Facile synthesis of 1,6-bis(2-furyl)-2,5-bis(2-hydroxy-3-formyl-5- methylbenzyl)-2,5-diazahexane: A new dinucleating ligand

Article abstract of DOI:10.3390/61201001

A convenient three-step preparation of the dinucleating ligand, 1,6-bis(2-furyl)-2,5-bis(2-hydroxy-3-formyl-5-methylbenzyl)-2,5-diazahexane (3) starting from 2,6-bis(hydroxymethyl)-4-methylphenol (4) is reported. Compound 4 was partially oxidized with preactivated manganese dioxide to form compound 5, which was converted to 2-hydroxy-3-chloromethyl-5-ethylbenzaldehyde (6) with conc.HCl/EtOH. Compound 6 in turn reacted with N,N′-bis (2-furyl)-1,2-diaminoethane (7) in the presence of K₂CO₃ in ethanol to give the title compound 3. No protecting groups were required in the whole process and the conditions were mild.

Full text of DOI:10.3390/61201001

Molecules 2001, 6, 1001-1005
molecules
ISSN 1420-3049
http://www.mdpi.org
Facile Synthesis of 1,6-Bis(2-furyl)-2,5-bis(2-hydroxy-3-formyl-5-
methylbenzyl)-2,5-diazahexane: a New Dinucleating Ligand
Gang-Chun Sun 1, Zhan-Hang He 2, Zhong-Jun Li 2, Xiao-Dong Yuan 3, Zhi-Juan Yang 2, Guo-Xi
Wang 4, Liu-Fang Wang 1* and Chang-Rang Liu 2,*
1
National Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou
University, Lanzhou 730000, China; E-mail:sungangchun@371.net.
Department of Chemistry, Zhengzhou University, ZhengZhou 450052, China.
Department of Applied Oil Engineering, Logistical Engineering University, Chongqing 400042,
2
3
China.
4 Department of Chemical Engineering, Anyang University, Anyang 455000, China.
*Author to whom correspondence should be addressed; E-mail: llyyjz@public.lz.gs.cn
Received: 15 April 2001; in revised form 29 October 2001 / Accepted: 30 October 2001 / Published:
30 November 2001
_______________________________________________________________________________
Abstract: A convenient three-step preparation of the dinucleating ligand, 1,6-bis(2-
furyl)-2,5-bis(2-hydroxy-3-formyl-5-methylbenzyl)-2,5-diazahexane (3) starting from
2,6-bis(hydroxymethyl)-4-methylphenol (4) is reported. Compound 4 was partially
oxidized with preactivated manganese dioxide to form compound 5, which was converted
to 2-hydroxy-3-chloromethyl-5-ethylbenzaldehyde (6) with conc.HCl/EtOH. Compound
6 in turn reacted with N,N’-bis (2-furyl)-1,2-diaminoethane (7) in the presence of K2CO3
in ethanol to give the title compound 3. No protecting groups were required in the whole
process and the conditions were mild.
Keywords: Synthesis, Dinucleating ligand, 2,5-Diazahexane derivative, Partial
oxididation, Manganese dioxide.

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Molecules 2001, 6
Introduction
The design and synthesis of dinucleating ligands that incorporate similar or dissimilar metal ions to
form dinuclear complexes is of importance in attempts to mimic the active sites of metalloenzymes, to
search for appropriate systems for binding and activating small molecules and for investigating the
mutual influences of two metal centers on the electronic, magnetic and the electronical properties of
such dinuclear systems [1-3]. Compound 1 [4] is a well known dinucleating ligand which can act as a
precursor of many macrocyclic di- or multinucleating ligands since it can easily react with diamines,
and much effort has gone into synthesizing its derivatives such as compounds 2 and 3, both of which
can been viewed as the ligands of the same type. It was also reported that when saturation of the
azomethine linkage and/or the introduction of some groups to the lateral chains of these acyclic or
macrocyclic ligands were carried out in the hope of obtaining di- or multinucleating complexes of
particular desired structures, the changes had significant effects upon the stereochemistry and redox as
well as other properties [5] of the metal ions of the complexes. When we first set out to obtain
analogues of ligand 2 we examined the published method, which involved a lengthy route [6].
Consequently we sought to both shorten the synthetic sequence and at the same time simplify the
manipulations required. We now report the successful synthesis of a new ligand 3, similar in structure
to compound 2, but obtained by a novel method This new route has the potential of facilitating the
synthesis of other analogues of compounds 2 and 3 with similar structural features.
Me
Me
Me
H
H
N
N
H
H
O
H
H
O
O
N
O
O
OH
OH
N
N
OH
OH
O
O
OH
OH
N
O
N
N
Me
Me
Me
3
2
1
Results and Discussion
The new three-step synthetic procedure followed is shown in Scheme 1. Using preactivated
manganese dioxide as a selective partial oxidation agent [7], which can oxidize only one
hydroxymethyl group to a formyl group, 2,6-bis(hydroxymethyl)-4-methylphenol (4) [8] was
converted to 5 in chloroform at room temperature in 38% yield (lit. [7] yield 40%). This step took
place under mild conditions and was easy to work up. Compound 5 was efficiently chlorinated to 6 in
the presence of concentrated hydrochloric acid while the formyl and the phenolic hydroxy groups
remained untouched. Coupling of benzyl chloride 6 with diamine 7 [9] under mild conditions gave the

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Molecules 2001, 6
title compound 3 with a yield of 42%. Although the yields of the first and third steps are not as high as
those previously reported, mainly because of the reactivity of the phenol derivatives 4 and 6, the fact
that no protecting groups were required makes this method quite attractive in view of the significant
simplification of the overall sequence that it represents.
As noted, the previously reported preparation of compound 2, similar in structure to 3, involves
nine steps [6]. Although the yields of each step in the earlier synthesis were relatively high (ranging
from 60% to nearly 100%), thus highlighting both the effectiveness of the use of protecting groups and
the elegance of the overall synthetic scheme, the final yield was not as high (about 22%) because of
the large number of steps involved. Furthermore, the procedure was cumbersome, requiring some
reagents which may be hard to obtain and expensive and some severe reaction conditions. The
sequence now presented gave compound 3 in higher yield by a shorter route starting from a common
starting material 4, mainly due to the fact that protecting groups were not used (and consequently did
not have to be removed). The reaction conditions were mild too.
1
In the H-NMR spectrum of compound 3 the signals belonging to the protons of the phenolic
hydroxy groups were broad which showed that the protons were acidic, and suggesting formation of
some O-H---N hydrogen bonds. This phenomenon has been observed in some similar systems [10,11]
and will be further confirmed by single crystal X-ray diffraction which will be reported elsewhere.
Scheme І
OH
OH
OH
OH
OH
Cl
OH
O
O
H
H
a
b
38%
95%
Me
Me
Me
4
5
6
Cl
OH
O
O
NH
NH
H
c
+
2
3
42%
O
Me
6
7
a). MnO2/CHCl3; b). conc.HCl/EtOH; c). K2CO3/EtOH
Acknowledgements
This research was supported by the NSF of China (No. 29671027) and the NSF of Gansu Province
(No. ZS991-A23-059-Y).

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Molecules 2001, 6
Experimental
General
1
Melting points were determined using a WC-1 melting point apparatus. H-NMR spectra were
recorded on Bruker DPX400 spectrometer using TMS as internal reference (chemical shifts reported in
δ ppm) and IR spectra on a Shimadzu IR435 infrared spectrometer (υmax in cm-1). Elemental analyses
were performed on a Carlo-Erba 1106 C, H and N analyzer. 2,6-Bis(hydroxymethyl)-4-methylphenol
(4) [8] and N,N’-bis(2-furyl)-1,2-diaminoethane (7) [9] were prepared according to the reported
methods. Other reagents were all obtained commercially. MnO2 was kept in a muffle oven at a
temperature of 300 to 320°C for 12 h until just prior to use.
2-Hydroxy-3-hydroxymethyl-5-methylbenzaldehyde (5).
This compound was synthesized by a modification of the previously reported method [7]. 2,6-
Bis(hydroxymethyl)-4-methylphenol (4) (20g, 0.12mol) was placed in a 500 mL flask and stirred with
a suspension of MnO2 (100g, 1.14mol) in CHCl3 (300mL) for 16 h at room temperature. The mixture
was filtered and washed with CHCl3 for several times until the filtrate became colourless. The solvent
was removed and the residue was recrystallized from EtOH/H2O (1:3, v:v) to give yellowish needles
(yield: 7.6g, 38%). M.p. 72-73° (lit. [7] 75-76°C). Anal. Calc for C9H10O3: C: 65.05%, H: 6.07%;
Found: C: 64.66%, H: 5.92%.
2-Hydroxy-3-chloromethyl-5-methylbenzaldehyde (6).
A solution of compound 5 (5 g, 0.03mol) in alcohol (25 mL) was added dropwise with stirring into
a 250 mL flask containing conc. HCl (75 mL) placed in a 40°C water bath. The mixture was stirred for
about 2 h, then filtered and washed with water until the pH was ~7 to give 4.8g (95%) of white needles
(m.p. 92-93°C). Anal. Calc. for C9H9O2Cl: C: 58.55%, H: 4.91%; Found: C: 58.84%, H: 4.96%;
1H-NMR (CDCl3/400MHz) δ: 2.35 (s, 3H), 4.67 (s, 2H), 7.31 (d, 1H), 7.46 (d, 1H), 9.87 (s, 1H), 11.26
(s, 1H). IR (KBr): 1661, 1599, 1469, 875 cm-1.
1,6-Bis(2-furyl)-2,5-bis(2-hydroxy-3-formyl-5-methylbenzyl)-2,5-diazahexane (3).
Compound 6 (4.1 g, 0.022mol) in ethanol (80mL) and anhydrous K2CO3 (5.5 g, 0.04mol) were
placed in a 250mL flask, then compound 7 (2.2 g, 0.01mol) in ethanol (20mL) was added dropwise at
room temperature. The mixture was stirred for 6 h at 40°C, then quenched and acdified to pH~2 with
5% aqueous HCl. Most of the solvent was removed by concentration in vacuo and the residue was
taken up in water (50mL). After filtration the filtrate was taken to pH~9 with 1:1 ammonia/water thus
forming a yellowish colloidal precipitate. After leaving the mixture standing overnight, the crude
product was filtered and washed with water to pH~7. Recrystallization from 95% ethanol gave

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Molecules 2001, 6
compound 3 (2.17 g, 42%) as off-white needles (m.p. 109-110°C). Anal. Calc. for C30H32N2O6: C:
69.78%; H: 6.20%; N: 5.43%). Found: C: 69.59%; H: 6.45%; N: 5.44%. 1H-NMR (CDCl3/400MHz) δ:
2.26 (s, 6H), 2.71 (s, 4H), 3.66 (s, 4H), 3.69 (s, 4H), 6.17 (d, 2H), 6.31 (s, 2H), 7.27 (d, 2H), 7.37 (s,
4H), 10.17 (s, 2H), 11.25 (br, 2H). IR (KBr): 2859, 1676, 1605, 1500, 1454, 874 cm-1.
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Sample Availability: Compounds 3, 5, 6, 7 are available from MDPI and the authors
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