Field of Invention
The current invention involves direct chemical preparation of aromatic amines/arylamines from N-heteroaromatic halides using various azides/amines. The developed protocol is catalyst free and proceeds without use of any metal salts or metal complexes as catalyst. Aromatic amines are important intermediates as well as raw material in the synthesis of large number of drugs and lead compounds. Aromatic amines are also structural backbone of many antibiotics, anti-inflammatories, antiallergics, antimetastasis agents, anticonvulsants, antidepressants etc. The current invention is ecofriendly, efficient, economic and commercially viable alternative for the existing protocols.
Background of the Invention
The arylamine moiety is a structural component in a variety of synthetic and naturally occurring biologically active compounds. Since derivatives based on aryl amine have a broad spectrum of activities, the organic synthesis of these compounds has attracted attention for many decades, and the development of new methods for the synthesis of these compounds is of great interest. The present invention relates to a novel method for preparing arylamines which are useful intermediates and end products in pharmaceutical and agricultural applications. The present invention further relates to applications of the method. Methods to construct the carbon-nitrogen bond in arylamines, however, are limited. Many synthetic methods for the construction of such an aryl-nitrogen bond suffer from severe reaction conditions and/or are applicable only for activated substrates using metal ions. There are generally two routes available for the synthesis of aromatic amines, first one involves nucleophilic aromatic substitution of aryl precursors and second one is the construction of the heterocycle aryl amine by the condensation of moieties containing required substituents. The first approach is generally a two-step process and involves metal ion for example Markiewicz et al. J. Org. Chem. 2010, 75, 4887–4890 (2010) described a method for the preparation of aryl
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amines from aryl halide and sodium azide using copper as catalyst and different set of ligands. Migita and coworkers Chem. Lett. 1983, 927–928 (1983) have described the preparation of N,N-diethylaminobenzenes from the palladium-catalyzed reaction of aryl bromides and N,N-diethylaminotributyltin. However, the general applicability of this synthetic route and other metal mediated reactions are limited due to their reactivity, instability and workup procedures. Inspite of these issues these metal complex waste are toxic and produces undesirable environmental effects as well as increases the cost also. Similarly Buchwald group US patent US 5,576,460 (1996) developed a method for preparing an arylamine compound, which includes reacting a metal amide comprising a metal (tin, boron, zinc, magnesium, indium and silicon) with an aromatic compound comprising an activated substituent in the presence of a transition metal catalyst to form an arylamine. They also used metals for these conversions and these metal complex produces toxic side products and thus have limited industrial applications.
Our invention is metal-free, greener and simple one step method for the conversion of aromatic halide to aromatic amine without using any metals.
Existing state-of-art related to the Invention
European Patent EP0802173B1: It discloses the process for producing a heterocyclic arylamine from heterocyclic aryl halide and an amine, using tertiary phosphine as reagent and palladium salts were used as catalysts. Similarly US Patent US3914311A describes preparation of secondary and tertiary amine using Nickel complex as a catalyst. Japanese Patent JP60048950A discloses preparation of aromatic amine from aromatic halide and ammonia in three steps using copper hydroxide as a catalyst.
Sajiki and co-workers (Chem. Eur. J. 2010, 16, 7372–7375) reported direct amination of aryl bromides by the use of trimethylsilyl azide (TMSN3) in the presence of CuF2 and Et3N or 2- aminoethanol. Qiao and co-workers (J. Org. Chem. 2010, 75, 3311–3316) developed closely related reaction conditions for the direct amination of ortho-
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functionalized haloarenes using NaN3 as the amino source in ethanol. All haloarenes studied contain an ortho-functionalized group (e.g.; -COOH, -CONH2, -NHCOR) that have been shown to be critical for the outcome of the reaction. In the case of 2-bromo derivatives, they required CuI (10 mol%) as the catalyst and Cs2CO3 (2 equiv) as the base but in case of chloro derivatives they required extra ligands such as DMEDA. Messsaoudi et al. (Adv. Synth. Catal. 2010, 352, 1677 – 1687) reported preparation of anilines and aminoheterocycles using (hetero)aryl halides and azide in the presence of copper as a catalyst. Markiewicz et al. (J. Org. Chem. 2010, 75, 4887–4890) described a method for the preparation of aryl amines from aryl halide and sodium azide using copper as catalyst and different set of ligands. Maejima et al. (J. Org. Chem. 2013, 78, 8980−8985) developed a method for copper catalyzed reductive amination of aryl halides using trimethylsilyl azides. Meng et al. (Eur. J. Org. Chem. 2010, 6149–6152) developed a method for the direct amination of aryl halides using aqueous ammonia and copper catalyst. Billingsley et al. (J. Org. Chem. 2016, 81, 330−335) designed an amination-oxidation process that successfully converts (hetero)aryl iodides and bromides to the corresponding monoarylamines using copper as a catalyst and cesium carbonate as base. Sukbok Chang et al. (J. Am. Chem. Soc. 2018, 140, 14350−14356) developed a copper-mediated approach that enables a chelation-assisted aromatic C−H bond amination using aqueous ammonia. Michael G. Organ et al. (Organometallics 2017, 36, 251−254) reported a method for the (hetero)- arylation of ammonia using a monoligated palladium-NHC complex. The new, rationally designed, precatalyst (DiMeIHeptCl)Pd(allyl)Cl features highly branched alkyl chains.
Objective of the Invention
The objective of the current invention is direct synthesis of aromatic amines from N-heteroaromatic halides using azide/amines. Use of fewer/minimum chemicals is the demand of chemical industries keeping in view the waste generation and environmental impact. Multi-step reactions for the synthesis of final products always generate lot of waste and its treatment add to the production cost of final products. Synthesis of
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aromatic amines from aromatic halides usually proceeds through two step process. The first step involves reaction of aromatic halides with azide salt leading to the formation of aromatic azide. In the second step, aromatic azide reacted with molecular hydrogen in the presence of metal catalysts (such as Cu, Pd, Ni etc.) for the formation of aromatic amine. The existing two-step process for the synthesis of final products, make use of acutely toxic chemicals and highly flammable and hazardous hydrogen gas. In this regard, the current invention is a major contribution in reducing the waste generation at source and eliminating the use of hazardous hydrogen gas.
Another objective of the present invention is to perform the reaction without using any metal catalyst.
Yet another objective of the present invention is to develop a large scale, safe and efficient procedure for the direct synthesis of aromatic amines using azide salts.
Summary of the Invention
The current invention involves direct synthesis of aromatic amines from aromatic halides using various azides/amines. Aromatic amines are important intermediates in the synthesis of large number of drugs and lead compounds. Aromatic amines are also structural backbone of many antibiotics, anti-inflammatories, antiallergics, antimetastasis agents, anticonvulsants, antidepressants etc. The current invention is related to a synthetic process which finds direct application in the chemical and pharmaceutical industries. Chemical and pharmaceutical industries involved in the synthesis of drugs and active pharmaceutical ingredients will be interested in the current invention. It is a green and economically viable invention and can be easily pursued for further R & D and scale up.
The current invention is a single step method for the direct synthesis of aromatic amines from N-heteroaromatic halides. No metal catalyst was used for carrying out the reaction. The available two-step process for the synthesis of intermediates/products is inferior in terms of waste generation, risk and cost.
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Brief Description of Drawing
Figures (Example 1 to 13) demonstrates direct synthesis of arylamines (as described in formula I) from aromatic halides using various azides/amines. It describes a method of preparing an arylamine compound, comprising the steps of reacting an N-heteroaromatic halide with an azide/metal azide/amine in the presence or absence of solvent at the temperature less than about 140 °C without using any catalyst wherein the N-hetroaromatic halide has a formula, Ar(R1R2)X, and Ar is an N-heteroaryl moiety, X is an activated substituent selected from the group consisting of chloride, bromide, iodide, triflate, mesylate, and tosylate, R1 is alkyl or substituted/unsubstituted aryl or bridged ring, R2 is alkyl or substituted/unsubstituted aryl or heteroaryl ring and amine (R3) is selected from the group consisting of primary or secondary amines with alkyl chain or cycloalkyl groups or allylamines or propargyl amine or aromatic amines.
Detailed Description of the Invention
Chemical industries are considered as one of the major factors for environmental degradation and global warming. Development of environmental friendly synthetic processes for the synthesis of final products has been perused on war footings. Use of fewer/minimum chemicals is the demand of chemical industries keeping in view the waste generation and environmental impact. Multi-step reactions for the synthesis of final products always generate lot of waste and its treatment add to the production cost of final products. A number of scientists and researchers are working for the development of green synthetic routes for the target compounds and in this regard reduction in the numbers of synthetic steps is one of the strategy in minimizing/eliminating waste generation.
Arylamines are important intermediates in the synthesis of large number of drugs and lead compounds. The arylamine moiety is a structural component in a variety of synthetic and naturally occurring biologically active compounds. Arylamines also act as structural backbone of many antibiotics, anti-inflammatories, antiallergics,
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antimetastasis agents, anticonvulsants, antidepressants etc. Methods to construct the carbon-nitrogen bond in arylamines, however, are limited. Many synthetic methods for the construction of such an aryl-nitrogen bond suffer from severe reaction conditions and/or are applicable only for activated substrates. Typical routes to aromatic amines include nucleophilic aromatic substitution of aryl precursors. Synthesis of aromatic amines from aromatic halides usually proceeds through two step process. The first step involve reaction of aromatic halides with azide salt leading to the formation of aromatic azide. In the second step, aromatic azide reacted with molecular hydrogen in the presence of metal catalysts (such as Pd, Ni etc.) for the formation of aromatic amine.
Synthesis of arylamines via copper-mediated Uhlmann condensation reactions also has been reported by Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496 (1987). Kosugi and coworkers Chem. Lett. 1983, 927–928 (1983) have described the preparation of N,N-diethylaminobenzenes from the palladium-catalyzed reaction of aryl bromides and N,N-diethylaminotributyltin. However, the general applicability of this synthetic route is limited due to the high reactivity and instability of the aminostannanes. Boger and coworkers J. Org. Chen. 1985 50,5782 reported the formation of an aryl nitrogen bond by reaction of an amine moiety with an aryl bromide without the use of a metal amide and, in particular, without the use of an aminostannane. However, the reaction required the use of stoichiometric amounts of palladium(0) in order for the reaction to occur . Wang and coworkers reported the C-N coupling products by reacting 1, 2‐di(pyrimidin‐2‐yl) disulfides with heterocyclic amines including 2‐amino pyrimidines and 1,3,4‐thiadiazol‐ 2‐amines under Pd catalyzed conditions Appl Organometal Chem. 2018;32(2)4020 US Patent US2018/0057444 describes the amination and hydroxylation of arylmetal compounds. In this process aryl grignard and aryl lithium are used as substrate for producing a heterocyclic arylamine. In addition, oxaziridine is used as source of oxygen or nitrogen in the presence of a weak acid.
It can be concluded that most of the reported methods for the preparation of aromatic amines from aromatic halides proceeds with use of metal catalysts such as copper,
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palladium or nickel. In many cases it was a two-step process. A general route to a wide range of arylamines under moderate reaction conditions is yet to be reported. Therefore, it is an object of the present invention to provide such a general synthetic route to a wide range of arylamines.
The objective of the current invention is direct synthesis of aromatic amines from aromatic halides using azide/amines.
Another objective of the present invention is to perform the reaction without using any metal catalyst.
Yet another objective of the present invention is to develop a large scale, safe and efficient procedure for the direct synthesis of aromatic amines using azides/amines.
The current invention is a novel finding and it satisfy most of the attributes of the green synthesis. Reduction in synthetic steps helped in the elimination of waste at source. The use of hazardous hydrogen gas has been eliminated in the current invention. Use of fewer chemicals in the single step process reduces the production cost of products/intermediates and thus making process economically viable.
The current invention involves direct synthesis of arylamines (formula I) from aromatic halides using various azides/amines. The invention describes a method of preparing an arylamine compound, comprising the steps of reacting an N-heteroaromatic halide with an azide/metal azide/amine in the presence or absence of solvent at the temperature less than about 140 °C without using any catalyst wherein the N-hetroaromatic halide has a formula, Ar(R1R2)X, and Ar is an N-heteroaryl moiety, X is an activated substituent selected from the group consisting of chloride, bromide, iodide, triflate, mesylate, and tosylate, R1 is alkyl or substituted/unsubstituted aryl or bridged ring, R2 is alkyl or substituted/unsubstituted aryl or heteroaryl ring and amine (R3) is selected from the group consisting of primary or secondary amines with alkyl chain or cycloalkyl groups or allylamines or propargyl amine or aromatic amines.
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An embodiment of the present invention discloses selection of N-heteroaromatic ring (Ar) from the group consisting of one or two or multiple nitrogen atoms in the ring. Further wherein, N-heteroaromatic ring (Ar) is selected from the group consisting of monocyclic or dicyclic or tricyclic rings.
Another embodiment of the invention discloses selection of azide from the group consisting of hydrazide, metal azide, trimethylsilyl azide and the mixture thereof. Wherein, the metal in the metal azide is selected from the group consisting of sodium, potassium, cesium and the like.
Yet another embodiment discloses selection of R3 wherein, primary amines with alkyl chain (R3) is selected from the group consisting of methylamine or ethylamine or propylamine or butylamine or pentylamine or hexylamine or benzylamine and the like; the secondary amines with alkyl chain (R3) is selected from the group consisting of dimethylamine or diethylamine or dipropylamine or butylamine or pentylamine or hexylamine and the like; secondary amines with cyclic group (R3) is selected from the group consisting of piperidine or morpholine or pyrrolidine or piperazine or methylpiperazine or phenylpiperazine and the like; and the aromatic amines (R3) is
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selected from the group consisting of aniline or imidazole or methylimidazole or 1,2,4-triazole or 1,2,3-triazole or indole or benztriazole or pyrrole and the like.
Further embodiment discloses selection of solvent from the group consisting of triethylamine, N,N-dimethylformamide, methylimidazole, imidazole, quinolone, N-methylpyrrolidone and the like.
Further other embodiment discloses selection of other substituents, wherein R1 is selected from the group consisting of hydrogen or methyl or ethyl or propyl or butyl or hexyl or cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl or aromatic ring or heteroaromatic ring or bridged C4H4 and the like; R2 is selected from the group consisting of hydrogen or methyl or ethyl or propyl or butyl or hexyl or cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl or substituted/unsubstituted aromatic ring or substituted/unsubstituted heteroaromatic ring or bridged C4H4 and the like; and wherein R1 and R2 may be similar or different.
Yet another embodiment discloses reaction conditions, wherein reaction temperature ranges from 40 to 140 ˚C preferably 120 to 140 ˚C; and wherein heating source may be microwave or conventional heating.
Procedure
Synthesis of 4-(4-methoxyphenyl)-6-(4-(prop-2-yn-1-yloxy)phenyl)pyrimidin-2-amine (Example-1): To a stirred solution of compound 2-iodo-4-(4-methoxyphenyl)-6-(4-(prop-2-yn-1-yloxy)phenyl)pyrimidine (100mg, 0.22mmol) in N-Methyl-2-
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pyrrolidone (NMP) (2ml) was added sodium azide (22mg, 0.33mmol) and mixture was heated at 140ºC for 1 hrs. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (10ml) and extracted with ethyl acetate (2×20ml), the combined organic layer was again washed with water (2×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol.
1H NMR (CDCl3, 400 MHz, δ with TMS = 0): 8.04 - 8.01 (4H, m), 7.35 (1H, s), 7.08 - 6.98 (4H, m), 5.22 (2H, s), 4.75 (2H, s), 3.86 (3H, s), 2.55 (1H, s); 13C NMR (CDCl3, 100 MHz, δ with TMS = 0) δ: 165.55, 165.33, 163.59, 161.66, 159.45, 131.24, 130.27, 128.66, 115.06, 114.15, 102.92, 77.45, 75.97, 55.92, 55.50. m/z=331
Synthesis of 4-(4-(prop-2-yn-1-yloxy)phenyl)-6-(p-tolyl)pyrimidin-2-amine (Example-2): To a stirred solution of compound 2-chloro-4-(4-(prop-2-yn-1-yloxy)phenyl)-6-(p-tolyl)pyrimidine (100mg, 0.29mmol) in N,N-dimethyl formamide (DMF) (2ml) was added trimethylsilyl azide (51mg, 0.44mmol) and mixture was heated at 140ºC for 30 hrs. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (10ml) and extracted with ethyl acetate (2×20ml), the combined organic layer was again washed with water (2×20ml) and brine (10ml). The organic fraction was dried with Na2SO4,
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concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol.
1H NMR (CDCl3, 400 MHz, δ with TMS = 0): 8.05 - 8.02 (2H, m), 7.95 - 7.93 (2H, m), 7.38 (1H, s), 7.29 (2H, s), 7.08 - 7.05 (2H, m), 5.25 (2H, s), 4.75 (2H, s), 2.55 (1H, s), 2.42 (3H, s); 13C NMR (CDCl3, 100 MHz, δ with TMS = 0) δ: 166.07, 165.47, 163.66, 159.51, 140.80, 135.08, 131.21, 129.60, 128.70, 127.11 115.09, 103.43, 77.47, 76.00, 55.94; m/z=316.14
Synthesis of 4-(3,4-dimethoxyphenyl)-6-(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)pyrimidine (Example-3): To a stirred solution of compound 4-(3,4-dimethoxyphenyl)-6-(4-methoxyphenyl)-2-tosylpyrimidine (200mg, 0.42mmol) in N,N-dimethylformamide (2ml) was added sodium azide (100mg, 0.50mmol) and mixture was subjected to microwave irradiation at 100W, 110ºC for 15 min. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (15ml) and extracted with ethyl acetate (2×40ml), the combined organic layer was again washed with water (3×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol.
1H NMR (CDCl3, 400 MHz, δ with TMS = 0): 8.08 (2H, d, J = 8Hz), 7.71 (1H,s), 7.69 (1H, d, J = 8Hz), 7.28 (1H, s), 6.99 (2H, d, J = 8Hz ), 6.95 (1H, d, J = 8Hz), 4.03 (4H,
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t, J12 = 4Hz), 3.99 (3H, s), 3.94 (3H, s), 3.86 (3H, s), 2.53 (4H, t, J12 = 8Hz ), 2.36 (3H, s): 13C NMR (CDCl3, 100 MHz, δ with TMS = 0) δ: 164.59, 164.54, 162.22, 161.56, 151.07, 149.13, 131.27, 130.84, 128.62, 120.19, 114.03, 110.93 110.07, 100.80, 56.09, 55.49, 55.24, 46.42, 43.91, 37.10. m/z = 420
Synthesis of 4-(4-isopropylphenyl)-2-(4-methylpiperazin-1-yl)-6-(thiophen-3-yl)pyrimidine (Example-4): To a stirred solution of compound 2-bromo-4-(4-isopropylphenyl)-6-(thiophen-3-yl)pyrimidine (200mg, 0.55mmol) in N,N-dimethylformamide (4ml) was added sodium azide (108mg, 0.1.67mmol) and mixture was subjected to microwave irradiation at 100W, 110ºC for 15 min. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (15ml) and extracted with ethyl acetate (2×40ml), the combined organic layer was again washed with water (3×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol.
1H NMR (CDCl3, 400 MHz, δ with TMS = 0): 7.99 (2H, d, J = 8Hz), 7.74 (1H,dd, J12= 4Hz; J34 = 4Hz), 7.44 (1H, d, J = 8Hz), 7.32 (2H, d , J =8Hz) 7.2 (1H, s), 7.12 (1H, d, J = 4Hz ), 4.0 (4H, t, J = 4Hz), 2.98-2.93 (1H, m),. 2.52 (4H, t, J = 4Hz ), 2.30 (3H, s), 1.27 (6H, d, J = 4Hz);13C NMR (CDCl3, 100 MHz, δ with TMS = 0) δ: 165.24, 161.95, 159.81, 151.61, 144.38, 135.79, 128.81, 128.06, 127.19, 126.83, 126.39, 100.15, 55.21, 46.45, 43.82, 34.17, 23.99 HRMS m/z: (M+1) 379.1967
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Synthesis of 4-(4-bromophenyl)-2-(4-methylpiperazin-1-yl)-6-(3,4,5-trimethoxyphenyl)pyrimidine (Example-5): To a stirred solution of compound 4-(4-bromophenyl)-2-chloro-6-(3,4,5-trimethoxyphenyl)pyrimidine (200mg, 0.46mmol) in N,N-dimethylformamide (4ml) was added hydrogen azide (89mg, 1.38mmol) and mixture was subjected to microwave irradiation at 100W, 110ºC for 15 min. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (15ml) and extracted with ethyl acetate (2×40ml), the combined organic layer was again washed with water (3×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol
1H NMR (CDCl3, 400 MHz, δ with TMS = 0): 8.00 (2H,d, J = 8 Hz ), 7.64 (2H,d, J = 8 Hz ), 7.35 (2H, d, 8Hz ), 7.28 (1H, s), ,4.10 (4H, t, J = 8Hz), 4.00 (6H, s), 3.94 (3H, s), 2.62 (4H, t, J = 8Hz ) 2.43 (3H, s); 13C NMR (CDCl3, 100 MHz, δ with TMS = 0) δ: 165.31, 164.09, 162.07, 153.47, 139.25, 133.62, 131.83, 128.65, 127.11, 114.04, 104.71, 101.60, 60.95, 56.40, 54.97, 43.63, 31.91, 29.68 MS (EI): m/z = 498, M+2 = 500
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Synthesis of 4-(3,4-dimethoxyphenyl)-6-(4-methoxyphenyl)-2-(4-methylpiperazin-1-yl)pyrimidine (Example-6): To a stirred solution of compound 4-(4-chlorophenyl)-6-(4-methoxyphenyl)pyrimidin-2-yl trifluoromethanesulfonate (200mg, 0.44mmol) in N,N-dimethylformamide (4ml) was added 1-phenylpiperazine (80mg, 0.49mmol) and mixture was subjected to microwave irradiation at 100W, 110ºC for 40 min. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (15ml) and extracted with ethyl acetate (2×40ml), the combined organic layer was again washed with water (3×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol.
1H NMR: (400 MHz, CDCl3, TMS = 0) δ: 8.10(2H, d, J=9.1Hz), 8.06(2H, d, J=8.5Hz), 7.45(2H, d, J=6.4Hz), 7.32(1H, s), 7.27(2H, t, J=20Hz), 7.01(2H, d, J=2.4Hz), 6.99(2H, d, J=1.8Hz), 6.8(1H, t, J=14.6Hz), 4.17(4H, t, J=10Hz), 3.88(3H, s), 3.3(4H, t, J=9.7Hz)13C NMR: (400 Mz, CDCl3, TMS =0) δ: 165.05, 163.85, 162.22, 161.76, 151.61, 136.83, 129.30, 128.93, 128.69, 128.47, 120.21, 116.65, 114.11, 101.21, 77.45, 77.12, 76.81, 55.52, 49.64, 43.99, 37.10, 29.81, 22.77, 14.26, 1.14. m/z = 456
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Synthesis of 4-(2-(4-phenylpiperazin-1-yl)-6-(thiophen-3-yl)pyrimidin-4-yl)benzonitrile (Example-7): To a stirred solution of compound 4-(4-cyanophenyl)-6-(thiophen-3-yl)pyrimidin-2-yl methanesulfonate (200mg, 0.56mmol) in N,N-dimethylformamide (4ml) was added 1-phenylpiperazine (109mg, 1.68mmol) and mixture was subjected to microwave irradiation at 100W, 110ºC for 40 min. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (15ml) and extracted with ethyl acetate (2×40ml), the combined organic layer was again washed with water (3×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol.
1H NMR: (400 MHz, CDCl3, TMS = 0) δ: 8.19(2H, d, J=8.5), 7.78(2H, d, J=1.8), 7.76(1H, s), 7.49(1H, d, J=4.8), 7.41(1H, d, J=8.5), 7.32-7.28(2H, t, J=7.9), 7.24(1H, s), 7(2H, d, J=7.96), 6.91-6.89(1H, t, J=3.68), 4.15-4.2(4H, t, J=5.2), 3.32-3.29(4H, t, J=5.2) 13C NMR: (400 Mz, CDCl3, TMS =0) δ: 163.09, 161.89, 160.70, 151.49, 143.65, 142.33, 132.55, 132.16, 130.43, 129.58, 129.32, 128.26, 127.73, 127.04,120.3, 118.74, 116.67, 113.76, 100.74, 77.42, 77.10, 76.79, 49.59, 43.89
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Synthesis of 4-(4-methoxyphenyl)-6-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)pyrimidine (Example-8) To a stirred solution of compound 2-bromo-4-(4-methoxyphenyl)-6-phenylpyrimidine (100mg, 0.33mmol) in 1-methylimidazole (4ml) was added 4-phenyl-1H-1,2,3-triazole (58mg, 0.40mmol) and mixture was heated at 140ºC for 2 hrs. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (10ml) and extracted with ethyl acetate (2×20ml), the combined organic layer was again washed with water (3×15ml) and brine (20ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was further purified through coloum chromatography.
1H NMR: (400 MHz, CDCl3, TMS = 0) δ: 8.89(1H, s), 8.22-8.21(4H, m), 8.20-8.00(3H, m), 7.54-7.53(5H, m), 7.52(1H, s), 7.02(2H, t, J=9.1Hz), 3.87(3H, s), 13C NMR: (400 Mz, CDCl3, TMS =0) δ: 166.99, 166.73, 166.56, 162.81, 154.90, 150.52, 147.82, 131.73, 129.30, 129.16, 128.97, 127.55, 126.47, 118.68, 114.52, 110.52, 110.03, 55.58. m/z = 405
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Synthesis of 4-(3-bromophenyl)-6-phenyl-2-(4-phenylpiperazin-1-yl)pyrimidine (Example-9): To a stirred solution of compound 4-(3-bromophenyl)-2-iodo-6-phenylpyrimidine (100mg, 0.22mmol) in N-Methyl-2-pyrrolidone (NMP) (2ml) was added sodium azide (44mg, 0.68mmol) and mixture was heated at 140ºC for 1 hrs. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (10ml) and extracted with ethyl acetate (2×20ml), the combined organic layer was again washed with water (2×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol
1H NMR: (400 MHz, CDCl3, TMS = 0) δ: 8.27(1H, s), 8.12-8.11(2H, m), 8.02(1H, d, J=7.9), 7.6(1H, d, J=7.92), 7.5-7.49(3H, m), 7.42-7.41(1H, m), 7.37(1H, s), 7.3(2H, t, J=7.6), 7.01(2H, d, J=7.9), 6.9(1H, t, J=7.3), 4.19(4H, t, J=4.9), 3.32(4H, t, J=4.8) 13C NMR: (400 Mz, CDCl3, TMS =0) δ 165.69, 163.82, 162.24, 151.58, 133.3, 130.66, 130.3,130.27, 129.32, 128.83, 127.24, 125.77, 123..08, 120.25, 116.67, 102.183, 77.46, 77.14, 76.83, 49.64, 43.99,32.02, 29.82, 22.76, 14.28
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Synthesis of quinolin-2-amine (Example-10): To a stirred solution of compound 2-chloroquinoline (100mg, 0.61mmol) in methylimidazole was added sodium azide (119 mg, 1.8 mmol) and mixture was subjected to microwave irradiation at 100W, 120ºC for 30 min. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (15ml) and extracted with ethyl acetate (2×40ml), the combined organic layer was again washed with water (3×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol.
Synthesis of 4-phenyl-N-(prop-2-yn-1-yl)-6-(p-tolyl)pyrimidin-2-amine (Example-11): To a stirred solution of compound 2-iodo-4-phenyl-6-(p-tolyl)pyrimidine (200mg, 0.53mmol) in methylimidazole was added prop-2-yn-1-amine (44mg, 0.80 mmol) and mixture was subjected to microwave irradiation at
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100W, 120ºC for 30 min. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (15ml) and extracted with ethyl acetate (2×40ml), the combined organic layer was again washed with water (3×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol. m/z = 299
Synthesis of 2-(4-methoxyphenyl)quinazolin-4-amine (Example-12): To a stirred solution of compound 4-chloro-2-(4-methoxyphenyl)quinazoline (100mg, 0.37mmol) in N-Methyl-2-pyrrolidone (NMP) (2ml) was added sodium azide (36mg, 0.55mmol) and mixture was subjected to microwave irradiation at 100W, 140ºC for 15 min. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (10ml) and extracted with ethyl acetate (2×20ml), the combined organic layer was again washed with water (2×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol.
1H NMR (400MHz, CDCl3, TMS = 0) δ = 8.46(2H, d), 7.90(1H, m), 7.75 (2H, m), 7.43(1H, m), 7.01 (2H, d), 5.75(2H, s), 3.87 (3H, s).13C NMR (100 MHz, CDCl3, TMS = 0) δ =161.53, 161.39, 160.66, 151.18, 133.29, 130.01, 128.72, 125.42, 121.67, 113.77, 55.45, 29.79. m/z=251
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Synthesis of 2-(3,4-dimethoxyphenyl)quinazolin-4-amine (Example-13): To a stirred solution of compound 4-chloro-2-(4-methoxyphenyl)quinazoline (100mg, 0.33mmol) in N-Methyl-2-pyrrolidone (NMP) (2ml) was added potassium azide (40mg, 0.5mmol) and mixture was subjected to microwave irradiation at 100W, 140ºC for 15 min. Progress of reaction was monitored by TLC, and on completion of reaction, reaction mixture was cooled, diluted with water (10ml) and extracted with ethyl acetate (2×20ml), the combined organic layer was again washed with water (2×20ml) and brine (10ml). The organic fraction was dried with Na2SO4, concentrated under vaccum.to afford desired crude product which was purified with recrystallization in ethanol.
1H NMR (400MHz, CDCl3, TMS = 0) δ = 8.12(1H, s), 7.80(1H, d), 7.75 (2H, m), 7.45(1H, m), 7.25 (1H, s), 6.94 (1H, d), 5.75(2H, s), 3.94 (3H, s), 4.02 (3H, s).13C NMR (100 MHz, CDCl3, TMS = 0) δ =161.35, 160.56, 151.16, 151.02, 148.82, 133.32, 128.75, 125.51, 121.67, 111.03, 110.68, 56.03, 29.79. m/z=281

We Claim:
1. A method of preparing an arylamine compound, comprising the steps of:
reacting an N-heteroaromatic halide with an azide/metal azide/amine in the presence or absence of solvent at the temperature less than about 140 °C without using any catalyst wherein the N-hetroaromatic halide has a formula, Ar(R1R2)X, and Ar is an N-heteroaryl moiety, X is an activated substituent selected from the group consisting of chloride, bromide, iodide, triflate, mesylate, and tosylate, R1 is alkyl or substituted/unsubstituted aryl or bridged ring, R2 is alkyl or substituted/unsubstituted aryl or heteroaryl ring and amine (R3) is selected from the group consisting of primary or secondary amines with alkyl chain or cycloalkyl groups or allylamines or propargyl amine or aromatic amines.
2. The method as claimed in claim 1, wherein N-heteroaromatic ring (Ar) is selected from the group consisting of one or two or multiple nitrogen atoms in the ring.
3. The method as claimed in claim 1, wherein N-heteroaromatic ring (Ar) is selected from the group consisting of monocyclic or dicyclic or tricyclic rings.
4. The method as claimed in claim 1, wherein the azide is selected from the group consisting of hydrazide, metal azide, trimethylsilyl azide and the mixture thereof.
5. The method as claimed in claim 1 and claim 4, wherein the metal in the metal azide is selected from the group consisting of sodium, potassium, cesium and the like.
6. The method as claimed in claim 1, wherein the primary amines with alkyl chain (R3) is selected from the group consisting of methylamine or ethylamine or propylamine or butylamine or pentylamine or hexylamine or benzylamine and the like.
7. The method as claimed in claim 1, wherein the secondary amines with alkyl chain (R3) is selected from the group consisting of dimethylamine or diethylamine or dipropylamine or butylamine or pentylamine or hexylamine and the like.
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8. The method as claimed in claim 1, wherein the secondary amines with cyclic group (R3) is selected from the group consisting of piperidine or morpholine or pyrrolidine or piperazine or methylpiperazine or phenylpiperazine and the like.
9. The method as claimed in claim 1, wherein the aromatic amines (R3) is selected from the group consisting of aniline or imidazole or methylimidazole or 1,2,4-triazole or 1,2,3-triazole or indole or benztriazole or pyrrole and the like.
10. The method as claimed in claim 1, wherein solvent is selected from the group consisting of triethylamine, N,N-dimethylformamide, methylimidazole,
imidazole, quinolone, N-methylpyrrolidone and the like.
11. The method as claimed in claim 1, wherein R1 is selected from the group consisting of hydrogen or methyl or ethyl or propyl or butyl or hexyl or cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl or aromatic ring or heteroaromatic ring or bridged C4H4 and the like.
12. The method as claimed in claim 1, wherein R2 is selected from the group consisting of hydrogen or methyl or ethyl or propyl or butyl or hexyl or cyclopropyl or cyclobutyl or cyclopentyl or cyclohexyl or substituted/unsubstituted aromatic ring or substituted/unsubstituted heteroaromatic ring or bridged C4H4 and the like.
13. The method as claimed in claim 1, wherein R1 and R2 may be similar or different.
14. The method as claimed in claim 1, wherein heating source may be microwave or conventional heating.