High-pressure-promoted condensation of isothiocyanates with aminopyridines: Efficient synthesis of pyridine-thiourea conjugates as building blocks for hydrogen-bonding receptors

Article abstract of DOI:10.1016/S0040-4039(01)02295-X

New N-pyridinothiourea derivatives have been prepared by the high-pressure-promoted condensation of isothiocyanates with aminopyridines under uncatalyzed conditions. Complexation of the prototype 3c with diphenyl hydrogen phosphate was investigated by ¹H NMR, and the results suggest that it may be useful as a building block for hydrogen-bonding receptors.

Full text of DOI:10.1016/S0040-4039(01)02295-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1035–1038
High-pressure-promoted condensation of isothiocyanates with
aminopyridines: efficient synthesis of pyridine–thiourea
conjugates as building blocks for hydrogen-bonding receptors†
Koji Kumamoto,a Yoshihiro Misawa,b Sumio Tokita,b Yuji Kubob,* and Hiyoshizo Kotsukia,*
aDepartment of Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
bDepartment of Applied Chemistry, Faculty of Engineering, Saitama University, Saitama 338-8570, Japan
Received 2 November 2001; accepted 30 November 2001
Abstract—New N-pyridinothiourea derivatives have been prepared by the high-pressure-promoted condensation of isothio-
cyanates with aminopyridines under uncatalyzed conditions. Complexation of the prototype 3c with diphenyl hydrogen phosphate
1
was investigated by H NMR, and the results suggest that it may be useful as a building block for hydrogen-bonding receptors.
© 2002 Elsevier Science Ltd. All rights reserved.
Thiourea and its related molecules are important as
structural components and as intermediates in agricul-
tural and pharmaceutical chemistry.2 Recently, these
compounds have attracted considerable attention for
their potential use as binding units for artificial recep-
tors in supramolecular chemistry because of their char-
acteristic behavior based on Lewis acids and strong
hydrogen-bond donors.3 Furthermore, in the field of
advanced material chemistry, thioureas can serve as a
useful scaffold by connecting them to electrolumines-
cent organic dyes.4 Their enormous potential has led to
the development of several methods for preparing
thiourea derivatives.5 The most common of these meth-
ods involves the condensation of isothiocyanates with
amino derivatives. However, despite its utility and sim-
plicity, limitations are sometimes encountered, particu-
larly with less reactive amine substrates.
and N,N%-diphenylthiourea (4, 38%) (Scheme 1). The
latter compound 4 must be formed by the self-recombi-
nation of 2a via decomposition to aniline. Considerable
attempts to facilitate the desired condensation reaction
under acid- or base-catalyzed conditions were unsuc-
cessful. These results can be easily understood by
invoking the weakly nucleophilic character of the
amino group of 1a. To overcome this difficulty and also
to suppress undesired side-reactions, we decided to
apply a high-pressure methodology, since our previous
experience suggested that such a condensation reaction
should be favorable at high pressure.7 We report here
the realization of this expectation. The results are sum-
marized in Table 1.8
When the reaction of 1a with 1.2 equiv. of 2a in THF
was conducted at 0.6 GPa and 40°C for 24 h,9 the
desired adduct 3a, mp 142–143°C (from methanol), was
obtained in a much better yield of 67%, contaminated
For example, in contrast to the case of aniline deriva-
tives,6 we found that 4-aminopyridine (1a) reacted fairly
slowly with phenylisothiocyanate (2a), even in refluxing
THF, to produce a complex mixture of products from
which, after 18 h, N-pyridinothiourea 3a could be
isolated in 29% yield along with unreacted 2a (22%)
NH2
2a (22%)
+
1a
S
N
N
+
THF
3a (29%)
4 (38%)
N
H
N
H
reflux, 18 h
NCS
+
S
Keywords: high-pressure condensation; isothiocyanates; aminopyridi-
nes; N-pyridinothioureas; hydrogen-bonding receptors.
2a
N
H
N
H
* Corresponding authors. Fax: +81-88-844-8359; e-mail: yuji@
apc.saitama-u.ac.jp; kotsuki@cc.kochi-u.ac.jp
† High-Pressure Organic Chemistry. Part 25. For Part 24, see: Ref. 1.
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02295-X

1036
K. Kumamoto et al. / Tetrahedron Letters 43 (2002) 1035–1038
Table 1. Synthesis of N-pyridinothioureasa

K. Kumamoto et al. / Tetrahedron Letters 43 (2002) 1035–1038
1037
by only a trace amount of 4 (entry 1). Based on this
general scheme, 3b–3g were prepared in good yields as
highly crystalline materials, but in some cases a longer
reaction period was needed to increase the product
yields (entries 2–7). Adduct 3h, mp 181–183°C (from
methanol), could be obtained by condensing amino-
bipyridine 1d with azo-derived isothiocyanate 2c (entry
8). This result implies that this procedure may be useful
for devising a new type of azo-chromophore-based
colorimetric receptor. The high-pressure technique was
also effective for aliphatic homologs such as cyclo-
hexylisothiocyanate (2d): the corresponding aminopy-
ridine adducts 3i and 3j were produced in respective
yields of 71 and 78% under slightly harsher conditions
(entries 9 and 10).10
data. Fig. 1 shows the results of titrations in which the
chemical shifts of two types of thiourea NH protons
(NHa and NHb, see Fig. 2) could be monitored as a
function of the amount of diphenyl hydrogen phos-
phate (5) in CD3CN at 23°C. In the absence of 5, the
resonances of NHa (13.80 ppm) and NHb (8.92 ppm)
are distinguishable from each other; the extreme low-
field signal of NHa can be ascribed to favorable
intramolecular hydrogen bonding between NHa and
pyridine-N.12 Adding 5 to a solution of 3c produced an
up-field shift for NHa and a down-field shift for NHb.
The former observation is attributable to the disruption
of hydrogen bonding by a 5-induced competitive bind-
ing event. We carefully analyzed the binding curve of
NHb based on a nonlinear curve-fitting procedure,13
which suggested two complexation steps, as follows:
H+G ? HG (Ka1), HG+G ? HGG (Ka2), [H]0=[H]+
[HG]+[HGG], where [H] and [G] refer to 3c and 5,
respectively. As a result, the analysis could fully repro-
duce the experimental data to estimate each association
constant (Ka1=51 14 M−1 and Ka2=1,100 220 M−1).14
The results (Ka1ꢀKa2) could be explained on the basis
of a Ka1 binding mode accompanied by the competitive
disruption of intramolecular hydrogen bonding (vide
supra), as well as a 5-assisted strong association (Ka2) of
a second 5.15 The plausible complex motifs are shown
in Fig. 2, where intermolecular hydrogen bonding
between pyridine-N and 5-OH has taken place, as
Another issue was whether the pyridine–thiourea conju-
gates obtained above could serve as potent building
blocks for artificial receptors in supramolecular chem-
istry. Each molecule contains both a hydrogen-bonding
acceptor (pyridine unit) and a hydrogen-bonding donor
(thiourea unit), and this prompted us to evaluate their
ability to bind to a phosphoric acid diester as a biolog-
ically important species.11 The prototype 3c was used
for this purpose; binding was assessed by 1H NMR
1
inferred from a H NMR dilution experiment16 of a 1:1
mixture of 3c and 5 in CD3CN, which showed a
concentration-dependent shift of the resonances due to
the spherical pyridine ortho- and para-positioned pro-
tons (Ho and Hp, see Fig. 2). In a control experiment,
when N-methyl-N-phenylthiourea, which lacks a pyri-
dine moiety, was used for complexation, such binding
behavior of 5 was not observed. Taken together, these
preliminary results suggest a new approach to the
development of new hydrogen-bonding molecular
receptors and carriers based on pyridine–thiourea
conjugates.
In conclusion, we have developed a convenient method
for preparing a variety of N-pyridinothiourea deriva-
tives using the high-pressure-promoted uncatalyzed
condensation of isothiocyanates with aminopyridines.
Our findings with this new class of compounds show
that a pyridine–thiourea bifunctionality is effective for
binding diphenyl hydrogen phosphate through hydro-
gen-bonding interactions. We believe that the present
cogent synthetic method warrants future study.
Figure 1. 1H NMR chemical shifts of 3c upon addition of
diphenyl hydrogen phosphate 5. [3c]=4 mM. See Fig. 2 for
proton positions, Ha and Hb.
Hp
S
S
S
Hb
N
Ha
K1
K2
N
N
N
N
H
Ho
N
N
N
H
Ha Hb
Ha Hb
N
Ph
O
O
O
P
O
3c
O
O
O
O
O
Ph
P
P
Ph
Ph
O
O
O
H
Ph
Ph
Figure 2. The plausible host–guest complexations.

1038
K. Kumamoto et al. / Tetrahedron Letters 43 (2002) 1035–1038
5. Satchell, D. P. N.; Satchell, R. S. In The Chemistry of
Acknowledgements
Sulfur-Containing Functional Groups; Patai, S.; Rappo-
port, Z., Eds.; Wiley: New York, 1993; Suppl. S, Chapter
12, pp. 599–631.
This work was supported in part by The Nishida
Research Fund for Fundamental Organic Chemistry
(Y.K.).
6. Otterbacher, T.; Whitmore, F. C. J. Am. Chem. Soc.
1929, 51, 1909–1911.
7. For a review of high-pressure-promoted condensation
reactions, see: Yamamoto, Y. In Organic Synthesis at
High Pressures; Matsumoto, K.; Acheson, R. M., Eds.;
Wiley: New York, 1991; Chapter 6. See also: Kotsuki, H.
Kagaku to Kogyo (Osaka) 1994, 68, 265–278; Kotsuki,
H.; Kumamoto, K. Rev. High Press. Sci. Technol. 2001,
11, 220–226.
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8. Typical experimental procedure: preparation of 3a. A mix-
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4-aminopyridine (1a, 47 mg, 0.5 mmol) in dry THF (1.5
mL) was placed in a Teflon reaction vessel and allowed to
react at 0.6 GPa and 40°C for 24 h. After evaporation of
the solvent, the crude product was purified by preparative
TLC (CHCl3/MeOH=9:1) to give 3a (77 mg, 67%) as a
colorless powder. 3a: FTIR (KBr) w 3160, 1595, 1535,
1508, 1487 cm−1 1H NMR (DMSO-d6) l 7.15 (1H, dt,
;
J=8.0, 1.2 Hz), 7.35 (2H, dt, J=8.0, 1.2 Hz), 7.47 (2H,
d-like, J=8.0 Hz), 7.61 (2H, AA%XX%, JAX=4.8 Hz), 8.40
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139.9, 149.5, 150.2 (×2), 181.4. Anal. calcd for
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H, 4.84; N, 18.19%.
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