Polyethylene glycol (PEG) mediated expeditious synthetic route to 1,3-oxazine derivatives

Available online at www.sciencedirect.comCHINES E: ScienceDirectCHEMICALL .ETTERSEL SEVIERChinese Chemical Letters 22 (2011) 915- -918www.elsevier.com/locate/ccletPolyethylene glycol (PEG) mediated expeditious syntheticroute to 1 ,3-oxazine derivativesPravin V. Shinde, Amol H. Kategaonkar, Bapurao B. Shingate, Murlidhar S. Shingare *Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada Universiy, Aurangabad 431004, Maharashtra, IndiaReceived 8 November 2010Available online 18 May 2011AbstractVarious 1,3-oxazine derivatives were synthesized in high yields, within shorter reaction times using PEG 400 as a safer medium/mediator. This synthetic route is exceedingly easy and avoids the use of acidbase catalysts.C 2011 Murlidhar S. Shingare. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All nights reserved.Keywords: Ecofriendly synthetic protocol; Green chemistry; 13-0xazines; Polyethylene glycol (PEG)In the recent years, there has been a growing demand for the development of more sustainable chemistry,particularly in the synthesis of value added materials, in order to minimize the great amounts of waste and consecutivetreatment [1,2]. One of the key principles of green chemistry is the elimination of solvents in chemical processes or thereplacement of volatile/hazardous solvents with environmentally benign solvents [3]. In performing the majority oforganic transformations, solvents play a critical role in making the reaction homogeneous and allowing molecularinteractions to be more efficient [4]In this connection, polyethylene glycol (PEG) is attracting much attention of organic chemists due to theirinexpensive and eco-friendly nature, high thermal stability, ease of workup, and the ability to act as phase transfercatalysts. Furthermore, PEG and its monomethylethers have a low vapor pressure, are nonflammable, non-volatile, recyclable, and are available in high quantities at low prices. The application of PEG as a reactionmedium is highly beneficial as the system remains neutral, which helps in maintaining a wide variety of functionalgroups unchanged that are either acid or base susceptible [2- -5]. For these reasons, PEG is considered to be anenvironmentally benign surrogate to volatile organic solvents and a highly practical medium for the synthesis ofbiodynamic heterocycles [6- 9].1,3-Oxazine ring system is a core structure present in a number of biodynamic heterocycles. They are pivotalintermediate for the synthesis of medicinally active molecules [10]. Increasing interest towards the synthesis of 1,3-oxazine derivatives is mainly due to their potential biological and pharmacological activities such as analgesic [1],antitubercular [12], anticancer [13], anti-HIV [14], antihypertensive [15], antithromobotic [16], and antiulcer [17]. Inaddition, naphthoxine derivatives possess therapeutic potential for the treatment of Parkinson's disease [18].Moreover, certain kinds of 1,3-oxazines are of interest as photochromic compounds [19].中国煤化工* Corresponding author.E mail adress: prof. msshingarerediffmail.com (M.S. Shingare).MHCNMHG1001-8417/5 -see front matter◎2011 Murlidhar s. Shingare. Published by Elsevier B.V. on behalf of Chinese Chemical Society. Al nights reserved.doi:10.01j.cel201.01.011916PV Shinde et al./Chinese Chemical Letters 22 (2011)915 -918The Mannich reaction involving phenol, formaldebyde and primary amines is the best method available for thesynthesis of 1,3-oxazines. Several methods involving the use of different catalysts [20] have been developed with theirown merits and demerits. Considering the above discussed significance of PEG and 1,3-0xazine compounds, and incontinuation of our endeavor towards the development of ecofriendly synthetic protocols [21], it was thoughtworthwhile to develop a new, simple, greener, and expeditious synthetic route to 1,3-oxazine derivatives.1. ExperimentalMelting points were determined on a Veego apparatus and are uncorrected. Infrared spectra were recorded on aBruker spectrophotometer in a KBr disc, and the absorption bands are expressed in cm '. 'H NMR and 'C NMRspectra were recorded on NMR spectrometer AC200 in DMSO-d6, chemical shifts (8) are in (parts per million) ppmrelative to TMS. Mass spectra were taken on a macro-mass spectrometer (waters) by electro-spray (ES) method.Typical experimental procedure for synthesis of compound (4a): a-Naphthol 1 (1 mmol), formaldehyde 2(2.2 mmol) and aniline 3a (1 mmol) were mixed in a dry round-bottomed fask (25 mL), to which PEG-400 (0.3 mL)was added and reaction mixture was allowed to stir vigorously. Progress of the reaction was monitored by TLC. Aftercompletion of the reaction, water (5 mL) was added to the reaction mass and obtained solid was filtered out andwashed with water. Thus obtained crude product was recrystallized from aqueous ethanol to afford the pure product(4a).3,4-Dihydro-3-phenyl-2H-naphtho[2,I-e][l,3]oxazine (4a): IR (KBr, cm -): v 1027, 1219; 'H NMR (DMSO-d,200 MHz): 84.73(s, 2H, -Ar CH2 N-), 5.50(s, 2H, 0 CH2- N-), 6.89 -7.58 (m, 11H, Ar H); '3C NMR (DMSO-ds,50 MHz): 848.9, 79.6, 112.2, 115.7, 117.0, 120.1, 120.7, 124.5, 125.9, 126.2, 126.8, 127.6, 129.5, 133.4, 147.7, 149.0;ES-MS: 262.18 (M*).3,4-Dihydro- 3-0- tolyl-2H-naphtho[2,1-e ][1,3]oxazine (4b): IR (KBr, cm-): v 1033, 1237; 'H NMR (DMSO-do,200 MHz): 82.24 (q, 3H, CH3), 4.86 (s, 2H,- Ar- CH2 -N-), 5.77 (s, 2H,-0- CH2- N-), 6.84- -7.61 (m, 10H, Ar- H); l3CNMR (DMSO do, 50 MHz): δ 19.9, 50.6, 78.6, 113.7, 116.4, 117.1, 119.5, 120.8, 125.1, 125.8, 126.1, 126.8, 127.9,129.7, 130.4, 147.0, 147.4, 149.5, 150.8; ES-MS: 276.31 (M).3,4-Dihydro- 3-p-tolyl-2H-naphtho[2,I-e][l,3}oxazine (4c): IR (KBr, cm-): v 1025, 1238; 'H NMR (DMSO-d6,200 MHz): 82.37 (s, 3H, CH3), 4.94(s, 2H,-Ar- -CH2 _N_), 5.67(s, 2H,- 0 CH2 -N_ -), 6.90- -7.82 (m, 10H, Ar -H); 1C .NMR (DMSO-ds, 50 MHz): 821.5, 49.1, 79.3, 110.7, 115.4, 117.8, 119.1, 120.1, 124.9, 125.5, 126.0, 126.6, 127.4,129.2, 132.0, 148.3, 148.2; ES-MS: 276.24 (M). .2. Results and discussionFor our initial study, one pot three-component reaction of a-naphthol, formaldehyde and aniline was considered asa standard model reaction (Scheme 1). To effect the model reaction, various attempts were made using polyethyleneglycol (PEG) 400 in different amounts (Table 1, entry 2) and best result was achieved when 0.3 mL of PEG 400 wasemployed for 1 mmol of aniline (Table 1, entry 2). Using more than 0.3 mL of PEG 400 did not improve the yield ofthe product, and at the same time, no reaction took place in the absence of PEG 400 (Table 1, entry 1). Thus, the use ofPEG found to be absolutely essential for the reaction.In subsequent optimization studies, PEG was used in combination with various solvent systems (Table 1, entries 3-7). However, use of solvents for the reaction failed to improve the product yield and rate of the reaction. Rather,solvent-free conditions worked well for the reaction. Since, only 0.3 mL of PEG 400 is used it cannot act as a solveat,but it plays the role of promoter for the reaction without need of any additional catalyst.PhOHPEG-400中国煤化工。EG-400 .+ HCHO+ Ph- NH2-MHCNMHG234a3n6nScheme 1.P.K Shinde et al/Chinese Chemical Letters 22 (2011) 915 -918917Table 1Screening of reaction medium."EntryPEG 400 (mL)Solvent (mL)Time (min)Yieldb (%)Trace0.1, 0.2, 0.3, 0.5, 1.020, 10.5, 5.577, 78, 91, 87, 880.3Water (5)3059Ethanol (5)57DMF (5)38THF (5)45CHzCN (5)62: Reation conditions: 1 (1 mmol), 2 (2.2 mmo), 3a (1 mmol).”Isolated yields.“Consider respective time and yield.In further set of experiments, optimized reaction condition was applied for the synthesis of another 1,3- oxazinederivative replacing a-naphthol with B-naphthol (Scheme 1). In this experiment, reaction of B-naphthol, aniline andformaldehyde was subjected to optimized reaction conditions and reaction was observed to proceed smoothly inagreement with the reaction of a-naphthol.This success of PEG 400 could be attributed to the following facts: () PEG possess two active sites viz freehydroxyl groups and ethereal oxygen linkages. (i) These hydroxyl groups, via hydrogen bonding with carbonyloxygen of formaldehyde increases its electrophilic character, whereas, ethereal oxygen linkages assists in enhancingthe nucleophilicity of amines and naphthols. (ii) Consequently. the chemical reactivity of the reactants considerablyincreases, which results in significant rate acceleration of chemical reaction leading to the formation of desired productwithin short reaction times, avoiding undesirable side products.Table 2Synthesis of 1,3- oxazine derivatives. aR)HNH22CH2O +PBG-400PEG 4004a-h236a-jProduct codeCompound 4a-hCompound 6-j.Yield" (%)M.P." (C)M.P. (°C)963-6550-522-Me887-8855- -574-Me193-1958:90-913-0Me278 (d)65- -664-OMe8&301 (d)79 -802-OEt202 (d)102-1044-OEt078- -80&68-694F117-118134-135中国煤化工113-1154-NO2166-168HCNMHG-# - reaction was not performed.●Reaction conditions: 1 or 5 (1 mmo), 2 (2.2 mmol), 3 (1 mmol) and PEG 400 (0.3 mL).b Isolated yields.“Meling points match with literature [20].918PV Shinde er al /Chinese Chemical Ltters 22 (2011) 915- 918To further establish the scope of optimized reaction conditions and in order to generalize the synthetic procedure,variety of electronically divergent aromatic amines were treated with a-naphthol as well as B-naphthol andformaldehyde solution, and all these substrates were found to be equally amenable to these conditions affording goodto excellent yields (see the supporting information). Notably, liquid amines underwent the reaction rapidly incomparison with solid amines. Representative results are summarized in Table 2. Structures of the products wereconfirmed on the basis of IR, 'H NMR, IC NMR and mass spectroscopic data.3. ConclusionsIn summary, we have developed an exceedingly simple, mild, clean and expeditious synthetic protocol for 1,3-oxazine derivatives. Remarkable advantages of this synthetic strategy over the others are (i) high yields, (i) no need ofacid/base catalyst and solvent, (ii) decreased reaction times, (iv) simplified work-up procedure, and (v) ambientreaction temperature.Appendix A. Supplementary dataSupplementary data associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2011.01.011.References[1] LT. Horvath, PT. Anastas, Chem. Rev. 107 (2007) 2169.[2] N.R. Candeias, L.C. Branco, PM.P. Gois, et al. Chem. Rev. 109 (2009) 2703.[3] IT. Horvath, Green Chem.10 (2008) 1024.[4] R. Kumar, P. Chaudhary, s. Nimnesh, R. Chandra, Green Chem. 8 (2006) 356.[5] C.K.Z. Andrade, L.M. Alves, Cur. Org. Chem. 9 (2005) 195.[6] JR. Mali, D.V. Jawale, B.S. 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