A convenient new route to tetradentate and pentadentate macrocyclic tetraamide ligands

Article abstract of DOI:10.1021/ol990155f

(matrix presented) A crucial diamide diamine intermediate in the synthesis of tetradentate macrocyclic tetraamide ligands protected against oxidative decomposition has been synthesized without the use of potentially hazardous organic azide intermediates.

Full text of DOI:10.1021/ol990155f

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1157-1159
A Convenient New Route to
Tetradentate and Pentadentate
Macrocyclic Tetraamide Ligands
Leonard C. Rorrer, Stephen D. Hopkins, Michele K. Connors, Daniel W. Lee III,
Matthew V. Smith, Hilary J. Rhodes, and Erich S. Uffelman*
Department of Chemistry, Washington and Lee UniVersity, Lexington, Virginia 24450
uffelman.e@wlu.edu
Received July 9, 1999
ABSTRACT
A crucial diamide diamine intermediate in the synthesis of tetradentate macrocyclic tetraamide ligands protected against oxidative decomposition
has been synthesized without the use of potentially hazardous organic azide intermediates. This intermediate has also been used to synthesize
a new class of pentadentate macrocyclic tetraamide ligands.
Since the potential importance to inorganic chemistry of
macrocyclic tetraamide ligands protected against oxidative
decomposition was first demonstrated,1 these ligands have
been used to synthesize a variety of rare or unprecedented
oxidation states, geometries, and spin states of chromium,
manganese, iron, cobalt, nickel, and copper.1,2 When a two-
step route to these macrocycles that did not involve organic
azides was developed,3 transition metal complexes of these
ligands suddenly had the potential to become valuable
homogeneous catalysts.4 Recent work has demonstrated the
utility of these catalysts in the important emerging field of
green chemistry (bleaching and pulp and paper applications).5
We have been working to produce expanded macrocyclic
tetraamide ligands for possible use with lanthanides and for
multimetallic applications. In the process of solving difficul-
ties we encountered in synthesizing a new class of tractable
pentadentate macrocyclic tetraamide ligands, we have gener-
(4) (a) Bartos, M. J.; Gordon-Wylie, S. W.; Fow, B. G.; Wright, L. J.;
Weintraub, S. T.; Kauffmann, K. E.; Mu¨nck, E.; Kostka, K. L.; Uffelman,
E. S.; Rickard, C. E. F.; Noon, K. R.; Collins, T. J. Coord. Chem. ReV.
1998, 174, 361-390. (b) Miller, C. G.; Gordon-Wylie, S. W.; Horwitz, C.
P.; Strazisar, S. A.; Peraino, D. K.; Clark, G. R.; Weintraub, S. T.; Collins,
T. J. J. Am. Chem. Soc. 1998, 120, 11540-11541. (c) Horwitz, C. P.;
Fooksman, D. R.; Vuocolo, L. D.; Gordon-Wylie, S. W.; Cox, N. J.; Collins,
T. J. J. Am. Chem. Soc. 1998, 120, 4867-4868. (d) Patterson, R. E.; Gordon-
Wylie, S. W.; Woomer, C. G.; Norman, R. E.; Weintraub, S. T.; Horwitz,
C. P.; Collins, T. J. Inorg. Chem. 1998, 37, 4748-4750.
(5) Collins, T. J.; Gordon-Wylie, S. W.; Bartos, M. J.; Horwitz, C. P.;
Woomer, C. G.; Williams, S. A.; Patterson, R. E.; Vuocolo, L. D.; Paterno,
S. A.; Strazisar, S. A.; Peraino, D. K.; Dudash, C. A. In Green Chemistry:
Frontiers in Benign Chemical Syntheses and Processes; Anastas, P. T.,
Williamson, T. C., Eds.; Oxford University Press: Oxford, U.K., 1998; pp
46-71.
(1) (a) Collins, T. J.; Uffelman, E. S. Angew. Chem., Int. Ed. Engl. 1989,
28, 1509-1511. (b) Uffelman, E. S. Ph.D. Dissertation, California Institute
of Technology, Pasadena, CA, 1991.
(2) (a) Collins, T. J.; Powell, R. D.; Slebodnick, C.; Uffelman, E. S. J.
Am. Chem. Soc. 1990, 112, 899-901. (b) Collins, T. J.; Kostka, K. L.;
Mu¨nck, E.; Uffelman, E. S. J. Am. Chem. Soc. 1990, 112, 5637-5639. (c)
Collins, T. J.; Nichols, T. R.; Uffelman, E. S. J. Am. Chem. Soc. 1991,
113, 4708-4709. (d) Collins, T. J.; Slebodnick, C.; Uffelman, E. S. Inorg.
Chem. 1990, 29, 3432-3436. (e) Collins, T. J.; Kostka, K. L.; Uffelman,
E. S.; Weinberger, T. Inorg. Chem. 1991, 30, 4204-4210. (f) Collins, T.
J.; Powell, R. D.; Slebodnick, C.; Uffelman, E. S. J. Am. Chem. Soc. 1991,
113, 8419-8425. (g) Collins, T. J. Acc. Chem. Res. 1994, 27, 279-285.
(3) (a) Gordon-Wylie, S. W. Ph.D. Dissertation, Carnegie Mellon
University, Pittsburgh, PA, 1995. (b) Gordon-Wylie, S. W.; Collins, T. J.
U.S. Patent Allowed.
10.1021/ol990155f CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

ated a valuable, convenient new method for synthesizing
tetradentate macrocyclic tetraamide ligands.
Our synthesis of 5 (R ) Me) proceeded by an organic
azide route to the diamide diamine intermediate 4 (Scheme
1). This route to 4 was known from prior work.1b,2f
synthesis patent literature,7 and it allows us to generate a
very reactive acylating agent (the acid chloride), using the
proton as a protecting group. As an example (Scheme 2),
Scheme 2. Synthesis of a Key Diamide Diamine Intermediate
and Its Conversion to Tractable Macrocyclesa
Scheme 1. Synthesis of an Intractable Macrocycle via an Old
Azide Routea
a Legend: (a) PCl5 (1 equiv), 2-oxazolidone (2 equiv), MeCN,
room temperature, 12 h; (b) 6 is added to the PCl5/2-oxazolidone
mixture and stirred, room temperature, 12 h, 92%; (c) solution of
1,2-phenylenediamine and pyridine (2.2 equiv) slowly added (2 h)
to suspension of acid chloride (2 equiv), CH2Cl2, room temperature,
12 h, 42%, see ref 8; (d) diethylmalonyl dichloride, CH2Cl2, 25%
(procedure similar to that in refs 1b and 2f); (e) 2,6-pyridinedicar-
bonyl dichloride, THF, 55%, see refs 9 and 13.
a Legend: (a-c) 2-bromoisobutyryl bromide, then NaN3, then
H2, Pd/C (see refs 1b and 2f); (d) product quite insoluble, yield
undetermined, product identified by FAB MS.
Unfortunately, 5 (R ) Me) is sparingly soluble in DMSO
and DMF and is insoluble in other common lower boiling
organic solvents. Conceptually, greater organic solubility
could be designed into the molecule in three places: by
varying the aromatic ring substituents, by varying the R
groups, or by varying the substituents on the pyridine ring.
Increasing the size of the R groups destroys the viability of
the azide route. Efforts to synthesize 5 (R ) Pr) via the azide
route were thwarted by considerable elimination.
In the redesign of the synthesis, we recognized that it is
desirable to employ highly reactive acylating agents with
1,2-phenylenediamines, since the production of benzimida-
zoles can be a competing side reaction even with acid
chlorides.6 Indeed, 1,2-phenylenediamines that are even
weakly deactivated by other substituents on the benzene ring
often yield benzimidazoles exclusively when acylation is
attempted with reagents less active than acid chlorides.6 This
factor renders much of the protected amino acid coupling
technology developed for biochemistry inapplicable to mac-
rocyclic systems such as 5, 9, and 10. Clearly, 5, 9, and 10
are conceptually composed of 1,2-phenylenediamine, 2 equiv
of an amino acid, and either 2,6-pyridinedicarboxylic acid
or diethylmalonic acid.
PCl5 was stirred with 2-oxazolidone, followed by the addition
of 1-amino-1-cyclohexanecarboxylic acid (6). The resulting
salt, 7, is easily isolated by filtration and is used as is, even
though it is slightly contaminated with 2-oxazolidone. Slow
addition of 1,2-phenylenediamine yields the diamide diamine
product 8.8 Addition of diethylmalonyl dichloride gives 9
in 25% yield (the NMR, electrospray MS, and IR data for
this compound are identical with the data for the same
compound produced by the patented method3,4d).
It should be noted that this synthetic method holds great
promise for introducing chirality into the macrocyclic tet-
raamide ligands via R-disubstituted amino acids bearing
different R groups. Furthermore, recent research has revealed
that although the metalated macrocyclic tetraamide ligands
are extraordinarily robust under oxidizing conditions, high-
valent iron-oxo species formed from these macrocycles
(7) Palomo Coll, A. L.; Meseguer, J. D. U.S. Patent 4 230 849, 1985.
(8) Characterization of 8: 1H NMR (in CDCl3) δ 1.3-2.2 (m, 20H,
cyclohexane H), 2.15 (br s, 4H, amine H), 7.15 (m, 2H, aromatic H), 7.65
(m, 2H, aromatic H), 9.95 (s, 2H, amide H); 13C NMR (in CDCl3) δ 21.4
(cyclohexane C-3 or C-4), 25.0 (cyclohexane C-3 or C-4), 34.5 (cyclohexane
C-2), 58.0 (cyclohexane C-1), 124.4 (aromatic C-3 or C-4), 125.6 (aromatic
C-3 or C-4), 130.5 (aromatic C-1), 176.5 (carbonyl C); NMR assignments
confirmed by CH correlation spectra, edited DEPT, and 2D COSY NMR;
IR (Nujol) νj (cm-1) 3409, 3324, 3201, 1654, 1590; electrospray MS
(positive ion mode) m/z 358.49 (M + 1, 100%). Anal. Calcd for diamide
diamine: C, 67.01; H, 8.44; N, 15.63. Found: C, 66.95; H, 8.40; N, 15.56.
Our new method of synthesizing these crucial diamide
diamine intermediates, 4 and 8, is derived from the antibiotic
(6) Keech, J. T. Ph.D. Dissertation, California Institute of Technology,
Pasadena, CA, 1986.
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Org. Lett., Vol. 1, No. 8, 1999

ultimately decompose slowly via intramolecular hydrogen
atom abstraction from the methylene carbon of the diethyl-
malonamide unit.4a Substitution chemistry at this site has
already generated even more robust catalyst systems.4c The
prior non-azide route involves coupling 2 equiv of amino
acid with diethylmalonyl dichloride to generate a diamide
dicarboxylic acid, which is then coupled with a 1,2-
phenylenediamine derivative to yield product.3 Large amounts
of pyridine solvent are used in both steps. Our new synthetic
route promises to make the systematic exploration of the
effect of varying the malonamide groups more efficient and
more economical. We anticipate that the prior method and
our new method will ultimately be complementary in terms
of commercial applicability; i.e., each method appears to have
complementary strengths and limitations.
for the amide protons, indicating that they are in close
proximity to each other. Not only is the geometric proximity
of the amide protons consistent with a hydrogen bond
template in the final coupling reaction, the pentadentate
1
tetraamide macrocycles do not exhibit a change in the H
NMR in the presence of strong acids, indicating that the
pyridine ring is extraordinarily difficult to protonate.
Not only is 10 stable in concentrated acid, it is also base-
stable. Addition of 4 equiv of LDA removes the amide
protons and generates a lithiated tetraanion which we have
characterized by NMR in THF-d8 and DMSO-d6. Addition
of water to the lithiated tetraanion quantitatively regenerates
10. We are surveying the reactivity of the lithiated tetraanion
with transition metals and with the lanthanide series of
trications. Coordinating the organic amido-N ligand to a
lanthanide series trication would not only have significant
implications for the fundamental coordination chemistry of
the lanthanides but could also, depending on hydrolytic
stability, have significance to the field of MRI contrast
agents.
Reaction of the diamide diamine intermediate 8 with 2,6-
pyridinedicarbonyl dichloride yields a new class of penta-
dentate tetraamide macrocycles in a remarkable 55% yield
(Scheme 2).9 Just as one class of the tetradentate macrocyclic
tetraamide ligands appears to be templated by a hydrogen
bond analogous to the â-turn seen in protein folding,1b,2e,10
it is possible that the new pentadentate tetraamide macrocycle
may be templated by a hydrogen bond involving the pyridine
that is analogous to hydrogen bonds seen with amides derived
from 2,6-pyridinedicarboxylic acid for catenanes11 and helical
supramolecular arrays.12 This new pentadentate tetraamide
Acknowledgment. This work was supported by the
Research Corp. (Grant No. CC3870), the donors of the
Petroleum Research Fund, administered by the American
Chemical Society (Grant No. 29495-GB3), and the National
Science Foundation (Grant No. DUE-9650033). This work
was also supported by Washington and Lee Summer
Research Student Fellowships, Glenn Grants, and a Class
of ’65 Excellence in Teaching Award. We thank Mr. Sayam
Sen Gupta of Carnegie Mellon University for the electrospray
MS data. We are indebted to Dr. Terrence J. Collins
(Carnegie Mellon University) and Dr. Scott Gordon-Wylie
(University of Vermont) for useful discussions and preprints
of publications. This work is dedicated to Dr. Collins in
recognition of his recent Presidential Green Chemistry
Challenge Award and to Dr. Charles A. Root on the occasion
of his retirement from Bucknell University.
1
macrocycle, 10, has been characterized by H NMR, 13C
NMR, C-H correlation spectra, edited DEPT, 2D COSY,
2D NOESY, IR, and electrospray MS.13 The new pentaden-
tate macrocycles show cross-peaks in the 2D NOESY spectra
(9) Synthesis of 10: compound 8 (0.615 g, 0.00172 mol) was dissolved
in anhydrous THF (7.5 mL) and triethylamine (0.7 mL, 0.00502 mol). 2,6-
Pyridinedicarbonyl dichloride (0.352 g, 0.00173 mol) was dissolved in
anhydrous THF (8.2 mL). Each solution was added to a common pool of
THF (75 mL) via syringe pump (1.5 h). The reaction mixture was stirred
(24 h) and then filtered, saving the filtrate. The filtrate was taken to dryness
under reduced pressure. The resultant solid was washed with distilled water,
filtered, and pumped to dryness. The solid was then washed with methylene
chloride, filtered, and dried under vacuum oven (∼40 °C). Net yield: 0.465
g, 0.000 949 mol, 55.4%. The macrocycle is recrystallized in high yield by
vapor diffusion of hexanes into a THF solution.
(10) (a) Dado, G. P., Desper, J. M.; Gellman, S. H. J. Am. Chem. Soc.
1990, 112, 8630-8632. (b) Gellman, S. H.; Dado, G. P.; Liang, G.-P.;
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(c) Carver, F. J.; Hunter, C. A.; Shannon, R. J. J. Chem. Soc., Chem.
Commun. 1994, 1277-1279.
OL990155F
(13) Characterization of 10: 1H NMR (in DMSO-d6) δ 1.3 (s, 2H,
cyclohexane H), 1.7 (s, 10H, cyclohexane H), 2.0 (d, 4H, cyclohexane H),
2.8 (m, 4H, cyclohexane H), 7.2 (m, 2H, benzene H), 7.45 (m, 2H, benzene
H), 8.18 (m, 3H, pyridine H), 9.34 (s, 2H, amide H), 9.72 (s, 2H, amide
H); 13C NMR in (DMSO-d6) δ 23.8 (cyclohexane C-2 or -3), 25.7
(cyclohexane C-4), 31.8 (cyclohexane C-2 or -3), 61.9 (cyclohexane C-1),
124.0 (pyridine C-4), 125.5 (benzene C-4 and C-5), 128.0 (benzene C-3
and C-6), 131.6 (benzene C-1 and C-2), 140.4 (pyridine C-3 and C-5), 149.6
(pyridine C-2 and C-6), 163.8 (carbonyl C), 171.8 (carbonyl C); NMR
assignments confirmed by CH correlation spectra, edited DEPT, 2D COSY
NMR, and 2D NOESY NMR; IR (Nujol) νj (cm-1) 3496, 3349, 3222, 1691,
1654; electrospray MS (negative ion mode) m/z 489.58 (M - 1, 100%).
(12) (a) Kawamoto, T.; Prakash, O.; Ostrander, R.; Rheingold, A. L.;
Borovik, A. S. Inorg. Chem. 1995, 34, 4294-4295. (b) Kawamoto, T.;
Hammes, B. S.; Haggerty, B.; Yap, G. P. A.; Rheingold, A. L.; Borovik,
A. S. J. Am. Chem. Soc. 1996, 118, 285-286.
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