Macrocyclic 5-bromouracil derivatives: synthesis and transformation of a uracil ring

Article abstract of DOI:10.1016/j.tetlet.2008.07.164

Cyclization of 1,3-bis(ω-bromoalkyl)-5-bromouracil with p-methoxybenzylamine or sodium sulfide led to a series of pyrimidinophanes containing heteroatoms in bridges. An unusual behaviour of the 5-bromouracil ring, namely its contraction into hydantoin units during the cyclization reactions with p-methoxybenzylamine was observed. Sodium sulfide does not affect the 5-bromouracil ring, and no transformation products were observed in the synthesis of pyrimidinophanes with sulfur bridges. A possible reaction mechanism is given.

Full text of DOI:10.1016/j.tetlet.2008.07.164

Tetrahedron Letters 49 (2008) 5994–5997
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Macrocyclic 5-bromouracil derivatives: synthesis and transformation
of a uracil ring
*
Anton E. Nikolaev, Vyacheslav E. Semenov , Dilyara R. Sharafutdinova, Yurii Ya. Efremov, Vladimir S. Reznik
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan 420088, Arbuzov Street 8, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Cyclization of 1,3-bis(x-bromoalkyl)-5-bromouracil with p-methoxybenzylamine or sodium sulfide led
Received 5 May 2008
Revised 18 July 2008
Accepted 30 July 2008
Available online 3 August 2008
to a series of pyrimidinophanes containing heteroatoms in bridges. An unusual behaviour of the 5-bro-
mouracil ring, namely its contraction into hydantoin units during the cyclization reactions with
p-methoxybenzylamine was observed. Sodium sulfide does not affect the 5-bromouracil ring, and
no transformation products were observed in the synthesis of pyrimidinophanes with sulfur bridges.
A possible reaction mechanism is given.
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Pyrimidinophanes
5-Bromouracil
Hydantoin
Transformation
There is a continuing interest in calixarenes as versatile hosts
and candidates for synthetic receptors and enzymes.1 Replacement
of the carbon in the bridge with another element affects the con-
formational and complexation properties of calixarenes by chang-
ing the mode of the characteristic circular intramolecular hydrogen
bonding. Besides, some of the heteroatoms can serve as additional
coordination sites due to the presence of lone electron pairs and
can undergo further modification easily. Different types of calixa-
rene analogues with heteroatoms have been reported, such as
homoazacalix[n]arenes with CH2NRCH2 bridges2 homooxaca-
lix[n]arenes with CH2OCH2 bridges,3 and homothiacalix[n]arenes
containing CH2SCH2 as linkages.4 All these calixarene analogues
have characteristics similar to those of calixarene. They also pos-
sess special properties due to the bridged substituents. Substitu-
tion of the phenol units with heterocyclic rings leads to the large
group of heterocalixarenes,5–7 which, depending on the nature of
the heterocyclic moieties, encompass numerous new opportunities
idine moieties, pyrimidinophanes, to be promising compounds,
and recently we obtained data regarding biological activity10 and
structural features of pyrimidinophanes.11 This work is a continu-
ation of our interest in macrocyclic pyrimidine derivatives and
deals mainly with our synthetic efforts towards uracil-based hom-
ocalixarene analogues, containing nitrogen and sulfur in bridges,
and also closely related macrocycles with flexible –(CH2)n-chains
which were synthesized to compare the properties of pyrimidino-
phanes with different bridges. As a result of our interest in further
functionalization of the target compounds, we decided to use
5-bromouracil (1) as a uracil motif. It is known that the Br at
C(5) of uracil can be easily substituted by nucleophiles and in
particular amines.12
We consider 1,3-bis(x-bromoalkyl)uracils to be excellent start-
ing compounds for the synthesis of pyrimidinophanes with various
structures.13 Treatment of these compounds with amines leads to
macrocycles with one uracil unit and a bridging N atom.11a,11b
Using an established procedure, dibromides 2a and 2b were pre-
for
p–p interactions with electron-rich and electron-deficient p-
systems. Calixarene analogues, in which both structural elements
(bridges and aromatic subunits) contain heteroatoms, have been
reported.7e
pared in good yields by reaction of an 8-fold excess of (a,
a0)-m-
dibromoxylene or 1,5-dibromopentane with the disodium salt of
1 in DMF (Scheme 1).
Despite the significance of nucleotide bases, and in particular
uracil and its derivatives towards complexation with H+ and other
biological cations,8 investigations on uracil-based synthetic cyclic
receptors are few.9 However, some interesting results concerning
cation extraction and transport properties of uracil-based calixare-
nes have been obtained.6a,6b We consider macrocycles with pyrim-
O
O
X
Br
N
N
Br
1. Na, BuOH
NH
Br
O
2. Br-X-Br, DMF
N
H
O
X
Br
1
(
a
) - 81%; (CH2)5 (b) - 67%
2
: X=
Scheme 1.
* Corresponding author. Tel.: +7 843 273 1862; fax: +7 843 273 2253.
E-mail address: sve@iopc.knc.ru (V. E. Semenov).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.164

A. E. Nikolaev et al. / Tetrahedron Letters 49 (2008) 5994–5997
5995
Cyclization of compound 2a with p-methoxybenzylamine (3) in
O
O
O
the presence of excess K2CO3 and catalytic amounts of NBu4HSO4
in BuOH afforded pyrimidinophane 4, which was isolated by
column chromatography in a yield of 4% (Scheme 2).
Further elution of the column gave a compound, the structure of
which was assigned using a variety of methods (HRMS, NMR and IR
spectroscopy). Surprisingly, the 5-bromouracil ring had contracted
into the 5-hydroxyhydantoin moiety to form macrocycle 5 in a
yield of 8%.
R
O
R
O
Br
R
O
N
N
OH
N
3
H
+
BuOH, K2CO3
[NBu4]HSO4
H
H
N
R
N
R
N
R
8: R=C5H11 (a);
9: R=C5H11(a);
Bn (b)
7: R=C5H11 (a); Bn (b)
R=Bn (b)
Scheme 4.
O
H3C
cal to those for the cyclization of 2a,b with 3. The products of the
reactions were not isolated, and the mass spectra of the reaction
mixtures indicated formation of hydantoin derivatives 8a,b and
9a,b (Scheme 4).
N
O
HO
N
O
N
The molecular ions of hydantoins 8a and 9a (m/z 240, 256), and
8b and 9b (m/z 280, 296) were observed in the mass spectra of the
reaction mixtures of 3 with 7a or 7b, respectively. However,
the relative intensities of the ions were different. The peak for
the molecular ion of 9a was three times more intensive than that
of 8a, in contrast, the peaks of the molecular ions of 8b and 9b
were of almost equal intensities. Thus, model alkyl derivatives of
1 were transformed into hydantoins in the reaction with amine
3, and it seems that contraction of the 5-bromouracil moiety
occurs in acyclic 2a,b but not in pyrimidinophanes 4 and 6. This
conclusion was confirmed by reaction of pyrimidinophane 4 with
amine 3 under the above conditions. The reaction afforded a series
of products, and mass spectral analysis of the reaction mixture did
not reveal any macrocyclic compounds except for traces of a
pyrimidinophane which was formed by substitution of the Br in
4 with amine 3 (m/z = 588).
5
The macrocycles
4
and
5
can be considered as homo-
calix[3]arene analogues. Compound 2b contains more flexible
chains compared with 2a. Cyclization of 2b with amine 3 led to
the expected pyrimidinophane 6 (Scheme 3) in a yield of 13%,
and the mass spectrum of the reaction mixture showed the
presence of trace amounts of the corresponding macrocycle with
a 5-hydroxyhydantoin moiety.
Macrocycles 4–6 have the same spectral features as reported for
pyrimidinophanes with similar structures prepared from 1,3-
bis(5-bromopentyl)thymine or 1,3-bis(5-bromopentyl)-6-methyl-
uracil and benzylamine.11a,11b In their 1H NMR spectra, the geminal
protons of the CH2-groups at the N(1) and N(3) atoms of the
heterocycle were observed as four doublets (macrocycles 4 and
5) or four broadened multiplets (pyrimidinophane 6) in d 3.20–
5.70 region. This results from the folded conformation and slow
exchange on the NMR time-scale.
Does the flexibility of the chains in compounds 2a and 2b influ-
ence the transformation of the 5-bromouracil ring? Does the trans-
formation of the 5-bromouracil moiety occur after the formation of
macrocycle 4 or is it an acyclic hydantoin derivative that is formed
first and then affords macrocycle 5? To elucidate the factors
responsible for the observed transformation, the reactions of
amine 3 with model compounds 1,3-bis(pentyl- and benzyl)-5-
bromouracils 7a and 7b were studied. The conditions were identi-
Cyclization of compounds 2a,b with Na2S led to pyrimidino-
phanes 10a,b with bridging S atoms in yields of 8% and 29%,
respectively (Scheme 5).
Similar to macrocycles 4 and 5, pyrimidinophane 10a can also
be considered as a homocalix[3]arene analogue. Homocalix[3]are-
nes are known to have a limited number of stable conformations,14
and though the introduction of the uracil moiety makes conforma-
tional analysis more complicated, the calculated15 possible confor-
mation for pyrimidinophane 10a appeared to be similar to
homooxacalix[3]arenes. Contrary to the reactions with an amine,
no traces of the 5-bromouracil transformation products were
observed in the mass spectra of the reaction mixtures of 2a or 2b
with Na2S. The 1H NMR spectra of homocalixarene analogues 4, 5
and 10a were almost the same, while broadening and coalescence
of the resonances of the geminal protons of the CH2-groups at N(1)
and N(3) of the uracil ring was observed in the 1H NMR spectrum of
10b compared with 6. Faster exchange in the solution of pyrimidi-
nophane 10a can be explained by the increasing flexibility of the
bridge in 10a due to the larger radius of the S atom compared with
N.
O
H2N
CH3
O
Br
CH3
O
N
3
N
O
2a
N
K2CO3, BuOH
[NBu4]HSO4
Several examples of similar transformations of 5-bromouracil
derivatives have been reported.16 In most cases, such transforma-
tions occur on exposure to strong oxidants (e.g., ozone16b,16c) or
in alkaline solutions as a result of hydroxy anion attack.16d–f As-
sumed mechanisms are probably not realized herein, because
4
Scheme 2.
O
O
N
Br
X
(CH2)5
O CH3
Br
N
Na2S
DMF
2a,b
3
N
O
X
2b
S
N
O
[NBu4]HSO4
K2CO3, BuOH
[NBu4]HSO4
N
(CH2)5
(a); (CH2)5 (b)
6
10: X=
Scheme 3.
Scheme 5.

5996
A. E. Nikolaev et al. / Tetrahedron Letters 49 (2008) 5994–5997
O
O
O
O
O
H
R
O
H
R
O
Br
R'NH2
R
O
R
O
Br
H
R
O
Br
H
N
N
N
N
N
NR'
H
NR'
H
H
N
R
N
R
N
R
N
R
NR'
H
N
R
NR'
H
O
R
H
N
H
HX
O
N
R
O
O
O
H
H
O
H
H
R
NR'
X
R
R
O
H
H
R
O
N
NR'
N
N
N
H
X
OH
OH
O2
NR'
O
N
R
O
N
R
N
R
N
R
H
Scheme 6.
model compounds 7a,b did not afford any transformation products
in the absence of the amine. Thus, it is attack of the amine 3 that
causes contraction of the 5-bromouracil moiety. It is possible that
the reaction proceeds in the following way. First, addition of the
amine 3 to the double bond of the uracil unit occurs with subse-
quent ring opening.16a Then, recyclization to the substituted
hydantoin takes place and finally the substituent is removed. The
proposed contraction mechanism is depicted in Scheme 6. In the
case of benzyl substituents at N(1) and N(3), it seems that the ring
contraction proceeds more easily. Oxidation of the anions proceeds
smoothly involving oxygen, and 5-hydroxyhydantoin derivatives
form with both benzyl and pentyl substituents. Neither compound
8a nor compound 9a was detected in the mass spectrum of the
reaction mixture of model compound 7a with amine 3 and K2CO3
after heating under an inert argon atmosphere (sealed tube, BuOH,
100 °C, 20 h).
Supplementary data
Synthetic routines, spectral and computational data are avail-
able. Supplementary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2008.07.164.
References and notes
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General procedure for the synthesis of macrocycles with S bridges:
A suspension of Na2S (1.3 equiv) and a catalytic amount of
[NBu4]HSO4 in DMF were added to a solution of compound 2a or
2b (1 equiv) in DMF at 60 °C. Stirring was continued at 90–100 °C
until consumption of the starting materials (monitored by TLC).
The solvent was removed under reduced pressure, and the residue
was purified using column chromatography (SiO2) to afford the
product.
Acknowledgements
The financial support of RFBR (Project #07-03-00392-a), RAS
Programmes #7 and #8 is acknowledged. A. E. Nikolaev is thankful
to the Russian Science Support Foundation for the personal grant.

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