synthesis and reactivity of enaminone of naphtho[b]1,4\u0002oxazine: one pot synthesis of novel...

$: Synthesis and Reactivity of Enaminone of Naphtho[b]1,4\u0002Oxazine: One Pot Synthesis of Novel Isolated and Heterocycle\u0002Fused Derivatives with Antimicrobial and Anti-fungal Activities$
ISSN 1068�1620, Russian Journal of Bioorganic Chemistry, 2015, Vol. 41, No. 4, pp. 421–436. © Pleiades Publishing, Ltd., 2015.

421

12 INTRODUCTION

The chemical and biological potentials of five�mem�bered heterocyclic compounds fused with aromaticnuclei have attracted the attention of organic andmedicinal chemists for several years. Amongst these,indole, benzofuran and their annulated derivatives havebeen extensively explored, since compounds containingthese scaffolds demonstrate diverse and interesting bio�logical activities. A survey of the literature on these ringsystems revealed a paucity of references tobenzo[b]thiophenes and naphtho[b]thiophenes. A fewsynthetic approaches are available in the literature forthe synthesis of benzo[b]thiophenes [1]. However, thereare fewer approaches to naphtho[b]thiophenes [2–4].Some interesting biological activities such as antifungal[5], anti�plasmodial [6], anti�trypansomal [6] and anti�malarial activities [7] are associated with the naph�tho[b]thiophene ring system.

On the other hand, 2�aryl substituted 4H�3,1�ben�zoxazin�4�ones have been shown to act as specificinhibitors in the activation of factor X (FX) throughthe “extrinsic pathway” in which factor VIIa (FVIIa)and its cofactor, tissue factor (TF), exert the proteoly�sis of FX to FXa. Hetero annulated 1,3�oxazin�4�oneshave been reported as anti�inflammatory agents [8, 9],human leukocyte elastase inhibitors [10, 11], herpes

1 The article is published in the original.2 Corresponding author: phone: +2097480446; fax: +2097480450;

e�mail: [email protected] & [email protected].

proteases inhibitors [12, 13], and anti allergia agents[14]. Also, 1�amidoalkyl�2�naphthols can be con�verted to 1,3�oxazine derivatives [15] of different bio�logical activities, such as antitumor [16], antibiotic[17], antipsychotic [18] anticonvulsant, [19] antima�larial [20] analgesic [21] antihypertensive [22] anti�rheumatic [23], and antianginal [24] properties. Vari�ous synthetic approaches to this group of compoundshave been described [25–30], however, only few ofthe reported compounds contain an aryl groupdirectly connected to the ring system, and none ofthe previously described compounds has beenreported as a specific inhibitor of the TF/FVIIa�induced coagulation pathway. We report herein thesynthesis of some new heterocycles with 2H�naph�tho[1,2�b][1,4]oxazin�2�one moiety starting from3�acetyl�2H�naphtho[1,2�b][1,4]oxazin�2�one.

RESULTS AND DISCUSSION

Chemistry

In the present study continuing our previous work[31–36] on the synthesis of fused and/or isolatedheterocyclic systems, we report the synthesis of newheterocyclic compounds based on 2H�naphtho[1,2�b][1,4]oxazin�2�one. Thus, the reaction of2�nitrosonaphthalen�1�ol with ethyl acetoacetate inboiling ethanolic piperidine solution afforded a browncrystalline product identified as 3�acetyl�2H�naph�tho[1,2�b][1,4]oxazin�2�one (I) (Scheme 1).

Synthesis and Reactivity of Enaminone of Naphtho[b]1,4�Oxazine: One Pot Synthesis of Novel Isolated and Heterocycle�Fused

Derivatives with Antimicrobial and Antifungal Activities1

Islam H. El Azaba, b, 2 and Khaled M. Khaledb, c

aOn Leave From Chemistry Department, Faculty of Science, Aswan University, Aswan 81528 EgyptbChemistry Department, Faculty of Science, Taif University,

Al�Haweiah, P.O. box 888, Zip code 21974, fax: (02)7274299, Taif, Saudi ArabiacChemistry Department, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt

Received December 8, 2014; in final form, January 23, 2015

Abstract—The synthesis of the multifunctional, hitherto unreported 3�(3�(dimethylamino)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one was described and its utility as a versatile building block was demonstratedfor the synthesis of some new pyrimidines, pyrazoles, isoxazoles, pyrazolo[a]pyrimidines, triazolo[a]pyrim�idines, pyrido[d]pyrimidines, pyrido[d]pyrimidines, piperidines, pyrido[a]benzimidazoles, 2H�pyran�3�carboxamides, benzofurans, naphtho[b]furans and pyrazolo[c][1, 2, 4]triazines of potential biological activ�ities. The synthesized compounds were characterized by IR, 1H NMR, 13C NHR and mass spectral data.Some of the compounds were evaluated for antimicrobial activities.

Keywords: 2�nitrosonaphthalen�1�ol, naphtho[b][1,4]oxazin�2�one, ethyl acetoacetate, dimethyformamide�dimethylacetal, enaminone

DOI: 10.1134/S106816201504007X

422

RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY Vol. 41 No. 4 2015

ISLAM H. EL AZAB, KHALED M. KHALED

The acetyl derivative (I) treated with dimethyfor�mamide�dimethylacetal (DMF�DMA) in boiling dryxylene yielded 3�(3�(dimethylamino)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (II) as a yellow crys�talline product (Scheme 2). The structure of enami�none (II) was established on the basis of its elementalanalysis and spectral data (IR, 1H NMR, and MS).The IR spectrum showed the presence of absorptionbands at 1695 and 1710 cm–1 due to (2 C=Ostr) func�

tion. The 1H NMR spectrum showed two singlet sig�nals assigned to two methyl groups at δ 3.01 and3.04 ppm, up field doublet signal was assigned to ole�finic proton at δ 5.15 ppm in addition to down fielddoublet signal due to azomethine proton (CH=N) atδ 8.22 ppm and aromatic protons in the region of7.61–7.82 ppm. The MS of compound displayed anintense molecular ion peak at m/z 294 (M+, 50%) cor�responding to C17H14N2O3.

The reactivity of enaminone (II) towards some nitro�gen nucleophiles was investigated. Enaminone (II)reacted with some primary aromatic amines inrefluxing AcOH to give corresponding acyclic sec�ondary amine derivatives (IIIa–d) (Scheme 3). Thestructures of the latter products were assigned on thebasis of their analytical and spectral data. The IRspectra of the products showed C=Cstr, C=Ostr andN–Hstr absorption bands in the region 1645, 1685and 3315–3348 cm–1, respectively. The 1H NMR

(DMSO�d6) spectrum of compound (IIIb) showedtwo singlet signals assigned to imino and hydroxylgroups at 10.98 and 12.18 ppm, respectively. A doubletsignal was due to olefinic proton at δ 5.81 ppm in addi�tion to down field doublet signal due to another ole�finic proton and aromatic protons in the region 7.61–8.87 ppm. Its mass spectrum showed a molecular ionpeak at m/z 386 (M+, 40%) corresponding to a molec�ular formula C22H14N2O5.

NO

OHOO

ON

O

O

CH3

O

EtOH/pip./reflux

–EtOH–H2O

+

(I)Scheme1. 3�Acetyl�2H�naphtho[1,2�b][1,4]oxazin�2�one.

N

O

O

CH3

O

H3C

H3C O

ON

CH3

CH3 N

O

O O

NMe

Me+ Xylene

–2MeOH

(I) (II)

Scheme 2. 3�(3�(Dimethylamino)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (II).

N

O

O O

NMe

Me

NH2

R

N

O

O O

NH R

AcOH

–NH(Me)2+

(IIIa–d)a, R = Hb, R = 2�COOHc, R = 2�NO2

d, R = 4�NO2

(II)

Scheme 3. Synthesis of acyclic secondary amine derivatives (IIIa–d).


SYNTHESIS AND REACTIVITY OF ENAMINONE OF NAPHTHO[b]1,4�OXAZINE 423

The reactivity of enaminone (II) towards thioureawas also investigated. Treatment of compound (II)with thiourea in refluxing EtOH, in the presence ofEtONa afforded pyrimidine�2�thione derivative (V)(Scheme 4). Its mass spectrum revealed a molecularion peak at m/z 307 (M+, 75%). Compound (V) is

assumed to be formed via addition of one of the NH2groups of thiourea to the activated exocyclic doublebond in enaminone (II) with subsequent eliminationof dimethylamine molecule followed by intramolecu�lar cyclization to form the final product (V) via lossof H2O.

Enaminone (II) reacted with guanidine to give apyrimidine derivative (VII) (Scheme 4). Its IR spec�trum showed the presence of carbonyl and aminoabsorption bands at 1685 and 3384 cm–1, respectively,which corresponded to the assigned structure. Themass spectrum of compound (VII) revealed a molecu�lar ion peak at m/z 290 (M+, 50%) [cf. Experimentalpart].

The reactivity of enaminone (II) towards hydrazineand hydroxyl amine was investigated. The reactionwith hydrazine hydrate in acetic acid afforded yellowproduct identified as 3�(1H�pyrazol�5�yl)�2H�naph�tho[1,2�b][1,4]oxazin�2�one (IX) (Scheme 5). Itsstructure was in agreement with elemental analysisand spectral data. Its IR spectrum displayed absorp�tion bands at 1685 and 3160 cm–1 due to C=Ostr andN–Hstr functions, respectively. The 1H NMR spec�trum (DMSO�d6) exhibited doublet signal due topyrazole proton at δ 6.32 (1H, J = 3.6 Hz), multipletsignal at δ 7.20–8.85 region owing to the other pyra�zole proton and an aromatic protons, in addition toD2O�exchangeable broad singlet due to pyrazole NH

at δ 10.82 ppm. Its mass spectrum revealed molecularion peak at m/z 263 (M+, 35%).

Enaminone (II) treated with NH2OH in refluxingEtOH afforded a single product which was identifiedas 3�(isoxazol�5�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XI) (Scheme 5). Its IR spectrum displayedabsorption bands at 1687 cm–1 due to C=Ostr function.Its 1H NMR spectrum exhibited a doublet signal dueto isoxazole proton at δ 6.35 (1H, J = 4.82 Hz ), a mul�tiplet signal in δ 7.20–8.15 ppm region owing toanother pyrazole proton and an aromatic protons. Themass spectrum revealed molecular ion peak at m/z 264(M+, 60%).

The behavior of 3�(3�(dimethylamino)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (II) in reac�tion with some heterocyclic amines as potential pre�cursors for fused heterocyclic systems was investi�gated. Enaminone (II) treated with 5�amino�3�phe�nyl�1H�pyrazole in refluxing yielded a productidentified as 3�(2�phenylpyrazolo[1,5�a]pyrimidin�7�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XIII)(Scheme 6). Its IR spectrum confirmed the presenceof intense absorption bands at ν 1690 cm–1 due to car�

–NH(Me)2

NH2CSNH2

EtONa(II)

N

O

O O

NH

NH2

S

N

O

O O

NH

NH2

NH

NH2CNH2

EtONa

•• ••

NH

–NH(Me)2

(IV) (VI)

–H2O –H2O

N

O

O NHN

S

N

O

O NN

NH2

(V) (VII)

Scheme 4. Synthesis of pyrimidine�2�thione (V) and pyrimidine (VII) derivatives.

424



bonyl group. The mass spectrum showed m/z 406 (M+,64%). The 1H NMR spectrum showed singlet signal atδ 5.40 due to pyrazole proton, multiplet signal due topyrimidine proton and aromatic protons in the region7.23–8.54 ppm in addition to doublet single at δ9.41 ppm due to another pyrimidine proton.

Similarly, enaminone (II) in reaction with 3�amino�1,2,4�triazole afforded 3�([1,2,4]triazolo[1,5�a]pyrimi�din�7�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XV)(Scheme 7). Its structure was in full agreement withelemental analysis and spectroscopic data (see Exper�imental).

The behavior of 3�(3�(dimethylamino)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (II) in reactionwith aminopyrimidine derivatives (XVIIa, b) [37] wasstudied. The reactions with 6�amino�1H�pyrimidin�2,4�dione and 6�smino�2�thioxo�2,3�dihydro�1H�pyrimidin�4�one in boiling AcOH acid afforded thepyrimido[1,2�d]pyrimidine derivatives (XVIIa) and(XVIIb), respectively (Scheme 8). The IR spectra ofderivative (XVIIa) revealed strong absorption bands at1686 and 3168 cm–1 attributed to C=Ostr and N–Hstrgroups, respectively. Its 1H NMR spectra revealed twosignals (D2O�exchangeable) assigned to 2NH protonsin addition to multiplet signal of seven protons (among

N

O

O O

NH

OH

N

O

O O

NH

NH2

–NH(Me)2

NH2NH2

AcOH(II)

NH2OH

EtOH

•• ••

–NH(Me)2

(VIII) (X)

–H2O –H2O

(IX) (XI)

N

O

O

NH

N

N

O

O

ON

Scheme 5. Synthesis of pyrazole (IX) and isoxazole (XI) derivatives.

N

O

O O

NMe

Me NNH

Ph

NH2N

O

O O

NH

NHNPh

N

O

O

N

N

N

Ph

Pyridine

–NH(Me)2+

••

(XII)(II)

–H2O

(XIII)Scheme 6. Synthesis of 2�phenylpyrazolo[1,5�a]pyrimidine derivative (XIII).



them six protons were assigned to Ar�H and one pro�ton to pyridine ring). Its mass spectrum showed a peakcorresponding to the molecular ion.

The formation of compounds (XVIIa, b) can beexplained on the basis of an initial Michael type addi�tion of the exocyclic amino group in aminopyrim�

idines to the activated double bond in enaminone (II)followed by elimination of dimethylamine to affordthe non isolable intermediates (XVIa, b). Though, theendocyclic imino group in aminopyrimidine is highlynucleophilic [38, 39], nevertheless, it is very hinderedsterically [40]. The products (XVIa, b) could cyclized

N

O

O O

NMe

Me

N

NNH

NH2N

O

O O

NH

N

NHN

N

O

O

N

N

NN

(II)

+Pyridine

–NH(Me)2

••

(XIV)

–H2O

(XV)Scheme 7. Synthesis of 3�([1,2,4]triazolo[1,5�a]pyrimidin�7�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XV).

N

O

O O

NMe

Me NH

HNH2N X

O

N

O

O O

NH

NHHN

X

O

N

O

O N

NH

NH

OON

O

O

N

N

NH

OO

+

AcOH –NH(Me)2

••

(II)

(XVIa, b)

–H2O

(XVIIa, b) (XVIIIa, b)a, X = Ob, X = S

Scheme 8. Synthesis of 5�(2�oxo�2H�naphtho[1,2�b][1,4]oxazin�3�yl)pyrido[2,3�d]�pyrimidine�2,4(1H,3H)�dione (XVIIa, b).

TCG

Highlight

TCG

Highlight

TCG

Cross-Out

TCG

Inserted Text

X

TCG

Cross-Out

TCG

Inserted Text

X

426



into pyridopyrimidine derivatives (XVIIa, b) orpyrimidopyrimidine derivatives (XVIIIa, b), respec�tively (Scheme 8). However, structures (XVIIIa, b)were easily excluded on the basis of the spectral data ofisolated products.

The reactivity of the enaminone (II) towards somesecondary amines was also investigated. Compound (II)in reaction with piperidine in refluxing EtOH affordedcorresponding tertiary amine (XX). Its IR spectrumconfirmed the presence of intense absorption bands atν 1650 and 1690 cm–1 due to two carbonyl groups. Itsmass spectrum showed m/z 334 (M+, 40%). Its1H NMR spectrum is free of signals characteristic forthe dimethylamine protons, with the presence of mul�tiplet signals at δ 2.34–2.49 ppm due to piperidineprotons, doublet signal at δ 5.15 ppm due toCO⎯CH=, multiplet signal due to an aromatic protonsin addition to =CH–N in the region 7.20–8.85 ppm.

The reaction of 3�(3�(dimethylamino)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (II) with 1H�benzimi�dazole�2�acetonitrile in refluxing pyridine gave 5�(2�oxo�2H�naphtho[1,2�b][1,4]oxazin�3�yl)pyrido[1,2�a]benzimidazole�4�carbonitrile (XXII) according to themechanism postulated in scheme 10. The formation ofcarbonitrile (XXII) can be explained on the basis ofinitial Michael type addition of the endocyclic NH[41, 42] in 1H�benzimidazole�2�acetonitrile to thedouble bond in enaminone (XXII) followed by elimi�nation of dimethylamine to afford the non isolableintermediate (XXI). The intermediate undergoesinteramolecular cyclization via loss of water moleculeto afford the final product (XXII). Its IR spectrumrevealed absorption band at ν 1690 and 2217 cm–1 dueto C=Ostr and C≡Nstr groups, respectively. Its massspectrum showed m/z 388 (M+, 70%). Its 1H NMRspectrum showed multiplet signal integral to twelveprotons (ten protons of Ar�H and two proton of pyri�dine ring) in region 7.23–8.51 ppm.

Enaminone derivative (II) in reaction with hippu�ric acid in refluxing Ac2O yielded 2�oxo�6�(2�oxo�2H�naphtho[1,2�b][1,4]oxazin�3�yl)�N�phenyl�2H�pyran�3�carboxamide (XXVI) (Scheme 11). Its IRspectrum revealed absorption band at ν 1650, 1690,1710 and 3109 cm–1 due to three carbonyl and N–Hstrgroups respectively. The mass spectrum of (XXVI)showed m/z 410 (M+, 75%). The 1H NMR spectrumof (XXVI) showed the protons of pyrane moiety inaddition to D2O�exchaneable broad singlet due to NHfunction.

Compound (XXVI) was assumed to be formedaccording to the following sequence: hippuric acid,was firstly cyclized under reaction conditions into theoxazolone intermediate, which then reacted with theenaminone (II) yielding (XXV) further rearranged intothe pyranone (XXVI) (Scheme 11) [43].

The reaction of enaminone (II) with P�benzo�quinone in AcOH at room temperature yielded onlyone isolable product. The product was formulated asbenzo[b]furan derivative (XXIX) on the basis of its ele�mental analysis and spectral data (IR, 1H NMR andMS). Its IR spectrum showed broad band of the O⎯Hstrgroup at 3475 cm–1 and revealed carbonyl absorptionband around 1690 cm–1. The mass spectrum of com�pound (XXIX) showed a peak corresponding to themolecular ion at m/z 357 (M+, 60%). The 1H NMRspectrum of derivative (XXIX) showed down field sin�glet signal at δ 8.90 ppm of furan proton and revealedD2O�exchangeable broad singlet at δ 9.55 ppm due tohydroxyl group. Compound (XXIX) is suggested to beformed via an initial addition of the electron�rich moi�ety C2 of the enaminone to the activated electron�poor double bond system of the quinone to form inter�mediate (XXVII) which readily aromatized andcyclized via dimethylamine elimination into the finalproduct (XXIX) (Scheme 12).

N

O

O O

N

N(Me)2

H HN

O

O O

N

Me

Me

N

O

O O

N

NH

+EtOH

(XIV)(II)

(XX)

–NH(Me)2

Scheme 9. Synthesis of 3�(3�(piperidin�1�yl)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XX).



NH

NCN

N

O

O O

NMe

Me

N

O

O O

NN

CN

N

O

O O

N

HN

CN

N

O

O NNC

N

N

O

O

N N

CN

+

–NH(Me)2(II) Pyridine

(XXI) (XXIII)

–H2O

(XXIV)(XXII)

–H2O

Scheme 10. Synthesis of 3�(2�oxo�2H�naphtho[1,2�b][1,4]oxazin�3�yl)benzo[4,5]imidazo[1,2�a]�pyridine�4�carbonitrile (XXII).

N

O

O O

NMe

Me

HONH

Ph

O

O

N

O PhO

N

O

O O

NN

O

O

PhH

N

O

O

O

NH

Ph

O

O

(XXV)

(XXVI)

(AcO)2O

–NH(Me)2

••

Scheme 11. Synthesis of 2�oxo�6�(2�oxo�2H�naphtho[1,2�b][1,4]oxazin�3�yl)�N�phenyl�2H�pyran�3�carboxamide (XXVI).

+

TCG

Highlight

TCG

Cross-Out

TCG

Inserted Text

C

428



Similarly, the reaction of enaminone (II) with 1,4�naphthoquinone in acetic acid at room temperatureafforded 3�(5�hydroxynaphtho[1,2�b]furan�3�carbo�

nyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XXXII)(Scheme 13).

The reaction of enaminone (II) with diazonium saltof 3�phenyl�5�amino�1H�pyrazole afforded non�isol�able azo coupling intermediate (XXXIII) which onintramolecular cyclization via elimination of dimethy�lamine yielded pyrazolo[5,1�c]1,2,4�triazine derivatives(XXXIV) (Scheme 14). Its IR spectrum revealed the lackof bands corresponding to endocyclic N–H and showed

absorption band at ν 1690 cm–1 due to C=Ostr. The massspectrum showed m/z 419 (M+, 75%). The 1H NMRspectrum is free of signals characteristic for the dimethy�lamine protons with the presence of singlet signal at6.53 ppm due to C4 proton in pyrazole moiety and mul�tiplet at 6.79–8.22 ppm attributed to aromatic protons inaddition to a proton of triazine moiety.

N

O

O O

NMe

Me

N

O

O O

O

OH

OO

AcOH N

O

O O

O

O

NMe

Me

H

HH

N

O

O O

OH

OH

NMe

Me

••

(II) (XXVII)

(XXVIII)(XXIX)

–NH(Me)2

Scheme 12. Systhesis of 3�(5�hydroxybenzofuran�3�carbonyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XXIX).

N

O

O O

NMe

Me

O

ON

O

O O

O

O

NMe

Me

H

HH

N

O

O O

O

OH

N

O

O O

OH

OH

NMe

Me

(II) (XXX)

(XXXI)

••

–NH(Me)2

(XXXII)Scheme 13. Synthesis of 3�(5�hydroxynaphtho[1,2�b]furan�3�carbonyl)�2H�naphtho[1,2�b]�

[1,4]oxazin�2�one (XXXII).



In addition, the reactivity of exocyclic C=C conju�gated with the carbonyl group in the chalcone (XX)was investigated in reactions with thiourea, hydrazinederivatives and/or some available active methylenecompounds such as 2�cyanoacetohydrazide and 2�cyano�N�phenylacetamide. The title compounds(XXXV–XXXVII) were synthesized by the routedepicted in Scheme 15. The products obtained werecharacterized by elemental and spectroscopic dataevidencing that the reaction proceeded via condensa�tion followed by a nucleophilic attack through α, β�unsaturated ketonic group (Scheme 6). Thus, the reac�tion of compound (XX) with thiourea in refluxing EtOH

containing piperidine as a catalyst afforded 3�(6�(piperi�din�1�yl)�2�thioxo�1,2,5,6�tetrahydropyrimidin�4�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XXXV)(Scheme 15). This thioxopyrimidine derivative wascharacterized using elemental and spectral analysis.Its IR showed strong absorption bands at ν 1232, 1685,3156 cm–1 due to C=Sstr, C=Ostr and N–Hstr groups,respectively. Its mass spectrum showed m/z 392 (M+,18%). The 1H NMR spectrum showed multiplet sig�nals at δ 2.34–2.49 due to piperidine protons, singletsignal at δ 4.56 due to methine of pyrimidine ring,multiplet signal due to an aromatic protons in additionto NH in the region 7.20–8.85 ppm.

N

O

O O

NMe

Me

NHN

N=NClPh

N

O

O O

NN N

N

(H3C)2N

Ph

H

N

O

O O

N

NN

NPh

+Pyridine

–HCl

(XXXIII)

–NH(Me)2

(XXXIV)

(II)

Scheme 14. Synthesis of 3�(7�phenylpyrazolo[5,1�c][1,2,4]triazine�3�carbonyl)�2H�naphtho[1,2�b]� [1,4]oxazin�2�one (XXXIV).

N

O

O N

N

NH

S

N

O

O

N

NNC

OY

N

O

O NNN

R

(XX)NH2CSNH2

EtOH

CNCH2CONHY

EtOH

(XXXV) (XXXVI) a, Y = NH2

b, Y = Ph

NH2NHRR = H, Ph

(XXXVII) a, R = COCH3b, R = Ph

Scheme 15. Reaction of the compound (II) with nucleophilic reagents.

TCG

Cross-Out

430



Antimicrobial Activity

The evaluation of antibacterial and antifungalactivity of the products was carried out at the Environ�mental Studies Unit at Aswan University, Aswan,Egypt. Selected ten compounds were tested againstfour fungal species, namely Aspergillus fumigates(RCMB�02568) (AF), Geotricum candidum (RCMB�05097) (GC), Syncephalastrum racemosum (RCMB�05922) (SR), and Candida albicans (RCMB�05036)(CA), as well as against four bacterial species, namelyStreptococcus pneumoniae (RCMB�010010) (SP),Pseudomonas aeruginosa (RCMB�010043) (PA),Bacillus subtilis (RCMB�010067) (BS), andEscherichia coli (RCMB�010052) (EC), using 5.0, 2.5and 1.0 mg/mL of each compound in DMSO. Inhab�itation zone diameter (IZD) in cm was taken as thecriterion for antimicrobial activity. The fungicide ter�binafin and the bactericide chloramphenicol wereused as references to evaluate the potency of the testedcompounds under the same conditions. The resultsobtained are presented in table.

The results indicated that compound (II) showedmoderately to highest degree antifungal and antimi�crobial activity against the tested organisms. Com�pound (XVIIb) showed high degree of inhibitionagainst (SR), (SP) and (EC) and moderate activity to(AF), (GC) and (PA) and not active against (CA) and(BS). Compounds (XIII) and (XVIIb) showed moder�ately to higher activity against (SR) and moderateactivity against (EC). Compounds (XVIIb) and (XX)showed activity against (EC). Compounds (XV),(XXVI) and (XXIX) showed very low concentrationagainst (SR) and (EC). All compounds, except (V) and(XV), exhibited no activity against (CA). Also, allcompounds except (XII) showed no activity against(CA). Moreover, all compounds showed no activityagainst (PA) except (XVIIb) and only (XXVII) hadweak inhibition against (PA).

EXPERIMENTAL

Reagents were purchased from Sigma Aldrich andused without further purification. Reaction progresswas monitored by TLC on silica gel precoated F254Merck plates. Spots were visualized by ultraviolet irra�diation. Melting points were determined on a Gallen�kamp electrothermal melting point apparatus and areuncorrected. IR spectra were recorded as potassiumbromide discs using Bruker�Vector 22 FTIR Spectro�photometer. 1H NMR and 13C NMR spectra wererecorded in DMSO�d6 on a Bruker WP spectrometer(300 MHz for 1H NMR and 75 MHz for 13C NMR)and the chemical shifts δ are reported in ppm down�field from TMS as an internal standard. Mass spectrawere recorded on a Hewlett Packard MS�5988 spec�trometer at 70 eV. Elemental analyses were carried outat the Micro�analytical Unit, Faculty of Science,Mansoura University, Egypt.

3�Acetyl�2H�naphtho[1,2�b][1,4]oxazin�2�one (I).A mixture of 2�nitrosonaphthalen�1�ol (1.73 g,0.01 mol) and ethyl acetoacetate (1.30 mL, 0.01 mol)in 20 mL of EtOH containing 0.1 mL piperidine wasrefluxed for 8 h. The reaction mixture was poured into150 g of crushed ice then the resultant solid was col�lected by filtration to provide a brown solid recrystal�lized from EtOH/ DMF (2 : 1). Yield: 75%, mp 238–240°C. IR spectrum: 1695, 1710 (2 COstr). 1H NMRspectrum: 2.42 (s, 3H, CH3) and 7.61–8.22 (m, 6H,Ar�H). 13C NMR spectrum: 27.1 (CH3), 115.1, 122.3.123.0, 126.6, 126.8, 133.2, and 145.0 (naphthalene),152.1 and 195.0 (2 C=O), 163.0 (C�3�[1,4]oxazine).MS (m/z %): 239 (M+, 65). Found: C 70.14, H 3.61,N 5.88%. Calcd.: C14H9NO3 (239.23): C 70.29,H 3.79, N 5.86%.

3�(3�(Dimethylamino)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (II). 3�acetyl�2H�naphtho[1,2�b][1,4]oxazin�2�one (I) (2.39 g, 0.01 mol), and dime�thylformamide�dimethylacetal (DMF�DMA) (1.19 g,0.01 mol) were taken in dry xylene (30 mL) and thereaction mixture was refluxed for 6 h. The solvent wasdistilled off at reduced pressure and the residual red�dish brown viscous liquid was washed in ether. Theresulting yellow crystals were collected by filtration,washed thoroughly with ether, dried and finally recrys�tallized from EtOH. Yield: 60%, mp 210–212°C. IRspectrum: 1695, 1710 (2 C=Ostr).

1H NMR spectrum:3.04 (s, 3H, CH3), 3.01 (s, 3H, CH3), 5.15 (d, J = 6.91 Hz,1H, –CH=), 7.61–7.82 (m, 6H, 6Ar�H), 8.22 (d, J =6.91 Hz, 1H, –CH=). 13C NMR spectrum: 43.1(2CH3), 92.6, 154.9 (–CH=CH–), 115.1, 122.3.123.0, 126.6, 126.8, 133.2, and 145.0 (naphthalene),152.1 and 190.0 (2 C=O), 163.0 (C�3�[1,4]oxazine).MS (m/z, %): 294 (M+, 50). Found: C, 69.45; H, 4.60;N, 9.73%. Calcd.: C17H14N2O3 (294.30): C, 69.38; H,4.79; N, 9.52%.

Reaction of Enaminone (II) with Primary Aromatic Amine. General Procedure

A mixture of enaminone (II) (1.47 g, 5 mmol), andthe appropriate primary aromatic amine (5 mmol) inacetic acid (20 mL) was refluxed for 5 h. The precipi�tated product was collected by filtration, washed withMeOH, dried and finally recrystallized from EtOH toafford the corresponding derivatives (IIIa–d).

3�(3�(Phenylamino)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (IIIa). Yield: 62%, mp 240–242°C (EtOH). IR spectrum: 1645 (C=Cstr), 1685 and1692 (2 C=Ostr), 3315 (NHstr). 1H NMR spectrum:5.81 (d, J = 10.11 Hz 1H, –CO–CH=), 7.61–8.22(m, 12H, 11Ar�H and 1H, =CH–N), 10.98 (br, s, 1H,NH, D2O�exchangeable). MS (m/z, %): 342 (M+, 20).Found: C, 73.54; H, 4.10; N, 9.03%. Calcd.:C21H14N2O3 (342.35): C, 73.68; H, 4.12; N, 8.18%.



Antimicrobial activity of some selected compounds*

Compounds [C]** (AF) (GC) (SR) (CA) (SP) (PA) (BS) (EC)

(II) 5 ++ +++ +++ ++ ++ +++ ++ ++

2.5 ++ ++ ++ ++ ++ ++ ++ ++

1 ++ ++ +++ ++ ++ ++ ++ ++

(IIIb) 5 0 0 0 0 + 0 0 0

2.5 0 0 0 0 0 0 0 +

1 0 0 0 0 0 0 0 0

(V) 5 + 0 + + + 0 0 0

2.5 + 0 + 0 0 0 0 0

1 + 0 + 0 0 0 0 0

(IX) 5 + + 0 0 0 0 0 +

2.5 + + 0 0 0 0 0 +

1 0 0 0 0 0 0 0 0

(XIII) 5 + + ++ 0 + 0 0 +

2.5 0 0 ++ 0 + 0 0 +

1 0 0 ++ 0 + 0 0 +

(XV) 5 0 0 + + + 0 0 +

2.5 0 0 + 0 0 0 0 +

1 0 0 + 0 0 0 0 +

(XVIIb) 5 + + ++ 0 ++ + 0 ++

2.5 + + ++ 0 0 0 0 ++

1 + + ++ 0 0 0 0 +

(XX) 5 + 0 + 0 0 0 + ++

2.5 + 0 0 0 0 0 + ++

1 + 0 0 0 0 0 + +

(XXVII) 5 + + + 0 0 + + +

2.5 0 0 + 0 0 0 0 +

1 0 0 + 0 0 0 0 +

(XXIX) 5 + + + 0 0 0 + +

2.5 0 0 + 0 0 0 0 +

1 0 0 + 0 0 0 0 0

5 +++ +++ ++ +++ 0 0 0 0

Terbinafin 2.5 +++ +++ ++ +++ 0 0 0 0

1 ++ +++ +++ +++ 0 0 0 0

5 0 0 0 0 +++ ++ +++ ++

Chloramphenicol 2.5 0 0 0 0 ++ ++ ++ +++

1 0 0 0 0 +++ ++ +++ ++

* Chloramphenicol was used as a standard in evaluation of antifungal activity. Terbinafin was used as a standard in evaluation of anti�bacterial activity. The tests were done using diffusion agar technique. Well diameter: 0.6 cm (100 µL of each conc. was tested). Inhi�bition values: “+” means 0.1–0.5 cm beyond control; “++” means 0.6–1.0 cm beyond control; “+++” means 1.1–1.5 cm beyondcontrol; and “0” means not detected.

** Concentration of the sample in mg/mL.

432



2�(3�Oxo�3�(2�oxo�2H�naphtho[1,2�b][1,4]oxazin�3�yl)prop�1�enylamino)benzoic acid (IIIb). Yield:56%, mp 270–272°C (DMF/H2O (2:1). IR spectrum:1645 (C=Cstr), 1685, 1692 (2 C=Ostr ), 3317 (N–Hstr). 1H NMR spectrum: 5.81 (d, J = 10.01 Hz, 1H,⎯CO⎯CH= ), 10.98 (br, s, 1H, NH, D2O�exchange�able), 12.18 (br, s, 1H, OH, D2O�exchangeable);13C NMR spectrum: 43.1 (2CH3), 92.6, 154.9(⎯CH=CH–), 115.1, 122.3. 123.0, 126.6, 126.8,133.2, and 145.0 (naphthalene), 152.1 and 190.0(2 C=O), 163.0 (C�3�[1,4]oxazine. MS (m/z, %): 386(M+, 25). Found: C, 68.24; H, 3.10; N, 10.23%.Calcd.: C22H14N2O5 (386.36): C, 68.39; H, 3.65;N, 10.85%.

3�(3�(2�Nitrophenylamino)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (IIIc). Yield: 85%, mp197–199°C (DMF/H2O (2 : 1)). IR spectrum: 1644(C=Cstr), 1685 (C=Ostr), 3215 (N–Hstr). 1H NMRspectrum: 5.81 (d, J = 10.01 Hz, 1H, –CO–CH=),7.61–8.22 (m, 11H, 10Ar�H and 1H, =CH–N),10.98 (br, s, 1H, NH, D2O�exchangeable). MS(m/z, %): 387 (M+, 40). Found: C, 65.04; H, 3.11;N, 10.24%. Calcd.: C21H13N3O5 (387.35): C, 65.12;H, 3.38; N, 10.85%.

3�(3�(4�Nitrophenylamino)acryloyl)�2H�naphtho[1,2�b[1,4]oxazin�2�one (IIId). Yield: 65%, mp 230–232°C (DMF/H2O (1 : 2)). IR specrum: 1645(C=Cstr), 1685 (C=Ostr), 3348 (NHstr); 1H NMR spec�trum: 5.81 (d, 1H, –CO–CH=), 7.61–8.22 (m, 11H,10Ar�H and 1H, =CH–N), 10.98 (br, s, 1H, NH,D2O�exchangeable). MS (m/z, %): 389 ([M + 2]+,15%). Calcd.: C21H13N3O5 (387.35): C, 65.12;H, 3.38; N, 10.85%.

3�(2�Thioxo�2,3�dihydropyrimidin�4�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (V). 3�(3�(Dimethy�lamino)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one(II) (2.94 g, 10 mmol) was added to an ethanolicsodium ethoxide solution, then thiourea (10 mmol)guanidine nitrate (10 mmol) was added. The reactionmixture was refluxed for 12 h. After cooling, the mix�ture was poured into ice/water mixture. The productwas collected by filtration and washed several timeswith cold ethanol to give V as deep yellow powder.Yield: 45% (EtOH), mp 256–258°C. IR spectrum:1230 (C=Sstr), 1690 (C=Ostr), 3184 (N–Hstr).1H NMR spectrum: 7.20–7.95 (m, 8H, 6 Ar�H and2H, phyrimidine), 10.98 (br, s, 1H, NH, D2O�exchangeable). MS (m/z, %): 307 (M+, 75). Found: C,62.35; H, 2.75; N, 12.44%. Calcd.: C16H9N3O2S(307.33): C, 62.12; H, 2.95; N, 13.67%.

3�(2�Aminopyrimidin�4�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (VII). Deep yellow powder. Yield: 45%(EtOH), mp 256–258°C. IR spectrum: 1685 (C=Ostr),3384 (NH2str); 1H NMR: 6.16 (br, s, 2H, NH2, D2O�exchangeable), 7.20–7.95 (m, 8H, 6 Ar�H and 2H, phy�rimidine; MS (m/z, %): 290 (M+, 50). Found: C, 65.71;

H, 3.14; N, 18.54%. Calcd.: C16H10N4O2 S (290.28):C, 66.20; H, 3.47; N, 19.30%.

3�(1H�Pyrazol�5�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (IX). A mixture of enaminone (II) (5 mmol) andhydrazine hydrate (1 mL, 99%) in AcOH acid (20 mL)was refluxed for 2 h. The solid product formed aftercooling was collected by filtration and crystallizedfrom EtOH as yellow crystals. Yield 80%, mp 256–258°C. IR specrum: 1685 (C=Ostr), 3160 (N–Hstr).1H NMR spectrum: 6.32 (d, J = 4.82 Hz, 1H, pyra�zole), 7.20–8.85 (m, 7H, 6Ar�H and 1H, pyrazole),10.82 (br, s, 1H, NH, D2O�exchangeable). 13C NMRspectrum: 105.1, 133.2, 135.1 (pyrazole), 115.1,122.3, 123.0, 126.6, 126.8, 133.2, 145.0 (naphtha�lene), 158 (C=O), 163.0 (C�3�[1,4]oxazine. MS(m/z, %): 263 (M +, 35). Anal. Found: C, 68.69;H, 3.41; N, 15.71%. Calcd.: C15H9N3O2 (263.25):C, 68.44; H, 3.45; N, 15.96%.

3�(Isoxazol�5�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XI). A mixture of enaminone (II) (10 mmol),hydroxylamine hydrochloride (10 mmol) and anhy�drous potassium carbonate (0.5 g) in absolute EtOH(25 mL) was refluxed for 5 h, then left to cool. Thereaction mixture was poured into cold water and thesolid product was collected by filtration, washed withwater, dried and finally recrystallized from EtOHyielding isoxazole derivative (XI) as yellow crystals.Yield 65%, mp 152–154°C. IR spectrum: 1687(C=Ostr).

1H NMR spectrum: 6.35 (d, J = 4.82 Hz, 1H,isoxazole), 7.20–8.85 (m, 7H, 6Ar�H and 1H, iso�xazole). MS (m/z, %): 264 (M +, 60). Found: C, 68.29;H, 3.14; N, 10.41%. Calcd.: C15H8N2O3 (364.24):C, 68.18; H, 3.05; N, 10.60%.

Reaction of Enaminone (II) with Heterocyclic Amines. General Procedure

A mixture of enaminone (II) (10 mmol) andappropriate heterocyclic amine (5�amino�3�1H�phe�nylpyrazole or 3�amino�1,2,4�triazole) (10 mmol) inpyridine (25 mL) was refluxed for 12 h, then left tocool. The reaction mixture was poured into cold waterand the solid product was collected by filtration,washed with water, dried and recrystallized fromMeOH yielding corresponding pyrazolo[1,5�a]pyrimi�dine derivative (XIII) or triazolo[1,5�a]pyrimidinederivative (XV), respectively.

3�(2�Phenylpyrazolo[1,5�a]pyrimidin�7�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XIII). Yellow crys�tals. Yield 45%, mp 257–259°C. IR spectrum: 1690(C=Ostr).

1H NMR spectrum: 5.40 (s, 1H, pyrazole),7.23–8.54 (m, 12H, 11Ar�H and 1H, pyrimidine),9.41 (d, J = 7.12 Hz, 1H, pyrimidine). MS (m/z, %): 406(M+, 64). Found: C, 70.89; H, 3.25; N, 13.57%.Calcd.: C24H14N4O3 (406.39): C, 70.93; H, 3.47;N, 13.79%.



3�([1,2,4]Triazolo[1,5�a]pyrimidin�7�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XV). Pale yellow crystals.Yield 55%, mp 297–298°C. IR spectrum: 1690(C=Ostr). 1H NMR spectrum: 7.20–8.85 (m, 7H, 6Ar�H and 1H, pyrimidine), 8.78 (s, 1H, triazole), 9.41 (d,J = 7.12 Hz, 1H, pyrimidine). MS (m/z, %): 315 (M+,80). Found: C, 63.54; H, 2.42; N, 21.58 %. Calcd.:C17H9N5O2 (315.29): C, 64.76; H, 2.88; N, 22.21%.

Reaction of the Enaminone (II) with Aminopyrimidine Derivatives.

General Procedure

A mixture of enaminone (II) (2.94 g, 10 mmol) andappropriate amino�pyrimidine derivatives (6�ami�nopyrimidine�2,4(1H,3H)�dione or 6�amino�2,3�dihydro�2�thioxopyrimidin�4(1H)�one) (10 mmol) inAcOH (25 mL) was refluxed for 12 h, then left to cool.The reaction mixture was poured into cold water and thesolid product was filtered off, washed with water, driedand finally, recrystallized from EtOH yielded corre�sponding pyrido[2,3�d]pyrimidine derivative (XVIIa, b),respectively.

5�(2�Oxo�2H�naphtho[1,2�b][1,4]oxazin�3�yl)pyrido[2,3�d]pyrimidine�2,4(1H,3H)�dione (XVIIa).White crystals. Yield 65%, mp 187–189°C. IR spec�trum: 1650, 1686, 1710 (3 C=Ostr), 3168, 3233(2 N⎯Hstr). 1H NMR spectrum: 7.20–8.85 (m, 7H,6Ar�H and 1H, pyrimidine), 9.41 (d, J = 7.12 Hz, 1H,pyrimidine), 10.56 (br, s, 1H, NH, D2O�exchange�able), 11.16 (br, s, 1H, NH, D2O�exchangeable).13C NMR spectrum: 113.3, 115.4, 142.0, 147.7, 152.9(pyridine), 115.1, 122.3, 123.0, 126.6, 126.8, 133.2,145.0 (naphthaline), 151.3, 158, 161.0 (3C=O), 163.0(C�3�[1,4]oxazine. MS (m/z, %): 358 (M +, 75).Found: C, 63.21; H, 2.67; N, 15.89%. Calcd.:C19H10N4O4 (358.31): C, 63.69; H, 2.81; N, 15.64%.

3�(1,2,3,4�Tetrahydro�4�oxo�2�thioxopyrido[2,3�d]pyrimidin�5�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XVIIb). White crystals. Yield 72%, mp 289–291°C. IR spectrum: 1233 (C=Sstr), 1650, 1710(2 C=Ostr), 3168, 3233 (2 N–Hstr). MS (m/z, %): 374(M+, 55). Found: C, 60.81; H, 2.47; N, 14.73%.Calcd.: C19H10N4O3S (374.37): C, 60.96; H, 2.69;N, 14.97%.

3�(3�(Piperidin�1�yl)acryloyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XX). A mixture of enaminone (II)(1.47 g, 5 mmol) and piperidine (5 mL) in EtOH(30 mL) was refluxed for 5 h, then left to cool. Theprecipitated product filtered off, washed with EtOH,dried and finally recrystallized from EtOH/DMF(2 : 1) yielding compound (XX) as pale yellow crystals.Yield 75%, mp 218–220°C. IR spectrum: 1650, 1690(2 C=Ostr). 1H NMR spectrum: 2.34–2.49 (m, 6H,piperidine), 3.32�3.49 (t, 4H, piperidine), 5.15 (d,J 10.12 Hz, 1H, –CO–CH=), 7.20–8.85 (m, 7H,6Ar�H and 1H, =CH–N). MS (m/z; %): 334 (M+,

40). Found: C, 71.44; H, 5.17; N, 8.22%. Calcd.:C20H18N2O3 (334.13): C, 71.84; H, 5.43; N, 8.38%.

5�(2�Oxo�2H�naphtho[1,2�b][1,4]oxazin�3�yl)pyrido[1,2�a]benzimidazole�4�carbonitrile (XXII). Amixture of enaminone (II (2.94 g, 10 mmol) and2�cyanomethylbenzimidazole (10 mmol) in pyridine(20 mL) was refluxed for 12 h, and then left to cool.The reaction mixture was poured into cold water andthe solid product filtered off, washed with water, driedand recrystallized from DMF/H2O (3 : 1) to affordpyrido[1,2�a]benzimidazole derivative (XXII) as yellowcrystals. Yield 55%, mp > 300°C. IR spectrum: 1690(C=Ostr), 2217 (C≡Nstr).

1H NMR spectrum: 7.23–8.51(m, 12H, 10Ar�H and 2H, pyridine). 13C NMR spec�trum (DMSO�d6): 117.1 (CN), 110.7, 120.9, 128.6,141.0 (pyridine), 115.1, 122.3, 123.0, 126.6, 126.8,133.2, 145.0 (naphthalene), 158 (C=O), 163.0 (C�3�[1,4]oxazine). MS (m/z, %): 388 (M +, 70). Found:C, 74.04; H, 3.01; N, 14.12%. Calcd.: C24H12N4O2

(388.38): C, 74.22; H, 3.11; N, 14.43%.2�Oxo�6�(2�oxo�2H�naphtho[1,2�b][1,4]oxazin�

3�yl)�N�phenyl�2H�pyran�3�carboxamide (XXVI). Amixture of enaminone (II) (1.47 g, 5 mmol) and hip�puric acid (1.7 g, 10 mmol) in Ac2O (20 mL) wasrefluxed for 3 h and the reaction mixture was concen�trated in vacuum. The solid product obtained uponcooling was filtered off and recrystallized fromDMF/H2O (3 : 1) to afford the pyran derivative (XXVI)as brown crystals. Yield 45%, mp 258–260°C. IR spec�trum: 1650, 1690, 1710 (3 C=Ostr), 3109 (N–Hstr).1H NMR spectrum: 6.82 (d, J = 8.12 Hz, 1H, pyran),7.31–8.22 (m, 12H, 11Ar�H and 1H, pyran), 9.61 (br,s, 1H, NH, D2O�exchangable). MS (m/z, %): 410(M+, 75). Found: C, 70.14; H, 3.17; N, 6.65%. Calcd.:for C24H14N2O5 (410.38): C, 70.24; H, 3.44;N, 6.83%.

Reaction of Enaminone (II) with p�Benzoquinone and 1,4�Naphthoquinone. General Procedure

To a stirred solution of enaminone (II) (2.94 g,10 mmol) in acetic acid (50 mL), p�benzoquinoneand/or 1,4�naphthoquinone (10 mmol) was addedand the reaction mixture was stirred overnight at roomtemperature. The reaction mixture was evaporated invacuum, and the solid product obtained was filteredoff and recrystallized from EtOH/DMF (2 : 1) toafford the corresponding derivatives (XXIX) and(XXXII), respectively.

3�(5�Hydroxybenzofuran�3�carbonyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XXIX). Brown crystals.Yield 45%, mp 218–220°C. IR spectrum: 1636, 1690(2 C=Ostr), 3475 (O–Hstr).

1H NMR spectrum: 6.79–8.22 (m, 9H, Ar�H), 8.90 (s, 1H, furan), 9.55 (br, s, 1H,OH, D2O�exchangable). MS (m/z, %): 357 (M+, 60).Found: C, 70.12; H, 3.07; N, 3.71%. Calcd.:C21H11N2O5 (357.32): C, 70.59; H, 3.10; N, 3.92%.

434



3�(5�Hydroxynaphtho[1,2�b]furan�3�carbonyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XXXII). Yel�low crystals. Yield 50%, mp 278–280°C. IR spectrum:1636, 1690 (2 C=Ostr), 3475 (O–Hstr).

1H NMR spec�trum: 6.79–8.22 (m, 11H, Ar�H), 8.90 (s, 1H, furan),9.55 (br, s, 1H, OH, D2O�exchangable). MS (m/z, %):407 (M+, 35). Found: C, 73.10; H, 3.10; N, 3.12%.Calcd.: C25H13NO5 (407.37): C, 73.71; H, 3.22;N, 3.44%.

3�(7�Phenylpyrazolo[5,1�c][1,2,4]triazine�3�carbo�nyl)�2H�naphtho[1,2�b][1,4]oxazin�2�one (XXXIV). Toa stirred cold solution of enaminone (II) (2 mmol) inpyridine (30 mL), 5�(chlorodiazenyl)�3�phenyl�1H�pyrazole (2 mmol) was added portion wise over aperiod of 30 min at 0–5°C. The solid product obtainedwas filtered off, washed with H2O, dried, and recrys�tallized from DMF/H2O (3 : 1) to afford the corre�sponding compound (XXXIV). Yellow crystals. Yield75%, mp > 300°C. IR spectrum: 1636, 1690(2 C=Ostr). 1H NMR spectrum: 6.53 (s, 1H, pyrazole),6.79–8.22 (m, 12H, 11Ar�H and 1H, triazine) MS(m/z, %): 419 (M+, 75). Found: C, 68.42; H, 2.39;N, 16.42%. Calcd.: C24H13N5O3 (419.39): C, 68.73;H, 3.12; N, 16.70%.

3�(6�(Piperidin�1�yl)�2�thioxo�1,2,5,6�tetrahydro�pyrimidin�4�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one(XXXV). A mixture of compound (XX) (3.34 g,10 mmol), thiourea (0.76 g, 10 mmol), and 0.1 mLpiperidine was refluxed for 8 h in 30 mL of EtOH. Thesolvent was evaporated under vacuum, and the residuewas poured to 30 mL of acidified cold water and thentriturated with MeOH. The product was filtered andcrystallized from EtOH as brown crystals. Yield 71%,mp 185–187°C. IR spectrum: 1232 (C=Sstr), 1685(COstr), 3156 (br, NHstr).

1H NMR spectrum: 1.71 (d,J 8.12 Hz, 2H, methylene of pyrimidine ring), 2.34–2.49 (m, 6H, piperidine), 3.32–3.49 (t, 4H, piperidine),3.82 (t, 1H, methine of pyrimidine ring), 7.20–8.85 (m,7H, 6Ar�H and 1H, NH of pyrimidine ring).13C NMR spectrum: 24.5, 25.9, 49.8 (piperidine),28.7, 67.7, 164.1 (pyrimidine), 115.1, 122.3, 123.0,126.6, 126.8, 133.2, 145.0 (naphthalene), 158 (C=O),163.0 (C�3�[1,4]oxazine, 187.1 (C=S); MS (m/z, %):392 (M +, 18). Found: C, 64.32; H, 5.04; N, 14.27%.Calcd.: C21H20N4O2S (390.46): C, 64.27; H, 5.14;N, 14.28%.

General Procedure of The Synthesis of 1�Amino�2�Oxo�4�(2�Oxo�2H�Naphtho[1,2�b]

[1,4]oxazin�3�yl)�6�(Piperidin�1�yl)�1,2,5,6�Tetrahydropyridine�3�carbonitrile (XXXVIa)

and Its Derivative (XXXVIb)

A mixture of chalcone (XX) (3.34 g, 10 mmol) and2�cyanoacetohydrazide (0.99 g, 10 mmol) in 30 mL ofEtOH in the presence of 0.1 mL of piperidine wasrefluxed for 8 h. The reaction mixture was concen�

trated under vacuum and the residue washed withacidified cold water and then triturated with metha�nol. The solid product formed was filtered and crystal�lized from EtOH to afford carbonitrile (XXXVIa).Analogously, chalcone (XX) was reacted with 2�cyano�N�phenylacetamide (1.6 g, 0.01 mol) to yield pyridinederivatives (XXXVIb).

Carbonitrile (XXXVIa). Brown crystals (MeOH).Yield 58%, mp 189–191°C. IR spectrum (KBr): 1685(C=Ostr), 2217 (C≡Nstr), 3480 (br, NH2str).

1H NMRspectrum: 2.13 (d, J = 8.12 Hz, 2H, methylene of pyri�dine ring), 2.34–2.49 (m, 6H, piperidine), 3.32–3.49(m, 4H, piperidine), 4.56 (t, 1H, methine of pyridinering), 5.76 (s, 2H, NH2), 7.20–7.85 (m, 6H, Ar�H). MS(m/z, %): 415 (M+, 30). Found: C, 66.32; H, 4.94; N,16.67%. Calcd.: C23H21N5O3 (415.44): C, 66.49; H,5.09; N, 16.86%.

2�Oxo�4�(2�oxo�2H�naphtho[1,2�b][1,4]oxazin�3�yl)�1�phenyl�6�(piperidin�1�yl)�1,2,5,6�tetrahydro�pyridine�3�carbonitrile (XXXVIb). Yellow crystals(MeOH). Yield 70%, mp 282–284°C. IR spectrum:ν (cm–1) 1685 (C=Ostr), 2217 (C≡Nstr).

1H NMR spec�trum: 2.13 (d, J = 8.12 Hz, 2H, methylene of pyridinering), 2.34–2.49 (m, 6H, piperidine), 3.32–3.49 (m,4H, piperidine), 4.56 (t, 1H, methine of pyridine ring),7.20–7.85 (m, 11H, Ar�H). MS (m/z, %): 476 (M+,35). Found: C, 73.12; H, 4.91; N, 11.57%. Calcd.:C29H24N4O3 (476.18): C, 73.09; H, 5.08; N, 11.76%.

General Procedure of the Synthesis of 3�(1�Acetyl�5�(Piperidin�1�yl)�4,5�Dihydro�1H�Pyrazol�3�yl)�2H�

Naphtho[1,2�b][1,4]oxazin�2�one (XXXVIIa) and Its Derivative (XXXVIIb)

An equimolar mixture of (XX) (1 mmol) andhydrazine hydrate (1 mmol) was dissolved in aceticacid (30 mL) was refluxed for 6 h. The reaction mix�ture was evaporated to dryness under reduced pres�sure. The solid product was separated off, washed withMeOH and crystallized from EtOH to afford oxazi�none (XXXVIIa). Analogously, enaminone (XX) wasreacted with phenyl hydrazine in ethanolic solutioncontaining 0.1 mL piperidine to afford derivative(XXXVIIb).

Compound (XXXVIIa): Pale yellow crystals(EtOH). Yield 74%, mp 255–257°C. IR spectrum:1685, 1707 (2 C=O). 1H NMR spectrum: 1.81 (s, 2H,methylene of pyrazole), 2.04 (s, 3H, methyl), 2.34–2.49 (m, 6H, piperidine), 3.32�3.49 (m, 4H, piperidine),4.76 (s, 1H, methine of pyrazole ring), 7.20–7.85 (m,6H, Ar�H). 13C NMR spectrum: 23.1 (CH3), 24.5,25.9, 49.8 (piperidine), 29.0, 60.1, 155.1 (pyrazole),115.1, 122.3, 123.0, 126.6, 126.8, 133.2, 145.0 (naph�thaline), 158, 168.0 (2C=O), 163.0 (C�3�[1,4]oxazine, 187.1 (C=S). MS (m/z, %): 390 (M+,60). Found: C, 67.48; H, 5.30; N, 14.14%. Calcd.:C22H22N4O3 (390.44): C, 67.68; H, 5.68; N, 14.35%.



3�(1�Phenyl�5�(piperidin�1�yl)�4,5�dihydro�1H�pyrazol�3�yl)�2H�naphtho[1,2�b][1,4]oxazin�2�one(XXXVIIb). Brown crystals (DMF/H2O (3 : 1). Yield67%, mp 295–297°C. IR spectrum: 1685 (C=Ostr).1H NMR spectrum: 1.71 (d, 2H, methylene of pyra�zole), 2.34–2.49 (m, 6H, piperidine), 3.32–3.49 (m,4H, piperidine), 3.81 (t, 1H, methine of pyrazole ring),7.20–7.85 (m, 6H, Ar�H). MS (m/z, %): 424 (M +, 15).Found: C, 73.34; H, 5.44; N, 13.08%. Calcd.:C26H24N4O2 (424.49): C, 73.56; H, 5.70; N, 13.20%.

CONCLUSIONS

In this study, we report the synthesis of some of iso�lated and heterocycle�fused derivatives of naph�tho[1,2�b][1,4]oxazin�2�one derivatives and the anti�microbial evaluation of some of the newly synthesisedcompounds. The results indicate that α, β�aminoni�trile and N�nucleophiles are useful precursors for thesynthesis of different functionalized azoles andoxazoles. The preliminary in vitro antimicrobial datademonstrated that, compound (II) showed moder�ately to highest degree antifungal and antimicrobialactivity against the tested organisms. Compound(XVIIb) showed high degree of inhibition against (SR),(SA) and (EC) and moderate activity to (AF), (GC)and (PA) and was not active against (CA) and (BS).Compounds (XIII) and (XVIIb) showed moderately tohigher activity against (SR) and moderate activityagainst (EC) Compounds (XVIIb) and (XX) showedactivity against (EC). Compounds (XV), (XXVI) and(XXIX) showed activity against (SR) and (EC) at verylow concentrations. All compounds, except (V) and(XV), exhibited no activity against (CA). Also, all com�pounds except (XII) showed no activity against (CA).Moreover, all compounds showed no activity against(PA) except compound (XVIIb) whereas compound(XXVI) exhibited only weak inhibition against (PA).

ACKNOWLEDGMENTS

The financial support of Aswan University, Egyptand Taif University, Kingdom of Saudi Arabia aregratefully acknowledged.

REFERENCES

1. Campaigne, E., in Comprehensive Heterocyclic Chemis�try, Katritzky, A.R. and Rees, C.W., Eds., Oxford: Per�gamon Press, 1984, vol.4, pp. 863–934.

2. Iwaa, M., Lee, M.L., and Castle, R.N., J. Heterocycl.Chem., 1980, vol. 17, pp. 1259–1264.

3. Tominaga, Y., Lee, M.L., and Castle, R.N., J. Hetero�cycl. Chem., 1981, vol. 18, pp. 977–979.

4. Song, K., Wu, L.�Z., Yang, C.�H., and Tung, C.�H.,Tetrahedron Lett., 2000, vol. 41, pp. 1951–1954.

5. Jalilian, A.R., Sattari, S., Bineshmarvasti, M., Danesh�talab, M., Shafiee, A., Il Farmaco, 2003, vol. 58,pp. 63–68.

6. Zani, C.L., Chiari, E., Krettli, A.U., Murta, S.M.F.,Cunningham, M.L., Fairlamb, A.H., and Romanha, A.,J. Bioorg. Med. Chem., 1997, vol. 5, pp. 2185–2192.

7. Das, B.P., Campbell, J.A., Samples, F.B., Wallace, R.A.,Whisenant, L.K., Woodard, R.W., and Boykin, D.W.,Jr., J. Med. Chem., 1972, vol. 15, pp. 370–374.

8. Daidone, G., Bajardi, M.L., Roccaro, A., Raffa, D.,Caruso, A., Cutuli, V., and DiPietro, E., Il Farmaco,1991, vol. 46, pp. 945–957.

9. Plescia, S., Bajardi, M.L., Daidone, G., and Roccaro, A.,Heterocycles, 1988, vol. 27, pp. 105–112.

10. Gutschow, M., and Neumann, U., J. Med. Chem.,1998, vol. 41, pp. 1729–1740.

11. Gutschow, M., Kuerschner, L., Neumann, U.,Pietsch, M., Löser, R., Koglin, N., and Eger, K.,J. Med. Chem., 1999, vol. 42, pp. 5437–5447.

12. Jarvest, R.L., Connor, S.C., Gorniak, J.G., Jennings, L.J.,Serafinowska, H.T., and West, A., Bioorg. Med. Chem.Lett., 1997, vol. 7, pp. 1733–1738.

13. Jarvest, R.L., Pinto, I.L., Ashman, S.M., Dabrowski, C.E.,Fernandez, A.V., Jennings, L.J., Lavery, P., andTew, D.G., Bioorg. Med. Chem. Lett., 1999, vol. 9,pp. 443–448.

14. Böhm, R., Pharmazie, 1990, vol. 45, pp. 282–283.15. Damodiran, M., Selvam, N.P. and Perumal, P.T.,

Tetrahedron Lett., 2009, vol. 50, pp. 5474–5478.16. Remillard, S., Rebhun, L.I., Howie, G.A., and

Kupchan, S.M., Science, 1975, vol. 189, pp. 1002–1005.

17. Kusakabe, Y., Nagatsu, J., Shibuya, M., Kawaguchi, O.,Hirose, C., and Shirato, S. J., Antibiot., 1972, vol. 25,pp. 44–47.

18. Peglion, J.L., Vian, J., Gourment, B., Despaux, N.,Audinot, V. and Millan, M., Bioorg. Med. Chem. Lett.,1997, vol. 7, pp. 881–886.

19. Mosher, H.S., Frankel, M.B., and Gregory, M., J. Am.Chem. Soc., 1953, vol. 75, pp. 5326–5328.

20. Ren, H., Grady, S., Gamenara, D., Heinzen, H.,Moyna, P., Croft, S., Kendrick, H., Yardley, V., andMoyna, G., Bioorg. Med. Chem. Lett., 2001, vol. 11,pp. 1851–1854.

21. Lesher, G.Y., and Surrey, A.R., J. Am. Chem. Soc.,1955, vol. 77, pp. 636–641.

22. Clark, R.D., Caroon, J.M., Kluge, A.F., Repke, D.B.,Roszkowski, A.P., Strosberg, A.M., Baker, S., Bitter, S.M.and Okada, M.D., J. Med. Chem., 1983, vol. 26,pp. 657–661.

23. Matsuoka, H., Ohi, N., Mihara, M., Suzuki, H., Miya�moto, K., Maruyama, N., Tsuji, K., Kato, N., Akim�oto, T., Takeda, Y., Yano, K., and Kuroki, T., J. Med.Chem., 1997, vol. 40, pp. 105–111.

24. Benedini, F., Bertolini, G., Cereda, R., Doná, G.,Gromo, G., Levi, S., Mizrahi, J. and Sala, A., J. Med.Chem., 1995, 38, pp. 130–136.

25. Wamhoff, H., Herrmann, S., Stölben, S., and Nieger, M.,Tetrahedron, 1993, vol. 49, pp. 581–594.

26. Delieza, V., Detsi, A., Bardakos, V., and Igglessi�Markopoulou, O., J. Chem. Soc., Perkin Trans., 1997,vol. 1, pp. 1487–1490.

27. Madkour, H.M.F., Salem, M.A.I., Abdel�Rahman, T.,and Azab, M.E., Heterocycles, 1994, vol. 38, pp. 57–69.

436



28. Wamhoff, H. and Kroth, E., Synthesis, 1994, pp. 405–410.

29. Ming, Y.�fu., Horlemann, N., and Wamhoff, H., Chem.Ber., 1987, vol. 120, pp. 1427–1431.

30. Garin, J., Loscertales, M.P., Meléndez, E., Merchan, F.L.,Rodriguez, R., and Tejero, T., Heterocycles, 1987,vol. 26, pp. 1303–1312.

31. El Azab, I.H. and El Rady, E.A., J. Heterocyclic Chem.,2012, vol. 49, pp. 135–149.

32. El Azab, I.H. and El Rady, E.A., Eur. J. Chem., 2012,vol. 3, pp. 81–86.

33. El Azab, I.H. and El Rady, E.A., Indian J. Chem.,(Sect. B), 2014, vol. 53B, pp. 1194–1204.

34. El Azab, I.H., J. Heterocyclic Chem., 2013, vol. 50 (S1),pp. 178–188.

35. El Azab, I.H. and Elkanzy, N.A.A., Synth. Commun.,2014, vol. 44, pp. 2692–2714.

36. El Azab, I.H., Youssef, M.M., and Amin M.A.,Molecules, 2014, vol. 19, pp. 19648–19664.

37. Hassneen, H.M. and Abdallah, T.A., Molecules, 2003,vol. 8, pp. 333–341.

38. Elnagdi, M.H., Abdel�All, E.A., and Elgemeie, G.E.H.,Heterocycles, 1985, vol. 23, pp. 3121–3153.

39. Sherief, S.M. and Hussein, A.M., Monatsh. Chem.,1997, vol. 128, pp. 687–696.

40. Joshi, K.C., Pathak, Y.N., and Grage, U., J. HeterocyclicChem., 1979, vol. 16, pp. 1141–1145.

41. Dawood, K.M., Kandeel, Z.E., and Farag, A.M.,J. Chem. Res., 1998, pp. 208–209.

42. Dawood, K.M., Kandeel, Z.E., and Farag, A.M.,J. Chem. Res., 1999, pp. 88–89A.

43. Al�Zaydi, K.M. and Hafez, E.A., J. Chem. Res., (S),1999, pp. 360–361.

synthesis and reactivity of enaminone of naphtho[b]1,4\u0002oxazine: one pot synthesis of novel...

Documents