Original Research Synthesis of some nuclear substitution derivatives of 4-acetyl pyridine Joohee Pradhan1,*, Anju Goyal2 1Dept. of Pharmaceutical sciences, Mohanlal Sukhadia University, Udaipur, Rajasthan, India -313001. 1Pacific College of Pharmacy, Pacific Academy of Higher Education and Research University, Pacific Hills, Udaipur, Rajasthan, India-313001 2B.N Institute of Pharmaceutical sciences, Sewashram Road, Udaipur, Rajasthan, India-313001 *Corresponding Author: E-mail: [email protected] ABSTRACT Five nuclear substitution derivatives of 4- acetyl pyridine (2a to 6a) were prepared via N-oxidation followed by either nitration or arylation in the yield of 60-80%. Substitution at 2- position is promoted due to the electron withdrawing and meta- directing ability of acetyl group at 4- position making the pyridine N-oxide vulnerable to attack at C-2. Keywords: 4- acetyl pyridine, N-oxidation, nitration, arylation, nuclear substitution. INTRODUCTION recently to generate dinitrogen pentoxide, the Substituted N-heterocycles are important anhydride of nitric acid, from nitric acid itself using structural motifs of bio-active compounds and phosphorus pentoxide,13 for the in situ reaction with advanced materials.1 Hence, methods that allow for pyridine. Some 3-nitropyridine was obtained, but in regioselective construction of C–C bonds to N- low yield. Katritzky et al. have reported the heterocycles have attracted continuous attention.2 In preparation of nitropyridines by nitration of pyridines particular, introduction of substituents in the C-2 with nitric acid using nitric acid– TFAA system.14 position of pyridines, quinolines and related six- membered nitrogenous heterocycles is an important RESULTS AND DISCUSSION strategy in heterocyclic synthesis that represents a As per our plan to synthesize some new significant synthetic challenge.3 One of the most pyridine containing compounds, we have prepared a commonly used strategies is based on transition set of 4- acetyl pyridine derivatives (table 1) as metal-catalyzed coupling reactions of organometallic described in scheme 1. Many electrophilic reagents with 2-haloazines,4 which are prepared from substitutions on pyridine either do not proceed or the corresponding N-oxides5. In recent years, direct proceed only partially; however, the heteroaromatic arylation has emerged as an attractive alternative to character can be activated by electron-donating typical cross-coupling reactions.6 In direct arylation, functionalization. Common alkylations and one of the preactivated cross-coupling partners acylations, such as Friedel–Crafts alkylation or (typically the organometallic species) is replaced by acylation, usually fail for pyridine because they lead an un functionalized arene. Consistent with an only to the addition at the nitrogen atom. electrophilic aromatic substitution (SEAr) pathway, Substitutions usually occur at the 3-position, which is electron-rich heterocyclic arenes have been featured the most electron-rich carbon atom in the ring and is, prominently in recent developments.7 While some therefore, more susceptible to an electrophilic simple arenes can now be used,8,9 direct arylation addition. Substitutions to pyridine at the 2- or 4- reactions with π-electron deficient heteroarenes, such position result in an energetically unfavorable σ as pyridine, remain a challenging goal.10 Bakke and complex. They can be promoted, however, using coworkers were the first to report a remarkable clever experimental techniques, such as conducting reaction of pyridines with dinitrogen pentoxide in electrophilic substitution on the pyridine-N-oxide sulfur dioxide solution, to give N-nitropyridinium ion followed by deoxygenation of the nitrogen atom. intermediates which, on treatment with water, gave 3- Addition of oxygen reduces electron density on the nitropyridines in good yield. They proposed that this nitrogen atom and promotes substitution at the 2- and reaction proceeds by a[1,5] sigma tropic shift of the 4-carbons. The oxygen atom can then be removed via nitro group from the 1- to the 3- position in the several routes, most commonly with compounds of pyridine ring rather than an electrophilic aromatic trivalent phosphorus or divalent sulfur, which are substitution. A mixture of 3-nitropyridine and 3, 5- easily oxidized.15 As the nuclear substitution on dinitropyridine was obtained in low yield by Suzuki pyridine ring itself is relatively difficult, we and coworkers from the reaction of pyridine with attempted to perform substitutions on pyridine N- dinitrogen pentoxide generated in situ from nitrogen oxide which is more nucleophilic and electrophilic, dioxide and ozone.11,12 A similar attempt was made having higher dipole moment (4.37D for pyridine N- International Journal of Pharmaceutical Chemistry and Analysis; July - September 2015;2(3):113-119 113 Joohee Pradhan et al. Synthesis of some nuclear substitution derivatives of 4-acetyl pyridine oxide vs. 2.03D for pyridine), much weaker base pyridine). It exists as many mesomeric forms (fig. (pKa 0.79 for pyridine N-oxide vs. pKa 5.2 for 1)16. The N-O moiety of pyridine N-oxides the resonance forms I and II depends on the nature of possesses a unique functionality which can act the substituent at position 4. The moderate electron- effectively as a push electron donor and as a pull acceptor acetyl group favors the charge transfer form electron acceptor group. This strong push-pull II. Thus, acetyl group being electron withdrawing and property has an essential chemical consequence; it meta directing group removes electron density from a accounts for the equally easy synthesis of 4- π system, making the π system more electrophilic, as substituted derivatives of pyridine N-oxides with well as directs the substitution on the ring, meta to it, donor as well as acceptor groups. The contribution of i.e. at position 2 (fig. 2). 17,18 Further, we were interested in the (4a). As a parallel path to some more 2- substituted production of nitro pyridines using nitric acid, which derivatives, Arylation of N-oxide was carried out as is readily available, cheap and overcomes the per the reported procedure of Fagnou et al.19 problem of handling the unstable and difficult-to- Reaction development was carried out with pyridine obtain reagent, dinitrogen pentoxide. We sought to N-oxide and 4-bromotoluene. From these studies, generate dinitrogen pentoxide easily in situ, under palladium acetate in combination with tri-tert- conditions in which it would react with pyridines butylphosphine (added to the reaction mixture as the immediately. These requirements led us to select the commercially available and air-stable HBF4 salt) nitric acid– TFAA system as reported in the emerged as the optimal metal-ligand combination. literature.14 As a result of nitration of 4- Potassium carbonate was deemed the optimal base, acetylpyridine-N-oxide (i1) we got 2-nitro-4- and toluene the optimal solvent. While the reaction acetylpyridine N-oxide which was reduced by Pd/C with bromobenzene under these conditions lead us to the base, 2-nitro-4-acetylpyridine (2a). The nitro 5a, the combination with 4- bromotoluene gave group of compound 2a was then reduced to amino compound 6a. The structures of all the compounds group through Sn/HCl system to get 2-amino-4- were confirmed through IR and proton NMR acetylpyridine (3a) which through Sandmayer spectroscopy (table 2) and elemental analysis carried reaction produced corresponding chloro compound out (table 3). many more N N N N N O O O O O Fig. 1: Mesomeric forms of pyridine N-oxide. O CH 3 O CH3 O CH C C C 3 N N N R O O O I II Fig. 2: Substitution at 2- position on 4- acetyl pyridine. International Journal of Pharmaceutical Chemistry and Analysis; July - September 2015;2(3):113-119 114 Joohee Pradhan et al. Synthesis of some nuclear substitution derivatives of 4-acetyl pyridine CONCLUSION the tin hydroxide completely and make the solution As a part of our synthetic strategy to get new sufficiently alkaline so as to be extracted with ether series of heterocyclic compounds, we have prepared thrice. The combined ether extract was washed with five new derivatives of 4-acetylpyridine either via water, dried over Na2SO4, and solvent was removed nitration or N-oxidation which were confirmed by distillation and the residue was recrystallized to through IR, NMR and Mass spectroscopy. give 0.64g (78%) of pale yellow product (M.P. 138ºC). Experimental All the chemicals and reagents used were of 2-Chloro-4-acetylpyridine[1-(2-chloropyridin-4- Synthetic grade and purchased from Alfa Aesar or yl)ethanone(4a)] Sigma Aldrich and used as such without purification. a. Preparation of copper (I) Chloride solution: Melting point was determined on Veego digital 3.5g (0.014 mol) of Copper Sulphate pentahydrate melting point apparatus and was uncorrected.IR and 0.92 g (0.0157 mol) of pure Sodium Chloride spectra were recorded using Bruker Alpha FTIR was dissolved in 12.5 ml. of water with warming. A Spectrometer equipped with ZnSe ATR crystal .1H solution of 0.84g (0.0044 mol) of sodium NMR spectra were recorded on Bruker Spectrometer metabisulphite in 9 ml. water was added to the hot (400 MHz) in CDCl3 using TMS as an internal solution during about 5 min. by constant shaking. standard. Mass spectra were recorded on LC-MSD The reaction mixture was cooled to room temperature Trap-SL 2010A-Shimadzu. Micro analysis was and the supernatant liquid was decanted from the performed on a Perkin Elmer-240 CHN elemental colorless copper (I) chloride. The precipitated Copper analyzer. (I) chloride was washed twice with SO2 dissolved water (to prevent oxidation), dissolved in 6 ml. conc. Preparation of 4-acetylpyridine-N-oxide (i1): For HCl and used within 24 hrs of its preparation. N-oxidation, 4-acetylpyridine (1 equivalent) was taken in a round bottom flask, and added to it, from a b. Preparation of Chloro- compound via dropping funnel, 1.2 equivalent 30% w/v solution of Sandmayer reaction: The freshly prepared Cu(I)Cl hydrogen peroxide at a temperature of 0-5ºC with solution in HCl was cooled in an ice-salt mixture constant stirring.