Five-membered heterocyclic ureas suitable for the donor-donor-acceptor hydrogen-bonding modules

Article abstract of DOI:10.1016/j.tetlet.2008.01.068

Five-membered heterocyclic ureas are capable of forming the unfolded conformer without preorganization by using the intramolecular hydrogen bond, and are suitable for the DDA hydrogen-bonding modules. In contrast, six-membered heterocyclic ureas are desta

Full text of DOI:10.1016/j.tetlet.2008.01.068

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Tetrahedron Letters 49 (2008) 2005–2009
Five-membered heterocyclic ureas suitable for the
donor–donor–acceptor hydrogen-bonding modules
Yosuke Hisamatsu *, Yuki Fukumi, Naohiro Shirai, Shin-ichi Ikeda, Kazunori Odashima *
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho, Nagoya 467-8603, Japan
Received 29 November 2007; revised 8 January 2008; accepted 15 January 2008
Available online 19 January 2008
Abstract
Five-membered heterocyclic ureas are capable of forming the unfolded conformer without preorganization by using the intramole-
cular hydrogen bond, and are suitable for the DDA hydrogen-bonding modules. In contrast, six-membered heterocyclic ureas are desta-
bilized by an effect of steric repulsion due to the closer distance of CHcÁ Á ÁO and their conformational equilibriums are biased toward the
stable folded conformer.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Five-membered heterocyclic urea; Multiple hydrogen bond; DDA hydrogen-bonding module; Oxazol-4-yl urea; Pyrid-2-yl urea
Both inter- and intramolecular hydrogen-bonding inter-
actions play important roles in regulating the structure and
the function of chemical and biological systems.1 In supra-
molecular chemistry, the development of multiple hydro-
gen-bonding modules as building blocks for well-defined
synthetic supramolecular structures and materials has
attracted considerable attention.2 Heterocyclic ureas
including the pyrid-2-yl urea structure have been expected
to provide a variety of hydrogen-bonding arrays to form
stable homo- or hetero-dimers.3 However, their complexa-
tion ability is much lower than the expected values3,4 due to
a conformational problem inherent in the pyrid-2-yl urea
structures. The pyrid-2-yl urea derivatives 1 prefer a folded
conformer f-1, which is stabilized by an intramolecular
hydrogen bond, rather than an unfolded conformer uf-1.5
Thus, the stability constants of 1 to complementary guest
molecules such as 1-octylcytosine3a or 2-acylamino-1,8-
naphthyridine derivative3b are very low in CDCl3 (Ks =
3.0 Â 101 MÀ1). To solve the conformational problem of
the pyrid-2-yl urea structure, the unfolded conformer is
preorganized by the intramolecular hydrogen bond.6
Although the concept of preorganization has been widely
accepted, the complexation systems are sometimes compli-
cated by all the possible conformers/tautomers.6 We have
been interested in the development of new heterocyclic
ureas suitable for the DDA hydrogen-bonding modules
without preorganization by using the intramolecular
hydrogen bond.7
We wish to report herein the development of new
five-membered heterocyclic ureas such as oxazol-4-yl urea,
thiazol-4-yl urea, and imidazo[1,2-a]pyrid-2-yl urea. They
are capable of forming the unfolded conformer, and suit-
able for the DDA hydrogen-bonding modules. Further-
more, we have found that the difference in ring size
(six- or five-membered ring) would be the predominant
factor in the equilibrium between the unfolded and the
folded conformers of the heterocyclic ureas. The six- and
five-membered heterocyclic ureas 2–7 used in the present
study are shown in Schemes 1 and 2.
First, it was expected that pyraz-2-yl urea 2 might be
capable of forming uf-2 by weakening the strength of the
intramolecular hydrogen-bonding, because the pKa value
of the conjugated acid of pyrazine was lower than that
of pyridine (Scheme 1).8 In a dilution study of 2
(100–2 mM) by 1H NMR spectroscopy in CDCl3, the
*
Corresponding authors. Tel.: +81 52 836 3461; fax: +81 52 836 3462.
E-mail addresses: ikeshin@pharm.nagoya-cu.ac.jp (Y. Hisamatsu),
odashima@phar.nagoya-cu.ac.jp (K. Odashima).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.068

2006
Y. Hisamatsu et al. / Tetrahedron Letters 49 (2008) 2005–2009
Hc
N
bond. On the other hand, the apparent downfield shift of
the NHb proton signal (Dd = 2.4 ppm) with increasing
concentration indicated the presence of the f-2 dimer. In
X
Hc
X
O
Hb
O
R1
N
N
N
N
1
Ha
the H NMR spectrum of 2 at À50 °C, only the proton
Hb Ha
N
R1
signals of f-2 were observed. These results showed that
the conformational equilibrium of 2 was biased toward
the stable f-2, similar to 1.
Unfolded conformer (uf)
Folded conformer (f)
f-1
f-2
uf-1
uf-2
Next, we attempted to develop heterocyclic ureas that
preferred the unfolded conformer. In our laboratory, the
adenine-selective host molecules with 2,6-bis(oxazol-2-yl)-
pyridine systems have been developed.9 The hosts have
the usefulness of oxazole system as hydrogen-bonding
acceptor. So, a new heterocyclic urea 3 with the oxazole
ring was prepared. A Curtius rearrangement was employed
as a key step for the synthesis of 3. A chemical shift sum-
mary from the dilution study of 3 (300–1 mM) by 1H
NMR spectroscopy in CDCl3 is displayed in Figure 1.
The NHa proton signal was observed between 6.0 and
6.3 ppm. Interestingly, the NHa proton signal of 3 was
observed ca. 3 ppm upfield from the corresponding NHa
signals of 13a,b,5b and 2. The apparent downfield shift of
the NHb proton signal of 3 (Dd = 2.1 ppm) with increasing
1: X = CH, R1 = Alkyl
2: X = N, R1 = (CH2)3CH3
Scheme 1.
Hc
N
Hc
O
O
O
R2
Hb
O
R2
R3
N
N
N
N
Ha
Ha
Hb
N
R3
Folded conformer (f)
Unfolded conformer (uf)
uf-3
uf-4
uf-5
f-3
f-4
f-5
3: R2 = Ph, R3 = (CH2)7CH3
4: R2, R3 = Ph
concentration indicated the presence of dimers (Kdimer
=
5: R2= CH2CH3, R3 = Ph
3.4 Â 101 MÀ1). The proposed dimer conformations
(uf-3Áuf-3, uf-3Áf-3, f-3Áf-3 dimers) are shown in Figure
1B.10 For the oxazole-Hc proton signal, no important shift
was observed.
Hc
Hc
S
O
N
O
R2
R3
R3
N
N
N
N
N
N
Hb
Ha
Hb Ha
To study the conformational property of 3 in more
1
6: R2 = Ph, R3 = (CH2)7CH3
7: R3 = (CH2)3CH3
detail, the H NMR spectra of 3 (40 mM) were measured
at 25 °C and À50 °C. As shown in Figure 2A, the average
proton signals of uf-3, f-3, and their dimers were observed
at 25 °C. On the other hand, the dimers constituted of uf-3
and f-3 were clearly observed at À50 °C as the two sets of
signals (Fig. 2B). While the NHa proton signal of uf-3 was
observed at 5.3 ppm, the NHa proton signal of f-3 was
Scheme 2.
NHa proton signal of 2 was observed between 8.8 and
8.9 ppm. The chemical shift of the NHa proton was signif-
icantly downfield due to the intramolecular hydrogen
Hc
R3 = (CH2)7CH3
R3
O
N
B
A
O
Ph
N
Hb
N
Ha
Ha Hb
uf-3•uf-3 dimer
9
N
N
N
O
R3
Ph
O
O
Hc
8
7
Hc
O
Ph
R3
N
N
Hb
N
Ha
Hb
N
Hc
uf-3•f-3 dimer
O
6
5
O
N
Ha
N
R3
Ph
O
Hc
0.0
0.1
0.2
0.3
R3
Concentration of 3 (M)
Ph
Hb
O
O
N
Ha
N
N
f-3•f-3 dimer
N
Ha
N
Hb
N
Ph
R3
O
Hc
Fig. 1. (A) The chemical shift summary from the dilution study of 3-NHa (j), 3-NHb (N) and 3-Hc (d). The conditions: solvent, CDCl3; temperature
25 °C. (B) The proposed dimer conformations of 3.

Y. Hisamatsu et al. / Tetrahedron Letters 49 (2008) 2005–2009
2007
Table 1
A
Stability constants of ureas 3–7 for 1:1 complexes with cytosine derivative
8 in CDCl3 at 25 °Ca
Hc
Complex
Ks (MÀ1
)
DG298 (kJ/mol)
4.0 Â 103
1.1 Â 104
8.6 Â 103
1.5 Â 103
2.0 Â 103
À20.6
À23.1
À22.5
À18.1
À18.8
NHb
3Á8
4Á8
5Á8
6Á8
7Á8
a
NHa
10
9
8
7
6
5
B
Duplicate runs gave Ks values that agreed within 12%.
Hc (uf-3)
shifts supported the formation of a DDAÁAAD complex.
The stability constant (Ks) of the 1:1 complex11 between
3 (400 lM) and 8 in CDCl3 was determined to be
4.0 Â 103 MÀ1 by the fit of the chemical shift data for the
Hc proton signal to the 1:1 binding isotherm (Table 1).12
Thus, the stability constant of 3 for the cytosine derivative
was 100-fold greater than that of 1. To improve the ability
of 3 to complex with 8, the phenylurea derivatives 4 and 5
were prepared. Unfortunately, the conformational pro-
perty of 4 could not be tested because of its low solubility
in CDCl3 (65 mM). The conformational property of 5
was similar to 3. The ratio of uf-5 and f-5 at À50 °C was
estimated to be 2.4:1. The stability constant of the complex
NHb
(uf-3)
NHa
(uf-3)
NHb
(f-3)
NHa
(f-3)
Hc (f-3)
10
9
8
7
6
5
δ/ppm
Fig. 2. 1H NMR spectra of 3 in CDCl3 (A) at 25 °C and (B) at À50 °C.
observed at 8.3 ppm due to the intramolecular hydrogen
bond. The two NHb proton signals (f-3: 9.3 ppm and
uf-3: 9.5 ppm) shifted downfield by temperature-dependent
dimerization. Since the Hc proton signal of uf-3 was
affected by an anisotropic effect of the carbonyl group,
the Hc proton signal of uf-3 (8.0 ppm) was observed ca.
1 ppm downfield from that of f-3. The ratio of uf-3 to f-3
at À50 °C was estimated to be 3.3:1 based on the integra-
tion values of the NHa proton signals of uf-3 and f-3.
The complex formation between 3 and the tert-butyl-
dimethylsilyl-protected cytosine derivative 8 was monitored
by 1H NMR spectroscopy in CDCl3 at 25 °C (Fig. 3).
When 3 was titrated with 8 (0.1–3.0 equiv), significant
downfield shifts were observed in both the NHa (Dd =
2.2 ppm) and the NHb (Dd = 3.3 ppm) proton signals.
The conformational preference for uf-3 was also supported
by the significant downfield shift of the NHa proton signal.
The oxazole Hc proton signal was shifted downfield
(Dd = 0.34 ppm) by the conformational change from minor
f-3 to uf-3 prior to complexation with 8. These downfield
between 4 (400 lM) and 8 was increased to 1.1 Â 104 MÀ1
,
which was comparable to guanine-cytosine base pairing in
CDCl3.13 On the other hand, the stability constant of 5
(400 lM) was determined to be 8.6 Â 103 MÀ1. These
stability constants, higher than that of pyridine system,
showed the usefulness of oxazole systems as the DDA
hydrogen-bonding modules.
For other five-membered heterocyclic ureas, thiazol-4-yl
urea 6 and imidazo[1,2-a]pyrid-2-yl urea 7 were investi-
gated. From the variable-temperature NMR studies of 6
(40 mM), the ratio of uf-6 and f-6 (40 mM) at À50 °C
was estimated to be 0.8:1. The stability constant of the
1:1 complex between 6 (400 lM) and 8 in CDCl3 was deter-
mined to be 1.5 Â 103 MÀ1. On the other hand, the ratio of
uf-7 and f-7 (40 mM) at À50 °C was estimated to be 1.9:1.
The stability constant of the 1:1 complex between 7
(400 lM) and
8
in CDCl3 was determined to be
A
B
11
Hc
O
O
10
9
Ph
(CH2)7CH3
N
N
N
Hb Ha
H
N
8
O
N
TBDMSO
R4 =
O
H
7
N
R4
OTBDMS
TBDMSO
6
5
0.00
0.01
0.02
0.03
Concentration of 6 (M)
Fig. 3. (A) The chemical shift summary from the titration of 3 (8 mM) with cytosine derivative 8: 3-NHa (j), 3-NHb (N) and 3-Hc (d). The conditions:
solvent, CDCl3; temperature 25 °C. (B) The proposed structure of the complex between uf-3Á8.

2008
Y. Hisamatsu et al. / Tetrahedron Letters 49 (2008) 2005–2009
2.0 Â 103 MÀ1. Thus, these five-membered heterocyclic
ureas were capable of forming both the unfolded and
folded conformers at each ratio, and suitable for the
DDA hydrogen-bonding modules.
CHcÁ Á ÁO intramolecular hydrogen bond influenced confor-
mational stabilization, the conformational preference of
uf-2 for the unfolded conformer would be higher than that
of oxazol-4-yl urea 3.
From these results, it was suggested that the difference in
ring size (six- or five-membered ring) was a predominant
factor in the conformational equilibrium of the heterocyclic
ureas. Although the strength of the intramolecular hydro-
gen bond in the folded conformer affected the equilibrium,
it would not be the predominant factor. Indeed, the ratios
between the unfolded and the folded conformers in the het-
erocyclic ureas were not in accord with the order of the pKa
values of conjugated acid in each heteroaromatic ring.9,14
Thus, we focused on the heterocyclic urea structures of
the unfolded conformer optimized by computational study
In conclusion, it was demonstrated that the new five-
membered heterocyclic ureas 3–7 were capable of forming
both the unfolded and the folded conformers at each ratio,
and suitable for the DDA hydrogen-bonding modules.17 In
this case, the greater usefulness of the five-membered ring
as the hydrogen-bonding acceptor is clearly shown, com-
pared with the six-membered ring. Additionally, we pro-
pose that the distance between CHcÁ Á ÁO in the unfolded
conformer is the predominant factor in the equilibrium
between the unfolded and the folded conformers of the
heterocyclic ureas. Understanding of the conformational
equilibriums inherent in heterocyclic ureas is broadening
the potential of multiple hydrogen-bonding modules. By
employing our concept, the development of new quadruple
hydrogen-bonding modules including five-membered
heterocyclic urea structures is ongoing.
(B3LYP/6-31+G ).15 Ureas uf-1a, uf-2a (R1 = CH2CH3),
**
uf-3a, uf-6a, and uf-7a (R3 = CH2CH3) were used as the
model compounds. The distances between the hydrogen
Hc on the heteroaromatic ring and the oxygen on the urea
carbonyl substitute of each heterocyclic urea are shown in
Table 2. The CHcÁ Á ÁO distances of six-membered hetero-
˚
cyclic ureas (2.2 A) were clearly shorter than those of
Acknowledgments
˚
five-membered heterocyclic ureas (2.4–2.5 A). In addition,
as shown in Table 2 and Figure 4, the angle of three nitro-
gen atoms (\N–N–N) of six-membered heterocyclic ureas
(uf-1a and uf-2a) were smaller than that of five-membered
heterocyclic ureas (uf-3a, uf-6a and uf-7a). The slightly con-
cave shape3d,e of uf-1a and uf-2a suggested the presence of
a steric strain. Thus, the six-membered heterocyclic ureas 1
and 2 would be destabilized as an effect of steric repulsion
due to the closer distance between CHcÁ Á ÁO and their con-
formational equilibriums were biased toward the stable
folded conformer. In contrast, the longer distance in the
five-membered heterocyclic ureas decreased such unfavour-
able interactions. Generally, the distance of CHcÁ Á ÁO in the
six-membered heterocyclic ureas suggested the presence of
a weak intramolecular hydrogen bond.16 In this case, if the
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. We are grateful
to Ms. S. Kato (Graduate School of Pharmaceutical
Sciences) for technical support with NMR measurements.
Supplementary data
Experimental details describing the synthesis of the
heterocyclic ureas, characterization of all new compounds,
1
the H NMR measurements and the calculation studies.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.01.068.
Table 2
References and notes
Calculated CHcÁ Á ÁO distances and \N–N–Na
c
˚
Ureas
Ring size
CH Á Á ÁO (A)
\N–N–N (°)
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