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.

Key words

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

References and Notes

• 1a Modern Acetylene Chemistry   Stang PJ. Diederich F. VCH; Weinheim: 1995. 
• 1b Chemistry of Triple-Bonded Functional Groups   Patai S. Wiley; New York: 1994. 
• 2a Takeda A. Kamijo S. Yamamoto Y. J. Am. Chem. Soc.  2000,  122:  5662 
• 2b Gabriele B. Salerno G. Fazio A. Org. Lett.  2000,  2:  351 
• 2c Arcadi A. Cacchi S. Del Rosario M. Fabrizi G. Marinelli F. J. Org. Chem.  1996,  61:  9280 
• 2d Cacchi S. Fabrizi G. Moro L. Tetrahedron Lett.  1998,  39:  5101 
• 3a Roesh KR. Larock RC. Org. Lett.  1999,  1:  553 
• 3b Roesh KR. Larock RC. J. Org. Chem.  2002,  67:  86 
• 3c Dai G. Larock RC. Org. Lett.  2001,  3:  4035 
• 3d Dai G. Larock RC. Org. Lett.  2002,  4:  193 
• 3e Zhang H. Larock RC. J. Org. Chem.  2002,  67:  7048 
• 4a Huang Q. Hunter JA. Larock RC. Org. Lett.  2001,  3:  2973 
• 4b Huang Q. Hunter JA. Larock RC. J. Org. Chem.  2002,  67:  3437 
• 5a Susvilo I. Brukstus A. Tumkevicius S. Synlett  2003,  1151 
• 5b Tumkevicius S. Susvilo I. Brukstus A. Chem. Heterocycl. Compd.  2004,  1546 
• 5c Cikotiene I. Morkunas M. Motiejaitis D. Rudys S. Brukstus A. Synlett  2008,  1693 
• 6 Cikotiene I. Pudziuvelyte E. Brukstus A. Tumkevicius S. Tetrahedron  2007,  63:  8145 
• 7a Raymond E. Faivre S. Armand JP. Drugs  2000,  60:  15 
• 7b Smaill JB. Palmer BD. Rewcastle GW. Denny WA. McNamara DJ. Dobrusin EM. Bridges AJ. Zhou H. Showalter HDH. Winters RT. Leopold WR. Fry DW. Nelson JM. Slintak V. Elliot WL. Roberts BJ. Vincent PW. Patmore SJ. J. Med. Chem.  1999,  42:  1803 

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.