Convenient synthesis of functionalized bis-ureidopyrimidinones based on thiol-yne reaction

Article abstract of DOI:10.1002/chem.201402955

The preparation of functionalized bis-ureidopyrimidinones (Bis-UPy) through the thiol-yne reaction is described. Various Bis-UPys with different functional groups were synthesized by using the readily available functionalized alkynes and UPy-thiol to affi

Full text of DOI:10.1002/chem.201402955

DOI: 10.1002/chem.201402955
Communication
&
Supramolecular Polymers
Convenient Synthesis of Functionalized Bis-ureidopyrimidinones
Based on Thiol-yne Reaction
Hui-Qing Peng,[a, b] Cai-Li Sun,[a, b] Jiang-Fei Xu,[a, b] Li-Ya Niu,[a] Yu-Zhe Chen,[a] Li-Zhu Wu,[a]
Chen-Ho Tung,[a] and Qing-Zheng Yang*[a]
addition of two thiols to one alkyne, which makes it perfectly
Abstract: The preparation of functionalized bis-ureidopyri-
midinones (Bis-UPy) through the thiol-yne reaction is de-
scribed. Various Bis-UPys with different functional groups
were synthesized by using the readily available functional-
suitable for synthesis of bis-adduct products (Scheme 1). Im-
pressive progress has been achieved in the construction of
dense functional polymer materials by using this accelerated
synthesis.[6] However, the synthesis of Bis-UPy by the thiol-yne
reaction remains unexplored. Herein, we reveal the use of the
ized alkynes and UPy-thiol to affirm the simplicity and ver-
satility of the methodology.
thiol-yne reaction for the synthesis of Bis-UPy to be an ex-
tremely simple synthetic approach. The easily available starting
alkynes were used to prepare promising Bis-UPys that are diffi-
The self-complementary 2-ureido-4[1H]-pyrimidinone (UPy)
quadruple H-bonding motif developed by Meijer is one of the
most commonly used building blocks in supramolecular poly-
mers due to its great binding strength (Kass =6ꢀ107 mÀ1) and
directionality.[1] Bis-ureidopyrimidinones (Bis-UPy) containing
functional groups have been used for constructing functional
supramolecular polymers.[2,3] To date, Bis-UPy have mainly
been synthesized by two different methods; either by reaction
of activated isocytosine with diamines or by reaction of isocy-
tosine with diisocyanates.[4] Their mild reaction conditions and
high yields have boosted developments of Bis-UPy based
supramolecular polymers in areas such as biomaterials, smart
materials and light-emitting devices.[2,3] Unfortunately, diamines
containing functional groups are not usually available and
need to be prepared by multistep synthesis, such as by the in-
troduction and reduction of nitro[2a] or azide[3f] groups under
harsh reaction conditions. Protection and deprotection of
amino groups are also necessary for storage or further molecu-
lar functionality due to its high reactivity. In the second strat-
egy, the reaction is performed under high temperature proba-
bly due to the low nucleophilicity of the amino group in the
isocytosine.[4] An alternative method that can efficiently pre-
pare Bis-UPy with functional groups is highly desirable.
cult to prepare by conventional synthetic strategies.
Scheme 1. Synthesis of bis-adducts from thiol-yne reaction.
The synthesis of Bis-UPy with the thiol-yne reaction is
shown in Scheme 2. Disulfide-thiol chemistry was employed to
provide UPy-functionalized thiol (UPy-thiol) for the thiol-yne re-
action, since disulfides are stable for storage and can be easily
cleaved to afford corresponding thiols in the presence of re-
ducing agents.[7] The commercially available cystamine dihy-
drochloride (A) was selected as the starting material to react
with the activated ureidopyrimidinones (B) to afford Bis-UPy
disulfide (C) in excellent yield. UPy-thiol was obtained by the
reduction of C with 1,4-dithiothreitol (DTT) quantitatively.[8]
Alkyne 1 (43 mm), UPy-thiol (6 equiv) and a catalytic amount
of 2,2-dimethoxy-2-phenylacetophenone (DMPA) as photoini-
tiator were combined in 1,2-dichloroethane (1.2 mL). The re-
sulting solution was irradiated under a high pressure Hg lamp
at room temperature. The functionalized alkyne precursor was
depleted in 2 h. We removed the solvent and obtained the
pure Bis-UPy 1 by column chromatography with a high yield
of up to 94%. Each alkyne group reacts firstly with a single
UPy-thiol to form a vinyl sulfide stage followed by reaction of
the vinyl sulfide with another UPy-thiol to yield the 1,2-disub-
stituted adduct (Scheme S1 in the Supporting Information).[9]
To prove the general suitability of this method, alkynes 2–5
containing different functional groups were selected as precur-
sor to prepare Bis-UPys (Table 1 and Table 2). The starting ma-
terials were mixed together with photoinitiator in photostable
1,2-dichloroethane, except Bis-UPy 3, which was synthesized
in chloroform due to the limited solubility of 3 in 1,2-dichloro-
The thiol-yne radical reaction has received significant inter-
est as the new click chemistry due to its mild reaction condi-
tion, rapid reaction rate and high yield.[5,6] It tolerates a wide
range of functional groups. In particular, this reaction involves
[a] H.-Q. Peng, C.-L. Sun, J.-F. Xu, Dr. L.-Y. Niu, Dr. Y.-Z. Chen, Prof. Dr. L.-Z. Wu,
Prof. Dr. C.-H. Tung, Prof. Dr. Q.-Z. Yang
Key Laboratory of Photochemical Conversion and Optoelectronic Materials
Technical Institute of Physics and Chemistry, Chinese Academy of Sciences
Beijing 100190 (P.R. China)
E-mail: qzyang@mail.ipc.ac.cn
[b] H.-Q. Peng, C.-L. Sun, J.-F. Xu
University of the Chinese Academy of Sciences Beijing 100049 (P.R. China)
1
ethane. All the Bis-UPys were thoroughly characterized by H
and 13C NMR spectroscopy and high-resolution mass spectrom-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402955.
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thiol were needed to deplete
alkyne 2 in 2 h (see the Support-
ing Information). We speculate
that steric hindrance is responsi-
ble for this deviation. The longer
ester linkage was favorable for
the addition of UPy-thiol radical
to give a bis-sulfide adduct. In
contrast, alkyne 2 was linked to
a large aromatic substrate by
a short ether groups. The addi-
tion of UPy-thiol may be blocked
to yield 1,2-disubstituted ad-
ducts.
The influence of steric hin-
drance on the thiol-yne reaction
is supported by two facts. First,
alkyne 1 gave Bis-UPy 1 in 94%
Scheme 2. Illustration for synthesis of bis-ureidopyrimidinones by disulfide-thiol chemistry and thiol-yne reaction.
1
etry (see the Supporting Information). H NMR spectra of Bis-
UPys 1–5 showed large downfield shifts of the UPy NÀH sig-
nals, indicating the dimerization of the UPy units, which is the
prerequisite for constructing supramolecular polymers (Fig-
ure S1 in the Supporting Information).[1b]
or even higher yields and alkyne 2 only gave Bis-UPy 2 in 84%
yield. The steric factor may lower the reactivity of 2 at the
vinyl sulfide stage, and consequently decrease the yield of bis-
adduct. The low reactivity of our thiol-yne reaction for the sub-
strates with the alkyne group directly linked to an aromatic
group provides the second solid evidence. Under identical con-
ditions, 1-ethylnylpyrene treated with 6 equivalents UPy-thiol
for 2 h yielded no bis-adducts and only a small amount of
monoadduct. This result may be attributed to the steric hin-
drance of the pyrene group to the bulk UPy-thiol radicals,
which further verified our speculation on synthesis of Bis-UPy
1 and Bis-UPy 2 requiring different equivalents of UPy-thiol.
Although impressive progress has been made using the
thiol-yne reaction, most of these studies have focused on new
materials synthesis and have rarely been concerned with the
experimental conditions affecting the reaction outcome.[6] One
intriguing observation in this methodology is that different
molar ratio of alkynes to UPy-thiol is required to complete the
reaction for different functional groups in 1–5 in 2 h. At UPy-
thiol concentration of 260 mm, we tuned the concentration of
alkynes to change their molar ratio. We found that a slight
excess of UPy-thiol (2.5 equiv) was needed to maximize the
bis-adducts for alkyne 3–5. It should be noted that 6 and
10 equiv of UPy-thiol were used to complete the reaction in
2 h for alkyne 1 and 2, respectively. This may be attributed to
the fact that the functional groups of these alkynes absorb
light of similar wavelength as the photoinitiator DMPA, which
reduces the initiation efficiency.[10] However, the completion of
Bis-UPy 1 required 6 equivalents of UPy-thiol, but for Bis-UPy
2, with the lower extinction coefficient, 10 equivalents of UPy-
Table 2. Summary of the Bis-UPys 1–5 synthesized by thiol-yne reactions
in 2 h under air.
Bis-UPy
UPy-thiol
[mm]
Alkyne
[mm]
UPy-thiol/alkyne
Solvent
Yield
[%]
1
2
3
4
5
260
260
260
260
260
43
26
104
104
104
6
10
2.5
2.5
2.5
ClCH2CH2Cl
ClCH2CH2Cl
CHCl3
ClCH2CH2Cl
ClCH2CH2Cl
94
84
74
87
97
Table 1. Chemical structures of alkyne-functionalized compounds 1–5 and their corresponding Bis-UPys 1–5.
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Communication
In addition to the study of the influence of the molar ratio
of the starting materials, we took the whole reaction concen-
tration into account to obtain insights into Bis-UPy synthesis.
The result shows that thiol-yne reaction for preparing Bis-UPy
is sensitive to the concentration of the UPy-thiol. As the UPy-
thiol concentration was diluted from 260 to 43 mm under the
same molar ratio of alkynes to UPy-thiols, the reaction mixture,
as monitored by TLC after 2 h, clearly showed much of the un-
reacted functionalized alkyne. However, 65 mm of UPy-thiol
was enough to complete the reaction. It is most likely that the
high reaction concentration is favorable to the radical transfer
in radical-mediated thiol-yne reaction. These correlations ena-
bled us to prepare Bis-UPy with satisfactory yield under appro-
priate conditions.
ligand in Bis-UPy 3 will allow to introducing metal-ligand bind-
ing which approaches the strength of covalent bonds to afford
a supramolecular polymer networks.[12] The combination of
host–guest chemistry of pillar[5]arene moiety[13] with quadru-
ple H-bonding from Bis-UPy 4 may be useful for fabricating
novel supramolecular polymers by orthogonal self-assembly.
Moreover, the thiol-yne reaction results in the functional
groups as pendants in side chains, which will endow the
supramolecular polymers with special properties, such as con-
venient further modification of the Bis-UPy. For example, the
hydroxyl in Bis-UPy 5 as a new reactive site can be used to
graft another functional group. The length of the linker be-
tween two UPy groups in Bis-UPy could be tuned by adjusting
the linkage between amino and disulfide groups of the start-
ing compound. Studies of applications of these new Bis-UPys
are now ongoing in our laboratory.
To further optimize the reaction conditions, we studied the
influence of oxygen and solvent on the reaction for preparing
Bis-UPy. Bis-UPy 1 was prepared in a solution exposed to air
and a solution degassed with nitrogen, respectively. It turned
out that our reactions are insensitive to oxygen, which is usual-
ly a factor in radical-mediated thiol-yne reaction.[6b] This leads
to a more simplified preparation method without tedious de-
gassing procedures. Moreover, in addition to nonpolar solvents
(e.g., 1,2-dichloroethane and chloroform), the efficiency of the
reaction was satisfied by using a polar solvent, such as a mix-
ture of THF/water (9:1, v/v), indicating that this new methodol-
ogy for the preparation of Bis-UPy was not restricted to a par-
ticular solvent (Table S2 in the Supporting Information).
In conclusion, we describe the preparation of bis-ureidopyri-
midinones by using the thiol-yne reaction. Five Bis-UPys with
different functional groups were synthesized successfully from
readily available alkyne precursors and Bis-UPy disulfide (C) in
excellent yields. The yield was not influenced by oxygen and
solvent, but was sensitive to molar ratio of alkynes/thiols and
the whole reaction concentration. The extremely simple syn-
thetic approach may offer great opportunities in preparing
new Bis-UPy for construction of useful functional supramolec-
ular polymers. Further studies in our laboratory are aimed at
developing a library of Bis-UPy and their use to construct
supramolecular polymers for various applications.
To illustrate the application of our Bis-UPys for construction
of supramolecular polymers, we took Bis-UPy 1 as an example
to study its self-assembly behavior in CHCl3. As shown in
Figure 1, the double logarithmic plot of specific viscosity
versus concentration of Bis-UPy 1 was linear with a slope of
2.10 over the whole concentration range (5–75 mm), indicating
the propensity of Bis-UPy 1 to supramolecular polymerize
even at low concentrations (Scheme S2 in the Supporting In-
formation).[11] This result combined with the NMR spectroscopy
result shown above, confirmed the formation of supramolec-
ular polymers in chloroform from Bis-UPy 1.
Acknowledgements
We are grateful for the financial support from the 973 Program
(2013CB933800, 2013CB834505), the National Natural Science
Foundation of China (21222210, 91027041, 21272243) and the
Chinese Academy of Sciences (100 Talents Program).
Keywords: bis-ureidopyrimidinones
·
hydrogen bonds
·
supramolecular chemistry · supramolecular polymers · thiol-
yne reaction
In our work, Bis-UPys 1–5 with different functional groups
are potentially useful for constructing novel supramolecular
polymers. Bis-UPys 1–2 containing chromophores with high
quantum yields can be employed to fabricate luminescent
supramolecular polymers. Terpyridine as a classical metal
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Received: April 4, 2014
Published online on July 23, 2014
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