national research centre, dokki, giza ,...

Hindawi Publishing CorporationJournal of ChemistryVolume 2013 Article ID 463515 7 pageshttpdxdoiorg1011552013463515

Research ArticleA Facile Synthesis of Pyrido[210158403101584034]pyrazolo[15-a]pyrimidineand Pyrido[210158403101584034]pyrazolo[51-c][124]triazine Bearinga Thiophene Moiety

Tilal Elsaman1 Mohamed Fares2 Hatem A Abdel-Aziz13 Mohamed I Attia14

Hazem A Ghabbour1 and Kamal M Dawood5

1 Department of Pharmaceutical Chemistry College of Pharmacy King Saud University PO Box 2457 Riyadh 11451 Saudi Arabia2Department of Pharmaceutical Chemistry College of Pharmacy Egyptian Russian University Badr City Cairo 11829 Egypt3 Department of Applied Organic Chemistry National Research Center Dokki Giza 12622 Egypt4 Pharmaceutical and Drug Industries Research Division Department of Medicinal and Pharmaceutical ChemistryNational Research Centre Dokki Giza 12622 Egypt

5 Department of Chemistry Faculty of Science Cairo University Giza 12613 Egypt

Correspondence should be addressed to Kamal M Dawood dr dawoodyahoocom

Received 12 September 2013 Revised 9 October 2013 Accepted 21 October 2013

Academic Editor Bartolo Gabriele

Copyright copy 2013 Tilal Elsaman et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Pyridinone derivative 8 was synthesized and transformed into the respective chloropyridine 9 which was allowed to react withhydrazine hydrate to afford pyrazolo[34-b]pyridin-3-amine derivative 11 Compound 11 was used as a key intermediate for a facilesynthesis of the title compounds 14 15 17 21ab and 24andashc where the reaction of 11 with some 13-dielecrophiles resulted in theformation of pyrido[210158403101584034]pyrazolo[15-a]pyrimidines 14 15 and 17 whereas diazotization of compound 11 gave the respectivediazonium salt 18 which was coupled with some active methylene-containing compounds to give the corresponding hydrazones19ab and 22andashc Cyclization of the latter hydrazones yielded the pyrido[210158403101584034]pyrazolo[51-c][124]triazines 21ab and 24andashcrespectively

1 Introduction

Thiophene moiety is present in a large number of bioactivemolecules having diverse biological activities such as antiin-flammatory [1] anticonvulsant [2] antibacterial [3] and anti-tumor [4] activities Moreover thiophene moiety is a well-known isostere for benzene for example the replacementof benzene ring of the antidepressant drug Viloxazine (IFigure 1) led to a prolongation of half-life [5]

On the other hand several pyrazolo[34-b]pyridinesrevealed interesting biological properties including antimi-crobial [6] antiviral [7] antiinflammatory [8] analgesic[9] and antitumor activities [10] In addition pyrazolo[34-b]pyridines represent the skeleton of pharmaceuticals pos-sessing significant biological activities as represented byEtazolate (II EHT-0202 Figure 1) an anxiolytic drug whichis now in clinical trials for the treatment of Alzheimerrsquos

disease [11] and by Glicaramide (III Figure 1) a potentantidiabetic agent [12]

Following a program dealing with the development ofbioactive heterocyclic derivatives [13ndash15] we report hereina facile synthesis of new pyrazolo[34-b]pyridines 14 1517 21ab and 24andashc bearing a thiophene moiety as newbioactive candidates

2 Experimental

21 General Melting points were determined on a Gal-lenkamp melting point apparatus and are uncorrectedInfrared (IR) spectra were recorded as KBr disks using thePerkin Elmer FT-IR Spectrum BX apparatus NMR Spectrawere measured in DMSO-d6 on a Jeol-NMR spectrome-ter operating at 400MHz for 1H NMR and at 100MHz

2 Journal of Chemistry

O

HN

SHN O

HN

NN

N

O

O

OOO

HN

O

N NN

NHN

O

O

I II III

H3C

H3C

H3C CH3CH3

Figure 1 Chemical structures of Viloxazine (I) Etazolate (II) and Glicaramide (III)

for 13C NMR Chemical shifts are expressed in 120575 values(ppm) relative to TMS as an internal standard Couplingconstants (J) are expressed in Hz D

2Owas added to confirm

the exchangeable protons Mass spectra were measured onAgilent Triple Quadrupole 6410 QQQ LCMS with ESI(Electrospray ionization) source

22 Synthesis of 56-Dimethyl-2-oxo-4-(2-thienyl)-12-dihy-dropyridine-3-carbonitrile (8) A mixture of thiophene-2-carbaldehyde (1) (112 g 01mol) ethyl 2-cyanoacetate (2a)(113 g 01mol) 2-butanone (3) (72 g 01mol) and ammo-nium acetate (450 g 06mol) in absolute ethanol (150mL)was heated to reflux for 12 h The precipitate formed aftercooling to rt was filtered washed with ethanol and driedCrystallization from ethanol gave compound 8 as yellowcrystals in 72 yield mp 152ndash154∘C IR (KBr) ] 3102 (NH)2219 (CequivN) 1654 (C=O) cmminus1 1H NMR (DMSO-d6) 120575 184(s 3H CH

3) 232 (s 3H CH

3) 721ndash732 (m 2H thiophene

H3 and H4) 785 (d J = 52Hz 1H thiophene H5) 1285 (sD2O exch 1H NH) 13C NMR (DMSO-d6) 120575 1560 2530

11525 12207 12776 12812 12830 12977 13531 1364215945 16832 ESI MSmz 2308 [M]+

23 Synthesis of 2-Chloro-56-dimethyl-4-(2-thienyl)nicotin-onitrile (9) A solution of pyridinone derivative 8 (23 g10mmol) in phosphorous oxychloride (10mL) was refluxedgently for 5 h It was then left to cool to rt and pouredcarefully onto crashed-ice with stirring The solid obtainedwas filtered washedwithwater dried and recrystallized fromethanol to give compound 9 as pale yellow crystals in 87yield Mp 285ndash287∘C IR (KBr) ] 2228 (CequivN) 1600 (C=N)cmminus1 1H NMR (DMSO-d6) 120575 216 (s 3H CH

3) 258 (s 3H

CH3) 726ndash735 (m 2H thiophene H3 and H4) 789 (d J =

52Hz 1H thiophene H5) 13C NMR (DMSO-d6) 120575 15622415 11923 12219 12775 12830 12833 12975 13528 1364114965 15945 ESI MSmz 2490 [M]+

24 Synthesis of 56-Dimethyl-4-(2-thienyl)-1H-pyrazolo[34-b]pyridin-3-amine (11) Amixture of 2-chloro-56-dimethyl-4-(thiophen-2-yl)nicotinonitrile (9) (0248 g 1mmol) andhydrazine hydrate (05mL 99) in absolute ethanol (25mL)was refluxed for 16 h The reaction mixture was cooled tort and poured onto an icewater mixture The precipitatethat formed was filtered washed with water dried and

recrystallized from EtOH to give compound 11 as yellowcrystals in 69 yield Mp 301ndash303∘C IR (KBr) ] 3301ndash3134(NH2 NH) 1664 (C=N) cmminus1 1H NMR (DMSO-d6) 120575 210

(s 3H CH3) 252 (s 3H CH

3) 491 (s D

2O exch 2H

NH2) 715ndash728 (m 2H thiophene H3 and H4) 782 (d J =

52Hz 1H thiophene-H5) 1198 (s D2O exch 1H NH) 13C

NMR (DMSO-d6) 120575 1571 2460 10373 12224 12819 1283012868 13540 13646 14725 15101 15808 ESIMSmz 2445[M]+

25 General Procedure for the Synthesis of Compounds 14and 15 To a solution of compound 11 (024 g 1mmol)in glacial acetic acid (25mL) acetyl acetone (12a) andorethyl acetoacetate (12b) (1mmol) were added The mix-ture was refluxed for 14 h and then allowed to cool to rtThe solid formed was filtered washed with ethanol andrecrystallized from EtOHDMF to afford the correspond-ing pyrido[210158403101584034]pyrazolo[15-a]pyrimidine derivatives 14and 15

251 2489-Tetramethyl-10-(2-thienyl)pyrido[210158403101584034]pyr-azolo[15-a]pyrimidine (14) Yield 77 yellow crystalsmp 220ndash222∘C IR (KBr) ] 1665 (C=N) cmminus11H NMR(DMSO-d6) 120575 229 (s 3H CH

3) 243 (s 3H CH

3) 268 (s

3H CH3) 281 (s 3H CH

3) 726ndash728 (m 3H pyrimidine

H thiophene H3 and H4) 78 (d J = 52Hz 1H thiopheneH5) 13CNMR (DMSO-d6) 120575 1647 1778 2485 2571 1030911329 12424 12756 12775 12935 13612 13665 1418914530 15634 15854 16343 ESI MSmz 3089 [M]+

252 289-Trimethyl-4-hydroxy-10-(2-thienyl)pyrido [210158403101584034]pyrazolo[15-a]pyrimidine (15) Yield 73 yellow powdermp 241ndash243∘C IR (KBr) ] 3350ndash2850 (OH) 1664 (C=N)cmminus1 1H NMR (DMSO-d6) 120575 221 (s 3H CH

3) 262 (s

3H CH3) 274 (s 3H CH

3) 667 (s 1H pyrimidine H)

723ndash728 (m 2H thiophene H3 and H4) 780 (d J = 52Hz1H thiophene H5) 1140 (s D

2O exch 1H OH) 13C NMR

(DMSO-d6) 120575 1636 1784 2571 12337 12347 12788 1279912915 12925 13615 13625 14878 15710 15820 1604516342 ESI MSmz 3106 [M]+

26 Synthesis of 4-Amino-89-dimethyl-10-(2-thienyl)pyrido[210158403101584034]pyrazolo[15-a]pyrimidine-2(1H)-one (17) A mix-ture of compound 11 (024 g 1mmol) and ethyl cyanoacetate

Journal of Chemistry 3

(2a) (034 g 30mmol) was heated to reflux for 15min andthen left to cool to rt The solid separated was collected byfiltrationwashedwith ethanol andfinally recrystallized fromEtOHDMF to afford compound 17 as a brown powder in84 yield Mp gt 360∘C IR (KBr) ] 3340ndash3150 (NH NH

2)

1685 (C=O) 1664 (C=N) cmminus1 1H NMR (DMSO-d6) 120575 221(s 3H CH

3) 268 (s 3H CH

3) 401 (s D

2O exch 2H NH

2)

722ndash746 (m 3H pyrimidineH thiopheneH3 andH4) 776ndash792 (m 2H ndashCONH and thiophene H5) 13CNMR (DMSO-d6) 120575 1444 2505 10235 11566 12234 12746 12767 1288513595 13613 14845 15824 16043 16488 16834 ESI MSmz 3116 [M]+

27 General Procedure for the Synthesis of Hydrazones 19aband 22andashc A solution of 56-dimethyl-4-(thiophen-2-yl)-1H-pyrazolo[34-b]pyridin-3-amine (11) (024 g 1mmol) inglacial acetic acid (10mL) obtained by heating was cooledto 5∘C and hydrochloric acid (15mL) was added A solutionof sodium nitrite (007 g 1mmol) in water (10mL) was thengradually added with stirring The resulting solution wasadded gradually within 2 h to a stirred cold solution (0ndash5∘C)of the appropriate active methylene-containg compounds12ab and 2andashc (1mmol) and sodium acetate trihydrate(026 g 20mmol) in ethanol (50mL) and then left for 8 hin a refrigerator (4∘C) The resulting solid was collected byfiltration washed thoroughly with water and dried to givethe respective crude hydrazones 19ab and 22andashc which wereused without any further purification in the next step

28 General Procedure for the Synthesis of Pyrido[210158403101584034]pyrazolo[51-c][124]triazines 21ab and 24andashc The crudehydrazones 19ab and 22andashc (1mmol) were refluxed in pyri-dine (20mL) for 1 h and then left to cool to rt The reactionmixture was then added to cold water and the formed solidwas filtered washed with ethanol and finally recrystallizedfrom EtOHDMF to afford the corresponding 124-triazines21ab and 24andashc respectively

281 3-Acetyl-489-trimethyl-10-(2-thienyl)pyrido[210158403101584034]pyrazolo[51-c][124]triazine (21a) Yield 68 yellowpowder mp 210ndash212∘C IR (KBr) ] 1694 (C=O) 1663 (C=N)cmminus1 1HNMR (DMSO-d6) 120575 239 (s 3H CH

3) 276 (s 3H

CH3) 284 (s 3H CH

3) 313 (s 3H CH

3) 735ndash737 (m 2H

thiophene H3 and H4) 791 (d J = 52Hz 1H thiophene H5)13C NMR (DMSO-d6) 120575 1403 1650 2586 2951 1048712811 12853 12853 12870 12979 13695 13746 1420014400 15935 16650 19938 ESI MSmz 3375 [M]+

282 Ethyl 489-Trimethyl-10-(2-thienyl)pyrido[210158403101584034]pyr-azolo[51-c][124]triazine-3-carboxylate (21b) Yield 62yellow powder mp 180ndash183∘C IR (KBr) ] 1710 (C=O) 1664(C=N) cmminus1 1H NMR (DMSO-d6) 120575 139 (t J = 75Hz 3HCH3) 242 (s 3H CH

3) 281 (s 3H CH

3) 316 (s 3H CH

3)

440 (q J = 75Hz 2H CH2) 723ndash728 (m 2H thiophene

H3 and H4) 781 (d J = 52Hz 1H thiophene H5) 13C NMR(DMSO-d6) 120575 1445 1461 1677 2590 6266 12807 1286912982 13552 13697 13790 13837 14013 14186 1440415900 16442 16637 ESI MSmz 3676 [M]+

283 Ethyl 4-Amino-89-dimethyl-10-(2-thienyl)pyrido [210158403101584034]pyrazolo[51-c][124]triazine-3-carboxylate (24a) Yield67 yellow powder mp 310ndash312∘C IR (KBr) ] 3143 (NH

2)

1694 (C=O) 1663 (C=N) cmminus11H NMR (DMSO-d6) 120575 122(t J = 75Hz 3H CH

3) 209 (s 3H CH

3) 262 (s 3H CH

3)

417 (q J = 75Hz 2H CH2) 690 (s D

2O exch 2H NH

2)

707ndash719 (m 2H thiophene H3 and H4) 770 (d J = 52Hz1H thiophene H5) 13C NMR (DMSO-d6) 120575 1444 16062489 6251 11613 12588 12843 12870 12936 1360313712 13840 14038 14375 15903 16115 16695 ESI MSmz 3686 [M]+

284 4-Amino-89-dimethyl-10-(2-thienyl)pyrido[210158403101584034]pyrazolo[51-c][124]triazine-3-carbo-nitrile (24b) Yield63 yellow powder mp 304ndash306∘C IR (KBr) ] 3292 (NH

2)

2224 (CequivN) 1664 (C=N) cmminus1 1H NMR (DMSO-d6) 120575235 (s 3H CH

3) 275 (s 3H CH

3) 649 (s D

2O exch 2H


52Hz 1H thiophene H5) 13C NMR (DMSO-d6) 120575 16702599 11525 12785 12874 13033 13435 13725 1384214199 14375 15565 16012 15911 16442 ESI MSmz 3221[M]+

285 3-(1H-Benzo[d]imidazole-2-yl)-89-dimethyl-10-(2-thienyl)pyrido[210158403101584034]pyrazolo[51-c][124]triazine-4-amine (24c) Yield 64 yellow powder mp 317ndash319∘C IR(KBr) ] 3300ndash3197 (NH+NH

2) 1635 (C=N) cmminus1 1H NMR

(DMSO-d6) 120575 216 (s 3H CH3) 264 (s 3H CH

3) 727ndash741

(m 6H thiophene H3 and H4+2H ArH+2H NH2) 754 (d J

= 74Hz 1H ArH) 780 (d J = 74Hz 1H ArH) 787 (d J =52Hz 1H thiophene H5) 1198 (s D

2O exch 1H imidazole

NH) 13C NMR (DMSO-d6) 120575 1615 2492 12264 1233012778 12839 12953 13001 13112 13375 13456 1352515062 15315 15502 15865 16173 16633 16714 ESI MSmz 4132 [M]+

3 Results and Discussion

Heating a mixture of thiophene-2-carbaldehyde (1) ethyl 2-cyanoacetate (2a) and 2-butanone (3) in absolute ethanol inthe presence of ammonium acetate pyridinone derivative 8was achieved (Scheme 1)The latter four-component reactionproduced the intermediate 4 via Knoevenagel condensa-tion between thiophene-2-carbaldehyde (1) and ethyl 2-cyanoacetate (2a) The intermediate 5 was instead producedby the condensation of 2-butanone (3) with ammoniumacetate Reaction between 4 and 5 eventually gave theintermediate 6 Cyclization of 6 gave the dihydropyridinederivative 7 which was oxidized to pyridinone derivative 8 asthe final product The IR spectrum of compound 8 exhibitedthe characteristic sharp absorption band of carbonitrile func-tionality at 2219 cmminus1 in addition to NH and C=O absorptionbands at 3102 and 1654 cmminus1 respectively 1HNMR spectrumof 8 showed three singlet signals at 120575 184 and 232 and 1285due to twomethyl groups and aNH group respectively whilethiophene protons signals appeared at 120575 721ndash732 and 785TheESI mass analysis of the pyridinone 8 exhibited a molecularion peak atmz = 2308


NH

O

S

N

S

91011

O

8

S

+O

N NH

SN

N N

S

S

O

4

5

6 7

NH

O

S

S

O

1

3

Me

MeMe

MeMe

MeMe

Me

Me

Me

Me

Me

Me

Me

Me

Me

NH2

NH2

NH2

NH2NH2 POCl3

AcONH4

+

+

2a

CN

CN CN

CN

CN

CN

OEt

NH

NH

EtO

EtO

CHO

Cl∙∙

Scheme 1 Synthetic protocol to achieve the pivotal intermediate pyrazolo[34-b]pyridine derivative 11

∙∙

N N

SO O

O

N N

SN

O

N NN

S

N

N NN

S

N

N N

S O

N

N NN

S

17

11

16

14 15

O

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me Me

Me

2a

NH NH

NH

EtO

NH2

NH2 CNR

R

13a b

R = OEt

OH

HN

HN

12a b

R = Me

Scheme 2 Synthetic pathway to achieve pyrido[210158403101584034]pyrazolo[15-a]pyrimidines 14 15 and 17


N NN

SNN

R

R

N N

S

O

N NN

SN

R O

N NN

SN

R

N N

S

H

N NN

SNN

R

N NN

SN

R

N NN

SN

R

N

NH

R

H

N

MeMe

Me

MeMe

Me

Me

Me

MeMe

Me

Me

Me

MeMe

Me

MeMe

Me

Me

NHNH

NH2 NaNO2HCl N equiv N Cl+ minus

1811

2andashc

22andashc19a b

12a b

23andashc20a b

21a b 24andashc

ab

ab

22ndash24

R

R

19ndash21

c

PyridinePyridine

minusCOOEtminusCN

NH2

HN

HNHN

HN

CN

NH

COMe

COOEt

minusH2O

OH

∙∙∙∙

0ndash5 ∘C

0ndash5 ∘C

0ndash5 ∘C

Scheme 3 Synthesis of pyrido[210158403101584034]pyrazolo[51-c][1 2 4]triazines 21ab and 24andashc

Subsequently reaction of pyridinone derivative 8with phosphorous oxychloride gave the corresponding2-chloropyridine 9 (Scheme 1) in 87 yield The reactionof compound 9 with hydrazine hydrate in ethanol at refluxgave the corresponding 56-dimethyl-4-(2-thienyl)-1H-pyrazolo[34-b]pyridin-3-amine (11) (Scheme 1) The IRspectrum of 11 showed absorption bands due to NH andNH2

functionalities in the region 3301ndash3134 cmminus1 The

signals of protons of NH and NH2groups appeared at 120575 1198

and 491 respectively and disappeared after D2O exchange

The reaction of the pyrazolo[34-b]pyridine derivative 11with acetylacetone (12a) or ethyl acetoacetate (12b) in glacialacetic acid gave in both cases a single product The reactionproducts were identified as pyrido[210158403101584034]pyrazolo[15-a]pyrimidines 14 and 15 respectively (Scheme 2) The struc-tures of the latter compounds were established on the basis of


their spectral data For example the 1H NMR of compound14 showed four singlet signals ofmethyl groups in the region120575229ndash281 in addition to a singlet signal due to the pyrimidineproton around120575 727while its 13CNMRexhibited four signalsin the region 120575 1647ndash2517 due to four methyl groups Themass spectrum of 14 showed a peak corresponding to itsmolecular ion atmz 3089 [M]+

The reaction of compound 11with ethyl cyanoacetate (2a)gave the pyrido[210158403101584034]pyrazolo[15-a]pyrimidine-2(1H)-one derivative 17 (Scheme 2) The IR spectrum of 17 showedbands due to NH

2and NH functionalities in the region

3340ndash3150 cmminus1 in addition to a carbonyl band at 1685 cmminus11H NMR spectrum of 17 revealed two signals (D

2O-

exchangeable) around 120575 40 and 78 which were assigned toNH2and NH protons respectively

Furthermore diazotization of compound 11 furnishedthe respective diazonium salt 18 which was smoothly cou-pled with acetyl acetone (12a) ethyl acetoacetate (12b)ethyl cyanoacetate (2a) malononitrile (2b) and 2-(1H-benzo[d]imidazol-2-yl)acetonitrile (2c) to give the corre-sponding hydrazones 19ab and 22andashc respectively

The hydrazones 19ab and 22andashc underwent intramolec-ular cyclization in boiling pyridine to yield the fused systems21ab and 24andashc respectively (Scheme 3)The IR spectra lackthe characteristic bands of NH groups for products 21a and21b and the nitrile absorption bands for compounds 24a and24c On the other hand themass spectra of compounds 21aband 24andashc showed a peak corresponding to their molecularions Mechanistically compounds 19a and 19b underwentan intramolecular cyclization via loss of a water moleculefrom the intermediates 20a and 20b to give compounds21a and 21b respectively Michael-addition of the endocyclicNH of the hydrazones 22andashc to their nitrile functionalitygave the corresponding compounds 24andashc as reported in theliterature for an analogous system [16]

4 Conclusion

Pyrazolo[34-b]pyridine derivative 11 acts as a key intermedi-ate for the straightforward synthesis of the title compounds14 15 17 21ab and 24andashc These derivatives were synthe-sized starting from readily available reagents using conve-nient procedures Further chemical and biological studies onsuch compounds will be reported in a due course

Conflict of Interests

Theauthors have declared that there is no conflict of interests

Acknowledgment

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

References

[1] N Murakami H Takase T Saito K Iwata H Miura andT Naruse ldquoEffects of a novel non-steroidal anti-inflammatorydrug (M-5011) on bone metabolism in rats with collagen-induced arthritisrdquo European Journal of Pharmacology vol 352no 1 pp 81ndash90 1998

[2] R Kulandasamy A V Adhikari and J P Stables ldquoA new classof anticonvulsants possessing 6Hz activity 34-dialkyloxy thio-phene bishydrazonesrdquo European Journal of Medicinal Chem-istry vol 44 no 11 pp 4376ndash4384 2009

[3] X Lu B Wan S G Franzblau and Q You ldquoDesignsynthesis and anti-tubercular evaluation of new 2-acylatedand 2-alkylated amino-5-(4-(benzyloxy)phenyl)thiophene-3-carboxylic acid derivatives Part 1rdquo European Journal of Medici-nal Chemistry vol 46 no 9 pp 3551ndash3563 2011

[4] N K Kaushik H S Kim Y J Chae et al ldquoSynthesisand anticancer activity of di(3-thienyl)methanol and di(3-thienyl)methanerdquo Molecules vol 17 no 10 pp 11456ndash114682012

[5] C Corral J Lissavetzky IManzanares et al ldquoSynthesis and pre-liminary pharmacological evaluation of thiophene analoguesof viloxazine as potentialantidepressant drugsrdquo Bioorganic andMedicinal Chemistry vol 7 no 7 pp 1349ndash1359 1999

[6] T E Ali ldquoSynthesis of some novel pyrazolo[34-b]pyridine andpyrazolo[34-d]pyrimidine derivatives bearing 56-diphenyl-124-triazine moiety as potential antimicrobial agentsrdquo Euro-pean Journal of Medicinal Chemistry vol 44 no 11 pp 4385ndash4392 2009

[7] T J Tucker J T Sisko R M Tynebor et al ldquoDiscoveryof 3-5-[(6-amino-1H-pyrazolo[34-b]pyridine-3-yl)methoxy]-2-chlorophenoxy-5-chlorobenzonitrile (MK-4965) a potentorally bioavailable HIV-1 non-nucleoside reverse transcriptaseinhibitor with improved potency against key mutant virusesrdquoJournal of Medicinal Chemistry vol 51 no 20 pp 6503ndash65112008

[8] S B Bharate T R Mahajan Y R Gole et al ldquoSynthesis andevaluation of pyrazolo[34-b]pyridines and its structural ana-logues as TNF-120572 and IL-6 inhibitorsrdquo Bioorganic and MedicinalChemistry vol 16 no 15 pp 7167ndash7176 2008

[9] L R S Dias M J F Alvim A C C Freitas E J Barreiroand A L P Miranda ldquoSynthesis and analgesic properties of5-acyl-arylhydrazone 1-H pyrazolo [34-b]pyridine derivativesrdquoPharmaceutica Acta Helvetiae vol 69 no 3 pp 163ndash169 1994

[10] M Chioua A Samadi E Soriano O Lozach L Meijer andJ Marco-Contelles ldquoSynthesis and biological evaluation of36-diamino-1H-pyrazolo[34-b]pyridine derivatives as proteinkinase inhibitorsrdquo Bioorganic and Medicinal Chemistry Lettersvol 19 no 16 pp 4566ndash4569 2009

[11] B Vellas O Sol P J Snyder et al ldquoEHT0202 in Alzheimerrsquosdisease a 3-month randomized placebo-controlled double-blind studyrdquo Current Alzheimer Research vol 8 no 2 pp 203ndash212 2011

[12] H Hohn I Polacek and E Schulze ldquoPotential antidiabeticagents Pyrazolo[34-b]pyridinesrdquo Journal of Medicinal Chem-istry vol 16 no 12 pp 1340ndash1346 1973

[13] H A Abdel-Aziz P Ahmad A Kadi K A Al-Rashood HA Ghabbour and H K Fun ldquoUnexpected ring-opening of3-aroylbenzo[b]furans at room temperature a new route forthe construction of phenol-substituted pyrazolesrdquo TetrahedronLetters vol 54 no 26 pp 3424ndash3426 2013


[14] A M Alafeefy S Isik H A Abdel-Aziz et al ldquoCarbonicanhydrase inhibitors benzenesulfonamides incorporating cy-anoacrylamide moieties are low nanomolarsubnanomolar in-hibitors of the tumor-associated isoforms IX and XIIrdquo Bioor-ganic and Medicinal Chemistry vol 21 no 6 pp 1396ndash14032013

[15] A M Farag K M Dawood H A Abdel-Aziz N A Hamdyand I M I Fakhr ldquoSynthesis of some new azole pyrimidinepyran and benzonaphtho[b]furan derivatives incorporatingthiazolo[32-a]benzimidazole moietyrdquo Journal of HeterocyclicChemistry vol 48 no 2 pp 355ndash360 2011

[16] N A Hamdy H A Abdel-Aziz A M Farag and I M IFakhr ldquoSynthesis of some 13-thiazole 134-thiadiazole pyra-zolo [51-c]-124-triazine and 124-triazolo[51-c]-124-triazinederivatives based on the thiazolo[32-a]benzimidazole moietyrdquoMonatshefte fur Chemie vol 138 no 10 pp 1001ndash1010 2007

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O

HN

SHN O

HN

NN

N

O

O

OOO

HN

O

N NN

NHN

O

O

I II III

H3C

H3C

H3C CH3CH3

Figure 1 Chemical structures of Viloxazine (I) Etazolate (II) and Glicaramide (III)

for 13C NMR Chemical shifts are expressed in 120575 values(ppm) relative to TMS as an internal standard Couplingconstants (J) are expressed in Hz D

2Owas added to confirm

the exchangeable protons Mass spectra were measured onAgilent Triple Quadrupole 6410 QQQ LCMS with ESI(Electrospray ionization) source

22 Synthesis of 56-Dimethyl-2-oxo-4-(2-thienyl)-12-dihy-dropyridine-3-carbonitrile (8) A mixture of thiophene-2-carbaldehyde (1) (112 g 01mol) ethyl 2-cyanoacetate (2a)(113 g 01mol) 2-butanone (3) (72 g 01mol) and ammo-nium acetate (450 g 06mol) in absolute ethanol (150mL)was heated to reflux for 12 h The precipitate formed aftercooling to rt was filtered washed with ethanol and driedCrystallization from ethanol gave compound 8 as yellowcrystals in 72 yield mp 152ndash154∘C IR (KBr) ] 3102 (NH)2219 (CequivN) 1654 (C=O) cmminus1 1H NMR (DMSO-d6) 120575 184(s 3H CH

3) 232 (s 3H CH

3) 721ndash732 (m 2H thiophene

H3 and H4) 785 (d J = 52Hz 1H thiophene H5) 1285 (sD2O exch 1H NH) 13C NMR (DMSO-d6) 120575 1560 2530

11525 12207 12776 12812 12830 12977 13531 1364215945 16832 ESI MSmz 2308 [M]+

23 Synthesis of 2-Chloro-56-dimethyl-4-(2-thienyl)nicotin-onitrile (9) A solution of pyridinone derivative 8 (23 g10mmol) in phosphorous oxychloride (10mL) was refluxedgently for 5 h It was then left to cool to rt and pouredcarefully onto crashed-ice with stirring The solid obtainedwas filtered washedwithwater dried and recrystallized fromethanol to give compound 9 as pale yellow crystals in 87yield Mp 285ndash287∘C IR (KBr) ] 2228 (CequivN) 1600 (C=N)cmminus1 1H NMR (DMSO-d6) 120575 216 (s 3H CH

3) 258 (s 3H

CH3) 726ndash735 (m 2H thiophene H3 and H4) 789 (d J =

52Hz 1H thiophene H5) 13C NMR (DMSO-d6) 120575 15622415 11923 12219 12775 12830 12833 12975 13528 1364114965 15945 ESI MSmz 2490 [M]+

24 Synthesis of 56-Dimethyl-4-(2-thienyl)-1H-pyrazolo[34-b]pyridin-3-amine (11) Amixture of 2-chloro-56-dimethyl-4-(thiophen-2-yl)nicotinonitrile (9) (0248 g 1mmol) andhydrazine hydrate (05mL 99) in absolute ethanol (25mL)was refluxed for 16 h The reaction mixture was cooled tort and poured onto an icewater mixture The precipitatethat formed was filtered washed with water dried and

recrystallized from EtOH to give compound 11 as yellowcrystals in 69 yield Mp 301ndash303∘C IR (KBr) ] 3301ndash3134(NH2 NH) 1664 (C=N) cmminus1 1H NMR (DMSO-d6) 120575 210

(s 3H CH3) 252 (s 3H CH

3) 491 (s D

2O exch 2H


52Hz 1H thiophene-H5) 1198 (s D2O exch 1H NH) 13C

NMR (DMSO-d6) 120575 1571 2460 10373 12224 12819 1283012868 13540 13646 14725 15101 15808 ESIMSmz 2445[M]+

25 General Procedure for the Synthesis of Compounds 14and 15 To a solution of compound 11 (024 g 1mmol)in glacial acetic acid (25mL) acetyl acetone (12a) andorethyl acetoacetate (12b) (1mmol) were added The mix-ture was refluxed for 14 h and then allowed to cool to rtThe solid formed was filtered washed with ethanol andrecrystallized from EtOHDMF to afford the correspond-ing pyrido[210158403101584034]pyrazolo[15-a]pyrimidine derivatives 14and 15

251 2489-Tetramethyl-10-(2-thienyl)pyrido[210158403101584034]pyr-azolo[15-a]pyrimidine (14) Yield 77 yellow crystalsmp 220ndash222∘C IR (KBr) ] 1665 (C=N) cmminus11H NMR(DMSO-d6) 120575 229 (s 3H CH

3) 243 (s 3H CH

3) 268 (s

3H CH3) 281 (s 3H CH

3) 726ndash728 (m 3H pyrimidine

H thiophene H3 and H4) 78 (d J = 52Hz 1H thiopheneH5) 13CNMR (DMSO-d6) 120575 1647 1778 2485 2571 1030911329 12424 12756 12775 12935 13612 13665 1418914530 15634 15854 16343 ESI MSmz 3089 [M]+

252 289-Trimethyl-4-hydroxy-10-(2-thienyl)pyrido [210158403101584034]pyrazolo[15-a]pyrimidine (15) Yield 73 yellow powdermp 241ndash243∘C IR (KBr) ] 3350ndash2850 (OH) 1664 (C=N)cmminus1 1H NMR (DMSO-d6) 120575 221 (s 3H CH

3) 262 (s

3H CH3) 274 (s 3H CH

3) 667 (s 1H pyrimidine H)

723ndash728 (m 2H thiophene H3 and H4) 780 (d J = 52Hz1H thiophene H5) 1140 (s D

2O exch 1H OH) 13C NMR

(DMSO-d6) 120575 1636 1784 2571 12337 12347 12788 1279912915 12925 13615 13625 14878 15710 15820 1604516342 ESI MSmz 3106 [M]+

26 Synthesis of 4-Amino-89-dimethyl-10-(2-thienyl)pyrido[210158403101584034]pyrazolo[15-a]pyrimidine-2(1H)-one (17) A mix-ture of compound 11 (024 g 1mmol) and ethyl cyanoacetate



2)


3) 268 (s 3H CH

3) 401 (s D

2O exch 2H NH

2)





3) 276 (s 3H

CH3) 284 (s 3H CH

3) 313 (s 3H CH

3) 735ndash737 (m 2H



3) 281 (s 3H CH

3) 316 (s 3H CH

3)




2)


3) 209 (s 3H CH

3) 262 (s 3H CH

3)

417 (q J = 75Hz 2H CH2) 690 (s D

2O exch 2H NH

2)



2)


3) 275 (s 3H CH

3) 649 (s D

2O exch 2H





(DMSO-d6) 120575 216 (s 3H CH3) 264 (s 3H CH

3) 727ndash741








NH

O

S

N

S

91011

O

8

S

+O

N NH

SN

N N

S

S

O

4

5

6 7

NH

O

S

S

O

1

3

Me

MeMe

MeMe

MeMe

Me

Me

Me

Me

Me

Me

Me

Me

Me

NH2

NH2

NH2

NH2NH2 POCl3

AcONH4

+

+

2a

CN

CN CN

CN

CN

CN

OEt

NH

NH

EtO

EtO

CHO

Cl∙∙


∙∙

N N

SO O

O

N N

SN

O

N NN

S

N

N NN

S

N

N N

S O

N

N NN

S

17

11

16

14 15

O

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me Me

Me

2a

NH NH

NH

EtO

NH2

NH2 CNR

R

13a b

R = OEt

OH

HN

HN

12a b

R = Me



N NN

SNN

R

R

N N

S

O

N NN

SN

R O

N NN

SN

R

N N

S

H

N NN

SNN

R

N NN

SN

R

N NN

SN

R

N

NH

R

H

N

MeMe

Me

MeMe

Me

Me

Me

MeMe

Me

Me

Me

MeMe

Me

MeMe

Me

Me

NHNH


1811

2andashc

22andashc19a b

12a b

23andashc20a b

21a b 24andashc

ab

ab

22ndash24

R

R

19ndash21

c

PyridinePyridine

minusCOOEtminusCN

NH2

HN

HNHN

HN

CN

NH

COMe

COOEt

minusH2O

OH

∙∙∙∙

0ndash5 ∘C

0ndash5 ∘C

0ndash5 ∘C












2O-




4 Conclusion




Acknowledgment


References



























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



2)


3) 268 (s 3H CH

3) 401 (s D

2O exch 2H NH

2)





3) 276 (s 3H

CH3) 284 (s 3H CH

3) 313 (s 3H CH

3) 735ndash737 (m 2H



3) 281 (s 3H CH

3) 316 (s 3H CH

3)




2)


3) 209 (s 3H CH

3) 262 (s 3H CH

3)

417 (q J = 75Hz 2H CH2) 690 (s D

2O exch 2H NH

2)



2)


3) 275 (s 3H CH

3) 649 (s D

2O exch 2H





(DMSO-d6) 120575 216 (s 3H CH3) 264 (s 3H CH

3) 727ndash741








NH

O

S

N

S

91011

O

8

S

+O

N NH

SN

N N

S

S

O

4

5

6 7

NH

O

S

S

O

1

3

Me

MeMe

MeMe

MeMe

Me

Me

Me

Me

Me

Me

Me

Me

Me

NH2

NH2

NH2

NH2NH2 POCl3

AcONH4

+

+

2a

CN

CN CN

CN

CN

CN

OEt

NH

NH

EtO

EtO

CHO

Cl∙∙


∙∙

N N

SO O

O

N N

SN

O

N NN

S

N

N NN

S

N

N N

S O

N

N NN

S

17

11

16

14 15

O

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me Me

Me

2a

NH NH

NH

EtO

NH2

NH2 CNR

R

13a b

R = OEt

OH

HN

HN

12a b

R = Me



N NN

SNN

R

R

N N

S

O

N NN

SN

R O

N NN

SN

R

N N

S

H

N NN

SNN

R

N NN

SN

R

N NN

SN

R

N

NH

R

H

N

MeMe

Me

MeMe

Me

Me

Me

MeMe

Me

Me

Me

MeMe

Me

MeMe

Me

Me

NHNH


1811

2andashc

22andashc19a b

12a b

23andashc20a b

21a b 24andashc

ab

ab

22ndash24

R

R

19ndash21

c

PyridinePyridine

minusCOOEtminusCN

NH2

HN

HNHN

HN

CN

NH

COMe

COOEt

minusH2O

OH

∙∙∙∙

0ndash5 ∘C

0ndash5 ∘C

0ndash5 ∘C












2O-




4 Conclusion




Acknowledgment


References



























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


NH

O

S

N

S

91011

O

8

S

+O

N NH

SN

N N

S

S

O

4

5

6 7

NH

O

S

S

O

1

3

Me

MeMe

MeMe

MeMe

Me

Me

Me

Me

Me

Me

Me

Me

Me

NH2

NH2

NH2

NH2NH2 POCl3

AcONH4

+

+

2a

CN

CN CN

CN

CN

CN

OEt

NH

NH

EtO

EtO

CHO

Cl∙∙


∙∙

N N

SO O

O

N N

SN

O

N NN

S

N

N NN

S

N

N N

S O

N

N NN

S

17

11

16

14 15

O

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me Me

Me

2a

NH NH

NH

EtO

NH2

NH2 CNR

R

13a b

R = OEt

OH

HN

HN

12a b

R = Me



N NN

SNN

R

R

N N

S

O

N NN

SN

R O

N NN

SN

R

N N

S

H

N NN

SNN

R

N NN

SN

R

N NN

SN

R

N

NH

R

H

N

MeMe

Me

MeMe

Me

Me

Me

MeMe

Me

Me

Me

MeMe

Me

MeMe

Me

Me

NHNH


1811

2andashc

22andashc19a b

12a b

23andashc20a b

21a b 24andashc

ab

ab

22ndash24

R

R

19ndash21

c

PyridinePyridine

minusCOOEtminusCN

NH2

HN

HNHN

HN

CN

NH

COMe

COOEt

minusH2O

OH

∙∙∙∙

0ndash5 ∘C

0ndash5 ∘C

0ndash5 ∘C












2O-




4 Conclusion




Acknowledgment


References



























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


N NN

SNN

R

R

N N

S

O

N NN

SN

R O

N NN

SN

R

N N

S

H

N NN

SNN

R

N NN

SN

R

N NN

SN

R

N

NH

R

H

N

MeMe

Me

MeMe

Me

Me

Me

MeMe

Me

Me

Me

MeMe

Me

MeMe

Me

Me

NHNH


1811

2andashc

22andashc19a b

12a b

23andashc20a b

21a b 24andashc

ab

ab

22ndash24

R

R

19ndash21

c

PyridinePyridine

minusCOOEtminusCN

NH2

HN

HNHN

HN

CN

NH

COMe

COOEt

minusH2O

OH

∙∙∙∙

0ndash5 ∘C

0ndash5 ∘C

0ndash5 ∘C












2O-




4 Conclusion




Acknowledgment


References



























Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






2O-




4 Conclusion




Acknowledgment


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

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