LETTER
Construction of Piperazine 2,5-Dione Derivatives
2123
was the best choice as it gave the maximum yield of 6a.
Accordingly the other substrates 3b–f were similarly
treated to give the desired cyclized products 6b–f in 88–
96% yields. The results are summarized in Table 1.
References and Notes
(1) Prasad, C. Peptides 1995, 16, 151.
(2) (a) Rothe, M.; Mazanek, R. B. Liebigs Ann. Chem. 1974,
439. (b) Rovero, P.; Vigano, S.; Pegoraro, S.; Quartara, L.
Lett. Peptide Sci. 1995, 2, 319. (c) Chiva, C.; Vilaseca, M.;
Giralt, E.; Albericio, F. J. Pept. Sci. 1999, 5, 131.
(d) Borsuk, K.; van Delft, F. L.; Eggen, I. F.; ten Kortenaar,
P. B. W.; Petersen, A.; Rutjes, F. P. J. T. Tetrahedron Lett.
2004, 45, 3585.
(3) (a) Martins, M. B.; Carvalho, I. Tetrahedron 2007, 63,
9923. (b) Li, W.-R.; Yang, J. H. J. Comb. Chem. 2002, 4,
106. (c) McCleland, K.; Milne, P. J.; Lucieto, F. R.; Frost,
C.; Brauns, S. C.; Venter, M. V. D.; Plessis, J. D.; Dyason,
K. J. Pharm. Pharmacol. 2004, 56, 1143.
(4) Sinha, S.; Srivastava, R.; De Clercq, E.; Singh, R.
Nucleosides, Nucleotides Nucleic Acids 2004, 23, 1815.
(5) (a) Houston, D. R.; Synstad, B.; Eijsink, V. G. H.; Stark,
M. J. R.; Eggleston, I. M.; van Aalten, D. M. F. J. Med.
Chem. 2004, 47, 5713. (b) Byun, H.-G.; Zhang, H.;
Mochizuki, M.; Adachi, K.; Shizuri, Y.; Lee, W.-J.; Kim,
S.-K. J. Antibiot. 2003, 56, 102. (c) Park, Y. C.;
Gunasekera, S. P.; Lopez, J. V.; McCarthy, P. J.; Wright,
A. E. J. Nat. Prod. 2006, 69, 580.
(6) (a) Nicholson, B.; Lloyd, G. K.; Miller, B. R.; Palladino,
M. A.; Kiso, Y.; Hayashi, Y.; Neuteboom, S. T. C. Anti-
Cancer Drugs 2006, 17, 25. (b) Kozlovsky, A. G.;
Vinokurova, N. G.; Adanin, V. M.; Burkhardt, G.; Dahse,
H.-M.; Grafe, U. J. Nat. Prod. 2000, 63, 698.
Table 1 Summarized Results of the Intramolecular Aza-Wittig
Reaction
Entry
1
R
Substrate Time
(min)
Product Yield
(%)
3a
3b
3c
30
30
30
6a
6b
6c
96
92
94
2
3
Me
4
5
3d
3e
30
30
6d
6e
95
92
MeO
6
3f
30
6f
88
(7) Lucietto, F. R.; Milne, P. J.; Kilian, G.; Frost, C. L.;
Van De Venter, M. Peptides 2006, 27, 2706.
O
N
(8) (a) Huberman, L.; Gollop, N.; Mumcuoglu, K. Y.; Breuer,
E.; Bhusare, S. R.; Shai, Y.; Galun, R. Med. Vet. Entomol.
2007, 21, 127. (b) Clark, B.; Capon, R. J.; Lacey, E.;
Tennant, S.; Gill, J. H. J. Nat. Prod. 2005, 68, 1661.
(c) Fdhila, F.; Vazquez, V.; Sanchez, J. L.; Riguera, R.
J. Nat. Prod. 2003, 66, 1299.
(9) Fuji, K.; Takasu, K.; Miyamoto, H.; Tanaka, K.; Taga, T.
Tetrahedron Lett. 1996, 37, 7111.
(10) Li, W.-R.; Kao, K.-C.; Yo, Y.-C.; Lai, C. K. Helv. Chim.
Acta 1999, 82, 1400.
Me
Although a recent report20 in the literature shows a one-
pot preparation of symmetrically 1,4-substituted pipera-
zine 2,5-diones but our methodology provides the synthe-
sis of 1-substituted piperazine 2,5-diones which can be
converted into pyrazino[2,1-b]quinazoline-3,6-dione,21
an important scaffold, present in a several families of nat-
ural products such as the fiscalins,22 the fumiquinazo-
lines,23 and N-acetylardeemin.24 However, this 1-
substituted piperazinones can also be used as other impor-
tant scaffolds by protection of the second nitrogen atom
and performing further substitution at C2/C5 position.
(11) Perez-Picaso, L.; Escalante, J.; Olivo, H. F.; Rios, M. Y.
Molecules 2009, 14, 2836.
(12) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R.
Tetrahedron Lett. 1997, 38, 2519.
(13) Marcaccini, S.; Pepino, R.; Pozo, M. C. Tetrahedron Lett.
2001, 42, 2727.
In summary we have developed a strategy to generate dif-
ferent mono-N-substituted piperazine 2,5-diones starting
from easily available amino esters using intramolecular
aza-Wittig reaction as the key step. The method allows
mild reaction conditions, easy separation of products, and
affords the products in excellent yields.
(14) Falorni, M.; Giacomelli, G.; Porcheddu, A.; Taddei, M. Eur.
J. Org. Chem. 2000, 1669.
(15) For recent contributions, see: (a) Cossío, F. P.; Alonso, C.;
Lecea, B.; Ayerbe, M.; Rubiales, G.; Palacios, F. J. Org.
Chem. 2006, 71, 2839. (b) Cassidy, M. P.; Oezdemir, A. D.;
Padwa, A. Org. Lett. 2005, 7, 1339. (c) Ding, M.-W.;
Huang, N.-Y.; He, H.-W. Synthesis 2005, 1601. (d) Snider,
B. B.; Zhon, J. J. Org. Chem. 2005, 70, 1087. (e) Gil, C.;
Bräse, S. Chem. Eur. J. 2005, 11, 2680. (f) Alajarín, M.;
Sánchez-Andrada, P.; Vidal, A.; Tovar, F. J. Org. Chem.
2005, 70, 1340.
Supporting Information for this article is available online at
(16) For reviews, see: (a) Palacios, F.; Alonso, C.; Aparicio, D.;
Rubiales, G.; de los Santos, J. M. Tetrahedron 2007, 63,
523. (b) Palacios, F.; Aparicio, D.; Rubiales, G.; Alonso, C.;
de los Santos, J. M. Curr. Org. Chem. 2006, 10, 2371.
(c) Eguchi, S. Top. Heterocycl. Chem. 2006, 6, 113.
(d) Arqués, A.; Molina, P. Curr. Org. Chem. 2004, 8, 827.
(e) Wamhoff, H.; Richardt, G.; Stölben, S. Adv. Heterocycl.
Chem. 1995, 64, 159. (f) Molina, P.; Vilaplana, M. J.
Synthesis 1994, 1197. (g) Nitta, M. Reviews on Heteroatom
Chemistry, Vol. 9; Oae, S., Ed.; MYU K. K.: Tokyo, 1993,
Acknowledgment
We thank (New Delhi) and CSIR (New Delhi) for financial assis-
tance. Two of us (K.R. and S.G.) are grateful to CSIR (New Delhi)
for their research fellowships.
Synlett 2010, No. 14, 2122–2124 © Thieme Stuttgart · New York