Synthesis of Phosphorus, arsenic and antimony ylides containing the 1,3- dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione fragments

Article abstract of DOI:10.2174/157017809787003106

The ylides Ph₃E-C₆H₆N₂O ₃ (7, E = P (a), As (b), Sb (c)) have been prepared through the reaction of Ph₃E and 5- bromo-1,3-dimethyl-2,4,6(1H,3H,5H)- pyrimidinetrione (5-bromo-1,3-dimethylbar

Full text of DOI:10.2174/157017809787003106

Letters in Organic Chemistry, 2009, 6, 1-3
1
Synthesis of Phosphorus, Arsenic and Antimony Ylides Containing the 1,3-
Dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione Fragments
Kamal Sweidan*,a, Ahmed Al-Sheikhb, Bassam Sweilehc, Mahmoud Sunjukd and Norbert Kuhne
aFaculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
bFaculty of Pharmacy, Petra University, Amman, Jordan
cDepartment of Chemistry, the University of Jordan, Amman, Jordan
dDepartment of Chemistry, Al-Hashemite University, Amman, Jordan
eInstitut für Anorganische Chemie der Universität Tübingen, Germany
Received April 24, 2008: Revised August 15, 2008: Accepted August 28, 2008
Abstract: The ylides Ph3E-C6H6N2O3 (7, E = P (a), As (b), Sb (c)) have been prepared through the reaction of Ph3E and 5-
bromo-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione (5-bromo-1,3-dimethylbarbituric acid) 6 in the presence of trieth-
ylamine. Their characterisation was performed by nuclear magnetic resonance (NMR), mass spectrometry (MS) and ele-
mental analysis.
Keywords: 1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione (1,3-dimethylbarbituric acid), nuclear magnetic resonance, synthe-
sis, zwitterionic state.
INTRODUCTION
R
O
R
R
O
O
Barbituric acid derivatives have found increasing atten-
tion due to their interaction with the central nervous system.
Recently, new biomedical applications have been developed
for cancer and AIDS therapy [1]. 5-Diaminomethyl-enebar-
biturate derivatives were synthesized starting from barbituric
acid and carbodiimide. Those compounds exhibit marked
charge separation as demonstrated by X-ray structural analy-
sis [2].
EPh3
EPh3
O
R
(E = As (a), Sb (b), Bi (c))
(E = As, Sb), R = Ph
4
5
Fig. (1). Chemical structures of cyclopentadienyl (4) and Mel-
drum's acid derivatives (5) ylides.
Phosphorus ylides (3) [3] are stabilized by methylene
fragments C(X)Y in which X and Y have ꢀ-acceptor proper-
ties the negative charge being delocalized efficiently [4], as
shown in Scheme 1. This has been demonstrated by Horner,
Oediger and Pappas [5-7] reacting triphenylphosphine dihal-
ides (1) with heterocycles containing a CH-acidic methylene
group (2) in the presence of bases.
We now report the synthesis of the barbituric acid ylides
Ph3E-C6H6N2O3 (7, E = P (a), As (b), Sb (c)) by the direct
reaction of Ph3E and 5-bromo-1,3-dimethylbarbituric acid
(6) and their characterization with NMR, MS and elemental
analyses.
RESULTS AND DISCUSSION
Y
Y
2Et3N
(C6H5)3PX2
H2C
(C6H5)3P
C
In general, phosphorus ylides (3) and their heavier ana-
logues are prepared by the reaction of R3E with in situ gen-
erated carbenes [9-11] or from the reaction of CH-acidic
methylene derivatives with R3EX2 (X2 = O, CO3, 2 Cl) com-
pounds [4,12-14]. Starting from 5-bromo-1,3-dimethyl-
barbituric acid (6) [15], which is more reactive compared to
the corresponding chlorine derivative [16], and Ph3E (E = P,
As, Sb) in the presence of triethylamine we obtained the title
compounds Ph3E-C6H6N2O3 (7, E = P (a), As (b), Sb (c)), as
shown in Scheme 2; for compound 6, an improved synthesis
is given which bases on a bromination reaction that takes
place in an alkaline aqueous medium under mild conditions
with cheap reagents and high yield.
X
X
2
3
1
Scheme 1.
Other procedures for the synthesis of Wittig type barbi-
turic acid ylides using a multistep sequence of reactions [8]
have been reported. The cyclopentadienyl ylides of the heav-
ier group 15 elements (4) [9-10] and the corresponding Mel-
drum’s acid derivatives (5) (E = As, Sb, Bi) [4] have been
published previously, Fig. (1).
*Address correspondence to this author at the Faculty of Pharmacy, Al-
Zaytoonah University of Jordan, Fax: + 962-6-4291432, P.O. Box 130
Amman, Jordan; E-mail: kamal_sweidan@hotmail.com
Supposedly, the reaction starts with the nucleophile at-
tack of Ph3E at C(5) of compound 6 followed by deprotona-
tion of the onium salt formed as an intermediate. The rate of
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

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Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Sweidan et al.
O
O
O
O
O
N
N
N
N
N
Ph3E
Et3N
Br
H
H
H
(NaOH : Br2)
1 : 1
Br
Et3NH
O
EPh3
O
O
N
O
(E = P (a), As (b), Sb (c))
6
7
Scheme 2.
ylide formation monitored by TLC, decreases in the order E
= P » As ꢀ Sb.
a Finnigan TQS 70 by 70 eV in nitrobenzylalcohol-matrix at
30 °C. Elemental analysis was determined by elemental ana-
lyzer from Carlo Erba Company, model 1106. Melting points
were obtained by device from Buechi, model 510.
Compounds 7 are obtained after recrystallisation in good
yields as stable solids, their composition and structures are
confirmed by NMR and MS data and by elemental analysis
(see Experimental). The properties of 7a correspond to those
reported in the literature [8]. Comparison of 7a with the data
of the methylene compound 8 [17] reveals a slight downfield
shift of the 31P NMR signal the hybridization of the carbon
atom attached at the phosphonium centre being subject of
change. On comparison with similar 1,3-dimethylbarbituric
5-Bromo-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione
(6)
5 mmol of 1,3-dimethylbarbituric acid was dissolved in
10.0 mL of 0.5 M of NaOH solution, the resulting solution
was kept at 0-3 °C while 0.26 mL of Br2 was added slowly.
The mixture was stirred at 25 °C for further 2 h. The
resulting precipitate was filtered and washed with water. The
product was dried under vacuum.
1
acid derivatives [18], we found the H and 13C NMR data of
the compounds 7 to be in the expected range. It should be
noted that the pyridinium ylide 9, prepared from 5,5-
dibromo-1,3-dimethylbarbituric acid and pyridine [19],
could not be obtained by the method reported here, Fig. (2).
1
Yield: 90%; m.p. 95-97 °C; H NMR (250.13 MHz,
CDCl3): 3.26 (s, 6H, 1,3B-Me); 5.81 (s, 1H, C5 H) ppm. 13C
B
NMR (62.90 MHz, CDCl3): 28.7 (1,3B-Me); 49.4 (C5 );
B
151.4 (C2 ); 162.3 (C4,6
)
B
ppm. Anal. Calcd. for
B
O
O
C6H7N2O3Br: C, 30.7; H, 3.0; N, 11.9. Found: C, 30.3; H,
3.2; N, 11.6%.
N
N
N
H2
C
H2
C
O
PPh3
O
N
General Procedure for the Synthesis of Ylides Ph3E-
C6H6N2O3 (7)
N
O
O
5 mmol of corresponding Ph3E [E = P (a), As (b), Sb (c)]
was added to a stirred solution of 5 mmol of 6 in 30 mL of
dichloromethane. After addition of 0.90 mL (6.5 mmol) of
triethylamine, stirring was continued at 25 °C for a specified
time (5 h for (7a), 24 h for (7b & 7c)). The resulting solution
was extracted with 10 mL of water. The organic layer was
dried over anhydrous sodium sulfate and evaporated in vac-
uum to dryness. The residue was recrystallised from di-
chloromethane/diethylether.
8
9
Fig. (2). Chemical structures of phosphonium (8) and pyridinium
(9) ylides of 1,3-dimethyl-5-methylene barbituric acid.
In addition, all attempts to prepare the phosphorus ylide
5 (E = P) by the analogous reaction described for the synthe-
sis of the corresponding arsenic, antimony and bismuth de-
rivatives (5), failed. The barbituric acid ylides presented here
may serve as useful precursors for the synthesis of 5-
methylenebarbituric acid derivatives in the direction of a
Wittig type reaction. We are currently investigating reactions
of compounds 7a with carbonyl compounds and will report
on our results as well as on the evaluation of their therapeu-
tic and pharmacological efficiency in near future.
1,3-Dimethyl-5-(triphenylphosphoranylidene)-2,4,6(1H,3H,
5H) pyrimidinetrione (7a)
1
Yield: 82%; m.p. 264-266 °C; H NMR (250.13 MHz,
CDCl3): 3.15 (s, 6H, 1,3B-Me); 7.55-7.85 (m, 15H, 3Ph)
ppm. 13C NMR (62.90 MHz, CDCl3): 27.3 (1,3B-Me); 123.7,
128.4, 132.3, 133.8 (Ph); 154.4 (C2 ); 163.4 (C4,6B) ppm. 31
P
B
NMR (101.20 MHz, CDCl3): 16.8 ppm.ꢀMS (FAB): m/z (%)
= 417 (100) [M+]; 403 (30); 390 (18); 375 (21); 209 (5).
Anal. Calcd. for C24H21N2O3P: C, 69.2; H, 5.1; N, 6.7.
Found: C, 68.8; H, 5.2; N, 7.1%.
EXPERIMENTAL
Materials and Instruments
All experiments have been performed in purified solvents
under argon. All the following chemicals and reagents were
purchased from Aldrich: 1,3-dimethylbarbituric acid, bro-
mine, sodium hydroxide, triethylamine, triphenylphosphine,
triphenylarsenic and triphenylantimony. Nuclear magnetic
resonance (NMR) spectra were acquired by a Brucker DRX
250 NMR spectrometer with tetramethylsilane (TMS) and
85% H3PO4 as external standards of (1H & 13C) and 31P
NMR, respectively. The FAB-mass spectra were obtained on
1,3-Dimethyl-5-(triphenylarsoranylidene)-2,4,6(1H,3H,5H)
pyrimidinetrione (7b)
Yield: 74%; m.p. 270-272 °C; 1H NMR (250.13 MHz,
CDCl3): 3.11 (s, 6H, 1,3B-Me); 7.44-7.63 (m, 15H, 3Ph)
ppm. 13C NMR (62.90 MHz, CDCl3): 26.8 (1,3B-Me); 125.4,
127.1, 133.0, 134.7 (Ph); 154.0 (C2 ); 164.4 (C4,6B)ppm.ꢀMS
B
(FAB): m/z (%) = 460 (100) [M+]; 421 (14); 407 (32); 314

Synthesis of Phosphorus, Arsenic and Antimony Ylides Containing
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
3
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B
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ACKNOWLEDGEMENT
Financial support by the Deutsche Forschungsgemein-
schaft and the Higher Council for Science and Technology
of Jordan is gratefully acknowledged.
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