Synthesis of Biphenylamine Derivatives via Suzuki Coupling Reaction
R. Margabandu and K. Subramani*
1Department of Chemistry, Islamiah College, Vaniyambadi, PIN- 635751, Tamil Nadu, India.
*Corresponding Author E-mail: drksubramani@yahoo.com
ABSTRACT:
The biphenyl amine derivatives has been prepared via suzuki coupling, oxidation of sulfide to sulfonyl and reductive amination. The palladium tetrakistriphenylphosphine was used as a catalyst in suzuki coupling. The sodium periodate and sodium triacetoxyborohydride are used as reagent in oxidation and reductive amination reactions. The intermediates are confirmed by corresponding functional peak in IR spectrum and characterization of final product were done with help of IR, 1H NMR and mass spectral data.
KEY WORDS: Suzuki coupling, Pd (0) complex, IR, NMR and Mass
The compounds with sulfonyl and amine functional group are showing good antimicrobial activity, So the preparation of such compound is very much interesting in synthetic organic chemistry. The compounds 9a-e are prepared by aryl coupling reactions and most useful reaction for ary coupling is suzuki coupling, The 0.1 equivalent Pd0 complex is sufficient as catalyst and also many different type of palladium(0) complexes can be employed for suzuki coupling1-9. Suzuki coupling proceeds with aryl halide containing Cl,Br and I but fluorine requires very extreme condition. The order of reactivity of aryl halide towards suzuki coupling is Br<Cl<I and this order of reactivity shows that less electro negativity atom prepares to react in suzuki coupling.
EXPERIMENTAL SECTION:
6-(methylthio)pyridin-3-yl boronic acid (2):
2,5-dibromopyridine 50gm (0.21 mole), 2.0gm tetrabutyl ammonium bromide as PTC, and 400ml 15% aqueous solution of NaSMe (0.85 mole,4.0equivalent) are heated upto reflux temperature and maintained at reflux temperature for 2.5 hr and reaction wa followed by TLC, Rf: 0.4 mobile phase: 3:7, (ethyl acetate : petroleum ether), then cooled to 40° C and 200ml toluene was added. The toluene layer was seperated and dried with anhydrous sodium sulfate. The 100ml of THF was added to the toluene layer and nitrogen purging was made and temperature of mass brought to -70°C with help of dry ice and acetone.
The 105 ml 15% n-BuLi in hexane (0.24 mole, 1.1 equivalent) is added to mass at -70°C in 20 minutes via syrenge and stirred for 20 minutes and 60gm (0.31mole, 1.5 equivalent) triisoprpylborate is added in one hour at -70°C and stirred for two hour and progress of reaction was monitored by TLC then reaction mass temperature allowed to rise up to room temperature. The 100ml HCl was added slowly drop by drop and the aqueous layer was separated and pH of aqueous layer was adjusted to 7 using NaOH solution (10%) and stirred for one hour and product was filtered. Yield: 19gm (53%). MP: 151-154°C. Rf value : 0. mobile phase: 3:7 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3436 (B-OH).
4- bromo-2,5-dimethylphenylbor -onic acid (3):
The 50gm 1,4-dibromo-2,5-dimethylbenzene 50gm (0.18 mole) in 100ml THF was taken and inert (nitrogen) atmosphere is made for reaction mass and temperature of mass brought to -70°C with help of dry ice and acetone. The 85ml n-BuLi (15% hexane, 0.19 mole, 1.1equivalent) was added to reaction mass in 45 minutes at -70°C and stirred for half an hour. The 40gm triisopropylborate (0.21 mole,1.1 equivalent) was added at -70°C in 30 minutes and stirred for two hour then temperature of mass was allowed to rise up to room temperature and the 100ml of HCl was added to the reaction mass. The product is extracted by 150 ml ethyl acetate. The product is obtained by distilling out ethyl acetate under reduced pressure. Yield : 21gm (50%). MP : 205°C. Rf value : 0. mobile phase: 1:9 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3437 (B-OH).
N-(3-fluoro-4-Iodophenyl) acetamide(4):
The 4-Iodo-3-fluoro aniline 50gm (0.21mole) and the 32gm(0.31mole, 1.5 equivalent) triethylamine in 100ml EDC were taken ,The acetyl chloride 22gm (0.28 mole, 1.1 equivalent) was added to the reaction mass in drop wise in 45 minutes at room temperature. The mass was stirred at 35°C for another one hour. The 150ml water was added and organic layer was separated the layer and washed with water. The product was obtained by distilling out EDC under reduced pressure. Yield: 38gm (65%). MP: 157 159°C. Rf value : 0.51, mobile phase: 3:7 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3370, 3170, 1672 (N-H), 1672 ( C=O).
N- (4- bromo-2-fluoro-2.5-dime- thyl-biphenyl-4-yl)acetamide(5):
The compound 4 36gm (0.12mole), palladium tetrakistriphenylphosphine 10gm (0.008mole, 0.1equivalent), 1,4-dioxane 200ml, 19gm Na2CO3 (0.17 mole, 2.2equivalent) in 100ml water were taken and inert(nitrogen) atmosphere was made to the reaction mass. The reaction mass was stirred for half an hour and then compound 3 20gm was added and heated to reflux and maintained at reflux temperature for 17 hour. The temperature of reaction mass was brought to room temperature and the 100ml water and the 100ml MDC were added and the organic layer was separated, washed with water. The product was obtained by distilling out organic solvent under reduced pressure. Yield :18gm (66%). MP: 149-152, Rf value : 0.42, mobile phase: 6:4 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3429, 3271,1585 (N-H), 1656 ( C=O).
N-(2-fluoro-2,5-dimethyl-4-{6-(methylthio)pyridin-3-yl}biphenyl-4-yl) acetamide(6):
The compound 5 (17gm,0.05 mole), 200ml 1,4-dioxane, 6gm palladium tetrakis triphenylphosphine (0.005 mole, 0.1 equivalent) and 12gm sodium carbonate in 100ml water (0.11mole,2.2 equivalent) were taken and inert (nitrogen) atmosphere was made to the reaction mass and stirred for half an hour. The compound 2 17 gm (0.1mole) was added. Reaction mass was stirred for half an hour at room temperature and heated to reflux and maintained for 17 hour. The 100ml water and 100ml MDC were added and organic layer was separated. The product was obtained by distilling out the organic solvent. Yield: 12gm (65%.). MP: 164-167., Rf value : 0.5, mobile phase : 6:4 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3434, 3272, 1585 (N-H), 1656 ( C=O).
N-(2-fluoro-2,3-dimethyl-4-{6-(methylsulfonyl)pyridin-3-yl}biphenyl-4-yl) acetamide(7):
The compound 6 (15gm,0.039 mole), 200ml acetonitrile and 19gm NaIO4 in 50ml water are stirred for 15 hr at room temperature. The 300ml water and 100ml MDC were added and separated the organic layer. The product was obtained by distilling out organic solvent. Yield: 14gm (86%). MP: 225-227°C. Rf value : 0.25, mobile phase: 6:4 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3423, 3280,1576 (N-H), 1651 ( C=O) 1308, 1153( SO2).
2-fluoro-2,5-dimethyl-4-{6-(methylulfonyl)pyridin-3-yl}biphenyl-4-amine (8):
The compound 7 (13gm, 0.03mole) and 100ml Con HCl were refluxed for 24 hour. The pH of reaction mass was adjusted to 7.5 using NaOH solution and product was filtered. Yield; 9.7gm (87%). MP : 219-222°C. Rf value : 0.6,mobile phase: 6:4 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3475, 3380, 1634 (NH2), 1306, 1158 ( SO2).
General procedure for 9a 9e:
The compound 9 (1.5gm), MDC, 3.0 equivalent acetic acid and 1.2 equivalent corresponding aldehyde were taken and 4.0 equivalent triacetoxysodium borohydride was added slowly pinch by pinch at room temperature and stirred for 30 minutes. The 100ml of water was added and organic layer was separated. The organic solvent was distilled out to obtain product. The characterization of the product were done by spectral data. The 1H NMR were taken in 400MHz using d6-DMSO as solvent and TMS as internal standard and IR spectra were taken in KBr pellets.
N-(2-methylbenzyl)-2-fluoro-2,5-dimethyl-4-{6-(methylsulfonyl) pyridin-3-yl} biphenyl-4-amine(9a).
Yield : 1.0gm, (60%). MP: 237°C. Rf value : 0.44, mobile phase: 6:4 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3394, 1628 (N-H), 1294, 1163 ( SO2). 1H NMR δ: 2.15 2.35 ( s,9H, Ar-CH3 ), 3.34(s, 3H, SO2-CH3), 4.25 ( d, J=4.8 ,2H, Ar-CH2), 7.01,( t, J=8.6, 1H, Ar-NH) , 6.4 8.3( m, 12H, Ar-H). Mass m/z value :475 base peak (M+1).
N-(3-methylbenzyl)-2-fluoro-2,5-dimethyl-4-{6-(methylsulfonyl) pyridin-3-yl} biphenyl-4-amine(9b).
Yield : 0.9gm, (56%). MP: 239°C, Rf value : 0.44, mobile phase: 6:4 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3384, 1627 (N-H), 1293, 1160 ( SO2). 1H NMR δ : 2.1 2.3 ( s,9H, Ar-CH3 ), 3.34(s, 3H, SO2-CH3), 4.26 ( d, J=4.7 Hz ,2H, Ar-CH2), 7.0,( t, J=8.7, 1H, Ar-NH) , 6.4 8.8( m, 12H, Ar-H). Mass m/z value :475 base peak(M+1).
N-(4-methylbenzyl)-2-fluoro-2,5-dimethyl-4-{6-(methylsulfonyl) pyridin-3-yl} biphenyl-4-amine(9c).
Yield : 1.0gm, (60%). MP: 243°C, Rf value : 0.44, mobile phase: 6:4 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3383, 1624 (N-H), 1296, 1161 ( SO2). 1H NMR δ :2.13 2.28 ( s,9H, Ar-CH3 ), 3.34(s, 3H, SO2-CH3), 4.25 ( d,J=5.3 Hz ,2H, Ar-CH2), 7.06,( t, J=8.8, 1H, Ar-NH) , 6.39 8.19( m, 12H, Ar-H). Mass m/z value :475 base peak (M+1).
N-(3-chlorobenzyl)-2-fluoro-2,5-dimethyl-4-{6-(methylsulfonyl) pyridin-3-yl} biphenyl-4-amine(9d).
Yield : 0.9gm, (47%). MP: 258°C, Rf value : 0.41, mobile phase: 6:4 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3380, 1627 (N-H), 1294, 1162 ( SO2). 1H NMR δ : 2.12 2.23 ( s,6H, Ar-CH3 ), 3.34(s, 3H, SO2-CH3), 4.33 ( d,J=5 Hz ,2H, Ar-CH2), 7.01,( t, J=8.6, 1H, Ar-NH) , 6.4 8.83( m, 12H, Ar-H). Mass m/z value : 495 base peak (M+1).
N-(4-chlorobenzyl)-2-fluoro-2,5-dimethyl-4-{6-(methylsulfonyl) pyridin-3-yl} biphenyl-4-amine(9e).
Yield : 1.0gm, (52%). MP: 256°C, Rf value : 0.41, mobile phase: 6:4 (ethyl acetate : petroleum ether). IR(KBr) cm-1: 3376, 1625 (N-H), 1297, 1162 (SO2).1H NMR δ : 2.13 2.23 (s,6H, Ar-CH3), 3.34(s, 3H, SO2-CH3), 4.31 (d,J=5.5 Hz, 2H, Ar-CH2), 7.01,(t, J=8.6, 1H, Ar-NH) , 6.4 8.83(m, 12H, Ar-H). Mass m/z value : 495 base peak (M+)
RESULT AND DISCUSSION:
The synthesis of biphenylamine derivatives are shown in the above scheme. In the synthesis the commercially available 2,5-dibromo pyridine ,1.4-dibromo-2,5-dimethyl benzene and 3-fluoro-4-iodo aniline are used as starting material. The 5-bromo-2(methylthio)pyridine(1) is prepared by treating 2,5-dibromo pyridine with sodium thiomethoxide and tetra-n-butyl ammonium bromide as phase transfer catalyst (PTC). In 2,5-dibromo pyridine the ortho bromine is reactive but meta bromine is not reactive towards NaSMe because lone pair of nitrogen favoring ortho bromo to be active. The compound 1 is converted to 6-(methylthio)pyridin-3-yl boronic acid(2) by treating with triisopropylborate and n-BuLi in hexane under nitrogen atmosphere. The 4-bromo-2,5-dimethyl-phenyl boronic acid(3) was prepared by treating1,4-dibromo-2,5 dimethylbenzene with triisopropylborate and n BuLi in hexane under inert (N2) atmosphere. The N-(3- fluoro-4-iodophenyl) acetamide (4) is prepared by treating 3-fluoro-4-iodo ainiline with acetyl chloride in dichloro methane solvent at room temperature10-11. The N-(4-bromo-2-fluoro-2,5-dimethylbiphen -yl-4-yl) acetamide (5) is prepared via suzuki coupling by treating the compound 3 and 4 in the presence of palladiun tetrakis triphenylphosphene as a catalsyt12 The N- (2- fluoro-2,5-dimethyl-4{6-(methylthio) pyridine-3-yl}biphenyl-4-yl) acetami -de (6) is prepared by treating the compound 2 and 5 in the presence of palladiun tetrakistriphenylphosphene as a catalyst. The N- (2- fluoro-2,5-dimethyl-4{6-(methylsulfonyl) pyridine-3-yl}biphenyl-4-yl)acetamide (7) is prepared by treating the compound 6 with sodium periodate13. The 2-fluoro-2,5-dimethyl-4-{6-(methylsulfonyl) pyridin-3-yl}biphenyl-4-amine(8) is prepared by hydrolysis of compound 7 with HCl. The N-(2-methylbenzyl)-2-fluoro-2,5-dimethyl-4-{6-methyl sulfonyl)pyridin-3-yl} biphenyl -4-amine(9) is prepared by treating compound 8 with 2-methyl benzaldehyde and triacetoxy sodiumborohydride14. In the step d amine group is protected as amide otherwise it will lead to buck-wald amine coupling and it is deproted at step g with HCl. All the synthesized compound were purified in column chromatography using silica gel having 60-120 mesh size and ethyl acetate, petroleum ether mixture as elutant. The molecules were characterized with help of 1H NMR(400MHz,Bruker, d6-DMSO as a solvent for NMR), IR (KBr pellet) and mass spectrometer. The melting points were determined in open capillary.
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Received on 12.10.2010 Modified on 25.10.2010
Accepted on 04.11.2010 © AJRC All right reserved
Asian J. Research Chem. 4(2): February 2011; Page 285-288