2,5-diformylbenzene-1,4-diol: A versatile building block for the synthesis of ditopic redox-active schiff base ligands

Article abstract of DOI:10.1515/znb-2007-0110

2,5-Diformylbenzene-1,4-diol (5) is a well-suited starting compound for the preparation of ditopic hydroquinone-based ligands. Here, we report an optimized synthesis of 5 which improves the overall yield from published 7 % to 42 %. Three new ditopic Schiff base ligands, 2,5-[ⁱPr₂N(CH ₂)₂N=CH]₂-1,4-(OH)₂-C ₆H₂ (8), 2,5-(pyCH₂N=CH)₂-1,4-(OH) ₂-C₆H₂ (9), and 2,5-[py(CH₂) ₂N=CH]₂-1,4-(OH)₂-C₆H₂ (10), have been synthesized from 5 and structurally characterized by X-ray crystal structure analysis (py = 2-pyridyl).

Full text of DOI:10.1515/znb-2007-0110

2
,5-Diformylbenzene-1,4-diol: A Versatile Building Block for the Synthesis
of Ditopic Redox-Active Schiff Base Ligands
Tonia Kretz, Jan Willem Bats, Hans-Wolfram Lerner, and Matthias Wagner
Institut f u¨ r Anorganische Chemie, Johann Wolfgang Goethe-Universit a¨ t Frankfurt am Main,
Max-von-Laue-Straße 7, 60438 Frankfurt am Main, Germany
Reprint requests to Prof. Dr. Matthias Wagner. Fax: +49 69 798 29260.
E-mail: Matthias.Wagner@chemie.uni-frankfurt.de
Z. Naturforsch. 2007, 62b, 66 – 74; received July 24, 2006
2
,5-Diformylbenzene-1,4-diol (5) is a well-suited starting compound for the preparation of ditopic
hydroquinone-based ligands. Here, we report an optimized synthesis of 5 which improves the overall
i
yield from published 7 % to 42 %. Three new ditopic Schiff base ligands, 2,5-[ Pr N(CH ) N=CH] -
2
2 2
2
1
,4-(OH) -C H (8), 2,5-(pyCH N=CH) -1,4-(OH) -C H (9), and 2,5-[py(CH ) N=CH] -1,4-
2 2 2 2 2 2 2 2 2
6
6
(OH) -C H (10), have been synthesized from 5 and structurally characterized by X-ray crystal
2 2
6
structure analysis (py = 2-pyridyl).
Key words: Aldehydes, N,O Ligands, π-Interactions, Quinones, Tridentate Ligands
Introduction
metal coordination. In the literature, only very
few chelating ditopic ligands derived from hydro-
The electrochemical properties of a metal complex quinone have been reported [8 – 11]. One example
are to a large extent determined by the ligand sphere. is the compound 2,5-bis(pyrazol-1-yl)-1,4-dihydroxy-
Careful ligand design is therefore crucial for the con- benzene [8] which we have used for the synthesis and
II
struction of efficient redox systems which in turn play structural characterization of the Cu -containing co-
an essential role both in homogeneous catalysis and in ordination polymer A (Fig. 1) [11, 12]. For an under-
materials science [1 – 4].
standing of its electronic properties it was also nec-
Our group is interested in the electrochemical prop- essary to synthesize dinuclear complexes B as sol-
erties of oligonuclear transition metal complexes with uble model systems (Fig. 1). However, attempts to
electronically interacting metal sites. We thus require prepare B-type molecules by treating 2,5-bis(pyrazol-
II
ligands capable of linking two or more transition metal 1-yl)-1,4-dihydroxy-benzene with appropriate Cu -
centers and of supporting an electronic communica- containing precursors in the presence of Brønsted
tion between them [5 – 7]. The concept is to modu- bases were hampered by the pronounced tendency
late the degree of metal-metal interactions by electro- of the system to form polymers A. The only dinu-
chemical manipulation of the bridging unit which thus clear complex B that could be isolated so far required
needs to be able to undergo reversible electron trans- PMDTA as an ancillary ligand and proved to be unsta-
fer itself. Currently, one focus lies on hydroquinone ble in solution [11].
derivatives as bridging ligands since they exist in three
Due to this fact we had to develop an alternative
different oxidation states (hydroquinone, semiquinone, hydroquinone linker and have chosen chelating Schiff
quinone) and their redox-activity is preserved after base ligands C as our target molecules (Fig. 1). In
Fig. 1. The CuII coordina-
tion polymer A based on the
2
,5-bis(pyrazol-1-yl)-1,4-di-
hydroxy-benzene ligand, the
corresponding dinuclear com-
plexes B, and the new ditopic
hydroquinone
Schiff
base
ligands C.
0932–0776 / 07 / 0100–0066 $ 06.00 © 2007 Verlag der Zeitschrift f u¨ r Naturforschung, T u¨ bingen · http://znaturforsch.com
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T. Kretz et al. · A Versatile Building Block for the Synthesis of Ditopic Redox-Active Schiff Base Ligands
67
Scheme 1. Synthesis of 5:
(
(
2
i) CH Oaq, HCl (yield: 86 %);
ii) 1. hexamethylenetetramine,
2
. H O, HCl (yield: 70 %);
2
(
6
iii) HBraq, CH COOH (yield:
9 %); (iv) CH Oaq.
2
3
order to give the resulting dinuclear complexes more alcohol. In the methoxy region of the spectrum, two
stability, we incorporated additional donor sites into signals at 3.87 and 3.80 ppm (integral ratio 1 : 1) indi-
the imine side-chains R. For the synthesis of C, the cated the presence of an unsymmetrically substituted
2
,5-diformylbenzene-1,4-diol(5) is required as the key 1,4-dimethoxy-benzene derivative. After isolation by
starting material. Compound 5 (Scheme 1) is already flash chromatography and structural characterization
known but was obtained in an overall yield of only by X-ray crystallography, the byproduct was identified
7
% to 20% [13 – 15]. Moreover, none of the reaction as compound 4. The formation of 4 can be explained
byproducts were identified. The purpose of this paper after a closer look at the mechanism of the Som-
is to report an improved synthesis of 5 together with melet reaction: addition of hexamethylenetetramine
a full characterization of the main reaction intermedi- to an organochloride RCH Cl leads to the formation
2
ates as well as some byproducts. Finally, the syntheses of a quaternary ammonium salt [RCH N(CH ) N ]Cl
2
2 6
3
and molecular structures of selected C-type ligands are which upon hydrolysis liberates formaldehydeand am-
described.
monia. The resulting primary amine RCH NH is then
2 2
oxidized to the imine which reacts further to the de-
sired aldehyde RC(O)H. There are three possibilities
Results and Discussion
for an alcohol RCH OH to be formed during this reac-
2
Syntheses
tion sequence: 1) hydrolysis of residual RCH Cl that
2
The synthesis of 5 starts with the chloromethylation has not been transformed into the ammonium salt,
of commercially available 1,4-dimethoxy-benzene (1) 2) nucleophilic substitution of C H N by water in
6
12
4
to give the p-bis(chloromethyl)-benzene2 (Scheme 1). the ammonium salt, and 3) a crossed Cannizzaro re-
Compared to the published protocol [13] the yield of 2 action [16, 17] between RC(O)H and formaldehyde.
was improved from 77% to 86 % by running the reac- Alcohol 4 may even react further with formaldehyde
◦
1
tion at 0 C as opposed to r. t., and by shortening the to give acetal 7 as indicated by the H NMR spec-
reaction time from 3 h to 1 h.
trum and the mass spectrum of the crude reaction mix-
In the subsequent step, 2 was subjected to a Som- ture. The formation of 7 was verified in an indepen-
melet reaction to afford the dialdehyde 3 [14]. To find dent experiment where we added an analytically pure
a way to improve the low reported yield [14] of 3 sample of 4 to aqueous formaldehyde. The reaction
(
32%), the nature of the byproducts was determined is reversible since compound 4 was fully recovered
by NMR spectroscopy. In addition to the resonances after treatment of 7 with hydrochloric acid. Follow-
of the desired dialdehyde, the proton spectrum of the ing the procedure described in the Experimental Sec-
crude reaction mixture showed a signal at δ = 4.69 tion of this paper, we have reproducibly obtained 3 in
assignable to the RCH OH fragment of an aliphatic a yield of 70 % rather than 32 % [14]. Phenolether 3
2
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8
T. Kretz et al. · A Versatile Building Block for the Synthesis of Ditopic Redox-Active Schiff Base Ligands
Scheme 2. Synthesis of the Schiff base
ligands 8 – 10.
was deprotected to give hydroquinone 5 using hydro- ands 8 – 10, resonance patterns in accord with the pos-
bromic and acetic acid. After the recommended [15] tulated molecular symmetry are observed. Moreover,
reaction time of 5 h, a mixture of the desired com- an integral ratio of 2 : 1 for the proton resonances of
pound 5 and the monomethylated dialdehyde 6 was the imine substituents as compared to the signals of
obtained. Flash chromatography gave 5 in the reported the central hydroquinone core indicates the quantita-
yield of 30 % [15]. The yield of 5 could be improved tive transformation of aldehyde groups into imino side
1
13
to 69 % by extending the reaction time and continuous chains. All H and C NMR signals of 8 – 10 appear
monitoring of the reaction progress by thin-layer chro- in the expected regions of the spectra and thus do not
matography (TLC).
merit further discussion.
The Schiff bases 8, 9, and 10 were prepared by treat-
ing 1 equiv. of 5 with 2 equiv. of 2-(diisopropylamino) X-Ray crystal structure analyses
ethylamine (8), 2-(aminomethyl)pyridine (9), or 2-
Details of the X-ray crystal structure analyses of 2 –
, 6, and 8 – 10 are summarized in Table 1. The molec-
ular structures are shown in Figs 2 – 8; selected bond
lengths and angles are listed in the corresponding fig-
ure captions.
In the crystal lattice, the planar molecules 2, 3, 4,
and 6 are arranged in stacks via intermolecular π ···π-
interactions. Adjacent stacks are linked via hydrogen
(2-aminoethyl)pyridine (10; Scheme 2) [18]. These
4
amines were chosen such that ligands of differing steric
demand (i. e. 8 and 9) and different length of the chelat-
ing tether (i. e. 9 and 10) are now available for com-
plexation studies.
NMR spectroscopic investigations
1
The H NMR spectrum of 2 is characterized by bonds. All bond lengths and angles possess typical val-
a signal at 4.64 ppm assignable to the chloromethyl ues for this type of compounds.
1
3
groups (δ( C) = 41.3). The successful synthesis of 3
The chloromethylated hydroquinone derivative 2
by the Sommelet reaction is proven by the presence of (Fig. 2) is centrosymmetric, with half a molecule
aldehyde resonances at δ( H) = 10.50 and δ( C) = in the asymmetric unit, and crystallizes in the tri-
89.2. In the NMR spectra of 5, methoxy signals are clinic space group P1. There are no short intramolec-
1
13
¯
1
absent and a broad proton resonance at 10.74 ppm ular interactions. The shortest intermolecular C···C
(
s, 2 H) appears instead, testifying to the presence of π-contact between molecules of the same stack
˚
two free hydroxyl groups. For all three Schiff base lig- amounts to 3.419(1) A. Neighboring stacks are con-
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T. Kretz et al. · A Versatile Building Block for the Synthesis of Ditopic Redox-Active Schiff Base Ligands
69
Fig. 2. Molecular structure of 2 in the solid state; ther-
mal ellipsoids are drawn at the 50 % probability level.
˚
Selected bond lengths (A), bond angles (deg), and tor-
sion angles (deg): C(3)–C(5) 1.493(1), C(5)–Cl 1.821(1),
C(2)–O 1.368(1), C(4)–O 1.430(1); C(3)–C(5)–Cl 110.9(1),
C(2)–O–C(4) 117.2(1); C(1)–C(2)–O–C(4) −0.7(1),
C(2)–C(3)–C(5)–Cl −77.9(1). Symmetry transformations
#
1
used to generate equivalent atoms: −x, −y+1, −z+1.
Fig. 3. Molecular structure of 3 in the solid state; thermal
ellipsoids are drawn at the 50 % probability level. Selected
˚
bond lengths (A), bond angles (deg), and torsion angles (deg)
of molecule 1: C(2)–C(5) 1.480(2), C(1)–O(1) 1.366(1),
C(4)–O(1) 1.438(1), C(5)–O(2) 1.208(2); C(1)–O(1)–C(4)
1
17.2(1), C(2)–C(5)–O(2) 123.6(1); C(1)–C(2)–C(5)–O(2)
−
174.4(1), C(2)–C(1)–O(1)–C(4) −177.8(1). Symmetry
#1
transformations used to generate equivalent atoms:
−x,
#
2
−
y, −z; −x+1, −y+2, −z.
σ
nected by C–H···Cl and C–H···O hydrogen bonds
˚
with H···Cl distances of 2.90(2) and 3.02(2) A, re-
˚
spectively, and an H···O distance of 2.60(2) A.
β
γ
µ
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0
T. Kretz et al. · A Versatile Building Block for the Synthesis of Ditopic Redox-Active Schiff Base Ligands
The byproduct 4 crystallizes from CH Cl (mono-
2
2
clinic space group C2/c, Fig. 4). There are one
molecule of 4 and half a solvent molecule in the
asymmetric unit. The X-ray crystal structure analysis
fully confirms our interpretation of the NMR spectra
in that 4 contains an aldehyde group together with
a hydroxymethyl substituent. The stacks of 4 have
short C···C distances in the range between 3.426(1)
˚
to 3.546(1) A. Adjacent stacks are connected by in-
termolecular hydrogen bonds between hydroxymethyl
˚
◦
groups (H···O = 1.90(2) A, angle O-H-O = 175(2) ).
The molecular structure of the partly depro-
tected byproduct 6 (monoclinic, P2 /n) is plotted in
1
Fig. 5. All side groups are nearly coplanar with the
central six-membered ring (C(2)–C(3)–C(7)–O(2) =
◦
◦
0
.8(2) , C(4)-C(5)-O(3)-C(8) = 1.7(1) , C(1)–C(6)–
◦
C(9)–O(4) = – 3.1(1) ). Each hydroxyl group estab-
lishes a bifurcated hydrogen bond to two aldehyde
˚
oxygen atoms (intramolecular: H···O = 1.92(2) A; in-
˚
termolecular: H···O = 2.29(2) A).
Fig. 4. Molecular structure of 4 in the solid state; ther-
In the three Schiff bases 8, 9, and 10 (Figures 6 –
mal ellipsoids are drawn at the 50 % probability level.
Selected bond lengths (A), bond angles (deg), and torsion
˚
8), the C(4)–N(1) bond lengths vary in the small range
angles (deg): C(3)–C(8) 1.473(2), C(6)–C(10) 1.510(1), between 1.273(2) (8) and 1.278(3) A˚ (10) which is
C(2)–O(1) 1.368(1), C(5)–O(3) 1.373(1), C(8)–O(2)
characteristic of imine double bonds. These C=N frag-
ments as well as the hydroxyl groups are largely copla-
nar with the respective central six-membered ring and
1
.218(1), C(10)–O(4) 1.425(1); C(2)–O(1)–C(7) 117.1(1),
C(3)–C(8)–O(2) 123.7(1), C(5)–O(3)–C(9) 116.2(1),
C(6)–C(10)–O(4) 113.1(1); C(1)–C(2)–O(1)–C(7) −14.2(2),
C(2)–C(3)–C(8)–O(2) 178.3(1), C(4)–C(5)–O(3)–C(9) linked by intramolecular hydrogen bonds (OH···N
1
3.3(2), C(1)–C(6)–C(10)–O(4) −5.0(1). Symmetry trans-
˚
distances vary from 1.77(3) to 1.90(2) A).
#1
formations used to generate equivalent atoms:
−
−x, y,
Fig. 6 shows the molecular structure of 8 (mono-
z+1/2.
clinic space group P2 /c). Because of the bulky 2-
1
Fig. 3 illustrates the structure of dialdehyde 3 in (diisopropylamino)ethyl substituents at the imino ni-
¯
the solid state (triclinic space group P1). Each of trogen atoms, 8 is the only compound which is not ar-
the two independent molecules is centrosymmetric, ranged in stacks in the solid state. The conformation
two half molecules thus being present in the asym- of the diisoproylamino groups can be regarded as in-
metric unit. Since their structural parameters do not termediate between planar and pyramidal (sum of the
◦
differ significantly from each other, only the val- three valence angles about N(2) = 345.7 ).
ues of molecule 1 are given here. The methoxy as
Compound 9 also crystallizes in the monoclinic
well as the aldehyde groups are almost coplanar with space group P21/c (Fig. 7). Each pyridyl ring in-
◦
the phenyl rings (deviation of C(4)/O(2) from the cludes a dihedral angle of 46.7 with the aromatic
˚
plane of the phenylene ring: 0.033/0.088 A). There is bridge. The crystal lattice consists of columns of
a short intramolecular interaction between the alde- molecules along the crystallographic b axis. Molecules
hyde hydrogen atom and its neighboring methoxy within each stack show intermolecular C···C dis-
˚
˚
oxygen atom of H(5)···O(1) = 2.40(2) A with a tances of 3.387(2) A between phenyl groups and
◦
˚
bond angle C(5)–H(5)···O(1) of 101(1) . The short- of 3.560(3) A between pyridyl groups.
est C···C contact between molecules of the same
In the solid state, 10 (monoclinic, P21/n; Fig. 8)
˚
stack is 3.293(2) A. Stacks are linked via intermolec- also features stacks of molecules along the crystallo-
ular C–H···O contacts between aldehyde oxygen graphic b axis. In contrast to 9, the pyridyl rings in 10
atoms and methoxy methyl groups (H···O = 2.53(2) are almost coplanar with the aromatic linker (dihedral
◦
˚
to 2.63(2) A).
angle = 6.7 ).
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T. Kretz et al. · A Versatile Building Block for the Synthesis of Ditopic Redox-Active Schiff Base Ligands
71
Fig. 5. Molecular structure of 6 in the solid state; thermal ellipsoids are drawn at the 50 % probability level. Selected
˚
bond lengths (A), bond angles (deg), and torsion angles (deg): C(3)–C(7) 1.464(1), C(6)–C(9) 1.478(1), C(2)–O(1)
.356(1), C(5)–O(3) 1.364(1), C(7)–O(2) 1.216(1), C(9)–O(4) 1.212(1); C(3)–C(7)–O(2) 124.3(1), C(5)–O(3)–C(8) 116.9(1),
C(6)–C(9)–O(4) 123.6(1); C(2)–C(3)–C(7)–O(2) 0.8(2), C(4)–C(5)–O(3)–C(8) 1.7(1), C(1)–C(6)–C(9)–O(4) −3.1(1).
1
Fig. 6. Molecular structure of 8 in the solid state; thermal ellipsoids are drawn at the 50 % probability level. Selected
˚
bond lengths (A), bond angles (deg), and torsion angles (deg): C(1)–O 1.361(2), C(2)–C(4) 1.456(3), C(4)–N(1) 1.273(2),
C(5)–N(1) 1.457(3), C(6)–N(2) 1.459(2); C(2)–C(4)–N(1) 122.3(2), C(4)–N(1)–C(5) 117.6(2), C(6)–N(2)–C(7) 115.0(2),
C(6)–N(2)–C(10) 113.8(2), C(7)–N(2)–C(10) 116.9(2); C(3)–C(2)–C(4)–N(1) 179.8(2), C(4)–N(1)–C(5)–C(6) −96.9(2),
#
1
N(1)–C(5)–C(6)–N(2) 62.7(2). Symmetry transformations used to generate equivalent atoms: −x, −y+1, −z.
Fig. 7. Molecular structure of 9 in the solid state; thermal ellipsoids are drawn at the 50 % probability level. Se-
˚
lected bond lengths (A), bond angles (deg), and torsion angles (deg): C(1)–O 1.364(2), C(3)–C(4) 1.465(2), C(4)–N(1)
.275(2), C(5)–N(1) 1.459(2); C(3)–C(4)–N(1) 122.0(2), C(4)–N(1)–C(5) 117.6(1); C(2)–C(3)–C(4)–N(1) −176.9(2),
C(3)–C(4)–N(1)–C(5) −179.1(1), C(4)–N(1)–C(5)–C(6) 129.1(2). Symmetry transformations used to generate equivalent
1
#
1
atoms: −x, −y+1, −z+2.
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2
T. Kretz et al. · A Versatile Building Block for the Synthesis of Ditopic Redox-Active Schiff Base Ligands
Fig. 8. Molecular structure of 10 in the solid state; C(1)–O 1.365(3), C(2)–C(4) 1.460(4), C(4)–N(1) 1.278(3), C(5)–N(1)
.466(3); C(2)–C(4)–N(1) 122.3(3), C(4)–N(1)–C(5) 117.7(2); C(1)–C(2)–C(4)–N(1) 1.0(4), C(2)–C(4)–N(1)–C(5) 177.3(2),
1
C(4)–N(1)–C(5)–C(6) −103.9(3), N(1)–C(5)–C(6)–C(7) −177.9(2). Symmetry transformations used to generate equivalent
#
1
atoms: −x+2, −y+3, −z.
◦
Conclusion
were added at intervals of 30 min with stirring at 0 C.
During the entire period, hydrogen chloride gas was passed
through the reaction mixture. After stirring for 1 h at r. t.,
more aqueous hydrochloric acid (37 %, 195 mL) was added
and the resulting solution cooled to 10 C. The colorless
precipitate formed was collected on a frit and dried un-
The synthesis of 2,5-diformylbenzene-1,4-diol (5)
has been improved from an overall yield of 7.4
to 41.5%. As unwanted side reactions, we identi-
fied the reduction of aldehyde substituents to hy-
◦
droxymethyl groups (cf. compound 4) and a non- der vacuum. Recrystallization of 2 from acetone afforded
1
quantitative deprotection of the hydroquinone core in
X-ray quality crystals. Yield: 101.33 g (86 %). – H NMR
the last step of the synthesis sequence. Both side reac- (250.13 MHz, CDCl3): δ = 6.93 (s, 2 H, CH), 4.64 (s,
1
3
tions could be suppressed to a considerable extent.
With this efficient synthesis of 5, a variety of di-
topic Schiff base ligands featuring a redox-active hy-
droquinone core are now readily available which are
promising bridging ligands for the preparation of di-
nuclear transition metal complexes.
4 H, CH2), 3.86 (s, 6 H, CH3). – C NMR (62.9 MHz,
CDCl ): δ = 151.1 (COCH ), 126.9 (CCH Cl), 113.4 (CH),
3
3
2
5
6.3 (CH ), 41.3 (CH ). – ESI-MS: m/z (%) = 199 (100)
M-Cl] . – C H Cl O (235.1): calcd. C 51.09, H 5.14;
3 2
+
[
10 12 2 2
found C 50.81, H 5.14.
Synthesis of 3
2
(10.00 g, 0.04 mol) and hexamethylenetetramine
Experimental Section
(
(
11.2 g, 0.08 mol) were dissolved in anhydrous chloroform
150 mL) and the mixture heated to reflux for 3 h. Subse-
General remarks
1H and 13C NMR spectra: Bruker AM 250, Bruker quent cooling to 5 C led to the formation of a yellow mi-
DPX 250 spectrometers. Chemical shift values (δ) are re- crocrystalline solid which was isolated by filtration and re-
ported relative to tetramethylsilane; abbreviations: s (sin- dissolved in water (130 mL). The solution was heated to re-
glet), d (doublet), t (triplet), vt (virtual triplet), sept (septet), flux for 2 h. After cooling to r. t., aqueous hydrochloric acid
m (multiplet), py (2-pyridyl). ESI mass spectra: Fisons (now (37 %, 5 mL) was added, whereupon a yellow solid precip-
Micromass) VG Platform II. MALDI-TOF spectra: Fisons itated from the solution. This crude product was collected
◦
(now Micromass) VG Tofspec. Elemental analyses were per- on a frit. The aqueous filtrate was extracted with chloroform
formed by the microanalytical laboratory of the University (5 × 30 mL), the extracts were dried over magnesium sul-
of Frankfurt. Flash column chromatography: Merck silica fate, filtered, and evaporated to dryness under reduced pres-
gel 60 (40 – 60 µm, 230 – 400 mesh). Thin-layer chromato- sure to yield a second crop of product. Subsequent flash
graphy (TLC): Merck silica plates (Kieselgel 60 F254 on alu- chromatography (dichloromethane/ethyl acetate, 2 : 1) pro-
minium with fluorescence indicator); spots on TLC plates vided 3 and 4 as yellow solids. Recrystallization of 3 from
were visualized by UV-detection at 254 nm. Solvents and dichloromethane/hexane (1 : 1) afforded X-ray quality crys-
reagents were purchased from Aldrich Chemicals, Merck and tals. Yield of 3: 5.40 g (70 %).
˚
Fluka. CHCl was dried over molecular sieves (4 A).
Analytical data of 3: R (dichloromethane/ethyl acetate,
3
f
1
2
: 1) = 0.87. – H NMR (250.13 MHz, CDCl ): δ = 10.50
3
Synthesis of 2
(
s, 2 H, CHO), 7.45 (s, 2 H, CH), 3.94 (s, 6 H, CH ). –
3
1
3
To a solution of 1,4-dimethoxybenzene (69.35 g,
.50 mol) in dioxane (400 mL) and aqueous hydrochlo- (COCH ), 129.1 (CCHO), 110.9 (CH), 56.2 (CH ). – ESI-
3 3
ric acid (37 %, 65 mL), three equal portions of aqueous MS: m/z (%) = 194 (100) [M] . – C H O (194.2): calcd.
C NMR (62.9 MHz, CDCl ): δ = 189.2 (CHO), 155.7
3
0
+
1
0
10
4
formaldehyde (37 %; overall amount: 100.5 mL, 1.35 mol) C 61.85, H 5.19; found C 61.61, H 5.24.
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+
Analytical data of 4: R (dichloromethane/ethyl acetate, 20.7 (CH ). – ESI-MS: m/z (%) = 419 (100) [M+H] . –
f
3
1
2
(
2
: 1) = 0.45. – H NMR (250.13 MHz, CDCl ): δ = 10.38 C24H42N4O2 (418.6): calcd. C 68.86, H 10.11, N 13.38;
3
s, 1 H, CHO), 7.24, 7.04 (2× s, 2 × 1 H, CH), 4.69 (s, found C 68.37, H 10.22, N 13.07.
H, CH ), 3.87, 3.80 (2× s, 2 × 3 H, CH ) 2.53 (s, 1H,
Analytical data of 9: Yield: 291 mg (84 %), orange solid.
2
13
3
OH). – C NMR (62.9 MHz, CDCl ): δ = 189.3 (CHO), – 1H NMR (250.13 MHz, CD2Cl2): δ = 12.48 (s, 2 H,
3
3
1
1
56.9, 150.8 (COCH ), 138.1 (CCH OH), 123.6 (CCHO), OH), 8.56 (d, JHH = 4.4 Hz, 2 H, py-H6), 8.51 (s, 2 H,
3
2
3
11.8, 107.9 (CH), 61.2 (CH ), 56.2, 55.7 (CH ). – ESI-MS: HC=N), 7.71 (vt, JHH = 7.7 Hz, 2 H, py-H4), 7.35 (d,
2
3
+
3
3
m/z (%) = 196 (100) [M] . – C H O ·0.33 H O (202.1):
JHH = 7.9 Hz, 2 H, py-H3), 7.22 (vt, JHH = 5.2 Hz, 2 H,
py-H5), 6.93 (s, 2 H, CH), 4.94 (s, 4 H, CH2). – C NMR
10
12
4
2
1
3
calcd. C 59.40, H 6.31; found C 59.13, H 6.34.
(
62.9 MHz, CD Cl ): δ = 166.4 (C=N), 157.9 (py-C2),
2
2
Synthesis of 5
152.8 (COH), 149.6 (py-C6), 136.8 (py-C4), 122.4, 122.1,
21.7 (CCHN, py-C3,5), 118.5 (CH), 65.4 (CH ). – MALDI-
1
2
A mixture of 3 (3.71 g, 0.02 mol), acetic acid (99.5 %,
TOF-MS [positive ions, matrix: 6-aza-2-thiothymine (ATT)]:
1
90 mL) and aqueous hydrobromic acid (48 %, 160 mL)
+
m/z = 346 [M] . – C H N O (346.4): calcd. C 69.35,
2
0
18
4 2
was heated to reflux for 14 h. After cooling to r. t., the so-
lution was poured into a mixture of chloroform and wa-
ter (150 mL, 1 : 1), the aqueous layer was extracted with
chloroform (3 × 75 mL) and the combined organic phases
were dried over magnesium sulfate. After filtration, the fil-
trate was evaporated to dryness under reduced pressure to
give 5 as a yellow solid. Yield: 2.31 g (69 %). – R (ethyl ac-
etate/hexane, 1 : 1) = 0.47. – H NMR (250.13 MHz, DMF):
δ = 10.74 (s, 2 H, OH), 10.42 (s, 2 H, CHO), 7.36 (s,
H 5.24, N 16.17; found C 69.19, H 5.26, N 16.07.
Analytical data of 10: Yield: 333 mg (89 %), orange solid.
– 1
H NMR (250.13 MHz, CD Cl ): δ = 12.45 (s, 2 H,
2 2
3
OH), 8.52 (d, JHH = 5.0 Hz, 2 H, py-H6), 8.25 (s, 2 H,
HC=N), 7.60 (vt, JHH = 7.8 Hz, 2 H, py-H4), 7.15 (m, 4 H,
3
3
py-H3,5), 6.75 (s, 2 H, CH), 4.02, 3.15 (2× t, JHH = 7.1 Hz,
f
13
2
×4 H, CH ). – C NMR (62.9 MHz, CD Cl ): δ = 165.2
2
2
2
1
(C=N), 159.6 (py-C2), 152.9 (COH), 149.8 (py-C6), 136.5
(py-C4), 123.8 (py-C3 or 5), 121.7, 121.6 (CCHN, py-C3
1
3
2
H, CH). – C NMR (62.9 MHz, DMF): δ = 191.8
or 5), 118.3 (CH), 59.6 (CH ), 39.5 (CH py). – MALDI-
2
2
(CHO), 153.8 (COH), 128.2 (CCHO), 116.6 (CH). – ESI-
TOF-MS [positive ions, matrix: 2,5-dihydroxybenzoic acid
−
MS: m/z (%) = 165 (100) [M-H] . – C H O · 0.25 H O
+
8
6
4
2
(DHB)]: m/z = 374 [M] . – C H N O ·0.5 H O (383.4):
2
2
22
4
2
2
(170.6): calcd. C 56.31, H 3.84; found C 56.66, H 3.77.
calcd. C 68.91, H 6.05, N 14.61; found C 68.57, H 5.92,
N 14.60.
Our optimised synthesis protocol does not lead to detectable
amounts of 6. In contrast, if the published [15] synthesis pro-
tocol is followed, substantial amounts of 6 are formed as
byproduct. Compounds 5 and 6 can be separated by flash
chromatography (ethyl acetate/hexane, 1 : 1).
X-Ray crystal structure analyses
The single crystal X-ray measurements were performed
on a Siemens SMART CCD diffractometer using monochro-
Analytical data of 6: R (ethyl acetate/hexane, 1 : 1) =
f
1
mated Mo K radiation. Repeatedly measured standard re-
0
.40. – H NMR (250.13 MHz, DMF): δ =10.72 (s, 1 H,
α
flections remained stable. Numerical absorption corrections
OH), 10.41 (s, 2 H, CHO), 7.46, 7.37 (2× s, 2 × 1 H, CH),
13
were performed for 2 and 3, empirical absorption correc-
tions [20] were applied for 4, 6, 8, and 9. No absorption
correction was made for 10. The structures were determined
3
1
1
.97 (s, 3 H, CH ). – C NMR (62.9 MHz, DMF): δ =
3
91.5, 189.4 (CHO), 155.1, 154.9 (COH, COCH ), 130.3,
3
27.4 (CCHO), 116.1, 112.1 (CH), 56.5 (CH3).
by Direct Methods using SHELXS-97 [21] and refined on
2
F
values using the program SHELXL-97 [21]. H-atoms
General procedure for the synthesis of 8, 9, and 10
(162 mg, 1 mmol) and the appropriate amine (2 mmol)
were geometrically positioned and were constrained for 8
and 10. H-atom positions were taken from a difference
Fourier map and were refined for 2, 3, 4, 6, and 9.
5
were dissolved in methylene chloride (70 mL) and the solu-
tion heated to reflux for 1 h. After cooling to r. t. all volatiles
were evaporated under reduced pressure and the remaining
crude product recrystallized from acetonitrile.
CCDC-608824 (2), CCDC-608825 (3), CCDC-608826
(
(
4), CCDC-608827 (6), CCDC-608828 (8), CCDC-608829
9) and CCDC-608830 (10) contain the supplementary crys-
Analytical data of 8: Yield: 376 mg (90 %), brown solid.
tallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk/datarequest/cif.
– 1
H NMR (250.13 MHz, CD Cl ): δ = 12.75 (s, 2 H,
2 2
OH), 8.24 (s, 2 H, HC=N), 6.83 (s, 2 H, CH), 3.58 (t,
3
3
JHH = 6.4 Hz, 4 H, CH ), 3.01 (sept, JHH = 6.6 Hz,
2
3
4
H, CH(CH ) ), 2.75 (t, JHH = 6.4 Hz, 4 H, CH ), 0.98
3
2
2
Acknowledgements
3
13
(d, JHH = 6.6 Hz, 24 H, CH ). – C NMR (62.9 MHz,
3
CD Cl ): δ = 164.9 (C=N), 152.8 (COH), 121.4 (CCHN),
This work was supported by the Deutsche Forschungsge-
17.9 (CH), 61.0 (CH ), 48.6 (CH(CH ) ), 45.7 (CH ), meinschaft and the Fonds der Chemischen Industrie.
2 3 2 2
2
2
1
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4
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