C2-chiral dinucleating ligands with a 3,6-disubstituted pyridazine core

Article abstract of DOI:10.1016/S0040-4039(01)02087-1

Reaction of the 3,6-bis(tosyloxymethyl)pyridazine (1) with two equivalents of (1R-2S)-norephedrine or (1S-2R)-1-amino-2-indanol leads to the formation of C₂-chiral dinucleating ligands containing a 3,6-disubstituted pyridazine core flanked by a

Full text of DOI:10.1016/S0040-4039(01)02087-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 11–13
C2-chiral dinucleating ligands with a 3,6-disubstituted
pyridazine core
Alexandre Picot and Franc¸ois P. Gabba¨ı*
Chemistry Department, Texas A&M University, 3255 TAMU, College Station, TX 77843-3255, USA
Received 12 October 2001; accepted 22 October 2001
Abstract—Reaction of the 3,6-bis(tosyloxymethyl)pyridazine (1) with two equivalents of (1R-2S)-norephedrine or (1S-2R)-1-
amino-2-indanol leads to the formation of C2-chiral dinucleating ligands containing a 3,6-disubstituted pyridazine core flanked by
aminoalcohol pendant arms, namely 3,6-bis((1R-2S)-(2-hydroxy-1-methyl-2-phenyl-ethyl)aminomethyl)pyridazine (2) and 3,6-
bis((1S-2R)-(2-hydroxy-indan-1-yl)aminomethyl)pyridazine (3). As shown by spectrometric titration experiments as well as
ESI/MS, ligands 2 and 3 bind copper(II) cations to form dinuclear complexes. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Recent investigations in the field of Lewis acid catalysis
have focused on the use of dinuclear metal complexes.1–7
As a result of distinct synergistic effects occurring at the
proximal metal centers, these complexes feature unique
catalytic properties. While original studies dealt with
mostly achiral systems,1–3 a variety of asymmetric com-
plexes have now emerged. An important aspect of this
research concerns the preparation of chiral ligands
designed to hold two metal cations in well defined
positions. Examination of the literature indicates that
the nature of the ligands so far investigated remains
somewhat restricted. In addition, the use of large and
flexible bifunctional chiral Schiff bases,4 the binol lig-
ands has received most of the attention and has been
successfully incorporated in bimetallic catalysts.5,6 In an
effort to diversify the palette of chiral dinucleating
ligands available,7 we have engaged into the synthesis
and coordination chemistry of C2-chiral derivatives
containing a 3,6-disubstituted pyridazine moiety as a
central core. We note that, despite the widespread use
of 3,6-disubstituted pyridazine ligands in the chemistry
of dinuclear metal complexes,8–13 only on one occasion
has the preparation of chiral examples of such ligands
been reported.14
It occurred to us that, in order to avoid aggregation,15
ligands able to present at least three basic sites to each
metal center should be prepared. For this reason, the
introduction of aminoalcohol pendant arms at the ben-
zylic positions of a 3,6-dimethylpyridazine was selected
as a synthetic target. 3,6-Bis(hydroxymethyl)pyridazine
was prepared by following the published procedure16
and was treated with p-toluenesulfonyl chloride to
afford the bistosylate 1. Following flash chromatogra-
phy purification and rapid evaporation of the solvent, 1
was isolated in 85% yield. Compound 1 is stable when
stored as a solid at −20°C but slowly decompose at
room temperature.
Keywords: dinucleating ligand; 3,6-pyridazine; C2-chiral; copper com-
plex.
Scheme 1. (i) (1R-2S)-norephedrine, Na2CO3, MeCN; (ii)
(1S-2R)-1-amino-2-indanol, Na2CO3, MeCN.
* Corresponding author. Tel.: +1-979-862-2070; fax: +1-979-845-4719;
e-mail: francois@tamu.edu
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02087-1

12
A. Picot, F. P. Gabba¨ı / Tetrahedron Letters 43 (2002) 11–13
Compound 1 reacts smoothly with various aminoalco-
hols. Thus, treatment with two equivalents of (1R-2S)-
norephedrine in the presence of Na2CO3 affords
3,6-bis((1R-2S)-(2-hydroxy-1-methyl-2-phenylethyl)-
aminomethyl)pyridazine (2) in 88% yield after recrystal-
lization from acetonitrile (Scheme 1). It is important to
note that this substitution reaction is regioselective and
that no O-substituted products or oligomers could be
observed in the reaction mixture. The nature of 2 was
that wavelength increased steadily until exactly two
equivalents of metals had been added (Fig. 2). With
further addition of Cu2+, the absorbance at that wave-
length remained constant thus indicating the nearly
quantitative formation of the dinuclear complexes. In
the case of 3, the existence of dinuclear complexes could
also be confirmed by ESI mass spectrometry of
methanol solutions containing 3 and two equivalents of
Cu(OTf)2. The base peak, observed at 675 amu, results
from the loss of two molecule of HOTf and one OTf−
anion from the parent complex 3·(CuOTf2)2. Loss of an
additional HOTf molecule results in a peak observed at
525 amu.
1
confirmed by H, 13C NMR and FAB mass spectrome-
try which allowed the detection of the molecular peak.
In a similar fashion, 1 reacts with (1S-2R)-1-amino-2-
indanol to afford 3,6-bis((1S-2R)-(2-hydroxyindan-1-
yl)aminomethyl)pyridazine (3) in a 76% yield (Scheme
1). As in the case of 2, the identity of 3 has been
confirmed by 1H, 13C NMR and FAB mass
spectrometry.
Despite repeated attempts, single crystals of 2 could not
been obtained. In the case of 3, however, slow cooling
of an ethanol solution lead to the formation of single
crystals that were subjected to an X-ray analysis. Com-
pound 3 crystallizes in the orthorhombic space group
P2(1)2(1)2 with two molecules per unit cell (Fig. 1).
Examination of the structure confirms the proposed
connectivity and in particular, the N-attachment of the
aminoalcohol moiety. Molecules of 3 have a crystallo-
graphically imposed C2 symmetry. The bond angles and
bond lengths observed in the structure of the pyridazine
core of 3 resemble those previously reported for related
molecules such as bis(hydroxymethyl)pyridazine17 or
3,6-dicarboxylic-pyridazine acid.18 There are no
unusual bond lengths and angles in the amino-indanol
moieties that flank each side of the pyridazine ring.
Figure 2. Spectrometric titration of 3 with CuCl2 in EtOH.
Change in absorbance variation at 365 nm as a function of
the number of equivalents of CuCl2 added.
3. Summary
In conclusion, we report the synthesis of simple chiral
ligands of C2 symmetry in which two copper(II) cations
can be embedded. Current studies are focused on the
use of these complexes in asymmetric catalysis.
With the preparation of binuclear complexes as a goal,
it became important to investigate the ligative behavior
of 2 and 3 toward a prototypical metal cation such as
copper(II). Addition of CuCl2 to a 10−4 M solution of 2
or 3 in EtOH resulted in the appearance of a charge
transfer band at 365 nm. In both cases, absorption at
4. Experimental
4.1. Synthesis
4.1.1. 3,6-Bis(tosyloxymethyl)pyridazine (1). A solution
of p-toluenesulfonyl chloride (13.7 g, 72 mmol) in THF
(30 mL) was added to a solution of 3,6-bis(hydroxy-
methyl)pyridazine (5 g, 36 mmol) and NaOH (4 g, 0.1
mol) in a mixture of water (20 mL) and THF (20 mL).
After stirring at 25°C for 3 h, the solution was concen-
trated by partial evaporation of the solvent, which
resulted in the precipitation of the product as a white
solid. The product was isolated by filtration and was
purified by flash chromatography (washed with
dichloromethane and eluted with ethylacetate) to give 1
Figure 1. ORTEP view of 3 in the crystal (50% elipsoids).
,
Selected bond length [A] and angles [°]: O(1)ꢀC(5) 1.432(5),
N(1)ꢀC(1) 1.325(5), N(1)ꢀN(1A) 1.349(7), N(2)ꢀC(4) 1.460(5),
N(2)ꢀC(3) 1.480(4), C(1)ꢀC(2) 1.390(6), C(1)ꢀC(3) 1.513(5),
C(2)ꢀC(2A) 1.384(8), C(4)ꢀC(5) 1.561(5), C(5)ꢀC(6) 1.538(5),
C(1)ꢀN(1)ꢀN(1A) 120.0(2), C(4)ꢀN(2)ꢀC(3) 113.0(3), N(1)ꢀ
C(1)ꢀC(2) 122.4(4), N(1)ꢀC(1)ꢀC(3) 113.4(4), C(2)ꢀC(1)ꢀC(3)
124.1(4), C(2A)ꢀC(2)ꢀC(1) 117.6(2), N(2)ꢀC(3)ꢀC(1) 108.8(3),
N(2)ꢀC(4)ꢀC(11) 113.2(3), N(2)ꢀC(4)ꢀC(5) 116.2(3), C(11)ꢀ
C(4)ꢀC(5) 101.6(3), O(1)ꢀC(5)ꢀC(6) 112.4(3), O(1)ꢀC(5)ꢀC(4)
104.9(3), C(6)ꢀC(5)ꢀC(4) 102.2(3), C(12)ꢀC(6)ꢀC(5) 103.2(3).
1
(13.7 g, 85% yield). Mp 118–120°C. H NMR (CDCl3,
3
300 MHz) l 2.46 (s, 6H), 5.36 (s, 4H), 7.36 (d, JHH
=
3
8.4 Hz, 4H), 7.65 (s, 2H), 7.83 (d, JHH=8.4 Hz, 4H).
13C NMR (CDCl3, 75 MHz) l 21.8, 69.8, 126.2, 128.3,
130.3, 132.7, 145.7, 157.1. MS (+FAB): m/z: 449 [MH+].
Elemental analysis: Anal. calcd for C20H20N2O6S2:
(448.5): C, 53.55; H, 4.45; N, 6.25; found: C, 53.56; H,
4.61; N, 6.27.

A. Picot, F. P. Gabba¨ı / Tetrahedron Letters 43 (2002) 11–13
13
4.1.2.
3,6-Bis((1R-2S)-(2-hydroxy-1-methyl-2-phenyl-
033; e-mail: deposit@ccdc.cam.ac.uk or http://
ethyl)aminomethyl)pyridazine (2) and 3,6-bis((1S-2R)-
(2-hydroxy-indan-1-yl)aminomethyl)pyridazine (3). Com-
pounds 2 and 3 were prepared by reaction of 1 with
two equivalents of (1R-2S)-norephedrine and (1S-2R)-
1-amino-2-indanol, respectively, in the presence of four
equivalents Na2CO3 in MeCN. The reactions were com-
plete after 3 h and the products were purified by
recrystallization from MeCN. 2: 88% yield, mp 152–
www.ccdc.cam.ac.uk).
Acknowledgements
We thank the US Army Medical Research and Materiel
Command as well as the Department of Chemistry at
Texas A&M for making this work possible.
1
3
154°C. H NMR (CDCl3, 300 MHz) l 0.93 (d, JHH
=
6.6 Hz, 6H), 3.03 (qd, 3JHH=6.6 Hz, 3JHH2=3.6 Hz,
2
2H), 4.17 (d, JHH=14.7 Hz, 2H), 4.25 (d, JHH=14.7
3
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58.7, 73.8, 126.3, 126.7, 127.4, 128.3, 140.8, 160.7. MS
(+FAB): m/z: 407 [MH+]. 3: 76% yield, mp 164–166°C.
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