A streamlined synthesis for 2,3-dihydroxyterephthalamides

Article abstract of DOI:10.1021/ol016253u

(equation presented) 2,3-Dihydroxyterephthalamides have been synthesized through a route that avoids the protection and deprotection of the phenol groups. The procedure allows for symmetric and unsymmetric amide linkages. This synthetic sequence significa

Full text of DOI:10.1021/ol016253u

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2827-2830
A Streamlined Synthesis for
2,3-Dihydroxyterephthalamides
Christine J. Gramer and Kenneth N. Raymond*
Chemical Sciences DiVision, Lawrence Berkeley National Laboratory and Department
of Chemistry, UniVersity of California, Berkeley, California 94720
raymond@socrates.berkeley.edu
Received June 8, 2001
ABSTRACT
2,3-Dihydroxyterephthalamides have been synthesized through a route that avoids the protection and deprotection of the phenol groups. The
procedure allows for symmetric and unsymmetric amide linkages. This synthetic sequence significantly decreases the time and cost of preparation
and increases the overall yield of this class of metal chelators.
Catecholate ligands incorporating a variety of electron-
withdrawing substituents have been extensively investigated
for their extraordinarily high affinity for high oxidation state
metals.1-5 Catecholamides (CAM) are commonly found in
nature in siderophores, a class of bacterially secreted ligands
that function to sequester and acquire Fe(III) from the
environment.6 The siderophore enterobactin has an Fe(III)
stability constant of 1049, the highest known for any aqueous
ferric complex, due to the three catecholamides suspended
from its trilactone backbone.7
the 2,3-dihydroxyterephthalamides (TAM), display higher
Fe(III) affinity, are harder to oxidize, and are more acidic
than the CAM.8,9 The increased acidity of CAMC and TAM
relative to other catecholates broadens their utility because
they can fully complex Fe(III) in lower pH solutions. These
properties prompted successful investigations of catechol-
amide ligands as in vivo decorporation agents for Pu(IV)
and the in vitro stability of complexes with Ce(IV), a Pu(IV)
analogue.10-12 In addition, the two amide-linked substituents
can be modified to tailor the solubility of the ligand and allow
several ligands to be linked together to maximize the chelate
effect. Herein we report a shorter synthetic route to the TAMs
that decreases the time, cost, and hazards associated with
the synthesis.
While the catecholate anion itself is highly sensitive to
oxidation, amide substitution reduces this sensitivity. Cat-
echol derivatives containing two carbonyl substituents, e.g.,
the carboxamido-2,3-dihydroxyterephthalates (CAMC) and
The typical TAM synthesis8,9,13 involves six steps (Scheme
1) in an overall 30% yield: carboxylation of catechol to form
2, conversion of the carboxylic acids to methyl esters 3,
(1) Pierpont, C. G.; Lange, C. W. The Chemistry of Transition Metal
Complexes Containing Catechol and Semiquinone Ligands. In Progress in
Inorganic Chemistry; Karlin, K. D., Ed.; John Wiley & Sons: New York,
1994; pp 331-442.
(2) Raymond, K. N.; Mu¨ller, G.; Matzanke, B. F. Complexation of Iron
by Siderophores. A Review of Their Solution and Structural Chemistry and
Biological Function. In Topics in Current Chemistry; Boschke, F. L., Ed.;
Springer-Verlag: Berlin, Heidelberg, 1984; pp 50-102.
(8) Weitl, F. L.; Raymond, K. N.; Durbin, P. W. J. Med. Chem. 1981,
24, 203-206.
(9) Garrett, T. M.; Miller, P. W.; Raymond, K. N. Inorg. Chem. 1989,
28, 128-133.
(3) Raymond, K. N. Specific Sequestering Agents for Iron and Actinides.
In U.S.-Italy International Workshop on EnVironmnetal Inorganic Chem-
istry; San Miniato, Italy; VCH Publishers: Deerfield Beach, Florida, 1985.
(4) Raymond, K. N. Coord. Chem. ReV. 1990, 105, 136-153.
(5) Telford, J. R.; Raymond, K. N.; Siderophores. In ComprehensiVe
Supramolecular Chemistry; Atwood, J. L., Davies, J. E. D., MacNicol, D.
D., Vogtle, F., Eds.; Elsevier Science Ltd.: Oxford, 1996; pp 245-266.
(6) Drechsel, H.; Winkelmann, G. Iron Chelation and Siderophores. In
Transition Metals in Microbial Metabolism; Winkelmann, G., Carrano, C.
J., Eds.; Harwood Academic Publishers: Newark, NJ, 1997.
(10) Raymond, K. N.; Smith, W. L. Actinide-Specific Sequestering
Agents and Decontamination Applications. In Structure and Bonding;
Goodenough, J. B. et al., Eds.; Springer-Verlag: Berlin, Heidelberg, 1981;
pp 159-186.
(11) Lloyd, R. D.; Bruenger, F. W.; Mays, C. W.; Atherton, D. R.; Jones,
C. W.; Taylor, G. N.; Stevens, W.; Durbin, P. W.; Jeung, N.; Jones, E. S.
et al. Rad. Chem. 1984, 99, 106-128.
(12) Kappel, M. J.; Nitsche, H.; Raymond, K. N. Inorg. Chem. 1985,
24, 605-611.
(13) Rodgers, S. J.; Ng, C. Y.; Raymond, K. N. J. Am. Chem. Soc. 1985,
107, 4094-4095.
(7) Loomis, L. D.; Raymond, K. N. Inorg. Chem. 1991, 30, 906-911.
10.1021/ol016253u CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/10/2001

chloride 6 with octylamine, cyclohexylamine, or ethylamine
followed by extraction with 1 M HCl and recrystallization
yields the pure product in 40-90% yield, depending on the
hydrophobicity of the product.
Scheme 1
Activation of the dicarboxylic acid 2 with SOCl2 was
proposed on the basis of previous work on the SOCl2
activation of 2,3-dihydroxybenzoic acid, for which there was
originally some confusion about the product composition.14-16
The product was first reported as 2,3-dihydroxybenzoyl
chloride 9 on the basis of the previously reported formation
of 2,4-dihydroxybenzoyl chloride 11,17 although character-
ization was limited to a melting point of 84 °C for the
sublimed crystals (Figure 1). However it was later shown
methyl or benzyl protection of the catecholate oxygens 4,
saponification of the esters to provide 5, activation to the
acid chloride, coupling with the desired amine, and depro-
tection of the catecholate oxygens to yield the desired TAM.
The CAMC synthesis differs in that it requires the saponi-
fication of only one ester of 4 followed by amide bond
formation and hydroxyl deprotection.
Figure 1. Phenolic acid chlorides 9-11 that have been described
in the literature. What was originally reported as 9, on the basis of
analogy to 11, was later shown to be 10.
The more efficient synthesis reported here for TAMs does
not require protection of the phenolic oxygens; the direct
activation of 2,3-dihydroxyterephthalic acid 2 with SOCl2
is followed by reaction with an amine. By avoiding the
protecting group the number of synthetic steps are reduced
from seven to three. This eliminates two steps involving the
hazardous reagents dimethyl sulfate and BBr3, decreases the
synthetic time from approximately 9 to 2 days, increases the
overall yield to 75%, and decreases the cost for alkyl TAMs
10-fold. This synthetic sequence also broadens the diversity
of available TAMs since deprotection of methyl ether
protecting groups with BBr3 is incompatible with certain
functional groups that might be desired in the amide side
chains. Finally, this procedure has been adapted to allow for
the preparation of CAMC ligands and the installation of two
different amides, generating a much wider range of com-
pounds.
that the phenol groups react to form a sulfite ester, a
convenient and effective in situ protecting group.16 The
resulting sublimed crystals of 2,3-dioxosulfinylbenzoyl chlo-
ride 10 were characterized by melting point and elemental
analysis. This acid chloride has been useful for several
syntheses requiring the installation of a catecholamide.18-22
The formation of the catecholate sulfinic anhydride is also
precedented; the synthesis of 1,2-dioxosulfinyl benzene from
the reaction of catechol with SOCl2 has been reported.23,24
The key intermediate for making the symmetric TAMs is
the product of the reaction between 2 and SOCl2. By analogy
to 10 and 11, both 2,3-dihydroxyterephthaloyl chloride 12
and 2,3-dioxosufinylterephthaloyl chloride 13 could be
considered as products (Figure 2). One product isolated from
refluxing dioxane exhibits a singlet in the 1H NMR spectrum
at ca. 8 ppm. We assign this as the labile intermediate 13.
The decomposition of 13 via loss of SO2 to form the less
For the current synthesis, compound 2 was activated with
an excess of SOCl2 in refluxing dioxane for 6 h (Scheme
2). Although a variety of organic solvents were used
successfully, the use of dioxane ensures the removal of
excess SOCl2 during evaporation. Coupling the crude acid
1
reactive phenol acid chloride 12 can be monitored by H
(14) Corey, E. J.; Bhattacharyya, S. Tetrahedron Lett. 1977, 45, 3919-
3922.
(15) Corey, E. J.; Hurt, S. D. Tetrahedron Lett. 1977, 45, 3923-3924.
(16) Weitl, F. L.; Raymond, K. N. J. Am. Chem. Soc. 1979, 101, 2728-
2731.
Scheme 2a
(17) Scott, A. W.; Kearse, W. O. J. Org. Chem. 1940, 5, 598-605.
(18) Husson, A.; Besselievre, R.; Husson, H. P. Tetrahedron Lett. 1983,
24, 1031-1034.
(19) Lowe, C.; Pu, Y.; Vederas, J. C. J. Org. Chem. 1992, 57, 10-11.
(20) Pu, Y.; Lowe, C.; Sailer, M.; Vederas, J. C. J. Org. Chem. 1994,
59, 3642-3655.
(21) Slama, S.; Stong, J. D.; Neilands, J. B.; Spiro, T. G. Biochemistry
1978, 17, 3781-3785.
(22) Corey, E. J.; Cashman, J. R.; Kanter, S. S.; Wright, S. W. J. Am.
Chem. Soc. 1984, 106, 1503-1504.
a (a) SOCl2, dioxane, reflux; (b) NH2R, TEA.
(23) Anschutz, R.; Posth, W. Chem. Ber. 1894, 27, p 2751-2753.
(24) Green, A. J. Chem. Soc. 1927, 500-503.
2828
Org. Lett., Vol. 3, No. 18, 2001

Scheme 3. Two Different Amide Linkages Can Be Prepared
with a Modification of This Procedurea
a (a) 1 equiv of NaHCO3 aqueous, 70 °C; (b) SOCl2, dioxane,
reflux; (c) NH2R, TEA, 0 °C; (d) 1 M KOH; (e) SOCl2, dioxane,
reflux; (f) 1-(2-aminoethyl)piperidine, 0 °C.
Figure 2. Reaction of 2 with SOCl2 affords the labile intermediate
13 and the resultant 12, which has been structurally characterized
by X-ray crystallography (ORTEP). Thermal ellipsoids are drawn
at the 50% probability level. Reaction of 14 with SOCl2 also affords
both 20 and 21.
ester 3 with aqueous NaHCO3 affords 14 in 70% yield. The
acid chloride was prepared by treatment of 14 with SOCl2
in refluxing dioxane. The crude acid chloride was then
coupled to octylamine in the presence of TEA to yield 15,
which was converted to the acid 17 using degassed 1 M
KOH. Halting the synthesis at this point provides the CAMC
ligands. Finally, 17 was activated with SOCl2 and treated
with 1 equiv of 1-(2-ethylamino)piperidine to afford 19 in
40% yield. In general, it was found that installing the more
hydrophobic of the two amides first eased the separation of
the product from the excess amine. For monitoring the
progress of any reaction, thin-layer chromatography was used
with one of three solvent systems, 5:4:1 benzene/ethyl
formate/formic acid, 5:4:1:1 ethyl acetate/acetone/methanol/
water, or 4:3:1:1 ethyl acetate/acetic acid/methanol/water.
NMR spectroscopy, as the singlet at 8 ppm disappears and
another appears at ca. 7.5 ppm. The starting compound 2
1
exhibits a singlet in the H NMR spectrum at ca. 7.2 ppm.
Sublimation of the resultant yellow solid yielded crystals
suitable for X-ray diffraction.25 This confirmed that the
1
activated intermediate with a H NMR signal at 7.5 is 12
and not an ester polymer formed from the reaction of the
phenol oxygens with the acid chloride. As is seen with all
TAMs in the solid state, the carbonyl is oriented such that
the oxygen is hydrogen-bonded to the phenolic proton.26 The
stability of this chelate hydrogen bond possibly in part
hinders the formation of a polymeric ester. An amine can
be coupled with a mixture of 12 and 13 without a loss in
yield, and the transitory protecting group is easily cleaved
during the aqueous workup following the amine coupling.
This procedure was modified so a TAM with two different
amide linkages can be prepared (Scheme 3). This methodol-
ogy is demonstrated with the synthesis of ligand 19 and is
general for most amides. Monosaponification of the dimethyl
During the course of activating mono ester 14 with SOCl2,
1
one product is initially observed in the H NMR spectrum
that is tentatively assigned as 21. As with 13, the decomposi-
tion of this to the acid chloride 20 is observed (Figure 2).
Sublimation of the resultant yellow solid affords a pure
yellow powder, confirmed by elemental analysis as the acid
chloride 20.
In summary, a synthesis for 2,3-dihydroxyterephthalamides
has been developed that obviates the need for protection of
the catecholates. The synthesis has been adapted to permit
the introduction of two different amide linkages and can be
used for the synthesis of the CAMC ligands. These routes
avoid the costly BBr3 deprotection and shorten the synthesis
(25) C8H4O4Cl2: yellow tablet shaped crystal, size 0.50 × 0.14 × 0.05
mm3, FW ) 235.02, T ) -109 °C, orthorhombic space group, Pccn, a )
13.781(3) Å, b ) 4.835(1) Å, c ) 13.241(3) Å, V ) 882.3(8) Å3, Z ) 4,
R ) 0.050, Rw ) 0.060, GOF ) 1.79.
(26) Garrett, T. M.; Cass, M. E.; Raymond, K. N. J. Coord. Chem. 1992,
25, 241-253.
Org. Lett., Vol. 3, No. 18, 2001
2829

of a symmetric TAM from 1 week to 1 day. This methodol-
ogy could enable broad application in large-scale production
of sequestering agents based on this class of ligands.
gram, Office of Science and Technology, Office of Envi-
ronmental Management, U.S. DOE. We thank Dr. Jide Xu
for helpful suggestions.
Acknowledgment. This research was supported by the
Director, Office of Energy Research, Office of Basic Energy
Sciences, Chemical Sciences Division, U.S. Department of
Energy (DOE), under contract number DE-AC03-76SF00098.
Additionally, this research was supported in part under grant
no. SF17SP23, Environmental Management Science Pro-
Supporting Information Available: Full experimental
details and characterization of all new compounds, including
crystallography. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL016253U
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Org. Lett., Vol. 3, No. 18, 2001