A one-pot synthesis and X-ray crystallographic and computational analyses of methyl-2,4-dimethoxysalicylate - A anti-tumour agent

Article abstract of DOI:10.1139/v04-113

The thermal decarboxylation of 2-methoxycarbonyl-5-(4′-nitrophen-oxy) tetrazole (1a) with the electron-rich, aromatic compounds (anisole, N,N-dimethylaniline, 1,4-dimethoxybenzene, and 1,3,5-trimethoxybenzene), neat or in polar solvents (DMSO, DMF, and CH₃CN), is investigated. The solid phase thermal decomposition of a mixture of 1a, 1,3,5-trimethoxybenzene, and a Lewis acid (AlCl₃) produces methyl-2,4-dimethoxysalicylate (8) in good yield, instead of the expected 2,4,6-trimethoxybenzoic acid. The X-ray structure of 8 shows intramolecular hydrogen bonds between the carbonyl oxygen and hydrogens of Me and OH groups. A measured pK_a value of 6.8 compares well with a value of 6.4 estimated using the [C=O...H...O] hydrogen bond distances.

Full text of DOI:10.1139/v04-113

1
179
A one-pot synthesis and X-ray crystallographic
and computational analyses of methyl-2,4-
dimethoxysalicylate — a potential anti-tumour
agent
Hossein A. Dabbagh, Nader Noroozi-Pesyan, Brian O. Patrick, and
Brian R. James
Abstract: The thermal decarboxylation of 2-methoxycarbonyl-5-(4′-nitrophen-oxy)tetrazole (1a) with the electron-rich,
aromatic compounds (anisole, N,N-dimethylaniline, 1,4-dimethoxybenzene, and 1,3,5-trimethoxybenzene), neat or in po-
lar solvents (DMSO, DMF, and CH CN), is investigated. The solid phase thermal decomposition of a mixture of 1a,
3
1
,3,5-trimethoxybenzene, and a Lewis acid (AlCl ) produces methyl-2,4-dimethoxysalicylate (8) in good yield, instead
3
of the expected 2,4,6-trimethoxybenzoic acid. The X-ray structure of 8 shows intramolecular hydrogen bonds between
the carbonyl oxygen and hydrogens of Me and OH groups. A measured pK value of 6.8 compares well with a value
a
of 6.4 estimated using the [C=O···H···O] hydrogen bond distances.
Key words: anti–tumor, novel synthesis, X-ray structure, hydrogen bonds, computational analysis.
Résumé : On a étudié la décarboxylation thermique du 2-méthoxycarbonyl-5-(4′-nitrophényl)tétrazole (1a) en présence
de composés aromatiques riches en électrons (anisole, N,N-diméthylaniline, 1,4-diméthoxybenzène et 1,3,5-triméthoxy-
benzène) à l’état pur ou dans des solvants polaires (DMSO, DMF et CH CN). La décomposition thermique en phase
3
solide d’un mélange de 1a, de 1,3,5-triméthoxybenzène et d’un acide de Lewis (AlCl ) conduit à la formation du 2,4-
3
diméthoxysalicylate de méthyle (8) avec un bon rendement au lieu de l’acide 2,4,6-triméthoxybenzoïque attendu. La
structure du composé 8 telle que déterminée par diffraction des rayons X montre la présence de liaisons hydrogènes in-
tramoléculaires entre l’oxygène du carbonyle et les atomes d’hydrogène des groupes méthyle et hydroxyle. La valeur
mesurée de 6,8 pour le pK se compare bien avec la valeur de 6,4 évaluée sur la base des longueurs des liaisons hy-
a
drogènes [C=O···H···O].
Mots clés : antitumoral, synthèse nouvelle, structure par diffraction des rayons X, liaisons hydrogènes, analyse confor-
mationnelle.
[
Traduit par la Rédaction] Dabbagh et al. 1185
Introduction
2-OH-4-NH . Other derivatives of dimethoxybenzoic acid
have also received considerable attention (4).
Numerous methods have been reported for the synthesis
of hydroxybenzoic acids and their methoxy derivatives (e.g.,
2
Trimethoxybenzoic acid derivatives are important because
of their pharmaceutical and biological activities (1), and in-
dustrial applications (2). A recent patent reported that a wide
range of benzoic acid derivatives have good anti-tumour
properties, their activity being related to novel synergistic
compositions that selectively control tumour tissue (3); the
mixtures contain at least two of the following benzoic acid
derivatives: 2-OH, 2-O CMe, 2,4-(OMe) , 2,4,6-(OMe) ,
2
3
,3-(OH) (5), 2,4-(OH) (6), 2,5-(OH) (7), 2,6-(OH) (8),
,4-(OH)2 (9), 2,3,4-(OH)3 (10), 2,3,5-(OH)3 (11), 2,3,6-
2 2 2 2
(
OH) (12), 2,4,5-(OH) (13), and 2,4,6-(OH) (14)). 2,4,6-
3 3 3
Trimethoxybenzoic acid has been synthesized by methyl-
ation of 2,4,6-trihydroxyphenyl allyl ether using Me SO ,
2
4
2
2
3
followed by oxidation using KMnO (15), or from phloro-
4
glucinol (16) or β-resorcinol (17). The best known derivative
Received 24 January 2004. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 17 September
of benzoic acid is the most often recommended drug aspirin
(
acetylsalicylic acid), which is an analgesic, effective in re-
lieving headaches, and has anti-inflammatory and other ben-
eficial properties (18).
2
004.
1
H.A. Dabbagh and N. Noroozi-Pesyan. Department of
Chemistry, Isfahan University of Technology, P.O. Box
One of our groups recently reported the equilibria, kinet-
ics, and mechanism for the isomerization of 2-methoxycar-
bonyl-5-(p-X-phenoxy)tetrazoles (X = H, Me, NHCOMe,
8
4155, Isfahan, Iran.
B.O. Patrick and B.R. James. Department of Chemistry,
The University of British Columbia, Vancouver, BC
V6T 1Z1, Canada.
Cl, Br, and NO ; 1 → 2 (Scheme 1, pathways a and b)) (19,
2
2
0), and also their thermal decarboxylation to form in high
1Corresponding author (e-mail: dabbagh@cc.iut.ac.ir).
yield 5-(aryloxy)tetrazoles (3, 4 (Scheme 1, pathways c and
Can. J. Chem. 82: 1179–1185 (2004)
doi: 10.1139/V04-113
© 2004 NRC Canada

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Can. J. Chem. Vol. 82, 2004
Scheme 1. Summary of chemistry for the tetrazoles 1 and 2.
Scheme 2. Formation of 8.
other electron-rich reagents. We initially thought that the
0% product was 2,4,6-trimethoxybenzoic acid (7D)
3
1
(
Scheme 1). This was based on H NMR (90 MHz) in
DMSO-d : δ 3.63 (br s, 3H), 3.66 (s, 6H), and 6.0 (br s, 2H),
6
+
and MS data that showed a parent M peak at 212. However,
the melting point (96–98 °C) did not match the value of
1
58 °C (decomp.) given for 7D in the Lancaster Chemicals
1
catalogue. Further examination by H NMR (300 MHz) in
CDCl revealed a well-resolved spectrum (δ 3.73 (s, 3H),
3
3
1
.74 (s, 3H), 3.83 (s, 3H), 5.89 (d, 1H, J = 8 Hz), 6.02 (d,
H, J = 8.3 Hz), 11.91 (s, 1H)), while the corresponding 13
C
NMR spectrum showed 10 signals (see Experimental). The
NMR data show the presence of three inequivalent OMe
groups and two inequivalent aromatic protons. We consid-
ered as a possibility the H-bonded structure 7X, but an X-
ray structure revealed that the product was, in fact, methyl-
2
,4-dimethoxysalicylate (8, Fig. 1; see Table 1 for crystal
and structure refinement data), which accounts for the NMR
data; formally, this has been formed from the “expected 7D”
by the interchange of a Me group (of a 2- or 6-OMe) with
the carboxylic acid proton. The co-products isolated with 8
are 1- and 2-Me-5-aroyltetrazole (4a and 3a, respectively)
and the tetrazole 5.
d)) (21), when CO is released at temperatures below the
2
melting points of the precursor methoxycarbonyl derivatives.
In the work reported here, we attempted to utilize 1 as a
potential carboxylation and (or) alkylation agent (Scheme 1,
pathways e and f ) for electron-rich aromatic compounds
such as N,N-dimethylaniline, anisole, 1,4-dimethoxybenzene,
and 1,3,5-trimethoxybenzene (Schemes 1 and 2), the plan
being to trap any released (free) alkyl or acyl groups during
the reaction. However, we unexpectedly synthesized methyl-
2
,4-dimethoxysalicylate by a method that might aid in the
synthesis of new compounds or compounds previously diffi-
cult to prepare. The new findings also shed more light on the
mechanism of isomerization, decarboxylation, alkylation,
and (or) acylation of 2-alkloxycarbonyl-5-aryloxytetrazoles.
Of note, the structure of 2,4,6-trimethoxybenzoic acid
7D) has not been determined, although the structure of an
Results and discussion
(
The thermal decomposition of 1a–1e in polar aprotic sol-
vents (DMSO, DMF, and MeCN) gives 3a–3e and 4a–4e in
high yield (21). In the present study, the reaction of 1a–1e in
the presence of the electron-rich aromatic compounds men-
tioned above was investigated both in polar aprotic solvents
and solvent-free conditions. There was no trace of the
carboxylation or alkylation of the electron-rich aromatic ring
inclusion compound of this acid with 2′,6′-dimethoxyflavone
(in which the carboxylic acid proton is H-bonded to the
flavone carbonyl) reveals a nonplanar benzoic acid compo-
nent, the carboxylic acid moiety being ~66° out of the plane
of the rest of the acid molecule (4c).
The carbon–oxygen framework of the molecular structure
of 8 is essentially planar; bond lengths and angles are sum-
marized in Table 2, while a structural diagram is shown also
in Scheme 3. Planarity is maintained by a strong intramole-
cular H-bonding interaction between the carbonyl oxygen
and phenolic H atom (H(1)···O(1) = 1.68(4) Å; O(5)-H(1) =
1.00(4) Å), and a much weaker intramolecular H-bond of
distance 2.535 Å between Me hydrogens (H(8)) and the
(
Scheme 2). With 1,3,5-trimethoxybenzene (the most
electron-rich aromatic ring) under solvent-free conditions, a
low yield product was obtained (<2%), while in the presence
of a Lewis acid (AlCl ), the yield was increased to 30%.
3
There were no akylation (6A–6C) or carboxylation (7A–7C)
products (see Scheme 1) detected from reactions with the
©
2004 NRC Canada

Dabbagh et al.
1181
Fig. 1. Molecular structure for 8 with 50% probability ellipsoids.
Table 1. Crystal data and structure refinement for 8.
Empirical formula
C H O
10 12 5
Formula weight
Temperature (K)
Crystal system
Space group
Unit cell dimensions
a (Å)
212.20
173(1)
Monoclinic
P2 /c
1
7.634(1)
b (Å)
8.931(2)
c (Å)
14.274(3)
β (°)
91.82(1)
972.7(3)
3
Volume (Å )
Z
4
–
3
Density (calculated) (Mg m )
Absorption coefficient (mm )
1.449
0.117
–
1
F(000)
Crystal size (mm )
448.00
0.13 × 0.10 × 0.04
3
θ range for data collection (°)
Index ranges
Reflections collected
2.67–23.65
–8 ≤ h ≤ 8, –9 ≤ k ≤ 9, –15 ≤ l ≤ 15
6441
Independent/observed reflections
1390 (R(int) = 0.102)/671 (I >3σ(I))
46.5
2θmax (°)
Data/parameters
Goodness-of-fit on F
Weight parametersa
1390/140
0.99
p = 0.0310
2
Final R indices (I >3σ(I))
R1 = 0.039, wR = 0.074
2
R indices (all data)
R1 = 0.086, wR = 0.106
2
b
–3
Largest diff. peak and hole (e Å )
0.64 and –0.45
a
2
2
2
2
–1
w = [σ (F ) + p F /4] .
c
o
o
b
At ~1.1 Å from O(1).
©
2004 NRC Canada

1
182
Can. J. Chem. Vol. 82, 2004
Table 2. Bond lengths (Å) and angles (°) of 8 (esds in parentheses).
Atomsa
Bond lengths (Å)
Atoms
Bond angles (°)
O(1)—C(7)
O(2)—C(7)
O(2)—C(8)
O(3)—C(2)
O(3)—C(9)
O(4)—C(4)
O(4)—C(10)
C(1)—C(2)
C(1)—C(6)
C(1)—C(7)
C(2)—C(3)
C(3)—C(4)
C(4)—C(5)
C(5)—C(6)
O(5)—C(6)
1.247(4)
1.325(4)
1.465(4)
1.363(4)
1.438(4)
1.362(4)
1.443(4)
1.432(4)
1.393(4)
1.465(4)
1.378(4)
1.406(4)
1.364(4)
1.402(5)
1.349(4)
C(7)-O(2)-C(8)
C(2)-O(3)-C(9)
C(4)-O(4)-C(10)
C(2)-C(1)-C(6)
C(2)-C(1)-C(7)
C(6)-C(1)-C(7)
O(3)-C(2)-C(1)
O(3)-C(2)-C(3)
C(1)-C(2)-C(3)
C(2)-C(3)-C(4)
O(4)-C(4)-C(3)
O(4)-C(4)-C(5)
C(3)-C(4)-C(5)
C(4)-C(5)-C(6)
O(5)-C(6)-C(1)
O(5)-C(6)-C(5)
C(1)-C(6)-C(5)
O(1)-C(7)-O(2)
O(1)-C(7)-C(1)
O(2)-C(7)-C(1)
116.1(3)
117.1(3)
115.8(2)
116.9(3)
124.7(3)
118.3(3)
117.1(3)
121.9(3)
121.03
119.8(3)
114.4(3)
125.1(3)
120.6(3)
119.7(3)
122.3(3)
115.7(3)
122.0(3)
120.7(3)
122.0(3)
117.3(3)
a
Atom numbering is as in Fig. 1.
Scheme 3. Structure of 8. Corresponding structures calculated by
ab initio, AM1, and PM3 methods are available as Supplemen-
tary material.2
Scheme 4. Diagrams showing the favored so-called bisected
(left) and eclipsed (right) conformations of 8.
was 2.574 Å. The ab initio calculation also revealed a
1
.40 kcal (1 cal = 4.1868 J) higher energy, eclipsed confor-
mation with C symmetry (Figs. 2c and 2d, Scheme 4, Ta-
1
ble 3) with an H(8)-carbonyl bond length of 2.14 Å.
The proposed mechanism for the formation of 8 is out-
lined in Scheme 5. The Lewis acid activates the carbonyl
group of the tetrazole 1a and initiates a nucleophilic aro-
matic substitution reaction with 1,3,5-trimethoxybenzene to
form a resonance-stabilized intermediate (9 ↔ 10) and the
tetrazolide anion (B:); this then reacts with the Me group of
the 2-OMe of 10 (via a bimolecular nucleophilic substitution
process) to produce intermediate 11 that isomerizes to 8, a
strongly resonance-stabilized compound (Scheme 6). That
methyl-4-hydroxy-2,6-dimethoxy benzoate is not formed is a
good indication that intermediate 10 is involved. Compound
8 is not sensitive to air, moisture, or heat, and could be con-
verted easily to other useful derivatives such as 2-hydroxy-
4,6-dimethoxybenzoic acid, methyl-2,4,6-trimethoxybenzoate,
and 1,3,5-trimethoxybenzoic acid. The mechanism accounts
nicely for the observed methyltetrazole co-products 3a and
4a, while 5 is a hydrolysis product (see Scheme 1). Corre-
C=O double bond (in what we label a “bisected” conforma-
tion with C symmetry (Figs. 2a and 2b, and Scheme 4)).
s
The orientations of the o-OMe and ester-OMe are such to
minimize steric interactions. The structure of 8 was also cal-
culated by semiempirical ab-initio, PM3, and AM1 methods,
and data for bond lengths and angles, and the torsion angles
2
match well the experimental ones (Tables S1–S3) , while the
corresponding calculated H(1)···O(1) bond lengths were
1
.57, 1.78, and 1.97 Å, respectively, and the calculated
O(5)-H(1) values were 1.00, 0.980, 0.970 Å, respectively.
The ab initio value for the weaker H-bonding interaction
2
Supplementary data may be purchased from the Depository of Unpublished Data, Document Delivery, CISTI, National Research Council
Canada, Ottawa, ON K1A 0S2, Canada (http://nrc.ca/cisti/irm/unpub_e.shtml for information on ordering electronically). CCDC 229696
contains the supplementary crystal data for this paper, and can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html
(
or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, UK; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).
©
2004 NRC Canada

Dabbagh et al.
1183
Fig. 2. Molecular structures for 8 from ab initio analysis (side view: bisected (a), eclipsed (c)), and front view: bisected (b), eclipsed
d)).
(
a
Table 3. Experimental and calculated hydrogen bond lengths and energies (kcal/mol) for bisected and eclipsed structures of 8 (see
Scheme 4 and Fig. 2).
Bisected
Eclipsed
Etotal
[C=O···H-C]
[C=O···H-O]
Etotal
[C=O···H-C]
[C=O···H-O]
Relative energy
Method
(kcal/mol)
(Å)
(Å)
(kcal/mol)
(Å)
(Å)
(Eeclip – Ebist)
X-ray
Ab initio
PM3
AM1
a
—
2.535
2.574
2.647
2.554
1.68(4)
1.565
1.780
1.974
—
—
—
—
–470 792.80
–2 812.50
–2 813.50
–470 791.40
–2 811.10
–2 812.50
2.139
2.309
2.186
1.557
1.780
1.969
1.40
1.40
1.0
Average of three calculations.
Scheme 5. Proposed mechanism for the formation of 8.
sponding reactions with the tetrazoles 1b–1e (containing
weaker electron-donor substituents in the Ar′ moiety,
Scheme 1) generate, respectively, the tetrazoles 3b–3e, 4b–
Comparison of the strength of the H-bond in 8 with those
in the 2′-6′-dimethoxyflavone-carboxylic acid derivatives re-
ported by Wallet and co-workers (4) allows for the determi-
4
e, 5b–5e and CO , but no 8.
nation of the pK of the flavone acid compounds (Fig. 3).
2
a
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2004 NRC Canada

1
184
Can. J. Chem. Vol. 82, 2004
Scheme 6. Resonance forms for 8.
refinement, and data reduction (see Table 1) were done us-
ing the d*TREK program (22a), and the structure was
solved by direct methods (SIR97) (22b). All calculations
were performed using the teXsan crystallographic software
package (22c).
Synthesis of aryloxytetrazoles
2
-Methoxycarbonyl-5-aryloxytetrazoles (aryl = 4-nitrophenyl
(
1a), 4-methylphenyl (1b), 4-methoxyphenyl (1c), 2,6-
dimethylphenyl (1d), 2,6-dimethoxyphenyl (1e)) were syn-
3
thesized by reported methods (21).
Synthesis of methyl-2,4-dimethoxysalicylate (8)
Compound 1a (3.8 mmol), 1,3,5-trimethoxy-benzene
(
3.8 mmol). and 1.5 mol equiv. of AlCl were mixed and
3
Fig. 3. Correlation of H-bond distances in 2′,6′-dimethoxyflavone-
ground to a homogeneous powder, and heated at 100 °C for
20 min; the TLC spot for the trimethoxybenzene gradually
disappeared. The mixture was then transferred to a separat-
ing funnel using 10 mL CH Cl , 10 mL H O, and 5 mL HCl
carboxylic acid adducts (O···H···O) with increasing pK values of
a
trichloroacetic, chloroacetic, formic, acetic, and propionic acids
(
4a, 4b). Estimation of the pK value for 8 (··· ).
a
2
2
2
(
5%), and the organic phase was washed several times with
brine. The orange organic phase was dried over CaCl and
2
the solvent evaporated off. The residue was passed through a
silica gel column and elution with cyclohexane:ethyl acetate
(
3
95:5) gave 8 (30% yield, mp. 96–98 °C), 4a (30% yield),
a (15% yield), and tetrazole 5 (25%). This procedure was
repeated with tetrazoles 1b–1e; the product tetrazoles 3b–3e
and 4b–4e were detected, but there was no trace of 8. The
1
H NMR and IR data for the 3b–4e and 4b–4e have been re-
–
1
ported (19–21). For 8: FT-IR (KBr, cm ): 3200–3600 (s),
2
1
8
3
925 (m), 2800 (w), 1642 (s), 1615 (s), 1440 (m), 1380 (s),
273 (s), 1250 (s), 1165 (s), 1119 (s), 1051 (m), 944 (w),
1
28 (m), 460 (s). H NMR (CDCl ): δ 3.73 (s, 3H, p-CH O),
3
3
They used this method when the experimental pK determi-
a
3
.74 (s, 3H, o-CH O), 3.83 (s, 3H, CH OCO), 5.89 (d, 1H ,
3
3
nation was impractical. The estimated pK value for 8 is
a
5
J = 8.0 Hz), 6.02 (d, 1H , J = 8.3 Hz), 11.91 (s, 1H, OH).
equal to ~6.4; an experimental value of 6.8 is in the range
1
3
C NMR (CDCl ): δ 53.48, 56.81, 57.43, 92.92, 94.88,
3
6
.5–7 determined for similar derivatives of 8 with anti-
9
8.00, 163.56, 166.74, 167.22, 173.00. MS (70 eV): 212
tumour properties (3).
+
(
M , 40), 211.1 (72), 180.5 (92), 178.9 (100), 152.2 (36),
1
37.2 (40). A crystal of 8 was grown over 2 days at room
Experimental
temperature from a cyclohexane:CH Cl (~4:1) solution of
the compound.
2
2
The key 1H NMR and 13C NMR data were recorded on a
Bruker AV 300 (300 MHz) instrument, and the FT-IR spec-
tra were obtained on a Shimadzu IR-470. MS data were
measured on a GC–MS Fission Trio 1000 instrument
Acknowledgements
We thank the Isfahan University of Technology Research
Council (grant No. IUT-1CHI 821) and the Natural Sciences
and Engineering Research Council of Canada (NSERC) for
financial support.
(
70 eV). Melting points (mp) (uncorrected) were taken on a
Gallenkamp apparatus. The computational analyses were
performed using HyperChem pro 6.0, with the ab initio,
AM1, and PM3 calculations optimized using Polak–Ribiere
or Fletcher–Reeves algorithms.
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2004 NRC Canada