research article a novel synthesis of 1,2,3-benzotriazinones...

Research ArticleA Novel Synthesis of 123-Benzotriazinones from2-(o-Aminophenyl)oxazolines

Fernando Rocha-Alonzo1 Daniel Chaacutevez2 Adriaacuten Ochoa-Teraacuten2 David Morales-Morales3

Enrique F Velaacutezquez-Contreras1 and Miguel Parra-Hake2

1Departamento de Ciencias Quımico Biologicas Universidad de Sonora Hermosillo SON Mexico2Centro de Graduados e Investigacion en Quımica Instituto Tecnologico de Tijuana Tijuana BC Mexico3Instituto de Quımica Universidad Nacional Autonoma de Mexico Ciudad de Mexico Mexico

Correspondence should be addressed to Fernando Rocha-Alonzo fernandorochaguayacanusonmx

Received 29 September 2016 Accepted 13 December 2016 Published 19 January 2017

Academic Editor Hakan Arslan

Copyright copy 2017 Fernando Rocha-Alonzo et alThis is an open access article distributed under theCreative CommonsAttributionLicense which permits unrestricted use distribution and reproduction in anymedium provided the originalwork is properly cited

123-Benzotriazinones were synthesized in excellent yields by the reaction of 2-(o-aminophenyl)oxazolines and isoamyl nitrite inmethanol The crystal structure of the acetyl derivative of one of the 123-benzotriazinones provided additional support for thespectroscopic structural characterization of the title compounds

1 Introduction

123-Benzotriazinones are compounds widely investigateddue to their interesting biological and chemical proper-ties These heterocyclic compounds have been studied asanaesthetic [1] anti-inflammatory [2] anticancer [3 4] andantitumoral [5 6] agents In organic synthesis triazinonesare used as an activating moiety in coupling agents for thepreparation of peptides and amino acids [7ndash9] As a resultof their biological and synthetic importance there is stillinterest in the development of methods for the synthesis ofcompounds which contain the 123-triazinone moiety

In general 123-benzotriazinones are prepared via intra-molecular cyclization through diazonium ion condensationwith an adjacent nucleophilic function Using this strategy123-triazinones have been obtained from aminobenzamides[10ndash12] aminonitriles [13 14] and triazenes [15ndash17] Otherworkers have reported the synthesis of 123-benzotriazinonesby the oxidation of indazol-3-amines with hydrogen peroxidein the presence of sodium carbonate though in low yieldsand by the cyclization of 2-azido-N-4-toluoylbenzamide inmoderate yields [18]

In this report we describe facile access to the title com-pounds from chiral and nonchiral 2-(o-aminophenyl)oxa-zolines Since racemization is not possible during the reac-tion this method allows the preparation of enantiopure 123-benzotriazinones in excellent yields

2 Results and Discussion

The first step for the synthesis of 123-benzotriazinones wasthe preparation of 2-(o-aminophenyl)oxazolines 3andash3c (see(1)) These oxazolines were prepared in high yields (58ndash80) by cyclization of anthranilonitrile with ethanolaminesunder basic conditions in a mixture of glycerol and ethyleneglycol following the methodology reported by Gomez andcoworkers [19] In the literature it has been reported thatoxazolines 3a and 3b were obtained as oils whereas in ourwork both were isolated as solids we believe this fact is dueto problems in the purification process in the previous reportNevertheless NMR and IR spectroscopic and mass spec-trometry data are consistent with those previously reported[20]

Hindawi Publishing CorporationJournal of ChemistryVolume 2017 Article ID 2384780 5 pageshttpsdoiorg10115520172384780

2 Journal of Chemistry

CN R

HO+

O N

R1 2

3a R = H 58

(R)-b R = Ph 72

(R)-c R = Et 80

Glycerolethylene glycol 105∘CNH2

NH2NH2

K2CO3

(1)

Once the necessary 2-(o-aminophenyl)oxazolines wereobtained the next step was the synthesis of the 123-benzotriazinones 4andash4c Compounds 4andash4c were synthe-sized by diazotization reaction involving oxazolines 3andash3c and methanolic isoamyl nitrite In all cases the new123-benzotriazinones were obtained in quantitative yields(Scheme 1)

It is assumed that the reaction takes place by theintermediacy of the diazonium ion 5 formed from 2-(o-aminophenyl)oxazoline (3) using a large excess of isoamylnitrite in order to ensure formation of the diazonium salt(Scheme 1)The electronwithdrawing effect of the diazoniumgroup in 5 could promote oxazolinyl ring hydrolysis takingwater from the alcoholic media and producing the 2-carbamoylbenzenediazonium 6 The 123-triazinone moietyin 4 is then achieved by ring closure between the amideand the adjacent diazonium group in 6 Similar mechanisticassumptions were proposed by Colomer and Moyano in thesynthesis of this kind of compound from aminonitriles [1321]

Infrared spectroscopy of compounds 4andash4c showed asingle band at ca (]) 3430 cmminus1 due to the O-H stretchingthe bands at ca (]) 1687 cmminus1 and at ca (]) 1657 cmminus1correspond to the N=N and the C=O stretching respec-tively 1HNMR spectroscopy showed the following aromatichydrogen from the 123-benzotriazinone moiety appearedas an ABCD system with the characteristic two doubletsand two triplets between 829 and 787 ppm slightly shiftedto lower field relative to the 2-(o-aminophenyl)oxazolinesaliphatic protons appeared between 639 and 090 ppm Forcompound 4b the phenyl protons are at (120575) 743 ppm13C NMR spectroscopy showed carbonyl carbon at ca (120575)1565 ppm aromatic carbon appeared in the range 1461ndash1203 ppm and aliphatic carbon in the range 642ndash108 ppmThe proton of hydroxyl group in the proposed structurewas not identified by 1H NMR but the carbinol moietywas inferred from the chemical shifts on 13C NMR dataSince compounds 4andash4c are novel high-resolution massspectrometry was run with no significant difference betweencalculated and obtained values (less than plusmn0003 amu)In general the molecular formula assignment and thespectroscopic characterization were consistent with theirstructures

In order to corroborate the presence of the hydroxylgroup the acetyl derivative 7a was obtained by reaction of4a with acetic anhydride in pyridine (see (2)) NMR spectrafor the acetyl derivative 7a turned out to be similar to 4a but

with new signals for the acetyl moiety at 120575H 195 and 120575C 215for the methyl group and 120575C 1719 for the ester carbonyl

4a

N

N

O

OH

N pyr rt

7a

N

N

O

OAc

NO(Ac)2

(2)

Suitable crystals for X-ray diffraction studies of 123-benzotriazinone 7a were grown by slow vapor diffusion ofhexane into a saturated solution in ethyl acetate Compound7a crystallized in the triclinic system with the space group PıMolecular structure of 123-benzotriazinone 7a is shown inFigure 1 which confirms the presence of the 123-triazinonesystem and indirectly corroborates the hydroxyl group in123-benzotriazinones 4andash4c

In the molecular structure of 7a the N1=N2 bond[12715(19) A] is longer than the typical value for N=N doublebond (1236 A) [22] whereas the N2-N3 bond [13728(19) A]is slightly shorter than the typical value for N-N singlebond (1404 A) [22]The structure shows coplanarity betweenthe two rings These data are in agreement with crystalstructure reports of related 123-benzotriazinones [17 23ndash25] Crystallographic data of 7a are included as supplemen-tary material (in Supplementary Material available online athttpsdoiorg10115520172384780)

Of interest to pharmaceutical applications Reingruberet al have suggested that the coplanar structure in 123-benzotriazinones could haveDNA-intercalating abilities suchas those displayed by some anticancer agents [17]

In summary we have presented an efficient method forthe synthesis of 123-benzotriazinones from 2-(o-amino-phenyl)oxazolines in high yields

3 Experimental Section

31 General Procedures All reagents were purchased in thehighest quality available and were used without furtherpurification The solvents used in column chromatographywere obtained from commercial suppliers and used without

Journal of Chemistry 3

O N

R

3

O N

R

NHO

OHR

4

N

N

O

OHR

N

5 6

MeOH rt

a R = H(R)-b R = Ph(R)-c R = Et

NH2

N2N2

C2H11ONO

Scheme 1 Synthesis of 123-benzotriazinones 4andash4c

C8

C7

C6 C4aC5 C4

C8a

N2

N1

N3C10

C9

C1

O1

O3

C2

O2

Figure 1 Molecular structure of 7a (ORTEP drawing showing 50ellipsoids)

distillation Infrared spectra (FTIR) were recorded on aPerkin Elmer FT-IR 1600 spectrophotometer Nuclear mag-netic resonance 1H(at 200MHz) and 13C (at 50MHz) spectrawere recorded on a Varian Mercury 200MHz spectrometerin (CD

3)2CO with TMS as internal standard Melting points

were obtained on an Electrothermal 88629 apparatus Opticalrotations were determined using an Autopol III polarimeterEIMS were recorded on an Agilent Technologies 5975C massspectrometer The ESI-HRMS data were performed at High-Resolution Mass Spectrometry Facility UC Riverside

32 General Procedure for the Synthesis of 2-(o-Aminophe-nyl)Oxazoline (3) Anthranilonitrile (1 equiv) potassiumcarbonate (01 equiv) and ethanolamine (17 equiv) wereplaced in a Schlenk flask followed by a solution of glycerolin dry ethylene glycol (5 9) (33mL of solution per mmol ofanthranilonitrile) The resulting mixture was stirred at 105∘Cunder argon until the disappearance of the nitrile (followedby TLC hexaneethyl acetate 3 1) The mixture was cooledto room temperature and then poured over crushed iceThe resulting white solid was filtered and then dissolvedin dichloromethane The organic solution was washed withwater dried over anhydrous Na

2SO4 and filtered and the

solvent was evaporated under reduced pressure to give a

crude product that was purified by flash chromatography onneutral alumina (hexaneethyl acetate 20 1) to give the pureproduct

2-[45-Dihydro-13-oxazol-2-yl]aniline (3a) White solid (58yield) mp 52-53∘C FTIR (KBr) ] 3384 3264 16301254 cmminus1 1H NMR [(CD

3)2CO 200MHz] 120575 769 (dd 119869 =

79 17Hz 1H) 719 (ddd 119869 = 83 71 16Hz 1H) 666 (m2H) 604 (s 2H) 430 (m 2H) 408 (m 2H) 13C NMR[(CD3)2CO 50MHz] 120575 1644 1481 1316 1293 1157 1154

1089 656 548 EI-MS (Int ) [M]+ 162 (100) 131 (36) 118(33)

2-[(4R)-4-Phenyl-45-dihydro-13-oxazol-2-yl]aniline (3b)Yellow solid (72 yield) mp 62-63∘C [120572]119863

20= minus182 (c 022

MeOH) FTIR (KBr) ] 3416 3272 1631 1249 cmminus1 1H NMR[(CD3)2CO 200MHz] 120575 770 (dd 119869 = 80 18Hz 1H) 732

(m 5H) 721 (ddd 119869 = 84 70 14Hz 1H) 683 (dd 119869 = 8608Hz 1H) 680 (br s 2H) 660 (ddd 119869 = 82 70 12Hz 1H)543 (dd 119869 = 100 82Hz 1H) 466 (dd 119869 = 100 83Hz 1H)411 (dd 119869 = 82 82Hz 1H) 13CNMR [(CD

3)2CO 50MHz]

120575 1650 1488 1427 1323 1298 1287 1275 1266 1160 11571086 730 702 EI-MS (Int ) [M]+ 238 (100) 207 (48) 118(50)

2-[(4R)-4-Ethyl-45-dihydro-13-oxazol-2-yl]aniline (3c) Brownoil (80 yield) [120572]119863

20= +10 (c 022 MeOH) FTIR (NaCl) ]

3461 3286 1632 1263 cmminus1 1HNMR [(CD3)2CO 200MHz]

120575 762 (dd 119869 = 79 16Hz 1H) 715 (ddd 119869 = 80 60 20Hz1H) 677 (dd 119869 = 85 07Hz 1H) 674 (br s 2H) 655 (ddd119869 = 82 70 12Hz 1H) 428 (m 2H) 390 (m 1H) 159 (m2H) 097 (t 119869 = 74Hz 3H) 13CNMR [(CD

3)2CO 50MHz]

120575 1641 1503 1324 130 1161 1154 109 708 688 295 104EI-MS (Int ) [M]+ 190 (81) 161 (100) 133 (59) 118 (31)

33 General Procedure for the Synthesis of 123-Benzotriazi-nones To a solution of 2-(o-aminophenyl)oxazoline (3)(1 equiv) in methanol a solution of isoamyl nitrite (8 equiv)in methanol was added The reaction mixture was stirredat room temperature until the disappearance of the aniline(followed by TLC hexaneethyl acetate 3 1)The solvent wasevaporated under reduced pressure to give a crude productthat was purified by washing with petroleum ether andrecrystallization from hexaneethyl acetate

3-(2-Hydroxyethyl)-123-benzotriazin-4(3H)-one (4a) Whitesolid (gt99 yield) mp 111-112∘C FTIR (KBr) ] 3431 16911646 1300 cmminus1 1H NMR [(CD

3)2CO 200MHz] 120575 829

(ddd 119869 = 78 15 07Hz 1H) 815 (ddd 119869 = 81 15 06Hz1H) 806 (ddd 119869 = 81 70 15Hz 1H) 791 (ddd 119869 = 7969 16Hz 1H) 457 (t 119869 = 56Hz 2H) 402 (t 119869 = 56Hz2H) 13C NMR [(CD

3)2CO 50MHz] 120575 1571 1461 1368

1342 1298 1265 1217 612 541 ESI-HRMS 1920778 (100)calculated for [M+H]+ C

9H10N3O2 1920768

3-((R)-2-Hydroxy-1-phenylethyl)-123-benzotriazin-4(3H)-one(4b) White solid (gt99 yield) mp 79-80∘C [120572]119863

20= minus183

(c 022 MeOH) FTIR (KBr) ] 3419 1683 1661 1294 cmminus1


1H NMR [(CD3)2CO 200MHz] 120575 827 (ddd 119869 = 78 15

06Hz 1H) 816 (ddd 119869 = 81 13 06Hz 1H) 804 (ddd119869 = 81 71 15Hz 1H) 787 (ddd 119869 = 78 71 13Hz 1H) 743(m 5H) 639 (dd 119869 = 97 52Hz 1H) 470 (dd 119869 = 11497Hz 1H) 425 (dd 119869 = 114 52Hz 1H) 13C NMR[(CD3)2CO 50MHz] 120575 1561 1446 1386 1360 1333 1294

1289 1289 1287 1257 1205 640 633 ESI-HRMS 2681094(100) calculated for [M+H]+ C

15H14N3O2 2681081

3-((R)-1-Hydroxybutan-2-yl)-123-benzotriazin-4(3H)-one (4c)White solid (gt99 yield) mp 89-90∘C [120572]119863

20= minus5 (c 022

MeOH) FTIR (KBr) ] 3439 1686 1663 1296 cmminus1 1HNMR[(CD3)2CO 200MHz] 120575 829 (ddd 119869 = 79 15 06Hz 1H)

816 (ddd 119869 = 81 15 06Hz 1H) 807 (ddd 119869 = 82 7015Hz 1H) 791 (ddd 119869 = 79 70 15Hz 1H) 522 (m 1H)410 (dd 119869 = 113 84Hz 1H) 396 (dd 119869 = 113 51 Hz1H) 199 (quin 119869 = 74Hz 2H) 090 (t 119869 = 74Hz 3H) 13CNMR [(CD

3)2CO 50MHz] 120575 1566 1445 1358 1332 1288


11H14N3O2 2201081

34 Procedure for the Synthesis of Acetylated Derivative 3-(2-Hydroxyethyl)-123-benzotriazin-4(3H)-onyl Acetate (7a)To a solution of 123-benzotriazinone (4a) (200mg 10mmolin 30mL pyridine) excess of acetic anhydride (30mL32mmol) was added The reaction mixture was stirred atroom temperature for 24 h To purify the acetylated derivative7a sodium hydroxide (26 g 64mmol in 30mL of water) wasadded to the reaction mixture and then extracted with ethylacetate (3 times 10mL) The organic phase was washed with 2MHCl (3 times 40mL) dried over anhydrous sodium sulfate andfiltered The solvent was evaporated under reduced pressureand the white solid dried in vacuum for 24 h

A white solid was obtained (240mg 10mmol quanti-tative yield) FTIR (KBr) ] 3072 1741 1685 1230 cmminus1 1HNMR [(CD

3)2CO 200MHz] 120575 830 (ddd 119869 = 78 15

06Hz) 817 (ddd 119869 = 81 16 06Hz) 809 (ddd 119869 = 81 7015Hz) 793 (ddd 119869 = 78 69 16Hz) 470 (t 119869 = 56Hz 2H)455 (t 119869 = 56Hz 2H) 195 (s 3H) 13C NMR [(CD

3)2CO

50MHz] 120575 1719 1570 1460 1369 1344 1300 1265 1216630 504 215

X-Ray Data Collection and Refinement The details of thestructure determination are given in Table S1 atomiccoordinates are given in Table S2 and bond lengths (A)and angles (∘) are given in Table S3 in Supporting Infor-mation Crystallographic data for the structural analyseshave been deposited with the Cambridge CrystallographicData Centre CCDC 903418 Further details of the crys-tal structure investigation are available free of charge viahttpswwwccdccamacukcontsretrievinghtml (or fromtheCCDC 12UnionRoad CambridgeCB2 1EZUK fax +441223 336033 e-mail depositccdccamacuk)

Competing Interests

The authors declare that there are no competing interestsregarding the publication of this paper

Acknowledgments

The authors gratefully acknowledge support from Con-sejo Nacional de Ciencia y Tecnologıa (CONACyT Grant36435-E and ldquoSupramolecular ChemistryThematicNetworkrdquoGrant 271884) Programa de Mejoramiento del Profeso-rado (Apoyo a la Incorporacion de Nuevos PTC GrantPromep1035114462) and Consejo del Sistema Nacionalde Educacion Tecnologica (COSNET Grant 486-02-P) Theauthors are indebted to IgnacioRiveroEspejel andRatnasamySomanathan for their support in this work

References

[1] G Caliendo F Fiorino P Grieco et al ldquoPreparation and localanaesthetic activity of benzotriazinone and benzoyltriazolederivativesrdquo European Journal of Medicinal Chemistry vol 34no 12 pp 1043ndash1051 1999

[2] G Z Zheng P Bhatia J Daanen et al ldquoStructure-activity rela-tionship of triazafluorenone derivatives as potent and selectivemGluR1 antagonistsrdquo Journal of Medicinal Chemistry vol 48no 23 pp 7374ndash7388 2005

[3] A Vaisburg N Bernstein S Frechette et al ldquo(2-Amino-phenyl)-amides of 120596-substituted alkanoic acids as new histonedeacetylase inhibitorsrdquo Bioorganic amp Medicinal Chemistry Let-ters vol 14 no 1 pp 283ndash287 2004

[4] A-M Chollet T Le Diguarher N Kucharczyk et al ldquoSolid-phase synthesis of120572-substituted 3-bisarylthioN-hydroxy propi-onamides as specific MMP inhibitorsrdquo Bioorganic amp MedicinalChemistry vol 10 no 3 pp 531ndash544 2002

[5] T Le Diguarher A-M Chollet M Bertrand et al ldquoStereospe-cific synthesis of 5-substituted 2-bisarylthiocyclopentane car-boxylic acids as specific matrix metalloproteinase inhibitorsrdquoJournal of Medicinal Chemistry vol 46 no 18 pp 3840ndash38522003

[6] A S Clark B Deans M F G Stevens et al ldquoAntitumor imi-dazotetrazines 32 Synthesis of novel imidazotetrazinones andrelated bicyclic heterocycles to probe the mode of action of theantitumor drug temozolomiderdquo Journal ofMedicinal Chemistryvol 38 no 9 pp 1493ndash1504 1995

[7] L A Carpino J Xia C Zhang andA El-Faham ldquoOrganophos-phorus and nitro-substituted sulfonate esters of 1-hydroxy-7-azabenzotriazole as highly efficient fast-acting peptide couplingreagentsrdquo Journal of Organic Chemistry vol 69 no 1 pp 62ndash712004

[8] V Janout B Jing I V Staina and S L Regen ldquoSelectivetransport of ATP across a phospholipid bilayer by a molecularumbrellardquo Journal of the AmericanChemical Society vol 125 no15 pp 4436ndash4437 2003

[9] T M Gierasch M Chytil M T Didiuk et al ldquoA modularsynthetic approach toward exhaustively stereodiversified ligandlibrariesrdquo Organic Letters vol 2 no 25 pp 3999ndash4001 2000

[10] T Okuzumi E Nakanishi T Tsuji and S Makino ldquoEfficientsolid-phase synthesis of diverse 123-benzotriazin-4-ones usingtert-butyl nitriterdquo Tetrahedron Letters vol 44 no 29 pp 5539ndash5542 2003

[11] A Deeb M Kotb and M El-Abbasy ldquoPyridazine derivativesand related compounds part 12 synthesis of some pyridazino[410158403101584045]thieno[32-d]-123-triazinesrdquo Phosphorus Sulfur andSilicon and the Related Elements vol 180 no 2 pp 591ndash5992005


[12] K M Dawood A M Farag and N A Khedr ldquoFacile routeto novel 2-pyridone pyrazolo[34-d]-123-triazine and pyra-zolo[34-d]- and [15-a]-pyrimidine derivativesrdquo Arkivoc vol2008 no 15 pp 166ndash175 2008

[13] J P Colomer and E L Moyano ldquoNew application of hetero-cyclic diazonium salts Synthesis of pyrazolo[34-d][123]tri-azin-4-ones and imidazo[45-d][123]triazin-4-onesrdquo Tetrahe-dron Letters vol 52 no 14 pp 1561ndash1565 2011

[14] M Tisler and B Stanovnik ldquoHeterocyclic diazo compounds asstarting materials in organic synthesis (review)rdquo Chemistry ofHeterocyclic Compounds vol 16 no 5 pp 443ndash463 1980

[15] C Gil and S Brase ldquoSolid-phase synthesis of biologically activebenzoannelated nitrogen heterocycles an updaterdquo Journal ofCombinatorial Chemistry vol 11 no 2 pp 175ndash197 2009

[16] C Gil A Schwogler and S Brase ldquoThe Synthesis of 3-Sub-stituted 6-Aryl-3 H-benzo[a][123]triazinones Using Polymer-Bound Triazenesrdquo Journal of Combinatorial Chemistry vol 6no 1 pp 38ndash42 2004

[17] R Reingruber S Vanderheiden T Muller M Nieger M Es-Sayed and S Brase ldquoEfficient synthesis of substituted 3-acyl-34-dihydrobenzo[d][123]triazinesrdquo Tetrahedron Letters vol50 no 26 pp 3439ndash3442 2009

[18] H Dopp and D Dopp ldquoProduct class 2 six-membered het-arenes with three heteroatomsrdquo in Science of Synthesis Chapter17 Category 2 Hetarenes and Related Ring Systems 2004

[19] M Gomez S Jansat G Muller G Aullon and M A MaestroldquoRuthenium complexes containing chiral N-donor ligands ascatalysts in acetophenone hydrogen transfermdashnew amino effecton enantioselectivityrdquo European Journal of Inorganic Chemistryvol 2005 no 21 pp 4341ndash4351 2005

[20] A S Gajare N S Shaikh G K Jnaneshwara V H DeshpandeT Ravindranathan and A V Bedekar ldquoClay catalyzed con-version of isatoic anhydride to 2-(o-aminophenyl)oxazolinesrdquoJournal of the Chemical Society Perkin Transactions 1 no 6 pp999ndash1001 2000

[21] E L Moyano J P Colomer and G I Yranzo ldquoNew applicationof heterocyclic diazonium salts synthesis of new pyrazolo[34-d][123]triazin-4-onesrdquoEuropean Journal ofOrganic Chemistryvol 2008 no 19 pp 3377ndash3381 2008

[22] F H Allen O Kennard D G Watson L Brammer A GOrpen and R Taylor ldquoTables of bond lengths determinedby x-ray and neutron diffraction Part 1 Bond lengths inorganic compoundsrdquo Journal of the Chemical Society PerkinTransactions 2 no 12 pp S1ndashS19 1987

[23] W E Hunt C H Schwalbe and K Vaughan ldquo3-Hydroxy-123-benzotriazin-4(3H)-one C

7H5N3O2rdquo Acta Crystallographica

Section C vol 39 no 6 pp 738ndash740 1983[24] J Hjortas ldquoThe crystal and molecular structure of 123-

benzotriazin-4(3H)-onerdquo Acta Crystallographica Section BStructural Crystallography and Crystal Chemistry vol 29 no 9pp 1916ndash1922 1973

[25] F Rocha-Alonzo G Aguirre and M Parra-Hake ldquoN-(2-Hyd-roxy-ethyl)-2-[3-(p-tol-yl)triazen-1-yl]benzamiderdquo Acta Crys-tallographica Section E vol 65 no 5 pp o990ndasho991 2009

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CatalystsJournal of


CN R

HO+

O N

R1 2

3a R = H 58

(R)-b R = Ph 72

(R)-c R = Et 80

Glycerolethylene glycol 105∘CNH2

NH2NH2

K2CO3

(1)

Once the necessary 2-(o-aminophenyl)oxazolines wereobtained the next step was the synthesis of the 123-benzotriazinones 4andash4c Compounds 4andash4c were synthe-sized by diazotization reaction involving oxazolines 3andash3c and methanolic isoamyl nitrite In all cases the new123-benzotriazinones were obtained in quantitative yields(Scheme 1)

It is assumed that the reaction takes place by theintermediacy of the diazonium ion 5 formed from 2-(o-aminophenyl)oxazoline (3) using a large excess of isoamylnitrite in order to ensure formation of the diazonium salt(Scheme 1)The electronwithdrawing effect of the diazoniumgroup in 5 could promote oxazolinyl ring hydrolysis takingwater from the alcoholic media and producing the 2-carbamoylbenzenediazonium 6 The 123-triazinone moietyin 4 is then achieved by ring closure between the amideand the adjacent diazonium group in 6 Similar mechanisticassumptions were proposed by Colomer and Moyano in thesynthesis of this kind of compound from aminonitriles [1321]

Infrared spectroscopy of compounds 4andash4c showed asingle band at ca (]) 3430 cmminus1 due to the O-H stretchingthe bands at ca (]) 1687 cmminus1 and at ca (]) 1657 cmminus1correspond to the N=N and the C=O stretching respec-tively 1HNMR spectroscopy showed the following aromatichydrogen from the 123-benzotriazinone moiety appearedas an ABCD system with the characteristic two doubletsand two triplets between 829 and 787 ppm slightly shiftedto lower field relative to the 2-(o-aminophenyl)oxazolinesaliphatic protons appeared between 639 and 090 ppm Forcompound 4b the phenyl protons are at (120575) 743 ppm13C NMR spectroscopy showed carbonyl carbon at ca (120575)1565 ppm aromatic carbon appeared in the range 1461ndash1203 ppm and aliphatic carbon in the range 642ndash108 ppmThe proton of hydroxyl group in the proposed structurewas not identified by 1H NMR but the carbinol moietywas inferred from the chemical shifts on 13C NMR dataSince compounds 4andash4c are novel high-resolution massspectrometry was run with no significant difference betweencalculated and obtained values (less than plusmn0003 amu)In general the molecular formula assignment and thespectroscopic characterization were consistent with theirstructures

In order to corroborate the presence of the hydroxylgroup the acetyl derivative 7a was obtained by reaction of4a with acetic anhydride in pyridine (see (2)) NMR spectrafor the acetyl derivative 7a turned out to be similar to 4a but

with new signals for the acetyl moiety at 120575H 195 and 120575C 215for the methyl group and 120575C 1719 for the ester carbonyl

4a

N

N

O

OH

N pyr rt

7a

N

N

O

OAc

NO(Ac)2

(2)

Suitable crystals for X-ray diffraction studies of 123-benzotriazinone 7a were grown by slow vapor diffusion ofhexane into a saturated solution in ethyl acetate Compound7a crystallized in the triclinic system with the space group PıMolecular structure of 123-benzotriazinone 7a is shown inFigure 1 which confirms the presence of the 123-triazinonesystem and indirectly corroborates the hydroxyl group in123-benzotriazinones 4andash4c

In the molecular structure of 7a the N1=N2 bond[12715(19) A] is longer than the typical value for N=N doublebond (1236 A) [22] whereas the N2-N3 bond [13728(19) A]is slightly shorter than the typical value for N-N singlebond (1404 A) [22]The structure shows coplanarity betweenthe two rings These data are in agreement with crystalstructure reports of related 123-benzotriazinones [17 23ndash25] Crystallographic data of 7a are included as supplemen-tary material (in Supplementary Material available online athttpsdoiorg10115520172384780)

Of interest to pharmaceutical applications Reingruberet al have suggested that the coplanar structure in 123-benzotriazinones could haveDNA-intercalating abilities suchas those displayed by some anticancer agents [17]

In summary we have presented an efficient method forthe synthesis of 123-benzotriazinones from 2-(o-amino-phenyl)oxazolines in high yields

3 Experimental Section

31 General Procedures All reagents were purchased in thehighest quality available and were used without furtherpurification The solvents used in column chromatographywere obtained from commercial suppliers and used without


O N

R

3

O N

R

NHO

OHR

4

N

N

O

OHR

N

5 6

MeOH rt


NH2

N2N2

C2H11ONO


C8

C7

C6 C4aC5 C4

C8a

N2

N1

N3C10

C9

C1

O1

O3

C2

O2










3)2CO 200MHz] 120575 769 (dd 119869 =


1089 656 548 EI-MS (Int ) [M]+ 162 (100) 131 (36) 118(33)


20= minus182 (c 022



3)2CO 50MHz]

120575 1650 1488 1427 1323 1298 1287 1275 1266 1160 11571086 730 702 EI-MS (Int ) [M]+ 238 (100) 207 (48) 118(50)


20= +10 (c 022 MeOH) FTIR (NaCl) ]



3)2CO 50MHz]

120575 1641 1503 1324 130 1161 1154 109 708 688 295 104EI-MS (Int ) [M]+ 190 (81) 161 (100) 133 (59) 118 (31)



3)2CO 200MHz] 120575 829


3)2CO 50MHz] 120575 1571 1461 1368


9H10N3O2 1920768


20= minus183



1H NMR [(CD3)2CO 200MHz] 120575 827 (ddd 119869 = 78 15



15H14N3O2 2681081


20= minus5 (c 022



3)2CO 50MHz] 120575 1566 1445 1358 1332 1288


11H14N3O2 2201081



3)2CO 200MHz] 120575 830 (ddd 119869 = 78 15


3)2CO

50MHz] 120575 1719 1570 1460 1369 1344 1300 1265 1216630 504 215


Competing Interests


Acknowledgments


References






































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O N

R

3

O N

R

NHO

OHR

4

N

N

O

OHR

N

5 6

MeOH rt


NH2

N2N2

C2H11ONO


C8

C7

C6 C4aC5 C4

C8a

N2

N1

N3C10

C9

C1

O1

O3

C2

O2










3)2CO 200MHz] 120575 769 (dd 119869 =


1089 656 548 EI-MS (Int ) [M]+ 162 (100) 131 (36) 118(33)


20= minus182 (c 022



3)2CO 50MHz]

120575 1650 1488 1427 1323 1298 1287 1275 1266 1160 11571086 730 702 EI-MS (Int ) [M]+ 238 (100) 207 (48) 118(50)


20= +10 (c 022 MeOH) FTIR (NaCl) ]



3)2CO 50MHz]

120575 1641 1503 1324 130 1161 1154 109 708 688 295 104EI-MS (Int ) [M]+ 190 (81) 161 (100) 133 (59) 118 (31)



3)2CO 200MHz] 120575 829


3)2CO 50MHz] 120575 1571 1461 1368


9H10N3O2 1920768


20= minus183



1H NMR [(CD3)2CO 200MHz] 120575 827 (ddd 119869 = 78 15



15H14N3O2 2681081


20= minus5 (c 022



3)2CO 50MHz] 120575 1566 1445 1358 1332 1288


11H14N3O2 2201081



3)2CO 200MHz] 120575 830 (ddd 119869 = 78 15


3)2CO

50MHz] 120575 1719 1570 1460 1369 1344 1300 1265 1216630 504 215


Competing Interests


Acknowledgments


References






































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


1H NMR [(CD3)2CO 200MHz] 120575 827 (ddd 119869 = 78 15



15H14N3O2 2681081


20= minus5 (c 022



3)2CO 50MHz] 120575 1566 1445 1358 1332 1288


11H14N3O2 2201081



3)2CO 200MHz] 120575 830 (ddd 119869 = 78 15


3)2CO

50MHz] 120575 1719 1570 1460 1369 1344 1300 1265 1216630 504 215


Competing Interests


Acknowledgments


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 a novel synthesis of 1,2,3-benzotriazinones...

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