The First Synthesis of Novel 7-Oxo-7H-pyrrolo[3,2-d]pyrimidine 5-Oxides from 1-(5-Nitro-6-pyrimidinyl)-2-arylacetylenes

Abstract

Palladium-catalysed reaction of 4-amino-6-chloro-5-nitropyrimidine with arylacetylenes affords the corresponding 1-(4-amino-5-nitro-6-pyrimidinyl)-2-arylacetylenes, which in dry pyridine undergo smooth cyclisation to give 4-amino-6-aryl-7-oxo-7H-pyrrolo[2,3-d]pyrimidine 5-oxides in excellent yields.

catalysis - cyclisation - palladium - pyrimidines - pyrrolopyrimidines

References

<A NAME="RD03603ST-1A">1a</A> Montgomery JA. Niwas S. Rose JD. Secrist JA. Babu YS. Bugg CE. Erion MD. Guida WC. Ealick SE. J. Med. Chem.  1993,  36:  55 

<A NAME="RD03603ST-1B">1b</A> Farutin V. Masterson L. Andricopulo AD. Cheng J. Riley B. Hakimi R. Frazer JW. Cordes EH. J. Med. Chem.  1999,  42:  2422 

<A NAME="RD03603ST-1C">1c</A> Miles RW. Tyler PC. Furneaux RH. Bagdassarian CK. Schramm VL. Biochemistry  1998,  37:  8615 

<A NAME="RD03603ST-2">2</A> Bavetsias V. Jackman AL. Curr. Med. Chem.  1998,  5:  265 

<A NAME="RD03603ST-3">3</A> Norman MH. Chen N. Chen ZD. Fotsch C. Hale C. Han NH. Hurt R. Jenkins T. Kincaid J. Liu LB. Lu YL. Moreno O. Santora VJ. Sonnenberg JD. Karbon W. J. Med. Chem.  2000,  43:  4288 

<A NAME="RD03603ST-4">4</A> Grahner B. Winiwarter S. Lanzner W. Muller CE. J. Med. Chem.  1994,  37:  1526 

<A NAME="RD03603ST-5A">5a</A> Pfleiderer M. Chem. Ber.  1957,  90:  738 

<A NAME="RD03603ST-5B">5b</A> Kawahara N. Nakajima T. Itoh T. Ogura H. Chem. Pharm. Bull.  1985,  33:  4740 

<A NAME="RD03603ST-5C">5c</A> Sizova OS. Glushkov RG. Pharm. Chem. J.  1984,  18:  420 

<A NAME="RD03603ST-5D">5d</A> Brahta M. Daves GD. J. Chem. Soc., Perkin Trans. 1  1992,  1883 

<A NAME="RD03603ST-5E">5e</A> Sakamoto T. Satoh C. Kondo Y. Yamanaka H. Chem. Pharm. Bull.  1993,  41:  81 

<A NAME="RD03603ST-5F">5f</A> Okamoto Y. Takagi K. Takada A. Ueda T. J. Org. Chem.  1984,  49:  908 

<A NAME="RD03603ST-5G">5g</A> Majumdar KC. Das U. Jana NK. J. Org. Chem.  1998,  63:  3550 

<A NAME="RD03603ST-5H">5h</A> De Jong RL. Davidso JG. Dozeman GJ. Fiore PJ. Giri P. Kelly ME. Puls TP. Seamans RE. Org. Process Res. Dev.  2001,  5:  216 

<A NAME="RD03603ST-6">6</A> Rodriguez AL. Koradin C. Dohle N. Knochel P. Angew. Chem. Int. Ed.  2000,  39:  2488 

<A NAME="RD03603ST-7A">7a</A> Cupps TL. Wise DS. Townsend LB. J. Org. Chem.  1983,  48:  1060 

<A NAME="RD03603ST-7B">7b</A> Tkachenko JN. Tsupak EB. Posharskij AF. Khim. Geterotsikl. Soed.  2000,  368 

<A NAME="RD03603ST-7C">7c</A> Cupps TL. Wise DS. Townsend LB. Tetrahedron Lett.  1982,  23:  4759 

<A NAME="RD03603ST-7D">7d</A> Otmar M. Masojidkova M. Holy A. Collect. Czech. Chem. Commun.  1996,  61:  49 

<A NAME="RD03603ST-7E">7e</A> Otmar M. Masojidkova M. Budesinsky M. Holy A. Tetrahedron  1998,  54:  2931 

<A NAME="RD03603ST-7F">7f</A> Evans GB. Furneaux RH. Hutchison TL. Kezar HS. Morris PE. Schramm LT. Tyler PC. J. Org. Chem.  2001,  66:  5723 

<A NAME="RD03603ST-8A">8a</A> Tumkevicius S. Agrofoglio LA. Kaminskas A. Urbelis G. Zevaco TA. Walter O. Tetrahedron Lett.  2002,  43:  695 

<A NAME="RD03603ST-8B">8b</A> Tumkevicius S. Kaminskas A. Kulbokaite J. J. Chem. Res., Synop.  2000,  287 

<A NAME="RD03603ST-8C">8c</A> Kaminskas A. Dailide M. Tumkevicius S. Polish J. Chem.  2002,  76:  725 

<A NAME="RD03603ST-9A">9a</A> Nepveu R. Souchard J.-P. Rolland Y. Dorey G. Spedding M. Biochem. Biophys. Res. Commun.  1998,  242:  272 

<A NAME="RD03603ST-9B">9b</A> Rosen GM. Tsai P. Barth ED. Dorey G. Casara P. Spedding M. Halpern HJ. J. Org. Chem.  2000,  65:  4460 

<A NAME="RD03603ST-9C">9c</A> Genisson VB. Bouniol A.-V. Nepveu F. Synlett  2001,  700 

<A NAME="RD03603ST-10">10</A> Boon WR. Jones GM. Ramage GR. J. Chem. Soc.  1951,  96 

<A NAME="RD03603ST-11">11</A>

Typical Procedure for the Preparation of 1-(4-amino-5-nitro-6-pyrimidinyl)-2-arylacetylenes 2a-c. A mixture of compound 1 (0.2 g, 1.15 mmol), PdCl₂(PPh₃)₂ (0.016 g, 0.023 mmol), CuI (0.0022 g, 0.0115 mmol) and dry Et₃N (10 mL) was stirred under Ar atmosphere for 1 min. Then the corresponding arylacetylene (1.38 mmol) was added, the mixture was flushed with Ar and heated under stirring at 40 °C for 3 h. After cooling to r.t. the precipitate was filtered off and recrystallised to give compounds 2a-c.
Compound 2a: Yield 75%, mp 158-160 °C (from 1-butanol). IR (nujol): ν_max = 3358, 3286 (NH₂), 2214 (C≡C), 1582 (NO₂) cm^-1. ¹H NMR (CDCl₃): δ = 1.42 (2 H, br s, NH₂), 7.31-7.89 (5 H, m, Ar-H), 8.62 (1 H, s, C₂H). ¹³C NMR (DMSO-d ₆): δ = 84.6, 84.9, 97.6, 120.1, 128.9 (2 C), 130.6, 132.1 (2 C), 144.03, 155.9, 159.1. MS: m/z (%) = 240 (26) [M⁺]. Anal. Calcd for C₁₂H₈N₄O₂: C, 60.00; H, 3.36; N, 23.32. Found: C, 60.19; H, 3.32; N, 23.60.
Compound 2b: Yield 89%, mp 175-177 °C (from EtOH). IR (nujol): ν_max = 3457, 3314 (NH₂), 2210 (C≡C), 1574 (NO₂) cm^-1. ¹H NMR (DMSO-d ₆): δ = 2.38 (3 H, s, CH₃), 7.32 (2 H, d, J = 8 Hz, Ar-H), 7.52 (2 H, d, J = 8 Hz, Ar-H), 8.33 (2 H, br s, NH₂), 8.56 (1 H, s, C₂H). MS: m/z (%) = 254(48) [M⁺]. Anal. Calcd for C₁₃H₁₀N₄O₂: C, 61.41; H, 3.96; N, 22.04. Found: C, 61.52; H, 4.0; N, 21.99.
Compound 2c: Yield 68%, mp 160-162 °C (from 2-PrOH). IR(nujol): ν_max = 3430, 3380 (NH₂), 2211 (C≡C), 1578 (NO₂) cm^-1. ¹H NMR (CDCl₃): δ = 1.64 (2 H, br s, NH₂), 6.89-7.31 (2 H, m, Ar-H), 7.40-7.93 (2 H, m, Ar-H), 8.64 (1 H, s, C₂H). Anal. Calcd for C₁₂H₇FN₄O₂: C, 55.82; H, 2.73; N, 21.70. Found: C, 55.89; H, 2.68; N, 21.86.

<A NAME="RD03603ST-12">12</A>

Typical Procedure for the Preparation of 4-Amino-6-aryl-7-oxo-7 H -pyrrolo[3,2- d ]pyrimidine 5-oxides 3a-c. A solution of the corresponding 2a-c (1 mmol) in dry pyridine (5 mL) was refluxed for 15 min. After cooling to r.t. the precipitate was filtered off, the filtrate was concentrated under reduced pressure. The precipitate was combined with the earlier obtained and recrystallised to give compounds 3a-c as dark violet solids.
Compound 3a: Yield 95%, mp>250 °C (dec.) (from toluene). IR (nujol): ν_max = 3328, 3237 (NH₂), 1724 (CO)
cm^-1. ¹H NMR (DMSO-d ₆): δ = 7.41-8.52 (5 H, m, Ar-H), 7.72 (1 H, br s, NH), 8.22 (1 H, br s, NH), 9.61 (1 H, s, C₂H). ¹³C NMR (DMSO-d ₆): δ = 122.0, 125.4, 126.9 (2 C), 128.4 (2 C), 130.0, 149.0, 151.4 (2 C), 160.5, 186.3. MS: m/z
(%) = 240 (96) [M⁺]. Anal. Calcd for C₁₂H₈N₄O₂: C, 60.00; H, 3.36; N, 23.32. Found: C, 60.26; H, 3.29; N, 23.35.
Compound 3b: Yield 90%, mp>250 °C (dec.) (from toluene). IR (nujol): ν_max = 3363, 3231 (NH₂), 1728 (CO)
cm^-1. ¹H NMR (DMSO-d ₆): δ = 2.4 (3 H, s, CH₃), 7.41 (2 H, d, J = 8 Hz, Ar-H), 7.43 (1 H, br s, NH), 8.31 (1 H, br s, NH), 8.38 (2 H, d, J = 8 Hz, Ar-H), 8.74 (1 H, s, C₂H). MS: m/z (%) = 254 (33) [M⁺]. Anal. Calcd for C₁₃H₁₀N₄O₂: C, 61.41; H, 3.96; N, 22.04. Found: C, 61.45; H, 3.98; N, 22.09.
Compound 3c: Yield 87%, mp>250 °C (dec.) (from toluene). IR (nujol): ν_max = 3330, 3245 (NH₂), 1727 (CO)
cm^-1. ¹H NMR (DMSO-d ₆): δ = 6.93 (1 H, br s, NH), 7.71 (1 H, br s, NH), 6.86-7.87 (4 H, m, Ar-H), 8.58 (1 H, s, C₂H). Anal. Calcd for C₁₂H₇FN₄O₂: C, 55.82; H, 2.73; N, 21.70. Found: C, 55.79; H, 2.66; N, 21.65.