Synthesis of a new series of ditopic proligands for metal salts: Differing regiochemistry of electrophilic attack at 3{5}-amino-5{3}-(pyrid-2-yl)-1H- pyrazole

Article abstract of DOI:10.1016/j.tetlet.2006.02.053

An improved synthesis of 3{5}-amino-5{3}-(pyrid-2-yl)-1H-pyrazole (I) is described, which affords the compound on a multi-gram scale. Reaction of I with acid chloride and isothiocyanate electrophiles in MeCN cleanly results in attack at its amino group, y

Full text of DOI:10.1016/j.tetlet.2006.02.053

Tetrahedron Letters 47 (2006) 2531–2534
Synthesis of a new series of ditopic proligands for metal
salts: differing regiochemistry of electrophilic attack
at 3{5}-amino-5{3}-(pyrid-2-yl)-1H-pyrazole
Christopher M. Pask, Kenneth D. Camm, Colin A. Kilner and Malcolm A. Halcrow*
School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK
Received 11 January 2006; accepted 9 February 2006
Available online 28 February 2006
Abstract—An improved synthesis of 3{5}-amino-5{3}-(pyrid-2-yl)-1H-pyrazole (I) is described, which affords the compound on a
multi-gram scale. Reaction of I with acid chloride and isothiocyanate electrophiles in MeCN cleanly results in attack at its amino
group, yielding N-(3-{pyrid-2-yl}-1H-pyrazol-5-yl)amide and N-(3-{pyrid-2-yl}-1H-pyrazol-5-yl)thiourea products. These are good
candidates as proligands for the simultaneous complexation of metal cations and anions. However, treatment of I with isocyanates
under the same conditions instead yields attack at the pyrazole ring, giving 3-(pyridin-2-yl)-5-aminopyrazole-1-carboxylic acid
amides as the only isolable products. The differing regiochemistries of these reactions were confirmed by 1H NMR and X-ray
crystallography.
Ó 2006 Elsevier Ltd. All rights reserved.
We1–3 and others4 have found that metal complexes of
simple NH pyrazoles can present a structurally defined
binding pocket for halides or other anions. tert-Butyl
and other hydrocarbon substituents at the 5-position
of the metal-bound pyrazole groups appear to promote
these anion-binding capabilities through hydrophobic
interactions. For our own part, we have used zinc-
coordinated pyrazole ligands to bind a range of
inorganic anions,1 and have found that supramolecular
pyrazoleꢀ ꢀ ꢀanion interactions can be used to template
new metal cluster structures.2,3 More generally, organic
Scheme 1. Synthesis of 3{5}-(pyrid-2-yl)-5{3}-aminopyrazole (1).
Reagents and conditions: (i) CH3CN, NaH, toluene, 65 °C, 40 h; (ii)
dil HCl; (iii) N2H4ÆH2O, EtOH, reflux, 20 h.
ligands that can bind simultaneously to a metal cation
and its charge balancing anions are also of great current
interest for hydrometallurgy, waste water treatment and
other applications in supramolecular chemistry.5 As an
extension of our work, we proposed that 5-amino-3-
(pyrid-2-yl)-1H-pyrazole (I, Scheme 1),6 should chelate
to both the cation and anion(s) of a coordinated metal
salt. An initial study of two copper(II) complexes of I
has proven the validity of that suggestion.7 We reasoned
that a wide range of new ditopic ligands could be
accessed from I, by electrophilic derivitisation of its
amine substituent. We were particularly keen to incor-
porate amide, urea and thiourea functions onto the
3{5}-(pyrid-2-yl)-1H-pyrazole framework, since these
are particularly useful donor groups in anion receptors.8
Towards that end, we describe here an improved synthe-
sis of I and its reactions with electrophiles.
The preparation of I by the basic procedure shown in
Scheme 1 has been briefly discussed, but no experimen-
tal details are given.6 The synthesis of the intermediate
3-oxo-3-pyridin-2-yl-propionitrile (II, Scheme 1) under
Knoevenagel conditions is better known, although very
variable yields of between 7% and 60% have been
reported for this reaction.9 We have synthesised II in
Keywords: 3-Amino-5-(pyrid-2-yl)-1H-pyrazole; Electrophilic substitu-
tion; Regiochemistry; Crystal structure.
*
Corresponding author. Tel.: +44 113 343 6506; fax: +44 113 343
6565; e-mail: M.A.Halcrow@leeds.ac.uk
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.053

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C. M. Pask et al. / Tetrahedron Letters 47 (2006) 2531–2534
68% yield from ethyl picolinate and acetonitrile using
sodium hydride as base, and modified reaction condi-
tions and work-up. Treatment of II with hydrazine
monohydrate affords I in 89% yield. Compound I can
be prepared on a 10 g scale by this route, making it a
convenient synthetic intermediate. The NMR spectra
and melting point of II match those previously reported
for this compound.9 No characterisation data for I have
been presented before.
provided some insight into this problem, showing that
its crystal lattice contains channels that are occupied
by the (disordered) solvent.10 After many attempts we
found that IIIÆH2O and solvent-free V can be obtained
cleanly, but with substantial solubility losses, by recrys-
tallisation from MeOH, while small amounts of IV can
be obtained in pure form from ethyl acetate. Given the
difficulties in handling III–V, it is probably more
convenient to use their hydrochloride salts as reagents
in further chemical transformations or metal salt
complexation reactions, deprotonating them in situ if
required.
Reaction of I with acid chlorides RC{O}Cl (R = Me, Ph
or t-Bu) in refluxing MeCN yields white precipitates
of the appropriate N-(3-{pyrid-2-yl}-1H-pyrazol-5-yl)-
amide as its hydrochloride salt, IIIÆHCl–VÆHCl (Scheme
2), in ca. 70% yield. The free bases of these compounds
can be obtained in low yield by treating the hydrochlo-
ride salts with aqueous Na2CO3 under biphasic condi-
tions. Acid-free III–V were also obtained directly in
10–25% yield by performing the acetylations using
pyridine instead of MeCN as solvent, although these
reactions required more extended purifications. Our
difficulties in obtaining the free bases III–V reflect the
fact that they strongly retain solvent in the solid state,
being obtained as analytically impure solids from many
of the common organic solvents. A structure determina-
tion of crystals of formula IIIÆn-CH2Cl2 (n ꢁ 0.25)
Treatment of
I with the isothiocyanates RNCS
(R = Me, Ph or Cy) in refluxing MeCN affords the
N-(3-{pyrid-2-yl}-1H-pyrazol-5-yl)thioureas VI–VIII as
analytically pure white precipitates in 44–81% yield
(Scheme 2). However, an analogous reaction using
t-BuNCS gave only unreacted starting material follow-
ing the usual work-up, for reasons that are unclear. In
contrast, reaction of
I with isocyanates RNCO
(R = Ph, Cy or t-Bu) under the same conditions instead
gave the 3-(pyridin-2-yl)-5-aminopyrazole-1-carboxylic
acid amides IX–XI as the only isolable products, in
48–71% isolated yield (Scheme 2). The different regio-
chemistry of these reactions has some literature prece-
dent in the chemistry of 3{5}-aminopyrazole itself. It
is known that N-(pyrazol-1H-3-yl)thioureas are ob-
tained cleanly by treatment of 3{5}-aminopyrazole with
isothiocyanates.11 However, reaction of 3{5}-amino-
pyrazole with acid chlorides12,13 or isocyanates14 can
result in functionalisation of the amino group or either
of the pyrazole N atoms, yielding up to three different
products.13,14 Our isolation of regioisomerically pure
products III–V (as their HCl adducts) and IX–XI in
good yields contrasts with these earlier studies, where
mixtures of products were commonly observed.12–14
Treatment of I with (Boc)2O under the same conditions
did lead to a crude mixture of XII [d{N–H} = 6.35 (2H)
ppm] and XIII [d{N–H} = 9.51 (1H) and 12.83 (1H)
1
ppm] according to the H NMR criteria in {CD3}2SO
described below, however, in an approximate yield
ratio of 3:1. Unfortunately, we were unable to separate
these two products by crystallisation or flash
chromatography.
The different regiochemistry of the reactions in Scheme 2
was confirmed by crystal structure determinations of III
(as its CH2Cl2 solvate), VI, X and XI (Fig. 1).10,15–17
Although III and VI crystallise as their 5-pyridyl-1H
tautomers, the rapid tautomeric interconversion under-
gone by many pyrazoles in solution18 (including III–V,
see below) means that the 3-pyridyl-1H tautomer
required for chelation to a metal ion through N(1) and
N(8) (Fig. 1) should be readily accessible under suitable
conditions. The amide N–H group in III is syn to the
pyrazole N atoms, which is the conformation required
for III to chelate to an anion by hydrogen-bonding
through N(9) and N(12) (in the alternative 3-pyridyl-
1H form; Fig. 1). The amide and pyrazole groups are
not coplanar, however, the torsion C(11)–C(10)–
N(12)–C(13) angle being 16.5(5)°. This reflects a steric
contact between O(15) and the H atom bound to
Scheme 2. Reactions of 1 with electrophiles. Reagents and conditions:
(i) RCOCl, MeCN, reflux, 16 h; (ii) Na2CO3, CHCl3/H2O, reflux, 16 h;
(iii) RNCS, MeCN, reflux, 16 h; (iv) RNCO, MeCN, reflux, 16 h; (v)
[t-BuOC(O)]2O, MeCN, reflux, 16 h.

C. M. Pask et al. / Tetrahedron Letters 47 (2006) 2531–2534
2533
hydrogen bonds (Fig. 1): between the NH2 group
N(12) and carbonyl O atom O(14); and, from the amide
NH group N(15) to the pyrazole pyridinic N atom
N(8). All four compounds also take part in intermole-
cular hydrogen bonding in their crystal lattices. In
IIIÆn-CH2Cl2, X and XI this leads to three-connected
2-D hydrogen-bond networks with 63 ‘herringbone’
topologies,21 while in VI the molecules associate into
1D hydrogen-bonded chains zig-zagging along the
crystallographic [011] direction.
The regioisomeric structures of the products in Scheme 2
are also evident from their 1H NMR spectra in
(CD3)2SO. Compounds III–V and VI–VIII afford two
and three N–H NMR signals, respectively, lying
between 10 and 13 ppm and with equal integrals (but
see below). That is the distribution expected if the
primary amine group has been functionalised in these
compounds, as observed. Conversely, IX–XI show two
N–H NMR peaks with a 2:1 integral ratio, one near
6.5 ppm (2H) from the primary NH2 amino group,
and one at a more variable chemical shift of between 7
1
and 10 ppm (1H) from the urea N–H function. The H
spectra of the amide derivatives III–V in (CD3)2SO all
show two distinct pairs of N–H peaks. The two reso-
nances within a pair have equal integrals, and the inte-
grals of the major and minor peaks for each H
environment sum to 1H relative to the other peaks in
the spectra. We ascribe this behaviour to the existence
of both the 3-pyridyl-5-amido and 5-pyridyl-3-amido
tautomers of the pyrazole ring in solution, since it is
quite common to resolve the different tautomers of pyr-
azole derivatives by NMR in this strongly associating
solvent.18 The NMR spectra show that the minor tauto-
mer forms have no more than 25% of the samples under
these conditions, although it is unfortunately not possi-
ble to assign which of the two tautomeric structures is
the major one from these data alone.18 In CDCl3, III–
V show only a single pair of N–H NMR resonances,
implying that the tautomeric equilibrium occurs more
rapidly, or that only a single tautomeric form is popu-
lated in this solvent. Thioureas VI–VIII all exhibit only
one set of three N–H NMR peaks in both (CD3)2SO and
CDCl3.
Figure 1. Views of the single crystal structures of IIIÆn-CH2Cl2 (top),
VI (centre) and XI (bottom). Only one of the two crystallographically
independent molecules in IIIÆn-CH2Cl2 is shown. The other molecule is
visually near-identical to this one, but shows some disorder in its amide
group. Thermal ellipsoids are at the 50% displacement level, except for
H atoms which have arbitrary radii. A view of X is given in
Supplementary data.
In conclusion, we have shown that I can be prepared on
a multi-gram scale in two steps from commercial
reagents, and that it is a versatile precursor for amide
(III–V) and thiourea (VI–VIII) derivatives that have
the potential to chelate concurrently to both metal
cations and anions. However, attempts to prepare urea
derivatives analogous to VI–VIII instead afforded
the 3-(pyridin-2-yl)-5-aminopyrazole-1-carboxylic acid
amides IX–XI. We ascribe the different regiochemistry
of addition of isocyanates and cyanates to I to the par-
ticular hardness of the cyanate electrophiles. This gener-
ates a more polar transition state during the cyanate
addition reactions that can be delocalised around the
pyrazole ring more effectively when attack takes place
at a heterocyclic N atom. Preliminary investigations
have shown that reaction of IX–XI with first-row transi-
tion metal ions results in their rapid, Lewis acid-effected
deacylation to regenerate I. Studies of the binding
˚
C(11), which are 2.5 A apart (with the H atom in an
idealised calculated position). For comparison, the
sum of the van der Waals radii of an H and O atom is
2.6 A.19 The thiourea function in VI adopts the Z,E con-
˚
formation that is usually preferred for N,N0-disubsti-
tuted thioureas,20 giving rise to an intramolecular N–
Hꢀ ꢀ ꢀN hydrogen bond from the distal N–H group
N(15) to the pyrazole pyridinic N atom N(9) (Fig. 1).
Chelation of an anion to this group would require rota-
tion of the thiourea group to a Z,Z conformation (for
which there is substantial precedent)8 and cleavage of
this hydrogen bond. The dihedral angle between the pyr-
azole and thiourea groups in this structure is 3.0(2)°,
showing that they are effectively coplanar. The confor-
mations of X and XI in the crystal are essentially identi-
cal, with near-coplanar pyrazole and carboxamido
functions positioned to afford two intramolecular

2534
C. M. Pask et al. / Tetrahedron Letters 47 (2006) 2531–2534
9. (a) Hromatka, O.; Binder, D.; Stanetty, P.; Marischler, G.
Monatsh. Chem. 1976, 107, 233; (b) Cossy, J.; Pete, J.-P.
Bull. Soc. Chim. Fr. 1979, 559; (c) Fray, M. J.; Bull, D. J.;
Kinns, M. J. Chem. Res. (S) 1992, 10; (d) Baraldi, P. G.;
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properties of III–VIII towards metal salts are more
promising, and will be reported separately.
Acknowledgements
The authors thank Professor Ronald Grigg (University
of Leeds), for helpful discussions. This work was funded
by the Leverhulme Trust, the EPSRC and the University
of Leeds.
10. Crystal data for IIIÆn-CH2Cl2 (n ꢁ 0.25): C10.25H10.5
-
Cl0.5N4O, Mr 223.45, monoclinic, space group C2/c,
˚
a = 18.1473(7), b = 25.0031(10), c = 9.3864(4) A, b =
3
ꢂ3
˚
97.153(2)°, V = 4225.8(3) A , Z = 16, Dc = 1.405 g cm
,
l(Mo-Ka) = 0.217 mmꢂ1
,
k = 0.71073 A, T = 150 K,
˚
R1 = 0.073, wR2 = 0.227. The asymmetric unit contains
two molecules of III, with essentially identical conforma-
tions although the amide group in one of them is
disordered; and, a region of ca. 0.5 mol equiv of disor-
dered solvent occupying channels in the crystal lattice. See
Supplementary data for more details. CCDC 293593.
11. (a) Kobe, J.; Robins, R. K.; O’Brien, D. E. J. Heterocycl.
Chem. 1974, 11, 199; (b) Singh, B. N.; Rao, R. P.; Raj, S.;
Rao, A. P. J. Chem. Eng. Data 1978, 23, 98; (c) Singh, B.
N. Agric. Biol. Chem. 1978, 42, 1285; (d) Bell, F. W.;
Cantrell, A. S.; Hogberg, M.; Jaskunas, S. R.; Johansson,
N. G.; Jordan, C. L.; Kinnick, M. D.; Lind, P.; Morin, J.
Supplementary data
Electronic supplementary data: experimental procedures
and characterisation data for the compounds in this
study, and further detail about the crystal structures,
their data collection and refinement. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2006.02.053.
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˚
˚
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˚
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˚
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