Synthesis of New N-Arylpyrimidin-2-amine Derivatives Using a Palladium Catalyst

New N-aryl-4-(pyridin-3-yl)pyrimidin-2-amine derivatives were synthesized from the corresponding amines, applying optimized Buchwald-Hartwig amination conditions using dichlorobis(triphenylphosphine)Pd(II), xantphos and sodium tert-butoxide in refluxing toluene under a nitrogen atmosphere. The target N-aryl derivatives were obtained in moderate to good yields ranging from 27% to 82%. The procedure described could be widely employed for the preparation of new heterocyclic compounds. The structures of the new compounds were confirmed by FT-NMR, FT-IR and elemental analysis.

In most of the reported literature, the synthesis of N-arylpyrimidin-2-amines was achieved by condensation of substituted guanidines with enones [13][14][15]. This approach however is of restricted use for the preparation of diverse derivatives of N-arylpyrimidin-2-amines because of the limited availability of substituted guanidines. Herein we will describe a detailed synthesis for a number of Naryl-4-(substituted)pyrimidin-2-amines by applying a Buchwald-Hartwig amination protocol [16].
iii iv The most challenging step in our work was to apply an electrophilic substitution using a benzyl or phenylbromide derivative at the highly electron deficient amino group of the pyrimidin-2-amine. The reaction was easier in case of benzylation of the amino group, since we applied a dropwise addition of 2,4-dimethylbenzyl bromide to a heated solution of 2 and K 2 CO 3 in DMF for the preparation of compound 3 (39% yield). This dropwise addition during 4 hours was essential to avoid N,Ndibenzylation. On the other hand, when K 2 CO 3 was replaced with NaHCO 3 , no product was obtained at all, which is probably due to the weak basicity of NaHCO 3 relative to K 2 CO 3 .
As shown in Scheme 2, a completely different procedure was followed for the preparation of the 6methylpyrimidin-2-amine scaffold, whereby 4-chloro-6-methylpyrimidin-2-amine underwent Suzuki coupling with pyridine-3-boronic acid in a mixed solvent of acetonitrile and water (1:1, v/v) at 78 o C under nitrogen atmosphere, and in the presence of dichlorobis(triphenylphosphine)Pd(II) and Na 2 CO 3 to yield 4-methyl-6-(pyridin-3-yl)pyrimidin-2-amine (5) in 74% yield [20]. The benzylation of compound 5 was achieved by following the same procedure used for the preparation of compound 3, that is by dropwise addition of 2,4-dimethylbenzyl bromide to a heated solution of 5 and K 2 CO 3 in DMF to yield the target compound 6 in 43% yield. Compound 7 was prepared by the reaction of 5 with 1-bromo-2,4-dimethylbenzene following the optimized conditions for Buchwald-Hartwig reaction; in refluxing toluene under nitrogen atmosphere, using dichlorobis(triphenylphosphine)Pd(II), xantphos and sodium tert-butoxide in yield of 35%.

Scheme 3
The target of the reaction sequence shown in Scheme 3 was to obtain new pyrimidine scaffolds substituted with aryl or heteroaryl moieties. In order to achieve this target, 2,5-dibromopyridine was converted into 5-acetyl-2-bromopyridine (8) in 51% yield according to a literature procedure [21], by lithiation of 2,5-dibromopyridine in diethylether at -78 o C under nitrogen atmosphere, followed by acetylation at 5-position by N,N-dimethylacetamide. 1-(6-(Substituted)pyridin-3-yl)ethanones 9a and 9b were obtained by Suzuki coupling of 8 with the appropriate boronic acid derivatives in a mixed solvent of acetonitrile and water (1:1, v/v) at 78 o C under nitrogen atmosphere, and in the presence of dichlorobis(triphenylphosphine)Pd(II) and Na 2 CO 3 in good yields of 67% for 9a and 74% for 9b. The Ar-Br fusion of 9a and 9b with 2 equivalents of N,N-dimethylformamide dimethylacetal yielded the target compounds 10a and 10b in yield of 99% and 88%, respectively. The reaction of the resulted prop-2-en-1-one derivatives 10a and 10b with guanidine hydrochloride in refluxing absolute ethanol and in the presence of sodium ethoxide afforded the desired amines 11a and 11b in 84% and 90% yields, respectively. The arylation of these amines with a number of aryl bromides using the previously mentioned optimized Buchwald-Hartwig amination conditions in refluxing toluene under nitrogen atmosphere, using dichlorobis(triphenylphosphine)Pd(II), xantphos and sodium tert-butoxide yielded the target compounds 12a, 12b and 12c in 82%, 31% and 27% yield, respectively.
In summary, we have developed a facile and general approach for the synthesis of new N-aryl-4-(pyridine-3-yl)pyrimidin-2-amine derivatives. The functionalities of pyrimidine derivatives proceeded Suzuki coupling and Buchwald-Hartwig type reactions smoothly in moderate to good yield.

General
1 H-NMR (300 MHz) and 13 C-NMR (75 MHz) were recorded on a Bruker Avance 300 spectrometer with TMS as an internal reference. The IR spectra were recorded on Perkin Elmer Spectrum GX spectrometer. Melting points were taken on a Thomas-Hoover capillary melting apparatus and were uncorrected. Chemical analyses were carried out by EA 1108 CHNS-O from Fisons Instruments. Column chromatography was performed on Merck silica gel 60 (230 -400 mesh). TLC was carried out using glass sheets precoated with silica gel 60 F254 prepared by E. Merck. All the commercially available reagents were obtained from Aldrich and Tokyo Kasei Chemical and generally used without further purification.  (2). To a solution of NaOEt in absolute ethanol, made by dissolving sodium metal (0.69 g, 30.0 mmoles) in absolute ethanol (100 mL), guanidine hydrochloride (2.86 g, 30.0 mmoles) was added in one portion and stirred at room temperature for one hour. Compound 1 (5.28 g, 30.0 mmoles) was dissolved in absolute ethanol (20 mL) and added to the reaction mixture.

4-(Pyridin-3-yl)pyrimidin-2-amine
The mixture was heated under reflux for 6 hours, and was then left to cool at room temperature, followed by cooling in an ice bath. The formed product was separated by filtration, washed with cold ethanol (20 mL), then with water (50 mL), and left to dry.

N-(4-Methoxyphenyl)-4-(pyridin-3-yl)pyrimidin-2-amine (4b).
After trituration with water, the formed solid was filtered, washed with cold water, dried, and then crystallized from ethanol to give 4b as yellow crystals: 0.   (5). A mixture of 2-amino-4-chloro-6-methyl-pyridine (2.70 g, 18.76 mmoles), 3-pyridineboronic acid (2.54 g, 20.66 mmoles), dichlorobis(triphenylphosphine)Pd(II) (0.36 g, 0.512 mmoles) and Na 2 CO 3 (1.40 g, 13.2 mmoles) was placed in mixed solvent of acetonitrile and water (1:1, 150 mL). N 2 gas was bubbled into this mixture for 10 minutes, and then the mixture was heated at 78 o C while stirring under N 2 atmosphere for 7 hours. The reaction mixture was left to cool at room temperature, poured into ice water (100 mL), and then extracted with ethylacetate (100 ml x 3). The organic layer was separated, washed with water (100 mL x 3), dried over anhydrous MgSO 4 , and then evaporated under vacuum to yield the crude product which was then crystallized from ethanol to yield the pure yellow crystals  (6). The procedure used for the synthesis of compound 3 was adapted for the preparation of this compound. After pouring the reaction mixture over ice water, the aqueous solution was extracted with ethyl acetate (100 mL x 2). The organic layer was separated, dried over anhydrous MgSO 4 , then evaporated under vacuum to yield the crude product, which was then purified by column chromatography (silica gel, ethyl acetate-hexane, 1:1) to give 6 as brown needle-like crystals: 0.   Methyl-N-(2,4-dimethylphenyl)-6-(pyridin-3-yl)pyrimidin-2-amine (7). The procedure used for the synthesis of compound 4a was adapted for the synthesis of this compound to give 7 as an off-white powder: 88 mg (35%); m.p. 95-96 o C; IR υ/cm

General procedure for the synthesis of compounds 9a-9b
A mixture of 5-acetyl-2-bromopyridine (8, 2.0 g, 10 mmoles), the appropriate aryl boronic acid (11.0 mmoles), dichlorobis(triphenylphosphine)Pd(II) (0.19 g, 0.27 mmoles) and Na 2 CO 3 (0.75 g, 7.0 mmoles) was placed in mixed solvent of acetonitrile and water (1:1, 80 mL). N 2 gas was bubbled into this mixture for 10 minutes, and then the mixture was heated at 78 o C while stirring under N 2 atmosphere for 4 hours. The reaction mixture was left to cool at room temperature, poured into ice water (100 mL), and then extracted with methylene chloride (150 mL x 3). The organic layer was separated, dried over anhydrous MgSO 4 , and then evaporated under vacuum to yield the crude product which was then crystallized from ethanol to yield the pure compounds 9a and 9b.  18, 127.39, 128.96, 130.11, 136.43, 138.13, 150.12, 160.60 (C=O). General procedure for the synthesis of compounds 10a-10b

1-(6-(Pyridin-3-yl)pyridin-3-yl)ethanone
The appropriate 1-(6-(substituted)pyridin-3-yl)ethanone 9a or 9b (2.5 mmoles) and N,N-dimethylformamide dimethylacetal (0.6 g, 5.0 mmoles) were refluxed together in an oil bath for 3 hours. The excess unreacted N,N-dimethylformamide dimethylacetal was removed by distillation, followed by removal of the residual part under vacuum. The solid residue was triturated with water (30 mL) and then extracted with methylene chloride (100 mL x 2). The organic layer was separated, dried over anhydrous MgSO 4 , and then evaporated under vacuum to yield the crude product which was used for the next step without further purification.

General procedure for the synthesis of compounds 11a-11b
To a solution of NaOEt in absolute ethanol, made by dissolving sodium metal (27 mg, 1.19 mmoles) in absolute ethanol (20 mL), guanidine hydrochloride (0.11 g, 1.19 mmoles) was added in one portion and stirred at room temperature for one hour. The appropriate 3-(dimethylamino)-1-(6-(substituted)pyridin-3-yl)prop-2-en-1-one 10a or 10b (1.19 mmoles) was dissolved in absolute ethanol (10 mL) and added to the reaction mixture. The mixture was heated under reflux for 5 hours, and was then left to cool at room temperature, followed by cooling in an ice bath. The formed product was separated by filtration, washed with cold ethanol (20 mL), then with water (50 mL), and left to dry.