Reaction of barbituric acid with organic azides and phosphonium ylides

Article abstract of DOI:10.2478/s11532-013-0233-4

Amination by organic azides has been carried out to provide aminobarbiturates by fusion of a triazole ring to the 5,6-positions of barbituric acid followed by cleavage and thermal elimination of nitrogen, whereas aza-Wittig reaction gave phosphoranylidene barbituric acid salts. Versita Sp. z o.o.

Full text of DOI:10.2478/s11532-013-0233-4

Cent. Eur. J. Chem. • 11(6) • 2013 • 1019-1022
DOI: 10.2478/s11532-013-0233-4
Central European Journal of Chemistry
Reaction of barbituric acid with organic
azides and phosphonium ylides
Research Article
Iryna O. Lebedyeva1, Sean M. Sileno1, Kunal Patel1,
Ion Ghiviriga2, Peter J. Steel3, Alan R. Katritzky1,4*
1Center for Heterocyclic Compounds, Department of Chemistry,
University of Florida, Gainesville, FL 32611-7200, USA
2Department of Chemistry, University of Florida,
PO box 117200, Gainesville, FL 32611, USA
3Chemistry Department, University of Canterbury,
Christchurch 8140, New Zealand
4Chemistry Department, King Abdulaziz University,
Jeddah 21589, Saudi Arabia
Received 25 January 2013; Accepted 17 February 2013
Abstract:
Amination by organic azides has been carried out to provide aminobarbiturates by fusion of a triazole ring to the 5,6-positions of
barbituric acid followed by cleavage and thermal elimination of nitrogen, whereas aza-Wittig reaction gave phosphoranylidene barbituric
acid salts.
Keywords: Azide • Aza-Wittig reaction • Pyrimidine • Barbiturate
© Versita Sp. z o.o.
1. Introduction
2. Experimental procedure
Barbituric acid (BA) 1, first synthesized in 1864, is used Melting points were determined on a capillary point
to provide barbiturate pigments [1], supramolecular units apparatus equipped with a digital thermometer and are
[2], and to perform colorimetric assays [3]. A great many uncorrected. 1H NMR spectra were recorded at 300 and
barbiturates have been prepared many of which affect 500 MHz and 13C NMR spectra were recorded at 75 and
GABAA receptor functions in a concentration-dependent 125 MHz on Gemini or Mercury spectrometers at room
manner [4–6]. Barbiturates are used to treat insomnia, temperature. The chemical shifts were reported in ppm
dementia, neonatal jaundice [7], and are known to inhibit relative to TMS as internal standard (1H NMR) or to the
tumor growth [8–9].
residual solvent peak (13C NMR). Elemental analysis
Barbituric acid remains an attractive target for was performed on a Carlo Erba-1108 instrument. High
modification due to the extensive medicinal properties Resolution Mass Spectra were recorded using Thermo
of its derivatives as sedatives and anticonvulsants. Scientific LCQ Ion Trap. Crystallographic data of 6f
Numerous C5 mono- and bis functionalizations include including atomic coordinates, bond lengths and thermal
Knoevenagel condensation of 1 with substituted aromatic parameters have been deposited at the Cambridge
aldehydes producing merocyanine-type dyes [10], Crystallographic Data Centre (CCDC). These data can
pigments [1], and protein tyrosine phosphatase inhibitors be obtained free of charge via www.ccdc.cam.uk/conts/
[11].
retrieving.html (or from CCDC, 12 Union Road, Camridge
* E-mail: katritzky@chem.ufl.edu
1019

Reaction of barbituric acid with organic
azides and phosphonium ylides
CB2 1EZ, UK, fax: +44 1223 336 033, or deposit@ccdc. C21H42N3O3P: C, 60.70; H, 10.19; N, 10.11. Found: C,
cam.ac.uk). Any request to the CCDC for data should 60.92; H, 10.38; N, 10.29.
quote the full literature citation and CCDC reference
number 909437.
N - ( T r i b u t y l - λ 5 - p h o s p h a n y l i d e n e )
cyclohexanaminium
2,6-dioxo-1,2,3,6-
General procedure for synthesis of 4a-b:
tetrahydropyrimidin-4-olate 6b:
To a solution of organic azide 2a-b (0.150 mmol) in dry Light yellow solid (81%, 0.346 g, 0.081 mmol). Mp
1
THF (20 mL), barbituric acid 1 (116 mg, 0.1 mmol) was 266.3–268.5oC; H NMR (300 MHz, DMSO-d6): δ 9.87
added and the mixture was heated in a sealed tube at (br s, 3H), 5.25 (t, J = 9.5 Hz, 1H), 2.94 (br s, 1H), 2.14
110oC for 12 h. The solvent was evaporated and the (br s, 6H), 1.80–1.60 (m, 4H), 1.60-1.10 (m, 18H), 0.91
solid residue was recrystallized from ethyl acetate/ (br s, 9H); 13C NMR (75 MHz, CD3OD): δ 176.1, 161.9,
hexanes (1:2).
114.0, 59.6, 45.3, 34.4, 32.9, 32.7, 32.1, 30.7, 30.0,
5-(Benzylamino)-6-hydroxypyrimidine- 23.0. Anal. Calcd for C22H42N3O3P: C, 61.80; H, 9.90; N,
2,4(1H,3H)-dione 4a:
9.83. Found: C, 62.01; H, 9.97; N, 10.03.
Pinksolid(63%,0.147g,0.063mmol).Mp287.8–290.9oC
1-Phenyl-N-(tributyl-λ5-phosphanylidene)
(lit. Mp 290 [13]); 1H NMR (500 MHz, DMSO-d6): δ 9.60 methanaminium
(s, 3H), 7.33–7.31 (m, 5H), 4.22 (s, 2H); 13C NMR (125 tetrahydropyrimidin-4-olate 6c:
2,6-dioxo-1,2,3,6-
MHz, DMSO-d6): δ 160.5, 151.5, 132.2, 130.4, 128.7, Light yellow solid (90%, 0.392 g, 0.09 mmol). Mp
1
128.2, 86.9, 50.7. Anal. Calcd for C11H11N3O3: C, 56.65; 131.0–133.8oC; H NMR (300 MHz, DMSO-d6): δ 9.04
H, 4.75; N, 18.02. Found: C, 56.77; H, 4.43; N, 18.38.
5-((4-Chlorobenzyl)amino)-6-hydroxypyrimidine- (dd, J = 11.3, 7.1 Hz, 2H), 3.74 (s, 1H), 2.23–2.13 (m,
2,4(1H,3H)-dione 4b:
6H), 1.43–1.22 (m, 12H), 0.86 (t, J = 6.9 Hz, 9H); 13C
(s, 2H), 7.42–7.22 (9m, 5H), 6.14–6.09 (m, 1H), 4.13
Pink solid (67%, 0.169 g, 0.067 mmol). Mp ≥ 300oC; NMR (75 MHz, DMSO-d6): δ 165.7, 153.0, 139.4, 128.4,
1H NMR (300 MHz, DMSO-d6): δ 11.14 (br s, 2H), 7.47– 127.5, 127.3, 74.8, 43.5, 23.3, 23.1, 22.4, 20.8, 20.1,
7.37 (m, 4H), 4.45 (s, 2H); 13C NMR (75 MHz, DMSO- 13.3; HRMS (ESI) calcd for C19H35NP [M-C4H3N2O3+H]+
d6): δ 160.2, 151.3, 132.1, 130.2, 128.4, 128.0, 86.5, 308.2502, found 308.2491.
50.5. Anal. Calcd for C11H10ClN3O3: C, 49.36; H, 3.77; N,
15.70. Found: C, 49.60; H, 3.81; N, 15.88.
2-Chloro-N-(tributyl-λ5-phosphanylidene)
benzenaminium 2,6-dioxo-1,2,3,6-
General procedure for the in situ synthesis of tetrahydropyrimidin-4-olate 6d:
1,1,1-tributyl-N-substituted-λ5-phosphanimines Light yellow solid (92%, 0.419 g, 0.092 mmol). Mp
5a-g:
183.3–185.6oC; 1H NMR (300 MHz, DMSO-d6): δ 10.18
To a solution of azide 2a-g (0.01 mmol) in dry THF (br s, 3H), 7.50 (d, J = 8.1 Hz, 1H), 7.27 (s, 2H), 7.12 (br
(20 mL), tributyl phosphine (0.025 mmol, 0.615 mL) s, 1H), 2.44–2.12 (m, 6H), 1.78–1.22 (m, 12H), 0.86 (t,
was added and the solution was stirred vigorously for J = 6.9 Hz, 9H); 13C NMR (75 MHz, DMSO-d6): δ 166.6,
20 mins at room temperature.
152.2, 137.0, 130.2, 128.2, 125.1, 124.8, 23.3, 23.1,
General procedure for synthesis of 6a-g:
a
22.6, 22.2, 21.4, 13.3. Anal. Calcd for C22H35ClN3O3P:
To
solution of 1,1,1-tributyl-N-substituted-λ5- C, 57.95; H, 7.74; N, 9.22. Found: C, 58.11; H, 7.93; N,
phosphanimine 5a-g (0.1 mmol) in dry THF (20 mL) 9.45.
barbituric acid 1 was added (116 mg, 0.1 mmol).
3-Bromo-N-(tributyl-λ5-phosphanylidene)
The reaction was stirred at room temperature for benzenaminium
2,6-dioxo-1,2,3,6-
2 h and consumption of the starting materials was tetrahydropyrimidin-4-olate 6e:
monitored by TLC. The precipitate formed was filtered Light yellow solid (83%, 0.410 g, 0.083 mmol). Mp
1
off and recrystallized from ethyl acetate/hexanes 139.4–141.0oC; H NMR (300 MHz, CD3OD): δ 7.38–
(1:2).
7.24 (m, 4H), 7.12 (dd, J = 3.2, 2.3 Hz, 1H), 2.54–2.38
N-(Tributyl-λ5-phosphanylidene)pentan-1- (m, 6H), 1.64–1.28 (m, 12H), 0.86 (t, J = 6.8 Hz, 9H); 13
C
aminium
olate 6a:
2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4- NMR (75 MHz, CD3OD): δ 169.4, 141.4, 132.7, 128.3,
124.6, 124.5, 119.6, 119.5, 24.9, 24.7, 24.2, 24.1, 22.8,
Pink solid (89%, 0.369 g, 0.089 mmol). Mp 171.2– 22.1, 13.8. Anal. Calcd for C22H35BrN3O3P: C, 52.80; H,
1
173.7oC; H NMR (300 MHz, CD3OD): δ 2.94 (q, J = 7.05; N, 8.40. Found: C, 53.08; H, 7.24; N, 8.85.
7.2 Hz, 2H), 2.63–2.54 (m, 2H), 2.25–2.09 (m, 6H),
4-Methoxy-N-(tributyl-λ5-phosphanylidene)
1.69 (s, 2H), 1.61–1.45 (m, 12H), 1.43–1.32 (m, 4H), benzenaminium
1.32–1.23 (m, 2H), 1.09–0.92 (m, 9H); 13C NMR tetrahydropyrimidin-4-olate 6f:
2,6-dioxo-1,2,3,6-
(75 MHz, CD3OD): δ 169.4, 78.2, 42.2, 32.6, 30.1, 25.1, Light yellow solid (84%, 0.379 g, 0.084 mmol). Mp
1
24.8, 24.2, 23.6, 22.5, 21.7, 14.5, 13.9. Anal. Calcd for 178.9–180.1oC; H NMR (300 MHz, DMSO-d6): δ 9.12
1020

I. O. Lebedyeva et al.
O
H+P
N
O
R
N3
2a,b
O
O
(Bu)3
R
HN
NH
OH
HN
NH
OH
HN
NH
5a-g
HN
NH
OH
PBu3
H+N
O-
O
O
- N2
N
O
R
O
HN
N
N
R
R
1
6a
: R = C5H11 (89%)
b: R = C6H11 (81%)
4a
3a,b
: R = Bn (63%)
b: R = 4-ClBn (67%)
e: 3-BrPh (83%)
f
: 4-MeOPh (84%)
c
: R = Bn (90%)
g: 4-NO2-Ph (73%)
d: 2-ClPh (92%)
Scheme 1. Synthesis of C5-amino barbiturates 4a-b and tributylphosphoranylidene salts of BA 6a-g.
(br s, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 9.0
Hz, 2H), 3.72 (s, 3H), 2.42–2.22 (m, 6H), 1.62–1.24
(m, 12H), 0.87 (t, J = 7.1 Hz, 9H); 13C NMR (75 MHz,
DMSO-d6): δ 165.8, 155.7, 152.9, 131.2, 122.6, 114.9,
55.3, 23.2, 23.0, 22.4, 21.2, 20.5, 13.3. Anal. Calcd
for C23H38N3O4P: C, 61.18; H, 8.48; N, 9.31. Found: C,
61.27; H, 8.71; N, 9.22.
Crystal data for 6f: C23H38N3O4P, MW 451.53,
orthorhombic, space group Pbca, a = 12.0018(3), b =
14.1177(2), c = 28.6949(6) Å, V = 4858.6(2) Å3, F(000)
Figure 1. Structure determination for C5-amino barbiturate 4a with
= 1952, Z = 8, T = -153oC, µ (CuKα) = 1.269 mm-1,
calcd = 1.235 g.cm-3, 2θmax 135 o (Supernova Dual CCD
gHMBC experiment.
D
area detector, CuKα radiation), GOF = 1.03, wR(F2) 10.5, 0.3 Hz). Thermal elimination of nitrogen led to the
= 0.101 (all 4380 data), R = 0.037 (3595 data with formation of 4a,b.
I > 2σI).
The structure of 4a was determined based on the
4-Nitro-N-(tributyl-λ5-phosphanylidene) one-bond and long-range couplings seen in the gHMBC
spectra. The benzyl protons at 4.22 ppm, excluding the
expected cross-peaks with the phenyl carbons, display
a coupling with the carbon at 87.0 ppm, which in turn
couples with the protons at 9.65 ppm. As seen in the 1H-
benzenaminium
tetrahydropyrimidin-4-olate 6g:
Light yellow solid (73%, 0.341 g, 0.073 mmol). Mp
171.1–174.4oC; 1H NMR (300 MHz, CD3OD): δ 16.0 (br
2,6-dioxo-1,2,3,6-
s, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 15N gHMBC spectrum, these protons are on the nitrogen
2.60–2.50 (m, 6H), 1.62–1.47 (m, 12H), 0.97 (t, J = 7.1 at 141 ppm and they couple with two carbonyl carbons.
Hz, 9H); 13C NMR (75 MHz, CD3OD): δ 169.4, 147.0, The apparent symmetry of the barbiturate moiety is
144.7, 127.1, 119.8, 119.7, 24.9, 24.7, 24.2, 22.7, 21.9, due to the rapid exchange of the OH proton between
13.8. Anal. Calcd for C22H35BrN4O5P: C, 56.64; H, 7.56; positions 4 and 6. The NH protons are also involved in
this exchange, and the two of them appear as a broad
peak in the 7.5–10.0 ppm region.
N, 12.01. Found: C, 56.92; H, 7.81; N, 12.33.
A
potential route towards C2 (4 or/and 6)
3. Results and discussion
iminobarbiturates 6a-g was studied using aza-Wittig
reaction [15] of phosphoro aza-ylides 5a-g with 1. This
reaction was expected to give either one or a mixture
of mono-, di- or tri-iminosubstituted barbiturates. In fact,
reaction of 5a-g with 1 gave stable tributylphosphorano
aza-ylidenes 6a-g (Scheme 1).
The structure of the reaction products 6a-g was
determined by an X-Ray study of 6f which confirmed
that the NH of the cation was H-bonded to the anion
of the salt. Interestingly, the positive charge transfer
of 5 from phosphorus to nitrogen stabilized the salt 6
thus preventing the usual aza-Witting imine formation.
Salts 6a-g occurred on addition of 1 to the in situ formed
tributylphosphoran aza-ylidenes 5a-g.
In this work we investigated the reaction of barbituric
acid C5 enol with various organic azides and phosphoro
aza-ylides.
To provide amination of 1 at C5 it was reacted it with
benzyl and 4-chlorobenzyl azides 2a,b following the
previously described method [12-14] (Scheme 1). 2D
NMR spectroscopy showed that the isolated products
4a,b were formed by amination reaction at C5 (Fig. 1).
Enol 1 undergoes a regioselective two-step amination
to form triazolines 3a,b which were observed in the
1H spectrum crude reaction mixture. The C5 proton
was detected as doublet of doublets at 6.63 ppm (J =
1021

Reaction of barbituric acid with organic
azides and phosphonium ylides
Figure 2. Molecular structure of 6f according to an X-ray diffraction study.
4. Conclusions
Acknowledgements
We report amination of barbituric acid at C5 with This work was supported by the Kenan Foundation
organic azides (benzyl and 4-chlorobenzyl azides) (University of Florida) and the King Abdulaziz University
through the in situ formation of triazolines followed (Saudi Arabia). The authors are grateful to Dr. C. D.
by thermal elimination of nitrogen. The aza-Wittig Hall, Mrs. Galyna Vakulenko, Dr. Eric Scriven and Mr.
reaction of barbituric acid with phosphoro aza-ylides Khanh Ha for reading the manuscript, and to Dr. M. C. A.
led to the unexpected formation of barbituric acid Dancel (University of Florida) for HRMS analyses.
tributylphosphoranylidene salts. The structure of the
final product representatives was determined using
X-ray and 2D NMR techniques.
References
[1] D. Thetford, A.P. Chorlton, J. Hardman, Dyes Pigm. [9] P. Singh, M. Kaur, P. Verma, Bioorg. Med. Chem.
59(2), 185 (2003)
Lett. 19(11), 3054 (2009)
[2] N.D. McClenaghan, C. Absalon, D.M. Bassani, [10] M.C. Rezende, P. Campodonico, E. Abuin,
J. Am. Chem. Soc. 125(43), 13004 (2003)
[3] R. Bartzatt, J. Pharm. Biomed. Anal. 29(5), 909
(2002)
[4] I. Bolz, M. Bauer,A. Rollberg, S. Spange, Macromol.
Symp. 287, 8 (2010)
[5] J.A. Vida, C.M. Samour, M.H. O’Dea, J.F. Reinhard,
J. Med. Chem. 18(7), 694 (1975)
[6] P.Y. Savechenkov, X. Zhang, D.C. Chiara,
J. Kossanyi, Spectrochim. Acta, Part A 57(6), 1183
(2001)
[11] B. Kafle, R.B. Bhattarai, H. Cho, Bull. Korean Chem.
Soc. 32(1), 31 (2011)
[12] Th. Curtius, Ber. Dtsch. Chem. Ges. 56B, 1577
(1923)
[13] Th. Curtius and K. Kaschig, J. Prakt. Chem. 125,
466 (1930)
D.S. Stewart, R. Ge, X. Zhou, D.E. Raines, [14] M. Regitz, Justus Liebigs Ann. Chem. 676, 101
J.B. Cohen, S.A. Forman, K.W. Miller, K.S. Bruzik,
J. Med. Chem. 55(14), 6554 (2012)
[7] S.R. Guillen, C.M. Guzman, Pharmazie 43(12), 827
(1988)
(1964)
[15] F. Palacios, C. Alonso, D. Aparicio, G. Rubiales,
J. M. de los Santos, Tetrahedron 63 (3), 523
(2007)
[8] K.M. Khan, M. Ali, A. Ajaz, S. Perveen,
M.I. Choudhary, Atta-ur-Rahman, Lett. Drug Des.
Discovery 5(4), 286 (2008)
1022