Helicity-encoded molecular strands: Efficient access by the hydrazone route and structural features

Article abstract of DOI:10.1002/hlca.200390137

Control over the folding of molecular strands may be achieved by appropriate choice of the constituting subunits, in particular for chains of specific heterocycles such as sequences of directly connected pyridine (py) and pyrimidine (pym) rings, which are known to fold into extended helical structures. Since the hydrazone (hyz) group represents an isomorphic analogue of a py site, the condensation of hydrazine and carboxaldehyde derivatives of pym offers a very efficient approach to strands incorporating hyz instead of py units and constituted by sequences of alternating hyz and pym group. A. series of such strands of different lengths, up to ten hyz units, i.e., 1-7, were synthesized. Their spectral properties indicate that they fold indeed into helical shapes. Extensive characterization was performed in solution by IH-NMR spectroscopy and in the solid state by determination of the crystal structures of eight such strands. They all display the expected helical geometry with up to 3 1/3, turns and direct stacking contacts. The efficiency and flexibility of the synthetic approach as well as its wide potential for generation of diversity through lateral decoration make the (hyz - pym) subunit a particularly attractive helicity codon.

Full text of DOI:10.1002/hlca.200390137

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Helvetica Chimica Acta Vol. 86 (2003)
Helicity-Encoded Molecular Strands: Efficient Access by the Hydrazone
Route and Structural Features
by Jean-Louis Schmitta), Adrian-Mihail Stadlera), Nathalie Kyritsakasb), and Jean-Marie Lehn*a)
a
¬
) ISIS-ULP-CNRS UMR 7006 8, allee Gaspard Monge, BP 70028, F-67083 Strasbourg cedex
(phone: 0390245145; fax 0390245140; lehn@isis.u-strasbg.fr)
b
¬
) Service Commun de Rayons X, Institut Le Bel, Universite Louis Pasteur, 4, rue Blaise Pascal,
F-67000 Strasbourg
Dedicated to Professor Jack D. Dunitz on the occasion of his 80th birthday
Control over the folding of molecular strands may be achieved by appropriate choice of the constituting
subunits, in particular for chains of specific heterocycles such as sequences of directly connected pyridine (py)
and pyrimidine (pym) rings, which are known to fold into extended helical structures. Since the hydrazone (hyz)
group represents an isomorphic analogue of a py site, the condensation of hydrazine and carboxaldehyde
derivatives of pym offers a very efficient approach to strands incorporating hyz instead of py units and
constituted by sequences of alternating hyz and pym groups. A series of such strands of different lengths, up to
ten hyz units, i.e., 1 7, were synthesized. Their spectral properties indicate that they fold indeed into helical
shapes. Extensive characterization was performed in solution by 1H-NMR spectroscopy and in the solid state by
determination of the crystal structures of eight such strands. They all display the expected helical geometry with
up to 3 1/3 turns and direct stacking contacts. The efficiency and flexibility of the synthetic approach as well as its
wide potential for generation of diversity through lateral decoration make the (hyzÀpym) subunit a particularly
attractive helicity codon.
Introduction. The design of molecular strands capable of taking up defined and
predictable shapes is of much interest in view of its relation to biological folding
processes in proteins as well as of the access it provides to the generation of well-
defined geometries for functional devices and materials. Intense activity has recently
been displayed in this area, implementing various types of supramolecular, noncovalent
interactions (H-bonding, stacking and electrostatic interactions, metal-ion coordina-
tion) as well as medium effects, to induce the self-organization of a molecular strand
into specific architectures [1]. A range of geometries from entirely helical to fully linear
may thus be targetted.
In our laboratories, we have made use of different interaction patterns and
structuration subunits to generate single helices [2 8] and double helices [8a][9 11]
as well as extended linear chains [12]. In particular, we have shown that specific sets of
connected heterocyclic rings such as pyridineÀpyrimidine (pyÀpym) [2 4], pyridi-
neÀpyridazine [5], or naphthyridineÀpyrimidine [6] units represent helicity codons
that enforce the helical wrapping of polyheterocyclic strands. In addition to their static
structural features, such strands present, by virtue of the potential coordination sites
they possess, dynamic functional features as demonstrated by the extension/contraction
motional processes resulting from the reversible interconversion between helical and
linear states triggered by metal-ion binding [12][13]. Furthermore, various other

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functional properties may be accessible through the precise positioning of photoactive,
electroactive, etc., groups, made possible by folding control.
In view of this rich palette of features, an efficient synthetic access to shape-
programmed molecular strands is highly desirable. We present here a general scheme to
achieve this goal together with extensive structural characterization of the resulting
compounds through X-ray crystallography.
Synthetic and Structural Principles. For the helical strands based on pyÀpym
sequences previously synthesized in our laboratory [2 4], we made use of a well-
defined but laborious synthetic procedure for building up such chains of directly
connected heterocycles. The isomorphic correspondence between a 2,6-disubstituted
pyridine ring (see A) and a hydrazone (hyz) group (see A') provides a solution for
greatly facilitating the synthetic procedure by replacing the formation of inter-
heterocyclic CÀC connections by hydrazone condensation [7].
R
N
N
N
N
N
N
N
N
N
N
N
A
A′
Generalizing this earlier work, a strand consisting of a sequence of repeating
hydrazoneÀpyrimidine (hyzÀpym) units is expected to undergo enforced self-
organization into a helical shape. Thus, the hyzÀpym group is a helicity codon
isomorphic to the pyÀpym one. We describe here the synthesis and structural
characterization, both in solution (by NMR spectroscopy) and in the solid state (by X-
ray crystallography), of a series of molecular strands of various lengths, i.e., of 1 7,
implementing the hyzÀpym subunit.
Some general considerations concerning the construction of the ligands were taken
into account for planning the synthetic procedures. First, one helical turn is constituted
of three hyzÀpym units. A sequence pymÀhyzÀpym corresponds to a tridentate
coordination site so that a hydrazone unit is associated with a coordination site (see B).
On the other hand, a strand containing 4, 6, 8, or 10 hyz groups should be a molecular
2
helix presenting, respectively 11/3, 2 , 2/3, and 31/3 turns.
Second, the isomorphic correspondence between a 2,6-disubstituted pyridine and a
hydrazone group allows the synthetic connection at this site and, thus, the use of simple
pyrimidine building blocks for generating the helical strand. Consequently, the
synthesis is greatly facilitated and presents more flexibility as well as wider potential. A
strand having an even number of hydrazone functions may be prepared via a route
involving a desymmetrization step followed by a symmetrical double-chain extension, a

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methodology used in natural-product synthesis [14]. In the case of an odd number of
hyz groups, the double-chain extension is not possible, but, due to the flexibility of the
synthetic pathway, a ligand of this type could be easily synthesized. For example, the 3-
sites strand 6 was obtained following two pathways (Scheme 1). Both linear (building-
blocks stringing) and convergent synthetic pathways may be followed.
Scheme 1
CH3
N
CH3
N
CH3
N
N
N
NH2
O
+
N
N
N
N
N
N
CH3
N
CH3
N
CH3
N
N
N
N
N
N
N
N
N
N
CH3
CH3
N
CH3
N
N
N
6
N
O
NH2
+
N
N
N
N
N
N
CH3
N
CH3
CH3
N
CH3
CH3
CH3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
MeO
OMe
OMe
3e
The broader potential of the synthesis results from the use of simple and easily
functionalizable building blocks giving access to numerous combinations as illustrated
by compound 3e where differently substituted hyz and pym groups are combined,
bearing diverse groups at both the pym and the hyz units.
It is, thus, possible to use the ternary hydrazone N-atom, in addition to the 2
position of the pym ring, for −decorating× the strand by grafting lateral groups
possessing specific properties. This is in particular of interest for modulating the
solubility in different media. For instance, to increase the solubility in organic solvents,
one may use as starting material N-alkylhydrazine groups or a pyrimidine ring bearing a
trimethoxyphenyl substituent at C(2). The introduction of lateral residues bearing
functional groups such as allyl, hydroxyethyl (by using N-allyl- or N-(hydroxyethyl)-
hydrazine) makes possible further functionalization of the strands.
The replacement of a 2,6-disubstituted pyridine ring by a hydrazone group also
confers more flexibility to the hyzÀpym strand due to the greater conformational
mobility of the hyz unit.
Finally, the condensation of a 4,6-dihydrazinopyrimidine with a pyrimidine-4,6-
dicarboxaldehyde gives access to helical polymers, thus extending the procedure
towards the preparation of novel materials [15].

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Synthesis of Strands 1 7. For the synthesis of the strands 1 5 and 7 having an
even number of sites, a chain-doubling strategy was used. In this case, the aldehyde or
hydrazine precursor chain was constructed in a linear manner by a procedure of
repetitive condensation-disymmetrization of the starting pyrimidine-dicarboxaldehyde
or dihydrazinopyrimidine (yields of 20 80%), and the final strand was obtained by
symmetric double condensation of this precursor with either a dialdehyde or a
dihydrazine (yields of 8 75%) (Schemes 2 and 4). The 2-sites chain 1 was obtained by
condensation of a 4,6-dihydrazinopyrimidine 9 (synthesized from 8, see Scheme 2) with
pyridine-2-carboxaldehyde1).
Scheme 2. Synthesis of the 2- and 4-Sites Strands 1 and 2 and of the Precursors 11 (uncoiled representation)
For the longer strands 2 5, a disymmetrization procedure was required to
progressively build up the components. The synthesis may be conducted along two
different pathways, which lead to reverse positioning of the hydrazone functions along
the final chains. They involve the use of either pyridine-2-carboxaldehyde to
1
)
Compound 1c was first synthesized by George Blasen.

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desymmetrize a 4,6-dihydrazinopyrimidine (in 1:1 stoichiometry; Schemes 2 and 3) or
2-hydrazinopyridine to desymmetrize pyrimidine-4,6-dicarboxaldehyde (in 1:1 stoi-
chiometry; see Scheme 4). This strategy was successfully employed for preparing the 4-
sites strands 2 (from 9 via 10, see Scheme 2) and their analog 7 (from 14a via 15, see
Scheme 4). During the first desymmetrization step involving the condensation of
1 equiv. of pyridine derivative (pyridine-2-carboxaldehyde or a 2-hydrazinopyridine
26) and 1 equiv. of a pyrimidine derivative (9 or 14a,b, resp.) in EtOH, the precursors
10 or 15 could not be obtained pure, but were contaminated by the dihydrazone of type
1. Increasing the amount of pyrimidine derivative (2, 3, or 4 equiv. of pyrimidine-
dicarboxaldehyde 14a,b to 1 equiv. of hydrazinopyridine derivative) and working at
low temperature, did not preclude the formation of the corresponding 2-sites
compounds due to the high reactivity of the aldehyde. Purification by flash
chromatography (FC; alumina or silica gel) was necessary to obtain the precursors
10 (40 80% yield) and 15 (30 40% yield). A possible alternative could be the
generation of ketone precursors, by using the diketone 14c, in view of the lower
reactivity of ketones compared to the aldehydes. On the other hand, this nonselectivity
was useful, since it generated in one step both the 2-sites compounds 1 and the
precursors 10 and 15 of the 4-sites strands.
It was noted that the reactions involving N-hexylhydrazine derivatives were faster
than those with hydrazine or methylhydrazine derivatives. Furthermore, the two
dialdehydes 14a and 14b (Scheme 5) showed different reactivities due to the presence
of the phenyl ring, 14a being much more reactive than 14b.
Interestingly, the reactivity of the precursor components decreased with increasing
chain length. For example, to obtain 13, it was necessary to heat 12a (1 equiv.; obtained
from 11a) and dialdehyde 14a (2equiv.) to 40 45 8 during several hours (Scheme 3).
Similarly, prolonged heating (ca. 50 h under reflux) was required in the case of the
preparation of the 10-sites strand 5 by the double condensation of aldehyde 13 with
dihydrazine 9b in EtOH/CHCl3 3 :1 (Scheme 3). This decrease in reactivity may result
from a combination of steric and electronic effects: a longer chain corresponds to an
increase in helical turns, which may hinder the approach towards the reaction centers;
on the other hand, the helical structure involving p-p stacking of the quasi-super-
imposed pyrimidine rings may modify the electronic structure of the molecule and
influence the reactivity.
The reaction of the hydrazone-type precursor 10a (1 equiv.) with 1 4 equiv. of
dialdehyde 14a at room temperature in EtOH yielded a mixture containing excess
dialdehyde 14a, monoaldehyde precursor 11a, and the 4-sites entity 2a (Scheme 2). The
latter was not soluble in EtOH and precipitated; filtering and washing with EtOH gave
a filtrate containing 11a and 14a. The monoaldehyde 11a was soluble in EtOH but not
in MeCN, while the dialdehyde 16a was soluble in MeCN, which allowed isolation of
11a in satisfactory purity by precipitation with MeCN from its EtOH solution. A similar
procedure was used to obtain the precursor hydrazine 12a and aldehyde 13. Due to the
decrease in reactivity with increasing chain length noted above, the reaction of 12 and
13 may be controlled by means of the stoichiometry (dialdehyde or dihydrazine in
excess) and the temperature (heating to 40 508).
The 3-sites species 6 presenting mixed hydrazone positioning was prepared from
14a via 15 as shown in Scheme 4. The methyl-bearing 4-sites species 2d was obtained by

Scheme 3. Synthesis of the 6-, 8-, and 10-Sites Strands 3 5 (uncoiled representation)

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Scheme 4. Synthesis of the 2- and 4-Sites Strands 1' and 7 Starting from 2-Hydrazinopyridine and of the 3-Sites
Strand 6 (uncoiled representation)
double condensation of 1,1'-(pyrimidine-4,6-diyl)bis[ethanone] (14c) [3] with the
precursor 10a (Scheme 2).
The preparation of the starting building blocks 8d and 14 26 is summarized in
Scheme 5.
All compounds gave mass spectroscopic and microanalytical data in agreement
with their structures.
Spectroscopic Properties of the Strands 1 7. IR Spectra. The IR spectra agree
with the primary structure of the strand 1 7. The absorption bands arising from CÀH
stretching vibrations (medium intensity) were found between 3000 and 2840 cmÀ1 with
asymmetrical (nÄas(CH3) 2970 2940 cmÀ1) and symmetrical stretching modes (nÄs(CH3)
2880 2865 cmÀ1). In the case of the compounds containing hexyl or hydroxyethyl
substituents, the methylene asymmetrical (nÄas(CH2) 2925 2920 cmÀ1) and symmetrical
stretching bands (nÄs(CH2) 2855 2920 cmÀ1) were observed. The OH derivatives
(primary alcohols) displayed bands corresponding to the OÀH stretching vibrations
(nÄ(OH) 3427 cmÀ1) and the CÀO stretching vibrations (nÄ(CÀO) 980 cmÀ1). The strong

Scheme 5. Synthesis of the Heterocyclic Building Blocks

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absorption bands between 1580 and 1594 cmÀ1, and 1420 and 1480 cmÀ1, respectively,
correspond to the stretching vibration of the CˆN hydrazone bond and to the
pyrimidine- or pyridine-ring stretching vibrations (skeletal bands).
UV/VIS Spectra. The UV/VIS spectra of 1 7 in CH2Cl2 display two absorption
regions. The first one lies between 225 and 235 nm and corresponds mainly to a p-p
transition characteristic of the conjugate CˆN groups (hydrazones). The second region
ranges from 270 to 380 nm and contains two or three absorption maxima arising mainly
from the p-p* transitions of the pyridine and the pyrimidine rings.
The comparison of the UV/VIS spectra of compounds 1 7 shows two general
trends. First, a hyperchromic effect is observed for the compounds presenting p-p
stacking only within the helical chain. This is the case for compounds having no
aromatic-ring substituent at C(2) of the pyrimidine ring, or those in which such
substituents are not superimposable. The absorption coefficient e increases when the
number of turns of the helical strands increases, ranging, e.g., from 34000
2
50000 mÀ1 cmÀ1 (for a /3 turn strand) to 150000 160000 mÀ1 cmÀ1 for a strand of ca.
3 turns. This trend agrees with that observed in the case of the pyÀpym strands
previously studied in our laboratory [4]. However, the e values are lower in the present
compounds, due probably to a decrease in conjugation resulting from the replacement
of the pyridine ring by a hydrazone group.
When the helical strand presents superimposed lateral phenyl substituents,
generating a supplementary or −secondary× p-p stacking, a hypochromic effect is
observed, as is the case for compounds 2c (e ˆ 83000mÀ1 cmÀ1), a 11/3-turn strand, and 3c
(e ˆ 44800mÀ1 cmÀ1), a 2-turns strand.
These trends may be understood by taking into account the fact that two factors
may affect the molar extinction coefficient e: the conjugation length increasing the e
value, and the p-p stacking decreasing the e value (as for base-pair stacking in the DNA
double helix).
The analysis of the X-ray structures of the present strands (see below) shows that
the stacking within the helices having no superimposed lateral groups is not a perfect
one, so that the increase in conjugation with strand length has a stronger effect than the
p-p stacking, resulting in an increase in absorption intensity. On the other hand, when
lateral phenyl groups able to generate secondary stacking are present, the conjugation
effect becomes less important than the p-p stacking so that e decreases due to the
stacking, a hypochromic effect similar to that observed for DNA hybridization.
The second trend observed is a blue shift (a hypsochromic effect) that occurs when
the number of turns increases, as in the case of the ligands bearing no lateral phenyl
group. This effect may be rationalized by noting that, in the crystal structures of the
strands, the primary stacking of the pyrimidine rings is not perfect and is worse in the
longer molecules (3 turns) than in the shorter ones (1 or 2turns). The weak
bathochromic effect observed in the case of the ligands presenting −secondary× stacking
between the decorating phenyl substituents may be due to the fact that this lateral
stacking stabilizes the primary one and becomes stronger as the number of phenyl
groups increases.
The red shift observed in some cases may be assigned to the presence of a more
extensively conjugated pyrimidinedicarboxaldehyde dihydrazone, unit, which also
increases the absorption; thus, 1'a has a lmax higher than that of 1b, and 7 (containing

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two dicarboxaldehyde dihydrazone units) has lmax 331 nm, while 2a (containing only
one dicarboxaldehyde dihydrazone unit) has lmax 316 nm.
1
1H-NMR Spectroscopy. The H-NMR data provide clear indications of the helical
shape of the strands 1 7 in solution. One of the characteristic features of all the helical
pyÀpym oligomers previously reported [2 4] is the upfield shift in the 1H-NMR
spectrum of the terminal pyridine protons in the helical structure, resulting from the
shielding effect due the aromatic heterocyclic rings positioned above the terminal
pyridine ring. In the present case, the signal of HÀC(4) of the terminal pyridine shows a
shift from d 8.18 for 11b, which does not form a helical turn, to d 7.13 for 2c, where the
proton is shielded by the aromatic rings lying above. The same behavior is observed for
3c with an increase in 0.2ppm in the upfield shift probably resulting from the increase
in the number of stacked rings. Such a cumulative effect was already observed in the
helical structures composed of pyÀpym sequences possessing from 1 to 4 turns [2 4]
and in 1- and 2-turns helices incorporating two hydrazone fragments [7]. A comparison
of the 1H-NMR shifts of the terminal pyridine protons for different strands is given in
the Table. Similar remarks concern the pyrimidine-ring protons, which also display a
progressive upfield shift with the increase of the number of turns.
Table 1. 1H-NMR Chemical Shifts of the Four Protons of the Terminal Pyridine Rings of Different Strands
Strand
Number of turns
Chemical shifts [ppm]
HÀC(3)
8.13
HÀC(4)
7.68
HÀC(5)
7.23
8.2
HÀC(6)
8.58
2
1b
2a
3a
4
/
3
11/3
7.727.13
6.91
6.73
9
27.47
6.97
6.78
8.18
22/3
7.426.86
7.33
8.13
6.728.13
5
31/3
6.83
The most-revealing features confirming the helical structure of strands 1 7 are
provided by the 2D NMR nuclear Overhauser effect (NOE) data obtained from
NOESY and ROESY experiments, which indicate correlations due to the spatial
proximity of the protons. Distinct NOE effects are observed between the protons
oriented towards the interior of the helix, e.g., between the pyrimidine protons at C(5)
of the ring and the proton at C(2) of the pyrimidine ring. The intensity of the
correlation trace is in line with the distance between the protons, as observed in the
crystal structure: the relative intensity of the trace decreases as the distance increases.
As an example, the NOESY trace of the aromatic domain of the 10-turns strand is
shown in Fig. 1.
Crystal Structures of Eight hyzÀpym Strands. An extensive radiocrystallographic
investigation was performed with several of the synthesized hyzÀpym strands to
specify their solid-state structures and to correlate them with the data provided by
NMR spectroscopy in solution. Single crystals suitable for X-ray crystallography were
i
obtained by diffusion of a nonsolvent (MeCN, MeOH, heptane, Et2O, Pr2O, EtOH)
into a CH2Cl2 or CHCl3 solution of the strands 1c, 2a, 2c, 3a, 3c, or 5 7 at room
temperature in a glass tube. Of these eight strands, five have no phenyl group attached

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Fig. 1. Nuclear-Overhauser-effect (NOE) correlations for the 10-hydrazone-sites strand 5 in the 6.5 9 ppm
region (NOESY experiment on a Bruker-300-MHz spectrometer)
to the pyrimidines (2a, 3a, and 5 7) and three bear phenyl groups at C(2) of the
pyrimidine ring (1c, 2c, and 3c). The crystal structures of all eight strands (see Figs. 2
5) confirm their helical shape (as shown in Fig. 6 for 5) and suggest that the polymeric
strands obtained by polycondensation of a pyrimidinedicarboxaldehyde with a
dihydrazinopyrimidine have also a helical shape [15].
In all cases, the unit-cell contains an even number of molecules (Z), corresponding
to Z/2enantiomer pairs so that the crystal is achiral (compounds ( Z molecules/unit): 5
(2), 3a (4), 3c (2), 2a (8), 7 (2), 2c (8), 6 (2), 1c (8)). The same feature was observed
for the hydrazone-containing strands investigated earlier [7], whereas, in the case of the
pyÀpym strands, chiral channels were generated in the solid-state assembly from the
achiral linear strands [4].
The N-methyl substituted N-sites are practically planar due to conjugation with the
pyrimidine ring and the hydrazone bond. The torsional angles between the plane
defined by the hydrazone group and the pyrimidine ring are between 5 and 158 and may
be as small as 0.2 3 8, whereas the related angles in the pyÀpym based helices lie
around 10 148 [4]. This may result from the higher flexibility of the present strands
due to the replacement of the pyridine ring by a hydrazone group.
The internal void of the helices is ca. 1.1 1.5 ä in diameter, as compared to 2ä in
the pymÀpy helices (considering a projection in a plane and taking into account the
Van der Waals radii of diagonally located N and CÀH sites). The N-atoms lining the
internal void might serve as coordination sites for metal ions in a potential ion-channel
fashion. On the other hand, these helical strands represent coiled molecular wires of
nanometric length (30 80 ä), which may be switched into a linear wire by
coordination of suitable metal ions (Pb2‡, Zn2‡, etc.); this is the case for the pyÀpym
strands [13] as well as for the present hydrazone strands [12].

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Fig. 2. Crystal structures of a) b) strand 1c and c) d) strand 6. Stick (right) and space-filling (left)
representations; a) c) side views and b) d) axial views.
The helical pitch of the helices lies between 3.50 3.70 ä, depending on the
presence or absence of lateral phenyl groups. The heights of these molecular coils range
from 3.50 (2) to 11.60 ä (5).
The crystals contain some solvent molecules (as also indicated by elemental
analysis), but these molecules are too large for inclusion into the internal void of the
helices or do not have interactions that could lead to such inclusion.

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Fig. 3. Crystal structures of a) b) strand 7 and c) d) strand 2a. Stick (right) and space-filling (left)
representations; a) c) side views and b) d) axial views.
The strands bearing a phenyl group generate more-regular helices with better
overlap of the pym rings, due probably to the additional stacking provided by the lateral
phenyl groups. Conversely, the strands without phenyl groups present imperfect pym
stacking and a somewhat deformed helical structure; the stacking of the pyrimidine
rings becomes worse as the strand length increases. Thus, a comparison of the axial view

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Fig. 4. Crystal structures of a) b) strand 2c and c) d) strand 3c. Stick (right) and space-filling (left)
representations; a) c) side views and b) d) axial views.
for the 11/3-turn strand 2a (Fig. 3,d) and for the 2-turns strand 3a (Fig. 5,b) (having no
decorating phenyl) with the corresponding strands 2c (Fig. 4,b) and 3c (Fig. 4,d),
(having a phenyl at C(2) of each pyrimidine unit), respectively, shows that the stacking
is better and the helix is more regular for the second ones. One may note that energy-
minimization computations (SPARTAN program, AM 1 force field) gave structures
for 2c and 3c very close to those determined by X-ray crystallography.

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Fig. 5. Crystal structures of a) b) strand 3a and c) d) strand 5. Stick (right) and space-filling (left)
representations; a) c) side views and b) c) axial views.

Helvetica Chimica Acta Vol. 86 (2003)
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N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Fig. 6. Structural formula of the helical strand 5
The effect of conjugated units may be seen by comparing the structure of the strand
2a (containing only one central pyrimidinedicarboxaldehyde-derived unit; Fig. 3,c and
d) with that of 7 (Fig. 3,a and b), which incorporates two pyrimidinedicarboxaldehyde-
derived units and presents, thus, more-extensive conjugation. The better stacking in the
second strand is reflected in a slow decrease in absorption coefficient e (from 68100 to
67000) and a red shift (from 316 to 330 nm) due to more-extensive conjugation.
Conclusions.
The results described here indicate that the hydrazone route
provides a very efficient approach to molecular chains constituted of extended
hyzÀpym sequences. Such strands are programmed to undergo folding into helical
shapes. The synthetic pathway offers great flexibility and presents wide potential for the
generation of structural diversity through the introduction, on both the pym and the hyz
sites, of various lateral groups decorating the exterior of the helix. These features make
the hyzÀpym subunit a particularly attractive helicity codon for the exploration of
numerous structural and functional variations.
¡
This work was supported by a doctoral fellowship from the Ministere de la Jeunesse, de la Recherche et de la
Technologie (J.-L. S. and A.-M. S.) and by the C.N.R.S. (N. K.). We thank Dr. Roland Graff (Service Commun
¬
¬
de RMN, Faculte de Chimie, Universite Louis Pasteur de Strasbourg) and Dr. Patrick Maltese (Laboratoire de
¬
Chimie Supramoleculaire, I.S.I.S., Strasbourg) for 2D-NMR measurements and helpful discussions as well as
¬
¬
¡
¬
Raymond Hueber (Service de Spectrometrie de Masse, Ecole Europeenne de Chimie, Polymeres et Materiaux,
¬
¬
Universite Louis Pasteur de Strasbourg) and Caroline Dietrich-Schneider (Service de Spectrometrie de Masse,
¬
Universite Louis Pasteur) for mass-spectrometry measurements and helpful discussions.
Experimental Part
General. All reagents were purchased from commercial suppliers and used without further purification
unless otherwise noted. Allylhydrazine (25d) [16] and hexylhydrazine (25b) [17] were prepared from the
corresponding bromides and hydrazine. The (2-hydroxyethyl)hydrazine (ˆ2-hydrazinoethanol; 25c) was
prepared as described [18] or purchased from Sigma-Aldrich. Pyrimidine-4,6-dicarboxaldehyde (14a), first
prepared by ozonolysis of 22 [19a,b], was also obtained here by ozonolysis of 22, but by using the same
procedure as described for the preparation of pyridazine-3,6-dicarboxaldehyde [19c] without purification by
sublimation under high vacuum, the yield being 30 40%. Dicarboxaldehyde 14a is an unstable, air-sensitive

1614
Helvetica Chimica Acta Vol. 86 (2003)
compound and was stored under Ar at low temp. (in a freezer). The 4,6-distyrylpyrimidine (22) was synthesized
by the condensation of benzaldehyde with 4,6-dimethylpyrimidine [20], the latter being obtained from
acetylacetone and formamide, as described [21]. The 2-phenylpyrimidine-4,6-dicarboxaldehyde (14b) was
prepared by oxidation of 4,6-dimethyl-2-phenylpyrimidine (21) with selenium dioxide [22] or with I2/tBuI in
DMSO [23] as described for other heterocyclic dimethyl derivatives [23a]; 21 was prepared from acetylacetone
and benzamidine hydrochloride (ˆ benzenecarboximidamide hydrochloride), as described [24], or by a new
method, reported below. The 1,1'-(pyrimidine-4,6-diyl)bis[ethanone] (14c) was prepared by the coupling of (1-
methoxyethenyl)tributylstannane [25] with 4,6-dichloropyrimidine (8a), followed by acid hydrolysis of the
methoxyvinyl groups of 23 [3b][26]. The 4,6-dichloro-2-(p-tolyl)pyrimidine (8c) was prepared from 2-(p-
tolyl)pyrimidine-4,6-diol [27] by treatment with POCl3, as described [28]. The 2-(1-methylhydrazino)pyridine
(26a) was prepared from 2-bromopyridine (24a) and methylhydrazine (25a), as described [29]. The 2-bromo-6-
phenylpyridine (24b) was synthesized by using a Grignard reagent, as described [30]. All org. solns. were
routinely dried (Na2SO4) and evaporated in a rotary evaporator. TLC: Polygram Alox N/UV254 precoated plastic
sheets or Polygram Sil-G/UV254 precoated plastic sheets. Prep. TLC: 20 Â 20-cm plates covered by aluminium
oxide 60 F254 (1.5 mm) from Merck. Flash chromatography (FC): 230 400 mesh silica-gel particles or neutral
alumina (act. 2) from Merck. M.p.: B¸chi B-540 melting-point apparatus; uncorrected. UV/VIS Spectra:
Varian-Cary-3 spectrometer; lmax in nm, e in mÀ1 cmÀ1. IR Spectra: Perkin-Elmer 1600 FTIR spectrometer;
KBr pellets; in cmÀ1. 1H-NMR (200, 300, 400, or 500 MHz), 13C-NMR (50, 75, 100, or 125 MHz), and 2D-NMR
Spectra: Bruker AC-200, Avance-300, Avance-400, or Avance-500 spectrometers, resp.; CDCl3 as solvent, unless
otherwise noted; chemical shifts d in ppm with a residual solvent proton peak as ref.; 2D-NMR experiments
were: COSY (correlation spectroscopy), HMBC (heteronuclear multiple-bond correlation), HMQC (hetero-
nuclear multiple-quantum correlation (coherence)), NOESY (nuclear Overhauser enhancement spectroscopy
or nuclear Overhauser and exchange spectroscopy), ROESY (rotating-frame Overhauser enhancement (effect)
spectroscopy). Electron-ionization (EI), fast-atom-bombardment (FAB) MS, matrix-assisted laser-desorption
¬
(MALDI) MS, and low- or high-resolution (HR) MS were carried out by the Service d×Analyse de l×Universite
Louis Pasteur, in m/z (rel. %). Microanalyses were performed by the Service Central de Microanalyse du
¬
CNRS, Faculte de Chimie, Strasbourg or at FZK, Karlsruhe.
Pyridine-2-carboxaldehyde [2-(3,4,5-Trimethoxyphenyl)pyrimidine-4,6-diyl]dihydrazone (1a). A soln. of
4,6-hydrazino-2-(3,4,5-trimethoxyphenyl)pyrimidine (9a; 15 mg, 0.045 mmol) and pyridine-2-carboxaldehyde
(15 mg, 0.140 mmol) in abs. EtOH (5 ml) was stirred at r.t. for 4 h under Ar. The solvent was evaporated and the
residue purified by FC (Al2O3, CHCl3): 1a (20 mg, 87%). White solid. M.p. 1288. 1H-NMR (CDCl3, 200 MHz):
10.02( s, 2H); 7.69 ( d, 2H); 7.41 ( s, 2 H); 7.23 (d, 2H); 7.15 ( t, 2H); 6.87 ( s, 2H); 6.96 ( s, 2H); 6.95 ( d, 2 H);
6.73 (t, 2H); 6.35 ( s, 1 H); 3.93 (s, 6 H); 3.82( s, 3 H). 13C-NMR (CDCl3, 50 MHz): 162.0; 154.0; 149.9; 142.8;
‡
137.0; 133.0; 124.0; 119.7; 105.0; 81.0; 56.3. MALDI-MS: 485.3 (100, [M ‡ H] ).
Pyridine-2-carboxaldehyde (Pyrimidine-4,6-diyl)dihydrazone (1b). A soln. of pyridine-2-carboxaldehyde
(40 mg, 0.374 mmol) and 9b (30 mg, 0.179 mmol) in EtOH (5 ml) was heated to reflux for 3 h. Then, the mixture
was cooled, concentrated under vacuum and filtered. The precipitate was washed with EtOH and dried for 10 h
under high vacuum: 1b (38 mg, 61%). White solid. M.p. 246 2488 (recryst. from pyridine). UV/VIS (CHCl3):
336.0. 1H-NMR (CDCl3, 200 MHz): 8.58 (d, 2H); 8.43 ( s, 1 H); 8.13 (d, 2H); 7.86 7.81 ( m, 3 H); 7.68 (t, 2 H);
7.23 ( t, 2H); 3.64 ( s, 6 H). 13C-NMR (CDCl3, 50 MHz): 162.7; 156.7; 155.0; 149.4; 136.9; 136.0; 122.9; 119.4;
‡
‡
‡
88.8; 29.6. EI-MS: 346.2 (18, M ), 268.2 (100, [M À 78] ). FAB-MS: 347.3 (100, [M ‡ H] ). HR-FAB-MS:
‡
347.1731 ([C18H18N8 ‡ H] ; calc. 347.1733). Anal. calc. for C18H18N8: C 62.41, H 5.24, N 32.35; found: C 62.21,
H 5.01, N 32.21.
Pyridine-2-carboxaldehyde [2-(4-Methylphenyl)pyrimidin-4,6-diyl]dihydrazone (1d). As described for 1b,
with pyridine-2-carboxaldehyde (45 mg, 0.421 mmol), 9d (50 mg, 0.194 mmol), and EtOH (3 ml): 1d (70 mg,
83%). White solid. M.p. 285 2878. UV/VIS (CHCl3): 300.0 (77900). 1H-NMR (CDCl3, 300 MHz): 8.61
(d, 2H); 8.36 ( d, 2H); 8.17 ( d, 2H); 7.83 ( s, 2H); 7.81 ( s, 1 H); 7.71 (td, 2 H); 7.27 (d, 2H); 7.22( td, 2H); 3.78
(s, 6 H); 2.36 (s, 3 H). 13C-NMR (CDCl3, 75 MHz): 163.2; 162.4; 155.6; 149.4; 140.5; 136.4; 136.03; 135.5; 129.0;
‡
‡
128.1; 122.9; 119.5; 86.9; 29.7; 21.5. FAB-MS: 437.1 (100, [M ‡ H] ). HR-FAB-MS: 437.2201 ([C25H24N8 ‡ H] ;
calc. 437.2202). Anal. calc. for C25H24N8: C 68.79, H 5.54, N 25.67; found: C 68.55, H 5.28, N 25.52.
Pyridine-2-carboxaldehyde [2-(3,4,5-Trimethoxyphenyl)pyrimidine-4,6-diyl]bis(methylhydrazone) (1e). As
described for 1a, with 4,6-bis(1-methylhydrazino)-2-(3,4,5-trimethoxyphenyl)pyrimidine (9e; 15 mg, 0.045 mmol),
pyridine-2-carboxaldehyde (15 mg, 0.140 mmol), and EtOH (5 ml): 1e (20 mg, 87%). White solid. M.p. 1288.
1H-NMR (CDCl3, 400 MHz): 7.50 (d, 2H); 7.18 ( d, 2H); 6.96 ( s, 2 H); 6.92 (s, 1 H); 6.87 (s, 2 H); 6.84 (t, 2 H);
6.48 (t, 2H); 4.05 ( s, 6 H); 3.99 (s, 3 H); 3.91 (s, 6 H). 13C-NMR (CDCl3, 100 MHz): 183.2; 182.12; 153.0; 149.4;
‡
147.6; 136.7; 136.1; 122.9; 119.5; 115.6; 105.3; 86.9; 56.1; 29.7. EI-MS: 512.3 (100, [M ‡ H] ).

Helvetica Chimica Acta Vol. 86 (2003)
1615
Pyridine-2-carboxaldehyde (Pyrimidine-4,6-diyl)bis(hexylhydrazone) (1f). As described for 1b, with
pyridine-2-carboxaldehyde (86 mg, 0.803 mmol), 9f (100 mg, 0.325 mmol) and EtOH (3 ml). To the mixture
concentrated under vacuum (0.5 1 ml), MeCN (2ml) was added. The precipitate was washed with MeCN and
dried for 10 h under high vacuum: 1f (145 mg, 92%). White solid. M.p. 123 1258. UV/VIS (CHCl3): 319.0
(38900). IR (KBr): 2925m, 2853w, 1591s, 1571s, 1542m, 1459s, 1426s, 1335w, 1174m, 1144m, 1099m, 981m, 909w,
1
771m. H-NMR (CDCl3, 200 MHz): 8.62 (d, 2H); 8.46 ( s, 1 H); 8.17 (d, 2H); 7.89 ( s, 2H); 7.84 ( s, 1 H); 7.71
(t, 2H); 4.31 ( t, 4 H); 1.68 (t, 4 H); 1.51 1.29 (m, 12H); 0.89 ( t, 6 H). 13C-NMR (CDCl3, 100 MHz): 162.6;
‡
157.0; 155.3; 149.3; 136.1; 135.9; 122.8; 199.4; 88.7; 42.0; 31.6; 26.6; 25.1; 22.6; 13.9. EI-MS: 486.2 (25, M ), 408.4
‡
‡
‡
(100, [M À 78] ). FAB-MS: 487.4 (100, [M ‡ H] ). HR-FAB-MS: 487.3292 ([C28H38N8 ‡ H] ; calc. 487.3298).
Anal. calc. for C28H38N8: C 69.10, H 7.87, N 23.03; found: C 68.85, H 7.53, N 22.88.
Pyridine-2-carboxaldehyde (Pyrimidine-4,6-diyl)bis(prop-2-enylhydrazone) (1g). As described for 1b, with
pyridine-2-carboxaldehyde (40 mg, 0.374 mmol), 9g (40 mg, 0.182mmol), and EtOH (5 ml): 1g (43 mg, 59%).
White solid. M.p. 200 2028. UV/VIS (CHCl3): 315.0 (35000). 1H-NMR (CDCl3, 200 MHz): 8.61 (d, 2H); 8.48
(s, 1 H); 8.18 (d, 2H); 7.95 ( s, 1 H); 7.85 (s, 2H); 7.73 ( t, 2 H); 7.25 (t, 2H); 5.97 5.79 ( m, 2H); 5.22( d, 2 H);
5.04 (d, 2H); 5.01 ( d, 4 H). 13C-NMR (CDCl3, 50 MHz): 162.7; 157.3; 155.1; 149.5; 138.0; 136.1; 130.1; 123.1;
‡
‡
119.6; 117.1; 88.6; 44.9. FAB-MS: 399.1 (100, [M ‡ H] ). HR-FAB-MS: 399.2058 ([C22H22N8 ‡ H] ; calc.
399.2046). Anal. calc. for C22H22N8: C 66.31, H 5.57, N 28.12; found: C 66.15, H 5.22, N 27.85.
Pyrimidine-4,6-dicarboxaldehyde Bis[methyl(pyridin-2-yl)hydrazone] (1'a). As described for 1b, with 26a
(72mg, 0.563 mmol), 14a (40 mg, 0.294 mmol), and EtOH (3 ml): 1'a (45 mg, 44%). Yellowish solid. M.p. 243
2458 (dec.). UV/VIS (CHCl3): 337.0 (39700). 1H-NMR (CDCl3, 200 MHz): 9.08 (s, 1 H); 8.42( s, 1 H); 8.29
(d, 2H); 7.83 ( d, 2H); 7.83 7.64 ( m, 4 H); 6.92( t, 2H); 3.73 ( s, 6 H). 13C-NMR (CDCl3, 50 MHz): 161.6; 158.9;
‡
157.0; 147.1; 137.6; 132.0; 117.0; 110.4; 110.0; 30.0. EI-MS: 346.1 (17, M ), 134.1 (100). FAB-MS: 347.1 (100,
‡
‡
[M ‡ H] ). HR-FAB-MS: 347.1743 ([C18H18N8 ‡ H] ; calc. 347.1733). Anal. calc. for C18H18N8: C 62.41, H 5.24,
N 32.35; found: C 62.14, H 4.97, N 32.17.
2-Phenylpyrimidine-4,6-dicarboxaldehyde Bis[methyl(6-phenylpyridin-2-yl)hydrazone] (1'b). As described
for 1b, with 26b (38 mg, 0.191 mmol), 14b (20 mg, 0.094 mmol), and EtOH (2 ml) for 5 h: 1'b (46 mg, 85%).
Yellowish solid. M.p. 280 2828. UV/VIS (CHCl3): 263.0 (77300). 1H-NMR (CDCl3, 400 MHz): 8.53 (dd, 2 H);
8.42( s, 1 H); 8.11 (d, 4 H); 7.85 (d, 2H); 7.81 ( s, 2H); 7.77 ( t, 2H); 7.57 7.40 ( m, 11 H); 3.91 (s, 6 H). 13C-NMR
(CDCl3, 100 MHz): 162.2; 158.7; 157.8; 156.8; 154.7; 139.2; 139.1; 138.4; 132.9; 130.5; 128.9; 128.6; 128.5; 128.2;
‡
‡
126.7; 120.9; 108.8; 29.9. FAB-MS: 575.5 (100, [M ‡ H] ). HR-FAB-MS: 575.2667 ([C36H30N8 ‡ H] ; calc.
575.2672).
Pyrimidine-4,6-dicarboxaldehyde Bis[hexyl(pyridin-2-yl)hydrazone] (1'c). As described for 1b, with 26c
(100 mg, 0.518 mmol), 14a (35 mg, 0.257 mmol), and EtOH (2 ml). To the mixture concentrated under vacuum
(0.5 ml), MeCN (1 2ml) was added. The precipitate formed after a while was filtered, washed with EtOH, and
dried for 10 h under high vacuum: 1'c (44 mg, 35%). Yellowish solid. M.p. 112 114 8. UV/VIS (CHCl3): 342.0
(44300). 1H-NMR (CDCl3, 200 MHz): 9.06 (s, 1 H); 8.45 (s, 1 H); 8.29 (d, 2H); 7.90 7.51 ( m, 6 H); 6.90
(t, 2H); 4.35 ( t, 4 H); 1.70 (t, 4 H); 1.57 1.19 (m, 12H); 0.89 ( t, 6 H). 13C-NMR (CDCl3, 100 MHz): 161.8;
158.9; 156.9; 147.3; 137.4; 131.1; 116.9; 110.2; 109.7; 42.5; 31.6; 26.7; 24.6; 22.6; 14.0. FAB-MS: 487.2 (100, [M ‡
‡
‡
H] ). HR-FAB-MS: 487.3289 ([C28H38N8 ‡ H] ; calc. 487.3298). Anal. calc. for C28H38N8: C 69.10, H 7.87,
N 23.03; found: C 68.90, H 7.65, N 23.13.
Pyrimidine-4,6-dicarboxaldehyde Bis[(2-hydroxyethyl)(pyridin-2-yl)hydrazone] (1'd). As described for 1b,
with 26d (113 mg, 0.738 mmol), 14a (50 mg, 0.367 mmol), and EtOH (5 ml): 1'd (62mg, 41%). Yellow solid.
M.p. 195 1968. UV/VIS (CHCl3): 333.0 (37800). IR (KBr): 3427m (br.), 1591m, 1560s, 1546s, 1437s, 1389w,
1349s, 772m. 1H-NMR (CDCl3/CD3OD 1:1, 200 MHz): 9.08 (d, 1 H); 8.40 (d, 1 H); 8.27 (d, 2H); 7.82 7.65
(m, 6 H); 6.98 (t, 2H); 4.52( t, 4 H); 4.35 (s, 2H); 3.99 ( t, 4 H). 13C-NMR (CDCl3/CD3OD 1:1, 50 MHz): 165.6;
‡
162.2; 161.1; 150.9; 142.1; 134.8; 121.7; 114.8; 114.7; 61.96; 49.44. EI-MS: 406.3 (11, M ), 1643 (100), 120.3 (17).
‡
‡
FAB-MS: 407.1 (100, [M ‡ H] ). HR-FAB-MS: 407.1950 ([C20H22N8O2 ‡ H] ; calc. 407.1944).
2-Phenylpyrimidine-4,6-dicarboxaldehyde Bis[methyl(pyridin-2-yl)hydrazone] (1'e). As described for 1b,
with 14b (30 mg, 0.142mmol), 26a (40 mg, 0.325 mmol), and EtOH (4 ml): 1'e (36 mg, 60%). Yellow solid. M.p.
259 2618. UV/VIS (CHCl3): 339.0. 1H-NMR (CDCl3, 200 MHz): 8.57 8.45 (m, 2H); 8.36 ( s, 1 H); 8.29
(d, 2H); 7.87 ( d, 2H); 7.77 ( s, 2H); 7.67 ( t, 2H); 7.58 7.45 ( m, 3 H); 6.91 (t, 2H); 3.78 ( s, 6 H). 13C-NMR
(CDCl3, 100 MHz): 164.8; 162.1; 157.1; 147.1; 137.9; 137.6; 132.9; 130.5; 128.5; 128.2; 116.9; 110.4; 107.7; 30.0.
‡
‡
FAB-MS: 423.2 (100, [M ‡ H] ). HR-FAB-MS: 423.2048 ([C24H22N8 ‡ H] ; calc. 423.2046).
Pyrimidine-4,6-dicarboxaldehyde Bis{methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazino]pyrimidin-
4-yl}hydrazone} (2a). As described for 1b, with 10a (250 mg, 0.973 mmol), 14a (66 mg, 0.485 mmol), and
EtOH (10 ml) for 5 h: 2a (235 mg, 39%). Yellow solid. M.p. 298 3008 (dec.) (recryst. from CHCl3/MeCN). UV/

1616
Helvetica Chimica Acta Vol. 86 (2003)
VIS (CHCl3): 316.0 (68100). IR (KBr): 1589s, 1480s, 1400m, 1351m, 1338m, 1270m, 1230m, 1188s, 1154m, 1075s,
1023s, 978s, 843m, 785m. 1H-NMR (CDCl3, 500 MHz): 9.18 (d, 1 H); 8.74 (d, 1 H); 8.29 (d, 2H); 8.19 ( d, 2 H);
7.76 (s, 2H); 7.72( d, 2H); 7.54 ( s, 2H); 7.53 ( d, 2H); 7.13 ( t, 2H); 6.91 ( t, 2H); 3.54 ( s, 6 H); 3.35 (s, 6 H).
13C-NMR (CDCl3, 100 MHz): 162.1; 161.7; 161.6; 159.2; 156.3; 153.9; 149.1; 136.9; 135.4; 134.1; 122.2; 119.3;
‡
109.4; 89.8; 29.9; 29.5. 2D-NMR (300 MHz): COSY, NOESY. FAB-MS: 615.2 (100, [M ‡ H] ). HR-FAB-MS:
‡
615.2912 ([C30H30N16 ‡ H] ; calc. 615.2918). Anal. calc. for C30H30N16: C 58.62, H 4.92, N 36.46; found: C 58.54,
H 4.81, N 36.32.
2-Phenylpyrimidine-4,6-dicarboxaldehyde Bis{methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazino]-
pyrimidin-4-yl}hydrazone} (2b). As described for 1b, with a suspension of 10a (23 mg, 89.5 mmol), 14b (9 mg,
42.5 mmol), and EtOH (0.5 ml) (concentration not necessary): 2b (22 mg, 75%). Yellowish solid. M.p. 368 3708
(dec.). UV/VIS (CHCl3): 314.0 (78200). IR (KBr): 3037w, 1591s, 1482s, 1427s, 1398m, 1356s, 1275s, 1192s,
1154m, 1074s, 1024s, 896m. 1H-NMR (CDCl3, 400 MHz): 8.67 (s, 1 H); 8.61 8.54 (m, 2H); 8.32( d, 2H); 8.23
(s, 2H); 7.91 ( s, 2H); 7.80 ( d, 2H); 7.65 7.51 ( m, 7 H); 7.18 (t, 2H); 6.94 ( t, 2H); 3.64 ( s, 6 H); 3.57 (s, 6 H).
13C-NMR (CDCl3, 100 MHz): 162.2; 161.7; 159.8; 156.2; 154.0; 153.5; 149.1; 137.0; 135.4; 135.0; 131.5; 130.8;
‡
128.7; 128.2; 122.2; 119.32; 107.2; 89.8; 29.9; 29.5. FAB-MS: 691.7 (100, [M ‡ H] ). HR-FAB-MS: 691.3226
‡
([C36H34N16 ‡ H] ; calc. 691.3231).
Pyridine-2-carboxaldehyde {(Pyrimidine-4,6-diyl)bis[ethylidyne(1-methylhydrazin-1-yl-2-ylidene)pyrimi-
dine-6,4-diyl]}bis(methylhydrazone) (2d). As described for 1b, with 10a (50 mg, 0.195 mmol), 14c (16 mg,
0.098 mmol), and EtOH (3 ml) for 15 h: 2d (19 mg, 30%). Yellow solid. M.p. 238 2398. UV/VIS (CHCl3): 330.0
(42600). IR (KBr): 1589s, 1484m, 1430s, 1397m, 1278m, 1189m, 1145m, 1077m, 1021m, 990m, 834w, 774m.
1H-NMR (CDCl3, 300 MHz): 9.39 (s, 1 H); 9.29 (s, 1 H); 8.50 (d, 2H); 8.31 ( s, 2H); 7.69 ( d, 2H); 7.41 7.36
(m, 4 H); 7.2 8 (t, 2H); 7.07 ( t, 2H); 3.50 ( s, 6 H); 3.12( s, 6 H); 2.53 (s, 6 H). 13C-NMR (CDCl3, 100 MHz):
165.1; 164.6; 162.9; 160.2; 160.1; 159.4; 157.0; 155.5; 149.9; 136.9; 136.4; 123.2; 120.4; 110.2; 90.5; 37.6; 29.4; 16.3.
‡
2D-NMR (300 MHz): COSY, NOESY. FAB-MS: 643.6 (100, [M ‡ H] ). HR-FAB-MS: 643.3226 ([C32H34N16
‡
‡
H] ; calc. 643.3231).
Pyrimidine-4,6-dicarboxaldehyde Bis{hexyl{6-[1-hexyl-2-(pyridin-2-ylmethylene)hydrazino]pyrimidin-4-
yl}hydrazone} (2e). As described for 1b, with 10c (42mg, 0.105 mmol), 14a (7 mg, 0.052mmol), and EtOH
(3 ml) for 4 h. The mixture was cooled and the EtOH evaporated. Purification by prep. TLC (Al2O3, AcOEt/
hexane 15 :85) gave, after drying for 10 h under high vacuum, 2e (19 mg, 40%). 1H-NMR (CDCl3, 200 MHz):
9.17 (s, 1 H); 8.68 (s, 1 H); 8.27 (d, 2H); 8.19 ( s, 2H); 7.81 7.70 ( m, 4 H); 7.55 (s, 2H); 7.42 ( s, 2H); 7.14
(t, 2H); 6.88 ( t, 2H); 4.21 4.08 ( m, 8 H); 1.76 1.25 (m, 32H); 1.00 0.78 ( m, 12 H). 13C-NMR (CDCl3,
50 MHz): 162.0; 161.9; 161.4; 159.1; 156.6; 154.2; 149.0; 136.5; 136.1; 135.6; 133.3; 122.3; 119.3; 109.0; 89.5; 42.8;
‡
‡
42.3; 31.7; 25.2; 24.8; 22.8; 14.1. FAB-MS: 895.5 (100, [M ‡ H] ). HR-FAB-MS: 895.6056 ([C50H70N16 ‡ H] ;
calc. 895.6048).
2-Phenylpyrimidine-4,6-dicarboxaldehyde Bis{hexyl{6-[1-hexyl-2-(pyridin-2-ylmethylene)hydrazino]pyri-
midin-4-yl}hydrazone} (2f). As described for 1b, with 14b (20 mg, 94.3 mmol), 10c (85 mg, 214.1 mmol), and
EtOH (10 ml) for 5 h. The mixture was cooled, the EtOH evaporated, and the residue purified by FC (Al2O3,
AcOEt/hexane 1 :9): 2f (54 mg, 60%). 1H-NMR (CDCl3, 200 MHz): 8.62 8.50 (m, 3 H); 2 .2 8 d(, 2H); 8.20
(s, 2H); 7.88 ( s, 2H); 7.79 ( d, 2H); 7.62 7.48 ( m, 5 H); 7.46 (s, 2H); 7.14 ( t, 2H); 6.88 ( t, 2H); 4.27 4.05
(m, 8 H); 1.85 1.12( m, 32H); 1.05 0.70 ( m, 12 H). 13C-NMR (CDCl3, 40 MHz): 162.4; 162.1; 156.6; 154.2;
148.9; 136.5; 135.6; 134.3; 130.9; 128.9; 128.3; 119.3; 89.6; 65.6; 42.8; 42.4; 30.7; 30.1; 29.8; 26.7; 22.8; 14.1. 2D-
‡
‡
NMR (200 MHz): NOESY. FAB-MS: 971.6 (100, [M ‡ H] ). HR-FAB-MS: 961.6336 ([C56H74N16 ‡ H] ; calc.
971.6361).
Pyrimidine-4,6-dicarboxaldehyde 4,4'-Bis{methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazino]pyrimi-
din-4-yl}hydrazone} 6,6'-[(Pyrimidine-4,6-diyl)bis(methylhydrazone)] (3a). As described for 1b, with 11a
(146 mg, 0.389 mmol), 9b (30 mg, 0.179 mmol), and EtOH (6 ml) for 6 h: 3a (120 mg, 76%). Yellowish solid.
M.p. >3508 (dec.). UV/VIS (CHCl3): 306.0 (80500). IR (KBr): 3023w, 1591s, 1477s, 1429m, 1399m, 1339w,
1270w, 1023s, 906m, 784m. 1H-NMR (CDCl3, 400 MHz): 8.86 (s, 2H); 8.36 ( s, 2H); 8.33 ( s, 2H); 8.18 ( d, 2 H);
7.90 (s, 1 H); 7.54 7.40 (m, 10 H); 7.2 0 (s, 1 H); 6.97 (t, 2H); 6.78 ( t, 2H); 3.57 ( s, 6 H); 3.54 (s, 6 H); 3.43
(s, 6 H). 13C-NMR (CDCl3, 100 MHz): 161.7; 161.1; 160.7; 159.1; 156.6; 155.7; 153.6; 148.9; 136.9; 135.2; 134.2;
134.1; 122.2; 119.2; 90.8; 89.4; 30.0; 29.8; 29.5. 2D-NMR (500 MHz): COSY, ROESY. FAB-MS: 883.2 (100,
‡
‡
[M ‡ H] ). HR-FAB-MS: 883.4107 ([C42H42N24 ‡ H] ; calc. 883.4103). Anal. calc. for C42H42N24 ¥ CH2Cl2:
C 53.36, H 4.58, N 34.75; found: C 53.70, H 4.63, N 35.02.
2-Phenylpyrimidine-4,6-dicarboxaldehyde 4,4'-Bis{methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazi-
no]pyrimidin-4-yl}hydrazone} 6,6'-[(Pyrimidine-4,6-diyl)bis(methylhydrazone)] (3b). As described for 1b,
with a suspension of 11b (14 mg, 31.0 mmol), 9b (2mg, 11.9 mmol), and EtOH (2ml) for 15 h: 3b (8 mg, 65%).

Helvetica Chimica Acta Vol. 86 (2003)
1617
Yellow solid. M.p. >3508. UV/VIS (CHCl3): 307.0 (66700). IR (KBr): 2922m, 1590s, 1482s, 1371m, 1025m.
1H-NMR (CDCl3, 500 MHz): 8.48 (d, 4 H); 8.31 (s, 2H); 8.18 ( d, 2H); 7.92( s, 1 H); 7.89 (s, 2H); 7.61 7.54
(m, 12H); 7.47 ( d, 2H); 7.46 ( s, 2 H); 7.24 (s, 1 H); 6.96 (t, 2H); 6.78 ( t, 2H); 3.59 ( s, 6 H); 3.52( s, 6 H); 3.49
(s, 6 H). 13C-NMR (CDCl3, 100 MHz): 168.9; 164.6; 161.9; 161.6; 161.2; 161.0; 156.0; 155.8; 137.6; 135.3; 135.1;
132.0; 130.6; 128.5; 128.3; 126.2; 122.2; 119.4; 106.8; 89.1; 30.0; 29.9; 29.7. 2D-NMR (500 MHz): COSY, ROESY.
‡
‡
FAB-MS: 1035.8 (100, [M ‡ H] ). HR-FAB-MS: 1035.4734 ([C54H50N24 ‡ H] ; calc. 1035.4729).
2-Phenylpyrimidine-4,6-dicarboxaldehyde 4,4'-Bis{methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazi-
no]-2-phenylpyrimidin-4-yl}hydrazone} 6,6'-[(2-Phenylpyrimidine-4,6-diyl)bis(methylhydrazone)] (3c).
A
soln. of 11b (20 mg, 0.035 mmol) and 9c (4.6 mg, 0.018 mmol) in CHCl3 (3 ml) was stirred at 458 for 2h
under Ar. The mixture was evaporated and the residue submitted to FC (Al2O3, CHCl3): 3b (15 mg, 66%). M.p.
>2508. UV/VIS (CHCl3): 305.0 nm (44800). IR (KBr): 1591s, 1550s, 1482m, 1390s, 1370m, 1248w, 1169m, 1083w,
1030m, 980w, 904w, 753w, 695m. 1H-NMR (CD2Cl2, 500 MHz): 8.44 (s, 2H); 8.25 ( m, 2H); 8.20 ( d, 4 H); 8.02
(d, 4 H); 7.92( d, 2H); 7.62( m, 4 H); 7.55 (m, 7 H); 7.47 (s, 2H); 7.34 ( m, 5 H); 7.2 3 (m, 8 H); 6.99 (t, 2H); 6.71
(t, 2H); 3.72( s, 6 H); 3.66 (s, 6 H); 3.60 (s, 6 H). 13C-NMR (CDCl3, 100 MHz): 164.3; 162.0; 161.4; 161.2; 161.0;
135.1; 130.0; 129.9; 129.8; 129.7; 129.6; 128.0; 127.9; 127.8; 127.7; 121.8; 106.7; 87.3; 31.7; 29.7. FAB-MS: 1263.5
‡
(100, [M ‡ H] ).
2-Phenylpyrimidine-4,6-dicarboxaldehyde 4,4'-Bis{methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazi-
no]-2-phenylpyrimidin-4-yl}hydrazone} 6,6'-{[2-(4-Methylphenyl)pyrimidine-4,6-diyl]bis(methylhy drazone)}
(3d). As described for 1b, with 11a (6 mg, 15.9 mmol), 9d (2mg, 7.8 mmol), and EtOH (2ml) for 8 h: 3d
(4 mg, 53%). Yellowish solid. M.p. >3508 (dec.). UV/VIS (CHCl3): 305.0 (62000). 1H-NMR (CDCl3,
400 MHz): 8.88 (d, 2H); 8.39 ( s, 2H); 8.37 ( d, 2H); 8.17 ( d, 2H); 7.92( d, 2H); 7.57 ( d, 2H); 7.51 ( s, 2H); 7.49
(s, 4 H); 7.42( s, 2H); 7.33 ( d, 2H); 7.09 ( s, 1 H); 6.94 (t, 2H); 6.63 ( t, 2H); 3.63 ( s, 6 H); 3.61 (s, 6 H); 3.59
(s, 6 H); 2.51 (s, 3 H). 13C-NMR (CDCl3, 100 MHz): 162.7; 162.2; 161.6; 161.4; 160.9; 159.0; 156.5; 153.5; 148.9;
148.5; 148.2; 141.1; 137.3; 135.3; 134.5; 133.6; 129.0; 128.0; 122.2; 119.1; 119.0; 108.9; 90.2; 88.5; 30.1; 29.9; 29.7.
‡
2D-NMR (300 MHz): 1H,13C HMQC, 1H,13C HMBC. FAB-MS: 973.5 (100, [M ‡ H] ). HR-FAB-MS: 973.4567
‡
([C49H48N24 ‡ H] ; calc. 973.4572).
2-Phenylpyrimidine-4,6-dicarboxaldehyde 4,4'-Bis{methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazi-
no]-2-phenylpyrimidin-4-yl}hydrazone} 6,6'-{[2-(3,4,5-Trimethoxyphenyl)pyrimidine-4,6-diyl]bis(methylhydra-
zone)} (3e). As described for 3c, with 11c (10 mg, 0.019 mmol), 4,6-bis(1-methylhydrazino)-2-(3,4,5-
trimethoxyphenyl)pyrimidine (9e; 3 mg, 0.009 mmol), and CHCl3 (3 ml): 2 (22 mg, 85%). M.p. >2508.
1H-NMR (CD2Cl2, 500 MHz): 8.32( s, 2H); 8.18 ( m, 2H); 8.08 ( m, 4 H); 8.02( d, 2H); 7.68 ( d, 2H); 7.64
(s, 2H); 7.59 ( s, 2H); 7.55 ( s, 4 H); 7.41 (s, 2 H); 7.23 (m, 12H); 7.10 ( s, 1 H); 6.96 (t, 2H); 6.58 ( t, 2H); 4.08
(s, 6 H); 3.99 (s, 3 H); 3.77 (s, 6 H); 3.66 (s, 6 H); 3.61 (s, 6 H). 13C-NMR (CDCl3, 100 MHz): 164.5; 162.5;
162.2; 161.8; 161.4; 161.0; 153.8; 153.0; 148.3; 137.64; 137.2; 135.6; 135.4; 130.2; 129.9; 128.2; 128.0; 127.9; 127.8;
‡
121.9; 119.3; 106.8; 105.3; 88.9; 87.5; 60.9; 56.3; 30.2; 30.2; 29.8; 29.6. FAB-MS: 1353.7 (100, [M ‡ H] ).
Pyrimidine-4,6-dicarboxaldehyde Bis{methyl{6-{1-methyl-2-{{6-{{2-methyl-2-{6-[1-methyl-2-(pyridin-2-yl-
methylene)hydrazino]pyrimidin-4-yl}hydrazono}methyl}pyrimidin-4-yl}methylene}hydrazino}pyrimidin-4-yl}-
hydrazone} (4). As described for 1b, with a suspension of 12a (47 mg, 89.4 mmol), 14a (6 mg, 44.1 mmol), and
EtOH (4 ml) for 12h: 4 (15 mg, 30%). Yellowish solid. M.p. >3008 (dec.). UV/VIS (CHCl3): 302. IR (KBr):
2928w, 1590s, 1481s, 798m. 1H-NMR (CDCl3, 400 MHz): 8.74 (s, 2H); 8.51 ( s, 1 H); 8.23 (s, 2H); 8.13 ( d, 2 H);
8.12( s, 2H); 8.05 ( s, 2H); 7.98 ( s, 1 H); 7.44 7.29 (m, 8 H); 7.2 0 (s, 2H); 7.12 ( s, 2H); 7.05 ( s, 2H); 6.86
(t, 2H); 6.73 ( t, 2H); 3.46 3.40 ( m, 2 4 H). 13C-NMR (CDCl3, 100 MHz): 164.3; 161.0; 160.3; 159.7; 158.9;
156.4; 156.1; 153.9; 148.9; 141.8; 139.0; 136.7; 135.2; 134.2; 134.0; 133.9; 128.5; 122.0; 119.0; 117.5; 108.8; 90.2;
‡
89.1; 87.5; 29.9; 29.8; 29.7; 29.5. 2D-NMR (500 MHz): COSY, ROESY. FAB-MS: 1151.4 (100, [M ‡ H] ). HR-
‡
FAB-MS: 1151.5285 ([C54H54N32 ‡ H] ; calc. 1151.5287).
Pyrimidine-4,6-dicarboxaldehyde 4,4'-Bis{methyl{6-{1-methyl-2-{{6-{{2-methyl-2-{6-[1-methyl-2-(pyridin-
2-ylmethylene)hydrazino]pyrimidin-4-yl}hydrazono}methyl}pyrimidin-4-yl}methylene}hydrazino}pyrimidin-4-
yl}hydrazone} 6,6'-[(Pyrimidine-4,6-diyl)bis(methylhydrazone)] (5). A soln. of 13 (63 mg, 0.098 mmol; purified
by FC (Al2O3, CHCl3/EtOH 98 :2) and 9a (8 mg, 0.048 mmol) in EtOH/CHCl3 3 :1 (5 ml) was heated to reflux
for 48 h. Then, the mixture was cooled, concentrated under vacuum (to remove the CHCl3), and filtered. The
precipitate was washed with EtOH and dried for 10 h under high vacuum: 5 (40 mg, 59%). Yellowish solid. M.p.
>3508 (dec.). UV/VIS (CHCl3): 300.0 (165000). IR (KBr): 2925w, 1597s, 1479s, 1397m, 1022m. 1H-NMR
(CDCl3, 400 MHz): 8.73 (s, 2H); 8.43 ( s, 2H); 8.24 ( s, 1 H); 8.22 (s, 2H); 8.13 ( d, 2H); 8.06 ( s, 2H); 7.98
(s, 2H); 7.78 ( s, 2H); 7.37 7.27 ( m, 10 H); 7.13 (s, 2H); 7.06 ( s, 2H); 6.97 ( s, 2H); 6.93 ( s, 1 H); 6.89 (s, 2 H);
6.83 (t, 2H); 6.72( t, 2H); 3.45 3.40 ( m, 24 H); 3.29 (s, 6 H). 13C-NMR (CDCl3, 75 MHz): 161.9; 161.3; 161.0;
160.8; 160.7; 160.5; 160.4; 159.6; 159.3; 158.9; 158.8; 156.3; 156.0; 153.4; 148.9; 135.2; 134.2; 134.0; 133.9; 133.7;

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Helvetica Chimica Acta Vol. 86 (2003)
122.1; 118.9; 108.7; 108.6; 90.0; 89.4; 89.1; 76.6; 30.9; 30.0; 29.9; 29.8; 29.5. 2D-NMR (300 MHz): COSY,
‡
NOESY, 1H,13C HMQC. FAB-MS: 1419.6 (100, [M ‡ H] ).
Pyrimidine-4,6-dicarboxaldehyde Methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazino]pyrimidin-4-
yl}hydrazone Methyl(pyridin-2-yl)hydrazone (6). a) As described for 1b, with 11a (4 mg, 10.7 mmol), 26a
(2mg, 16.3 mmol), and EtOH (3 ml) for 4 h: 6 (5 mg, 98%).
b) As described for 1b, with 10a (5 mg, 19.5 mmol), 15 (5 mg, 20.7 mmol), and EtOH (3 ml): 6 (9 mg, 96%).
Yellowish solid. M.p. 262 2648. UV/VIS (CHCl3): 336.0 (52600). IR (KBr): 3025w, 1592s, 1478s, 1398m, 1352m,
1235w, 1129m, 1074m, 1023m, 977m, 906m, 777s. 1H-NMR (CDCl3, 400 MHz): 9.17 (s, 1 H); 8.59 (s, 1 H); 8.54
(s, 1 H); 8.25 (d, 1 H); 8.04 (d, 1 H); 8.01 (s, 1 H); 7.86 (d, 1 H); 7.79 (s, 1 H); 7.70 (s, 1 H); 7.66 (s, 1 H); 7.40
(d, 1 H); 7.24 7.20 (m, 2H); 6.93 ( t, 1 H); 6.70 (t, 1 H); 3.76 (s, 3 H); 3.72( s, 3 H); 3.64 (s, 3 H). 13C-NMR
(CDCl3, 100 MHz): 162.6; 162.1; 161.4; 159.0; 156.8; 156.0; 154.1; 148.9; 146.5; 137.8; 136.9; 135.7; 134.7; 131.4;
122.5; 119.4; 117.0; 110.4; 109.8; 89.4; 85.7; 30.1; 29.9; 29.6. 2D-NMR (500 MHz): COSY, NOESY. EI-MS: 480.3
‡
‡
‡
‡
(100, M ), 402.3 (20, [M À 78] ), 268.2 (54, [M À 132] ), 134.3 (100, [M À 264] ). FAB-MS: 481.3 (100, [M ‡
‡
‡
H] ). HR-FAB-MS: 481.2341 ([C24H24N12 ‡ H] ; calc. 481.2325).
Pyrimidine-4,6-dicarboxaldehyde 4,4'-Bis[methyl(pyridin-2-yl)hydrazone] 6,6'-[(Pyrimidine-4,6-diyl)bis-
(methylhydrazone)] (7). As described for 1b, with 15 (8 mg, 33.2 mmol), 9b (2mg, 11.9 mmol), and EtOH (1 ml)
for 8 h: 7 (7.5 mg, 73%). Yellowish solid. M.p. >2508. UV/VIS (CHCl3): 331.0 (67000). IR (KBr): 1595s, 1564s,
1476s, 1393m, 1346m, 1232m, 1155w, 1127m, 1024m, 979s, 768m. 1H-NMR (CDCl3, 200 MHz): 8.61 (s, 2H); 8.57
(s, 1 H); 8.31 (s, 2H); 8.16 ( s, 1 H); 8.14 (d, 2H); 7.51 ( s, 2H); 7.34 ( s, 2H); 7.22( d, 2H); 7.17 ( t, 2H); 6.77
(t, 2H); 3.74 ( s, 6 H); 3.56 (s, 6 H). 13C-NMR (CDCl3, 100 MHz): 162.9; 161.1; 160.5; 158.7; 157.1; 155.8; 146.8;
136.7; 135.1; 131.1; 117.0; 109.9; 109.5; 89.8; 29.9; 29.8. 2D-NMR (300 MHz): COSY, NOESY. FAB-MS: 615.2
‡
‡
(100, [M ‡ H] ). HR-FAB-MS: 615.2944 ([C30H30N16 ‡ H] ; calc. 615.2918).
4,6-Dichloro-2-(3,4,5-trimethoxyphenyl)pyrimidine (8d). POCl3 (20 ml) was slowly added to 19 (0.28 g,
1.007 mmol), and the suspension was heated to reflux for 5 h. The excess POCl3 was evaporated, the remaining
paste dissolved in CH2Cl2, and the soln. washed consecutively with ice water and sat. NaHCO3 soln. dried
(MgSO4), and evaporated: The crude product was submitted to FC (SiO2, CH2Cl2/AcOEt 15 :5) and
recrystallized from MeOH: 8d (0.65 g, 82%). M.p. 1688. IR (KBr): 3478w, 1655s, 1523s. 1H-NMR (CDCl3,
200 MHz): 7.70 (s, 2 H); 7.23 (s, 1 H); 3.17 (s, 6 H); 3.12( s, 3 H). 13C-NMR (CDCl3, 50 MHz): 165.32; 161.1;
153.4; 141.8; 118.4; 61.0; 56.4; 26.0. EI-MS: 314.1. Anal. calc. for C13H12Cl2N2O3: C 41.54, H 3.84, N 8.81; found:
C 41.40, H 3.65, N 8.01.
4,6-Dihydrazino-2-(3,4,5-trimethoxyphenyl)pyrimidine (9a). To a soln. of 8d (700 mg, 2.21 mmol) in EtOH
(30 ml) was added hydrazine monohydrate (2.2 ml, 4.5 mmol). The mixture was heated to reflux for 72 h under
Ar. The soln. was allowed to cool to r.t. and then cooled further to 08. The crystalline solid that formed was
filtered, washed with EtOH, and air-dried: 5 (470 mg, 61%). M.p. 2238. IR (KBr): 1651s, 1575s, 1542. 1H-NMR
((D6)DMSO, 200 MHz): 8.84 (s, 1 H); 7.58 (s, 2H); 6.68 ( s, 1 H); 4.53 (s, 2H); 3.85 ( s, 6 H); 3.73 (s, 3 H). EI-
MS: 306.3. Anal. calc. for C13H18N6O3 ¥ 0.25 HCl: C 41.81, H 5.81, N 26.60; found: C 41.15, H 5.54, N 26.20.
4,6-Bis(1-methylhydrazino)pyrimidine (9b). Under magnetic stirring, 4,6-dichloropyrimidine (8a; 1 g,
6.711 mmol) was slowly added by portions to ice-cooled methylhydrazine (15 g, 326.087 mmol). The mixture
was refluxed for 2h under Ar. After cooling, methylhydrazine was evaporated, K 2CO3 (1 g, 7.246 mmol) and
CHCl3 (150 ml) were added to the solid residue, and the mixture was stirred during 10 min. The liquid phase was
filtered. The solid-liquid extraction procedure was repeated 3 times with CHCl3 (without adding K2CO3), and
the combined liquid fraction was evaporated: 9b (quant.), NMR pure and so used without further purification.
White solid, unstable in air. M.p. 143 1458. 1H-NMR (CDCl3, 200 MHz): 8.17 (s, 1 H); 6.18 (s, 1 H); 3.98
‡
(s, 4 H); 3.23 (s, 6 H). 13C-NMR (CDCl3, 50 MHz): 164.7; 156.9; 80.9; 39.9. FAB-MS: 169.0 (100, [M ‡ H] ).
‡
HR-FAB-MS: 169.1202 ([C6H12N6 ‡ H] ; calc. 169.1202).
4,6-Bis(1-methylhydrazino)-2-phenylpyrimidine (9c). As described for 9a, with 4,6-dichloro-2-phenyl-
pyrimidine (8b; 2.5 g, 11.2 mmol), EtOH (30 ml), and methylhydrazine (2.4 ml, 45.1 mmol) for 48 h: 9c
(300 mg, 70%). M.p. 1268. 1H-NMR (CDCl3, 200 MHz): 8.40 (m, 2H); 7.42 ( m, 3 H); 6.14 (s, 1 H); 3.37
(s, 6 H). 13C-NMR (CDCl3, 50 MHz): 172.1; 165.4; 161.9; 139.0; 129.9; 128.1; 79.3; 39.9. FAB-MS: 245.1 (100,
‡
[M ‡ H] ). Anal. calc. for C12H16N6: C 59.00, H 6.60, N 34.40; found: C 58.76, H 6.76, N 34.20.
4,6-Bis(1-methylhydrazino)-2-(4-methylphenyl)pyrimidine (9d). As described for 9b, with 4,6-dichloro-2-
(4-methylphenyl)pyrimidine (8c; 0.3 g, 1.255 mmol), methylhydrazine (25a; 3 g, 65.217 mmol), K2CO3 (0.3 g,
2.174 mmol), and CHCl3 (100 ml) (1 solid-liquid extraction): 9d (quant.). White solid. M.p. 177 1798. 1H-NMR
(CDCl3, 300 MHz): 8.29 (d, 2H); 7.22( d, 2H); 6.09 ( s, 1 H); 4.20 (s, 4 H); 3.35 (s, 6 H); 2.39 (s, 3 H). 13C-NMR
‡
(CDCl3, 75 MHz): 163.4; 162.2; 139.9; 136.2; 128.8; 127.9; 79.1; 40.0; 21.5. FAB-MS: 259.4 (100, [M ‡ H] ).

Helvetica Chimica Acta Vol. 86 (2003)
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4,6-Bis(1-methylhydrazino)-2-(3,4,5-trimethoxyphenyl)pyrimidine (9e). As described for 9a, with 8d
(400 mg, 1.27 mmol), EtOH (30 ml), and methylhydrazine (0.350 ml, 6.34 mmol) for 48 h. The crude solid
was redissolved in CHCl3, the soln. washed with sat. aq. NH4Cl soln. dried (MgSO4), and the solvent removed
by distillation on a waterbath: 9e (300 mg, 70%) after air-drying. M.p. 1708. 1H-NMR (CDCl3, 200 MHz): 7.68
(s, 2H); 6.2( s, 1 H); 4.12( s, 2H); 3.88 ( s, 3 H); 3.53 (s, 6 H); 3.14 (s, 6 H). 13C-NMR (CDCl3, 50 MHz): 165.5;
‡
161.8; 152.1; 134.5; 71.2; 60.1; 56.2; 40.1; 25.4; 13.1. FAB-MS: 335.6 (100, [M ‡ H] ). Anal. calc. for C15H22N6O3:
C 53.88, H 6.63, N 25.13; found: C 54.01, H 6.62, N 24.00.
4,6-Bis(1-hexylhydrazino)pyrimidine (9f). As described for 9b, with 8a (1 g, 6.711 mmol), hexylhydrazine
(25b; 20 g, 172.414 mmol) (at 1508 for 3 h), K2CO3 (1 g, 7.246 mmol), and CH2Cl2 (50 ml). The solid/liquid
mixture was stirred for 20 min and then filtered, and the filtrate evaporated. The residue was dissolved in the
minimal volume of CH2Cl2, and heptane was added until a light cloudiness appeared. The mixture was put in a
fridge (48) overnight, and the resulting precipitate filtered: 9f (0.85 g, 41%). White solid, unstable in air and
stored under Ar in a freezer. M.p. 58 608. IR (KBr): 3322w, 3188w, 2927s, 2855s, 1587s, 1474s, 1372w, 1332w,
1
1252w, 1189w, 972m, 895m, 807m. H-NMR (CDCl3, 200 MHz): 8.18 (s, 1 H); 6.19 (s, 1 H); 3.87 (s, 4 H); 3.62
(t, 4 H); 1.62( t, 4 H); 1.43 1.23 (m, 12H); 0.86 ( t, 6 H). 13C-NMR (CDCl3, 50 MHz): 164.3; 157.0; 80.4; 51.2;
‡
31.7; 26.5; 22.6; 13.9. EI-MS: 308.2 (42, M ), 292.2 (100), 223.2 (38), 222.1 (62). FAB-MS: 309.2 (100, [M ‡
‡
‡
H] ). HR-FAB-MS: 309.2771 ([C16H32N6 ‡ H] ; calc. 309.2767).
4,6-Bis[1-(prop-2-enyl)hydrazino]pyrimidine (9g). As described for 9b, with 8a (0.1 g, 0.671 mmol), (prop-
2-enyl)hydrazine (25d; 2g, 27.778 mmol) (for 3 h), K 2CO3 (0.1 g, 0.724 mmol), and CHCl3 (100 ml) (1 solid-
liquid extraction): 9g (quant.). H-NMR (CDCl3, 200 MHz): 8.10 (s, 1 H); 6.44 (s, 1 H); 6.85 5.60 (m, 2 H);
5.05 5.25 (m, 4 H); 4.24 (dd, 4 H); 3.76 (s, 4 H). 13C-NMR (CDCl3, 50 MHz): 164.9; 157.1; 132.7; 117.9; 82.0;
1
‡
‡
‡
‡
54.1. EI-MS: 220.1 (35, M ), 179 (100, [M À 41] ), 138 (97, [M À 82] ). FAB-MS: 221.1 (100, [M ‡ H] ). HR-
‡
FAB-MS: 221.1505 ([C10H16N6 ‡ H] ; calc. 221.1515).
Pyridine-2-carboxaldehyde Methyl[6-(1-methylhydrazino)pyrimidin-4-yl]hydrazone (10a). A soln. of
pyridine-2-carboxaldehyde (1.14 g, 10.654 mmol) and 9b (2.5 g, 14.881 mmol) in EtOH (500 ml) was stirred
at r.t. under Ar for 3 h. Then, the soln. was filtered, the EtOH from the filtrate evaporated, and the solid residue
purified by FC (Al2O3, CHCl3, then CHCl3/EtOH 95 :5: 10a (2.1 g, 55%). White solid. M.p. 157 1598. UV/VIS
(CHCl3): 336.0. IR (KBr): 3294w, 3180w, 3000w, 2924w, 2853w, 1589s, 1490s, 1407m, 1284s, 1186m, 1109m,
1
1080m, 978s, 844m, 805m, 62 5m. H-NMR (CDCl3, 200 MHz): 8.58 (d, 1 H); 8.32( s, 1 H); 8.03 (d, 1 H); 7.81
(s, 1 H); 7.71 (t, 1 H); 7.2 1 (t, 1 H); 7.01 (s, 1 H); 4.11 (s, 2H); 3.64 ( s, 3 H); 3.34 (s, 3 H). 13C-NMR (CDCl3,
50 MHz): 164.5; 161.8; 156.4; 154.5; 148.9; 136.5; 136.2; 123.5; 119.2; 84.3; 39.6; 29.4. EI-MS: 257.2 (22, M ),
179.2(100). FAB-MS: 258.1 (100, [ M ‡ H] ). HR-FAB-MS: 258.1471 ([C12H15N7 ‡ H] ; calc. 258.1467).
Pyridine-2-carboxaldehyde Methyl[6-(1-methylhydrazino)-2-phenylpyrimidin-4-yl]hydrazone (10b). As
described for 10a, with pyridine-2-carboxaldehyde (33 ml, 0.21 mmol), 9c (170 mg, 0.61 mmol), and abs. EtOH
(35 ml) for 4 h. FC (Al2O3, CHCl3) gave 10b (77 mg, 80%). White solid. M.p. 1288. 1H-NMR (CDCl3,
200 MHz): 8.51 (d, 1 H); 8.44 (m, 2H); 8.02( d, 1 H); 7.85 (s, 1 H); 7.73 (t, 1 H); 7.45 (m, 3 H); 7.2 1 (t, 1 H); 6.16
(s, 1 H); 3.80 (s, 3 H); 3.44 (s, 3 H). 13C-NMR (CDCl3, 50 MHz): 214.6; 144.0; 130.7; 125.0; 122.1; 122.8; 117.5;
‡
‡
‡
‡
114.1; 24.3. HR-FAB-MS: 334.1777 ([C18H19N7 ‡ H] ; calc. 334.1780). Anal. calc. for C18H19N7: C 64.85, H 5.74,
N 29.41; found: C 65.2, H 6.01, N 27.10.
Pyridine-2-carboxaldehyde Hexyl[6-(1-hexylhydrazino)pyrimidin-4-yl]hydrazone (10c). As described for
10a, with pyridine-2-carboxaldehyde (0.364 g, 3.402 mmol), 9f (1.5 g, 4.870 mmol), and EtOH (300 ml). FC
(Al2O3, CHCl3/hexane 8 :2gave 10c (0.9 g, 47%). 1H-NMR (CDCl3, 200 MHz): 8.55 (d, 1 H); 8.29 (s, 1 H); 7.95
(d, 1 H); 7.79 (s, 1 H); 7.66 (t, 1 H); 7.17 (t, 1 H); 6.93 (s, 1 H); 4.22 (t, 2H); 3.99 ( s, 2H); 3.66 ( t, 2H); 1.75 1.51
(m, 16 H); 0.91 0.75 (m, 6 H). 13C-NMR (CDCl3, 50 MHz): 172.4; 164.5; 162.2; 157.1; 155.1; 149.2; 136.3;
‡
136.0; 122.8; 119.4; 84.3; 51.4; 42.1; 31.7; 26.5; 25.1; 22.7; 14.0. EI-MS: 397.2 (16, M ), 319.3 (100), 292.3 (21).
‡
‡
FAB-MS: 398.2(100, [ M ‡ H] ). HR-FAB-MS: 398.3044 ([C22H35N7 ‡ H] ; calc. 398.3032).
Pyrimidine-4,6-dicarboxaldehyde Mono{methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazino]pyrimi-
din-4-yl}hydrazone} (11a). A soln. of 10a (450 mg, 1.751 mmol) and 14a (500 mg, 3.676 mmol) in EtOH
(150 ml) was stirred overnight at 408 under Ar. Then, the soln. was filtered and the precipitate washed with
EtOH to give 2a (150 mg, 28%), which was recrystallized from CHCl3/EtOH. The filtrate was concentrated (1
2ml) in vacuo, and MeCN (20 30 ml) was added. Then, the mixture was stirred at r.t. for 6 h to precipitate 11a,
which was filtered, washed with MeCN, and then dried under vacuum for 10 h: 330 mg (50%) of 11a. Yellow
solid. M.p. > 2508 (dec.). UV/VIS (CHCl3): 322.0 (50000). IR (KBr): 2922w, 1718s, 1595s, 1456s, 1332s, 1275m,
1239m, 1186m, 1155m, 1075s, 1025s, 980s, 837s, 783s. 1H-NMR (CDCl3, 200 MHz): 1012 (s, 1 H); 9.39 (s, 1 H);
8.62( d, 1 H); 8.51 (s, 1 H); 8.48 (s, 1 H); 8.28 (d, 1 H); 8.12( t, 1 H); 7.95 (s, 1 H); 7.85 (s, 1 H); 7.80 (s, 1 H); 7.32
(t, 1 H); 3.73 (s, 3 H); 3.71 (s, 3 H). 13C-NMR (CDCl3, 100 MHz): 192.8; 163.8; 162.9; 162.1; 159.8; 157.4; 156.7;

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Helvetica Chimica Acta Vol. 86 (2003)
‡
154.1; 149.1; 139.1; 137.7; 133.9; 123.5; 119.8; 111.4; 77.7; 30.5; 29.9. EI-MS: 375.2 (37, M ), 297.1 (100), 268.2
‡
‡
(73), 163.1 (58). FAB-MS: 376.4 (100, [M ‡ H] ). HR-FAB-MS: 376.1636 ([C18H17N9O ‡ H] ; calc. 376.1634).
2-Phenylpyrimidine-4,6-dicarboxaldehyde Mono{methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazi-
no]pyrimidin-4-yl}hydrazone} (11b). A soln. of 10a (300 mg, 1.167 mmol) and 14b (500 mg, 2.358 mmol) in
EtOH (100 ml) was stirred at r.t. under Ar for 30 h. Then, the soln. was filtered, the filtrate concentrated (2
3 ml) in vacuo, MeCN (20 30 ml) added, and the precipitate filtered, washed with MeCN, and dried under
vacuum for 10 h: 11b (220 mg, 42%). Yellow solid. M.p. >2508. IR (KBr): 2928w, 1718s, 1591s, 1465s, 1393s,
1
1359s, 1277m, 1208m, 1155m, 1073s, 1023s, 980s, 690s. H-NMR (CDCl3, 200 MHz): 10.24 (s, 1 H); 8.67 8.56
(m, 4 H); 8.39 (s, 1 H); 8.29 (d, 1 H); 8.16 (t, 1 H); 7.98 (s, 1 H); 7.91 (s, 1 H); 7.87 (s, 1 H); 7.62 7.49 ( m, 3 H);
7.32( t, 1 H); 3.81 (s, 3 H); 3.77 (s, 3 H). 13C-NMR (CDCl3, 50 MHz): 193.6; 167.7; 162.2; 158.4; 156.8; 154.3;
151.4; 143.5; 139.2; 137.8; 136.8; 135.0; 131.5; 128.9; 128.5; 123.6; 119.9; 109.8; 109.0; 88.8; 30.0; 29.8. EI-MS:
‡
‡
451.2(29, M ), 373.1 (100), 268.1 (81), 136.1 (49). FAB-MS: 452.2 (100, [M ‡ H] ). HR-FAB-MS: 452.1953
‡
([C24H21N9O ‡ H] ; calc. 452.1947).
2-Phenylpyrimidine-4,6-dicarboxaldehyde Mono{methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazi-
no]-2-phenylpyrimidin-4-yl}hydrazone} (11c) and 2-Phenylpyrimidine-4,6-dicarboxaldehyde Bis{methyl{6-[1-
methyl-2-(pyridin-2-ylmethylene)hydrazino]-2-phenylpyrimidin-4-yl}hydrazone} (2c). A soln. of 10b (88 mg,
0.26 mmol) and 14b (56 mg, 0.27 mmol) in CHCl3 (20 ml) was stirred at r.t. for 2 h under Ar. The mixture was
then evaporated and the residue purified by FC (Al2O3, CHCl3): 11c (70 mg, 60%) and 2c (20 mg, 8%).
1
Data of 11c: M.p. >2508. H-NMR (CDCl3, 200 MHz): 10.23 (s, 1 H); 8.62( m, 1 H); 8.58 (m, 2H); 8.50
(m, 2H); 8.44 ( s, 1 H); 8.33 (d, 1 H); 8.18 (t, 1 H); 7.83 (s, 1 H); 7.53 (m, 6 H); 7.31 (t, 1 H); 7.11 (d, 2H); 3.92
(s, 3 H); 3.87 (s, 3 H). 13C-NMR (CDCl3, 125 MHz): 193.6; 165.7; 164.2; 163.3; 162.6; 162.1; 158.1; 154.3; 149.0;
138.5; 137.9; 137.8; 136.7; 134.5; 131.4; 130.5; 128.7; 128.3; 128.1; 123.4; 119.9; 118.4; 115.2; 113.8; 108.8; 86.9;
‡
30.4; 30.0; 29.7. FAB-MS: 529.4 (100, [M ‡ H] ). Anal. calc. for C30H25N9O ¥ 0.7 C2H6O: C 67.37, H 5.26, N 22.52;
found: C 67.67, H 5.10, N 22.17.
Data of 2c: M.p. >2508. UV/VIS (CHCl3): 303.0 (83000). IR (KBr): 2921m, 1591s, 1551s, 1483s, 1429m,
1385s, 1368s, 1246w, 1168m, 1084w, 1029s, 981w, 901w, 802w, 752w, 698. 1H-NMR (CDCl3, 500 MHz): 8.64
(s, 1 H); 8.56 (m, 2H); 8.40 ( m, 4 H); 7.83 (d, 2H); 7.63 ( s, 2H); 7.56 ( m, 3 H); 7.50 (m, 6 H); 7.47 (s, 2H); 7.13
(t, 2H); 7.11 ( d, 2H); 7.15 ( s, 2H); 6.72( t, 2H); 3.84 ( s, 6 H); 3.61 (s, 6 H). 13C-NMR (CDCl3, 50 MHz): 162.6;
162.2; 161.8; 165.1; 138.0; 137.7; 135.3; 130.8; 130.3; 128.7; 128.3; 128.2; 128.1; 122.9; 122.2; 119.3; 107.1; 87.9;
‡
87.1; 30.2; 29.7. FAB-MS: 843.3 (100, [ M ‡ H] ).
Pyrimidine-4,6-dicarboxaldehyde Methyl[6-(1-methylhydrazino)pyrimidin-4-yl]hydrazone Methyl{6-[1-
methyl-2-(pyridin-2-ylmethylene)hydrazino]pyrimidin-4-yl}hydrazone (12a).
A soln. of 11a (410 mg,
1.093 mmol) and 9b (350 mg, 2.083 mmol) in EtOH/CHCl3 7:3 (70 ml) was stirred at 358 under Ar for 15 h.
Then, the soln. was filtered, the filtrate concentrated (3 4 ml) in vacuo, MeCN (20 30 ml) added, and the
precipitate filtered, washed with MeCN, and dried under vacuum for 10 h: 12a (360 mg, 63%). Yellow solid.
M.p. >2508. 1H-NMR (CDCl3, 300 MHz): 9.15 (s, 1 H); 8.63 (s, 1 H); 8.51 (s, 1 H); 8.31 (d, 1 H); 8.07 (s, 1 H);
7.95 (s, 1 H); 7.82 7.69 ( m, 4 H); 7.15 (t, 1 H); 6.95 (t, 1 H); 6.69 (s, 1 H); 3.75 (s, 3 H); 3.73 (s, 3 H); 3.58
(s, 3 H); 3.07 (s, 3 H). 13C-NMR (CDCl3, 75 MHz): 165.1; 164.2; 162.9; 162.8; 161.7; 161.5; 159.2; 157.1; 156.5;
153.7; 149.3; 138.5; 135.7; 134.9; 133.5; 122.7; 119.5; 109.9; 88.8; 85.4; 39.7; 30.23; 29.9; 29.8. FAB-MS: 526.4
‡
‡
(100, [M ‡ H] ). HR-FAB-MS: 526.2667 ([C24H27N15 ‡ H] ; calc. 526.2652).
2-Phenylpyrimidine-4,6-dicarboxaldehyde Methyl[6-(1-methylhydrazino)pyrimidin-4-yl]hydrazone Meth-
yl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazino]pyrimidin-4-yl}hydrazone (12b). As described for 12a, with
11b (200 mg, 0.433 mmol), 9b (100 mg, 0.595 mmol), and EtOH/CHCl3 6 :4 (50 ml) at 408: 12b (150 mg, 56%).
1
Yellow solid. M.p. >2508. H-NMR (CDCl3, 200 MHz): 8.51 8.45 (m, 4 H); 8.23 (d, 1 H); 8.01 (s, 1 H); 7.91
(s, 1 H); 7.84 7.77 (m, 4 H); 7.68 (s, 1 H); 7.51 7.48 (m, 4 H); 7.14 (t, 1 H); 6.93 (t, 1 H); 6.61 (s, 1 H); 3.71
(s, 3 H); 3.68 (s, 3 H); 3.54 (s, 3 H); 3.00 (s, 3 H). 13C-NMR (CDCl3, 50 MHz): 165.2; 164.0; 162.8; 162.1; 162.0;
161.1; 159.9; 157.0; 156.4; 148.9; 137.8; 137.5; 136.1; 135.8; 134.5; 130.9; 128.7; 128.3; 122.8; 119.6; 107.7; 104.4;
‡
‡
88.8; 85.4; 39.6; 30.2; 29.9; 29.8. FAB-MS: 602.3 (100, [M ‡ H] ). HR-FAB-MS: 602.2960 ([C30H31N15 ‡ H] ;
calc. 602.2965).
Pyrimidine-4,6-dicarboxaldehyde 4-{Methyl{6-[1-methyl-2-(pyridin-2-ylmethylene)hydrazino]pyrimidin-4-
yl}hydrazone} 6,6'-[(Pyrimidine-4,6-diyl)bis(methylhydrazone)] (13). As described for 12a, with 12a (300 mg,
0.570 mmol), 14a (120 mg, 0.882 mmol), and EtOH/CHCl3 5 :5 (50 ml) at 458: 13 (234 mg, 64%). Yellow solid.
M.p. >3008 (dec.). UV/VIS (CHCl3): 309.0 (79800). IR (KBr): 1712w, 1590s, 1479s, 1401m, 1339m, 1190m,
1
1153w, 1075m, 1025s, 981m, 786w. H-NMR (CDCl3, 300 MHz): 9.70 (s, 1 H); 9.21 (s, 1 H); 9.02( s, 1 H); 8.62
(s, 1 H); 8.28 8.24 (m, 3 H); 8.06 (s, 1 H); 7.84 (s, 1 H); 7.71 7.65 (m, 2H); 7.56 ( s, 1 H); 7.51 (s, 1 H); 7.46
(s, 1 H); 7.34 (s, 1 H); 7.11 (t, 1 H); 6.82( t, 1 H); 3.67 (s, 3 H); 3.61 3.52( m, 12 H). 13C-NMR (CDCl3,

Helvetica Chimica Acta Vol. 86 (2003)
1621
100 MHz): 191.7; 182.2; 163.0; 162.0; 161.9; 161.6; 161.5; 161.3; 159.7; 159.1; 156.7; 156.6; 156.3; 153.6; 149.0;
135.7; 135.6; 135.5; 133.2; 122.4; 119.4; 111.6; 109.4; 103.9; 90.4; 88.9; 30.2; 30.0; 28.9; 29.6. 2D-NMR
‡
‡
(300 MHz): COSY, NOESY. FAB-MS: 644.4 (100, [M ‡ H] ). HR-FAB-MS: 644.2819 ([C30H29N17O ‡ H] ;
calc. 644.2819).
Pyrimidine-4,6-dicarboxaldehyde Methyl(pyridin-2-yl)hydrazone (15). To
a soln. of 14a (280 mg,
2.059 mmol) in EtOH (20 ml), cooled at À788, 26a (100 mg, 0.813 mmol) in EtOH (20 ml) was slowly added
under magnetic stirring during 1 h. Then, the mixture was allowed to slowly warm to r.t. and was filtered. The
filtrate was concentrated (1 1.5 ml) in vacuo, then MeCN (15 ml) was added. The precipitate was further
purified by FC (Al2O3, CHCl3, then CHCl3/EtOH 97:3) to give the hydrate of aldehyde 15, which was further
dried overnight under vacuum at 358: 15 (60 mg, 31%). Yellow solid. M.p. >1508. 1H-NMR (CDCl3, 300 MHz):
10.09 (s, 1 H); 9.46 (s, 1 H); 8.35 (s, 1 H); 8.28 (d, 1 H); 7.76 (d, 1 H); 7.70 (t, 1 H); 7.62( s, 1 H); 6.95 (t, 1 H);
3.75 (s, 3 H). 13C-NMR (CDCl3, 100 MHz): 193.1; 164.5; 157.2; 156.6; 147.1; 138.0; 130.9; 117.8; 111.5; 110.7;
‡
58.4; 30.3. 2D-NMR (300 MHz): COSY, NOESY. FAB-MS: 242.3 (100, [M ‡ H] ). HR-FAB-MS: 242.1041
‡
([C12H11N5O ‡ H] ; calc. 242.1042).
Methyl 3,4,5-Trimethoxybenzenecarboximidate Hydrochloride (17). A cooled soln. of 3,4,5-trimethoxy-
benzonitrile (2g, 51.7 mmol) in dry MeOH (120 ml) was stirred for 2days at r.t. under an atmosphere of dry
HCl. The soln. was concentrated and Et2O added until precipitation was complete. The solid was isolated by
vacuum filtration and washed with Et2O: 17 (1.3 g, 68%). M.p. 1798. IR: 3052w (br.), 1702w, 1631s, 1262m.
1H-NMR ((D6)DMSO, 200 MHz): 7.42 (s, 2 H); 7.21 (s, 1 H); 4.23 (s, 3 H); 3.86 (s, 6 H); 3.71 (s, 3 H). 13C-NMR
‡
((D6)DMSO, 50 MHz): 175.2; 173.3; 167.1; 152.3; 55.8; 26.6; 24.1; 23.1. EI-MS: 225.1 ([M À HCl] ). Anal. calc.
for C11H16ClNO4: C 50.48, H 6.16, N 5.35; found: C 50.30, H 5.13, N 5.65.
3,4,5-Trimethoxybenzenecarboximidamide Hydrochloride (18). To a sat. soln. of dry ammonia in anh.
MeOH (120 ml) was added 17 (5.00 g, 20.2 mmol), and the mixture was stirred at r.t. in a closed flask for 2 days.
Then the soln. was concentrated, Et2O was added and the precipitate filtered and washed with Et2O: 18 (4.25 g,
85%). White powder. M.p. 2288. IR (KBr): 3350m, 1676s, 1420s. 1H-NMR ((D6)DMSO, 200 MHz): 7.32 (s, 2 H);
3.87 (s, 6 H); 3.75 (s, 3 H); 1.2 0 (m, 3 H). 13C-NMR ((D6)DMSO, 50 MHz): 164.7; 152.7; 122.3; 60.1; 56.2; 25.1.
‡
EI-MS: 210.2 ([M À HCl] ). Anal. calc. for C2H15ClN2O3 ¥ 0.4 HCl: C 45.15, H 6.01, N 11.01; found: C 45.14,
H 6.05, N 11.05.
2-(3,4,5-Trimethoxyphenyl)pyrimidine-4,6-diol (19). To a soln. of 18 (0.5 g, 2.02 mmol) and diethyl
malonate (0.35 ml, 2.1 mmol) in anh. MeOH (2 ml) was added 30% MeONa/MeOH (1.1 ml). Then the milky
soln. was heated to reflux for 24 h under Ar. After evaporation, the resulting paste was dissolved in H2O and
acidified to pH 1 and the white precipitate collected, washed with H2O, and dried for 48 h under high vacuum at
1
408: 3 (0.28 g, 41.6%). White solid. M.p. >2508. IR (KBr): 2600 2800m, 1621s, 1520s. H-NMR ((D6)DMSO,
200 MHz): 7.46 (s, 2H); 5.30 ( s, 1 H); 3.85 (s, 6 H); 3.72( s, 3 H). 13C-NMR ((D6)DMSO, 50 MHz): 167.2; 156.7;
152.7; 140.4; 127.0; 88.1; 60.0; 56.0; 25.1. EI-MS: 278.2. Anal. calc. for C13H14N2O5 ¥ 0.75 H2O: C 53.51, H 5.35,
N 9.60; found: C 53.56, H 5.33, N 9.64.
4,6-Dimethyl-2-phenylpyrimidine (21). A mixture of 2-chloro-4,6-dimethylpyrimidine (20; 2g, 14 mmol),
phenylboronic acid (2.17 g, 14.2 mmol), [Pd(PPh3)4] (200 mg), and K3PO4 (6.4 g, 30 mmol) was heated to reflux
for 12h in degassed toluene (20 ml). After cooling, the soln. was washed twice with H 2O and the org. phase
dried (MgSO4) and purified by FC (SiO2, CH2Cl2/AcOEt 15 :1): 21 (2.1 g, 80%). 1H-NMR (CDCl3, 200 MHz):
8.41 (m, 2H); 7.47 ( m, 3 H); 6.12( s, 1 H); 2.54 (s, 6 H).
2-(1-Methylhydrazino)-6-phenylpyridine (26b). To ice-cooled 25a (10 g, 0.217 mol), 2-bromo-6-phenyl-
pyridine (24b; 145 mg, 0.619 mmol) was slowly added. Then the mixture was refluxed under Ar during 1 h. The
excess of 25a was evaporated, the residue dissolved in CHCl3 (10 ml), K2CO3 (150 mg, 1.087 mmol) added, and
the suspension stirred for 10 min. The suspension was filtered and the filtrate evaporated: 26b (120 mg, 97%).
1
Yellowish oil, unstable in air, stored at low temp. under Ar. H-NMR (CDCl3, 200 MHz): 8.05 (d, 2H); 7.56
(t, 1 H); 7.51 7.40 (m, 3 H); 7.13 (d, 1 H); 6.9 (d, 1 H); 4.15 (s, 2H); 3.35 ( s, 3 H). 13C-NMR (CDCl3,
‡
100 MHz): 160.9; 154.7; 139.8; 137.9; 128.6; 128.5; 126.7; 109.4; 105.9; 41.0. FAB-MS: 200.1 (100, [M ‡ H] ).
‡
HR-FAB-MS: 200.1193 ([C12H13N3 ‡ H] ; calc. 200.1188).
2-(1-Hexylhydrazino)pyridine (26c). To ice-cooled 25b (7 g, 60.345 mmol), 24a (1.6 g, 10.256 mmol) was
slowly added, and the mixture was heated for 3 h at 1408 under Ar. Then the excess of 25b was evaporated under
high vacuum and the residue purified by FC (Al3O3, CHCl3/hexane 7:3: 26c (0.750 g, 38%). Yellowish oil,
unstable in air, stored at low temp. under Ar. 1H-NMR (CDCl3, 200 MHz): 8.29 (d, 1 H); 7.38 (t, 1 H); 6.84
(d, 1 H); 6.50 (t, 1 H); 3.89 (s, 2H); 3.56 ( t, 2H); 1.59 ( t, 2H); 1.41 1.25 ( m, 6 H); 0.84 (t, 3 H). 13C-NMR
‡
(CDCl3, 50 MHz): 147.3; 136.8; 112.2; 106.8; 52.1; 31.6; 27.0; 26.5; 22.5; 13.9. EI-MS: 193.1 (M ). FAB-MS:
‡
‡
194.1 (100, [M ‡ H] ). HR-FAB-MS: 194.1652([C 11H19N3 ‡ H] ; calc. 194.1657).

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Helvetica Chimica Acta Vol. 86 (2003)
2-[1-(Pyridin-2-yl)hydrazino]ethanol (26d). To ice-cooled 25c (1 g, 13.158 mmol), 24a (2g, 12.658 mmol)
was slowly added. Then the mixture was heated at 1208 under Ar for 10 h. Purification by FC (Al2O3, CHCl3,
then CHCl3/MeOH 93 :7 gave 26d (730 mg, 38%). Yellowish oil, unstable in air, stored at low temp. under Ar.
1H-NMR (CDCl3, 200 MHz): 8.03 (d, 1 H); 7.43 (t, 1 H); 6.96 (d, 1 H); 6.56 (t, 1 H); 4.15 (s, 3 H); 3.85 (t, 2 H);
‡
3.72( t, 2 H). 13C-NMR (CDCl3, 100 MHz): 158.7; 147.1; 146.8; 137.6; 113.3; 61.6; 55.6. EI-MS: 153.3 (33, M ),
‡
‡
122.3 (100), 78.4 (95). FAB-MS: 154.0 (100, [M ‡ H] ). HR-FAB-MS: 154.0979 ([C7H11N3O ‡ H] ; calc.
154.0980).
Crystal-Structure Analyses. The crystals were placed in oil, and a single crystal was selected, mounted on a
glass fiber and placed in a low-temp. N2 stream. The X-ray-diffraction data were collected on a Nonius-Kappa-
CCD diffractometer with graphite monochromatized MoKa radiation (l 0.71071 ä), f scans, by means of a −f
scan× type scan mode. The structures were solved by direct methods and refined (based on F2 with all
independent data) by full-matrix least-squares methods (OpenMoleN package).
Crystal Structure of 1c. A suitable crystal of 1c was obtained by diffusion-recrystallization from CHCl3
(solvent)/MeOH (nonsolvent). Diffraction data were collected at 173 K. C24H22N8, Mr 422.50. Yellow crystal,
crystal size 0.10  0.10  0.08 mm. Unit-cell parameters: a ˆ 7.8112(1) ä, b ˆ 24.7505(3) ä, c ˆ 21.8993(4) ä,
a ˆ 908, b ˆ 908(5), g ˆ 908; crystal system: orthorhombic; space group Pbca; Vˆ 4233.8(1) ä3; F(000) ˆ 1776;
Z ˆ 8; calc. density ˆ 1.33 g ¥ cmÀ3; linear absorption coefficient m ˆ 0.084 mmÀ1. Of 6360 reflections measured,
3364 reflections were unique (l > 3 s(l)); 289 variables refined. The q range for data collection was 2.58 29.118
with hkl limits 0 to 10, 0 to 29, and 0 to 33, resp. The final indices were R ˆ 0.066 and Rw ˆ 0.071, with a goodness-
of-fit of 1.177. The largest peak in final difference was 0.525 eäÀ3. Trans. min and max: 0.991 and 0.993, resp.
Crystal Structure of 2a. A suitable crystal of 2a was obtained by diffusion-recrystallization from CH2Cl2
(solvent)/MeCN (nonsolvent). Diffraction data were collected at 173 K. C31H32Cl2N16 ˆ C30H30N16 ¥ CH2Cl2, Mr
699.61. Yellow crystal, crystal size 0.12  0.10  0.08 mm. Unit-cell parameters: a ˆ 31.6897(5) ä, b ˆ
10.4646(2) ä, c ˆ 25.977(4) ä, a ˆ 908, b ˆ 126.9518(5), g ˆ 908; crystal system: monoclinic; space group C12/
c 1; Vˆ 6783.7 ä3 (5); F(000) ˆ 2912; Z ˆ 8; calc. density ˆ 1.37 g ¥ cmÀ3; linear absorption coefficient m ˆ
0.975 mÀ1. Of 17113 reflections measured, 3887 reflections were unique (l > 3s(l)); 442variables refined. The
q range for data collection was 2.58 30.068 with hkl limits À44 to 44, À13 to 14, and À36 to 35, resp. The final
indices were R ˆ 0.058 and Rw ˆ 0.068, with a goodness-of-fit of 1.031. The largest peak in final difference was
0.375 eäÀ3. Trans. min and max: 0.971 and 0.981, resp.
Crystal Structure of 2c. A suitable crystal of 2c was obtained by diffusion-recrystallization from CHCl3
(solvent)/MeOH (nonsolvent). Diffraction data were collected at 173 K. C48H42N16, Mr 842.98. Yellow crystal,
crystal size 0.14  0.12  0.08 mm. Unit-cell parameters: a ˆ 8.5901(1) ä, b ˆ 23.3589(2) ä, c ˆ 42.3853(4) ä,
a ˆ 908, b ˆ 908(5), g ˆ 908; crystal system: orthorhombic; space group Pbca; Vˆ 8504.8(1) ä3; F(000) ˆ 3536;
Z ˆ 8; calc. density ˆ 1.32g ¥ cm À3; linear absorption coefficient m ˆ 0.084 mmÀ1. Of 24014 reflections measured,
4553 reflections were unique (l > 3 s(l)); 577 refined variables. The q range for data collection was 2.58 30.028
with hkl limits À12to 12, À32to 32, and À59 to 59, resp. The final indices were R ˆ 0.042and Rw ˆ 0.062, with a
goodness-of-fit of 1.133. The largest peak in final difference was 0.386 eäÀ3. Trans. min and max: 0.988 and
0.993, resp.
Crystal Structure of 3a. A suitable crystal of 3a was obtained by diffusion-recrystallization from CHCl3
(solvent)/MeOH (nonsolvent). Diffraction data were collected at 173 K. C43H44Cl2N24 ˆ C42H42N24 ¥ CH2Cl2, Mr
967.90. Yellow crystal, crystal size 0.12  0.10  0.08 mm. Unit-cell parameters: a ˆ 20.5729(6) ä, b ˆ
16.6524(6) ä, c ˆ 14.7563(5) ä, a ˆ 908, b ˆ 106.0628(5), g ˆ 908; crystal system: monoclinic; space group
C12/c 1; Vˆ 4858.0 ä3 (3); F(000) ˆ 2016; Z ˆ 4; calc. density ˆ 1.32g ¥ cm À3; linear absorption coefficient m ˆ
0.193 mmÀ1. Of 10990 reflections measured, 2381 reflections were unique (l > 3 s(l)); 326 variables refined. The
q range for data collection was 2.58 29.208 with hkl limits À28 to 28, À22 to 19, and À20 to 20, resp. The final
indices were R ˆ 0.099 and Rw ˆ 0.128, with a goodness-of-fit of 1.109. The largest peak in final difference was
0.532eä À3. Trans. min and max: 0.977 and 0.985, resp.
Crystal Structure of 3c. A suitable crystal of 3c was obtained by diffusion-recrystallization from CHCl3
(solvent)/MeOH (nonsolvent). Diffraction data were collected at 173 K. C146H129Cl3N48O ˆ 2(C72H62N24) ¥
CHCl3 ¥ MeOH, Mr 2678.34. Colorless crystal, crystal size 0.14  0.10  0.08 mm. Unit-cell parameters: a ˆ
11.8926(2) ä, b ˆ 16.3930(2) ä, c ˆ 19.9753(3) ä, a ˆ 105.840(5)8, b ˆ 102.7768(5), g ˆ 98.848(5)8; crystal
system: triclinic; space group P À 1; Vˆ 3557.20(18) ä3; F(000) ˆ 1400; Z ˆ 2; calc. density ˆ 1.25 g ¥ cmÀ3; linear
absorption coefficient m ˆ 0.134 mmÀ1. Of 28392 reflections measured, 8329 reflections were unique (l > 3 s(l));
910 refined variables. The q range for data collection was 2.58 30.068 with hkl limits À16 to 14, À19 to 23, and
À28 to 27, resp. The final indices were R ˆ 0.106 and Rw ˆ 0.147, with a goodness-of-fit of 1.200. The largest peak
in final difference was 0.973 eäÀ3. Trans. min and max: 0.981 and 0.989, resp.

Helvetica Chimica Acta Vol. 86 (2003)
1623
Crystal Structure of 5. A suitable crystal of 5 was obtained by diffusion-recrystallization from CHCl3
(solvent)/MeOH (nonsolvent). Diffraction data were collected at 173 K. C70H71Cl6N41 ˆ C66H66N40 ¥ 2CHCl
¥
3
MeCN, Mr 1699.33. Colorless crystal, crystal size 0.10  0.08  0.08 mm. Unit-cell parameters: a ˆ 12.8281(3) ä,
b ˆ 17.2593(6) ä, c ˆ 18.4109(5) ä, a ˆ 87.7018(5), b ˆ 79.5468(5), g ˆ 78.6978(5); crystal system: triclinic;
space group P À 1; Vˆ 3930.8 ä3 (2); F(000) ˆ 1754; Z ˆ 2; calc. density ˆ 1.43 g ¥ cmÀ3; linear absorption
coefficient m ˆ 0.291 mmÀ1. Of 19688 reflections measured, 6898 reflections were unique (l > 3 s(l)); 1054
variables refined. The q range for data collection was 2.58 28.788 with hkl limits 0 to 17, À22 to 23, and À2 4 to
24, resp. The final indices were R ˆ 0.136 and Rw ˆ 0.157, with a goodness-of-fit of 1.473. The largest peak in final
difference was 0.912eä À3. Trans. min and max: 0.6607 and 1.1084, resp.
Crystal Structure of 6. A suitable crystal of 6 was obtained by diffusion-recrystallization from CH2Cl2/
CHCl3 1:1 (solvent mixture) and MeCN (nonsolvent). Diffraction data were collected at 173 K. C24H24N12, Mr
480.54. Yellow crystal, crystal size 0.16  0.10  0.08 mm. Unit-cell parameters: a ˆ 10.7540(3) ä, b ˆ
11.5938(4) ä, c ˆ 11.7085(3) ä, a ˆ 112.2598(5), b ˆ 110.6178(5), g ˆ 110.6698(5); crystal system: triclinic;
space group P À 1; Vˆ 1165.59 ä3 (12); F(000) ˆ 504; Z ˆ 2; calc. density ˆ 1.37 g ¥ cmÀ3; linear absorption
coefficient m ˆ 0.090 mmÀ1. Of 9564 reflections measured, 3721 reflections were unique (l > 3 s(l)); 325
variables refined. The q range for data collection was 2.58 29.998 with hkl limits À14 to 15, À16 to 15, and À15
to 16, resp. The final indices were R ˆ 0.053 and Rw ˆ 0.082, with a goodness-of-fit of 1.413. The largest peak in
final difference was 0.436 eäÀ3
.
Crystal Structure of 7. A suitable crystal of 7 was obtained by diffusion-recrystallization from CHCl3
(solvent)/MeCN (nonsolvent). Diffraction data were collected at 173 K. C32H32Cl6N16 ˆ C30H30N16 ¥ 2CHCl 3, Mr
853.44. Colorless crystal, crystal size 0.10  0.08  0.06 mm. Unit-cell parameters: a ˆ 11.4802(2) ä, b ˆ
13.4750(2) ä, c ˆ 13.7730(3) ä, a ˆ 110.8058(5), b ˆ 96.4508(5), g ˆ 101.8308(5); crystal system: triclinic; space
group P À 1; Vˆ 1909.06 ä3 (11); F(000) ˆ 876; Z ˆ 2; calc. density ˆ 1.48 g ¥ cmÀ3; linear absorption coefficient
m ˆ 0.500 mmÀ1. Of 15488 reflections measured, 4278 reflections were unique (l > 3 s(l)); 487 variables refined.
The q range for data collection was 2.58 30.078 with hkl limits À16 to 16, À18 to 18, and À12to 19, resp. The
final indices were R ˆ 0.104 and Rw ˆ 0.113, with a goodness-of-fit of 1.020. The largest peak in final difference
was 0.977 eäÀ3. Trans. min and max: 0.950 and 0.970, resp.
Crystallographic data for the structures reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as depositions Nos. CCDC-205254 (1c), CCDC-205249 (2a), CCDC-205255 (2c),
CCDC-205251 (3a), CCDC-205253 (3c), CCDC-205252 (5), CCDC-205248 (6), and CCDC-205250 (7). Copies
of the data can be obtained, free of charge, on application to the CCDC, 12Union Road, Cambridge CB IEZ
UK (fax: ‡44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
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Received March 7, 2003