The one-pot halomethylation of 5-substituted salicylaldehydes as convenient precursors for the preparation of heteroditopic ligands for the binding of metal salts

Article abstract of DOI:10.1016/j.tetlet.2006.09.149

The one-pot bromo- and chloro-methylation of various 5-substituted salicylaldehydes with paraformaldehyde and hydrobromic or hydrochloric acid has been achieved. This approach establishes a convenient and flexible method to attach functional arms to salic

Full text of DOI:10.1016/j.tetlet.2006.09.149

Tetrahedron Letters 47 (2006) 8983–8987
The one-pot halomethylation of 5-substituted salicylaldehydes
as convenient precursors for the preparation of heteroditopic
ligands for the binding of metal salts
Qiang Wang,a Claire Wilson,a Alexander J. Blake,a Simon R. Collinson,a
Peter A. Taskerb and Martin Schro¨dera,*
aSchool of Chemistry, The University of Nottingham, Nottingham NG7 2RD, UK
bSchool of Chemistry, The University of Edinburgh, West Main Road, Edinburgh EH9 3JJ, UK
Received 9 August 2006; revised 18 September 2006; accepted 29 September 2006
Abstract—The one-pot bromo- and chloro-methylation of various 5-substituted salicylaldehydes with paraformaldehyde and hydro-
bromic or hydrochloric acid has been achieved. This approach establishes a convenient and flexible method to attach functional
arms to salicylaldehydes for further applications in organic and coordination chemistry. Examples are described using 3-bromo-
methyl-5-t-butylsalicylaldehyde in the synthesis of piperazine-containing heteroditopic ligands as receptors for metal salts.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Salicylaldehyde and its derivatives have been widely
tBu
N
O
N
O
used both in the industry and academia. They have been
used widely in synthetic co-ordination chemistry, partic-
ularly to synthesise the salen family of ligands for cata-
lytic applications.1 For example, several asymmetric
diiron complexes have been synthesized2 from 5-methyl-
salicylaldehyde, and these complexes mimic the spectro-
scopic properties of purple acid phosphatase enzymes.
The use of bifunctional ligand systems is an attractive
method of emulating the reactivity of natural enzymes.3
DiMauro and Kozlowski have developed4 powerful cat-
alysts using 5-t-butylsalicylaldehyde to prepare a set of
bifunctional salen complexes containing Zn(II) as a
Lewis acid, with the pendant amine arms acting as Lewis
base activating groups. These acid and basic groups
can be altered independently to control the nucleophilic
and electrophilic activations of the reacting substrates
(Scheme 1a). Similar bifunctional acyclic and macro-
cyclic systems have also been used successfully by Tasker
et al. as ditopic ligands for the simultaneous extraction
of both anionic and cationic moieties of transition metal
salts5 (Scheme 1b). The zwitterionic form of the ligand
generated by transfer of the phenolic protons from the
M
tBu
tBu
N
Zn
NR2
nucleophilic
centre
electrophilic
O
N
O
+
+
R2N
NR2
H
H
centre
tBu
NR2
-
2
O
O
O
S
O
(a)
(b)
Scheme 1. Examples showing some bifunctional systems.
metal binding site to the pendant tertiary amine groups
creates a dipositive cavity wherein the anion is bound by
a combination of both electrostatic and hydrogen bond-
ing interactions. Additionally, piperazine rings have
been appended to salicylaldehydes and used in the syn-
thesis of unsymmetrical imino-macrocyclic complexes
with the vanadium complexes showing activity as insulin
mimetics.6
The introduction of halomethyl substituents at C3 of the
5-substituted salicylaldehyde has been used as a general
approach to precursors to bifunctional ligands.2,4,7
Indeed, halomethyl-substituted aromatics are versatile
synthons in organic synthesis as the halide functionality
acts as a synthetic handle for the attachment of further
Keywords: Bromomethylation; Chloromethylation; Salicylaldehyde
derivatives; Heteroditopic ligands.
*
Corresponding author. Tel.: +44 0 115 9513490; fax: +44 0 115
9513563; e-mail: m.schroder@nottingham.ac.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.149

8984
Q. Wang et al. / Tetrahedron Letters 47 (2006) 8983–8987
components.8,9 The preparation of halomethyl-substi-
tuted aromatics has been well documented,10 with the
chloromethylation of aromatic compounds having been
much more widely studied9 compared to the bromo-
methylation, despite the fact that the resulting benzyl
bromides are more reactive in subsequent nucleophilic
displacement reactions.11 Surprisingly, the only example
of direct halomethylation of salicylaldehyde derivatives
is the synthesis of 3-chloromethyl-5-methylsalicylalde-
hyde via the reaction of 5-methylsalicylaldehyde and
formaldehyde in hydrochloric acid.12 There appears to
be no direct bromomethylation procedure reported in
the literature. The preparation of 3-bromomethyl-5-t-
butylsalicylaldehyde has recently been reported via a
five-step procedure,4 and a similar approach has also
been reported for the preparation of 3-chloromethyl-5-
methylsalicylaldehyde using concentrated hydrochloric
acid in the last step.13 Given the increasing interest in
bifunctional ligand systems,2,4,5 the development of an
economical and straightforward synthetic route to
halomethyl derivatives of 5-substituted salicylaldehydes
is highly desirable; we report herein such a route.
Table 1. Synthesis of halomethylated salicylaldehydes
Product
Reaction time
Yield (%)
1
2
3
4
5
6
7
8
20 h
2 h
9 days
66 h
45 h
4 h
10 days
6.5 days
98
95
93
85
93
97
ꢁ50
ꢁ40
The experimental results in Table 1 confirm that the bromo-
methylation reaction is faster than the corresponding
chloromethylation, an observation which can be ratio-
nalized by the greater acidity of hydrobromic acid.
According to the 1H NMR spectra of the crude reaction
mixtures, compounds 7 and 8 were produced in yields of
approximately 50% and 40%, respectively, after reaction
for 10 and 6.5 days and, therefore, further detailed stud-
ies for these two very slow reactions were not pursued.
The bromo-analogues 3 and 4 can, however, be pre-
pared in yields of 93% and 85% after reaction for 9 days
and 66 h, respectively. The experimental results also
show that relatively long reaction times help to generate
the desired products in high yields.
The present study has developed a one-pot synthetic
method that affords bromomethyl or chloromethyl
derivatives of 5-substituted salicylaldehydes in high pur-
ity and in synthetically useful quantities (Scheme 2). 3-
Bromomethyl-5-t-butylsalicylaldehyde 114 was synthe-
sized by heating a mixture containing 5-t-butylsalicylal-
dehyde,15 paraformaldehyde and 48% HBr in aqueous
solution at 70 ꢁC with concentrated H2SO4 as a cata-
For the three compounds 2, 4 and 6, single crystals suit-
able for study by X-ray crystallography were obtained
and their structures are shown in Figure 1.18 In each
case, an intramolecular O–Hꢀ ꢀ ꢀO hydrogen bond is
formed between the phenolic hydrogen and the carbonyl
1
lyst.16 The reaction could be readily monitored by H
˚
NMR spectroscopy, which showed that a reaction time
of 20 h was optimum to furnish a pale yellow solid in a
yield of 98%.
oxygen, with Hꢀ ꢀ ꢀO distances of around 1.95 A in each
case. As a result of this hydrogen bond, the OH moiety
and the atoms O1, C2, C1, C8 and O8 are co-planar.
Additionally, within the solid-state structure, molecules
are linked into pairs by longer intermolecular hydrogen
bonds between the phenolic hydrogen and the carbonyl
oxygen of an adjacent molecule. Here the Hꢀ ꢀ ꢀO dis-
Compounds 2–6 were synthesized according to a similar
procedure as for 1 with different reaction times as shown
in Table 1.17 The advantage of bromomethylation over
chloromethylation is apparent. The choice of group at
C-5 of the benzene ring clearly affects the rate of the
halomethylation of the salicylaldehydes. Modifying the
R-group from methyl, t-butyl, bromo to n-nonyl
increases the reaction time for bromomethylation at the
meta-position from 2 to 20 to 66 h and further to 9 days,
respectively. Fuson and McKeever also found that the
presence of a halogen atom inhibits the chloromethyla-
tion of aromatic compounds.10 Therefore, the difference
in the reaction time is probably due to a combined effect
of both steric and electronic properties of the R-group.
˚
tances are 2.31, 2.31 and 2.29 A for compounds 2, 4
and 6, respectively, and the resulting motif has the graph
set notation R2 ð4Þ.
2
Initially, the use of 3-bromomethyl-5-t-butylsalicylalde-
hyde 1 in the synthesis of heteroditopic ligands was
investigated by the synthetic sequence shown in Scheme
3. 3-Bromomethyl-5-t-butylsalicylaldehyde 1 was trea-
ted with excess piperazine in CH2Cl2 in the presence of
triethylamine to give the monoaldehyde 9 as a minor
product and the dialdehyde 10 as the major product.
Consequently, 3-bromomethyl-5-t-butylsalicylaldehyde
1 was reacted with half an equivalent of piperazine in
MeCN in the presence of Et3N to yield solely the dialde-
hyde 10.19 Subsequently, the dialdehyde 10 underwent a
Schiff-base condensation with ethane-1,2-diamine to
yield a mixture of the symmetric macrocyclic ligands
L1H2 and L2H4, as identified by mass spectrometry
O
O
(HCHO)n, HX
70 oC
R
OH
R
OH
X
X=Cl
X=Br
R:
1
and H NMR spectroscopy.20 Unfortunately, we were
t-butyl
1
5
unable to separate these two products effectively.
methyl
n-nonyl
2
3
4
6
7
8
The dialkylation of piperazine is not surprising, as it has
been reported that the direct alkylation of piperazine
produces a mixture of substitution products from which
Br
Scheme 2. Halomethylation reactions studied in this work.

Q. Wang et al. / Tetrahedron Letters 47 (2006) 8983–8987
8985
Figure 1. Views of the single crystal X-ray structures for 2, 4 and 6. Displacement ellipsoids are drawn at the 50% probability level.
Et3N
CH2Cl2
excess
O
O
O
O
But
OH
But
OH
+
But
OHHO
But
HN
NH
Br
N
NH
N
N
1
9
10
major product
minor
product
Et3N
0.5 HN
NH
CH2Cl2
O
O
N
N
N
N
H2NCH2CH2NH2
But
OHHO
But
But
OHHO
But But
OHHO
But
EtOH,
reflux 3 h
+
N
N
H2O
N
N
N
N
L1H2
10
N
N
But
OHHO
But
N
N
L2H4
Scheme 3. Synthesis of heteroditopic macrocyclic ligands L1H2 and L2H4.
N
N
O
O
KHCO3
But
OH
But
OH
But
OH HO
But
MeCN
reflux 6 h
NH2CH2CH2NH2
MeOH
1
Br
N
N
N
N
N
+
O
N
O
O
O
HN
N
CH3
H3C
H3C
H3C
11
L3H2
i. 2N HCl, 100 oC
4 days
ii. Na2CO3
O
N
N
But
OH
But
NH2CH2CH2NH2
MeOH
OH HO
But
N
N
N
N
H
9
N
H
N
H
L4H2
Scheme 4. Synthesis of heteroditopic ligands L3H2 and L4H2.
the isolation of monosubstituted compounds is difficult
and very low yielding.21 However, a better yield can be
achieved by the reaction of an alkyl halide with 1-carb-
ethoxypiperazine followed by hydrolysis of the result-
ing product.22 Therefore, the synthetic sequence shown
in Scheme 4 was performed. 3-Bromomethyl-5-t-butyl-

8986
Q. Wang et al. / Tetrahedron Letters 47 (2006) 8983–8987
H.; Fenton, D. E.; Shindo, K.; Murata, S.; Kitko, D. J.
Inorg. Chem. 1998, 37, 6281–6287.
salicylaldehyde 1 was reacted with 1-acetylpiperazine in
MeCN in the presence of KHCO3 to yield the aldehyde
11. Compound 11 underwent a Schiff-base condensation
with ethane-1,2-diamine to yield L3H2.23 Alternatively,
compound 11 could be deprotected by hydrolysis of
the acetyl group to yield the monoaldehyde 9 which then
similarly reacted with ethane-1,2-diamine to give ligand
L4H2.24
8. (a) Mitchell, R. H.; Iyer, V. S. Synlett 1989, 55–57; (b) Ott,
S.; Kritikos, M.; Akermark, B.; Sun, L. C.; Lomoth, R.
Angew. Chem., Int. Ed. 2004, 43, 1006–1009; (c) Fernan-
dez, F.; Gomez, G.; Lopez, C. Synthesis 1988, 802.
9. Grag, N.; Lee, T. R. Synlett 1998, 310–312.
10. Fuson, R. C.; McKeever, C. H. Org. React. 1942, 1, 63.
11. van der Made, A. W.; van der Made, R. H. J. Org. Chem.
1993, 58, 1262–1263.
In conclusion, we have described herein the direct and
convenient one-pot synthesis of bromo- and chloro-
methylated salicylaldehydes. The rate of reaction is
strongly influenced by both the electronic and steric con-
figurations of the R-group at the C5 position; further-
more, the bromomethylation is faster than the
chloromethylation reaction. This convenient synthesis
of bromomethylated salicylaldehydes provides a versa-
tile methodology for attaching a functional arm to sali-
cylaldehydes. We have also prepared a range of
heteroditopic ligands for use in the extraction of metal
salts via the reactions of the 3-bromomethyl-5-t-butyl-
salicylaldehyde with secondary amines followed by
Schiff-base condensation reactions. Their coordination
chemistry is currently being studied with a variety of
metal salts.
12. (a) Lock, G. Chem. Ber. 1930, 63, 551–559; (b) Murugan,
E.; Siva, A. Synthesis 2005, 2022–2028.
13. Chirakul, P.; Hampton, P. D.; Bencze, Z. J. Org. Chem.
2000, 65, 8297–8300.
14. Typical procedure for the synthesis of 1 (3-bromomethyl-5-
t-butylsalicylaldehyde): To a mixture of 5-t-butylsalicylal-
dehyde (2.00 g, 10.90 mmol) and paraformaldehyde
(0.49 g, 16.4 mmol) was added 48% HBr (13.68 g,
81.07 mmol) and several drops of concentrated H2SO4.
The mixture was stirred at 70 ꢁC for 20 h before it was
allowed to cool to room temperature. Water (20 cm3) was
added to the mixture and the product was extracted into
CH2Cl2 (20 cm3), and the organic phase was dried over
anhydrous Na2SO4. The CH2Cl2was then removed under
reduced pressure to afford the product as a thick yellow
oil, which solidified upon standing.
15. Lindoy, L. F.; Meehan, G. V.; Svenstrup, N. Synthesis
1998, 1029–1032.
16. Buchler, C. A.; Kirchner, F. K.; Deebel, G. F. Org. Synth.
1940, 20, 59–61.
17. All compounds were fully characterized by spectroscopic
and elemental analysis; 2, 4 and 6 were also characterized
by crystal structure determinations on single crystals
grown from CH2Cl2/n-hexane.
Acknowledgements
We thank EPSRC for funding and the EPSRC National
Mass Spectrometry Service at the University of Wales,
Swansea (UK) for mass spectra. M.S. gratefully
acknowledges receipt of a Royal Society Wolfson Merit
Award and of a Royal Society Leverhulme Trust Senior
Research Fellowship.
Compound 1: A pale yellow solid. Mp 42–43.5 ꢁC. IR
(KBr)
m . Anal. Calcd for
1654 (vs, C@O) cmꢂ1
C12H15BrO2: C, 53.15; H, 5.58. Found: C, 53.02; H,
5.54. 1H NMR (CDCl3, 300.13 MHz): d 11.35 (1H, s,
CHO), 9.92 (1H, s, OH), 7.66 (1H, d, J = 2.5 Hz, Ph–H),
7.53 (1H, d, J = 2.5 Hz, Ph–H), 4.61 (2H, s, CH2Br), 1.36
(9H, s, CH3) ppm. 13C NMR (CDCl3, 75.42 MHz): d
196.4, 157.4, 142.5, 135.5, 130.3, 125.5, 120.5, 34.2, 31.3,
27.2 ppm. ES+-MS (m/z) 191 [MꢂBr]+.
References and notes
Compound 2: A white solid. Mp 115.9–117.2 ꢁC. IR (KBr)
m 1662 (vs, C@O) cmꢂ1. Anal. Calcd for C9H9BrO2: C,
47.16; H, 3.93. Found: C, 47.24; H, 3.95. 1H NMR
(CDCl3, 300.13 MHz): d 11.31 (1H, s, CHO), 9.87 (1H, s,
OH), 7.45 (1H, s, Ph–H), 7.35 (1H, s, Ph–H), 4.57 (2H, s,
CH2Br), 2.36 (3H, s, CH3) ppm. 13C NMR (CDCl3,
75.42 MHz): d 195.4, 156.4, 137.8, 133.2, 128.3, 125.0,
119.5, 25.7, 19.2 ppm. ES+-MS (m/z) 230 [M]+.
1. Cozzi, P. G. Chem. Soc. Rev. 2004, 410–421.
2. Lambert, E.; Chabut, B.; ChardonNoblat, S.; Deronzier,
A.; Chottard, G.; Bousseksou, A.; Tuchagues, J. P.;
Laugier, J.; Bardet, M.; Latour, J. M. J. Am. Chem. Soc.
1997, 119, 9424–9437.
3. (a) Murthy, N. N.; Mahrooftahir, M.; Karlin, K. D. J.
Am. Chem. Soc. 1993, 115, 10404–10405; (b) Gobel, M. W.
Angew. Chem., Int. Et. Engl. 1994, 33, 1141–1143; (c)
Young, M. J.; Chin, J. J. Am. Chem. Soc. 1995, 117,
10577–10578; (d) Kodera, M.; Shimakoshi, H.; Kano, K.
Chem. Commun. 1996, 1737–1738.
4. DiMauro, E. F.; Kozlowski, M. C. Org. Lett. 2001, 3,
3053–3056, and references cited therein.
5. (a) Plieger, P. G.; Tasker, P. A.; Galbraith, S. G. Dalton
Trans. 2004, 313–318; (b) White, D. J.; Laing, N.; Miller,
H.; Parsons, S.; Coles, S.; Tasker, P. A. Chem. Commun.
1999, 2077–2078.
6. (a) Ramachandran, B.; Ravi, K.; Narayanan, V.; Kanda-
swamy, M.; Subramanian, S. Clin. Chim. Acta 2004, 345,
141–150; (b) Manonmani, J.; Kandaswamy, M. Polyhe-
dron 2003, 22, 989–996; (c) Karunakaran, S.; Kandasw-
amy, M. J. Chem. Soc., Dalton Trans. 1994, 1595–1598.
7. (a) Koval, I. A.; Pursche, D.; Stassen, A. F.; Gamez, P.;
Krebs, B.; Reedijk, J. Eur. J. Inorg. Chem. 2003, 1669–
1674; (b) Uozumi, S.; Furutachi, H.; Ohba, M.; Okawa,
Compound 3: A viscous yellow oil. IR (neat) m 1656 (vs,
C@O) cmꢂ1. Anal. Calcd for C17H25BrO2: C, 59.82; H,
7.33. Found: C, 60.12; H, 7.51. 1H NMR (CDCl3,
300.13 MHz): d 11.35 (1H, s, CHO), 9.91 (1H, s, OH),
7.35–7.70 (2H, m, Ph–H), 4.61 (2H, s, CH2Br), 0.61–1.80
(19H, m, nonyl-H) ppm. 13C NMR (CDCl3, 75.42 MHz):
d 196.9, 157.3, 142.7, 142.5, 139.9, 139.8, 13.0, 136.9, 136.6
(m), 132.4 (m), 125.7, 120.2, 51.6–8.7 (m) ppm. ES+-MS
(m/z) 261 [MꢂBr]+.
Compound 4: A white solid. Mp 134.9–136.4 ꢁC. IR (KBr)
m 1667 (vs) cmꢂ1. Anal. Calcd for C8H6Br2O2: C, 32.65; H,
2.04. Found C, 32.98; H, 1.92. 1H NMR (CDCl3,
300.13 MHz): d 11.44 (1H, s, CHO), 9.87 (1H, s, OH),
7.73 (1H, d, J = 2.4 Hz, Ph–H), 7.68 (1H, d, J = 2.4 Hz,
Ph–H), 4.53 (2H, s, CH2Br) ppm. 13C NMR(CDCl3,
75.42 MHz): d 195.4, 158.5, 140.4, 136.1, 128.9, 121.8,
111.3, 25.4 ppm. ES-MS (m/z) 215 [MꢂBr+H]+, 294
[M]+.

Q. Wang et al. / Tetrahedron Letters 47 (2006) 8983–8987
8987
Compound 5: A yellow oil. IR (neat) m 1657 (vs, C@O)
cmꢂ1. Anal. Calcd for C12H15ClO2: C, 63.58; H, 6.62.
Found C, 63.75; H, 6.74. 1H NMR (CDCl3, 300.13 MHz):
d 11.30 (1H, s, CHO), 9.92 (1H, s, OH), 7.68 (1H, d,
J = 2.5 Hz, Ph–H), 7.54 (1H, d, J = 2.5 Hz, Ph–H), 4.72
(2H, s, CH2Cl), 1.36 (9H, s, CH3) ppm. 13C NMR (CDCl3,
75.42 MHz): d 196.8, 157.4, 142.9, 135.4, 130.6, 125.5,
120.2, 40.3, 34.3, 31.3 ppm. ES+-MS (m/z) 191 [MꢂCl]+.
Compound 6: White solid. Mp 96.9–97.6 ꢁC. IR (KBr) m
1663 (vs, C@O) cmꢂ1. Anal. Calcd for C9H9ClO2: C,
58.54; H, 4.88. Found C, 58.31; H, 4.80. 1H NMR (CDCl3,
300.13 MHz): d 11.26 (1H, s, CHO), 9.88 (1H, s, OH), 7.48
(1H, d, J = 1.98 Hz, Ph–H), 7.36 (1H, d, J = 1.98 Hz, Ph–
H), 4.68 (2H, s, CH2Cl), 2.37 (3H, s, CH3) ppm. 13C NMR
(CDCl3, 75.42 MHz): d 196.5, 157.4, 138.7, 134.1, 129.3,
125.8, 120.5, 39.9, 20.3 ppm. ES+-MS (m/z) 186 [M]+.
18. CCDC 239620 (2), 239621 (4) and 239622 (6) contain the
supplementary data for this paper and they can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html.
(95:5) as eluent and the first band was collected. Removal
of the solvent afforded 11 as an off-white solid. Yield 1.0 g
(85%). Mp 90–92 ꢁC. Anal. Calcd for C18H26N2O3: C,
67.90; H, 8.23; N, 8.80. Found: C, 67.45; H, 8.22; N, 8.65.
1H NMR (CDCl3, 300.13 MHz): d 1.32 (s, 9H, CH3), 2.11
(s, 3H, CH3CO), 2.56 (m, 4H, CH2CH2), 3.51 (s, 2H, Ph–
CH2N), 3.69 (br, 4H, CH2CH2), 7.48 (s, 1H, Ph–H), 7.59
(d, 1H, J = 2.52 Hz, Ph–H), 10.17 (s, 1H, CHO); 13C
NMR (CDCl3, 75.42 MHz): d 193.9 (CHO), 169.0 (CO),
158.7, 142.2, 134.3, 126.9, 123.7, 121.4, 58.2, 52.9, 52.5,
46.2, 41.3, 34.2, 31.4, 21.4 ppm. ES+-MS (m/z) 319
[M+1]+.
Synthesis of L3H2: To a solution of compound 11 (0.46 g,
1.44 mmol) with MgSO4 (0.27 g, 2.25 mmol) and molec-
3
˚
ular sieve 4 A (1 g) in dry MeOH (20 cm ) was added a
solution of ethane-1,2-diamine (0.043 g, 0.72 mmol) in dry
MeOH (3 cm3). The resulting mixture was stirred at room
temperature under N2 overnight. After filtration, the
mixture was crystallized from CHCl3–Et2O to afford a
yellow powder. Yield = 84%. Mp 100–103 ꢁC. IR (KBr)m
1636 (mC@N) cmꢂ1. Anal. Calcd for C38H56N6O4, C,
69.06; H, 8.54; N, 12.72. Found: C, 69.14; H, 8.47; N,
12.69. 1H NMR (CDCl3, 300.13 MHz): d 8.41 (s, 2H,
HC@N), 7.47 (s, aromatic, 2H), 7.19 (s, aromatic, 2H),
3.94 (s, 4H, CH2N@), 3.64 (s, 8H, CH2), 3.47 (s, 4H, CH2),
2.51 (s, 8H CH2), 2.09 (s, 6H, CH3), 1.31 (s, 18H,
C(CH3)3). 13C NMR (CDCl3,75.42 MHz): d 169.0 (C@N),
166.8 (C@N), 157.4, 157.0, 140.9, 131.3, 127.2, 124.1,
117.9, 59.9, 56.2, 53.2, 52.8, 46.4, 41.5, 34.0, 31.5,
21.5 ppm. MS (LR-ES), (m/z) 661 [M+H]+.
19. The synthesis of 10: To a solution of Et3N (1.11 g,
11.0 mmol) in CH2Cl2 (20 cm3) were added over 6 h
solutions of 1 (1.50 g, 5.54 mmol) and piperazine (0.24 g,
2.77 mmol) each dissolved in dry CH2Cl2 (15 cm3). The
yellow solution was stirred for a further 24 h at room
temperature. The solution was washed with water
(3 · 70 cm3) and the organic phase dried over anhydrous
Na2SO4. Removal of the solvent afforded a yellow solid,
which was recrystallised by adding EtOH to a concen-
trated solution of the compound in CHCl3 to afford a pale
yellow powder. Yield = 46%. Mp 169–171 ꢁC. Anal. Calcd
for C28H38N2O4ÆH2O: C, 69.39; H, 8.32; N, 5.78. Found,
C, 69.69; H, 8.16; N, 5.62. 1H NMR (CDCl3,
300.13 MHz): d 1.23 (s, 18H, CH3), 2.56 (br, 8H, CH2),
3.67 (s, 4H, Ph–CH2N), 7.30 (d, J = 2.43 Hz, 2H, Ph–H),
7.53 (d, J = 2.45 Hz, 2H, Ph–H), 10.18 (s, 2H, CHO).
ES+-MS (m/z) 467 [M+1]+.
24. 5-t-Butyl-2-hydroxy-3-(piperazinomethyl)benzaldehyde 9.
A solution of compound 11 (549 mg, 1.72 mmol) in 2 M
HCl (15 cm3) was heated under reflux for 4 days. After
cooling to room temperature, the mixture was brought to
pH ꢁ 7 with saturated Na2CO3 solution. The aqueous
layer was then extracted with CHCl3 and the organic layer
dried over anhydrous Na2SO4 and concentrated to yield
compound 9 as a yellow solid. Yield = 83%. Mp 220–
225 ꢁC (dec.). IR (KBr)m 3433 (br, NH), 1679 (s, C@O)
cmꢂ1. Anal. Calcd for C16H24N2O2Æ0.15CH2Cl2: C, 67.09;
H, 8.47; N, 9.69. Found, C, 67.11; H, 8.43; N, 9.30. 1H
NMR (CDCl3, 300.13 MHz): d 1.31 (s, 9H, CH3), 2.61 (br,
4H, CH2NH), 2.99 (t, 4H, J = 4.80 Hz, CH2CH2N), 3.74
(s, 2H, Ph–CH2N), 7.33 (d, J = 2.53 Hz, 1H, Ph–H), 7.61
(d, J = 2.51 Hz, 1H, Ph–H), 10.25 (s, 1H, CHO). 13C
NMR (CDCl3, 75.42 MHz): d 192.0, 159.3, 141.9, 133.1,
125.0, 122.8, 122.1, 60.6, 53.7, 45.9, 34.2, 31.4 ppm. ES+-
MS (m/z) 277 [M+1]+.
20. Synthesis of L1H2 and L2H4: Dialdehyde 10 (0.3 g,
0.64 mmol) was suspended in dry EtOH (20 cm3) and to
it was added a solution of ethane-1,2-diamine (0.038 g,
0.64 mmol). The mixture was refluxed for 3 h, and after
cooling to room temperature the solvent was removed
under reduced pressure to give
a
yellow solid.
1
Yield = 95%. H NMR (CDCl3, 300.13 MHz): d 1.29 (s,
9H, CH3), 2.60 (s, 4H, CH2), 3.64 (s, 2H, Ph–CH2N), 3.91
(s, 2H, CH2C@N), 7.17 (s, 1H, Ph–H), 7.37 (s, 1H, Ph–H),
8.39 (s, 1H, CH@N). ES+-MS (m/z) 491 [L1H2+1]+ and
981 [L2H4+1]+.
21. Baltzly, R.; Buck, J. S.; Lorz, E.; Schon, W. J. Am. Soc.
Chem. 1944, 66, 263–266.
22. Swain, A. P.; Naegele, S. K. J. Am. Soc. Chem. 1954, 76,
5091–5093.
Synthesis of L4H2: To a solution of 9 (0.17 g, 0.62 mmol)
in dry MeOH (10 cm3) was added a solution of ethane-1,2-
diamine (0.019 g, 0.31 mmol) in dry MeOH (3 cm3). The
solution was stirred for 3 days and removal of the MeOH
23. The synthesis of aldehyde 11: 1-Acetylpiperazine (0.47 g,
under reduced pressure afforded
a
yellow solid.
3.69 mmol) was dissolved in dry MeCN (40 cm3) and to it
Yield = 95%. Mp 134–137 ꢁC. IR (KBr)m: 1632 (vs,
C@N) cmꢂ1. Anal. Calcd for C34H52N6O2Æ2CH3OHÆ
0.5H2O: C, 66.53; H, 9.46; N, 12.93. Found, C, 66.57;
H, 8.99; N, 12.92. 1H NMR (CDCl3, 300.13 MHz): d 1.32
(s, 18H, CH3), 2.57 (br, 8H, CH2NH), 2.99 (t, 8H,
J = 4.75 Hz, CH2CH2N), 3.63 (s, 4H, Ph–CH2N), 3.93 (s,
4H, CH2N@C), 7.18 (d, J = 2.45 Hz, 2H, Ph–H), 7.38 (d,
J = 2.45 Hz, 2H, Ph–H), 8.41 (s, 2H, CH@N); 13C NMR
(CDCl3, 75.42 MHz): d 167.3 (HC@N), 157.7, 141.1,
132.0, 127.5, 124.4, 118.0, 61.0, 59.0, 57.2, 53.8, 45.9, 34.4,
31.8, 19.0. ES+-MS (m/z) 577 [M+1]+.
was added 3-bromomethyl-5-t-butyl-salicylaldehyde
1
(1.00 g, 3.69 mmol) and KHCO3 (0.56 g, 5.60 mmol).
The mixture was heated to reflux under N2 for 6 h and
then allowed to cool to room temperature. The resulting
yellow solution was filtered and after removal of the
solvent under reduced pressure
a yellow solid was
obtained. The solid was re-dissolved in CH2Cl2, and the
yellow solution filtered. Removal of the CH2Cl2 from the
filtrate afforded a bright yellow solid which was purified by
chromatography upon silica gel with CH2Cl2–MeOH