Regioselective alkylation of hydroxysalicylaldehydes

Article abstract of DOI:10.1016/j.tet.2009.03.104

Schiff-base ligands are often used as backbone ligands for mono- and dinuclear complexes that serve as catalysts during aerobic oxidation reactions. However, their water solubility is low and limits their applicability as catalysts to transform highly water-soluble biomolecules, such as carbohydrates or amino alcohols. A new method to regioselectively incorporate water solubility-promoting polyethylene glycol side chains into a frequently used aldehyde building block of Schiff-base ligands has been developed.

Full text of DOI:10.1016/j.tet.2009.03.104

Tetrahedron 65 (2009) 4917–4922
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective alkylation of hydroxysalicylaldehydes
*
Moses G. Gichinga, Susanne Striegler
Auburn University, Department of Chemistry and Biochemistry, 179 Chemistry Building, Auburn, AL 36849, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Schiff-base ligands are often used as backbone ligands for mono- and dinuclear complexes that serve as
catalysts during aerobic oxidation reactions. However, their water solubility is low and limits their ap-
plicability as catalysts to transform highly water-soluble biomolecules, such as carbohydrates or amino
alcohols. A new method to regioselectively incorporate water solubility-promoting polyethylene glycol
side chains into a frequently used aldehyde building block of Schiff-base ligands has been developed.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 16 February 2009
Received in revised form 30 March 2009
Accepted 30 March 2009
Available online 10 April 2009
1. Introduction
Toward that end, we choose commercially available 4-hydroxy-
salicylaldehyde (1) as starting material for
a regioselective
Many complexes based on salen-type ligands derived from
commercially available salicylaldehydes and diamines have been
reported.1–4 The synthesis of these ligands is based on a facile
condensation reaction of two aldehyde moieties with an aromatic
or aliphatic diamine.5–15 The use of dinuclear metal complexes with
Schiff-base backbone ligands as catalysts includes stereoselective
organic transformations, hydroxylation of alkenes, aldol reactions,
alkene epoxidations, Baeyer–Villiger oxidations, and Diels–Alder
reactions.16–22 The metal complexes are tailored with groups that
derivatization of the 4-hydroxy group with polar side chains.
Moreover, the regioselective alkylation of n-hydroxysalicylaldehydes
is still not well understood and consequently still cumbersome. To
overcome this obstacle, we report our experimental results sup-
ported by theoretical calculations.
2. Results and discussion
The incorporation of water solubility promoting polyethylene
glycol (PEG) side chains into 1 using literature procedures de-
veloped for the monoalkylation of n-hydroxysalicylaldehydes
resulted in disappointing overall yields (<5%) as concluded from 1H
and 13C NMR spectroscopic data.22,30 The attempted derivatization
was conducted as a Williamson ether synthesis of 1 using poly-
(ethylene glycol) chlorides 2a–c, then poly(ethylene glycol)
monomethyl ethers 3a–c22 and last tetrahydro-2H-pyranyl poly-
(ethylene glycol) monomethyl ethers 4a–c in DMF, acetone,
dichloromethane, or acetonitrile at 60–100 ꢀC over a period of 24–
72 h as described by others (Fig. 1).22,30
promote, e.g., p–p stacking, hydrogen donor or acceptor abilities, or
emission of fluorescence signals, depending on their potential use
as catalysts, sensors, or screens for bioactivity upon interaction
with carbohydrates, proteins, DNA or viruses.23
UsingSchiff-basecomplexestooxidizealcoholorphenolgroupsof
biomolecules, such as in carbohydrates or lignin, appears favorable
due to their demonstrated oxidation ability and the ease of prepara-
tion. However, increased water solubilityof the complexes is required
forthetransformationofbiomolecules inhomogeneouscatalysis. The
synthetic efforts to alter salen-type ligands accordingly usually focus
on derivatization of the aldehyde building block to avoid alteration of
the geometry around the metal ion core in the resulting ligand.
While peralkylation of phenols with water solubility-promoting
site chains has been frequently described since the pioneering work
of Cram and Peterson on crown ethers,24–28 this method is not
applicable here. The peralkylation of salicylaldehydes as building
blocks for salen complexes limits the number of coordination sites
available for metal ions and consequently decreases their stability.
A reliable method for the regioselective alkylation of hydroxy-
salicylaldehydes with polar, water solubility-promoting side chains
is therefore needed.29
CHO
HO
OH
1
H
Me
THP
Cl
n
Cl
n
Cl
n
O
O
O
4a; n = 1
4b; n = 2
4c; n = 3
2a
2b
2c
3a
3b
3c
Figure 1. 4-Hydroxysalicylaldehyde 1, polyethylene glycol chlorides 2a–c, poly-
ethylene glycol monomethyl ethers 3a–c, and polyethylene glycol tetrahydro-2H-py-
rans 4a–c.
* Corresponding author. Tel.: þ1 344 844 6954; fax: þ1 334 844 6959.
E-mail address: striesu@auburn.edu (S. Striegler).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.104

4918
M.G. Gichinga, S. Striegler / Tetrahedron 65 (2009) 4917–4922
RO
OH
HO
OR
RO
OR
K2CO3
1
+ R-OTs
+
+
O
O
O
CH3CN, 70 °C, 48 h
R= aliphatic
5
6
7
8
Scheme 1. Regioselective alkylation of 1.
Table 1
Distribution of mono-alkylated alkoxysalicylaldehydes 6 and 7 and di-alkylated product 8 after tosylation of 1 with 5
Entry
Tosylate
5
Ratio 6/7/8 (yield in %)a
Alkylated aldehyde
6 or 8
Yieldb of 6 (%)
O
O
O
O
O
1
a
1:<0.1c:4.4 (75)
8a
25
TsO
TsO
O
O
O
OH
O
O
>99.9:<0.1c:<0.1c (46)
>99.9:<0.1c:<0.1c (62)
>99.9:<0.1c:<0.1c (71)
>99.9:<0.1c:<0.1c (74)
>99.9:<0.1c:<0.1c (32)
6b
6c
6d
6e
6f
37
55
48
50
dd
O
O
2
3
4
5
6
b
c
d
e
f
O
2
3
2
OH
TsO
O
3
O
OH
TsO
O
Cl
O
OH
O
O
TsO
Cl
O
O
O
TsO
O
OH
O
TsO
dd
6g
17
O
OH
7
g
O
a
The total yield of the alkylation is given in percent and based on the conversion of 5 as determined by HPLC analysis.
The isolated yield is determined after column chromatography on silica gel.
Below detection limit.
b
c
d
Not isolated or determined.
Increasing the catalytic amount of potassium iodide to a stoi-
Keeping all of these results in mind, we achieved regioselective
4-alkoxylation of 1 with water solubility-promoting aliphatic
polyethylene glycol chains in a one-step reaction after activation of
polyethylene glycol monomethyl ethers by tosylation and fine-
tuning of the reaction conditions.34 The tosylates 5a–g (Table 1)
were prepared from commercially available aliphatic alcohols and
tosyl chloride as described.35 The compounds were purified when
necessary by distillation or column chromatography over silica gel
using ethyl acetate–cyclohexane mixtures as eluent. The identity of
the tosylates was confirmed by 1H and 13C NMR spectroscopy prior
to use (Supplementary data).36–42
chiometric quantity, which usually enhances the reactivity of the
halide,31 did not promote alkylation of 1. Changing the base from
potassium carbonate to sodium/potassium bicarbonate32 or so-
dium/potassium hydroxide33,21 leads to recovery of starting mate-
rial when polar aliphatic instead of benzyl halides are employed.
The use of sodium hydride to deprotonate 1 and subsequent ad-
dition of the alkylhalide promotes undesired peralkylation as
well.24–28 Considerable amounts of di-substituted product (up to
50%) were also observed during the alkylation of 1 with 2 or 4 in
DMF in the presence of potassium carbonate and potassium iodide
above 100 ꢀC, even when stoichiometric amounts of the chlorides
were used. A similar observation was reported by Mendelson et al.
for the regioselective 4-benzylation of 1 with benzyl bromide in
acetone.32 Mono-alkylated products derived from 1 were not ob-
served at all when an excess of 2 or 4 was used, as concluded from
1H and 13C NMR spectra.
In subsequent attempts, benzyl halides were used as model
compounds for the alkylation of 1. These studies revealed that
the use of a slight molar excess of 1 over the halide (1.35:1)
results in the formation of mono-alkylated 1 as the pre-
dominant product in acetonitrile. The product can be easily
separated from the excess of starting material and traces of di-
substituted product (if any) by column chromatography over
silica gel. The separation of an almost equimolar mixture of
mono- and di-substituted 1, which results after use of stoi-
chiometric amounts or excess of halide, was found to be very
tedious.
2.1. Regioselective monoalkylation of hydroxy-
salicylaldehydes with aliphatic tosylates
The tosylates 5a–g were treated with excess of 1 in the presence
of potassium carbonate at 60–70 ꢀC in dry acetonitrile for 48 h
(Scheme 1). Purification of the crude reaction products by column
chromatography over silica gel using ethyl acetate–cyclohexane
mixtures as eluent removed the remaining excess of 1 and
unreacted tosylate.
The analysis of crude reaction mixtures by analytical HPLC,
combined with the analysis of the isolated compounds by 1H and 13
C
NMR spectroscopy and ESI mass spectrometry revealed the forma-
tion of 4-alkoxysalicylaldehydes 6b–f as major reaction products in
moderate yields; the formation of 2-alkoxysalicylaldehydes 7 was
not observed in any case. Surprisingly, the di-substituted product 8a
is the major product for the transformation of 1 with tosylate 5a (see

M.G. Gichinga, S. Striegler / Tetrahedron 65 (2009) 4917–4922
4919
below). Alkylation of 1 with 5e that contains both a chloride and
a tosylate confirmed the increased reactivity of the tosylate over the
halide as leaving group in aprotic polar solvents; the obtained re-
action product 6e contains the chloride.
As both phenol oxygen atoms in 1 allow conjugation with the
carbonyl oxygen after deprotonation, alkylation of the dianion 12
should be equally likely at both phenolate oxygen atoms. The ob-
served regioselective alkylation of 1 with tosylates 5b–g is there-
fore remarkable and requires further investigation. In this regard,
we examined the alkylation of 1 with the tosylates 5a and 5c by
computational methods. The bimolecular nucleophilic substitution
SN2 is among the most widely used organic reactions, and has been
frequently studied both experimentally and with a computational
approach using density functional theory.40,41,43–45
The allocation of structures tothe reactionproducts was based on
the combination of several observations: firstly, the amounts of
protons in the 1H NMR spectra of the isolated compounds 6b–f in-
dicate the formation of mono-alkylated products only and do not
support the presence of di-alkylated 8; this assignment was con-
firmed by ESI mass spectrometry of the corresponding isolated
compounds. Secondly, the composition of the crude reaction mix-
tures was obtained by quantitative analysis using analytical HPLC on
RP 18; the analysis furthermore revealed the selectivity for the for-
mation of 6 versus 7 or 8 and the totalyield of the alkylationbased on
the amount of remaining tosylate 5 (Table 1; Supplementary data).
Thirdly, the structure assignment for the products was further
supported by 13C NMR spectroscopy. The 13C NMR spectra of the
reaction products 7 or 8 with an alkylated 2-hydroxyl group show
a shift of the signal of the carbonyl carbon from 196 ppm (in 1) to
188 ppm (in 7 or 8)indicating alkylation of 1 in close proximitytothe
aldehyde group (see Supplementary data). The 13C NMR spectra of
the 4-alkylated reaction products 6 show signals for the carbonyl
carbon at 196 ppm (see Supplementary data).
2.2. Putative causes for regioselectivityda theoretical
investigation
All computations were performed using the Gaussian 03
suite.46 The geometry of all structures was optimized using Becke’s
three-parameter functional coupled with the correlation function
of Lee et al. (B3LYP) and the basis set 6-31G(d).47,48 This level of
theory was proven to be applicable for the investigation of nu-
cleophilic substitutions including the transition states of SN2
reactions.43,44
The Gibbs free energies DG
298 for the reaction of 12 with 5a and
5c as representative examples of all other alkyl tosylates were
calculated using the B3LYP/6-31G(d) level of theory. Vibrational
frequencies were computed at the same level of theory in order to
define optimized geometries as minima or as saddle points with
one unique imaginary frequency; its vibrational stretching corre-
sponds to the forming and breaking of bonds in the transition state.
To estimate the amount of de-alkylation of the reaction products
during the prolonged reaction time (48 h), 6g was treated with an
excess of potassium carbonate in dry acetonitrile. Formation of 1
was not observed and only starting material, i.e., 6g, was recovered
as shown by HPLC analysis of the crude reaction mixture (see
Supplementary data). The amount of de-alkylation due to pro-
longed reaction times is therefore negligible. Attempts to derive
mono-alkylated products with the developed reactions from 3-
hydroxysalicylaldehyde (9) failed. Instead, peralkylated products
10d and 10e were isolated after reactions of 9 with tosylates 5d or
5e as major products (Fig. 2). The alkylation of 5-hydroxysalicyl-
aldehyde 11 with 5e yielded an equimolar mixture of 2- and
5-alkylated products 11A and 11B in very poor yield (<1%, see
Supplementary data) and was not further investigated.
Activation energies
D
(D
G#) and overall changes in free reaction
D(DGf) were predicted from solvation free energies
energies
Table 2
Relative free energies
G#f ,298) (in kcal/mol) of the TS of the mono- and di-alkylation of dianion 12 with
D(D ) (in kcal/mol) and relative activation energies
G2f 98
D(D
alkyl tosylates 5a and 5c at the B3LYP/6-31þG(d) level of theory in acetonitrile at
298.15 K, 1 atma
IR spectra reveal the absence of any hydroxyl group and intra-
molecular hydrogen bond after exposing 1 to excess potassium
carbonate in dry acetonitrile, which supports the formation of
dianion 12 as first step in the reaction prior to alkylation with
tosylate 5 (Fig. 3).
6a
7a
20
6c
7c
0
OH
OR
OH
K2CO3
CH3CN, 70 °C, 48 h
R= aliphatic
OR
-20
-40
-60
+ R-OTs
O
O
9
5
10
Figure 2. Alkylation of 3-hydroxysalicylaldehyde.
100
HO
OH
TS
6,7
TS
12
8
O
75
50
25
G2f 98
)
D(D )
G#,298
1
Starting material
Product
D
(
D
12
12
12
12
12
12
6a
7a
6c
7c
5a
5a
5a
5c
5c
5c
5a
5a
5c
5c
6a
7a
8a
6c
7c
8c
8a
8a
8c
8c
ꢁ41.0
ꢁ40.4
ꢁ72.8
ꢁ42.6
ꢁ41.7
ꢁ65.3
ꢁ31.7
ꢁ32.4
ꢁ22.8
ꢁ23.6
15.9
17.8
−
−
O
O
O
16.1
23.6
12
27.5
29.8
27.3
30.5
4000
3000
2000
1000
wavenumbers [cm−1
]
a
Solvation free energies in acetonitrile are computed at the CPCM/B3LYP/6-
31þG(d) level of theory.
Figure 3. IR spectra of 12 (solid line) and 1 (dotted line).

4920
M.G. Gichinga, S. Striegler / Tetrahedron 65 (2009) 4917–4922
computed as single point calculations of the geometry-optimized
structures at the CPCM/B3LYP/6-31þG(d) level of theory in
acetonitrile.
Initially, the changes in free energies for the alkylation of 12
with 5 yielding 6, 7, and 8 were calculated (Table 2). Both the
mono- and di-alkylation reactions are spontaneous. The differ-
ences in the reaction free energies for the formation of 2- or 4-
mono-alkylated products 6a and 7a, and 6c and 7c, respectively,
are 0.6–0.9 kcal/mol and therefore insignificant.
aldehydes (which was recognized as a major drawback of com-
mon reaction procedures by others32) with bulky tosylates and
provides comparable or slightly higher yields to described pro-
cedures22,49,50,51 by using acetonitrile and a weak base that
avoids handling of sodium hydride in dry solvents.52 We fur-
thermore provide insight in the reaction pathway by theoretical
investigations and reveal the trapping of mono-substituted re-
action products as intermediates under kinetically controlled
reaction conditions.
The activation energies for the formation of the transition
states TS6 and TS7 from the reaction of 12 with 5a or 5c favor the
substitution at 4- over a substitution at 2-position (Table 2).
While both reactions show comparable activation energies for the
substitution at 4-position of 12, the required activation energy for
the formation of TS7a and TS7c leading to substitution at 2-po-
sition is by 1.9 kcal/mol and 7.5 kcal/mol, respectively, higher. The
computational results are thus in line with the experimental
observations.
The relative free energies of the mono-substituted products
indicate furthermore a competition between 6, 7, and 12 for the
alkylation reagent. The alkylation of 6 at the 2-position is pre-
dicted to require 2.3–3.2 kcal/mol more activation energy than an
alkylation of 7 at the 4-position. Thus, once formed, 4-alkylated
mono-substituted product 6 is easier to trap at that level than 7.
The activation energy for the second transition state is about 11.6–
12 kcal/mol larger than for the first, while the di-substituted
products 8 are thermodynamically the most stable overall re-
action products (Fig. 4). Product 8a is more stable by 7.5 kcal/mol
than 8c, which is ascribed to a decreased flexibility in a shorter
side chain.
3. Experimental
3.1. Instrumentation
1H and 13C NMR spectra were recorded on a Bruker AV400 or
AC250 spectrometer (400.2 or 250 MHz for 1H, and 100.6 or
62.9 MHz for 13C). Chemical shifts ( ) in 1H NMR are expressed in
d
parts per million and coupling constants (J) in hertz. Signal multi-
plicities are denoted as s (singlet), d (doublet), t (triplet), and m
(multiplet). Deuterated chloroform was used as solvent, and
chemical shift values are reported relative to the residual signals of
this solvent (
d
¼7.24 for 1H and
d
¼77.0 for 13C). IR spectra were of
the samples were recorded as thin films on KBr or KBr pellets; n in
cmꢁ1. Elemental analysis was performed by Atlantic Microlab Inc.,
Atlanta, GA. HRMS data were measured in the Laboratory for Bi-
ological Mass Spectrometry, Texas A & M University, College Sta-
tion, TX. Semi-preparative and analytical HPLC were performed on
a Shimadzu HPLC system on RP18 (Luna 3
m
m, 50ꢂ3 mm or
100ꢂ10 mm, respectively) and UV–vis detection of the eluting
compounds at 230 nm.
Overall, the calculations are in line with the experimental re-
sults and provide further insides into the alkylation of 1. The for-
mation of 4-substituted alkylation products 6b–f upon reaction of
12 with 5b–f correlates to the trapping of kinetically controlled
reaction products. The developed reaction conditions do not lead to
the thermodynamically most stable di-substituted products 8b–f.
Steric hindrance by bulky tosylates appears to hamper an attack of
the 2-oxo phenolate of 12 on tosylates 5b–f, and therefore 2- and
di-substituted products are not observed. However, the small size
of tosylate 5a allows the formation of the thermodynamically most
stable product 8a and results in an energy gain based on decreased
flexibility of the side chains compared to a reaction with 5c
(7.5 kcal/mol).
Thin layer chromatography (TLC) was done using silica gel TLC
plates from SORBENT Technologies, 200
m
m, 4ꢂ8 cm, aluminum
backed, with fluorescence indicator F254 with detection by charring
with anthrone sulfate, and/or by UV light when applicable. Column
chromatography was carried out using silica gel 60 from SilicycleÒ
(40–63 mm, 230–240 mesh) as stationary phase. All melting points
were recorded on a Mel-Temp melting point apparatus; the values
are uncorrected. All chemicals were reagent grade or better and
were used as received from commercial suppliers.
All electronic structure calculations in gas phase and solution
were performed with the Gaussian 03 program at the Alabama
Supercomputer Center.46 Low energy conformers of the reactants 1
and 3 (or 5), and of the products 6 were calculated with density
functional theory at the B3LYP/6-31G(d) theory level through-
out.48,47 All stationary points were examined with vibrational
analyses and confirmed as minima. The transition states were ini-
tially optimized at the B3LYP/3-21G level, and the obtained struc-
tures re-optimized at the B3LYP/6-31G(d) level of theory as low
energy conformers. All transition states were characterized by
a single imaginary frequency (nimag). The solvation free energies are
computed as single point calculations at the CPCM/B3LYP/6-
31þG(d) level of theory in acetonitrile at 298.15 K and 1 atm.53 The
free energy of the reaction in acetonitrile was computed using Eq.
In summary, our method allows regioselective 4-alkoxylation
of the least expensive hydroxysalicyl-aldehyde 1, facilitates
separation and isolation of the 4-alkylated product from the
crude reaction mixture, avoids formation of di-alkylated
1;
3
(CH3CN)¼36.64.
D
GðCH3CNÞ ¼
D
GðgasÞ þ
D
GðsolvationÞ
(1)
3.2. 4-(2-Methoxyethoxy)-salicylaldehyde (6a)
A mixture of 2,4-dihydroxybenzaldehyde (3.04 g, 22 mmol),
toluene-4-sulfonic acid 2-methoxy-ethyl ester (4 g,17.6 mmol), and
potassium carbonate (3 g, 22 mmol) in 150 mL acetonitrile was
stirred for 48 h at 60 ꢀC. The reaction mixture was then cooled to
ambient temperature, filtered, and the solvent evaporated to obtain
a crude yellow oil. The crude product was purified by column
chromatography over silica gel using CH2Cl2/MeOH (98:2) to obtain
Figure 4. TS for the alkylation of 12 with 5c yielding 6c; carbon atoms are colored in
gray, hydrogen atoms in white, oxygen atoms in red, sulfur atoms in yellow.

M.G. Gichinga, S. Striegler / Tetrahedron 65 (2009) 4917–4922
4921
a crystalline colorless solid (750 mg, 21%). Rf 0.87, SiO2, CH2Cl2/
MS) m/z, found: 179.0709; calcd for
179.0708.
C
10H10O3þHþ (MþHþ)
MeOH (98:2); mp 63–64 ꢀC. Found: C 61.27, H 6.16%; C10H12O4 re-
quires C 61.22, H 6.16%. dH (400.2 MHz, CDCl3) 11.50 (s, 1H, OH), 9.74
(s,1H, CHO), 7.46 (d, 8.6,1H, ArH), 6.61 (dd, 8.7, 2.4,1H, ArH), 6.47 (d,
2.3, 1H, ArH), 4.19 (t, 4.9, 2H, ArOCH2–), 3.79 (t, 4.9, 2H, –CH2–O–),
3.48 (s, 3H, –OCH3); dC (100.6 MHz, CDCl3) 194.5, 166.0, 164.4, 135.3,
115.3, 108.9, 101.2, 71.9, 70.6, 67.8, 59.3; nmax (thin film) 2929,
2890w (CH), 1627s (C]O), 1225m, 1173s (C–O–C) cmꢁ1; HRMS
(þTOF MS) m/z found: 197.0811; calcd for C10H12O4þHþ (MþHþ)
197.0814.
3.7. 4-[2-(2-Chloroethoxy)ethoxy]-salicylaldehyde (6e)
A mixture of 0.6 g (4.4 mmol) 2,4-dihydroxybenzaldehyde, 1 g
(3.6 mmol) 2-(2-chloroethoxy)ethyl 4-methylbenzenesulfonate,
and 0.72 g (5.2 mmol) potassium carbonate was stirred in 100 mL
acetonitrile at 70 ꢀC for 48 h. The reaction mixture was then cooled
to room temperature, filtered over Celite and evaporated. A crude
brown oil was obtained that was purified by column chromato-
graphy over silica gel using cyclohexane–ethyl acetate (7:3) as el-
uent to yield 0.44 g (1.8 mmol, 50%) of a colorless oil. Found: C
54.19, H 5.41%; C11H13ClO4 requires: C 54.00, H 5.36%. nmax (thin
3.3. 2,4-Bis(2-methoxyethoxy)benzaldehyde (8a)
Colorless oil; dH (400.2 MHz, CDCl3) 10.31 (s, 1H, CHO), 7.78 (d,
8.6, 1H, ArH), 6.54 (dd, 8.6, 1.5, 1H, ArH), 6.49 (d, 2.0, 1H, ArH), 4.16
(m, 4H, ArOCH2–), 3.75 (m, 4H, –CH2–O–CH3), 3.43 (s, 6H, –CH3); dC
(100.6 MHz, CDCl3) 188.3, 162.9, 130.3, 119.4, 106.4, 99.7, 70.7, 70.6,
68.1, 67.6, 59.3, 59.2; HRMS (þTOF MS) m/z found 255.1224; calcd
for C13H18O5þHþ (MþHþ) 255.1232.
film) 3088br (OH), 2942s (C–H), 1651s (C]O), 1121s (C–O) cmꢁ1
; dH
(400.2 MHz, CDCl3) 11.44 (s, 1H, OH), 9.69 (s, 1H, CHO), 7.41 (d, 8.6,
1H, ArH), 6.54 (dd, 8.7, 2.4, 1H, ArH), 6.40 (d, 2.4, 1H, ArH), 4.16 (t,
4.8, 2H, ArOCH2–), 3.87 (t, 4.7, 2H, –CH2Cl), 3.80 (m, 2H, –CH2–),
3.63 (m, 2H, –CH2–); dC (100.6 MHz, CDCl3) 194.6, 166.0, 164.6,
135.5, 115.5, 108.9, 101.5, 71.8, 69.5, 68.5, 68.0, 42.9; HRMS (þTOF
MS) m/z, found 251.0665; calcd for C11H13ClLiO4 (MþLiþ) 251.0662.
3.4. 4-[2-(2-Methoxyethoxy)-ethoxy]-salicylaldehyde (6b)
A mixture of 1.41 g (10 mmol) 2,4-dihydroxybenzaldehyde,
1.81 g (7.1 mmol) 2-(2-methoxyethoxy)ethyl-4-methylbenzene-
sulfonate, and 1.41 g (10 mmol) potassium carbonate was stirred in
150 mL acetonitrile at 70 ꢀC for 48 h. The reaction mixture was then
cooled to room temperature and filtered over a silica gel with
CH2Cl2. A crude brown oil (1.8 g) was obtained that was purified by
column chromatography over silica gel with cyclohexane–ethyl
acetate (1:1) yielding 0.6 g (2.50 mmol, 37%) of a colorless oil. dH
(400.2 MHz, CDCl3) 11.46 (s, 1H, OH), 9.71 (s, 1H, CHO), 7.42 (d, 8.6,
1H, ArH), 6.56 (dd, 8.7, 2.4, 1H, ArH), 6.43 (d, 2.3, 1H, ArH), 4.19 (t,
4.9, 2H, ArOCH2–), 3.87 (t, 4.9, 2H, –CH2CH2O–), 3.72 (m, 2H, –CH2–),
3.58 (m, 2H, –CH2–), 3.39 (s, 3H, –CH3); dC (100.6 MHz, CDCl3) 194.6,
166.2, 164.6, 135.4, 115.4, 108.9, 101.5, 72.1, 71.0, 69.5, 68.0, 59.3;
nmax (thin film) 3247br (OH), 3063w, 2868s, 1646s (C]O), 1109s (C–
3.8. 4-Cyclohexylmethoxysalicylaldehyde (6g)
A mixture of 2.1 g (14.5 mmol) 2,4-dihydroxybenzaldehyde 1,
2 g (7.5 mmol) cyclohexylmethyl p-tosylate 5g, and 2 g (14.5 mmol)
potassium carbonate was stirred in 150 mL acetonitrile at 60 ꢀC for
48 h. The reaction mixture was then allowed to cool to ambient
temperature, and filtered; the solvent was evaporated to obtain
a dark brown oil. The residue was dissolved in 15 mL of 1 M HCl(aq)
and extracted with dichloromethane (2ꢂ50 mL). The combined
organic layers were washed with 5% NaHCO3 and water, and dried
over anhydrous sodium sulfate. The crude product (1.78 g) was
purified by column chromatography over silica gel with petroleum
ether–diethyl ether (9:1) yielding 0.3 g (1.3 mmol, 17%) of a color-
less solid; mp 55–57 ꢀC. Found: C 71.77, H 7.60%; C14H18O3 requires
C 71.77, H 7.74%. dH (250.1 MHz, CDCl3) 11.46 (s, 1H, ArOH), 9.67 (s,
1H, ArCHO), 7.39 (d, 8.7,1H, ArH), 6.50 (dd, 8.7, 2.4,1H, ArH), 6.38 (d,
2.4,1H, ArH), 3.77 (d, 6.0, 2H, –OCH2–), 1.72 (m, 6H, –C6H11), 1.14 (m,
5H, –C6H11); dC (62.9 MHz, CDCl3) 194.3, 166.6, 164.5, 135.2, 115.0,
108.8, 101.1, 73.9, 37.4, 29.7, 26.4, 25.7; nmax (thin film) 3136w
(arom. CH), 2922, 2852s (aliph. CH), 1636s (C]O), 1222s (C–O–
C) cmꢁ1; HRMS (ꢁTOF MS) m/z, found: 233.1186; calcd for C14H17O3
(MꢁHþ)ꢁ 233.1178.
O) cmꢁ1
;
HRMS (þTOF MS) m/z found: 247.1160; calcd for
C12H16LiO5 (MþLiþ) 247.1158.
3.5. 4-[2-(2-(Methoxyethoxy)-ethoxy)-ethoxy]-
salicylaldehyde (6c)
Compound 6c was synthesized and characterized previously.54
3.6. 4-Allyloxysalicylaldehyde (6d)
Acknowledgements
A mixture of 1.5 g (10.6 mmol) 2,4-dihydroxybenzaldehyde,
1.5 g (7.1 mmol) allyl tosylate, and 1.2 g (10.8 mmol) potassium
carbonate was stirred in 150 mL acetonitrile at 60 ꢀC for 12 h. The
reaction mixture was then cooled to ambient temperature, filtered,
and the solvent evaporated to obtain a brown solid. The residue was
dissolved in 10 mL of distilled water and extracted using chloro-
form (2ꢂ50 mL). The combined organic layers were dried over
anhydrous sodium sulfate and evaporated to obtain 1.10 g of
a crude product that was purified by column chromatography over
silica gel with cyclohexane/ethyl acetate (9:1) as eluent yielding
0.61 g (3.42 mmol, 48%) of a colorless oil. Found: C 67.13, H 5.65%;
C10H10O3 requires C 67.41, H 5.66%. dH (400.2 MHz, CDCl3) 11.44 (s,
1H, ArOH), 9.68 (s, 1H, ArCHO), 7.40 (d, 8.6, 1H, ArH), 6.53 (dd, 8.6,
2.3, 1H, ArH), 6.41 (d, 2.3, 1H, ArH), 6.00 (m, 1H, –CH]CH2), 5.40
(ddd, 17.2, 3.0, 1.6, 1H, –CH]CH2), 5.31 (ddd, 10.5, 2.7, 1.4, 1H,
–CH]CH2), 4.56 (dt, 5.3, 1.5, 2H, –CH2–); dC (100.6 MHz, CDCl3)
194.4, 165.7, 164.4, 135.2, 131.9, 118.5, 115.2, 108.8, 101.4, 69.1; nmax
(thin film) 3259w (OH), 3084w (arom. C–H), 2840, 2748w (CHO),
1628s (C]O), 1577m (C]C), 1222s (C–O–C) cmꢁ1; HRMS (þTOF
This work was stimulated by an interesting discussion with Akin
Akdag. The authors gratefully acknowledge support from Auburn
University and the National Science Foundation (CAREER award
CHE-0746635 to S.S.); thanks is given to Orlando Acevedo for advice
during initial stages of the DFT calculations; the work was made
possible in part by a grant of high performance computing re-
sources and technical support from the Alabama Supercomputer
Authority.
Supplementary data
The Supplementary data includes all traces of all HPLC analyses,
the experimental details and spectra of all tosylates, 1H and 13C
NMR, HRMS, and IR data of all new compounds and the complete
citation for the Gaussian 03 package. Supplementary data associ-
ated with this article can be found in the online version, at
doi:10.1016/j.tet.2009.03.104.

4922
M.G. Gichinga, S. Striegler / Tetrahedron 65 (2009) 4917–4922
31. Dewick, P. M. Synth. Commun. 1981, 11, 853–857.
References and notes
32. Mendelson, W. L.; Holmes, M.; Dougherty, J. Synth. Commun. 1996, 26, 593–601.
33. Daly, J.; Homer, L.; Witkop, B. J. Am. Chem. Soc. 1961, 83, 4787–4792.
34. Lottner, C.; Bart, K.-C.; Bernhardt, G.; Brunner, H. J. Med. Chem. 2002, 45,
2079–2089.
35. Kazemi, F.; Massah, A. R.; Javaherian, M. Tetrahedron 2007, 63, 5083–5087.
36. Heathcote, R.; Howell, J. A. S.; Jennings, N.; Cartlidge, D.; Cobden, L.; Coles, S.;
Hursthouse, M. Dalton Trans. 2007, 1309–1315.
37. MacDowell, D. W. H.; Purpura, J. M. J. Org. Chem. 1986, 51, 183–188.
38. Oh, H. K.; Song, S. J.; Jo, D.-S.; Lee, I. J. Phys. Org. Chem. 1997, 10, 91–96.
39. Benco, J. S.; Nienaber, H. A.; Dennen, K.; McGimpsey, W. G. J. Photochem. Pho-
tobiol., A: Chem. 2002, 152, 33–40.
40. Kohmoto, S.; Mori, E.; Kishikawa, K. J. Am. Chem. Soc. 2007, 129, 13364–13365.
41. Nakamura, M.; Yokono, H.; Tomita, K.-i.; Ouchi, M.; Miki, M.; Dohno, R. J. Org.
Chem. 2002, 67, 3533–3536.
1. Matsumoto, K.; Saito, B.; Katsuki, T. Chem. Commun. 2007, 3619–3627.
2. Baleizao, C.; Garcia, H. Chem. Rev. 2006, 106, 3987–4043.
3. Rokita, S.E.; Burrows, C.J. Salen-metal complexes. In Small Molecule DNA and
RNA Binders, Demeunyuck, M., Bailly, W.D., Wilson, W.D., Eds.; Wiley VCH,
2003; Vol. 1, pp 126–145.
4. Leadbeater, N. E.; Marco, M. Chem. Rev. 2002, 102, 3217–3273.
5. Sessler, J. L.; Melfi, P. J.; Pantos, G. D. Coord. Chem. Rev. 2006, 250, 816–843.
6. Drozdzak, R.; Allaert, B.; Ledoux, N.; Dragutan, I.; Dragutan, V.; Verpoort, F.
Coord. Chem. Rev. 2005, 249, 3055–3074.
7. Lewinski, J.; Zachara, J.; Justyniak, I.; Dranka, M. Coord. Chem. Rev. 2005, 249,
1185–1199.
8. Cozzi, P. G. Chem. Soc. Rev. 2004, 33, 410–421.
9. Katsuki, T. Chem. Soc. Rev. 2004, 33, 437–444.
42. Kabalka, G. W.; Varma, M.; Varma, R. S.; Srivastava, P. C.; Knapp, F. F., Jr. J. Org.
Chem. 1986, 51, 2386–2388.
43. Bento, A. P.; Sola, M.; Bickelhaupt, F. M. J. Comput. Chem. 2005, 26, 1497–1504.
44. Vayner, G.; Houk, K. N.; Jorgensen, W. L.; Brauman, J. I. J. Am. Chem. Soc. 2004,
126, 9054–9058.
10. Beckmann, U.; Brooker, S. Coord. Chem. Rev. 2003, 245, 17–29.
11. Che, C.-M.; Huang, J.-S. Coord. Chem. Rev. 2003, 242, 97–113.
12. Tsuchida, E.; Oyaizu, K. Coord. Chem. Rev. 2003, 237, 213–228.
13. Brooker, S. Eur. J. Inorg. Chem. 2002, 2535–2547.
14. Sunatsuki, Y.; Motoda, Y.; Matsumoto, N. Coord. Chem. Rev. 2002, 226, 199–
209.
15. Ziessel, R. Coord. Chem. Rev. 2001, 216-217, 195–223.
16. Prajapati, A. K.; Bonde, N. Liq. Cryst. 2006, 33, 1189–1197.
17. Yelamaggad, C. V.; Shashikala, I. S.; Rao, D. S. S.; Nair, G. G.; Prasad, S. K. J. Mater.
Chem. 2006, 16, 4099–4102.
18. Aiello, I.; Ghedini, M.; Grisolia, A.; Pucci, D.; Francescangeli, O. Liq. Cryst. 2005,
32, 763–769.
45. Bento, A. P.; Bickelhaupt, F. M. J. Org. Chem. 2007, 72, 2201–2207.
46. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth,
G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A.
D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox,
D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, Revision D.01, Gaussian: Wallingford, CT, 2004.
19. Pinol, R.; Ros, M. B.; Serrano, J. L.; Sierra, T.; de la Fuente, M. R. Liq. Cryst. 2004,
31, 1293–1303.
20. Zell, P.; Moegele, F.; Ziener, U.; Rieger, B. Chem.dEur. J. 2006, 12, 3847–3857.
21. Binnemans, K.; Galyametdinov, Y. G.; van Deun, R.; Bruce, D. W.; Collinson, S. R.;
Polishchuk, A. P.; Bikchantaev, I.; Haase, W.; Prosvirin, A. V.; Tinchurina, L.;
Litvinov, I.; Gubajdullin, A.; Rakhmatullin, A.; Uytterhoeven, K.; Van Meervelt, L.
J. Am. Chem. Soc. 2000, 122, 4335–4344.
22. Kocian, O.; Chiu, K. W.; Demeure, R.; Gallez, B.; Jones, C. J.; Thornback, J. R.
J. Chem. Soc., Perkin Trans. 1994, 527–535.
23. Striegler, S. Curr. Org. Chem. 2007, 11, 1543–1565.
24. Kyba, E. P.; Siegel, M. G.; Sogah, K. R. S. D. Y.; Cram, D. J. J. Am. Chem. Soc. 1973,
95, 2691–2692.
25. Jarosz, S.; Listkowski, A. Curr. Org. Chem. 2006, 10, 643–662.
26. Steed, J. W.; Wallace, K. J. Adv. Supramolecular Chem. 2003, 9, 219–260.
27. Simonneaux, G.; Le Maux, P. Coord. Chem. Rev. 2002, 228, 43–60.
28. Pu, L. Chem. Rev. 1998, 98, 2405–2494.
47. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. 1988, 37, 785–789.
48. Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
49. van Staveren, C. J.; van Eerden, J.; van Veggel, F. C. J. M.; Harkema, S.; Reinhoudt,
D. N. J. Am. Chem. Soc. 1988, 110, 4994–5008.
50. Kilenyi, S. N.; Mahaux, J. M.; van Durme, E. J. Org. Chem. 1991, 56, 2591–2594.
51. van Doorn, A. R.; Bos, M.; Harkema, S.; van Eerden, J.; Verboom, W.; Reinhoudt,
D. N. J. Org. Chem. 1991, 56, 2371–2380.
52. Kessar, S. V.; Gupta, Y. P.; Mohammad, T.; Goyal, M.; Sawal, K. K. J. Chem. Soc.,
Chem. Commun. 1983, 400–401.
53. Takano, Y.; Houk, K. N. J. Chem. Theory Comput. 2005, 1, 70–77.
54. Gichinga, M. G.; Striegler, S. J. Am. Chem. Soc. 2008, 130, 5150–5156.
29. Hu, Z.; Hardie, M. J.; Burckel, P.; Pinkerton, A. A.; Erhardt, P. W. J. Chem. Crys-
tallogr. 1999, 29, 185–191.
30. Kyba, E. P.; Helgeson, R. C.; Madan, K.; Gokel, G. W.; Tarnowski, T. L.; Moore,
S. S.; Cram, D. J. J. Am. Chem. Soc. 1977, 99, 2564–2571.