Regioselective, Solvent-Free Synthesis of 3-Aminoimidazo[1,2-a]pyrimidines Under Microwave Irradiation Promoted by Zeolite HY

 

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Abstract

Microwave-assisted, solvent-free condensation of 2-aminopyrimidine with aldehydes and isonitriles gave the desired 3-aminoimidazo[1,2-a]pyrimidine products with good to excellent regioselectivity. A hydrogen zeolite (‘zeolite HY’) was found to be a novel and effective promoter for the reaction, generally leading to clean conversion and also permitting use of the normally unreactive 4,6-dimethyl-2-aminopyrimidine.

References and Notes

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The amount of montmorillonite K-10 added proved important; too little gave low conversion, whereas too much resulted in more side reactions and lower isolated yields.

Zeolite Y, hydrogen form, also known as zeolite HY; purchased from Zeolyst International (product ref. CBV400).

CCDC-693378 (7a), CCDC-693379 (8a) and CCDC-693380 (10) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request_cif.

2-(Trifluoromethyl)benzyl isocyanide and 2-(thiophen-2-yl)ethyl isocyanide were prepared from the requisite amines using a known procedure. [¹4] Representative experimental procedures for each of the two methods described (Table  [¹] ) are detailed below.
2-(4-Methoxyphenyl)- N -(2,4,4-trimethylpentan-2-yl)-imidazo[1,2- a ]pyrimidin-3-amine (3a): Method A:
2-Aminopyrimidine (951 mg, 10 mmol), zeolite HY [¹¹] (500 mg) and p-anisaldehyde (1.22 mL, 1.36 g, 10 mmol) were mixed in a 100-mL round-bottomed flask, which was supported in a sand bath and placed inside a household microwave oven (800 W power rating). The mixture was irradiated at full power for 3 × 30 s intervals with a 30 s cooling period between heating, during which the flask was swirled gently to allow good mixing of the reagents. Once preformation of the imine was complete, Walborsky’s reagent (1.75 mL, 1.39 g, 10 mmol) was added and irradiation was continued for an additional 4 × 30 s intervals, again allowing a brief cooling period between each and ensuring efficient mixing. After the reaction, the material was cooled to r.t. and taken up in CH₂Cl₂. The suspension was filtered to remove the zeolite, washed with sat. aq NaHCO₃, dried over MgSO₄ and evaporated. Purification was carried out by flash column chromatography on basic alumina, [¹5] eluted with ethyl acetate-toluene mixture (20:80 → 33:67 → 50:50 → 33:67 → 0:100) then 1% MeOH-CH₂Cl₂, to provide firstly 3b (orange oil; 33 mg, 0.9%), [¹6] followed by 3a (thick brown gum, crystallised on standing; 1.71 g, 49%). [¹7] An analytically pure sample was obtained by recrystallisation from CHCl₃-cyclohexane, as was also the case for other examples.
Method B: Carried out as for method A, with the exception that after addition of Walborsky’s reagent (1.75 mL, 1.39 g, 10 mmol), heating was continued for 8 × 30 s intervals at 50% of full power, still allowing a brief cooling period between each and ensuring efficient mixing. After workup and purification as above, 3b (85 mg, 2.4%) and 3a (1.55 g, 44%) were obtained.
2-Phenyl- N -[2-(trifluoromethyl)benzyl]imidazo[1,2- a ]pyrimidin-3-amine (7a) by Direct Crystallisation: Imine preformation using 2-aminopyrimidine (792 mg, 8.33 mmol), zeolite HY (420 mg) and benzaldehyde (1.02 mL, 1.06 g, 10 mmol) was carried out as per method A above. 2-(Trifluoromethyl)benzyl isocyanide (1.85 g, 10 mmol) was added, and heating was continued as detailed in method A. After the reaction, and cooling to r.t., the material was taken up in a small volume (ca. 10 mL) of CH₂Cl₂ and the suspension was filtered to remove the zeolite. After washing through the sinter with a little extra CH₂Cl₂, hexane was added slowly until precipitation commenced. Once crystallisation was complete, the product was collected by filtration and dried to afford 7a as golden brown needles (1.01 g, 33%). [¹8]

Due to their acid sensitivity, compounds containing the 1,1,3,3-tetramethylbutyl group were best columned on basic (2, 3, 5, 6, 9, 10) or neutral (4) alumina, rather than silica, which was suitable for the other examples (7, 8).

3-(4-Methoxyphenyl)- N -(2,4,4-trimethylpentan-2-yl)imidazo[1,2- a ]pyrimidin-2-amine (3b): ^¹H NMR (400 MHz, CDCl₃): δ = 8.19-8.25 (m, 2 H), 7.39 (d, 2 H, J = 8.5 Hz), 7.09 (d, 2 H, J = 8.5 Hz), 6.67-6.72 (m, 1 H), 4.19 (s, 1 H), 3.90 (s, 3 H), 1.91 (s, 2 H), 1.58 (s, 6 H), 1.00 (s, 9 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.1, 151.1, 146.1, 144.1, 129.8, 126.5, 120.9, 115.3, 107.4, 102.9, 56.1, 55.4, 53.0, 31.8, 31.7, 30.2. IR (solid): 3259, 2946, 2899, 1605, 1564, 1246, 1231, 1189, 1174, 836, 758, 587 cm^-¹. MS (ES): m/z = 353 [M + H]⁺. HRMS: m/z [M + H]⁺ calcd for C₂₁H₂₉N₄O: 353.2341; found: 353.2348.

2-(4-Methoxyphenyl)- N -(2,4,4-trimethylpentan-2-yl)imidazo[1,2- a ]pyrimidin-3-amine (3a): ^¹H NMR (400 MHz, CDCl₃): δ = 8.58 (dd, 1 H, J = 1.5, 6.5 Hz), 8.48-8.51 (m, 1 H), 7.89 (d, 2 H, J = 8.5 Hz), 6.98 (d, 2 H, J = 8.5 Hz), 6.87 (dd, 1 H, J = 4.5, 6.5 Hz), 3.87 (s, 3 H), 3.40 (s, 1 H), 1.60 (s, 2 H), 1.05 (s, 9 H), 0.98 (s, 6 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 159.5, 149.3, 144.8, 140.9, 131.1, 129.9, 126.8, 121.2, 113.8, 107.9, 60.9, 57.0, 55.3, 31.8, 31.7, 29.0. IR (solid): 3235, 2924, 2849, 1615, 1504, 1245, 1204, 1030, 786, 764, 498, 485 cm^-¹. MS (ES): m/z = 353 [M + H]⁺. HRMS: m/z [M + H]⁺ calcd for C₂₁H₂₉N₄O: 353.2341; found: 353.2333.

2-Phenyl- N -[2-(trifluoromethyl)benzyl]imidazo[1,2- a ]pyrimidin-3-amine (7a): ^¹H NMR (400 MHz, CDCl₃): δ = 8.45 (dd, 1 H, J = 2.0, 4.0 Hz), 8.12 (dd, 1 H, J = 2.0, 6.5 Hz), 8.01-8.06 (m, 2 H), 7.64-7.69 (m, 1 H), 7.40-7.46 (m, 2 H), 7.31-7.39 (m, 3 H), 7.19-7.24 (m, 1 H), 6.75 (dd, 1 H, J =  4.0, 6.5 Hz), 4.34 (d, 2 H, J = 6.5 Hz), 3.71 (t, 1 H, J =6.5 Hz). ^¹³C NMR (100 MHz, CDCl₃): δ = 149.4, 144.6, 138.2, 137.0, 133.3, 132.2, 131.1, 129.8, 128.6, 128.3 (q, J = 31.5 Hz), 128.0, 127.9, 127.3, 126.3 (q, J = 5.5 Hz), 124.5 (q, J = 270 Hz), 123.2, 108.2, 49.0. ^¹9F NMR (235 MHz, CDCl₃): δ = -58.8 (s). IR (solid): 3248, 1612, 1500, 1309, 1116, 762, 692 cm^-¹. MS (ES): m/z = 369 [M + H]⁺. HRMS: m/z [M + H]⁺ calcd for C₂₀H₁₆F₃N₄: 369.1327; found: 369.1331.