A novel and efficient domino reaction for the one-pot synthesis of spiro-2-aminopyrimidinones

Article abstract of DOI:10.1016/j.tetlet.2008.04.092

A novel and efficient protocol is developed for the synthesis of various spiro-2-amino pyrimidinones via the three-component condensation of alkyl cyanoacetates, guanidinium carbonate and N-substituted 4-piperidinones in ethanol at reflux. High yields, neutral conditions, and short reaction times are advantages of this method.

Full text of DOI:10.1016/j.tetlet.2008.04.092

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3980–3982
A novel and efficient domino reaction for the one-pot synthesis
of spiro-2-aminopyrimidinones
Sorour Ramezanpour a, Mehri Seyed Hashtroudi b, Hamid Reza Bijanzadeh c,
Saeed Balalaie a,*
a Peptide Chemistry Research Group, K.N. Toosi University of Technology, PO Box 15875-4416, Tehran, Iran
b Marine Chemistry Laboratory, Iranian National Center for Oceanography (INCO), PO Box 14155-4781, Tehran, Iran
c Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
Received 13 January 2008; revised 4 April 2008; accepted 16 April 2008
Available online 20 April 2008
Abstract
A novel and efficient protocol is developed for the synthesis of various spiro-2-amino pyrimidinones via the three-component conden-
sation of alkyl cyanoacetates, guanidinium carbonate and N-substituted 4-piperidinones in ethanol at reflux. High yields, neutral
conditions, and short reaction times are advantages of this method.
Ó 2008 Published by Elsevier Ltd.
Keywords: One-pot three-component reaction; Spiro-2-aminopyrimidinones; Domino reaction; Domino Knoevenagel-cyclocondensation; Neutral
conditions; Guanidinium carbonate
There are many natural and biologically active com-
pounds that contain ring systems connected to each other
through a spiro carbon atom. The aza-spirocyclic system
is present in some alkaloids with anti-leukemic activity
such as pinnaic acid, halichlorine, cephalotaxine, and its
ester derivative.1–3 Compounds with spiro skeletons not
only constitute subunits in numerous alkaloids, but are
also templates for drug discovery and have been used as
scaffolds for combinatorial libraries.4 Spiro compounds
display pronounced antitumor and antiviral activities and
some have been shown to inhibit efficiently monoamine
oxidase A and to bind with nanomolar affinity to secroto-
nin receptors in the central nervous system.5,6
2-Aminopyrimidinone derivatives have various biologi-
cal activities and there is widespread interest in their syn-
thesis because of this, along with their capacity to form
hydrogen bonds and to undergo coagulation.8
Developing new environmentally benign and clean syn-
thetic methods is important in organic synthesis. Domino
reactions are such examples with high potential in organic
synthesis. They have several advantages such as (a) rapid
transformations, (b) minimizing the number of reaction
steps and chemical waste, and (c) the occurrence of two
or more bond-forming reactions under identical reaction
conditions.9
Following our interest in using domino reactions for the
synthesis of heterocyclic compounds,10 we herein present a
straightforward route for the synthesis of spiro-2-amino-
pyrimidinones via an efficient three-component reaction
of N-substituted piperidinones, guanidinium carbonate,
and alkyl cyanoacetates via a domino Knoevenagel-cyclo-
condensation reaction (Scheme 1).
One of the main synthetic challenges for the synthesis of
novel alkaloids and related products is the selective con-
struction of the spiro fragment. Several methods have been
devised for solving this problem, for example, ring closing
metathesis, rearrangement, and cycloaddition.7
Guanidinium carbonate was used as a source of free
guanidine via refluxing methanol. This led to the formation
of free guanidine within 15 min. This basic media was
*
Corresponding author. Fax: +98 21 2285 3650.
E-mail address: balalaie@Kntu.ac.ir (S. Balalaie).
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.04.092

S. Ramezanpour et al. / Tetrahedron Letters 49 (2008) 3980–3982
3981
O
N
O
4
+
NH2
CN
X
NC
2 -
CO3
N
3
2
+
+
5
H2N
NH2
1
7
8
10
N
H
11
NH2
2
N
R
R
1
2
3
4
X=CO2Me, CO2Et
Scheme 1.
R= Bn, CH2CH2Ph, PhCH(CH3)
Table 1
Synthesis of spiro-2-amino pyrimidinones 4a–f
suitable for deprotonation of alkyl cyanoacetates 2 which
on reaction with N-substituted piperidone 1 produced the
desired alkene 5 through a Knoevenagel condensation.
Formation of the alkene intermediate 5 was confirmed by
the reaction of starting materials 1 and 2 in a separate ves-
sel and comparison by TLC. Alkene 5 acts as a Michael
acceptor and the reaction proceeds via a domino Knoeve-
nagel-cyclocondensation reaction. The free guanidine
probably adds to the alkene, and after cyclization, the
desired spiro-2-aminopyrimidinone is formed (Scheme 2).
The results obtained for the synthesis of spiro-2-aminopyri-
midinones 4a–f from various N-substituted 4-piperidinones
are shown in Table 1.
R
X
Time (min)
Yielda (%)
Ph
Ph
CO2Me
CO2Et
CO2Me
CO2Et
CO2Me
CO2Et
50
45
30
20
90
80
96
95
94
CH2-Ph
CH2-Ph
(CH3)–CH-Ph
(CH3)–CH-Ph
a
96
70b
86b
Yields refer to those of pure isolated products characterized by IR, 1H,
and 13C NMR spectroscopy and CHN analysis data.
b
Mixture of two diastereomers with a ratio of 1:1.
In all cases, for products 4a–f, in the piperidine ring the
axial and equatorial protons of H-7 and H-11 appeared as
multiplets in the region 1.5–1.8 ppm. Meanwhile, H8ax and
H10ax were observed as multiplets which were shielded
compared to H8eq and H10eq. The equatorial hydrogens,
H-8 and H-10, resonated at d 2.1 ppm. When compound
1c with a chiral center was used as starting material, prod-
ucts 4e and 4f were formed as mixtures of two diastereoiso-
mers with a ratio of 1:1.
In conclusion, we have developed a novel domino Knoe-
venagel-cyclocondensation reaction for the synthesis of
spiro-2-aminopyrimidinone in good to excellent yields with
high purity and in short reaction times.
The active carbonyl group in the N-alkyl-4-piperidinon-
es makes them suitable starting materials for the synthesis
of pharmaceutical compounds such as Fentanyl, Sufenta-
nil, and the synthesis of spiro compounds with high r1
receptor affinity.
Formation of the spiro-2-aminopiperidinone structure
was unambiguously supported by spectroscopic and ana-
lytical data. A singlet in the region d 3.92–3.97 ppm in
1
the H NMR spectra was assigned to H-5 of the pyrimidi-
none ring. In the 13C NMR spectra, the quaternary C-6
spiro carbon typically appeared between 60.0 and
64.3 ppm. The nitrile and carbonyl carbons resonated at
ca. d 117 and 168 ppm, respectively.11
NC
CO2R
NH
O
NC
O
N
CN
X
1)
2)
NH2
NH2
OR
NH
N
+
N
Proton exchange
R
N
H
NH2
R
R
X=
CO2R
O
O
NC
NC
N
NH
+
N
N
H
NH2
NH2
N
H
N
R
R
Scheme 2. The proposed mechanism for the synthesis of spiro-2-amino pyrimidinones 4a–f.

3982
S. Ramezanpour et al. / Tetrahedron Letters 49 (2008) 3980–3982
Bararjanian, M. Catal. Commun. 2007, 8, 1724–1728; (f) Balalaie, S.;
Acknowledgment
Bararjanian, M.; Hekmat, S.; Sheikh-Ahmadi, M.; Salehi, P. Synth.
Commun. 2007, 37, 1097–1108; (g) Abdolmohammadi, S.; Balalaie, S.
Tetrahedron Lett. 2007, 45, 3299–3303.
Saeed Balalaie would like to thank the Iran National
Science Foundation (INSF) (Grant No. 85043/11) for
financial support.
11. General procedure for the preparation of compounds 4a–f: A solution of
guanidinium carbonate (180 mg, 1.5 mmol) in methanol (20 ml) was
heated under reflux for 15 min. After the mixture had cooled to room
temperature, N-substituted piperidinone 1 (1 mmol) and alkyl cya-
noacetate 2 (1.2 mmol) were added and the mixture heated under
reflux. The progress of the reaction was monitored by TLC (EtOAc/
methanol 10:1). After completion of the reaction, the solid product was
collected by filtration and the solid washed with cold water to remove
excess guanidinium carbonate.
References and notes
1. (a) Nieto, M. J.; Philip, A. E.; Poupaert, J. H.; McCurdy, C. R. J.
Comb. Chem. 2005, 7, 258–263; (b) Bienayme, H.; Chene, L.; Grisoni,
S.; Grondin, A.; Kaloun, E. B.; Poigny, S.; Rahali, H.; Tam, E.
Bioorg. Med. Chem. Lett. 2006, 16, 4830–4833; (c) Habashita, H.;
Kokubo, M.; Hamano, S. I.; Hamanaka, N.; Toda, M.; Shibayama,
S.; Tada, H.; Sagawa, K.; Fukushima, D.; Maeda, K.; Mitsuya, H. J.
Med. Chem. 2006, 49, 4140–4152.
2. (a) Carson, M. W.; Kim, G.; Hentemann, M. F.; Trauner, D.;
Danishefsky, S. D. Angew. Chem., Int. Ed. 2001, 40, 4450–4452; (b)
Carson, M. W.; Kim, G.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2001, 40, 4453–4456.
Data for compounds 4a, 4c, and 4e:
Compound 4a: 2-Amino-9-benzyl-5-cyano-1,3,9-triazaspiro[5,5]-
undeca-2-en-4-one Mp = 268–269 °C; IR (KBr, cmÀ1): 3327, 3116,
2926, 2166, 1688, 1617, 1590; 1H NMR (300 MHz, DMSO-d6): d 1.56–
1.76 (m, 4H, H-7ax,eq, H-11ax,eq, 2CH2), 2.11–2.24 (m, 2H, H-8ax
,
H-10ax), 2.68 (m, 2H, H-8eq, H-10eq), 3.49 (s, 2H, –CH2N), 3.95 (s, 1H,
H-5), 6.40 (br s, 2H, NH2), 7.32 (m, 5H, H-Ar), 7.74 (br s, 1H, NH);
13C NMR (75 MHz, DMSO-d6) d 31.96, 34.30, 45.02, 48.12, 48.28,
52.22, 62.40, 117.25, 127.45, 128.70, 129.18, 138.70, 160.55, 168.25;
Anal. Calcd for C16H19N5O: C, 64.63; H, 6.44; N, 23.55. Found: C,
64.54; H, 6.34; N, 23.38.
3. Trauner, D.; Schwarz, J. B.; Danishefsky, S. J. Angew. Chem., Int. Ed.
1999, 38, 3542–3545.
4. (a) Weinreb, S. M.; Auerbach, J. J. Am. Chem. Soc. 1975, 97, 2503–
2507; (b) Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.;
Rogenson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975,
97, 2507–2516; (c) Isuno, N.; Mori, M. J. Org. Chem. 1995, 60, 115–
119; (d) Tietze, L. F.; Schirok, H.; Woehrmann, M.; Schradre, K. Eur.
J. Org. Chem. 2000, 2433–2444.
5. Lang, G.; Pinkert, A.; Blunt, J. W.; Munro, M. H. G. J. Nat. Prod.
2005, 68, 1796–1798.
6. Maier, C. A.; Wuensch, B. J. Med. Chem. 2002, 45, 438–448.
7. (a) Sannigrahi, M. Tetrahedron 1999, 55, 9007–9071; (b) Grubbs, R.
Compound 4c: 2-Amino-9-(2-phenylethyl)-5-cyano-1,3,9-triazaspiro-
[5,5]undeca-2-en-4-one Mp = 264–265 °C; IR (KBr, cmÀ1): 3394,
3312, 3108, 2926, 2166, 1663, 1611, 1581; 1H NMR (300 MHz,
DMSO-d6): d 1.56–1.73 (m, 4H, H-7ax,eq, H-11ax,eq, 2CH2), 2.14–2.27
(m, 2H, H-8ax, H-10ax), 2.52 (t, 2H, J = 6.9 Hz, –CH2Ph), 2.72 (t, 2H,
J = 6.9 Hz, –CH2N), 2.77 (m, 2H, H-8eq, H-10eq), 3.97 (s, 1H, H-5),
6.70 (br s, 2H, NH2), 7.16–7.26 (m, 5H, H-Ar), 7.90 (br s, 1H, NH). 13
C
NMR (75 MHz, DMSO-d6): d 31.97, 33.33, 34.26, 44.96, 48.11, 48.23,
52.31, 60.03, 117.19, 126.31, 128.71, 129.07, 140.81, 160.51, 168.44;
Anal. Calcd for C17H21N5O: C: 65.57, H: 6.79, N: 22.49. Found: C:
65.45, H: 6.79, N: 22.47.
H.; Chang, S. Tetrahedron 1998, 54, 4413–4450; (c) Furstner, A.
¨
Angew. Chem., Int. Ed. 2000, 39, 3012–3043; (d) Nieczypor, P.; Mol,
J. C.; Bespalova, N. B.; Bubnov, Y. N. Eur. J. Org. Chem. 2004, 812–
819.
Compound 4e: Mixture of two diastereomers (1:1) 2-Amino-9-(S-1-
phenylethyl)-5(R or S)-cyano-1,3,9-triazaspiro[5,5]undeca-2-en-4-one
Mp = 271–273 °C; IR (KBr, cmÀ1): 3420, 3311, 3132, 2931, 2171,
1668, 1615, and 1580; 1H NMR (500 MHz, DMSO-d6): d 1.31 (d, 6H,
J = 6.7 Hz, 2CH3), 1.60–1.67 (m, 8H, H7ax,eq, H-11ax,eq, 4 CH2), 2.05–
2.20 (m, 4H, H-8ax, H-10ax), 2.62 (m, 2H, H-8eq, H-10eq one
diastereomer), 2.85 (m, 2H, H-8eq, H-10veq another diastereomer),
3.48 (q, 2H, J = 6.8 Hz, 2-CH), 3.91 (s, 1H, H-5), 3.93 (s, 1H, H-5 ),
6.20 (br s, 4H, 2NH2), 7.23–7.35 (m, 10H, H-Ar), 7.65 (br s, 2H, 2NH);
13C NMR (75 MHz, DMSO-d6) 45.99, 52.67, 64.29, 117.71, 127.72,
128.16, 129.14, 144.43, 160.94, and 168.57. Anal. Calcd for
8. (a) Toledo, L. M.; Musa, K.; Lauher, J. W.; Fowler, F. W. Chem.
Mater. 1995, 7, 1639–1647; (b) Brown, D. J.; Evans, R. F.; Cowden,
W. B.; Fenn, M. D. The Pyrimidines; John Wiley & Sons: New York,
1994.
9. Tietze, L. F.; Brasche, G.; Gericke, M. Domino Reactions in Organic
Synthesis; John Wiley-VCH: Weinheim, 2006.
10. (a) Balalaie, S.; Soleiman-Beigi, M.; Rominger, F. J. Iranian Chem.
Soc. 2005, 2, 319–329; (b) Balalaie, S.; Bararjanian, M.; Amani, M.
A.; Movassagh, B. Synlett 2006, 263–266; (c) Balalaie, S.; Bararja-
nian, M.; Rominger, F. J. Heterocycl. Chem. 2006, 43, 821–826; (d)
Mohammadnejad, M.; Bararjanian, M.; Balalaie, S. Heterocycl.
Commun. 2006, 12, 467–472; (e) Balalaie, S.; Sheikh-Ahmadi, M.;
C
17H21N5O: C: 65.57, H: 6.79, N: 22.49. Found: C: 65.39, H: 6.79,
N: 22.51.