Synthesis, structure and reactions of 1,3-dimethyl-5-bis(thiomethyl) methylenebarbituric acid

Article abstract of DOI:10.1515/znb-2009-0114

1,3-Dimethyl-5-bis(thiomethyl)methylenebarbituric acid (8) is obtained from 1,3-dimethylbarbituric acid and CS₂/NEt₃ followed by alkylation with methyl iodide. Compound 8 reacts with aqueous ammonia to give 5-amino(thiomethyl)methyle

Full text of DOI:10.1515/znb-2009-0114

Synthesis, Structure and Reactions of
1,3-Dimethyl-5-bis(thiomethyl)methylenebarbituric Acid
Kamal Sweidana, Ahmed Abu-Rayyanb, Ahmad Al-Sheikhc, Ca¨cilia Maichle-Mo¨ßmerd,
Manfred Steimannd, and Norbert Kuhnd
a Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P. O. Box (130) 11733, Amman, Jordan
b Faculty of Pharmacy, Al Isra Private University, P. O. Box 22 and 23, Al Isra University Post Office,
11622 Jordan
c Department of Pharmacy, The University of Petra, P. O. Box 961343, Amman, Jordan
d Institut fu¨r Anorganische Chemie der Universita¨t Tu¨bingen, Auf der Morgenstelle 18,
D-72076 Tu¨bingen, Germany
Reprint requests to Dr. K. Sweidan. E-mail: kamal sweidan@hotmail.com, or to
Prof. Dr. N. Kuhn. E-mail: norbert.kuhn@uni-tuebingen.de
Z. Naturforsch. 2009, 64b, 106 – 110; received October 22, 2008
Dedicated to Professor Otto J. Scherer on the occasion of his 75th birthday
1,3-Dimethyl-5-bis(thiomethyl)methylenebarbituric acid (8) is obtained from 1,3-dimethyl-
barbituric acid and CS2/NEt3 followed by alkylation with methyl iodide. Compound 8 reacts with
aqueous ammonia to give 5-amino(thiomethyl)methylene-1,3-dimethylbarbituric acid (9). With ben-
zylamine, the thiomethyl substituent in 9 is replaced to give 5-amino(benzylamino)methylene-1,3-
dimethylbarbituric acid (10) while with methanesulfonic acid the sulfonate salt 11 is formed. The
crystal structures of 8 and 9 are reported.
Key words: Heterocycles, Barbituric Acid, Alkene, Crystal Structure
Introduction
In heterocycles, the carbon atoms of exocyclic
methylene substituents act as nucleophilic or elec-
trophilic centers depending on the electronic prop-
erties of the heterocycle. Thus, 1,3,4,5-tetramethyl-
2-methyleneimidazoline (1) [1] exhibits ylidic prop-
erties and can be coordinated at electron-poor cen-
ters [2] while 2,2-dimethyl-5-methylene-4,6-dioxo-
1,3-dioxane (2) [3], a Meldrum’s acid derivative, is
attacked by nucleophiles to form zwitterionic com-
pounds (3, E = C5H5N, PPh3) [3, 4]. Similarly, 1,3-
dimethyl-5-methylene-2,4,6-trioxopyrimidine (4), the
corresponding barbituric acid derivative, forms stable
base adducts (5) [5] and dimerizes in the condensed
phase [6] (Scheme 1).
Though 2,2-dimethyl-5-bis(thiomethyl)methylene-
4,6-dioxo-1,3-dioxane (6) [7] has been widely used
as precursor for Meldrum’s acid derivatives [8 –
13], 5-bis(thiomethyl)methylene-2,4,6-trioxopyrimid-
ine (7) as the corresponding barbituric acid derivative
has been mentioned to a much lesser extent [7, 10, 14].
Owing to their medical relevance, we are interested in
Scheme 1.
1,3-dimethylbarbituric acid derivatives and report on a
new facile synthesis of 8 (Scheme 2), its crystal struc-
ture and some reactions.
c
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K. Sweidan et al. · 1,3-Dimethyl-5-bis(thiomethyl)methylenebarbituric Acid
107
Table 1. Crystal data and structure refinement for C9H12N-
O3S2 (8) and C8H11N3O3S (9).
8
9
Empirical formula
Formula weight
Temperature, K
C9H12N2O3S2
260.33
173
MoKα ; 0.71073
monoclinic monoclinic
C8H11N3O3S
229.26
˚
Radiation; λ, A
Crystal system
Space group
P21/c
C2/c
˚
a, A
4.041(1)
13.218(3)
20.592(4)
91.09(3)
1099.7(4)
4
9.220(1)
16.329(2)
13.283(2)
103.70(1)
1942.8(4)
8
˚
b, A
˚
c, A
β, deg
3
˚
Volume, A
Z
Density, calculated, g cm−3
1.572
1.568
0.324
Absorption coefficient, mm−1 0.477
F(000), e
544
3.24 – 26.37
15186 / 2230
960
3.16 – 26.37
13719 / 1994
θ Range data collection, deg
Reflections collected /
independent
Scheme 2.
Results and Discussion
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final indices R1/wR2
[I ≥ 2σ(I)]
full-matrix least-squares on F2
2230 / 0 / 194
1.200
1994 / 0 / 181
1.132
Synthesis and crystal structure of 1,3-dimethyl-5-bis-
(thiomethyl)methylenebarbituric acid (8)
0.0543 / 0.0918 0.0592 / 0.1140
Bis(thioalkyl)ylidene derivatives may commonly be
prepared from CH-acidic methylene compounds and
carbon disulfide in the presence of bases, followed by
S-alkylation [8]. We obtained 1,3-dimethyl-5-bis(thio-
methyl)methylenebarbituric acid (8) from 1,3-dimeth-
ylbarbituric acid as yellow crystals in good yield.
A single crystal structure analysis of 8 was per-
formed to get further insight into its structure and
bonding (Tables 1 and 2). Compound 8 crystallizes in
the monoclinic space group P21/c with Z = 4.
Final indices R1/wR2
(all data)
0.0767 / 0.0.978 0.0808 / 0.1218
Extinction coefficient
Largest diff. peak / hole, e A
0.000(1)
+0.29 / −0.28
0.000(1)
+0.34 / −0.22
−3
˚
˚
Table 2. Bond lengths (A) and angles (deg) for C9H12
N2O3S2 (8).
-
S(1)–C(1)
S(2)–C(1)
N(1)–C(7)
N(1)–C(6)
1.727(3)
1.740(3)
1.380(4)
1.468(4)
1.399(4)
1.221(4)
1.222(3)
1.452(4)
S(1)–C(2)
S(2)–C(3)
N(1)–C(5)
N(2)–C(7)
N(2)–C(8)
O(2)–C(7)
C(1)–C(4)
C(4)–C(9)
1.799(3)
1.801(3)
1.402(4)
1.378(4)
1.471(4)
1.225(4)
1.399(4)
1.456(4)
The structure (Fig. 1) reveals the folded arrange- N(2)–C(9)
ment of the planes adjacent to the exocyclic olefinic
O(1)–C(5)
O(3)–C(9)
C(4)–C(5)
C(1)–S(1)–C(2)
108.8(2)
124.7(3)
117.8(3)
118.0(3)
126.5(2)
113.4(2)
119.2(3)
118.8(3)
116.1(3)
121.3(3)
118.6(3)
116.2(2)
C(1)–S(2)–C(3)
C(7)–N(1)–C(6)
C(7)–N(2)–C(9)
C(9)–N(2)–C(8)
C(4)–C(1)–S(2)
C(1)–C(4)–C(5)
C(5)–C(4)–C(9)
O(1)–C(5)–C(4)
O(2)–C(7)–N(2)
N(2)–C(7)–N(1)
O(3)–C(9)–C(4)
104.5(2)
117.5(3)
124.5(2)
117.4(3)
120.1(2)
121.8(3)
118.6(2)
125.0(3)
121.8(3)
116.8(3)
125.1(3)
C(7)–N(1)–C(5)
C(5)–N(1)–C(6)
C(7)–N(2)–C(8)
C(4)–C(1)–S(1)
S(1)–C(1)–S(2)
C(1)–C(4)–C(9)
O(1)–C(5)–N(1)
N(1)–C(5)–C(4)
O(2)–C(7)–N(1)
O(3)–C(9)–N(2)
N(2)–C(9)–C(4)
bond (interplanar angle S(1)C(1)S(2)/C(5)C(4)C(9)
29.8(1)◦) which may be a consequence of sterical in-
˚
Fig. 1. View of the molecule of C9H12N2O3S2 (8) in the teraction (S(1)···O(1) 3.142, S(2)···O(3) 2.681 A).
crystal.
Apparently, the different orientation of the SMe sub-
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K. Sweidan et al. · 1,3-Dimethyl-5-bis(thiomethyl)methylenebarbituric Acid
˚
Table 3. Bond lengths (A) and angles (deg) for C8H11N3O3S
stituents towards the olefinic bond is influenced by
packing effects. The elongation of the central olefinic
bond (C(1)–C(4) 1.399(4) A) is also caused by the
push-pull effect of the substituents attached thereon.
For further bond lengths and angles see Table 2. Over
all, the structure of 8 confirms its zwitterionic nature
and parallels that of 6 reported by us recently [15].
(9).
˚
C(1)–C(12)
C(1)–C(2)
C(2)–N(3)
N(3)–C(8)
C(4)–N(5)
N(5)–C(10)
C(12)–N(13)
S(14)–C(15)
1.425(4)
1.436(4)
1.405(4)
1.478(4)
1.381(4)
1.478(4)
1.324(4)
1.808(3)
C(1)–C(6)
C(2)–O(7)
N(3)–C(4)
C(4)–O(9)
N(5)–C(6)
C(6)–O(11)
C(12)–S(14)
1.437(4)
1.225(3)
1.374(4)
1.221(3)
1.398(3)
1.228(3)
1.748(3)
Thiomethylate substitution in 1,3-dimethyl-5-bis(thio-
methyl)methylenebarbituric acid (8) and subsequent
reactions. The crystal structure of 5-amino(thiometh-
yl)methylene-1,3-dimethylbarbituric acid (9)
C(12)–C(1)–C(6)
C(6)–C(1)–C(2)
O(7)–C(2)–C(1)
C(4)–N(3)–C(2)
C(2)–N(3)–C(8)
O(9)–C(4)–N(5)
C(4)–N(5)–C(6)
C(6)–N(5)–C(10)
O(11)–C(6)–C(1)
N(13)–C(12)–C(1)
C(1)–C(12)–S(14)
119.5(2)
120.9(2)
124.6(3)
124.6(2)
118.1(2)
121.3(3)
125.1(2)
116.8(2)
125.9(2)
120.1(3)
120.7(2)
C(12)–C(1)–C(2)
O(7)–C(2)–N(3)
N(3)–C(2)–C(1)
C(4)–N(3)–C(8)
O(9)–C(4)–N(3)
N(3)–C(4)–N(5)
C(4)–N(5)–C(10)
O(11)–C(6)–N(5)
N(5)–C(6)–C(1)
N(13)–C(12)–S(14)
C(12)–S(14)–C(15)
119.5(2)
119.0(2)
116.5(2)
117.2(2)
122.1(3)
116.6(2)
118.0(2)
118.0(2)
116.1(2)
119.2(2)
102.3(2)
Thiomethylate substitution by nucleophiles start-
ing from active electrophilic bis(thiomethyl)methyl-
ene compounds is a useful synthetic method [8]. With
aqueous ammonia, 8 reacts to give 5-amino(thiometh-
yl)methylene-1,3-dimethylbarbituric acid (9). The re-
sults of its crystal structure analysis are shown in Ta-
ble 1 and Fig. 2. The structure parallels that of 8 con-
cerning the six-membered ring including the exocyclic
N(13)–H(13a)···O(9a) 147.2◦) to form a polymeric
chain structure (Fig. 3). For further bond lengths and
angles see Table 3.
˚
olefinic bond (C(1)–C(12) 1.425(4) A). Though the
Neither excess ammonia nor more forcing condi-
tions led to the substitution of the second thiomethy-
late substituent which apparently needs stronger bases
or, alternatively, the use of acidic conditions. In fact,
the thiomethylate substituent in 9 is replaced by ben-
zylamine in refluxing ethanol to give amino(benz-
ylamino)methylenebarbituric acid (10), while with
methanesulfonic acid the thiomethylate substituent in 9
is replaced selectively after protonation of the amino
group to give the salt 11.
amino substituent preferentially acts as a +M donor,
there is only minor lengthening of the olefinic C–S
˚
bond (C(12)–S(14) 1.748(3), C(12)–N(13) 1.324(4) A;
N(13)–C(12)–S(14) 119.2(2)◦). The interplanar angle
between the planes C(2)C(1)C(6) and N(13)C(12)–
S(14) is 2.9◦; the almost coplanar orientation of
these fragments may be influenced by an intramolec-
ular hydrogen bond as a result of the enolate-type
˚
charge distribution (O(11)···H(13b) 1.840 A; C(6)–
O(11)···H(13b) 97.6, O(11)···H(13b)–N(13) 143.3◦).
In addition, the molecules of 9 are linked by in-
Concluding Remarks
˚
termolecular NHO bonds (H(13a)···O(9a) 2.071 A;
The synthesis of 1,3-dimethyl-5-bis(thiomethyl)-
methylenebarbituric acid (8) follows the conception of
the analogous Meldrum’s acid derivative 6 which plays
an important role in organic synthesis. Thus, 9 enables
us to parallel the nucleophilic attack at the exocyclic
methylene carbon atom of 6 on which we reported re-
cently [16]. In contrast to Meldrum’s acid, barbituric
acid is stable towards acids. Therefore, we are inves-
tigating the oxidation of the thiomethyl substituents to
sulfinyl and sulfonyl groups to make the push-pull-type
olefinic bond in 9 a less polarized electron-poor one.
We will report on our results in the near future.
Experimental Section
All starting materials were purchased from commercial
sources and used without further purification. Experiments
Fig. 2. View of the molecule of C8H11N3O3S (9) in the crys-
tal.
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K. Sweidan et al. · 1,3-Dimethyl-5-bis(thiomethyl)methylenebarbituric Acid
109
Fig. 3. View of the poly-
meric hydrogen-bonded
chain of C8H11N3O3S
(9) in the crystal.
were performed in purified solvents under argon. Single crys- recrystallization from DMSO/CH2Cl2 as colorless crystals. –
tals of C9H12N2O3S2 (8) and C8H11N3O (9) were obtained 1H NMR (400.13 MHz, [D6]DMSO): δ = 2.41 (s, 3 H, SMe),
by slow evaporation of a diethyl ether solution (8) or by slow 3.20 (s, 6 H, NMe), 8.43, 11.63 (2 s, 2 H, NH2). – 13C NMR
cooling of a nitromethane solution (9).
(100.64 MHz, [D6]DMSO): δ = 13.7 (SMe), 27.2 (NMe),
88.9 (C5), 150.5 (C2), 162.7 (C4,6), 177.5 (C–SMe). – MS
(EI, 70 eV): m/z (%) = 229 (16) [M]+, 214 (12) [M – Me]+,
182 (100) [M – SMe]+ and further fragments. – Elemental
analysis for C8H11N3O3S (229.26): calcd. C 41.91, H 4.84,
N 18.33; found C 41.62, H 5.19, N 17.93.
CCDC 705675 (8) and CCDC 705674 (9) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data request/cif.
C
H N O (10)
14 16 4 3
C H N O S (8)
9
12 2 3 2
To a solution of 9 (0.6 g, 2.6 mmol) in ethanol (15 mL),
To a solution of 1,3-dimethylbarbituric acid (7.2 g,
benzylamine (0.37 mL, 3.4 mmol) was added. The mix-
ture was refluxed for 15 h. The precipitate was filtered off
and dried in vacuo to give 0.55 g (73 %) of the product af-
ter recrystallization from CHCl3/diethyl ether. – 1H NMR
(400.13 MHz, CDCl3): δ = 3.24 (s, 6 H, NMe), 4.39 (s,
2 H, CH2), 5.12 (s, 1 H, NH), 7.26 – 7.43 (m, 5 H, Ph),
10.46, 11.20 (2 s, NH2). – 13C NMR (100.64 MHz, CDCl3):
δ = 27.6 (NMe), 44.7 (CH2), 79.8 (C5), 127.3, 129.2, 130.3,
134.5 (Ph), 151.0 (C2), 162.7 (C4,6), 163.5 (C–NH2). – MS
(EI, 70 eV): m/z (%) = 288 (100) [M]+, 271 (82) [M –
NH2]+, and further fragments. – Elemental analysis for
C14H16N4O3 (288.30): calcd. C 58.32, H 5.59, N 19.43;
found C 58.68, H 5.87, N 19.01.
46 mmol) in DMSO (20 mL) triethylamine (12.9 mL,
92 mmol) and carbon disulfide (2.8 mL, 46 mmol) were
added. The mixture was stirred for 1 h at r. t., and
iodomethane (6.0 mL, 92 mmol) was added dropwise
at −18 ◦C. The mixture was stirred for further 5 h at r. t. and
then diluted with a small amount of ice. Scratching of the
walls of the vessel containing the mixture precipitated the
product which was filtered off and washed with water and
light petroleum/THF to give 6.5 g (54 %) from diethyl ether
1
as yellow crystals. – H NMR (400.13 MHz, [D6]DMSO):
δ = 2.52 (s, 6 H, SMe), 3.30 (s, 6 H, NMe). – 13C NMR
(100.64 MHz, [D6]DMSO): δ = 21.6 (SMe), 27.4 (NMe),
106.4 (C5), 150.1 (C2), 158.5 (C4,6), 194.1 (C–SMe). – Ele-
mental analysis for C9H12N2O3S2 (260.33): calcd. C 41.52,
H 4.65, N 10.76; found C 41.13, H 4.88, N 10.43.
C H N O S (11)
9
15 3 9 2
To a solution of 9 (0.8 g, 3.1 mmol) in CH2Cl2 (10 mL),
methanesulfonic acid (0.2 mL, 3.1 mmol) was added slowly.
C H N O S (9)
8
11 3 3
To a solution of 8 (1.2 g, 4.6 mmol) 25 mL of a 25 % aque- The mixture was stirred at r. t. for 6 h. The resulting precipi-
ous ammonia solution were added. The mixture was stirred tate was filtered off and dried in vacuo to give 0.50 g (45 %)
at r. t. for 30 min. The resulting precipitate was filtered off of the product after recrystallization from DMSO/CH2Cl2 as
and dried in vacuo to give 0.86 g (82 %) of the product after colorless crystals. – 1H NMR (400.13 MHz, [D6]DMSO):
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110
K. Sweidan et al. · 1,3-Dimethyl-5-bis(thiomethyl)methylenebarbituric Acid
δ = 2.68 (s, 6 H, MeSO3), 3.07 (s, 6 H, NMe), 7.20 (t, 3 calcd. C 28.95, H 4.05, N 11.25; found C 28.53, H 4.48,
H, NH3, 1J = 52 Hz). – 13C NMR (100.64 MHz, D2O): N 11.43.
δ = 27.8 (NMe), 38.4 (MeSO3), 68.4 (C5), 153.4 (C2), 165.8
Acknowledgement
(C4,6), C–SMe not observed. – MS (EI, 70 eV, M = cation):
m/z (%) = 278 (4) [M]+, 276 (37) [M – 2 H]+, 229 (97)
[M – MeOOH]+, 200 (100) [M – SO2Me]+ and further frag-
ments. – Elemental analysis for C9H15N3O9S2 (373.36):
Financial support by the Deutsche Forschungsgemein-
schaft and the Higher Council for Science and Technology
of Jordan is gratefully acknowledged.
[1] N. Kuhn, H. Bohnen, J. Kreutzberg, D. Bla¨ser,
R. Boese, J. Chem. Soc., Chem. Commun. 1993, 1136.
[2] N. Kuhn, H. Bohnen, R. Boese, D. Bla¨ser, Chem. Ber.
1994, 127, 1405; H. Schumann, M. Glanz, J. Win-
terfeld, H. Hemling, N. Kuhn, H. Bohnen, D. Bla¨ser,
R. Boese, J. Organomet. Chem. 1995, 493, C14;
N. Kuhn, H. Bohnen, G. Henkel, J. Kreutzberg, Z. Na-
turforsch. 1996, 51b, 1267; N. Kuhn, M. Go¨hner,
M. Steimann, Z. Anorg. Allg. Chem. 2001, 627, 2048;
N. Kuhn, A. Abu-Rayyan, M. Steimann, M. Stro¨bele,
Z. Anorg. Allg. Chem. 2004, 630, 1229.
[3] R. F. C. Brown, F. W. Eastwood, G. L. McMullen, Aust.
J. Chem. 1977, 30, 179; M. Zia-Ebrahimi, G. W. Huff-
man, Synthesis 1996, 215.
[4] N. Kuhn, A. Al-Sheikh, S. Schwarz, M. Steimann, Z.
Naturforsch. 2005, 60b, 398.
[5] N. Kuhn, A. Kuhn, E. Niquet, M. Steimann, K. Swei-
dan, Z. Naturforsch. 2005, 60b, 924.
[6] K. Sweidan, N. Kuhn, unpublished results.
[7] X. Huang, B. Chen, Synthesis 1986, 967.
[8] W. Doelling, Science of Synthesis 2005, 24, 461.
[9] A. Ben Cheik, J. Cuche, N. Manisse, J. C. Pommelet,
K. P. Netsch, P. Lorencak, C. Wentrup, J. Org. Chem.
1991, 56, 970; C. O. Kappe, G. Kollenz, R. Leung-
Toung, C. Wentrup, J. Chem. Soc., Chem. Commun.
1992, 487; D. W. J. Moloney, M. W. Wong, R. Flam-
mang, C. Wentrup, J. Org. Chem. 1997, 62, 4240;
H. Bibas, D. J. W. Moloney, R. Neumann, M. Shtaiwi,
P. V. Bernhardt, C. Wentrup, J. Org. Chem. 2002, 67,
2619.
[10] F. Ye, B. Chen, X. Huang, Synthesis 1989, 317.
[11] X. Huang, B. Chen, Synthesis 1987, 480; Z. Huang,
X. Shi, Synth. Commun. 1990, 20, 1321; X. Huang,
B. Chen, G. Wu, H. Chen, Synth. Commun. 1991, 21,
1213.
[12] A. J. Blake, G. A. Hunter, H. McNab, J. Chem. Soc.,
Chem. Commun. 1990, 734; G. A. Hunter, H. McNab,
J. Chem. Soc., Perkin Trans. 1 1995, 1209.
[13] F. Chulburu, S. Lacombe, G. Pfister-Guilouzo, A. Ben
Cheik, J. Cuche, J. C. Pommelet, J. Am. Chem. Soc.
1991, 113, 1954; M. Beit-Yannai, X. Chen. Z. Rap-
poport, J. Chem. Soc., Perkin Trans. 2 2001, 1354;
B. Erb, B. Rigo, B. Pirotte, D. Couturier, J. Heterocycl.
Chem. 2002, 39, 15.
[14] K. A. Jensen, L. Henriksen, Acta Chem. Scand. 1968,
22, 1107; W. Ried, M. A. Jacobi, Chem. Ber. 1987, 121,
805.
[15] N. Kuhn, A. Al-Sheikh, C. Maichle-Mo¨ßmer,
M. Steimann, K. Sweidan, Z. Naturforsch. 2007, 62b,
1221.
[16] A. Al-Sheikh, K. Sweidan, C. Maichle-Mo¨ßmer,
M. Steimann, N. Kuhn, Z. Naturforsch. 2009, 64b, 101.
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