Efficient One-Pot Synthesis of 6-Arylpyrrolo[3,2-d]pyrimidines from 6-Arylethynyl-5-nitropyrimidines

Abstract

A highly concise one-pot synthesis of 6-arylpyrrolo[3,2-d]pyrimidines via conjugative addition reaction of secondary amines to 6-arylethynyl-5-nitropyrimidines and subsequent reduction is described.

Key words

pyrrolo[3,2-d]pyrimidines - 6-arylethynyl-5-nitropy­rimi­dines - enamines - cyclization

References and Notes

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11

Typical Procedure for the Preparation of 2,4-Disubstituted 6-Arylpyrrolo[3,2- d ]pyrimidines 4a-o To a solution of the corresponding 6-arylethynyl-5-nitro­-pyrimidine 1a-p (0.3 mmol) in MeOH (5 mL) freshly distilled Et₂NH (21,9 mg, 0.3 mmol) was added. The resulting reaction mixture was refluxed for 15 min, then deeply red solution was cooled to r.t., 10% Pd/C (0.33 mg, 0.03 mmol) was added, and the resulted mixture was stirred under H₂ atmosphere for 2 h. After the completion of the reaction, the catalyst was filtered off, the mother liquid was evaporated under reduced pressure, the residue washed with H₂O, filtered, and recrystallized to give compounds 4a-p.
4-Amino-6-phenylpyrrolo[3,2- d ]pyrimidine (4a)
Yield 98%; mp 226-227 ˚C (from DMF-H₂O). IR (KBr): ν_max = 3444, 3441, 3396 (NH, NH₂) cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 6.81 (br s, 2 H, NH₂), 6.86 (s, 1 H, C7H), 7.38 (t, J = 7.5 Hz, 1 H, ArH), 7.51 (t, J = 7.5 Hz, 2 H, ArH), 7.87 (d, J = 7.5 Hz, 2 H, ArH), 8.11 (s, 1 H, C2H), 11.64 (br s, 1 H, NH) ppm. ^¹³C NMR (75 Hz, DMSO-d ₆): δ = 98.6, 114.7, 125.1, 128.3, 129.0, 131.1, 131.4, 139.4, 150.2, 150.7 ppm. Anal. Calcd for C₁₂H₁₀N₄: C, 68.56; H, 4.79; N, 26.65. Found: C, 68.37; H, 4.51; N, 26.88.
4-Amino-2-methylthio-6-phenylpyrrolo[3,2- d ]pyrimi-dine (4e)
Yield 82%; mp 235-237 ˚C (from DMF-H₂O). IR (KBr): ν_max = 3446, 3443, 3398 (NH, NH₂) cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 2.45 (s, 3 H, SCH₃), 6.77 (s, 1 H, C7H), 7.14 (br s, 2 H, NH₂), 7.36 (t, J = 7.5 Hz, 1 H, ArH), 7.49 (t, J = 7.5 Hz, 2 H, ArH), 7.91 (d, J = 7.5 Hz, 2 H, ArH), 12.19 (br s, 1 H, NH) ppm. ^¹³C NMR (75 Hz, DMSO-d ₆): δ = 13.4, 98.8, 112.9, 125.2, 127.4, 128.1, 131.5, 139.5, 148.8, 150.3, 160.6 ppm. Anal. Calcd for C₁₃H₁₂N₄S: C, 60.91; H, 4.72; N, 21.86. Found: C, 60.77; H, 4.66; N, 21.99.
4-Morpholino-6-phenylpyrrolo[3,2- d ]pyrimidine (4p)
Yield 88%; mp >230 ˚C (dec.; from MeOH). IR (KBr): ν_max = 3341 (NH) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 3.87 (br s, 8 H, morpholino), 6.86 (s, 1 H, C7H), 7.41-7.48 (m, 3 H, ArH), 7.72 (d, J = 7.2 Hz, 2 H, ArH), 8.52 (s, 1 H, C2H), 9.23 (br s, 1 H, NH) ppm. ^¹³C NMR (75 Hz, CDCl₃): δ = 46.8, 66.6, 100.9, 116.4, 125.9, 129.1, 129.2, 131.2, 142.1, 150.8, 150.9, 151.4 ppm. Anal. Calcd for C₁₆H₁₆N₄O: C, 68.55; H, 5.75; N, 19.99. Found: C, 68.50; H, 5.66; N, 20.08.

12

Compounds 4b-d,f-o and 5a were also fully characterized by IR, ^¹H NMR, ^¹³C NMR spectroscopic and microanalytical data.