Synthesis of 7,8,9-Trisubstituted Dihydropurine Derivatives via a ‘tert-Amino Effect’ Cyclization

Abstract

7,8,9-Trisubstituted dihydropurine derivatives were prepared from 5-amino-4-(N,N-disubstituted)aminopyrimidines and aromatic aldehydes via a cascade of reactions. The key transformation for the reaction is a [1,6]-hydrogen shift due to a ‘tert-amino effect’.

tert-amino effect - dihydropurine - hydrogen transfer - imines - cyclizations

References and Notes

1 Lin Y.-L. Huang R.-L. Chang C.-M. Kuo Y.-H. J. Nat. Prod.  1997,  60:  982 

2 Hecht SM. Adams BL. Kozarich JW. J. Org. Chem.  1976,  41:  2303 

3 Kelley JL. Linn JA. J. Org. Chem.  1986,  51:  5435 

4 Booth BL. Dias AM. Proenca MF. Zaki MEA. J. Org. Chem.  2001,  66:  8436 

5a Meth-Cohn O. Suschitzky H. Adv. Heterocycl. Chem.  1972,  14:  211 

5b Meth-Cohn O. Adv. Heterocycl. Chem.  1996,  65:  1 

5c Mátyus P. Éliás O. Tapolcsányi P. Polonka-Bálint Á. Halász-Dalka B. Synthesis  2006,  2625 

6a Jiang S. Janousek Z. Viehe HG. Tetrahedron Lett.  1994,  35:  1185 

6b De Boeck B. Jiang S. Janousek Z. Viehe HG. Tetrahedron  1994,  50:  7075 

6c De Boeck B. Janousek Z. Viehe HG. Tetrahedron  1995,  51:  13239 

7a Ojea V. Peinador C. Vilar J. Quintela JM. Synthesis  1993,  152 

7b Ojea V. Maestro MA. Quintela JM. Tetrahedron  1993,  49:  2691 

7c Ojea V. Peinador P. Quintela JM. Synthesis  1992,  798 

7d Ojea V. Muinelo I. Figueroa MC. Ruiz M. Quintela JM. Synlett  1995,  622 

7e Ojea V. Muinelo I. Quintela JM. Tetrahedron  1998,  54:  927 

7f Mátyus P. Fuji K. Tanaka K. Heterocycles  1994,  37:  171 

7g Schwartz A. Beke G. Kovári Z. Böcskey Z. Farkas Ö. Mátyus P. J. Mol. Struct. (Theochem)  2000,  528:  49 

7h Kaval N. Dehaen W. Mátyus P. Van der Eycken E. Green Chem.  2004,  6:  125 

7i Dajka-Halász B. Földi AA. Ludányi K. Mátyus P. ARKIVOC  2008,  (iii):  102 

8 Che X. Zheng L. Dang Q. Bai X. J. Org. Chem.  2008,  73:  1147 

9 Yang J. Che X. Dang Q. Wei Z. Gao S. Bai X. Org. Lett.  2005,  7:  1541 

10

General Procedure for Syntheses of 6-Chloro-7,8,9-trisubstituted Dihydropurines
Pyrimidinediamine 1 (0.65 mmol), the appropriate aldehyde (0.975 mmol), and TFA (0.6 mL) were dissolved in MeCN (10.0 mL) and stirred under reflux for 1-12 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (15 mL), and washed with sat. NaHCO₃ (3 × 15 mL). The water layer was extracted with EtOAc (3 × 10 mL). The combined EtOAc layer was washed with brine, dried over anhyd Na₂SO₄, concentrated in vacuo, and purified by flash chromatography on SiO₂ to furnish the cyclized product 3.
6-Chloro-8-(3-methoxyphenyl)-9-methyl-7-(4-nitrobenzyl)-8,9-dihydro-7 H -purine (3a)
Orange solid, yield 67% (elution with EtOAc-PE, 1:2); mp 119.2-120.6 ˚C. ES-MS: m/z = 411.8 [M + 1]⁺. ^¹H NMR (300 MHz, CDCl₃): δ = 8.14 (d, J = 8.4 Hz, 2 H), 7.92 (s, 1 H), 7.30-7.35 (m, 3 H), 6.96 (dd, J = 8.4, 1.8 Hz, 1 H), 6.88 (d, J = 7.5 Hz, 1 H), 6.82 (t, J = 1.8 Hz, 1 H), 5.71 (s, 1 H), 5.05 (d, J = 16.8 Hz, 1 H), 4.32 (d, J = 16.5 Hz, 1 H), 3.80 (s, 3 H), 2.77 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 155.8, 154.2, 144.6, 142.8, 140.0, 132.6, 125.7, 124.1, 122.5, 119.3, 115.7, 111.1, 108.8, 80.4, 50.9, 43.5, 23.9.
6-Chloro-9-methyl-7-(4-nitrobenzyl)-8-phenethyl-8,9-dihydro-7 H -purine (8a)
Yellow solid, yield 65% (elution with EtOAc-PE, 1:2); mp 123-125 ˚C. ES-MS: m/z = 410.1 [M + 1]⁺. ^¹H NMR (500 MHz, DMSO): δ = 8.23 (d, J = 8.5 Hz, 2 H), 7.70 (s, 1 H), 7.63 (d, J = 8.5 Hz, 2 H), 7.17-7.20 (m, 2 H), 7.10-7.13 (m, 1 H), 7.02-7.03 (m, 2 H), 5.32 (s, 1 H), 4.85 (d, J = 17.5 Hz, 1 H), 4.69 (d, J = 17.0 Hz, 1 H), 2.89 (s, 3 H), 2.46-2.56 (m, 1 H), 2.40-2.44 (m, 1 H), 2.05-2.10 (m, 1 H), 1.85-1.91 (m, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 159.4, 149.6, 149.5, 147.5, 144.8, 140.4, 128.5, 128.0, 127.6, 126.2, 123.9, 82.5, 50.3, 33.0, 28.4, 27.7.

11

Crystallographic data for structure 8a reported in this paper in the form of CIF file has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication No. CCDC-689708. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 IEZ, UK [fax: [phone]; e-mail: deposit @ccdc.cam.ac.uk].