EHOOPrAHH^ECKAa XHMH3, 2015, moM 41, № 4, c. 475-490
SYNTHESIS AND REACTIVITY OF ENAMINONE OF NAPHTHO[S]1,4-OXAZINE: ONE POT SYNTHESIS OF NOVEL ISOLATED AND HETEROCYCLE-FUSED DERIVATIVES WITH ANTIMICROBIAL
AND ANTIFUNGAL ACTIVITIES
© 2015 Islam H. El Azab*, ** # and Khaled M. Khaled**' ***
*On leave from Chemistry Department, Faculty of Science, Aswan University, Aswan 81528, Egypt **Chemistry Department, Faculty of Science, Taif University, Al-Haweiah, P.O. box 888, Zip code 21974, Taif, Saudi Arabia ***Chemistry Department, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt Received December 8, 2014; in final form January 23, 2015
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 demonstrated for the synthesis of some new pyrimidines, pyrazoles, isoxazoles, pyrazolo[a]pyrimidines, triazolo[a]pyrimidines, pyri-do[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 activities. The synthesized compounds were characterized by IR, ^H 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.
The chemical and biological potentials of five-mem-bered heterocyclic compounds fused with aromatic nuclei have attracted the attention of organic and medicinal chemists for several years. Amongst these, indole, benzofuran and their annulated derivatives have been extensively explored, since compounds containing these scaffolds demonstrate diverse and interesting biological activities. A survey of the literature on these ring systems revealed a paucity of references to benzo[b]thiophenes and naphtho[b]thiophenes. A few synthetic approaches are available in the literature for the synthesis of ben-zo[b]thiophenes . However, there are fewer approaches to naphtho[b]thiophenes [2—4]. Some interesting biological activities such as antifungal , anti-plasmodial , anti-trypansomal  and antimalarial activities  are associated with the naphtho[b]thiophene ring system.
On the other hand, 2-aryl substituted 4H-3,1-ben-zoxazin-4-ones have been shown to act as specific inhibitors in the activation of factor X (FX) through the "extrinsic pathway" in which factor Vila (FVIIa) and its cofactor, tissue factor (TF), exert the proteolysis of FX to FXa. Hetero annulated 1,3-oxazin-4-ones have been reported as anti-inflammatory agents [8, 9], human leukocyte elastase inhibitors [10, 11], herpes proteases inhibitors [12, 13], and anti allergia agents .
# Corresponding author (phone: +2097480446; fax: +2097480450; e-mail: email@example.com & firstname.lastname@example.org).
Also, 1-amidoalkyl-2-naphthols can be converted to 1,3-oxazine derivatives  of different biological activities, such as antitumor , antibiotic , antipsychotic , anticonvulsant , antimalarial , analgesic , antihypertensive , antirheumatic , and antianginal  properties. Various synthetic approaches to this group of compounds have been described [25—30], however, only few of the reported compounds contain an aryl group directly connected to the ring system, and none of the previously described compounds has been reported as a specific inhibitor of the TF/FVIIa-induced coagulation pathway. We report herein the synthesis of some new heterocycles with 2H-naphtho[1,2-b][1,4]oxazin-2-one moiety starting from 3-acetyl-2H-naph-tho[1,2-b][1,4]oxazin-2-one.
RESULTS AND DISCUSSION
In the present study continuing our previous work [31—36] on the synthesis offused and/or isolated heterocy-clic systems, we report the synthesis of new heterocyclic compounds based on 2H-naphtho[1,2-b][1,4]oxazin-2-one. Thus, the reaction of 2-nitrosonaphthalen-1-ol with ethyl acetoacetate in boiling ethanolic piperidine solution afforded a brown crystalline product identified as 3-acetyl-2H-naphtho[1,2-b][1,4]oxazin-2-one (I) (Scheme 1).
EtOH/pip./reflux -EtOH -H2O
O T CH3 N
The acetyl derivative (I) treated with dimethyforma-mide-dimethylacetal (DMF-DMA) in boiling dry xy-lene yielded 3-(3-(dimethylamino)acryloyl)-2H-naph-tho[1,2-b][1,4]oxazin-2-one (II) as a yellow crystalline product (scheme 2). The structure of enaminone (II) was established on the basis ofits elemental analysis and spectral data (IR, 1H NMR, and MS). The IR spectrum showed the presence of absorption bands at 1695 and 1710 cm-1 due to (2 C=Oi(r) function. The 1H NMR
spectrum showed two singlet signals assigned to two methyl groups at 5 3.01 and 3.04 ppm, up field doublet signal was assigned to olefinic proton at 5 5.15 ppm in addition to down field doublet signal due to azomethine proton (CH=N) at 5 8.22 ppm and aromatic protons in the region of 7.61—7.82 ppm. The MS of compound displayed an intense molecular ion peak at m/z 294 (M+, 50%) corresponding to C17H14N2O3.
Scheme 2. 3-(3-(Dimethylamino)acryloyl)-2H-naphtho[1,2-b][1,4]oxazin-2-one (II).
The reactivity of enaminone (II) towards some nitrogen nucleophiles was investigated. Enaminone (II) reacted with some primary aromatic amines in refluxing AcOH to give corresponding acyclic secondary amine derivatives (IIIa—d) (Scheme 3). The structures of the latter products were assigned on the basis of their analytical and spectral data. The IR spectra of the products showed C=Cstr, C=Ostr and N-H^ absorption bands in the region 1645, 1685 and 3315-3348 cm-1, respectively. The 1H NMR
(DMSO-d6) spectrum of compound (IIIb) showed two singlet signals assigned to imino and hydroxyl groups at 10.98 and 12.18 ppm, respectively. A doublet signal was due to olefinic proton at 5 5.81 ppm in addition to down field doublet signal due to another olefinic proton and aromatic protons in the region 7.618.87 ppm. Its mass spectrum showed a molecular ion peak at m/z 386 (M+, 40%) corresponding to a molecular formula C22H14N2O5.
a, R = H
b, R = 2-
c, R = 2d, R = 4-
COOH NO2 NO2
Scheme 3. Synthesis of acyclic secondary amine derivatives (IIIa-d).
The reactivity of enaminone (II) towards thiourea was also investigated. Treatment of compound (II)
with thiourea in refluxing EtOH, in the presence of EtONa afforded pyrimidine-2-thione derivative (V)
(Scheme 4). Its mass spectrum revealed a molecular ion peak at m/z 307 (M+, 75%). Compound (V) is assumed to be formed via addition of one of the NH2 groups of thiourea to the activated exocyclic double
bond in enaminone (II) with subsequent elimination of dimethylamine molecule followed by intermolecular cyclization to form the final product (V) via loss
O HN N
O N N
Scheme 4. Synthesis of pyrimidine-2-thione (V) and pyrimidine (VII) derivatives.
Enaminone (II) reacted with guanidine to give a pyrimidine derivative (VII) (Scheme 4). Its IR spectrum showed the presence of carbonyl and amino absorption bands at 1685 and 3384 cm-1, respectively, which corresponded to the assigned structure. The mass spectrum of compound (VII) revealed a molecular ion peak at m/z 290 (M+, 50%) [cf Experimental part].
The reactivity of enaminone (II) towards hydrazine and hydroxyl amine was investigated. The reaction with hydrazine hydrate in acetic acid afforded yellow product identified as 3-(1#-pyrazol-5-yl)-2#-naph-tho[1,2-6][1,4]oxazin-2-one (IX) (Scheme 5). Its structure was in agreement with elemental analysis and spectral data. Its IR spectrum displayed absorption bands at 1685 and 3160 cm-1 due to C=Ostr and N-Hstr functions, respectively. The 1H NMR spectrum (DMSO-d6) exhibited doublet signal due to pyrazole proton at 5 6.32 (1H, J = 3.6 Hz), multiplet signal at 5 7.20-8.85 region owing to the other pyrazole proton and an aromatic protons, in addition to D2O-exchange-able broad singlet due to pyrazole NH at 5 10.82 ppm. Its mass spectrum revealed molecular ion peak at m/z 263 (M+, 35%).
Enaminone (II) treated with NH2OH in refluxing EtOH afforded a single product which was identified as 3-(isoxazol-5-yl)-2#-naphtho[1,2-è][1,4]oxazin-2-one (XI) (Scheme 5). Its IR spectrum displayed absorption bands at 1687 cm-1 due to C=Ostr function. Its 1H NMR spectrum exhibited a doublet signal due to isoxazole proton at 6 6.35 (1H, J = 4.82 Hz ), a multiplet signal in 6 7.20-8.15 ppm region owing to another pyrazole proton and an aromatic protons. The mass spectrum revealed molecular ion peak at m/z 264 (M+, 60%).
The behavior of 3-(3-(dimethylamino)acryloyl)-2#-naphtho[1,2-è][1,4]oxazin-2-one (II) in reaction with some heterocyclic amines as potential precursors for fused heterocyclic systems was investigated. Enaminone (II) treated with 5-amino-3-phenyl-1#-pyrazole in refluxing yielded a product identified as 3-(2-phe-nylpyrazolo [1,5- a]pyrimidin-7-yl)-2#-naphtho [1,2-è][1,4]oxazin-2-one (XIII) (Scheme 6). Its IR spectrum confirmed the presence of intense absorption bands at v 1690 cm-1 due to carbonyl group. The mass spectrum showed m/z 406 (M+, 64%). The 1H NMR spectrum showed singlet signal at 6 5.40 due to pyra-zole proton, multiplet signal due to pyrimidine proton and aromatic protons in the region 7.23-8.54 ppm in
Scheme 5. Synthesis of pyrazole (IX) and isoxazole (XI) derivatives.
Scheme 6. Synthesis of 2-phenylpyrazolo[1,5-a]pyrimidine derivative (XIII).
addition to doublet single at 5 9.41 ppm due to another pyrimidine proton.
Similarly, enaminone (II) in reaction with 3-amino-1,2
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