methoxybenzylidene)hydrazono)indolin-2-one(4d) Yield (69) mp = 182-183∘C (lit mp = 182∘C [14]) IR(KBr) v 3194 (NH) 1732 (C=O) 1606 (C=N) cmminus1 1H NMR(DMSO-d6) 120575 387 (s 6H 2OCH

3) 689 (d 1H J = 75Hz

H4 of isatin) 704 (t 1H J = 78Hz H5 of isatin) 712 (d 2HJ = 84 ArndashH) 739 (t 1H J = 75Hz H6 of isatin) 794 (d2H J = 84Hz ArndashH) 802 (d 1H J = 78Hz H7 of isatin)861 (s 1H N=CH) 1076 (s D


13C NMR (DMSO-d6) 120575 5555 (OCH3) 11058 11081 11462

11487 11659 12213 12236 12632 12879 12886 1309113103 13329 13352 14480 14515 15065 16181 1619316258 16336 16469 (C=O) MS mz () 279 (M+ 3031)251 (100) 134 (1779)

23 Hydrolysis of Isatin Aldazines 4andashd

Method A A solution of isatin aldazines 4andashd (1mmol) inH2OAcOH (1 3 v v 25mL) was refluxed for 4 hThe given

331015840-(hydrazine-12-diylidene)bis(indolin-2-one) (5) was fil-tered while hot and crystallized from EtOHDMFThe filtrateof the latter reaction was concentrated The solid formedwas washed with 50 ethanol dried and crystallized fromEtOH to give 12-di(arylidene)hydrazines 6andashd The physicalconstants of 5 and 6andashd were identical with that reported

Method B A mixture of 3-hydrazonoindolin-2-one (2)(0161 g 1mmol) and the appropriate aldehyde from 3andashc(1mmol) in H

2OAcOH (1 3 v v 25mL) was refluxed for

4 h Ketazine 5 was filtered while hot and crystallized fromEtOHDMF while aldazines 6andashd were isolated from thefiltrate after evaporation of the solvent

231 331015840-(Hydrazine-12-diylidene)diindolin-2-one (5) [8]Yield (46) mp gt 300∘C IR (KBr) v 3276 (2NH) 1722(2C=O) 1615 (2C=N) cmminus1 1H NMR (DMSO-d6) 120575 682 (d


NN

N

NN

N N

NH

HNHN

HN

HN

O

OO

O

O

OAr

Ar

ArH2OAcOH

reflux

H2OAcOHreflux

AcOH rt

ArPh4-Cl-C6H4

4-MeO-C6H4

4-NO2-C6H4

3 4 6abcd

1a 2 5

2 + 3

+

NH2

3andashd

4andashd

3andashd

6andashd

andashd

H2NndashNH2

ArndashCHO

ArndashCHO



2O exchangeable 2H

2NH) 13C NMR (DMSO-d6) 120575 11159 11626 12303 1286613489 14522 14568 16389 (2C=O)




3)


3)

11423 12653 12983 16035 16162 (2C=N) MSmz () 268(M+ 1837) 161 (3172) 134 (2680) 107 (1607)




2) 1687


2O exch amino H)


2O








2of 2 and its mass


N

NNN

N

N

NN

N

NN

N

N

N

N N

N

N

H

H

H H

H HH

HH

H H

H

H

H

H

H

H

H

HN

HN

O

O O

OO

O

O

OO

O

O

O

OO

O

O

O

O

O

O

HN

HN

HN

HN

OH

OH

HN

HN

HN

HN

HNHN

Ar

Ar

Ar

Ar

Ar

ArAr

Ar

Ar

Ar

H2O

H2O

H2O

H2O

H2O

H2O

OH2

16

NH2

NH2

HOH2

HOH2

2

2

5

H2O

H2O

H3O+

+

H3O+

H3O+

NN+

++

+

+

+

+

+

+

+

NH2NH2 +

+

++

+

1a

1a

1a

3a d + NH2NH2

Ar + H2O

Ar + H3O+

∙∙ ∙∙∙∙

∙∙

∙∙

12andashd

14andashd

13andashd

15andashd

10andashd

11andashd

17andashd

17andashd

+ +

+

4andashd

3andashd

6andashd3andashd

7andashd 8andashd

9andashd




6H4) 172∘C (Ar =


2-C6H4) respec-






N N

N N

NN

N

N

NN N

N N NN

NN

H

H

H

H

HH

HN N

N

N N

NH

NH2

NH2

NH2

NH2

HN

HN

HN

O

O

O

O

OO

O

O

2

HN

HN

HN HN

HN

Ar

Ar

Ar Ar Ar Ar

Ar

Ar

Ar

Ar Ar

H2N

NH2ndashNH2

NH2ndashNH2

∙∙

∙∙∙∙

NH2ndashNH2

∙∙

+

+

+2

2

4andashd

4andashd

6andashd

4andashd

6andashd

18andashd 19andashd

17andashd

20andashd


HN

N N

NH NHNH2NH2

H

H

NNN

N

21

O

O

O

O

O

25

HN

HN

∙∙

∙∙

NH2ndashNH2







4 Conclusion




Acknowledgments




References
































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


NN

N

NN

N N

NH

HNHN

HN

HN

O

OO

O

O

OAr

Ar

ArH2OAcOH

reflux

H2OAcOHreflux

AcOH rt

ArPh4-Cl-C6H4

4-MeO-C6H4

4-NO2-C6H4

3 4 6abcd

1a 2 5

2 + 3

+

NH2

3andashd

4andashd

3andashd

6andashd

andashd

H2NndashNH2

ArndashCHO

ArndashCHO



2O exchangeable 2H

2NH) 13C NMR (DMSO-d6) 120575 11159 11626 12303 1286613489 14522 14568 16389 (2C=O)




3)


3)

11423 12653 12983 16035 16162 (2C=N) MSmz () 268(M+ 1837) 161 (3172) 134 (2680) 107 (1607)




2) 1687


2O exch amino H)


2O








2of 2 and its mass


N

NNN

N

N

NN

N

NN

N

N

N

N N

N

N

H

H

H H

H HH

HH

H H

H

H

H

H

H

H

H

HN

HN

O

O O

OO

O

O

OO

O

O

O

OO

O

O

O

O

O

O

HN

HN

HN

HN

OH

OH

HN

HN

HN

HN

HNHN

Ar

Ar

Ar

Ar

Ar

ArAr

Ar

Ar

Ar

H2O

H2O

H2O

H2O

H2O

H2O

OH2

16

NH2

NH2

HOH2

HOH2

2

2

5

H2O

H2O

H3O+

+

H3O+

H3O+

NN+

++

+

+

+

+

+

+

+

NH2NH2 +

+

++

+

1a

1a

1a

3a d + NH2NH2

Ar + H2O

Ar + H3O+

∙∙ ∙∙∙∙

∙∙

∙∙

12andashd

14andashd

13andashd

15andashd

10andashd

11andashd

17andashd

17andashd

+ +

+

4andashd

3andashd

6andashd3andashd

7andashd 8andashd

9andashd




6H4) 172∘C (Ar =


2-C6H4) respec-






N N

N N

NN

N

N

NN N

N N NN

NN

H

H

H

H

HH

HN N

N

N N

NH

NH2

NH2

NH2

NH2

HN

HN

HN

O

O

O

O

OO

O

O

2

HN

HN

HN HN

HN

Ar

Ar

Ar Ar Ar Ar

Ar

Ar

Ar

Ar Ar

H2N

NH2ndashNH2

NH2ndashNH2

∙∙

∙∙∙∙

NH2ndashNH2

∙∙

+

+

+2

2

4andashd

4andashd

6andashd

4andashd

6andashd

18andashd 19andashd

17andashd

20andashd


HN

N N

NH NHNH2NH2

H

H

NNN

N

21

O

O

O

O

O

25

HN

HN

∙∙

∙∙

NH2ndashNH2







4 Conclusion




Acknowledgments




References
































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N

NNN

N

N

NN

N

NN

N

N

N

N N

N

N

H

H

H H

H HH

HH

H H

H

H

H

H

H

H

H

HN

HN

O

O O

OO

O

O

OO

O

O

O

OO

O

O

O

O

O

O

HN

HN

HN

HN

OH

OH

HN

HN

HN

HN

HNHN

Ar

Ar

Ar

Ar

Ar

ArAr

Ar

Ar

Ar

H2O

H2O

H2O

H2O

H2O

H2O

OH2

16

NH2

NH2

HOH2

HOH2

2

2

5

H2O

H2O

H3O+

+

H3O+

H3O+

NN+

++

+

+

+

+

+

+

+

NH2NH2 +

+

++

+

1a

1a

1a

3a d + NH2NH2

Ar + H2O

Ar + H3O+

∙∙ ∙∙∙∙

∙∙

∙∙

12andashd

14andashd

13andashd

15andashd

10andashd

11andashd

17andashd

17andashd

+ +

+

4andashd

3andashd

6andashd3andashd

7andashd 8andashd

9andashd




6H4) 172∘C (Ar =


2-C6H4) respec-






N N

N N

NN

N

N

NN N

N N NN

NN

H

H

H

H

HH

HN N

N

N N

NH

NH2

NH2

NH2

NH2

HN

HN

HN

O

O

O

O

OO

O

O

2

HN

HN

HN HN

HN

Ar

Ar

Ar Ar Ar Ar

Ar

Ar

Ar

Ar Ar

H2N

NH2ndashNH2

NH2ndashNH2

∙∙

∙∙∙∙

NH2ndashNH2

∙∙

+

+

+2

2

4andashd

4andashd

6andashd

4andashd

6andashd

18andashd 19andashd

17andashd

20andashd


HN

N N

NH NHNH2NH2

H

H

NNN

N

21

O

O

O

O

O

25

HN

HN

∙∙

∙∙

NH2ndashNH2







4 Conclusion




Acknowledgments




References
































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N N

N N

NN

N

N

NN N

N N NN

NN

H

H

H

H

HH

HN N

N

N N

NH

NH2

NH2

NH2

NH2

HN

HN

HN

O

O

O

O

OO

O

O

2

HN

HN

HN HN

HN

Ar

Ar

Ar Ar Ar Ar

Ar

Ar

Ar

Ar Ar

H2N

NH2ndashNH2

NH2ndashNH2

∙∙

∙∙∙∙

NH2ndashNH2

∙∙

+

+

+2

2

4andashd

4andashd

6andashd

4andashd

6andashd

18andashd 19andashd

17andashd

20andashd


HN

N N

NH NHNH2NH2

H

H

NNN

N

21

O

O

O

O

O

25

HN

HN

∙∙

∙∙

NH2ndashNH2







4 Conclusion




Acknowledgments




References
































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



References
































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

research article hydrolysis and hydrazinolysis of isatin...

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