Synthesis and structure of pyrimidinophanes with a sulfur atom in the spacer

Article abstract of DOI:10.1016/j.mencom.2010.01.002

The cyclization of 1,3-bis(ω-bromoalkyl)uracils with sodium sulfide led to pyrimidinophanes, containing one uracil unit and an S atom in the spacer, macrocyclic structure was confirmed by X-ray data; the S atom in bridge can be oxidized into sulfoxide or sulfone or converted into sulfonium ion.

Full text of DOI:10.1016/j.mencom.2010.01.002

Mendeleev
Communications
Mendeleev Commun., 2010, 20, 4–6
Synthesis and structure of pyrimidinophanes
with a sulfur atom in the spacer
Anton E. Nikolaev,* Vyacheslav E. Semenov, Olga A. Lodochnikova,
Shamil K. Latypov and Vladimir S. Reznik
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Centre of the Russian Academy
of Sciences, 420088 Kazan, Russian Federation. Fax: +7 843 273 2253; e-mail: aenikolaev@iopc.knc.ru
DOI: 10.1016/j.mencom.2010.01.002
The cyclization of 1,3-bis(ω-bromoalkyl)uracils with sodium sulfide led to pyrimidinophanes, containing one uracil unit and an
S atom in the spacer, macrocyclic structure was confirmed by X-ray data; the S atom in bridge can be oxidized into sulfoxide or
sulfone or converted into sulfonium ion.
We consider pyrimidine-containing macrocycles – pyrimidino-
O
phanes – to be promising compounds, which are of interest as
O
(CH2)5Br
biologically active compounds,1 as compounds capable of self-
Na2S
DMF
N
N
N
organization in solution,2 and as ligands capable of forming com-
plexes with both metal ions3(a)–(d) and organic substrates.3(e)–(g)
Introduction of a heteroatom (such as the N atom) into the
structure of a pyrimidinophane is an effective way to enhance
complexation ability3(d),(e) and to enable further functionaliza-
tion, e.g., quaternization of N atoms in bridges with alkyl
bromides. Thus, a series of amphiphilic pyrimidinophanes
with onium groups in bridges was obtained, which possess
antimicrobial1(a) and cholinolytic1(d) activity and are capable of
forming aggregates used as nanoreactors,2 in water solutions.
1,3-Bis(ω-bromoalkyl)uracils were used as starting com-
pounds in the synthesis of pyrimidinophanes with N atoms in
bridges, their reactions with amines led to pyrimidinophanes,
containing one4 or two uracil units.1(a),2 One can expect the
formation of macrocycles containing S atoms in bridges, if the
cyclization is performed using Na2S instead of amines. In our
opinion, such pyrimidinophanes, as well as previously obtained
pyrimidinophanes with N atoms, are promising ligands and
biologically active compounds. This work deals with the syn-
thesis and properties of pyrimidinophanes with S atoms in
polymethylene chains.
O
S
N
O
(CH2)5Br
3
4 (38%)
Scheme 2
pentyl)quinazoline-2,4-dione 3 with Na2S afforded the macro-
cycle 4 (Scheme 2). The yields of macrocycles in these reactions
(up to 40%) are significantly higher than those of pyrimidino-
phanes obtained by the cyclization of 1,3-bis(ω-bromoalkyl)-
uracils with amines.4
The structure and purity of the synthesized compounds were
confirmed using a variety of methods (HRMS, IR and NMR
spectroscopy), the structure of compound 4 was additionally
confirmed by X-ray analysis‡ (Figure 1). Note that the torsion
angles in the decamethylene bridge of pyrimidinophane 4 deviate
significantly from 180°, and thus the polymethylene chain ‘hangs
over’ the quinazoline unit. Such a shape of pyrimidinophane 4
is very much alike the ‘bent’ geometry of pyrimidinophanes with
the –(CH2)5N(CH2)5– bridge.4(a)
Reactions of compounds 1 with Na2S lead to complex mix-
tures of products: besides the target pyrimidinophanes, which
are only minor products, a large amount of oligomers is formed.
Although these reactions can lead to macrocyclic products
Initial 1,3-bis(ω-halogenoalkyl)-5,6-substituted uracils 1 were
obtained according to established routines.1(a),4 Reactions of
dihalides 1 with Na2S in DMF at 100–110 °C afforded a series
of pyrimidinophanes 2† containing various numbers of methylene
groups or ethoxyethyl fragments (Scheme 1). This synthetic
approach allows one to vary uracil derivatives, in particular,
pyrimidine derivatives with the fused aromatic system can be used
in the cyclization reactions. Thus, reaction of 1,3-bis(5-bromo-
†
Pyrimidinophanes with one uracil unit and a sulfur atom in spacer.
Catalytic amounts of [NBu4]HSO4 and a suspension of 8.5 mmol of Na2S
in DMF were added to a solution of 6.5 mmol of 1,3-bis(ω-bromoalkyl)-
uracil or quinazoline-2,4-dione in DMF at 60 °C. Stirring was continued
at 100–110 °C until the consumption of the starting materials (monitored
by TLC). The solvent was removed under reduced pressure, and the
residue was purified using column chromatography (SiO2, EtOAc–light
petroleum, 1:1) to afford the product.
O
Z
O
Z
O
Z
N
N
X
X
N
N
Na2S
DMF
R1
R1
O
S
2a: mp 98–102 °C. HRMS (EI), m/z: 300.1141 [M+] (C13H20N2O4S
requires 300.11438).
R2
R2
Z
2b: mp 85.5–86.5 °C. HRMS (EI), m/z: 324.1869 [M+] (C17H28N2O2S
requires 324.1872).
1
2
a R1 = H, R2 = Me, Z = CH2OCH2, X = Cl (28%)
b R1 = H, R2 = Me, Z = (CH2)4, X = Br (24%)
c R1 = C10H21, R2 = Me, Z = (CH2)4, X = Br (19%)
d R1 = NO2, R2 = H, Z = (CH2)3, X = Br (13%)
2c: mp 60–61 °C. HRMS (EI), m/z: 464.3432 [M+] (C27H48N2O2S
requires 464.34366).
2d: mp 118–121 °C. MS (MALDI-TOF), m/z: 327 [M+] (C14H21N3O4S
requires 327).
4: mp 106–107 °C. HRMS (EI), m/z: 332.1560 [M+] (C18H24N2O2S
requires 332.1558).
Scheme 1
– 4 –
© 2010 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2010, 20, 4–6
S(7)
C(8)
C(6)
O
i, H2O2, MnSO4, 0–20 °C
ii, H2O2, NaHCO3, MnSO4
N
N
4
O
X
C(9)
C(10)
C(5)
8a X = SO (i, 77%)
8b X = SO2 (ii, 46%)
C(11)
C(4)
Scheme 4
C(12)
O(14)
C(16)
C(3)
C(14)
C(15)
C(21)
O(21)
pyrimidinophanes containing two uracil units. First, thiuronium
salt 5 was obtained by the reaction of 1,3-bis(5-bromopentyl)-
6-methyluracil 1e with thiourea, which was subsequently
decomposed with water alkali to give compound 6. Then,
dithiol 6 was reacted with initial dibromide 1e in MeCN in the
presence of Cs2CO3, this reaction afforded isomeric pyrimi-
dinophanes 7a and 7b with different mutual arrangements of
carbonyl groups C(4)=O at pyrimidine units (cis and trans
arrangements, respectively)§ (Scheme 3). We did not succeed
in isolating macrocycles 7a and 7b, and they were further used
and characterized as a mixture of isomers.
N(13)
C(20)
C(2)
N(1)
C(17)
C(19)
C(18)
Figure 1 Molecular structure of independent molecule A of compound 4.
Selected torsion angles for molecule A (molecule B) (°): C(21)–N(1)–
C(2)–C(3) 100.6(4) [–103.1(4)], N(1)–C(2)–C(3)–C(4) –59.6(4) [61.1(5)],
C(2)–C(3)–C(4)–C(5) –179.4(4) [62.2(5)], C(3)–C(4)–C(5)–C(6) 179.8(4)
[165.0(4)], C(4)–C(5)–C(6)–S(7) 65.7(5) [50.8(5)], C(5)–C(6)–S(7)–C(8)
–96.0(3) [89.3(3)], C(6)–S(7)–C(8)–C(9) 119.5(4) [–81.6(4)], S(7)– C(8)–
C(9)–C(10) 178.4(4) [–54.7(5)], C(8)–C(9)–C(10)–C(11) 177.2(4) [–164.4(4)],
C(9)–C(10)–C(11)–C(12) –86.2(5) [–65.1(5)], C(10)–C(11)–C(12)–N(13)
71.9(5) [–64.1(5)], C(11)–C(12)–N(13)–C(14) 79.7(4) [–80.8(5)].
Sulfur atoms in the bridges of the synthesized pyrimidino-
phanes can be modified in different ways; e.g., they can be oxi-
dized or converted into the sulfonium group. Thus, the oxidation
of macrocycles with hydrogen peroxide affords sulfoxide 8a or
sulfone 8b depending on the reaction conditions5 (Scheme 4).¶
Amination of the S atom in pyrimidinophane 2a utilizing
O-mesitylenesulfonylhydroxylamine6 in CH2Cl2 led to macro-
cyclic salt 9, which decomposed to initial sulfide 2a on attempt
to convert it to sulfimine using DBU (Scheme 5).
Pyrimidinophanes with S atoms in bridges do not react with
alkyl halides, though we obtained macrocycles 10 and 11 with
the sulfonium group in the bridge†† by reaction of pyrimidino-
phanes 2b,c and 4 with methyl and nonyl esters of p-toluene-
containing several uracil units, only pyrimidinophanes with one
uracil moiety were detected in the mass spectra of the reaction
mixtures. We applied another strategy for the synthesis of
NH2
(CH2)5Br
(CH2)5
S
S
O
O
NH2
N
N
H2N
NH2
NaOH
2 Br–
S
O
O
MeOH
N
N
NH2
NH2
Me
Me
O
(CH2)5Br
(CH2)5
1e
5
(CH2)5
S
S
(CH2)5
O
O
N
N
N
N
O
O
O
O
MesSO3NH2
CH2Cl2
O
2a
S NH2
O
N
N
S
O
Me
Me
(CH2)5
(CH2)5
(CH2)5SH
O
O
Me
7a
+
N
9 (79%)
Scheme 5
1e
O
Cs2CO3
MeCN
N
(CH2)5
S
(CH2)5
O
Me
O
Me
(CH2)5SH
6 (24%)
N
N
N
§
To the solution of dibromide 1e (4.72 mmol) in 60 ml of methanol,
O
O
thiourea (9.44 mmol) was added. Reaction mixture was refluxed for
25 h, the solvent was removed and diethyl ether was added. The preci-
pitate of the thiuronium salt 5 was separated and the solution of 0.57 g of
NaOH (14.16 mmol) in 50 ml of water was added. Reaction mixture was
stirred for 2 h at 50 °C, acidified with HCl until pH < 7 and extracted
with dichloromethane. The solvent was removed under reduced pressure,
and the residue was purified using column chromatography (SiO2, EtOAc–
light petroleum, 2:1) to afford the product 6. Cs2CO3 (3.39 mmol) and a
catalytic amount of [NBu4]HSO4 were added to the solution of dibro-
mide 1e (1.13 mmol) and dithiol 6 (1.12 mmol) in MeCN. The reaction
mixture was stirred at 70–75 °C for 14 h. After cooling to room tem-
perature the solvent was removed under reduced pressure, and the residue
was purified using column chromatography (SiO2, EtOAc–methanol, 20:1)
to yield the mixture of pyrimidinophanes 7a,b.
N
Me
(CH2)5
S
(CH2)5
7b
Scheme 3
‡
Crystallographic data for 4 at 20 °C: C18H24N2O2S, triclinic, crystal
–
size 0.5×0.2×0.1 mm, space group P1, a = 9.704(3), b = 9.881(3) and c =
= 20.023(8) Å, = 87.26(3)°, = 84.56(3)°,
= 62.34(3)°, V = 1692.8(10) Å3
a
b
g
,
Z = 4 (two independent molecules), dcalc = 1.304 g cm–3, m(CuKα) =
= 1.786 mm–1, F(000) = 712. The intensities of 7243 reflections were
measured on an Enraf-Nonius CAD-4 diffractometer at 20 °C (CuKα
radiation, w/2q scan, 4.44° < q < 74.22°), and 6829 independent reflec-
tions were used in further calculations and refinement. The structure was
solved by a direct method and refined using the full-matrix least-squares
method against F2 in the isotropic–anisotropic approximation. The refine-
ment is converged to wR2 = 0.2030 and GOF = 1.029 for all independent
reflections [R1 = 0.0622 is calculated against F for 4045 observed reflec-
tions with I > 2s(I)]. The number of refined parameters is 415. All the
calculations were performed using the SHELXS and SHELXL93 programs.
CCDC 694559 contains 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.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2010.
6: oil. Found (%): C, 54.33; H, 7.88; N, 8.61; S, 19.54. Calc. for
C15H26N2O2S2 (%): C, 54.51; H, 7.93; N, 8.48; S, 19.40.
7a,b: mp 60–90 °C. HRMS (EI), m/z: 592.3100 [M+] (C30H48N4S2O4
requires 592.3117).
¶
8a: mp 215 °C. HRMS (EI), m/z: 348.1500 [M+] (C18H24N2O3S requires
348.1508).
8b: mp 188–189 °C. HRMS (EI), m/z: 364.1441 [M+] (C18H24N2O4S
requires 364.1452).
9: oil. Found (%): C, 51.06; H, 6.59; N, 7.93; S, 12.18. Calc. for
C22H33N3O7S2 (%): C, 51.24; H, 6.45; N, 8.15; S, 12.44.
– 5 –

Mendeleev Commun., 2010, 20, 4–6
This work was supported by the Russian Foundation for
Basic Research (project no. 07-03-00392).
O
N
N
R3OTs
R1
O
R3
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2010.01.002.
2b,c
S
R2
TsO–
References
10a R1 = H, R2 = R3 = Me (85%)
10b R1 = C10H21, R2 = R3 = Me (89%)
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10c R1 = C10H21, R2 = Me, R3 = C9H19 (46%)
Scheme 6
sulfonic acid (Schemes 6 and 7). The nonyl ester was prepared
by analogy with a known protocol of p-toluenesulfonic esters
synthesis.7
O
N
MeOTs
O
S
Me
4
N
TsO–
11 (64%)
Scheme 7
E. Kuwabara, R. Kirkup, M. Selman, K. Aoki, A. Adeyemo and H. Yamazaki
,
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Chernova, G. M. Doroshkina, R. R. Shagidullin, R. Kh. Giniyatullin, A. S.
Mikhailov, V. D. Akamsin, A. E. Nikolaev, V. S. Reznik, Yu. Ya. Efremov,
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The bacteriostatic and fungistatic activities of macrocyclic
sulfides were in vitro tested towards a series of bacteria and
fungi. Compound 10b appeared to be the most potent towards
gram-positive bacteria – the minimal inhibitory concentration
towards Staphylococcus aureus is less than 1 µg cm–3.
In conclusion, we showed that 1,3-bis(ω-halogenoalkyl)-
5,6-substituted uracils and their derivatives are excellent starting
compounds for the synthesis of pyrimidinophanes with hetero-
atoms (N, S) in bridges. The macrocycles can be further func-
tionalized by different means, and it opens up possibilities for
the controllable synthesis of compounds with the desired pro-
perties, in particular, biologically active compounds.
†† Reactions of pyrimidinophanes with the esters of p-toluenesulfonic
acid. Pyrimidinophane was added to 4 g of methyl or nonyl ester of
p-toluenesulfonic acid and the reaction mixture was stirred for 6 h at
80 °C. After cooling diethyl ether was added, the formed precipitate was
separated, washed thrice with diethyl ether and dried in vacuo.
10a: oil. Found (%): C, 58.58; H, 7.34; N, 5.55; S, 12.77. Calc. for
C25H38N2O5S2 (%): C, 58.79; H, 7.50; N, 5.49; S, 12.56.
5 D. A. Alonso, C. Najera and M. Varea, Tetrahedron Lett., 2002, 43, 3459.
6 Y. Tamura, J. Minamikawa and M. Ikeda, Synthesis, 1977, 1.
7 W. Szeja, Synthesis, 1979, 822.
10b: oil. Found (%): C, 64.44, H, 9.06; N, 4.19; S, 10.01. Calc. for
C35H58N2O5S2 (%): C, 64.58; H, 8.98; N, 4.30; S, 9.85.
10c: oil. Found (%): C, 67.89; H, 9.54; N, 3.43; S, 8.69. Calc. for
C43H74N2O5S2 (%): C, 67.67; H, 9.77; N, 3.67; S, 8.40.
11: mp 210 °C. Found (%): C, 60.08; H, 6.53; N, 5.29; S, 12.48. Calc.
for C26H34N2O5S2 (%): C, 60.21; H, 6.61; N, 5.40; S, 12.36.
12: oil. Found (%): C, 64.21; H, 8.81; S, 10.88. Calc. for C16H26O3S
(%): C, 64.39; H, 8.78; S, 10.74.
Received: 5th June 2009; Com. 09/3343
– 6 –