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’.

Key words

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 

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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.

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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].