xazin-4-ones and 2-Methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one under Microwave Irradiation Conditions
Kyriakos C. Prousis,a,b Andromachi Tzani,a Nicolaos Avlonitis,b,c Theodora Calogeropoulou,b and Anastasia Detsia*
aLaboratory of Organic Chemistry, Department of Chemical Sciences, School of Chemical Engineering, NationalTechnical University of Athens, Heroon Polytechniou 9, Zografou Campus, GR 15780, Athens, Greece
bInstitute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, 48 VassileosConstantinou Avenue, 116 35, Athens, Greece
cCentre for Inflammation Research, The Queen’s Medical Research Institute, MRC/University of Edinburgh, 47 LittleFrance Crescent, EH16 4TJ, Edinburgh, UK
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
X N
O
X NH
X NHCOCH3
O
Y
OH
O
O
ROHHC
Y
CO2R
Z
Z
Z
X= CH, NHZ=H, 7-Cl, 6-Br, 6,7-diOMeY=CO2Me, CO2Et, COMe
R=Et, iPr, CH2 OMe,
OR
W W
The reactivity of variably substituted 2-methyl-4H-3,1-benzoxazin-4-ones and 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one towards carbon and oxygen nucleophiles under microwave irradiation conditions was investigated.Optimization of the reaction conditions of oxazinones with carbon nucleophiles led to the synthesis of a series of4-hydroxy-quinolin-2-ones and 4-hydroxy-1,8-naphthyridin-2-ones in high yields, whereas reaction with a varietyof alcohols proceeded smoothly to the formation of the corresponding N-acetyl-anthranilates and nicotinates.
J Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
The 4H-3,1-benzoxazin-4-one scaffold is present in nat-ural products, such as dianthalexin, the major phytoalexinfrom carnation, [1] and constitutes a reactive and versatilestarting material extensively used for the synthesis of avariety of important nitrogen heterocyclic systems suchas quinazolin-4(3H)-ones [2–4] and 4-hydroxy-quinolin-2(1H)-ones.[5,6] The reactivity of these heterocyclicsystems has been the subject of an excellent review byCoppola [7] in which all aspects of potential sites of reac-tions of these compounds are presented. The aza-analogsof 4H-3,1-benzoxazin-4-ones, namely 4H-pyrido[2,3-d][1,3]oxazin-4-ones, although much less studied from areactivity point of view, have also served as startingmaterials for the synthesis of bioactive compounds such
as pyrido[2,3-d]pyrimidinones [8] quinazolinone analogspossessing a nitrogen atom on the aromatic ring [9] and4-hydroxy-1,8-naphthyridin-2(1H)-ones.[10–12]
Microwave-Assisted Organic Synthesis (MAOS) hasemerged as a powerful synthetic tool that offers severaladvantages, such as decrease of reaction time, simplificationof product purification and enhancement of yields. Althoughat first it was mostly applied as a technique to accelerate veryslow, low yielding reactions, MAOS is nowadays gaining aplace in organic chemistry laboratories as a routine technique.As a result, numerous applications of the “microwavedielectric heating effect” have been studied providing newapproaches to known reactions or showing the ability ofmicrowave heating to contribute to reaction completion.[13,14] The application of MAOS in medicinal chemistry,
orporation
K. C. Prousis, A. Tzani, N. Avlonitis, T. Calogeropoulou, and A. Detsi Vol 000
a field in which rapid compound library production is ofgreat scientific and economic importance, is of special inter-est, as the constantly growing demand of the pharmaceuticalindustry for more structurally diverse compound collectionstowards the identification of novel drug leads causes a needfor more rapid and efficient synthesis of organic molecules.In the course of our research aimed at the synthesis and
study of novel bioactive 4-hydroxy-quinolin-2(1H)-onesand their derivatives,[15] we have decided to explorethe potential of MAOS in the construction of libraries of4-hydroxy-quinolin-2(1H)-one analogs. The quinolinonescaffold is encountered in natural products such as quinolinealkaloids.[16,17] Natural and synthetic quinolinone analogspossess a wide variety of biological activities includinganti-inflammatory,[15,18] antioxidant,[15,19,20] immuno-modulatory,[21] and enzyme inhibitory activity.[15,22]Characteristic examples of microwave-assisted synthesis
of quinolinone derivatives involve in most cases, reactionsbetween anilines and malonates.[23–26] The exploitationof microwave irradiation enabled Kappe et al. to synthesizea variety of 4-hydroxy-quinolinone bioactive derivativesusing Suzuki and Heck reactions under controlled micro-wave irradiation conditions [27] and Beccalli et al. toperform intramolecular Heck cyclization reaction of hetero-arylamides in an effort to obtain improved yields inthe synthesis of fused quinolone and naphthyridonederivatives.[28] The microwave-assisted condensation ofo-aminoarylketones with active methylene compounds inthe presence of a catalytic amount of cerium chloride hepta-hydrate under solvent-free conditions provides also a varietyof substituted 2-quinolones.[29]Our approach involves the exploitation of substituted
2-methyl-4H-3,1-benzoxazin-4-ones (2a–2d) and 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one (2e) as starting materials.Compounds 2a and 2e have proved to be excellent agentsfor the C-acylation of active methylene compoundsunder basic conditions leading to 3-substituted-4-hydroxy-quinolin-2-ones after basic or acidic cyclization, as hasbeen established in our previous work.[5] Moreover, theavailability of anthranilic acids bearing a variety of substituents
Reagents and conditions: (i) For compounds 2a, 2bcompounds 2a, 2c, 2e: (CH3CO)2O,130oC, 2h
Journal of Heterocyclic Chemi
on the aromatic ring and the ease of preparation of thecorresponding 2-methyl-4H-3,1-benzoxazin-4-ones rendersthem ideal starting materials for the synthesis of analogs.
RESULTS AND DISCUSSION
The synthesis of the starting 2-methyl-4H-3,1-benzoxa-zin-4-ones (2a–2d) and 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one (2e) was accomplished by treating thecorresponding anthranilic acids (1a–1d) and 2-aminonicotinic acid (1e) with acetic anhydride under microwaveirradiation conditions or conventional heating (Scheme 1).The reactivity of the synthesized oxazinones towards carbonnucleophiles under microwave irradiation conditions wasinvestigated aiming at the development of a concise and highyielding route to quinolinones and naphtyridinones.
An optimization study concerning the base, the solvent, andthe microwave reaction conditions (irradiation power, time,and temperature) was performed using the reaction between2-methyl-4H-3,1-benzoxazin-4-one (2a) and diethylmalonate(3a) as the model reaction. Five different bases were used,namely, triethylamine, DBU, t-BuOK, Cs2CO3, and NaH indifferent molar ratios. The results of this study are presentedin Table 1.
The reaction of benzoxazinone 2a with diethyl malonate(3a) in the presence of cesium carbonate or potassiumtert-butoxide was unsuccessful. On the other hand, whennonnucleophilic organic bases such as DBU and triethylaminewere used, ethyl N-acetyl-anthranilate (6a) was formed as themajor product in various yields, depending on the reactionconditions. An analogous phenomenon has been previouslyreported by Beutner et al.[30] during the investigation ofthe synthesis of 4-hydroxy-3-methoxycarbonyl-N-benzyl-quinolin-2-one by heating the corresponding isatoicanhydride with dimethyl malonate in basic conditions(N,N’-diisopropylethylamine (DIPEA) and NaH); largeamounts of methyl N-benzyl-anthranilate were isolated.The authors proposed that the formation of the ester is theresult of a nucleophilic attack to isatoic anhydride by themethanol released during the cyclization of the quinolinone
Month 2013 Reactivity of Oxazinones under Microwave Irradiation
ring. In an effort to clarify the reaction outcome, weperformed three different experiments, with dimethylmalonate, diethyl malonate, and with ethyl phenylacetateusing the conditions of entry 5. We obtained the methyland ethyl N-acetyl-anthranilates, respectively; therefore, itis evident that their formation can be attributed to therelease of the corresponding alcohol as a result of a thermaldecomposition of the esters. The formation of anthranilatesseems to be favored in higher temperatures and microwaveirradiation power (entries 4–8).The synthesis of the desired 4-hydroxy-3-substituted-qui-
nolin-2-one derivatives in very satisfactory yields wasfinally accomplished using sodium hydride as the baseunder less harsh reaction conditions (entry 10), in whichno trace of the ester product was observed. To explore thescope of this reaction, we performed it with the halogensubstituted benzoxazinones (2a–2c) and pyrido-oxazinone(2e) using diethyl and dimethyl malonate, 3a and 3b, as wellas methyl acetoacetate (3c) as the carbon nucleophiles
Journal of Heterocyclic Chemi
(Scheme 2). In all cases, we were gratified to find that weobtained the corresponding 4-hydroxy-3-substituted-qui-nolin-2-ones (4a–4f) and 4-hydroxy-3-substituted-1,8-naph-tyridin-2-ones (4g) and 4h in good yields (50–70%) assolids of satisfactory purity as proved by their NMRspectra. 6,7-Dimethoxy-2-methyl-benzoxazin-4-one (2d) failedto produce the corresponding quinolinones under the investi-gated reaction conditions.
The synthesis of compounds 4a–4c has been reported inour previous work [5] and involved a two-step proceduregiving the desired compounds in 49%, 62%, and 60% overallyield, respectively. The use of microwave irradiation enabledus to obtain the compounds in one short reaction step (10min)in higher yields (60–75%) and purity. In addition, this routeprovides access to naphthyridinones 4g and 4h, which couldnot be obtained by our conventional approach.[10]
The formation of ethyl N-acetyl-anthranilate (6a) observedin the first series of optimization reactions prompted us tofurther investigate the reactivity of 3,1-benzoxazin-4-ones
stry DOI 10.1002/jhet
Scheme 2. Microwave-assisted synthesis of 4-hydroxy-3-substituted-quinolin-2-ones (4a–4f) and 4-hydroxy-3-substituted-1,8-naphtyridin-2-ones (4g,4h).
K. C. Prousis, A. Tzani, N. Avlonitis, T. Calogeropoulou, and A. Detsi Vol 000
toward a variety of alcohols under microwave irradiationconditions and explore the possibility of developing analternative approach toward anthranilate esters.Esters of anthranilic acids are encountered in natural
products with important bioactivity such as the enediyneanticancer antibiotics esperamicins,[31,32]methyllycaconitine,a toxic alkaloid isolated from various Delphinium species,[33,34] which possesses high affinity and selectivity tomammalian acetylcholine receptors,[35] and the diterpenealkaloid lappaconitine, with psychotropic and analgesicactivity.[36] Moreover, a number of simple anthranilateesters are important flavor and fragrance compounds,[37] whereas synthetic anthranilates have been recentlyreported to possess anticancer,[38] anti-inflammatory,[39]and antiandrogenic activity.[40]Anthranilate esters are usually synthesized by heating
isatoic anhydride with the alcohol in the presence of a catalyticamount of base.[41] However, this procedure, apart fromusing very harsh conditions, works well only with primaryalcohols, whereas it fails to give the corresponding esters withtertiary alcohols. Alternative approaches for the synthesis ofanthranilate esters have been developed such as the alkylationof basic anthranilic acid salts [42] and coupling of primary andsecondary alcohols with N-(trifluoroacetyl)-anthranilic acidfollowed by sodium borohydride mediated cleavage of theamide functionality.[43,44]As observed from the first series of reactions, DBU in
1,4-dioxane promoted the formation of the esters in thebest yields (Table 1, entry 5). When carried out withoutthe presence of base, that is, using only the oxazinoneand the alcohol, the reaction did not proceed to the desiredester formation. This observation is in agreement with thework of Errede et al.[45] who studied the reactivity of 2awith various alcohols in neutral (or slightly acidic) andbasic conditions and concluded that the presence of acatalytic amount of base is required for the reaction toproceed via the nucleophilic attack of the alcohol to the
Journal of Heterocyclic Chemi
more electrophilic carbon of position 4 of the oxazinonering and form the corresponding ester.
Having established the requirement for the base, weinvestigated the effect of the molar ratios of the reactantsand found that optimum yields and purity of the desired com-pounds were achieved when a catalytic amount of DBU(0.2 equiv), in combination with an excess of the alcohol(5 equiv) was used. Using these reaction conditions (MethodA), we successfully obtained N-acetyl-anthranilates (6a–6e)from the reaction of 2-methyl-4H-3,1-benzoxazin-4-one (2a)and a variety of primary and secondary alcohols (Table 2).Method A was used also for the synthesis of N-acetyl-nicotinates 6j–6m starting from 2e. 6,7-Dimethoxy-2-methyl-4H-benzo[d][3,1]oxazin-4-one (2d) did not reactunder the same conditions, and after performing an optimiza-tion study, we concluded that this oxazinone required signifi-cantly higher temperature and microwave irradiation power(120�C, 150W, Method B) to produce the esters 6f–6i.
Esters 6a–6m were isolated as solids either directly afteracidification of the reaction mixture or after extraction withCH2Cl2 (see Experimental section). The yields of the reac-tions were more than satisfactory, ranging from 80%to 97%, and the products were pure as indicated bytheir 1H-NMR and 13C-NMR spectra. It is evident that thismicrowave-assisted synthesis of N-acetyl-anthranilates andN-acetyl-nicotinates provides a straightforward access tothese compounds.
CONCLUSIONS
The reactivity of oxazinones toward carbon and oxygennucleophiles using microwave irradiation conditions wasstudied. The reaction of oxazinones 2a–2e with carbonnucleophiles affords in one-step variably substituted4-hydroxy-quinolin-2-ones and 4-hydroxy-1,8-naphthyridin-2-ones. The synthesis is straightforward and fast and affordsthe final products in high purity and yields. The developed
stry DOI 10.1002/jhet
Table 2
Synthesis of anthranilates and nicotinates 6 under microwave irradiation conditions.
Entry
Oxazinone Alcohol
Methoda Ester Yield %b(1 equiv) (5 equiv)
R
1 2a CH2CH3 A 6a 972 2a A 6b 88
3 2a A 6c 82
4 2a A 6d 80
5 2a CH(CH3)2 A 6e 836 2d CH2CH3 B 6f 857 2d B 6g 90
8 2d B 6h 81
9 2d CH(CH3)2 B 6i 6510 2e CH2CH3 A 6j 8011 2e A 6k 66
12 2e A 6l 72
13 2e CH(CH3)2 A 6m 80
aMethod A: DBU (0.2 equiv), dioxane, 100W, 70�C, 10min; Method B: DBU (0.2 equiv), dioxane, 150W, 120�C, 10min.bAll yields are for isolated products after purification.
Month 2013 Reactivity of Oxazinones under Microwave Irradiation
route provides rapid access to these heterocycles bearing avariety of substituents on the aromatic ring as well as onposition 3 of the heterocyclic ring; it is therefore suitablefor the construction of libraries of analogs.Furthermore, 2-methyl-4H-3,1-benzoxazin-4-ones and
2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one react efficientlywith primary, secondary, and benzylic alcohols in thepresence of a catalytic amount of DBU under microwaveirradiation conditions to afford N-acetyl anthranilates andN-acetyl aminonicotinates, a series of compounds that canbe further exploited as starting materials for the synthesisof more complex derivatives and as potential bioactivecompounds. Studies in expanding the scope of this reactiontoward the synthesis of anthranilate esters possessing avariety of N-acyl-substituents starting from the corresponding2-substituted-4H-3,1-benzoxazin-4-ones as well as toward the
Journal of Heterocyclic Chemi
reactivity of benzoxazinones with tertiary and stericallyhindered alcohols are currently underway.
EXPERIMENTAL
General comments. Mps were determined on a GallenkampMFB-595 melting point apparatus (Weiss Gallenkamp, London,UK) and are uncorrected. The microwave assisted reactions wereperformed using a CEM Explorer Microwave Synthesizer (CEMCorporation, Matthews, NC, USA). The NMR spectra wererecorded at 300 (1H) and 75 (13C) MHz on a Varian 300MHz(Agilent Technologies, Santa Clara, CA, USA) spectrometer and600 (1H) and 150 (13C) MHz on a Varian 600MHz spectrometer;chemical shifts are quoted in parts per million (s = singlet,d = doublet, dd = doublet of douplet, t = triplet, pt = pseudotriplet,q = quartet, m=multiplet, and br = broad); J values are given inHertz. High-resolution mass spectra were obtained on an UltraHigh Pressure Liquid Chromatography Mass Spectrometer Mass
stry DOI 10.1002/jhet
K. C. Prousis, A. Tzani, N. Avlonitis, T. Calogeropoulou, and A. Detsi Vol 000
Accuracy and Ultra High Resolution (UHPLC–LTQ OrbitrapVelos, Thermo Scientific) (Thermo-Fischer Inc, Waltham, MA,USA). Mass spectra were obtained on an ESI–MS (HPLC–LCQFleet/Thermo Scientific). All commercially available startingmaterials were purchased from Sigma-Aldrich (Milwaukee WI,USA) and Alfa Aesar (Karlshrue, Germany) and were used withoutfurther purification. Commercially available THF (purchased fromPanreac, Barcelona, Spain) was dried prior to use by refluxing overNa. All other solvents (puriss. quality) were purchased from Panreacused without further purification. Column chromatography wasperformed with silica gel 60 with eluents given in parentheses.
General procedure for the synthesis of compounds 2a–2e. Thesynthesis of compounds 2a–2e was accomplished by treating thecorresponding anthranilic acids (1a–1d) and 2-aminonicotinic acid (1e)with acetic anhydride under microwave irradiation conditions (2a, 2b,and 2d) (Method I) or reflux (2a, 2c, and 2e) (Method II).
Method I. In a 10-mLmW-reaction tube were placed theappropriate anthranilic acid (1a, 1b, and 1d) (5mmol) and aceticanhydride (3mL), the tube was immediately sealed and irradiated ona CEMExplorer Microwave Synthesizer at 150�C, 250W for 20min.
Method II. A mixture of anthranilic acid (1a–1d) (10mmol)or 2-aminonicotinic acid (1e) (10mmol) and acetic anhydride washeated at 140�C for 2 h or at 170�C for 1 h (in the case of 1e).
2-Methyl-benzo[d][3,1]oxazin-4-one (2a). Synthesized fromanthranilic acid (1a) using both methods. When Method I wasused, the reaction mixture was cooled to RT, transferred to around-bottomed flask using a small amount of ethyl acetate, andthe solvents were evaporated. The crude solid mass wassuspended in hexane (30mL) with stirring, and the product wasdissolved by gentle heating (~50�C), for approximately 20min. Asmall amount of crude material remained undissolved and wasremoved by filtration. Hexane was evaporated under reducedpressure to afford a white solid that was dried in high vacuo overP2O5 for 2–3 h. Via Method II, upon completion of the reaction,excess acetic anhydride was removed under reduced pressure, andthe resulting solid was triturated with petroleum ether, collectedby filtration, and dried in vacuo. Yield: Method I (92%); MethodII (94%). mp 75–78�C [lit.[5] mp 74–78�C].1H-NMR (300MHz,CDCl3) d=2.48 (s, 3H), 7.45–7.54 (m, 2H), 7.78 (d, 2J=7.8Hz,1H), 8.17 (d, 2J=8.0Hz, 1H) ppm.
7-Chloro-2-methyl-4H-benzo[d][3,1]oxazin-4-one (2b). [46]Compound 2b was prepared via Method I using 2-amino-4-chlorobenzoic acid (1b, 1.72 g, 10.0mmol) and acetic anhydride(8.2mL, 86.4mmol). The reaction mixture was cooled using anice water bath, and the crystallized solid was filtered, washed withpetroleum ether, and dried over P2O5 for 2–3 h. The productwas isolated as light brown crystals. Yield (1.90 g, 97%). mp146–147�C. 1H-NMR (300MHz, CDCl3) d=2.47 (s, 3H), 7.45(dd, J=8.4Hz, J=2.1Hz, 1H,), 7.54 (d, J=2.0Hz, 1H), 8.10(d, J=8.4Hz, 1H) ppm.
6-Bromo-2-methyl-4H-benzo[d][3,1]oxazin-4-one (2c). [46]Compound 2c was prepared via Method II using 2-amino-5-bromobenzoic acid (1c, 2.16 g, 10.0mmol) and acetic anhydride(8.2mL, 86.4mmol). Cooling the reaction mixture in an ice waterbath afforded the desired compound as crystals, which werefiltered and washed with hexane. Recrystallization from hexaneyielded a white solid (1.68 g, 70%). mp 128–130�C. 1H-NMR(600MHz, CDCl3): d=2.46 (s, 3H), 7.43 (d, J=8.4Hz, 1H), 7.88(dd, J=8.4, 2.4Hz, 1H), 8.31 (d, J=2.4Hz, 1H) ppm.
6,7-Dimethoxy-2-methyl-4H-benzo[d][3,1]oxazin-4-one (2d). [46]Compound 2d was prepared via Method I using 2-amino-4,5-dimethoxybenzoic acid (1d, 1.11g, 5.0mmol) and acetic anhydride
Journal of Heterocyclic Chemi
(3.0mL, 27.2mmol). The product was isolated as light browncrystals, as described in the case of compound 2b. Yield: 0.94g, 85%.mp 186–188�C. 1H-NMR (300MHz, CDCl3): d=2.43 (s, 3H), 3.96(s, 6H), 6.93 (s, 1H), 7.47 (s, 1H) ppm.
2-Methyl-pyrido[2,3-d][3,1]oxazin-4-one (2e). Compound 2ewas prepared via Method II using 2-aminonicotinic acid (1e, 1.38 g,10.0mmol) and acetic anhydride (8.2mL, 86.4mmol). The productwas isolated as light brown crystals, as described for compound 2a(1.56 g, 96%). mp 176–178�C [lit.[10] mp 165–166�C]. 1H-NMR(300MHz, CDCl3): d=2.48 (s, 3H), 7.48 (dd, J=7.8, J=3.6Hz,1H), 8.51 (dd, J=7.8, J=1.2Hz, 1H), 8.97 (s, 1H) ppm.
General procedure for the synthesis of compounds 4a–4h. In a10-mLmW-reaction tube were placed NaH 60% dispersion in oil(120mg, 3mmol) in anhydrous THF (2mL), and the tube was sealedunder argon. The appropriate malonates or b-ketoesters (2mmol)were added dropwise under argon atmosphere to the stirredsuspension at 0�C. After 5–10min stirring at RT, the substituted2-methyl-4H-3,1-benzoxazin-4-ones (2a–d) (1mmol) or 2-methyl-4H-pyrido[2,3-d][3,1]oxazin-4-one (2e) (162mg, 1mmol) wereadded, the tube was immediately sealed and irradiated on a CEMExplorer Microwave Synthesizer at 70�C, 100W over 10min. Aftercooling to RT, water (5mL) was added slowly with cooling at 0�C.The mixture was extracted with diethyl ether (1� 20mL), and theaqueous layer was separated and acidified to pH=1–2 with 10% aq.HCl at 0�C to give the corresponding final products (4a–4i) as solids.The products were filtered, washed with diethyl ether, and dried inhigh vacuum over P2O5 for 2–3h.
Ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate(4a). Starting from 2-methyl-4H-3,1-benzoxazin-4-one (2a)(161mg, 1.0mmol) and using diethyl malonate (3a, 320mg,2.0mmol), the title compound was obtained as a white solid(163mg, 70%). mp: 213–215�C, (lit.[5] mp: 212–215�C).1H-NMR (300MHz, CDCl3): d= 1.54 (t, J= 6.9Hz, 3H), 4.53(q, J= 6.9Hz, 2H), 7.21 (t, J= 7.2Hz, 1H), 7.35 (d, J= 7.8Hz,1H), 7.59, (t, J= 7.2Hz, 1H), 8.06 (d, J= 7.8Hz, 1H), 11.91(s, 1H), 14.24 (s, 1H) ppm. 13C-NMR (75MHz, CDCl3):d= 14.3, 62.4, 97.8, 114.3, 116.0, 122.5, 125.0, 134.3, 140.0,162.1, 172.5, 173.6 ppm. ESI–MS: m/z 234.01 [M+H]+.
Methyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate(4b). Starting from 2-methyl-4H-3,1-benzoxazin-4-one (2a)(161mg, 1.0mmol) and using dimethyl malonate (3b, 260mg,2.0mmol), the title compound was obtained as a white solid(149mg, 68%). mp 223–224�C. (lit.[5] mp: 226–228�C). 1H-NMR(600MHz, DMSO-d6): d=3.86 (s, 3H), 7.22 (t, J=7.2Hz, 1H),7.27 (d, J=7.8Hz, 1H), 7.63, (t, J=7.2Hz, 1H), 7.94 (d, J=7.8Hz,1H), 11.53 (s, 1H), 13.32 (s, 1H) ppm. 13C-NMR (75MHz,DMSO-d6): d= 52.4, 99.8, 113.4, 115.3, 121.7, 124.1, 133.8,139.8, 159.3, 168.8, 171.6 ppm. ESI–MS: m/z 220.01 [M+H]+.
Ethyl7-chloro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (4d).Starting from 7-chloro-2-methyl-4H-benzo[d][3,1]oxazin-4-one(2b) (196mg, 1.0mmol) and using diethyl malonate (3a, 320mg,2.0mmol), the title compound was obtained as a white solid
stry DOI 10.1002/jhet
Month 2013 Reactivity of Oxazinones under Microwave Irradiation
Methyl 7-chloro-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate(4e). Starting from 7-chloro-2-methyl-4H-benzo[d][3,1]oxazin-4-one(2b) (196mg, 1.0mmol) and using dimethyl malonate (3b, 264mg,2.0mmol), the title compound was obtained as a white solid(165mg, 65%). mp 220C (dec.) (lit.[6] mp 240C). 1H-NMR(600MHz, DMSO-d6): d=3.85 (s, 3H), 7.25 (d, J=7.8Hz, 1H),7.28 (s, 1H), 7.93, (d, J=8.4Hz, 1H), 11.61 (s, 1H), 13.29 (br s,1H) ppm. 13C-NMR (75MHz, DMSO-d6): d=52.4, 100.6, 112.5,114.4, 122.0, 126.2, 138.0, 140.6, 159.4, 167.5, 169.9 ppm.ESI–MS: m/z 253.97 [M+H]+.
Ethyl 6-bromo-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate(4f). Starting from 6-bromo-2-methyl-4H-benzo[d][3,1]oxazin-4-one(2c) (240mg, 1.0mmol) and using diethyl malonate (3a, 264mg,2.0mmol), the title compound was obtained as a white solid (190mg,61%). mp 210�C (dec.) [lit.[47] mp 200�C (dec.)]. 1Η-NMR(600MHz, DMSO-d6/drops CDCl3): d=1.36 (t, J=7.2Hz, 3H),4.39 (q, J=7.2Hz, 2H), 7.18 (d, J=8.7Hz, 1H), 7.56 (dd, J=8.7,2.1Hz, 1H), 7.98, (d, J=2.1Hz, 1H), 11.47 (s, 1H) ppm. 13C-NMR(75MHz, DMSO-d6/drops CDCl3) d=13.8, 61.5, 98.4, 113.4, 117.3,126.2, 136.0, 138.7, 159.3, 170.2, 171.3ppm. ESI–MS: m/z 309.94,312.02 [M�H]�.
Ethyl 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3-carboxylate(4g). Starting from 2-methyl-4H-pyrido[2,3-d][3,1]oxazin-4-one (2e)(162mg, 1.0mmol) and using diethyl malonate (3a, 264mg,2.0mmol), the title compound was obtained as a white solid(117.5mg, 50%). mp 263�C (dec.). 1Η-NMR (300MHz, DMSO-d6):d=1.30 (t, J=7.2Hz, 3H), 4.33 (q, J=7.2Hz, 2H), 7.28 (dd, J=7.8,4.8Hz, 1H), 8.32 (d, J=7.2Hz 1H, Η-5), 8.61, (d, J=3.0Hz, 1H),11.91 (s, 1H), 13.12 (br s, 1H) ppm. 13C-NMR (150MHz, DMSO-d6):d=14.0, 61.4, 102.0, 109.5, 118,2, 133.4, 150.0, 153.5, 160.2, 166.2,168.7ppm. ESI–MS: m/z 233.07 [M�H]�. ESI–HRMS: m/z[M+H]+ Calcd for C10H9N2O4: 235.0713, found: 235.0712.
Methyl 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridin-3-carboxylate(4h). Starting from 2-methyl-4H-pyrido[2,3-d][3,1]oxazin-4-one (2e)(162mg, 1.0mmol) and using dimethyl malonate (3b, 264mg,2.0mmol), the title compound was obtained as a white solid (145mg,66%). mp >250�C (dec.) [lit.[48] mp 236�C (dec.)]. 1Η-NMR(300MHz, DMSO-d6, 45�C): d=3.84 (s, 3H, CH3), 7.25 (dd, J=7.8,4.8Hz, 1H), 8.31 (dd, J=7.8, 1.8Hz, 1H), 8.59 (dd, J=4.8, 1.8Hz,1H), 11.68, (br s, 1H) ppm. 13C-NMR (75MHz, DMSO-d6, 45�C):d=52.0, 101.3, 109.9, 117,9, 133.3, 150.0, 153.1, 160.3, 167.0,169.2ppm. ESI–MS: m/z 220.97 [M+H]+, 243.39 [M+Na]+.
General procedure for the synthesis of compounds 6a–6m. Ina 10-mLmW-reaction tube were placed dry 1,4-dioxane (1mL), theappropriate substituted 2-methyl-4H-3,1-benzoxazin-4-ones (2a,2d)(1mmol) or 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one (2e)(162mg, 1mmol), the alcohols (5) (5mmol), and a catalyticamount of DBU (20%, 30mg, 0.2 mmol). The tube wassealed under argon and then irradiated.
Method A. The reaction mixture was heated at 100�C, usingmicrowave power 100W for 10min.
Method B. The reaction mixture was heated at 120�C, usingmicrowave power 150W for 10min.
Ethyl 2-acetamidobenzoate (6a). Compound 6awas preparedvia Method A using 2-methyl-4H-3,1-benzoxazin-4-one (2a)
Journal of Heterocyclic Chemi
(161mg, 1.0mmol) and ethanol (230mg, 5.0mmol). Aftercooling to RT, the reaction was quenched with aq. HCl 10%(1mL), diluted with water (5mL), and the mixture was extractedwith dichloromethane (3� 20mL). The collected organic layerwas washed successively with aqueous solution of 5% NaOH(2� 10mL), water (10mL) and brine (10mL), dried withNa2SO4, and the solvent was evaporated under reduced pressure.The title compound was obtained as a colorless solid requiring nofurther purification, as observed by NMR. Yield: (201mg, 97%).mp 64–65�C (lit.[45] mp 65–66�C). 1H-NMR (300MHz, CDCl3):d=1.43 (t, J=7.2Hz, 3H), 2.25 (s, 3H), 4.38 (q, J=7.2Hz,2H), 7.06 (t, J=7.5Hz, 1H), 7.52, (t, J=7.5Hz, 1H), 8.02(d, J=8.1Hz, 1H), 8.68 (d, J=8.4Hz, 1H), 11.07 (br s, 1H) ppm.13C-NMR (75MHz, CDCl3): d=14.3, 25.6, 61.5, 115.1, 120.4,122.4, 130.9, 134.6, 141.7, 168.4, 169.2 ppm. ESI–MS: m/z207.83 [M+H]+.
Prop-2-ynyl 2-acetamidobenzoate (6b). Compound 6b wasprepared via Method A using 2-methyl-4H-3,1-benzoxazin-4-one(2a) (161mg, 1.0mmol) and prop-2-yn-1-ol (propargyl alcohol)(280mg, 5.0mmol). After cooling to RT, the reaction wasquenched with aq. HCl 10% (1mL) and diluted with water(5mL), and compound 6b precipitated as a white solid, which wasfiltered, washed with water and petroleum ether, and dried overP2O5. Yield: (194mg, 88%). mp 129–130�C. 1H-NMR (300MHz,CDCl3): d=2.25 (s, 3H), 2.57 (s, 1H), 4.92 (s, 2H), 7.08,(t, J=7.5Hz, 1H), 7.55 (t, J=7.5Hz, 1H), 8.05 (d, J=8.1Hz, 1H),8.69 (d, J=8.4Hz, 1H), 10.85 (br s, 1H) ppm. 13C-NMR (75MHz,CDCl3): d=25.6, 52.8, 75.6, 77.3, 114.2, 120.5, 122.6, 131.1,135.3, 141.9, 167.6, 169.2 ppm. ESI–MS: m/z 217.82 [M+H]+.ESI–HRMS: m/z [M+H]+ Calcd for C12H11NO3: 218.0812, found:218.0810.
4-Methoxybenzyl 2-acetamidobenzoate (6c). Compound 6cwas prepared via Method A using 2-methyl-4H-3,1-benzoxazin-4-one (2a) (161mg, 1.0mmol) and p-methoxybenzyl alcohol(691mg, 5.0mmol). After reaction work-up as described for 6a,followed by flash column chromatography (petroleum ether/ethyl8:2), compound 6c was obtained as a white solid. Yield: 232mg,82%. mp 107–108�C. 1H-NMR (300MHz, CDCl3): d=2.25 (s, 3H),3.83 (s, 3H), 5.30 (s, 2H), 6.93 (d, J=8.4Hz), 7.04, (t, J=7.5Hz,1H), 7.38 (d, J = 8.4 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 8.04(d, J= 7.8Hz, 1H), 8.69 (d, J= 8.4Hz, 1H), 11.02 (br s, 1H)ppm. 13C-NMR (75MHz, CDCl3): d= 25.6, 55.4, 67.0, 114.2,115.0, 120.4, 122.5, 127.6, 130.2, 131.0, 134.8, 141.7, 160.0,168.2, 169.1 ppm. ESI–MS: m/z 322.01 [M+Na]+. ESI–HRMS:m/z [M+Na]+ Calcd for C17H17NNaO4: 322.1050, found:322.1044.
Cyclohexyl 2-acetamidobenzoate (6d). Compound 6dwas prepared via Method A using 2-methyl-4H-3,1-benzoxazin-4-one (2a) (161mg, 1.0mmol) and cyclohexanol (501mg,5.0mmol). After work-up as described for 6a, followed byflash column chromatography (petroleum ether/ethyl acetate 9:1),compound 6d was obtained as a white solid. Yield: 209mg, 80%.mp 162–163�C. 1H-NMR (300MHz, CDCl3): d=1.28–1.95(m, 10H), 2.25 (s, 3H), 5.02 (s, 1H), 7.07, (t, J=7.5Hz, 1H),7.52 (t, J=7.5Hz, 1H), 8.03 (d, J= 7.8Hz, 1H), 8.68(d, J=8.4Hz, 1H), 11.13 (br s, 1H) ppm. 13C-NMR (75MHz,CDCl3): d=23.7, 25.5, 25.6, 31.6, 73.9, 115.6, 120.4, 122.4,130.9, 134.5, 141.7, 167.9, 169.1 ppm ESI–MS: m/z 261.86[M+H]+. ESI–HRMS: m/z [M+H]+ Calcd for C15H20NO3:262.1438, found: 262.1437.
Isopropyl 2-acetamidobenzoate (6e). Compound 6e wasprepared via Method A using 2-methyl-4H-3,1-benzoxazin-4-one
stry DOI 10.1002/jhet
K. C. Prousis, A. Tzani, N. Avlonitis, T. Calogeropoulou, and A. Detsi Vol 000
(2a) (161mg, 1.0mmol) and propan-2-ol (300mg, 5.0mmol). Afterwork-up as described for compound 6b, the title compound wasobtained as a white solid. Yield: 184mg, 83%. mp 58–59�C (lit.[45] mp 62–63�C). 1H-NMR (300MHz, CDCl3): d=1.41(d, J=6.3Hz, 6H), 2.25 (s, 3H), 5.18–5.31 (m, 1H), 7.06,(t, J=7.5Hz, 1H), 7.51 (t, J=7.5Hz, 1H), 8.02 (d, J=7.8Hz, 1H),8.68 (d, J=8.4Hz, 1H), 11.13 (br s, 1H). 13C-NMR (75MHz,CDCl3): d=23.7, 25.6, 31.6, 73.9, 115.5, 120.4, 122.4, 130.9,134.5, 141.7, 167.9, 169.2 ppm. ESI–MS: m/z 221.89 [M+H]+.
Ethyl 2-acetamido-4,5-dimethoxybenzoate (6f). Compound6f was prepared via Method B using 6,7-dimethoxy-2-methyl-4H-benzo[d][3,1]oxazin-4-one (2d) (221mg, 1.0mmol) andethanol (230mg, 5.0mmol). After work-up as described forcompound 6b, compound 6f was obtained as a white solid.Yield: 227mg, 85%. mp 131–133�C (lit.[49] mp 130�C dec.).1H-NMR (300MHz, CDCl3): d= 1.42 (t, J= 7.2Hz, 3H), 2.22(s, 3H), 3.88 (s, 3H), 3.95 (s, 3H), 4.30 (q, J= 7.2Hz, 2H), 7.43(s, 1H), 8.43 (s, 1H), 11.14 (br s, 1H) ppm. 13C-NMR (75MHz,CDCl3): d= 14.4, 25.6, 56.2, 61.2, 103.4, 106.7, 112.2, 138.0,143.8, 154.0, 168.1, 169.1 ppm. ESI–MS: m/z 267.89 [M+Na]+.
Prop-2-ynyl 2-acetamido-4,5-dimethoxybenzoate (6g). Compound6g was prepared via Method B using 6,7-dimethoxy-2-methyl-4H-benzo[d][3,1]oxazin-4-one (2d) (221mg, 1.0mmol) and prop-2-yn-1-ol(propargyl alcohol) (280mg, 5.0mmol). After work-up as described forcompound 6b, compound 6g was obtained as a white solid. Yield:207mg, 90%. mp 211–214�C. 1H-NMR (300MHz, CDCl3): d=2.24(s, 3H), 2.56 (t, J=2.4Hz, 1H), 3.90 (s, 3H), 3.97 (s, 3H), 4.91(d, J=2.4Hz, 2H), 7.45 (s, 1H), 8.45 (s, 1H), 10.94 (br s, 1H) ppm.13C-NMR (75MHz, CDCl3): d=25.7, 52.5, 56.2, 56.3, 75.4, 103.4,105.7, 112.2, 138.4, 143.9, 154.6, 167.2, 169.2ppm. ESI–MS: m/z300.02 [M+Na]+. ESI–HRMS: m/z [M+H]+ Calcd for C14H16NO5:278.1023, found: 278.1019.
Isopropyl 2-acetamido-4,5-dimethoxybenzoate (6i). Compound6i was prepared via Method B using 6,7-dimethoxy-2-methyl-4H-benzo[d][3,1]oxazin-4-one (2d) (221mg 1.0mmol) and propan-2-ol(300mg, 5.0mmol). After work-up as described for compound6b, compound 6i was obtained as a white solid. Yield: 181.5mg,65%. mp 127–131�C. 1H-NMR (300MHz, CDCl3): d=1.41(d, J=6.3Hz, 6H), 2.24 (s, 3H), 3.89 (s, 3H), 3.96 (s, 3H), 5.23(septet, J=6Hz, 1H), 7.43 (s, 1H), 8.44 (s, 1H), 11.19 (br s, 1H)ppm. 13C-NMR (75MHz, CDCl3): d=22.1, 25.7, 56.2/56.3, 68.9,103.4, 107.1, 112.4, 137.9, 143.8, 154.0, 167.6, 169.2ppm. ESI–MS:m/z 281.88 [M+H]+. ESI–HRMS: m/z [M+H]+ Calcd forC14H20NO5: 282.1336, found: 282.1332.
Ethyl 2-acetamidonicotinate (6j). Compound 6j wasprepared via Method A using 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one (2e) (162mg, 1.0mmol) and ethanol (230mg,5.0mmol). After work-up as described for 6b, compound 6j
Prop-2-ynyl 2-acetamidonicotinate (6k). Compound 6k wasprepared via Method A using 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one (2e) (162mg, 1.0mmol) and prop-2-yn-1-ol (propargyl alcohol),(280mg, 5.0mmol). After work-up as described for compound 6a,followed by flash column chromatography (petroleum ether/ethylacetate 4:6), compound 6k was obtained as a white solid. Yield:144mg, 66%. mp 77–81�C. 1H-NMR (300MHz, CDCl3): d=2.43(s, 3H), 2.58 (t, J=2.4Hz, 1H), 4.94 (d, J=2.4Hz, 2H), 7.07 (dd,J=7.8, 4.8Hz, 1H), 8.33 (dd, J=7.8, 2.1Hz, 1H), 8.58 (dd, J=1.8,4.8Hz, 1H), 10.52 (br s, 1H) ppm. 13C-NMR (75MHz, CDCl3):d=26.1, 29.8, 53.17, 76.0, 110.6, 118.2, 140.32, 152.5, 153.4, 165.9,169.8ppm. ESI–MS: m/z 218.98 [M+H]+. ESI–HRMS: m/z[M+H]+ Calcd for C11H11N2O3: 219.0764, found: 219.0756.
4-Methoxybenzyl 2-acetamidonicotinate (6l). Compound 6lwas prepared via Method A using 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one (2e) (162mg, 1.0mmol) and p-methoxybenzylalcohol (690mg, 5mmol). After work-up as described for 6a,followed by flash column chromatography (petroleum ether/ethylacetate 4:6), compound 6l was obtained as a white solid. Yield:239mg, 72%. mp 92–95�C. 1H-NMR (300MHz, CDCl3):d=2.43 (s, 3H), 3.83 (s, 3H), 5.31 (s, 2H), 6.92 (d, J=8.4Hz,2H), 7.02 (dd, J=4.8, 8.1Hz, 1H), 7.37 (d, J=8.4Hz, 2H), 8.30(dd, J=2.1, 7.8Hz, 1H), 8.55 (dd, J=4.8, 1.8Hz, 1H), 10.72 (brs, 1H) ppm. 13C-NMR (75MHz, CDCl3): d=26.1, 55.4, 67.6,114.2, 118.1, 127.2, 130.5, 140.21, 152.6, 153.0, 160.1, 166.5,169.8 ppm. ESI–MS: m/z 300.86 [M+H]+. ESI–HRMS: m/z[M+H]+ Calcd for C16H17N2O3: 301.1183, found: 301.1181.
Isopropyl 2-acetamidonicotinate (6m). Compound 6m wasprepared via Method A using 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one (2e) (162mg, 1.0mmol) and propan-2-ol (300mg,5.0mmol). After work-up as described for 6a, followed by flashcolumn chromatography (petroleum ether/ethyl acetate 7:3),compound 6m was obtained as a white solid. Yield: 188mg, 80%.mp 81–82�C. 1H-NMR (600MHz, CDCl3): d=1.37 (d, J=6Hz,6H), 2.40 (s, 3H), 5.24 (septet, J=6Hz, 1H), 7.04 (dd, J=7.8,4.8Hz, 1H), 8.30 (dd, J=7.8, J=2.1Hz, 1H), 8.56 (d, J=4.2Hz,1H), 10.83 (br s, 1H) ppm. 13C-NMR (75MHz, CDCl3): d=21.9,26.1, 70.0, 111.7, 118.1, 140.2, 152.6, 152.8, 166.2, 169.7 ppm.ESI–MS: m/z 222.95 [M+H]+. ESI–HRMS: m/z [M+H]+ Calcdfor C11H15N2O3: 223.1077, found: 223.1074.
Acknowledgments. Financial support from the Basic ResearchCommittee Program “ΠΕΒΕ 2008” of the National TechnicalUniversity of Athens is gratefully acknowledged.
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