Novel and Efficient Microwave-Assisted Three Component Reaction for the Synthesis Ofoxazine Derivatives

Introduction

Heterocyclic skeletonsserve as ideal scaffold on which pharmacophorecan be appended toyield potent and special drugs. (1) .this is especially true for heterocyclic compound (six member ring), that possess a wide range of interesting biological activities. (2) are corecomponentsof a large number of substances.Oxazinederivatives features prominently in many biologically important natural products (3) and otherbioactive molecules (4-7) the oxazine derivatives have been used as the basic framework for substance of interest in numeroustherapeutic areas such as antifungal(8) , antibacterial, anti-candinaalbicans(9) and kinase inhibitors(10) In chemistry (sustainable)(11) the design and development of sequence allowing highlyselective essence to determine molecularscaffolds when structuraldiversity combined (12) with eco- compatibility. (13)that is great challenges for organic chemists.in asingle operation they build one productfrom three or more reactant molecules with high atom economy (14) and multiple bond forming efficiency of multiple bond forming(15). It is their ability.to reachthis near ideal goal multicomponent reactions are now well established approaches(16). Solvent free reactions are of almost interest from the ecological point of view, and they often advantages, such as reduced reaction time, increased productyields, reduced environmental pollution, simple equipment (lab scale), increased selectivity and low cost compared withreactions carried out in solvents.As an alternative toorganic solvents,chemists should employ other strategies toperformchemical reactions, namely ionic liquid,supercritical fluids, water as solvent andsolvent freeconditions-like inpresence of MW irradiation. This techniquedoes not require solvents and considered“greener” method then the conventional methods. The largescale of applications of microwave chemistry has been increased recently too many aspects of organic synthesis (17-21)Microwave assisted synthesis are aparticularly attractive alternative to synthesis and several thermal conditions since they often proceed much faster and synthesis products with higher yields and higher purity. Although several methods for the preparation of oxazine derivatives have been reported previously (22-25). Some have been focusedon the multicomponent reactions method. This method is advantageous over previous reports due to its short reaction time and solvent free conditions.As per our interest (26-28) to develop better protocol for the synthesis of biologically active heterocyclic compounds, we would like to report the synthesis of oxazine derivatives by the reaction of naphthol, formalin, and aniline in presence of MW irradiation.

Experimental Method

from chemical companies Starting material were purchased and used without purification. All microwave assisted were performed by using microwave synthesizer (CEM corp.) (a discover ^TM single mode cavity) producing continuous microwave irradiations at 2450 MHz’s. All experiment was conducted under argon. on TLC aluminium roll silica gel 60 F₂₅₄ (merk) TLC was performed . Melting points weredetermined on a kofler melting point apparatus  Melting points were determined. IR spectra were taken on a spectrum one FT-IR spectrometer (Perkin Elmer).  UV spectra were measured using a CARY 4E spectrophotometer (Varian). NMR spectrawere recorded on a Varian  ^unity INOVA spectrometer (300/ 75 MHz ) in CDCl₃; the¹H and C¹³ chemical shift were referenced to residual solvent signals at δ_H  = 7.25and δ_C  = 77.1 relative to Tetra methyl silane. Mass spectra were recorded on a MAT 90 with 70 ev ionization energy (finnigan MAT)

Experiment

A Mixture of 1a (1.0 m mol), b (2.0 m mol) and c (1.0 m mol) were absorbed on Montmorillonite (76 mg) with methanol and mixed thoroughly and irradiated with Microwaves for a particular time till the reaction are completed., the mixture was allowed to cool to r.t. After completion of the reaction.  And washed With EE or TBME (5X5 ml). In vacuo the combined organic extracts were concentrated And by column chromatography the residue was purified on silica gel to yield (4a) Spectral data of compounds:- (4a)  yield- 76%, mp.-62-63^b , reaction time – 5 min, Anal. Found: C, 82.65%; H, 5.83%; N, 5.48%, Calc.C18H15NO: C, 82.73; H, 5.79; N, 5.36.IR (KBr, νmax/cm-1): 1032 (sym.C-O-C), 1213 (asym. C-O-C); 1H NMR (DMSO-d6, 4, 00 MHz, δ ppm): 4.78 (s, 2H, -Ar-CH2-N-), 5.42 (s, 2H, – O-CH2-N-), 6.81-7.55 (m, 11H, Ar-H); 13C NMR (DMSO-d6, 75 MHz,,δ ppm): 49.2, 79.3, 112.6, 115.2, 117.4, 119.7, 120.6, 124.1, 125.3, 125.3, 126.1, 127.5, 129.1, 132.8, 147.8, 148.7 (4b) yield- 74%, mp.- 300(d), reaction time – 5 min, Anal. Found: C, 78.45; H, 5.90; N, 4.72%, Calc. C19H17NO2: C, 78.33; H, 5.88; N, 4.81. IR (KBr, νmax/cm-1): 1018(sym.C-O-C), 1227(asym. C-O-C); 1H NMR (DMSO-d6, 400 MHz, δ ppm): 3.61 (s, 3H, OMe), 4.88 (s, 2H, -Ar-CH2-N-), 5.41 (s, 2H, -O-CH2-N-), 6.78-7.81 (m, 10H, Ar -H); 13C NMR (DMSO-d6, 75MHz,,δ ppm): 48.1, 52.1, 80.2, 111.1, 115.5, 117.3, 119.4, 121.2, 124.1, 125.6, 125.8, 126.7, 127.1, 130.2, 132.2, 146.7, 148.5 (4c)  Yield- 72%, mp. – 76-77⁰ c, reaction time- 5 min, Anal. Found: C, 78.71; H, 6.28; N, 4.24, Calc. C20H19NO2: C, 78.66; H, 6.72; N, 4.59.  IR (KBr, νmax/cm-1): 1027 (sym.C-O-C), 1223 (asym. C-O-C);1H NMR (DMSO-d6, 400 MHz, δ ppm): 1.21 (t, 3H, J = 8 Hz, O-CH2-CH3), 3.91 (q, 2H, J = 8 Hz ,O-CH2-CH3), 4.91 (s, 2H, -Ar-CH2-N-), 5.41 (s, 2H, -O-CH2-N-), 6.81-7.81 (m, 10H, Ar-H); 13C NMR (DMSO-d6, 75 MHz,,δ ppm): 14.5, 48.3, 65.2, 80.5, 112.5, 115.8, 117.3, 119.2, 120.2, 123.2, 124.7, 125.3, 125.5, 126.6, 127.8, 129.9, 132.1, 147.3 (4d) Yield- 76%, mp. – 72-74 c, reaction time – 5 min, Anal. Found: C, 43.58; H, 2.25; N, 2.64, Caic. : C18H12Br3NO, C: 43.41%; H: 2.43%; N: 2.81%; IR (KBr, νmax/cm-1):1015 (sym.C-O-C), 1225 (asym. C-O-C); 1H NMR (DMSO-d6, 400 MHz, δ ppm): 4.51 (s, 2H, -Ar- CH2-N-), 5.52 (s, 2H, -O-CH2-N-), 6.85-7.91 (m, 8H, Ar-H); 13C NMR (DMSO-d6, 75 MHz,,δ ppm):50.1, 79.2, 106.4, 107.8, 119.4, 124.6, 125.3, 125.8, 126.3, 127.1, 132.5, 133.4, 134.8, 142.7, 147.1, 150.2 (4e) Yield- 70%, mp. – 196-198 c, reaction time – 5 min, Anal. Found:  C: 82.71%, H: 6.30%, N: 5.04%., Calc.: C19H17NO, C: 82.88%; H: 6.22%; N: 5.09%; IR (KBr, νmax/cm-1): 1020 (sym.C- O-C), 1233 (asym. C-O-C); 1H NMR (DMSO-d6, 400 MHz, δ ppm): 2.41 (s, 3H, CH3), 4.91 (s, 2H, -Ar- CH2-N-), 5.61 (s, 2H, -O-CH2- N-), 6.61-7.91 (m, 10H, Ar-H); 13C NMR (DMSO-d6, 75 MHz,,δ ppm):21.1, 49.1, 78.7, 110.3, 115.1, 117.7, 119.5, 120.2, 124.4, 125.4, 125.8, 126.2, 127.3, 129.7, 132.2, 147.7, 148.1 (4f)  Yield – 72%, mp.– 200(d), reaction time – 5 min, Anal. Found: C: 78.48%, H: 6.37%, N: 4.67%., Calc: C20H19NO2,C: 78.66%; H: 6.27%; N: 4.59%; IR (KBr, νmax/cm-1): 1022 (sym.C-O-C), 1235 (asym. C-O-C); 1H NMR (DMSO-d6, 400 MHz, δ ppm): 1.28 (t, 3H, J = 14 Hz, O-CH2-CH3), 3.97 (q, 2H, J = 14 Hz ,O-CH2-CH3), 4.62 (s, 2H, -Ar-CH2-N-), 5.41 (s, 2H, -O-CH2-N- ), 6.18-7.45 (m, 10H, Ar-H); 13C NMR (DMSO-d6, 75 MHz,,δ ppm): 13.8, 48.7, 64.6, 81.4, 111.7, 114.6, 115.7, 117.4, 118.7, 121.1, 122.1, 124.4, 125.5, 125.6, 126.1, 127.5, 128.9, 133.1, 146.2, 149.2 (4g) Yield – 74%, mp. – 118-120 c, reaction time – 5 min, Anal. Found. – C: 77.87%, H: 5.14%, N: 5.15%., Calc.C18H14FNO, C: 77.40%; H: 5.05%; N: 5.01%; IR (KBr, νmax/cm-1): 1027 (sym.C-O-C), 1246 (asym. C-O-C);1H NMR (DMSO-d6, 400 MHz, δ ppm): 4.91 (s, 2H, -Ar-CH2-N-), 5.61 (s, 2H, -O-CH2-N-), 6.81-7.81 (m, 10H, Ar-H); 13C NMR (DMSO-d6, 75 MHz,,δ ppm): 49.1, 78.6, 112.1, 115.6, 116.2, 117.3, 118.1, 122.5, 123.2, 125.2, 125.7, 125.8, 127.6, 128.5, 130.5, 150.1 (4h) Yield – 72%, mp.– 280(d), reaction time – 5 min, Anal. Found – C: 78.21%, H: 5.78%, N: 4.90%., Calc C19H17NO2, C: 78.33 %; H: 5.88 %; N: 4.81 %; IR (KBr, νmax/cm-1): 1028sym.C-O-C), 1212 (asym. C-O-C); 1H NMR (DMSO-d6, 400 MHz, δ ppm): 3.55 (s, 3H, OMe.), 4.71 (s, 2H, -Ar-CH2-N-), 5.51 (s, 2H, -O-CH2-N-), 6.23-7.64 (m, 10H, Ar-H); 13C NMR (DMSO-d6, 75MHz, δ ppm): 49.4, 53.7, 79.5, 112.3, 114.6, 115.9, 117.4, 118.1, 120.8, 124.6, 125.7, 125.8, 126.6, 127.6, 130.2, 133.2, 146.8, 148.8, 151.2 (4i) Yield – 72%, mp. – 86-88 c, reaction time – 5 min, Anal. Found. – C: 82.84%, H: 6.68%, N: 5.14%.,Calc C19H17NO, C: 82.88%; H: 6.22%; N: 5.09%; IR (KBr, νmax/cm-1): 1028 (sym.C-O-C),1232 (asym. C-O-C); 1H NMR (DMSO-d6, 400 MHz, δ ppm): 2.21(q, 3H, CH3), 4.91 (s, 2H, -Ar- CH2-N-), 5.71 (s, 2H, -O-CH2-N-), 6.81- 7.91 (m, 10H, Ar-H); 13C NMR (DMSO-d6, 75 MHz,,δ ppm):20.1, 50.2, 79.2, 113.3, 116.2, 117.3, 119.1, 120.4, 124.6, 125.7, 126.0, 126.7, 127.8,129.6, 130.3, 147.1, 148.2, 149.1, 150.3

Antibacterial Screening

Prepare Muller Hinton agar medium and put into sterile Petriplates.On agarmedium ,200ul of the standard bacterial inoculumswasspread by using sterile cotton swab. In the inoculated agar medium the test impregnated discs were placed. To determinethe sensitivity of each microbial species tested Ciprofloxacin 10ug/ml capacity discs were used as positive references standard. For 24 hours allpetriplateswere incubated
at 37o c. Diameter of inhibition was measured after incubation

Antifungal Screening

Prepared a Sabouraud dextrose agar medium and transferred into sterile petriplates. On agar medium     200 ul of the standardized   fungal inoculums were spread by using cotton swab. On the inoculated agar medium the test impregnated discs wereplaced.To determine sensitivity of each microbial species testedClomatrimazole 10 ug/ml was used as positive references standard. For 24 hours all petriplates were incubated at 37 ^o c. diameter of zone of inhibition was measured After the incubation

Result and Discussing On

our results is present on the microwave – assisted three component synthesis of oxazinederivatives.When amounts of 1(a) aniline, 2(a) 1- naphthol, 3(a) formalin were reacted in the presence ofmontmorillonite in a sealed via under microwave conditions. A focused singlemode microwave reactor for5 minat 140⁰ c.hasbeenused.Underthese conditions [1, 3] oxazine derivatives 4(a) could be isolated app.In 76% yield.

Figure 1: microwave assisted three component synthesis of oxazine derivatives Click here to View Figure

 

Table 1: Reaction Of Various Aniline With 1- Naphthol And Formalin (1: 1: 2 )

Entry	Products     M.F	R	Reaction time (min)	Mp. (oc)
1234567  8   9	C18H15NOC19H17NO2 C20H19NO2 C18H12Br3NOC19H17NOC20H19NO2 C18H14FNO  C19H17NO2   C19H17NO	H4-OMe4-OEt2,4,6- tri Br4- Me2-OEt4-F  3- OMe   2-Me	5-105-105-105-105-105-105-10  5-10   5-10	62-63b 300(d)76-7772-74196-198200(d)118-120  280(d)   86-88

 

Table 2: SYNTHESIS OFOXAZINE DERIVATIVES Click here to View table

 

Table 3: Antibacterial Activity Of Compounds (Newly Synthesized Oxazine Derivatives (1A-1I)

Compound10µg/ml	S.aureus	B.subtillus	E.Coli	P. Aeruginosa
1(a)1(b)1(c)1(d)1(e)1(f)1(g)  1(h)   1(i)   ciprofloxacin	10151718111516  13   9   19	1219211771813  15   8   22	817182551921  18   6   26	699218817  10   7   22

 

Table 4: Antifungal  Activity Of Compounds (Newly Synthesized Oxazine Derivatives (1A-1I)

Compound 10µg/ml	C. Albicans	A.niger	Chrysosporium sp.	Trichoderma sp.
1a1b1c1d1e1f1g  1h   1i   Clomatrimazole	91718107177  16   8   19	81517129158  13   7   18	71419138169  15   9   20	61316146148  12   6   18

The structure assigned for the reaction products is established from practical data.

Antibacterial Screening

The bacterial inhibition values (mm) are shown in table-3. The antimicrobial activities of compounds S. Aureus, Escherichia Coli, Bacillus Subtillus and P. Aeruginosa were screened. Ciprofloxacin were used as a standard at 100 ug/ml. Compound 1a-1i were screened. S. Aureus for compound 1d was found to be highly active on the other hand for other compounds had low activity  with the ciprofloxacin. B. Subtillus shows highly activity for compound 1c, on the other hand for other compoundsshows low activity  with the standard ciprofloxacin. E. coli for compound 1d was found to be highly active, on the other hand for other compounds had low activity compared with the standard ciprofloxacin. P. Aeruginosa for compound 1d was found to be highly active, on the other hand for other compounds compound had low activity in comparison the standard ciprofloxacin

Antifungal Screening

The fungal inhibition zone values (mm) are given in table-4. The antifungal activity of compounds C. Albicans, Aspergillus Niger, Chrysosporium sp., Trichoderma sp.Were screened.  At a 100 µgmL^–1Clomatrimazole were used as a standard.Compound 1a-1i were screened. C. Albicansfor compound 1b and 1f   was found to be highly active, on the other hand for compound 1a, 1c, 1d, 1e, 1g, 1h, 1i, had low activity compared with standard Clomatrimazole. Aspergillus Niger for compound 1c was found to be highly active on the other hand for compound 1a, 1b, 1d, 1e, 1f, 1g, 1h, 1i, had low activity compared with standard Clomatrimazole.  Chrysosporium sp.  For compound 1c was found to be highly active  On the other hand for 1a, 1b, 1d, 1e, 1f, 1g, 1h, 1i show low activity with standard Clomatrimazole.Trichoderma sp. for compound 1c was found to be highly active, On the other hand for 1a, 1b, 1d, 1e, 1f, 1g, 1h, 1i show low activity  with standard Clomatrimazole.

Conclusion

we have designed an environmentally friendly, green and efficient approach for the synthesis of oxazine derivatives. By solvent free, the microwave assisted three component reactions with yield up to 76% within a few minutes. The method is important due to high conversion, less reaction time, and clean reaction profile, simple experimental and work-up procedure.

Acknowledgment

The author would like to thank the head, department of chemistry, Suresh gyanVihar University, Jaipur (raj.) for the financial support. xz and providing necessary laboratory facilities.

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