Covalent analogues of DNA base-pairs and triplets IV+. Synthesis of trisubstituted benzenes bearing purine and[s]or pyrimidine rings by cyclotrimerization of 6-ethynylpurines and[s]or 5-ethynyl-1,3-dimethyluracil

(C-6-PuC); 158.13 (C-6-PuA); 158.77 (C-6-PuB). FAB HRMS, found: 685.3128; C36H37N12O3

[M + H] requires: 685.3112.

1,3,5-Tris[9-(tetrahydropyran-2-yl)purin-6-yl]benzene (8b). Yellow amorphous solid. FAB MS, m/z (rel.%): 685 (27) [M + H], 601 (12) [M + H – THP], 517 (13) [M + 2 H – 2 THP], 433 (100) [M + 3 H – 3 THP]. 1H NMR (400 MHz, CDCl3): 1.65–2.22 (m, 18 H, CH2); 3.84 (dt, 3 H, J = 2.2, 11.5, CH2Oa); 4.22 (d, 3 H, J = 11.3, CH2Ob); 5.90 (dd, 3 H, J = 10.2, 2.4,

OCHN); 8.43 (s, 3 H, H-8-Pu); 9.15 (s, 3 H, H-2-Pu); 10.36 (s, 3 H, H-benzene).13C NMR (100 MHz, APT, CDCl3): 23.54, 25.64, 32.65 (3 × CH2); 69.55 (CH2O); 82.77 (OCHN); 132.21 (C-5-Pu); 134.51 (CH-benzene); 137.51 (C-benzene); 143.29 (C-8-Pu); 152.62 (C-6-Pu);

153.33 (C-2-Pu); 155.13 (C-4-Pu). FAB HRMS, found: 685.3135; C36H37N12O3 [M + H] requires: 685.3112.

1,3,4-Tris(9-methylpurin-6-yl)benzene (7c). Yellowish powder; m.p. 195–199 °C (EtOH/ toluene). EI MS, m/z (rel.%): 474 (18) [M], 446 (17), 210 (15), 129 (35), 57 (100). 1H NMR (500 MHz, CDCl3): 3.87 (s, 6 H, CH3); 3.95 (s, 3 H, CH3); 7.91 (d, 1 H, J = 9.5, H-benzene); 8.12, 8.20, 8.67, 8.72, 9.07, 9.59 (6 × s, 6 × 1 H, H-Pu); 8.43 (d, 1 H, J = 7.9, H-benzene); 9.16–9.21 (m, 1 H, H-benzene). 13C NMR (100 MHz, CDCl3): 29.74, 29.86 (CH3); 131.15, 132.57, 133.23 (CH-benzene); 131.32, 131.88, 131.93 (C-5-Pu); 136.14, 136.96, 137.81 (C-benzene); 144.97, 145.17, 145.36 (CH-8-Pu); 151.85, 151.93, 152.45 (CH-2-Pu); 152.01, 152.09, 153.03, 153.46, 157.30, 157.89 (C-4 and C-6). EI HRMS, found: 474.1759; C24H18N12 [M] requires: 474.1777.

1,2,4-Tris(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)benzene (9). Obtained in 43% yield from 4 (reaction time 12 h). Yellow amorphous solid. FAB MS, m/z (rel.%): 493 (21) [M + H], 279 (30), 75 (100). 1H NMR (500 MHz, CDCl3): 3.25 (s, 3 H); 3.29 (s, 3 H);

3.30 (s, 3 H); 3.32 (s, 6 H); 3.40 (s, 3 H, all CH3); 7.30 (d, 1 H, J = 7.8, H-arom.); 7.51 (s, 1 H, H-6-U); 7.60–7.64 (m, 3 H, 2 × H-arom. and H-6-U); 8.05 (s, 1 H, H-6-U). 13C NMR

(125.8 MHz, CDCl3): 27.63, 27.72, 36.30, 36.32, 36.47 (all CH3); 110.73, 111.86, 112.21, 132.45, 132.73, 133.39, 150.87, 151.09, 161.54, 161.60, 161.66 (C-arom.); 127.03, 130.29, 130.66, 142.64, 142.85 (CH-arom.). FAB HRMS, found: 493.1864; C24H25N6O6 [M+H] requires: 493.1836.

Co-cyclotrimerization of 3a and 4

Co-cyclotrimerization of 3a (234 mg, 1 mmol) and 4 (164 mg, 1 mmol) in presence of Ni(COD)2 and PPh3 was performed in the same way as described above (method A). A column chromatography gave 7a (59 mg, 25%), unreacted 4 (49 mg, 30%) and a complex mixture of other products which was re-chromatographed to give compound 10 (16 mg, 5%).

1,2-Bis(9-benzylpurin-6-yl)-4-(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)benzene

(10). Yellowish amorphous solid. FAB MS, m/z (rel.%): 633 (9) [M + H], 279 (12), 91 (100). 1H NMR (500 MHz, CDCl3): 3.43, 3.48 (2 × s, 2 × 3 H, CH3-U); 5.39 (s, 4 H, CH2Ph); 7.25–36 (m, 10 H, H-arom.); 7.54 (s, 1 H, H-6-U); 7.83, 7.85 (2 × s , 2 × 1 H, H-8-Pu); 7.95 (dd, 1 H, J = 8.2, 1.3, H-5-benzene); 8.29 (d, 2 H, J = 8.2, H-6-benzene); 8.31 (d, 2 H, J = 1.3, H-3-benzene); 8.65, 8.70 (2 × s, 2 × 1 H, H-2-Pu). 13C NMR (125.8 MHz, CDCl3): 28.28, 37.20 (CH3); 47.19 (CH2Ph); 113.23 (C-5-U); 127.73, 128.52, 129.09 (CH-arom.-Bn); 129.53 (C-5-benzene); 131.32 (C-3-benzene); 131.77 (C-5-Pu); 134.52, 135.00, 135.21, 135.91 (C-arom.); 141.19 (CH-6-U); 144.12 (CH-8-Pu); 151.71 (C=O-2-U and C-4-Pu); 152.01 (CH-2-Pu); 157.42, 157.85 (C-6-Pu); 161.97 (C=O-4-U). FAB HRMS, found: 633.2457; C36H29N10O2 [M + H] requires: 633.2475.

Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1,2,4-Tris(purin-6-yl)benzene (7e)

Dowex 50X8 (H+ form, 50 mg) was added to a solution of compound 7b (120 mg, 0.18 mmol) in 96% aqueous EtOH (20 ml) and the mixture was refluxed for 3 h (TLC showed completion of the reaction). Then the resin was filtered off and washed with hot EtOH (20 ml), saturated ethanolic ammonia (10 ml) and EtOH (10 ml). The collected filtrates were evaporated and the residue crystallized from EtOH. Yield 70 mg (90%). White microcrystals; m.p. 319–322 °C. FAB MS, m/z (rel.%): 433 (100) [M + H]. 1H NMR (500 MHz, DMSO-d6): 8.36 (d, 1 H, J = 8.1, H-6′′); 8.40 (s, 1 H, H-8A); 8.45 (s, 1 H, H-8B); 8.51 (s, 1 H,

H-2A); 8.59 (s, 1 H, H-8C); 8.61 (s, 1 H, H-2B); 8.97 (s, 1 H, H-8C); 9.21 (dd, 1 H, J = 1.3, 8.1, H-5′′); 9.50 (d, 1 H, J = 1.2, H-3′′). 13C NMR (125 MHz, DMSO-d6): 129.27 (C-5A,B);

129.85 (C-5′′); 130.64 (C-5C); 132.00 (C-6′′); 132.19 (C-3′′); 136.29 (C-2′′); 137.09 (C-1′′);

137.51 (C-4′′); 145.46 (C-8A); 145.74 (C-8B); 148.12 (C-8C); 149.80 (C-6C); 150.86 (C-2A);

151.10 (C-2B,C); 154.27 (C-6A); 154.61 (C-4A); 154.85 (C-4B); 155.12 (C-6B); 156.46 (C-4C). For C21H12N21·2EtOH (524.5) calculated: 57.24% C, 4.61% H, 32.04% N; found: 57.37% C, 4.25% H, 31.78% N. FAB HRMS, found: 433.1337; C21H13N12 [M + H] requires: 433.1386.

This work is a part of a research project Z4 055 905. It was supported by the Grant Agency of the Czech Republic (grants No. 203/00/0036 to M. H. and No. 203/02/0248 to I. S.). The cytostatic activity was studied by Dr I. Votruba whose contribution is gratefully acknowledged. The authors’ thanks are also due to Ms K. Havlíčková for excellent technical assistance.

REFERENCES

1.Review: Rajski S. R., Williams R. M.: Chem. Rev. (Washington, D. C.) 1998, 98, 2723.

2.Review: Baguley B. C.: Anti-Cancer Drug. Des. 1991, 3, 1.

3.Bhat B., Leonard N. J., Robinson H., Wang A. H. J.: J. Am. Chem. Soc. 1996, 118, 10744; and references therein.

4.a) Nagatsugi F., Uemura K., Nakashima S., Maeda M., Sasaki S.: Tetrahedron Lett. 1995, 36, 421; b) Nagatsugi F., Uemura K., Nakashima S., Maeda M., Sasaki S.: Tetrahedron 1997, 53, 3035; c) Nagatsugi F., Kawasaki T., Usui D., Maeda M., Sasaki S.: J. Am. Chem. Soc. 1999, 121, 6753; d) Nagatsugi F., Usui D., Kawasaki T., Maeda M., Sasaki S.: Bioorg. Med. Chem. Lett. 2001, 11, 343.

5.a) Quiao X., Kishi Y.: Angew. Chem., Int. Ed. 1999, 38, 928; b) Qiu Y. L., Li H. Y., Topalov G., Kishi Y.: Tetrahedron Lett. 2000, 41, 9425; c) Li H. Y., Qiu Y. L., Moyroud E., Kishi Y.: Angew. Chem., Int. Ed. 2001, 40, 1471; d) Li H. Y., Qiu Y. L., Kishi Y.:

ChemBioChem 2001, 2, 371.

6.a) Ogawa A. K., Abou-Zied O. K., Tsui V., Jimenez R., Case D. A., Romesberg F. E.: J. Am. Chem. Soc. 2000, 122, 9917; b) Abou-Zied O. K., Jimenez R., Romesberg F. E.: J. Am. Chem. Soc. 2001, 123, 4613.

7.De Riccardis F., Johnson F.: Org. Lett. 2000, 2, 293.

8.Hocek M., Votruba I.: Bioorg. Med. Chem. Lett. 2002, 12, 1055.

9.Havelková M., Dvořák D., Hocek M.: Tetrahedron 2002, 58, 7431.

10.a) Hocek M., Holý A., Votruba I., Dvořáková H.: J. Med. Chem. 2000, 43, 1817; b) Hocek M., Holý A., Votruba I., Dvořáková H.: Collect. Czech. Chem. Commun. 2000, 65, 1683; c) Hocek M., Holý A., Votruba I., Dvořáková H.: Collect. Czech. Chem. Commun.

Collect. Czech. Chem. Commun. (Vol. 67) (2002)

2001, 66, 483; d) Hocek M., Holý A., Dvořáková H.: Collect. Czech. Chem. Commun.

2002, 67, 325.

11.Hocek M., Stará I. G., Starý I., Dvořáková H.: Tetrahedron Lett. 2001, 42, 519.

12.Tanji K., Higashino T.: Chem. Pharm. Bull. 1988, 36, 1935.

13.Hirota K., Kitade Y., Isobe Y., Maki Y.: Heterocycles 1987, 26, 355.

14.Co catalysis; review: a) Vollhardt K. P. C.: Angew. Chem., Int. Ed. Engl. 1984, 23, 539; recent example: b) Stará I. G., Starý I., Kollárovič A., Teplý F., Šaman D., Tichý M.: J. Org. Chem. 1998, 63, 4046.

15.Rh catalysis: a) Grigg R., Scott R., Stevenson P. J.: J. Chem. Soc., Perkin Trans. 1 1988,

1357; b) Neeson S. J., Stevenson P. J.: Tetrahedron 1989, 45, 6239.

16.Ta catalysis: Štěpnička P., Císařová I., Sedláček J., Vohlídal J., Polášek M.: Collect. Czech. Chem. Commun. 1997, 62, 1577; and references therein.

17.Ru catalysis; recent examples: a) Blechert S., Peters J.-U.: Chem. Commun. 1997, 1983;

b)Roy R., Das S. K.: Tetrahedron Lett. 1999, 40, 4015.

18.Ni catalysis; recent examples: a) Sato Y., Nishimata T., Mori M.: J. Org. Chem. 1994, 59, 6133; b) Sato Y., Ohashi K., Mori M.: Tetrahedron Lett. 1999, 40, 5231; c) Stará I. G., Starý I., Kollárovič A., Teplý F., Vyskočil Š., Šaman D.: Tetrahedron Lett. 1999, 40, 1993.

19.Pd catalysis; review: a) Maitlis P. M.: Acc. Chem. Res. 1976, 9, 93; recent example:

b)Yamamoto Y., Nagata A., Itoh K.: Tetrahedron Lett. 1999, 40, 5035.

20.Hocek M., Holý A.: Collect. Czech. Chem. Commun. 1995, 60, 1386.

21.Leadbeater N. F.: J. Org. Chem. 2001, 66, 7539.

22.Votruba I.: Unpublished results.

23.Bakkestuen A. K., Gundersen L.-L., Langli G., Liu F. S., Nolsoe J. M. J.: Bioorg. Med. Chem. Lett. 2000, 10, 1207.

Czech. Chem. Commun. (Vol. 67) (2002)