Synthesis of Medicinally Interesting 2,4-Diamino-9H-pyrimido[4,5-b]indol-6-ols via Extension of the Nenitzescu Reaction

Bernd Dotzauer; Reinhard Troschütz

doi:10.1055/s-2004-822887

LETTER

Synthesis of Medicinally Interesting 2,4-Diamino-9H-pyrimido[4,5-b]indol-6-ols via Extension of the Nenitzescu Reaction

Bernd Dotzauer, Reinhard Troschütz*
Department of Medicinal Chemistry, Emil-Fischer-Center, Friedrich-Alexander-University, Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany
Fax: +49(9131)8522587; e-Mail: troschuetz@pharmazie.uni-erlangen.de;

Abstract

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Abstract

The title compounds 6 were prepared by a one-step procedure from 1,4-benzoquinone (1) and pyrimidine-2,4,6-triamines 2 via an extension of the Nenitzescu reaction. Formation of 9H-pyrimido[4,5-b]indoles 6 can be calculated by ¹³C NMR values of C-5 of the pyrimidine-2,4,6-triamines 2.

Key words

N-heterocycles - cyclizations - Nenitzescu reaction - 1,4-quinones - nucleophilic additions

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References

<A NAME="RG33703ST-1">1</A> Bundy GL. Ayer DE. Banitt LS. Belonga KL. Mizsak SA. Palmer JR. Tustin JM. Chin JE. Hall ED. Linseman KL. Richards IM. Scherch HM. Sun FF. Yonkers PA. Larson PG. Lin JM. Padbury GE. Aaron CS. Mayo JK. J. Med. Chem. 1995, 38: 4161

<A NAME="RG33703ST-2">2</A> Bundy G. Banitt LS. Doborowski PJ. Palmer JR. Schwartz TM. Zimmermann DC. Lipton MF. Mauragis MA. Veley MF. Appell RB. Clouse RC. Daugs ED. Org. Process Res. Dev. 2001, 5: 144

<A NAME="RG33703ST-3">3</A> Traxler PM. Furet P. Mett H. Buchdunger E. Meyer T. Lydon N. J. Med. Chem. 1996, 39: 2285

<A NAME="RG33703ST-4">4</A> Lowinger T, Shimazaki M, Sato H, Tanaka K, Tsuno N, Marx K, Yamamoto M, Urbahns K, Gantner F, Okigami H, Nakashima K, Takeshita K, Bacon K, Komura H, and Yoshida N. inventors; PCT Int. Appl. WO 03/037898.

<A NAME="RG33703ST-5A">5a</A> Glushkov RG. Volskova VA. Magidson OYu. Khim. Farm. Zh. 1967, 1: 25

<A NAME="RG33703ST-5B">5b</A> Grob CA. Weinbach OJ. Helv. Chim. Acta 1961, 44: 1748

<A NAME="RG33703ST-6">6</A> Showalter HDH. Bridges AJ. Zhou H. Sercel AD. McMichael A. Davis WF. J. Med. Chem. 1999, 42: 5464

<A NAME="RG33703ST-7">7</A> Eger K. Lanzner W. Rothenhäusler K. Liebigs Ann. Chem. 1993, 465

<A NAME="RG33703ST-8A">8a</A> Zhang YM. Razler T. Jackson PF. Tetrahedron Lett. 2002, 43: 8235

<A NAME="RG33703ST-8B">8b</A> Lapachev VV. Stadlbauer W. Kappe T. Monatsh. Chem. 1988, 119: 97

<A NAME="RG33703ST-8C">8c</A> Vlasova MI. Kogan NA. Khim. Geterotsikl. Soedin. 1982, 7: 935

<A NAME="RG33703ST-8D">8d</A> Wright GE. J. Heterocycl. Chem. 1976, 13: 539

<A NAME="RG33703ST-9A">9a</A> Pindur U. Pharm. Unserer Zeit 1987, 16: 47

<A NAME="RG33703ST-9B">9b</A> Anderson WK. Gopalsamy A. Peech SR. J. Med. Chem. 1994, 37: 1955

<A NAME="RG33703ST-9C">9c</A> Auclaire C. Paoletti C. J. Med. Chem. 1981, 24: 289

<A NAME="RG33703ST-10">10</A> Gribble GW. Synlett 1991, 289

<A NAME="RG33703ST-11">11</A> Gribble GW. Saulnier MG. Obaza-Nutaitis JA. Ketcha DM. J. Org. Chem. 1992, 57: 5891

<A NAME="RG33703ST-12">12</A> Allen GR. In Organic Reactions Vol. 30: Wiley; New York: 1973. p.337

<A NAME="RG33703ST-13A">13a</A> Troschütz R. Arch. Pharm. (Weinheim, Ger.) 1989, 322: 285

<A NAME="RG33703ST-13B">13b</A> Troschütz R. Arch. Pharm. (Weinheim, Ger.) 1984, 317: 709

<A NAME="RG33703ST-14">14</A> Bernier JL. Hénichart JP. Vaccher C. Houssin R. J. Org. Chem. 1980, 45: 1493

<A NAME="RG33703ST-15">15</A> Bernier JL. Hénichart JP. J. Org. Chem. 1981, 46: 4197

<A NAME="RG33703ST-16A">16a</A> Allen GR. Pidacks C. Weiss MJ. J. Am. Chem. Soc. 1966, 88: 2536

<A NAME="RG33703ST-16B">16b</A> Patrick JB. Saunders EK. Tetrahedron Lett. 1979, 20: 4009

<A NAME="RG33703ST-17">17</A> Troschütz R. Anders E. Arch. Pharm. (Weinheim, Ger.) 1992, 325: 341

<A NAME="RG33703ST-18">18</A> Kuckländer U. Tetrahedron 1973, 29: 921

<A NAME="RG33703ST-19">19</A> Barret R. Daudon M. Tetrahedron Lett. 1990, 34: 4871

<A NAME="RG33703ST-20">20</A> Malesani G. Marcolin F. Rodighiero G. J. Med. Chem. 1970, 13: 161

<A NAME="RG33703ST-21">21</A> Warren JD. Ving JL. Angier RA. J. Heterocycl. Chem. 1979, 16: 1617

The 6-aminopyrimidines 2 were prepared according to the following literature:

<A NAME="RG33703ST-22A">22a</A> Fletcher I. inventors; Ger. Offen, DE 2749902A1.

<A NAME="RG33703ST-22B">22b</A> Roth B. Smith J. Hultquist M. J. Chem. Soc. 1949, 2490

<A NAME="RG33703ST-22C">22c</A> Nishigaki S. Senga K. Yoneda F. Chem. Pharm. Bull. 1971, 19: 1526

<A NAME="RG33703ST-22D">22d</A> Meyer H, Wehinger E, Garthoff B, and Kazda S. inventors; Ger. Offen, DE 3501696A1.

Typical Procedure for the Preparation of 6a and 9d.
2,4-Diamino-9 H -pyrimido[4,5- b ]indol-5-ol ( 6a):
To a clear solution of 1.27 g (10 mmol) pyrimidine-2,4,6-triamine(2a) in 50 mL boiling glacial acetic acid 1.3 g (12 mmol) of 1,4-benzoquinone(1) was added, and the mixture refluxed for 6 h. The solvent was removed in vacuo and the dark residue purified by MPLC (silica gel) using CHCl₃/MeOH 4:1 as eluent. Colorless powder, yield 695 mg (31.8%); mp >300 °C.
IR (NaCl): ν_max = 3127, 1589, 1471, 1409, 1199 cm^-1. UV (CH₃OH): λ_max (log ε) = 209 nm (4.205), 237 (3.255), 259 (4.330), 293 (2.005), 316 (1.409), 324 (1.307). ¹H NMR (360 MHz, d ₆-DMSO): δ = 5.82 (s, 2 H, NH₂, with D₂O exchangeable), 6.49 (s, 2 H, NH₂, with D₂O exchangeable), 6.63 (dd, 1 H, H-7, J ₁ = 8.5 Hz, J ₂ = 2.2 Hz), 7.01 (d, 1 H, H-8, J = 8.5 Hz), 7.35 (d, 1 H, H-5, J = 2.2 Hz), 8.66 (s, 1 H, OH, with D₂O exchangeable), 10.76 (s, 1 H, NH, with D₂O exchangeable). ¹³C NMR (90.6 MHz, d ₆-DMSO): δ = 89.0 (C-4a), 105.7 (C-5), 110.0 (C-7), 110.3 (C-8), 122.3 (C-4b), 129.5 (C-8a), 151.2 (C-6), 159.0 (C-2), 158.3, 161.7 (C-4, C-9a). MS: m/z (%) = 215 (100) [M⁺], 198 (19.4), 173 (30.8). Found: C, 55.68; H, 413; N, 32.69. For C₁₀H₉N₅O (215.22) calcd: C, 55.81; H, 4.22; N, 32.54.
7,9-Bis(dimethylamino)-11 H -pyrimido[5′,4′:4,5]pyr-rolo[2,3- f ]quinoxalin-5-ol ( 9d): A mixture of 181 mg (1 mmol) of N ²,N ²,N ⁴,N ⁴-tetramethylpyrimidine-2,4,6-triamine (2d) and 160 mg (1 mmol) of quinoxaline-5,8-dione (8d) were dissolved in 25 mL of absolute EtOH. After addition of 0.5 mL glacial acetic acid the mixture was refluxed for 6 h. The solvent was removed in vacuo and the residue purified by MPLC (silica gel) using CHCl₃/MeOH 95:5 as eluent. Light green powder, yield 112 mg (34.6%); mp >300 °C.
IR (NaCl): ν_max = 3747, 3226, 2927, 2852, 1662, 1556, 1182, 1070 cm^-1. ¹H NMR (360 MHz, d ₆-DMSO): δ = 3.20 (s, 12 H, NMe₂), 7.58 (s, 1 H, H-6), 8.75 (d, 1 H, J = 1.8 Hz), 8.87 (d, 1 H, J = 1.8 Hz), 9.63 (s, 1 H, OH, with D₂O exchangeable), 12.2 (s, 1 H, NH, with D₂O exchangeable). MS: m/z (%) = 323 (100) [M⁺], 308 (25.8), 294 (78.8), 161,7 (14.5). Found: C, 59.61; H, 5.23; N, 30.39. For C₁₆H₁₇N₇O (323.36) calcd: C, 59.43; H, 5.30; N, 30.32.