Reaction of 1,3-dimethyl-5-acetyl-barbituric acid (DAB) with primary amines. Access to intermediates for selectively protected spermidines

Article abstract of DOI:10.1016/S0040-4039(03)00709-3

The ability of 1,3-dimethyl-5-acetyl-barbituric acid (DAB) to react with primary amines in a chemoselective fashion was applied to the synthesis of a selectively protected spermidine.

Full text of DOI:10.1016/S0040-4039(03)00709-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3621–3624
Reaction of 1,3-dimethyl-5-acetyl-barbituric acid (DAB) with
primary amines. Access to intermediates for selectively
protected spermidines
Emerson T. da Silva and Edson L. S. Lima*
Universidade Federal do Rio de Janeiro, Instituto de Qu´ımica, Departamento de Qu´ımica Orgaˆnica, Cidade Universita´ria,
21945-970 Rio de Janeiro, RJ, Brazil
Received 24 February 2003; revised 13 March 2003; accepted 14 March 2003
Abstract—The ability of 1,3-dimethyl-5-acetyl-barbituric acid (DAB) to react with primary amines in a chemoselective fashion was
applied to the synthesis of a selectively protected spermidine. © 2003 Elsevier Science Ltd. All rights reserved.
The addition of nitrogen-containing nucleophiles to
2-acylcycloalkane-1,3-diones to give exo-cyclic enamino
diketones is a well documented process, which has been
proven useful in the synthesis of several biologically
active compounds (Fig. 1).1
DAB at room temperature (entries 1–3). The reaction is
slowed by electron-withdrawing groups (entry 4), but is
chemoselective for functionalized amines (entries 5–9).6
Acid-sensitive functional groups are tolerated in the
reaction conditions (entry 6). Substrates which may
form intramolecular hydrogen bond react slowly at
room temperature, but the enamines can be efficiently
obtained under reflux (entries 7–9).7,8
This reactivity pattern has been applied by Bycroft et
al. in the development of Dde and related compounds
as protective groups for primary amines.2 While most
of the applications of Dde were addressed to the solid-
phase synthesis of polyamine conjugates, the solution-
phase synthesis of polyamines still demands for
protective groups orthogonal to those more commonly
used, such as carbamates and imides.3
We next turned our attention to the removal of DAB.
Given the precedent of solid-phase transamination reac-
tions with Dde, we attempted similar protocols.9,10
However, no reaction was observed when the DAB-
benzylamine adduct (entry 4) was subjected to the
treatment with either n-propylamine or ethanolamine in
THF at room temperature overnight. Deprotection was
successfully carried out with aqueous hydrazine in etha-
nol, leading to the recovery of the amine and the
formation of the hydrazone 1 (Scheme 1).11
In our attempts to prepare a selectively functionalized
spermidine we have observed that 1,3-dimethyl-5-ace-
tyl-barbituric acid (DAB) reacts with a range primary
amines under mild conditions to afford the correspond-
ing enamine in good yields (Table 1).4,5 Thus, both
unbranched and a-branched primary amines react with
Encouraged by these results we investigated the use of
this protective group in the synthesis of a selectively
protected spermidine. Accordingly, (3-aminopropyl)-
benzylamine was reacted with DAB to provide enamine
2 (Scheme 2, entry 7),8 which was then subjected to
N-alkylation
with
4-bromobutylphthalimide
(1
equiv.).12 The spermidine 3 was obtained as a colorless
oil in 76% yield after flash-chromatography. Since the
removal of phthalimide with hydrazine requires heating
in ethanol, we were able to selectively remove DAB
from 3 with aqueous hydrazine in THF at 0°C during
1.5 h, to obtain the known spermidine 4 as the sole
product in 79% yield.13
Figure 1. Reaction of amines with 2-acylcycloalkane-1,3-
diones.
* Corresponding author. Tel.: +55-21-2562-7369; fax: +55-21-2562-
7256; e-mail: edson@iq.ufrj.br
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00709-3

3622
E. T. da Sil6a, E. L. S. Lima / Tetrahedron Letters 44 (2003) 3621–3624
Table 1. Reaction of DAB with primary aminesa
a
General procedure: To a solution of 1,3-dimethyl-5-acetyl-barbituric acid (DAB) (0.51 mmol) in THF (10 mL) was added 1 equivalent of the
amine. The mixture was stirred under the conditions indicated in Table 1, and the reaction was monitored by TLC. After the reaction was judged
complete, the solvent was removed in the rotovap, and the residue was purified by flash chromatography.
Scheme 1. Removal of DAB with hydrazine.
Other features of DAB deserve note. For instance, it
vents. Additionally, we observed that DAB can be
1
provides quite simple H and 13C NMR spectra, and
quantitatively recovered by the nitrosation of
1
the imines are shelf-stable and soluble in organic sol-
(Scheme 3).14

E. T. da Sil6a, E. L. S. Lima / Tetrahedron Letters 44 (2003) 3621–3624
3623
Scheme 2. Synthesis of a selectively protected spermidine.
Huebscher, J.; Barner, R. Bioorg. Med. Chem. Lett. 1996,
6, 1525–1528.
3. (a) Kuksa, V.; Buchan, R.; Lin, P. K. T. Synthesis 2000,
1189–1207; (b) Bradshaw, J. S.; Krakowiak, K. E.; Izatt,
R. M. Tetrahedron 1992, 48, 4475–4515; (c) Bergeron, R.
J. Acc. Chem. Res. 1986, 19, 105–113.
4. DAB can be prepared by the reaction between acid
1,3-dimethyl-barbituric, acetic anhydride (two equiva-
lents), and cat. DMAP in CH2Cl2 at room temperature
for 5 h. Flash-chromatography affords DAB in 90% yield
(mp: 84–86°C).
Scheme 3. Recovery of DAB.
5. DAB has been previously used to protect aminosugars:
A. Alchemia Pty. Ltd., Toth, I.; Dekany, G.; Kellam, B.
(1999). Protecting and Linking Groups for Organic Syn-
thesis. WO 99/15510 PCT/AU98/00808. For a related
work see: Dekany, G.; Bornaghi, L.; Papageorgiou, J.;
Taylor, S. Tetrahedron Lett. 2001, 42, 3129–3132.
6. (a) For the preparation of (3-aminopropyl)benzylamine
(entry 7) see: Almeida, M. V.; Ce´sar, E. T.; Fel´ıcio, E. C.
A.; Fontes, A. P. S.; Robert-Gero, M. J. Braz. Chem.
Soc. 2000, 11, 154–158; (b) Preparation of (3-
aminopropyl)-(2-nitro)-benzenesulfonamide (entry 9)
from 1,3-diaminopropane was adapted from: Amssoms,
K.; Augustyns, K.; Yamani, A.; Zhang, M.; Haemers, A.
Synth. Commun. 2002, 32, 319–328.
In conclusion, we believe that based on the smooth
conditions required for introduction and removal of
DAB, this protective group will find application in the
synthesis of polyamines.
Acknowledgements
This work was supported by grants from European
Community
(ERBIC18-CT98-0372),
International
Foundation for Science (F/3267-1) and FAPERJ (E-26/
170.560/2001). E.T.S. would like to thank CAPES and
FAPERJ for a fellowship.
7. The reaction of DAB with anilines and a-aminoacids
afforded negligible yields of the corresponding enamine,
even after 24 h of reflux in THF.
References
8. Data for 5-[1-(3-Benzylaminopropylamino)ethylidene]-
1,3-dimethylhexahydro-2,4,6-pyrimidinetrione (entry 7):
Rf=0.50 (MeOH/CH2Cl2 10%) 1H NMR (CDCl3, 200
MHz): l 12.54 (1H, br s, -NH) 7.16–7.25 (5H, m, ArC-
H), 3.72 (2H, s, -CH2Ph), 3.48 (2H, m, CꢀC-N-CH2), 3.23
(6H, s, N-CH3) 2.70 (2H, t, J=6.28 Hz, -CH2NHBn),
2.62 (3H, s, C-CH3), 1.78 (2H, quintet, J=6.28 Hz,
-CH2CH2CH2-); 13C NMR (CDCl3, 50 MHz): 17.76,
27.62, 29.42, 41.79, 45.90, 53.81, 90.22, 126.98, 128.02,
128.82, 139.99, 151.32, 163.10, 166.45, 174.03; IR (film):
3339, 3086, 2954, 1699, 1655, 1608, 1591, 1472, 1363,
1222, 869, 755, 422 cm−1; LRMS m/z (relative intensity):
344 (M+ 2%), 224 (18%), 134 (14%), 106 (47%), 91
(100%), 57 (11%). HRMS for C18H24N4O3: 344.1848.
Found: 344.1797.
1. Rubinov, D. B.; Rubinova, I. L.; Akhrem, A. A. Chem.
Rev. 1999, 99, 1047–1065 and references cited therein.
2. (a) Chhabra, S. R.; Parekh, H.; Khan, A. N.; Bycroft, B.
W.; Kellam, B. Tetrahedron Lett. 2001, 42, 2189–2192;
(b) Chhabra, S. R.; Khan, A. N.; Bycroft, B. W. Tetra-
hedron Lett. 2000, 41, 1099–1102; (c) Chhabra, S. R.;
Khan, A. N.; Bycroft, B. W. Tetrahedron Lett. 2000, 41,
1095–1098; (d) Chhabra, S. R.; Khan, A. N.; Bycroft, B.
W. Tetrahedron Lett. 1998, 39, 3585–3588; (e) Chhabra,
S. R.; Hothi, B.; Evans, D. J.; White, P. D.; Bycroft, B.
W.; Chan, W. C. Tetrahedron Lett. 1998, 39, 1603–1606;
(f) Kellam, B.; Bycroft, B. W.; Chan, W. C.; Chhabra, S.
R. Tetrahedron 1998, 54, 6817–6832; (g) Kellam, B.;
Chan, W. C.; Chhabra, S. R.; Bycroft, B. W. Tetrahedron
Lett. 1997, 38, 5391–5394; (h) Kellam, B.; Bycroft, B. W.;
Chhabra, S. R. Tetrahedron Lett. 1997, 38, 4849–4852; (i)
Nash, I. A.; Bycroft, B. W.; Chan, W. C. Tetrahedron
Lett. 1996, 37, 2625–2628; (j) Chan, W. C.; Bycroft, B.
W.; Evans, D. J.; White, P. D. J. Chem. Soc., Chem.
Commun. 1995, 2209–2210. See also: (k) Bannwarth, W.;
9. See Refs. 2b and 2c.
10. Truffert, J.-C.; Lorthioir, O.; Asseline, U.; Thoung, N.
T.; Brack, A. Tetrahedron Lett. 1994, 35, 2353–2356.
11. Typical experimental: To a solution of 5-(1-benzyl-
aminoethylidene) - 1,3 - dimethylhexahydro - 2,4,6 - pyrim-
idinetrione (100 mg, 0.24 mmol) in EtOH (20 mL) was

3624
E. T. da Sil6a, E. L. S. Lima / Tetrahedron Letters 44 (2003) 3621–3624
added 2 equivalents of aqueous hydrazine. The resulting
homogeneous solution was stirred at room temperature
for 30 min, after which time the reaction was judged
complete by TLC. The solvent was removed under
reduced pressure and the residue was purified by column
chromatography (SiO2, 230–400 mesh, AcOEt/hexane
50%) to afford the free amine (28 mg, 75%) and the
corresponding hydrazone (74 mg, 99%). Data for 5-(1-
hydrazineethylidene)-1,3-dimethylhexahydro-2,4,6-pyrim-
idinetrione: mp 155–157°C. Rf=0.34 (AcOEt/Hex 50%);
1H NMR (CDCl3, 200 MHz): l 13.40 (1H, s br, -NH),
4.08 (2H, s br, NH2), 3.31 (6H, s, N-CH3), 2.86 (3H, s,
C-CH3); 13C NMR (CDCl3, 50 MHz): l 175.71, 151.62,
89.18, 27.94, 16.19; IR (KBr): 3329, 3240, 3195, 2998,
1697, 1632, 1462, 1361, 1019, 817, 754, 510 cm−1
.
12. Saab, N. H.; West, E. E.; Bieszk, N. C.; Preuss, C. V.;
Mank, A. R.; Casero, R. A., Jr.; Woster, P. M. J. Med.
Chem. 1993, 36, 2998–3004.
13. Silva, E. T.; Cunha, A. S.; Lima, E. L. S. Bioorg. Med.
Chem. Lett. 2002, 12, 3207–3208.
14. Carpino, L. A.; Carpino, B. A.; Crowley, P. J.; Giza, C.
A.; Terry, P. H. Org. Synth. Collect. Vol. 5 1973, 157.