Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Heterocyclic Communications

Editor-in-Chief: Strekowski, Lucjan

Ed. by Baumstark, Alfons L. / Saczewski, Jaroslaw / Stephens, Chad / Yamada, Hidetoshi

6 Issues per year

IMPACT FACTOR 2017: 0.700

CiteScore 2017: 0.66

SCImago Journal Rank (SJR) 2017: 0.199
Source Normalized Impact per Paper (SNIP) 2017: 0.263

See all formats and pricing
More options …
Volume 21, Issue 6


Synthesis of 2-amino-6,7,8,9-tetrahydro-6-phenethyl-3H-pyrimido[4,5-e][1,4]diazepin-4(5H)-one: a model for a potential pyrimido[4,5-e][1,4]diazepine-based folate anti-tumor agent

Austin W. Gann / Partha S. Ray
Published Online: 2015-11-26 | DOI: https://doi.org/10.1515/hc-2015-0216


Reductive cyclization of 2-{N-[(2-amino-4,6-dichloropyrimidin-5-yl)methyl]-N-phenethylamino}acetonitrile (5) with Raney nickel and hydrogen gave the chloropyrimido[4,5-e][1,4]diazepine 3 which could not be converted to 2 via an attempted nucleophilic aromatic substitution with hydroxide. The title compound (2) was prepared, however, by the reductive cyclization of 2-{N-[(2-amino-4-chloro-6-methoxypyrimidin-5-yl)methyl]-N-phenethylamino}acetonitrile (13) followed by treatment with trimethyliodosilane.

Keywords: pyrimidodiazepine; pyrimido[4,5-e][1,4]diazepine; reductive cyclization

Dedicated with admiration and affection to the memory of my (PSR) undergraduate and graduate mentor Professor Sandy McKillop.


  • [1]

    Baldwin, S. W.; Tse, A.; Gossett, L. S.; Taylor, E. C.; Rosowsky, A.; Shih, C.; Moran, R. G. Structural features of 5,10-dideaza-5,6,7,8-tetrahydrofolate that determine inhibition of mammalian glycinamide ribonucleotide formyltransferase. Biochemistry 1991, 30, 1997–2006.CrossrefGoogle Scholar

  • [2]

    Taylor, E. C.; Dowling, J. E. Synthesis of a pyrimido[4,5-b]azepin analog of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). Bioorg. Med. Chem. Lett. 1997, 7, 453–456.CrossrefGoogle Scholar

  • [3]

    Read, M. W.; Miller, M. L.; Ray, P. S. Synthesis of N-{[4-(2-amino-4(3H)-oxo-5,6,7,8- tetrahydro-(9H)-pyrimido[4,5-b]azepin-6-yl)benzoyl}-L-glutamic acid and two of its conformationally-restricted analogs. Tetrahedron 1999, 55, 373–392.CrossrefGoogle Scholar

  • [4]

    Parker, D. P.; Hughes, S. A.; Parker, D. L.; Ray, P. S. An unexpected dimer formation from a (2-aminoethylamino)-5-formylpyrimidine intermediate. Heterocycl. Commum. 2002, 8, 419–422.Google Scholar

  • [5]

    Huddleston, N. E.; Harris, J. L.; Nguyen, H. L.; Ray, P. S. Synthesis of 2-amino-4-chloro-6,9-bis-(2,4-dimethoxybenzyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e]diazepine: a potentially useful intermediate to pyrimido[4,5-e]diazepine-based folates. Heterocycl. Commum. 2004, 10, 405–406.Google Scholar

  • [6]

    Frick, M.; McAtee, D.; McAtee, J.; Wysocznski, C.; Ray, P. S. Synthesis of N1-alky-1,4- diazepin-5-ones via Schmidt ring expansion chemistry. Heterocycl. Commum. 2011, 17, 17–19.Google Scholar

  • [7]

    Bell, L.; McGuire, H. M.; Freeman, G. A. Chemistry of 5-pyrimidinecarboxaldehydes. J. Heterocyclic Chem. 1983, 20, 41–44.CrossrefGoogle Scholar

  • [8]

    Jeong, L. S.; Schinazi, R. F.; Beach, J. W.; Kim, H. O.; Nampalli, S.; Shanmuganathan, K.; Alves, A. J.; McMillan, A.; Chu, C. K.; Mathis, R. Asymmetric Synthesis and Biological Evaluation of b-L-(2R,5S)- and a-L-(2R,5R)-1,3-Oxathiolane-Pyrimidine and –Purine Nucleosides as Potential Anti-HIV Agents. J. Med. Chem. 1993, 36, 181–195.CrossrefGoogle Scholar

  • [9]

    Wong, C-H.; Provencher, L.; Porco, J. A.; Jung, S-H.; Wang, Y-F.; Chen, L.; Wang, R.; Steensma, D. H. Synthesis and Evaluation of Homoazasugars as Glycosidase Inhibitors. J. Org. Chem. 1995, 60, 1492–1501.CrossrefGoogle Scholar

  • [10]

    Sidhu, G. S.; Thyagarajan, G.; Mazharuddin, M. Cyanomethylation with chloroacetonitrile. Indian J. Chem., 1964, 2, 170–172.Google Scholar

About the article

Corresponding author: Partha S. Ray, Department of Chemistry, University of West Georgia, Carrollton, GA 30118, USA, e-mail:

Received: 2015-09-24

Accepted: 2015-11-04

Published Online: 2015-11-26

Published in Print: 2015-12-01

Citation Information: Heterocyclic Communications, Volume 21, Issue 6, Pages 349–353, ISSN (Online) 2191-0197, ISSN (Print) 0793-0283, DOI: https://doi.org/10.1515/hc-2015-0216.

Export Citation

©2015 by De Gruyter.Get Permission

Comments (0)

Please log in or register to comment.
Log in