ORGANIC
LETTERS
2008
Vol. 10, No. 16
3627-3629
Magnesium Nitride as a Convenient
Source of Ammonia: Preparation of
Dihydropyridines
Katy L. Bridgwood, Gemma E. Veitch, and Steven V. Ley*
Department of Chemistry, UniVersity of Cambridge, Lensfield Road,
Cambridge CB5 8BQ, U.K.
Received June 20, 2008
ABSTRACT
Magnesium nitride (Mg3N2) has been investigated for the preparation of dihydropyridines. This is a commercially available, bench-stable solid
that generates ammonia upon treatment with protic solvents. The main features of the process are the facile reaction setup and good yields
obtained in the majority of cases.
Dihydropyridines (DHPs) represent an important class of
biologically active molecules, several of which have found
use in the treatment of cardiovascular disease and hyperten-
sion.1 In addition, the dihydropyridine unit has been widely
employed as a hydride source for reductive amination:2 an
enantioselective variant of this reaction has recently been
developed, in which an H-bonding catalyst acts as an enzyme
analogue and a dihydropyridine as an NADH analogue.3
including the use of catalysts such as boronic acids,5 metal
triflates,6 molecular iodine,7 TMS iodide,8 Bu4NHSO4,9
bakers’ yeast,10 ceric ammonium nitrate,11 in situ generated
HCl,12 and silica-supported acids.13 Solvent free14 and
microwave irradiation15 conditions have also been reported.
Nonetheless, the synthesis of dihydropyridines remains of
interest, due to their prevalence in pharmaceutical agents.
(5) Sridhar, R.; Perumal, P. T. Tetrahedron 2005, 61, 2465–2470.
Debache, A.; Boulcina, R.; Belfaitah, A.; Rhouati, S.; Carboni, B. Synlett
2008, 509–512.
The preparation of dihydropyridines was first reported by
Hantzsch via the condensation of ethyl acetoacetate and
acetaldehyde with ammonia in refluxing alcohol or acetic
acid.4 Owing to the modest yield reported, numerous
improvements on this method have since been developed,
(6) Wang, L.-M.; Sheng, J.; Zhang, L.; Han, J.-W.; Fan, Z.-Y.; Tian,
H.; Qian, C.-T. Tetrahedron 2005, 61, 1539–1543.
(7) Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C.-F. Tetrahedron Lett. 2005,
46.
(8) Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S.
Tetrahedron Lett. 2003, 44, 4129–4131.
(1) Bossert, F.; Meyer, H.; Wehinger, H. Angew Chem., Int. Ed. 1981,
20, 762–769. Nakayama, H.; Kasoaka, Y. Heterocycles 1996, 42, 901–
909. Gordeev, M. F.; Patel, D.; Gordon, E. M. J. Org. Chem. 1996, 26,
924–928. Shan, R.; Velaskez, C.; Knaus, E. E. J. Med. Chem. 2004, 47,
254–261.
(9) Tewari, N.; Dwivedi, N.; Tripathi, R. P. Tetrahedron Lett. 2004,
45, 9011–9014.
(10) Lee, J. H. Tetrahedron Lett. 2005, 46, 7329–7330.
(11) Ko, S.; Yao, C.-F. Tetrahedron 2006, 62, 7293–7299.
(12) Sharma, G. V. M.; Reddy, K. L.; Lakshmi, P. S.; Krishna, P. R.
Synthesis 2006, 55–58.
(2) Itoh, T.; Nagata, K.; Miyazaki, M.; Ishikawa, H.; Kurihara, A.;
Ohsawa, A. Tetrahedron 2004, 60, 6649–6655.
(13) Maheswara, M.; Siddaiah, V.; Rao, Y. K.; Tzeng, Y.; Sridhar, C.
J. Mol Catal. A. Chem 2006, 17, 9–180. Gupta, R.; Gupta, R.; Paul, S.;
Loupy, A. Synthesis 2007, 2835–2838.
(3) Hoffman, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005,
44, 7424–7427. Rueping, M.; Suiono, E.; Azap, C.; Theissmann, T.; Bolte,
M. Org. Lett. 2005, 7, 3781–3783. Storer, R. I.; Carrera, D. E.; Ni, Y.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84–86.
(4) Hantzsch, A. Justus Liebigs Ann. Chem. 1882, 215, 1–82.
(14) Zolfigol, M. A.; Safaiee, M. Synlett 2004, 827–828.
¨
(15) Osberg, L.; Westman, J. Synlett 2001, 129, 6–1298. Salehi, H.;
Guo, Q. Synth. Commun. 2004, 34, 4349–4357.
10.1021/ol801399w CCC: $40.75
Published on Web 07/19/2008
2008 American Chemical Society