An Efficient One-Pot Synthetic Method for 2,4-Disubstituted 7-Arylpyrido[4,3-d]pyrimidines from 2,4-Disubstituted 6-(Arylethynyl)pyrimidine-5-carbaldehydes and tert-Butylamine

Abstract

Unexpected thermal cyclization of 2,4-disubstituted 6-(aryl-ethynyl)pyrimidine-5-carbaldehydes with tert-butylamine proceeded to give 2,4-disubstituted 7-arylpyrido[4,3-d]pyrimidines in good yields in the absence of any catalysts. The intermediate compounds were isolated and possible mechanism of the reactions is discussed.

cyclization - alkynes - aldehydes - pyrido[4,3-d]pyrimi­dines - 1,6-electrocyclic reaction

References and Notes

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8

Typical Procedure for the Preparation of 2,4-Disub-stituted 7-Arylpyrido[4,3- d ]pyrimidines 2a-u
The mixture of the corresponding 2,4-disubstituted 6-(arylethynyl)pyrimidine-5-carbaldehyde 1a-u (0.2 mmol) and t-BuNH₂ (3 mL) in tube was flushed with argon, and the tube was carefully sealed. The mixture was heated at 110-120 ˚C for 24 h. The solvent was evaporated under reduced pressure, residue recrystallized to give compounds 2a-u.
2-(Methylthio)-4-morpholin-1-yl-7-phenylpyrido[4,3- d ]-pyrimidine (2b)
Yield 95%, mp 145-147 ˚C (from 2-PrOH). ^¹H NMR (300 MHz, CDCl₃): δ = 2.66 (3 H, s, SCH₃), 3.93 [4 H, t, J = 3.9 Hz, N(CH₂)₂], 4.01 [4 H, t, J = 3.9 Hz, O(CH₂)₂], 7.49-7.55 (3 H, m, ArH), 7.95 (1 H, s, CH), 8.13-8.16 (2 H, m, ArH), 9.27 (1 H, s, CH). ^¹³C NMR (75 Hz, CDCl₃): δ = 14.3, 49.8, 66.6, 108.9, 115.4, 127.1, 128.9, 129.6, 138.2, 149.0, 157.1, 157.9, 161.9, 172.2. Anal. Calcd for C₁₈H₁₈N₄OS: C, 63.88; H, 5.36; N, 16.56. Found: C, 63.96; H, 5.44; N, 16.70.
2-(Methylthio)-7-phenyl-4-piperidin-1-ylpyrido[4,3- d ]-pyrimidine (2c) Yield 85%, mp 126-128 ˚C (from 2-PrOH). ^¹H NMR (300 MHz, CDCl₃): δ = 1.84 [4 H, br s, (CH₂)₃], 2.65 (3 H, s, SCH₃), 3.94 [4 H, br s, N(CH₂)₂], 7.49-7.54 (3 H, m, ArH), 7.90 (1 H, s, CH), 8.13 (2 H, d, J = 6.9 Hz, ArH), 9.24 (1 H, s, CH). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 1.74 [4 H, br s, (CH₂)₃], 2.56 (3 H, s, SCH₃), 3.92 [4 H, br s, N(CH₂)₂], 7.49-7.54 (3 H, m, ArH), 7.94 (1 H, s, CH), 8.22-8.25 (2 H, m, ArH), 9.25 (1 H, s, CH). ^¹³C NMR (75 Hz, CDCl₃): δ = 14.2, 24.6, 26.0, 50.5, 115.3, 127.1, 128.8, 129.5, 138.4, 149.3, 157.2, 157.6, 161.7, 172.0. Anal. Calcd for C₁₉H₂₀N₄S: C, 67.83; H, 5.99; N, 16.65. Found: C, 67.90; H, 6.07; N, 16.59.
4- N , N -Dimethylamino-2-(methylthio)-7-phenylpyrido-[4,3- d ]pyrimidine (2f) Yield 92%, mp 155-156 ˚C (from 2-PrOH). ^¹H NMR (300 MHz, CDCl₃): δ = 2.65 (3 H, s, SCH₃), 3.51 [6 H, s, N(CH₃)₂], 7.49-7.53 (3 H, m, ArH), 7.90 (1 H, s, CH), 8.13 (2 H, d, J = 7.2 Hz, ArH), 9.41 (1 H, s, CH). ^¹³C NMR (75 Hz, CDCl₃): δ = 14.2, 41.8, 109.3, 115.3, 127.1, 128.8, 129.5, 138.4, 149.6, 157.2, 157.4, 160.8, 171.7. Anal. Calcd for C₁₆H₁₆N₄S: C, 64.84; H, 5.44; N, 18.90. Found: C, 64.79; H, 5.32; N, 18.99.
7-(4-Ethylphenyl)-2-(methylthio)-4-morpholin-1-yl-pyrido-[4,3- d ]pyrimidine (2l)
Yield 90%, mp 127-128 ˚C (from hexane). ^¹H NMR (300 MHz, CDCl₃): δ = 1.32 (3 H, t, J = 7.5 Hz, CH₃), 2.63 (3 H, s, SCH₃), 2.76 (2 H, q, J = 7.5 Hz, CH₂), 3.92 [4 H, t, J = 2.1 Hz, N(CH₂)₂], 3.96 [4 H, t, J = 2.1 Hz, O(CH₂)₂], 7.38 (2 H, d, J = 8.1 Hz, ArH), 7.72 (1 H, s, CH), 7.79 (2 H, d, J = 8.1 Hz, ArH), 9.04 (1 H, s, CH). ^¹³C NMR (75 Hz, CDCl₃): δ = 14.3, 15.4, 28.7, 49.8, 66.7, 108.8, 114.5, 127.1, 128.4, 135.6, 146.2, 148.9, 157.1, 158.0, 161.9, 172.1. Anal. Calcd for C₂₀H₂₂N₄OS: C, 65.55; H, 6.05; N, 15.29. Found: C, 65.76; H, 5.93; N, 15.44.

9

Typical Procedure for the Preparation of N -{4-[( Z )-2-( tert -butylamino)-2-phenylvinyl]-2-(methylthio)-pyrimidin-5-ylmethylene}-2-methylpropan-2-amines 3a-c
The mixture of the corresponding 2,4-disubstituted 6-(arylethynyl)pyrimidine-5-carbaldehyde 1a-c (0.2 mmol) and t-BuNH₂ (3 mL) in tube was flushed with argon, and the tube was carefully sealed. The mixture was heated at 80-90 ˚C for 20 h. The solvent was evaporated under reduced pressure, compounds 3a-c were isolated by column flash chromatography.
N -{4-( Z )-2-[( tert- butylamino)-2-phenylvinyl]-2-(methyl-thio)-6-morpholin-1-ylpyrimidin-5-ylmethylene}-2-methylpropan-2-amine (3b)
Yield 62%, mp 140-142 ˚C (from MeOH-H₂O); R _f  = 0.78 (toluene-EtOAc, 1:1). IR (KBr): 3442 (NH) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.19 (9 H, s, t-Bu), 1.22 (9 H, s, t-Bu), 2.57 (3 H, s, SCH₃), 3.46 [4 H, t, J = 4.2 Hz, N(CH₂)₂], 3.79 [4 H, t, J = 4.2 Hz, O(CH₂)₂], 6.17 (1 H, s, CH), 7.34-7.36 (3 H, m, ArH), 7.46-7.49 (2 H, m, ArH), 8.15 (1 H, s, CH), 10.08 (1 H, br s, NH). ^¹³C NMR (75 Hz, CDCl₃): δ = 13.9, 29.5, 32.1, 49.8, 53.9, 57.7, 66.8, 96.3, 105.5, 127.3, 128.2, 128.8, 140.9, 153.4, 160.6, 162.2, 164.2, 168.0. Anal. Calcd for C₂₆H₃₇N₅OS: C, 66.77; H, 7.97; N, 14.95. Found: C, 66.49; H, 8.08; N, 15.10.

10

N -{4-( Z )-2-[( tert -butylamino)-2-phenylvinyl]-2-(methyl-thio)-6-piperidin-1-ylpyrimidin-5-ylmethylene}-2-methylpropan-2-amine (3c) Yield 58%, mp 109-110 ˚C (from 2-PrOH); R _f  = 0.81 (toluene-EtOAc, 1:1). IR (KBr): 3443 (NH) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 1.17 (9 H, s, t-Bu), 1.23 (9 H, s, t-Bu), 1.65 [6 H, br s, (CH₂)₃], 2.57 (3 H, s, SCH₃), 3.41 [4 H, br s, N(CH₂)₂], 6.31 (1 H, s, CH), 7.32-7.34 (3 H, m, ArH), 7.48-7.51 (2 H, m, ArH), 8.07 (1 H, s, CH), 9.98 (1 H, br s, NH). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 1.09 (9 H, s, t-Bu), 1.14 (9 H, s, t-Bu), 1.61 [6 H, br s, (CH₂)₃], 2.52 (3 H, s, SCH₃), 3.37 [4 H, br s, N(CH₂)₂], 6.50 (1 H, s, CH), 7.40 (5 H, s, ArH), 7.99 (1 H, s, CH), 9.88 (1 H, br s, NH). ^¹³C NMR (75 Hz, CDCl₃): δ = 13.9, 24.6, 26.1, 29.6, 32.1, 50.5, 53.9, 57.5, 97.3, 105.5, 127.3, 128.0, 128.9, 141.3, 153.9, 160.1, 161.9, 164.8, 167.7. Anal. Calcd for C₂₇H₃₉N₅S: C, 69.63; H, 8.44; N, 15.04. Found: C, 69.42; H, 8.59; N, 15.19.

11

Typical Procedure for the Cyclization of N -{4-[( Z )-2-( tert -butylamino)-2-phenylvinyl]pyrimidin-5-yl-methylene}-2-methylpropan-2-amines 3a-c into4-Substituted 2-(Methylthio)-7-phenylpyrido[4,3- d ]-pyrimidines 2a-c
The solution of compounds 3a-c (2 mmol) in DMSO (2 mL) was heated at 110-120 ˚C for 15 min. After cooling, reaction mixture was diluted with H₂O (10 mL), precipitate collected by filtration and recrystallyzed to give compounds 2a-c.

12

Compounds 2a,d-e,g-k,m-u and 3a were also fully characterized by IR, ^¹H NMR, and ^¹³C NMR spectroscopic and microanalytical data.