A synthetic quest for tris(imidazolyl) carboxylates and their metal complexes: Active site models for quercetin 2,3-dioxygenases and other non-heme redox metalloenzymes

Article abstract of DOI:10.1016/j.tet.2012.02.042

Synthetic routes to tris(imidazolyl)carboxylate ligands and representative metal complexes are reported, which provide more accurate active site models for several classes of redox metalloenzymes. In the first route a hydroxypivalate ester is converted in four regioselective steps to an imidazole diester 4; this is then converted to tris(imidazolyl)carboxylic acid ligand 9, featuring regiospecific double addition of an N-protected lithio-imidazole to an imidazole diester 8. Ligand 9 forms a Co(III) complex, (9)(9-H)Co (10), characterized by X-ray diffraction, coordinated via two imidazole units and the carboxylate. A second route was developed, which provides more soluble ligands that are less prone to form oligomeric complexes. It utilizes addition of the Grignard reagent from 4-iodo-2-isopropylimidazole 12 to an imidazole diester 13, producing atropisomeric tris(imidazolyl)carbinol esters 15M. Treatment of 15M with [Cu(CH₃CN)₄]PF₆ gives a trinuclear complex 16 having alkoxide bridges between neighboring Cu atoms. A third route avoids the bridging alkoxo groups by reduction of tris(imidazolyl)carbinol 15M to the tris(imidazolyl)methane ester 17, which is hydrolyzed to the tris(imidazolyl)methane carboxylic acid 11a. This ligand reacts with [Cu(CH ₃CN)₄]PF₆ to produce dinuclear complex [(11a-H)₂Cu₂](PF₆)₂ (18), whose X-ray crystal structure shows each copper in a distorted square pyramidal geometry with coordination to the three imidazoles and two bridging carboxylate oxygens. Complex 18 is geometrically similar to the active site copper in quercetin 2,3-dioxygenase.

Full text of DOI:10.1016/j.tet.2012.02.042

Tetrahedron 68 (2012) 3368e3376
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A synthetic quest for tris(imidazolyl) carboxylates and their metal complexes:
active site models for quercetin 2,3-dioxygenases and other non-heme redox
metalloenzymes
*
Jerome Volkman, Kenneth M. Nicholas
Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, University of Oklahoma, Norman, OK 73019, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetic routes to tris(imidazolyl)carboxylate ligands and representative metal complexes are reported,
which provide more accurate active site models for several classes of redox metalloenzymes. In the first
route a hydroxypivalate ester is converted in four regioselective steps to an imidazole diester 4; this is
then converted to tris(imidazolyl)carboxylic acid ligand 9, featuring regiospecific double addition of an
N-protected lithio-imidazole to an imidazole diester 8. Ligand 9 forms a Co(III) complex, (9)(9-H)Co (10),
characterized by X-ray diffraction, coordinated via two imidazole units and the carboxylate. A second
route was developed, which provides more soluble ligands that are less prone to form oligomeric
complexes. It utilizes addition of the Grignard reagent from 4-iodo-2-isopropylimidazole 12 to an im-
idazole diester 13, producing atropisomeric tris(imidazolyl)carbinol esters 15M. Treatment of 15M with
[Cu(CH3CN)4]PF6 gives a trinuclear complex 16 having alkoxide bridges between neighboring Cu atoms.
A third route avoids the bridging alkoxo groups by reduction of tris(imidazolyl)carbinol 15M to the
tris(imidazolyl)methane ester 17, which is hydrolyzed to the tris(imidazolyl)methane carboxylic acid 11a.
This ligand reacts with [Cu(CH3CN)4]PF6 to produce dinuclear complex [(11a-H)2Cu2](PF6)2 (18), whose
X-ray crystal structure shows each copper in a distorted square pyramidal geometry with coordination to
the three imidazoles and two bridging carboxylate oxygens. Complex 18 is geometrically similar to the
active site copper in quercetin 2,3-dioxygenase.
Received 9 February 2012
Accepted 16 February 2012
Available online 6 March 2012
Keywords:
Tris(imidazolyl)(carboxylate)
Imidazole synthesis
Quercetin model
Lipoxygenase model
Ó 2012 Published by Elsevier Ltd.
1. Introduction
models) would be enhanced by the development of efficient syn-
thetic routes to poly-imidazole based ligands.
Poly(imidazole) coordination of protein-derived histidine resi-
dues is the most common motif for the active site of non-heme,
redox metalloenzymes. This feature has stimulated extensive ef-
fort to prepare metal complexes of various poly(amine) ligands,
especially those derived from pyrazole, pyridine, and aliphatic
amines, to serve as structural and functional mimics of metal-
loenzymes.1 However, such imidazole substitutes are structurally
and electronically inaccurate and unlikely to reproduce the elec-
tronic character of the metal center. These different electronic
properties are reflected in the range of aqueous basicities of the
nitrogen donors (pKa imidazolium, 7.0; pyrazolium, 2.5; pyridinium
5.2; tertiary alkylammonium 9e11).2 Structurally, only the five-
membered pyrazoles are good models as hetero-aromatic rings,
We have conducted a research program that focuses on the
preparation and reactivity of bioaccurate poly(imidazole)-metal
complexes. Following pioneering studies by Breslow of the prepa-
ration of 2- and 4-substituted (imidazolyl)3COR and derived metal
complexes,4 we first reported an efficient one-pot, multistep route
to the parent ligand (2-imid)3COH via selective sequential metal-
ation/substitution reactions of N-sulfamoyl imidazole.5 Comple-
mentary synthetic routes to tripodal tris-imidazolyl ligands have
been provided by the Collman group6 and others.7 We then focused
our attention on the distinctive coordination and oxygen-activating
properties of copper complexes derived from tripodal (aryl-imid)3-
(N3) and (aryl-imid)2(thioether)-(N2S) type complexes8 that are
mimics of the CuH and CuM sites of the copper hydroxylases, do-
pamine beta hydroxylase (DbH),9 and peptidylglycine alpha hy-
droxylase (PAH).10
but they are stronger
p and s donors, as well as stronger p ac-
ceptors than the imidazole of histidine.3 Therefore, both our un-
derstanding of metalloenzymatic catalysis and the design of
efficient low molecular weight biomimetic catalysts (functional
A number of redox metalloenzymes possess an N3O-(His)3(car-
boxylate) coordination set, including soybean lipoxygenase (Fe,
Mn),11 acireductone dioxygenase (Ni),12 superoxide dismutase
(Mn)13 and quercetin dioxygenase (Cu, Fig. 1).14 Almost all of the
structural and functional model complexes synthesized for these
* Corresponding author. Fax: þ1 405 325 6111; e-mail address: knicholas@ou.edu
(K.M. Nicholas).
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
doi:10.1016/j.tet.2012.02.042

J. Volkman, K.M. Nicholas / Tetrahedron 68 (2012) 3368e3376
3369
O
O
X
OH
O
N
N
M
NR'
NR'
N
N
R'N
N
R'N
N
NR'
NR'
R
R
F
E
Fig. 3. Tris(imidazolyl)carboxylate ligands and complexes prepared.
2. Results and discussion
Fig. 1. Active site X-ray structure of quercetin 2,3-dioxygenase.14
Following initial ineffective efforts aimed at appending a car-
boxylate tether to a preformed tripodal tris-imidazole derivative,
we turned to the synthetic approach outlined in Scheme 1, in-
volving incorporation of the carboxylate unit during the genesis of
one of the imidazole rings. To provide the carboxylate tether,
hydroxypivalic acid methyl ester was oxidized to the corresponding
aldehyde by its TEMPO-catalyzed reaction with tri-
chloroisocyanuric acid (TCCA).23 Without purification the resulting
aldehyde was condensed with glyoxal/ammonia24 to afford the
imidazole ester 2 in 67% yield overall (two steps). To set up the
regio- and chemoselective introduction of the carboxyl group
needed for eventual generation of the tris-(imidazolyl)carbinol
ester, imidazole 2 was N-protected by the dimethylsulfamoyl group
(60%),25 which was instrumental in directing lithiation at the im-
idazole 5-position by BuLi (THF, ꢀ78 ꢁC). In situ treatment of
lithiated 3 with methyl chloroformate resulted in very efficient
mono-substitution to produce the 5-substituted diester 4 (96%).
Steric crowding of the side chain carboxy function by the gem-di-
methyl unit probably accounts for the apparent inertness of lithi-
ated 3 to self-addition. Surprisingly, however, attempts to produce
the target carbinols 6a,b by the addition of electronically varied
lithio-imidazoles, e.g., 5a,b, to diester 4 failed, with the starting
nucleophilic imidazole being largely recovered; NMR analysis of
the crude reaction mixture showed the formation of multiple un-
identified side products derived from the ester 4.
Suspecting that the sterically demanding sulfamoyl group and
tertiary alkyl 2-substituent of 4 could be depressing the reactivity of
the adjacent carboxy group, we decided to replace the former
group with a smaller one while simultaneously distancing the
functionalities from each other (Scheme 2). Acidic methanolysis of
4 to remove the sulfamoyl group cleanly gave the imidazole diester
7 (85%). Treatment of 7 with NaH then methoxymethyl chloride
(MOM-Cl) in THF at rt produced MOM-protected diester 8 as
a single regioisomer, whose 1,2,4-substitution was confirmed by
NOE experiments. This selectivity could be derived from electro-
philic attack by MOM-Cl at the more accessible (less hindered)
nitrogen of the intermediate imidazolide. Additions of lithio-
imidazole derivatives to diester 8 have also proven to be surpris-
ingly sensitive to the structure of the reaction partners. For exam-
ple, the reaction of 2-lithio-N-methoxymethylimidazole (5b) with 8
failed to produce an appreciable amount of 6d,26 while addition of
2-lithio-N-sulfamoylimidazole (5a) to 8 proceeded without diffi-
culty and afforded the tris(imidazolyl) ester 6c in good yield (74%).
A complete structure/reactivity account and theoretical analysis of
the seemingly capricious additions of substituted lithio-imidazoles
to various imidazoyl esters will be reported separately. Hydrolysis
of 6a with hydrochloric acid efficiently removed both the sulfamoyl
and the MOM protecting groups, providing the parent tris(imida-
zolyl)carboxylic acid 9 in excellent yield (85%) after basic elution
from an ion-exchange column.
enzymes to date, however, avoid the biomimetic imidazole (from
histidine) ligands.15 The structurally closest ligand to the (His)3-1-
carboxylate motif reported to date is found in iron complex A
(Fig. 2).16 Designed to mimic superoxide dismutase active sites,17
the complex incorporates two imidazole units and a tertiary alkyl
amine. The first fully characterized functional model of quercetin
2,3-dioxygenase was Cu(PPh3)2(fla) B (fla¼flavonolate anion). This
tetrahedral copper(I) complex is competent in the oxygenolysis of
flavonolate and was shown to correctly incorporate labeled
dioxygen and release carbon monoxide.18 The 1,3-bis(2-
pyridylimino)-isoindoline (IndH) ligand C was also used with CuI
and CuII to form flavonolate19,20 complexes as functional models.
The most structurally-relevant copper(II) complex incorporating an
N3O-donor set, D, is also a functional model with a moderate
turnover rate in DMF reducing in situ the copper center.21 Although
these functional models are competent, much room remains for
improvements, since the dioxygenation reactions were limited to
copper in its oxidation state (þI) rather than the biologically rele-
vant (þII) oxidation state and to high temperatures.
With the aim of providing the more accurate structural and
functional mimics of (His)3(carboxylate) enzyme active sites22 we
sought to prepare ligands of type E and corresponding complexes F
(Fig. 3). Reported herein is our successful achievement of this
challenging objective, which required the development of new
regioselective imidazole functionalization methodology.
Fig. 2. Model ligands and complexes for (His)3-carboxylate metalloenzymes.

3370
J. Volkman, K.M. Nicholas / Tetrahedron 68 (2012) 3368e3376
N
CO2Me
1) TEMPO, TCCA
OH
MeO2C
N
1
2) glyoxal, NH4OH
H
2
NaH/ClSO2NMe2
N
N
CO2Me
BuLi/ClCO2Me
CO2Me
MeO2C
N
N
Me2NO2S
Me2NO2S
3
4
Me2NO2S
P
OMe
N
OH
N
N
2
+ 4
Li
N
O
N
N
P N
N
P
5 a (P = SO2NMe2)
5 b (P = CH2OCH3)
(6 a ; P = SO2NMe2)
(6 b ; P = CH2OCH3)
Scheme 1.
MeO2C
N
N
N
H2SO4/MeOH
CO2Me
CO2Me
NaH, MOMCl
4
MeO2C
N
H
7
MOM
8
Me2NO2S
N
MOM
OH
OMe
N
N
2
+
8
Li
O
N
N
N
Me2NO2S N
N
P
5 a (P = SO2NMe2)
5 b (P = CH2OCH3)
6 c ; P = SO2NMe2
(6 d ; P = CH2OCH3)
H
H
N
OH
H3O+Cl-
OH
N
O
N
N
HN
N
9
Scheme 2.
An initial survey of the interaction of ligand 9 with metal salts
revealed its ready ability to form metal complexes as evidenced by
distinct color changes, but was often accompanied by the formation
of sparingly soluble, colored precipitates. A more soluble and
tractable derivative of 9 was produced in its aerobic reaction with
CoCl2$6H2O (1:1 or 2:1) in methanol, which led to the isolation of
a dark red CoIII complex, [Co(9)(9-H)]Cl2 (10) (Scheme 3). Complex
10 was characterized spectroscopically and its structure was
established by X-ray diffraction (Fig. 4). The observed octahedral
geometry about the cobalt atom in 10 is provided by two

J. Volkman, K.M. Nicholas / Tetrahedron 68 (2012) 3368e3376
3371
with a small amount of iodomethane in DMF.31 The required N-
methyl diester 13 was prepared efficiently (82%) and regiose-
lectively from 7 by treatment with sodium hydride and iodo-
methane (Scheme 4b). The regioselectivity of the alkylation was
established by NOESY NMR analysis, which supported the C4 car-
boxyl location.
With the building blocks 12 and 13 in hand, we probed the
addition of the Grignard reagent derived from 12 to the diester 13.4a
After magnesiation of 12, its reaction with 13 led to an inseparable
Scheme 3.
ꢁ
ꢀ
Fig. 4. (a) X-ray ORTEP diagram for the dication of 10. Selected bond lengths (A) and angles ( ): Co(1)eO(1B) 1.888(5), Co(1)eN(8A) 1.895(5), Co(1)eN(8B) 1.908(5), Co(1)eN(14A)
1.910(5); O(1B)eCo(1)eO(1A) 91.21(17), O(1B)eCo(1)eN(8A) 89.00(19), O(1A)eCo(1)eN(8A) 90.40(18), O(1B)eCo(1)eN(8B) 90.54(19), O(1B)eCo(1)eN(8B) 90.54(19), O(1A)e
Co(1)eN(8B) 87.33(17), N(8A)eCo(1)eN(8B) 177.67(19), O(1A)eCo(1)eN(14A) 177.55(19), O(1B)eCo(1)eN(14B) 179.34(17). (b) Model of 10 with Hs omitted.
(imid)3(CO2) ligands coordinated in a meridional fashion via a car-
boxylate oxygen and two imidazole nitrogens, with the third im-
mixture of addition products, assigned as a set of atropisomers 15M
based on its 1H NMR spectrum (Scheme 5), which exhibited mul-
tiple sets of resonances, and its eventual equilibration to a single
isomer (vide infra). Even though the material was not homoge-
neous, we established the metal-complexing ability of 15M by
treatment with [Cu(CH3CN)4]PF6. Crystallization of the mixture of
complexes from methanol provided a trimeric copper complex 16
whose unrefined crystal structure indicated coordination of both
the imidazole and alkoxo groups of the tripod ligand bridging the
three copper atoms, validating our concerns regarding potential
alkoxo-bridging from the carbinol unit.
ꢀ
idazole of each ligand free to engage in a novel, short (2.68 A)
imidazole-H-imidazolium hydrogen-bond.27 The fact that ligand 9
does not coordinate in a tetradentate manner to the cobalt center
may partly be the result of its inability to adopt the four nearly 90ꢁ
bite angles for tetradentate octahedral coordination.
To avoid unwanted coordination of the tripodal hydroxo group
of 15M its reduction to the hydrocarbon under acidic conditions
appeared to be a good option, which could also facilitate atro-
poisomer convergence via a carbocation intermediate. Indeed,
heating the isomeric mixture 15M with triethylsilane and tri-
fluoroacetic acid in 1,2-dichloroethane converted all atropoisomers
to a single product, the tripod ester 17, in 53% overall yield from 12
(Scheme 5). Ester 17 was then quantitatively hydrolyzed (6 N HCl)
to the tris-imidazole carboxylic acid as the hydrochloride salt
11a$HCl, which was fully characterized spectroscopically.
Based on examination of computational molecular models we
anticipated that the short carboxylate side chain of 11a would best
support a four or five-coordinate environment, so we chose
[(CH3CN)4Cu]PF6 as a metal ion source. When 11a was stirred in
methanol with 2 equiv of potassium carbonate and Cu(CH3CN)4PF6
in air, the solution turned green. Green crystals of a complex 18
were obtained from methylene chloride, which were structurally
determined by X-ray crystallography (Scheme 6, Fig. 5).
Scheme 3.
The synthetic route to ligand 9 outlined in Schemes 1e3 pro-
vides the first entry to tris(imidazole)carboxylate ligands. The
tendency of 9 to form insoluble metal complexes prompted us to
design second-generation ligands that would form more tractable
derivatives. In order to reduce the tendency to form oligomeric
species we sought to remove the potentially bridging NeH (imid-
azole)28,29 and OeH7a,30 units generally as in 11 and to include
strategically located alkyl groups to inhibit cluster formation and
increase solubility, exemplified by 11a (Scheme 4).
Seeking the isopropyl-substituted ligand 11a we adopted
a modified synthetic approach utilizing 4-iodo-imidazole 12 as the
pro-nucleophile (Scheme 4).7b The preparation of 12 was achieved
(Scheme 4a) starting from 2-isopropylimidazole via established
per-iodination and subsequent reduction to the mono-
iodoimidazole 14.7b,31 Although N-methylation of 14 gave
a nearly 1:1 mixture of regioisomers, the undesired 5-iodo isomer
could be isomerized to 4-iodo-N-methyl imidazole 12 by heating
The dimeric complex dication of 18 has two pentacoordinate
copper centers defined by the three imidazole nitrogen atoms and
two bridging carboxylate oxygens with two PFꢀ6 counter ions (not
shown). The geometry about each copper atom can be described as
distorted square pyramidal with a basal plane formed by O31, N24,

3372
J. Volkman, K.M. Nicholas / Tetrahedron 68 (2012) 3368e3376
R
H
N
CO2H
N
I
MeO2C
N
N
N
N
R'
R
+
CO2Me
N
Pri
N
N
N
R
R'
12
13
11
11a (R= Me, R'= CHMe2)
I
I
N
N
N
1) I2, KOH
1) NaH/MeI
(a)
(b)
2) Na2SO3,
EtOH/H2O
N
H
2) CH3I/DMF/Δ
N
H
N
14
12
MeO2C
N
N
CO2Me
CO2Me
NaH/CH3I
MeO2C
N
N
H
7
13
Scheme 4.
I
OH
N
CO2Me
N
N
1) 2 EtMgBr
2) 13
3) H2O
Cu(CH3CN)4PF6
N
2
N
Pri
(15M-H)3Cu3
16
N
N
N
12
Pri
15M
CF3CO2H/
Et3SiH
H
N
CO2H
N
H
N
CO2Me
6N HCl
N
N
N
Pri
N
N
Pri
N
. HCl
N
N
N
Pri
11a.HCl
Pri
17
Scheme 5.
N15, and O30* and with N1 as the apical atom. The
s
index value for
angles of the tripod ligand, which are better suited for facial co-
ordination in an octahedral environment.
18, a measure of distortion on the square pyramidal/trigonal bi-
pyramidal continuum (ssp¼0, stpy¼1.0),32 was calculated to be 0.27.
The coordination geometry of 18 can be compared to the active site
of 2,3-quercetin dioxygenase (Aspergillus japonicus)33 with bound
quercetin, which features also features a pentacoordinate Cu-
center with three coordinated imidazole nitrogens (from His),
a carboxylate oxygen (from Glu), and an oxygen from the quercetin.
Although the isolated complex 18 is dinuclear, we anticipated
that displacement of the bridging carboxylate with suitable sub-
strates should be possible, which would provide monomeric
structural and, possibly, functional models for the 3-His-1-
carboxylate tetrad with copper(II) in quercetinase. Indeed, initial
experiments showed a noticeable color change (blue-green to
green/yellow) upon addition of 3-hydroxyflavone (HF), a quercetin
model (Fig. 6), to a solution of 18 in methylene chloride. ESI-MS
analysis of this solution indicated the presence of a ternary
The
s value for the quercetinaseequercetin copper center is 0.41,
indicating a structure with a somewhat larger trigonal distortion.
The tris-imidazole donor set geometry in 18 is restricted by the bite

J. Volkman, K.M. Nicholas / Tetrahedron 68 (2012) 3368e3376
3373
H
N
CO2H
N
Cu(CH3CN)4PF6
-
[(11a-H)2Cu2]2+ 2PF6
N
N
Pri
K2CO3, MeOH
air
18
N
.
HCl
N
Pri
11a.HCl
Scheme 6.
ꢁ
ꢀ
Fig. 5. (a) X-ray ORTEP diagram of the dication of 18. Selected bond lengths (A) and angles ( ). Cu(1)eN(24) 1.9490(15), Cu(1)eO(30)#1 1.9534(13), Cu(1)eO(31) 2.0278(13), Cu(1)e
N(15) 2.0409(15), Cu(1)eN(1) 2.2873(16); N(24)eCu(1)eO(300) 172.85(6), N(24)eCu(1)eO(31) 83.91(6), O(30)#1eCu(1)eO(31) 90.36(5), N(24)eCu(1)eN(15) 86.40(6), O(30)
#1eCu(1)eN(15) 97.35(6), O(31)eCu(1)eN(15) 156.62(6), N(24)eCu(1)eN(1) 86.53(6), N(15)eCu(1)eN(1) 89.65(6). (b) Drawing of the dication of 18 with Hs omitted.
oligomeric polynuclear complexes can be suppressed by suitable
imidazole N- and C-alkylation and removal of the tripodal hydroxyl
group. Metal complexes derived from two of these ligands have
been structurally characterized, [L(L-H)Co]2þ (10) and [L2Cu2]2þ
(18). The former exhibits tridentate and the latter tetradentate
coordination with their respective tris(imidazole)carboxylate li-
gands. Preliminary experiments suggest that the copper complex
18 is reactive toward a quercetin model substrate. Having provided
synthetic access to these tris(imidazole)carboxylate ligands, the
stage is now set to evaluate the bio-relevant reactivity of the their
transition metal complexes. As our research priorities have
changed, we leave this new opportunity to the larger bio-organic
and -inorganic community.
Fig. 6. Hydroxyflavones.
4. Materials and methods
complex (11a-H)Cu(3-HF)þ (m/e¼748) and the appearance of new
4.1. General
features in the UVevis and IR spectra of this complex vis a vis 18
support the formation of an adduct incorporating HF. Attempts to
structurally characterize this adduct have not yet been successful.
Commercial chemicals (ꢂ99% pure) were used as received ex-
cept for the following solvents that were dried and distilled under
nitrogen before use: THF (Na/benzophenone), methanol (Mg),
3. Conclusions
dichloromethane (CaH2). Compounds 5a,34 5b,34 12,7b and 147b,31
were prepared by reported procedures or minor modifications
thereof; spectroscopic properties of 12 and 14 agreed with those
reported. Reactions involving moisture or oxygen-sensitive re-
agents were conducted under an atmosphere of argon (balloon).
CCDC 830309 and 829777 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
We have developed moderately efficient syntheses of a set of
tripodal tetradentate chelators, which possess the tris(imidazole)
carboxylate donor set, the most biologically faithful ligand models
available to date for the active sites of (His)3(Asp)/Glu-metal-
loenzymes. The synthetic schemes feature regioselective imidazole
functionalization reactions and chemoselective imidazolate addi-
tions to sterically differentiated diesters. The formation of

3374
J. Volkman, K.M. Nicholas / Tetrahedron 68 (2012) 3368e3376
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: þ44 1223 336033.
52.3, 47.4, 38.3, 27.0; HRMS (ESIþ): exact mass calculated for
C12H19N3O6SNa [MþNa]þ 356.0892. Found 356.0946.
4.1.1. 2-(1H-Imidazol-2-yl)-2-methyl-propionic acid methyl ester
4.1.4. 2-(1-Methoxycarbonyl-1-methyl-ethyl)-3H-imidazole-4-
carboxylic acid methyl ester (7). To a cooled solution of 4 (4.55 g,
13.6 mmol) in 120 mL of dry methanol 1.0 mL of concentrated
H2SO4 was added and the solution was refluxed for 20 h. The so-
lution was then cooled to rt and 40 mL of 1 N NaOH was added. The
aqueous layer was extracted three times with 100 mL of CH2Cl2.
Removal of the organic solvent afforded 7 in pure form (yield 85%).
Mp: 148e149 ꢁC; IR (KBr) 3003, 2956, 1741, 1725, 1528, 1443, 1347,
(2). To
a solution of hydroxypivalic methyl ester (10.00 g,
75.7 mmol) in 150 mL of dichloromethane was added 19.38 g
(83.4 mmol) of trichloroisocyanuric acid. The suspension thus
obtained was cooled to 0 ꢁC, before adding 150 mg (0.96 mmol) of
TEMPO. The reaction mixture was kept at 0 ꢁC for 15 min, warmed
to rt and stirred for 3.5 h. The suspension was then filtered through
Celite and washed sequentially with 100 mL of saturated Na2CO3,
1 N HCl, and brine. The organic layer was then dried over MgSO4
and the solvent removed under vacuum. The crude mixture was
used without further purification by dissolving it in 60 mL of
methanol and cooling to 0 ꢁC. Concentrated aqueous ammonia
(16 mL) was added at 0 ꢁC and the solution was stirred for 30 min at
rt. A solution of aqueous glyoxal (40 wt % in H2O, 11.0 g, 75.7 mmol)
in 20 mL of methanol was added dropwise over 2.5 h. The reaction
was left at rt overnight. The methanol was then evaporated under
reduced pressure and the remaining solution was dissolved in
200 mL of warm ethyl acetate. The organic phase was washed three
times with 20 mL of brine and dried over MgSO4. Upon evaporation
of the solvent an off-white solid precipitated, which was filtered to
yield 7.98 g of the ester 2 (yield 63%). Mp: 148e150 ꢁC; IR (KBr)
3439, 3115, 2956, 1887, 1729, 1555, 1453, 1374, 1262, 1196, 1162,
1262, 1200, 1169, 1108; 1H NMR (300 MHz, 4:1 MeOD/TFA)
1H), 3.94 (s, 3H), 3.75 (s, 3H), 1.77 (s, 6H); 13C NMR (100 MHz, 4:1
d 8.07 (s,
MeOD/TFA)
d 173.4, 159.6, 152.7, 126.8, 125.3, 54.1, 53.4, 45.4, 24.5;
HRMS (ESIþ): exact mass calculated for C10H14N2O4Na [MþNa]þ
249.0860. Found 249.0851.
4.1.5. 2-(1-Methoxycarbonyl-1-methyl-ethyl)-1-methoxymethyl-1H-
imidazole-4-carboxylic acid methyl ester (8). To a solution of 7
(1.00 g, 3.7 mmol) in 60 mL of THF at 0 ꢁC, NaH (60% mineral oil,
220 mg, 5.5 mmol) was added portion-wise and warmed to rt.
MOM-Cl (410 mL, 5.4 mmol) was then added neat and the reaction
was left stirring overnight. After adding 50 mL of ethyl acetate, the
organic phase was washed twice with 30 mL of saturated NaHCO3,
then 50 mL of brine and dried over MgSO4. The solvents were re-
moved under vacuum and the crude material purified by flash
column chromatography (6 EtOAc/4 hexanes) to yield 1.08 g of 8
(yield 90%). Mp: 45e46 ꢁC; IR (KBr) 3138, 2991, 2953, 1737, 1552,
1509, 1443, 1351, 1270, 1235, 1200, 1157, 1123, 1092, 1011; 1H NMR
1104, 903, 768 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 6.99 (s, 2H), 3.72
(s, 3H), 1.66 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 176.2, 149.6, 122.0
(br, 2C), 52.8, 43.9, 25.9; HRMS (ESIþ): exact mass calculated for
C8H13N2O2 [MþH]þ 169.0972. Found 169.0962.
(300 MHz, CDCl3) d 7.69 (s,1H), 5.11 (s, 2H), 3.87 (s, 3H), 3.66 (s, 3H),
4.1.2. 2-(1-Dimethylsulfamoyl-1H-imidazol-2-yl)-2-methyl-pro-
pionic acid methyl ester (3). To a solution of 2-(1H-imidazol-2-yl)-
2-methyl-propionic acid methyl ester (2) (5.00 g, 29.7 mmol) in
150 mL of dry THF cooled to 0 ꢁC, 1.8 g (45 mmol) of NaH (60%
dispersion in mineral oil) was added portion-wise over 30 min and
left at rt for 30 min. N,N-dimethylsulfamoyl chloride was then
added neat (3.8 mL, 35.4 mmol) and the solution was refluxed for
3 h. After cooling the reaction was quenched with H2O and ethyl
acetate was added (150 mL). The organic layer was then washed
twice with 25 mL of saturated NaHCO3, 25 mL of brine, and dried
over MgSO4. The organic solvents were removed under vacuum and
the crude material purified by flash column chromatography (75
EtOAc/25 hexanes) to yield 4.91 g of 3 (yield 60%). Mp: 83e85 ꢁC; IR
(KBr) 3154, 2992, 1742, 1536, 1491, 1380, 1281, 1262, 1097, 981; 1H
3.28 (s, 3H), 1.69 (s, 6H); 13C NMR (75.5 MHz, CDCl3)
d 175.5, 163.4,
150.8, 131.3, 128.0, 77.6, 56.6, 52.7, 51.9, 44.2, 25.8; HRMS (ESIþ):
exact mass calculated for C12H19N2O5 [MþH]þ 271.1288. Found
271.1258.
4.1.6. 2-{4-[Bis-(1-dimethylsulfamoyl-1H-imidazol-2-yl)-hydroxy-
methyl]-1-methoxymethyl-1H-imidazol-2-yl}-2-methyl-propionic
acid methyl ester (6c). N,N-dimethylsulfamoyl-imidazole (0.80 g,
4.6 mmol) was dissolved in 45 mL of dry THF under a slight positive
pressure of argon. The temperature was lowered to ꢀ78 ꢁC and
a solution of n-BuLi in pentane (5.1 mmol, 2.8 mL of 1.81 M) were
added dropwise. After stirring for 30 min, a solution of 8 (0.62 g,
2.3 mmol) in 5 mL of dry THF was added via a cannula. The reaction
was then left overnight to slowly warm up to rt. EtOAc (50 mL) was
added and the organic phase was washed twice with 30 mL of
saturated NaHCO3, 30 mL of brine, and dried over MgSO4. The or-
ganic solvents were removed under vacuum and the crude material
was purified by flash column chromatography (95 CH2Cl2/5 MeOH)
to yield 0.99 g of product 6c (yield 74%). Mp: dec 60e65 ꢁC; IR (KBr)
NMR (300 MHz, CDCl3)
d
7.11 (d, J¼1.5 Hz,1H), 7.01 (d, J¼1.5 Hz,1H),
3.70 (s, 3H), 2.90 (s, 6H), 1.71 (s, 6H); 13C NMR (100 MHz, CDCl3)
d
175.6, 152.1, 127.8, 118.5, 52.4, 45.8, 38.4, 26.5; HRMS (ESIþ): exact
mass calculated for C10H17N3O4S [MþH]þ 276.1013. Found
276.1006.
3439, 3122, 2941, 1737, 1389, 1266, 1177, 1153, 980 cmꢀ1
(300 MHz, CDCl3)
7.30 (d, J¼1.5 Hz, 2H), 6.92 (d, J¼1.5 Hz, 2H), 6.54
(s, 1H), 5.76 (s, 1H), 5.06 (s, 2H), 3.66 (s, 3H), 3.19 (s, 3H), 2.95 (s,
12H), 1.68 (s, 6H); 13C NMR (75.5 MHz, CDCl3)
175.9, 150.4, 147.9,
;
1H NMR
4.1.3. 3-Dimethylsulfamoyl-2-(1-methoxycarbonyl-1-methyl-ethyl)-
3H-imidazole-4-carboxylic acid methyl ester (4). To a solution of 3
(4.00 g, 14.5 mmol) in 120 mL of THF at ꢀ78 ꢁC under a slight
positive pressure of Ar, BuLi in pentane (16.0 mmol, 9.7 mL, 1.65 M)
was added dropwise. The solution was left 30 min at ꢀ78 ꢁC before
methyl chloroformate (2.3 mL, 29.8 mmol) was added neat. The
reaction was warmed to rt and left stirring for 2 h. The mixture was
then quenched with saturated NaHCO3 and ethyl acetate (100 mL)
was added. The organic layer was washed twice with 50 mL of
saturated NaHCO3, 50 mL of brine, and dried over MgSO4. The or-
ganic solvent was removed under vacuum and the crude material
was purified by flash column chromatography (9 CH2Cl2/1 EtOAc)
to yield 4.65 g of 4 (yield 96%). Mp: 92e95 ꢁC; IR (KBr) 3003, 2956,
d
d
139.3, 126.4, 121.9, 119.8, 77.7, 73.1, 56.2, 52.6, 44.1, 38.5, 25.9; HRMS
(ESIþ): exact mass calculated for C21H32N8O8S2Na [MþNa]þ
611.1677. Found 611.1663.
4.1.7. 2-{4-[Hydroxy-bis-(1H-imidazol-2-yl)-methyl]-1H-imidazol-
2-yl}-2-methyl-propionic acid (9). A solution of 6c (0.94 g,
1.60 mmol) in 40 mL of 6 N HCl was refluxed for 6 h. The solvent
was evaporated under reduced pressure. The crude product was
loaded on a column of Dowex 50WX8-100 resin (10 mL) and the by-
products were washed away with water. The product was eluted
with 6% aqueous ammonia. After removing almost all the solvent
by rotary evaporation, addition of acetone precipitated 0.43 g of 9
as an off-white solid (yield 85%). Mp: dec 130 ꢁC; IR (KBr) 3458,
1745, 1490, 1386, 1262, 1200, 1154, 980 cmꢀ1
CDCl3) 7.61 (s, 1H), 3.86 (s, 3H), 3.70 (s, 3H), 2.90 (s, 6H), 1.73 (s,
6H); 13C NMR (75.5 MHz, CDCl3)
175.1, 158.8, 158.6, 136.8, 124.9,
;
1H NMR (300 MHz,
d
d

J. Volkman, K.M. Nicholas / Tetrahedron 68 (2012) 3368e3376
3375
3207, 2983, 1660, 1617, 1567, 1532, 1447, 1404, 1355, 1115, 1077,
1027 cmꢀ1 1H NMR (300 MHz, CD3OD)
7.17 (s, 4H), 6.81 (s, 1H),
1H), 3.69 (s, 3H) 3.49 (s, 6H), 3.36 (s, 3H), 2.97 (sep, J¼6.9 Hz, 2H),
1.62 (s, 6H), 1.30 (d, J¼7.2 Hz, 12H); 13C NMR (75.5 MHz, CDCl3)
;
d
5.76 (s, 1H), 1.55 (s, 6H); 13C NMR (75.5 MHz, CD3OD)
d
181.1, 155.6,
d 176.6, 151.8, 147.8, 141.5, 141.4, 120.6, 118.3, 52.4, 43.5, 39.0, 33.2,
149.7, 138.7, 122.5, 117.8, 119.8, 71.0, 46.7, 26.1; HRMS (ESIþ): exact
26.0, 25.7, 21.5.
mass calculated for C14H17N6O3 [MþH]þ 317.1357. Found 317.1296.
4.4. Preparation of tricopper complex 16
4.2. Preparation of complex 10
Treatment of a solution of 15M (0.050 g) in 2 mL of CH2Cl2 with
Cu(CH3CN)4PF6 (0.060 g) with stirring at rt in the air produced
a green-blue precipitate within a few hours. The mixture was fil-
tered and the solid was redissolved in a minimum volume of
methanol and allowed to slowly evaporate, yielding green-blue
crystals of 16. X-ray diffraction analysis of 16 (unrefined) indicated
a structure with composition (15M-H)3Cu3 with coordination of
both the imidazole and alkoxo groups of the tripod ligand bridging
the three copper atoms (see SD for structure).
To a solution of 9 (0.10 g, 0.32 mmol) in 5 mL of methanol,
CoCl2$6H2O (38 mg, 0.16 mmol) was added. The reaction was left
stirring at rt for 2 h. The solution was then concentrated and left to
slowly evaporate open in the air, which yielded red crystals of 10
suitable for X-ray analysis. The crystals were washed with acetone
and dried under vacuum. Mp: dec 195e200 ꢁC; IR (KBr) 3425, 3146,
3003, 2933, 1591, 1477, 1405, 1378, 1351, 1119, 1088, 1061, 889,
772 cmꢀ1 1H NMR (300 MHz, DMSO-d6, 65 ꢁC)
; d 13.86 (br s, 2H),
13.35 (br s, 2H), 8.27 (s, 2H), 8.17 (br s, 2H), 6.90 (br s, 4H), 6.77 (d,
J¼1.8 Hz, 2H), 5.20 (d, J¼2.1 Hz, 2H), 1.70 (s, 6H), 1.55 (s, 6H); MS
(ESIþ): exact mass calculated for C28H30N12O6Co [MꢀH]þ 689.17.
Found 689.00.
4.4.1. 2-{4-[Bis-(2-isopropyl-1-methyl-1H-imidazol-4-yl)-methyl]-
1H-imidazol-2-yl}-2-methyl-propionic acid-hydrochloride
(11a$HCl). Ester 17 (0.33 g, 0.75 mmol) was dissolved in 6 N HCl
(20 mL) and the solution was refluxed for 2 h. The solvent was
removed under reduced pressure to yield the tris-imidazole acid
11a$HCl quantitatively (0.34 g). Mp: 82e84 ꢁC; IR (KBr, cmꢀ1) 3052,
4.3. X-ray structure determination of 10
Details of the X-ray data collection and crystal structure de-
;
2800, 1741, 1704, 1654, 1519, 1222, 1181 cmꢀ1 1H NMR (300 MHz,
termination of 10 are provided in the Supplementary data.
CD3OD) 7.61 (s, 1H), 7.45 (s, 2H) 6.00 (s, 1H), 3.85 (s, 6H), 3.82 (s,
d
3H), 3.49 (sep, J¼6.6 Hz, 2H),1.79 (s, 6H),1.45 (d, J1¼6.9 Hz, 6H),1.43
4.3.1. 2-(2-Methoxycarbonyl-2-methyl-propyl)-1-methoxymethyl-
1H-imidazole-4-carboxylic acid methyl ester (13). To a solution of
imidazole diester 7 (1.70 g, 7.51 mmol) in dry THF (75 mL) cooled to
(d, J¼7.0 Hz, 6H); 13C NMR (75.5 MHz, CD3OD)
d 172.8, 153.6, 149.7,
128.2, 127.8, 125.0, 122.9, 43.7, 35.8, 33.8, 29.8, 25.4, 23.1, 18.3;
HRMS (ESIþ): exact mass calculated for C23H35N6O2 [MþH]þ
427.2816. Found 427.2783.
0
ꢁC, NaH (0.45 g, 11.4 mmol, 60% dispersion in mineral oil) was
added portion-wise over 30 min and then the mixture was stirred
at rt for 30 min. After cooling to 0 ꢁC iodomethane was added
(0.58 mL, 9.0 mmol) and the solution was warmed to rt overnight.
The reaction was quenched with H2O and ethyl acetate was added
(50 mL). The organic phase was then washed with saturated
NaHCO3 (2ꢃ25 mL), brine (25 mL), and dried over MgSO4. The or-
ganic solvents were removed under vacuum and the resulting
residue purified by flash column chromatography (6 EtOAc/ 4
hexanes) to yield 13 as a white solid (1.48 g, 82% yield). Mp:
82e84 ꢁC; IR (KBr) 3129, 3084, 2993, 2956, 1737, 1704, 1556, 1440,
4.5. Preparation of bis-[2-{4-[bis-(2-isopropyl-1-methyl-1H-
imidazol-4-yl)-methyl]-1H-imidazol-2-yl}-2-methyl-
propionate]dicopper bis-hexafluorophosphate (18)
To a solution of imidazole acid 11a$HCl (50 mg, 0.10 mmol) in
MeOH (4 mL), tetrakis(acetonitrile)copper hexafluorophosphate
(35 mg, 0.10 mmol), and potassium carbonate (28 mg, 0.21 mmol)
were added. The stirred solution was exposed to air and soon
turned green. After removing methanol under reduced pressure
and redissolving the residue in methylene chloride, the filtered
solution was left overnight in the freezer to yield green crystals of
18 suitable for X-ray crystallography; after vacuum drying 18 was
obtained as a green-blue powder (25 mg, 26% yield).
Alternatively, complex 18 could also be prepared by stirring li-
gand 11a$HCl with K2CO3 (40 mg) and Cu(CF3SO3)2 (43 mg) in 4 mL
of acetonitrile at rt overnight. After solvent evaporation and tritu-
ration of the residue with CH2Cl2, the solution was filtered and the
filtrate evaporated to provide ca. 20 mg of green solid 18. The
paramagnetic Cu(II) state of 18 prevented the acquisition of well
resolved NMR spectra. MS (ESIþ) 488 [100, (L-H)63Cu(CH3CN)], 490
[55, (L-H)65Cu(CH3CN)], 1125 [15, (L-H)63,63Cu2(CF3SO3)], 1127 [17,
(L-H)63,65Cu2(CF3SO3)], 1129 [7, (L-H)65,65Cu2(CF3SO3)]. UVevis
(CH3OH) 750 nm (w), 270 nm (s).
; d 7.55 (s,
1346, 1251, 1226, 1012 cmꢀ1 1H NMR (300 MHz, CDCl3)
1H), 3.87 (s, 3H), 3.71 (s, 3H), 3.53 (s, 3H), 1.69 (s, 6H); 13C NMR
(75.5 MHz, CDCl3)
d 175.5, 163.3, 150.6, 130.9, 121.1, 52.7, 51.7, 43.7,
34.1, 25.3; HRMS (ESIþ): exact mass calculated for C11H16N2O4Na
[MþNa]þ 263.1002. Found 263.0943.
4.3.2. 2-{4-[Bis-(2-isopropyl-1-methyl-1H-imidazol-4-yl)-methyl]-
1H-imidazol-2-yl}-2-methyl-propionic acid methyl ester (17). To a rt
solution of iodoimidazole 12 (1.09 g, 4.35 mmol) in CH2Cl2 (20 mL)
under argon was added EtMgBr in diethyl ether (1.5 mL, 4.8 mmol,
3.05 M) dropwise. The mixture was stirred for 1 h before ester 13
(0.500 g, 2.18 mmol) was added in methylene chloride (2 mL). The
reaction mixture was stirred for 40 h and then quenched with
saturated NaHCO3. The organic phase was washed with saturated
NaHCO3 (2ꢃ50 mL), brine (50 mL), and dried over MgSO4. The or-
ganic solvent was removed under vacuum and to the crude product
15M, redissolved in 1,2-dichloroethane (20 mL), were added trie-
thylsilane (0.69 mL, 5.4 mmol) and trifluoroacetic acid (0.48 mL,
6.5 mmol). The reaction mixture was refluxed for 20 h. The solvent
was removed under reduced pressure and redissolved in EtOAc
(50 mL). The organic phase was then washed with saturated
NaHCO3 (2ꢃ50 mL), brine (50 mL), and dried over MgSO4. The
crude product was purified by chromatography over activity II
alumina in three phases: (1) 3 acetone/7 CH2Cl2; (2) CH2Cl2; and (3)
1 MeOH/9 CH2Cl2 to yield 0.33 g of ester 17 as an orange oil (yield
4.6. X-ray structure determination of 18
Details of the X-ray data collection and crystal structure de-
termination of 18 are provided in the Supplementary data.
4.7. Reaction of 18 with 3-hydroxyflavone
To a solution containing 18 mg (0.010 mmol) of complex 18 in
1 mL of CH2Cl2 was added 5 mg (0.21 mmol) of 3-hydroxyflavone
(HF). After a few minutes stirring at rt the solution changed color
to blue-green. ESI-MS analysis of the solution found: 444/446 (18-
53%). 1H NMR (300 MHz, CDCl3)
d 6.55 (s, 1H), 6.51 (s, 2H), 5.27 (s,

3376
J. Volkman, K.M. Nicholas / Tetrahedron 68 (2012) 3368e3376
H-CO2)Cuþ, 488/490 (18-H)Cuþ, 726/728 (18-H)Cu(HF)þ, 748/750
(18)Cu(HF-H)Naþ; calculated for (18)63Cu(3-HF) 748. UVevis
(CH3OH) 700 nm (w), 420 nm (s), 350 nm (s), 300 nm (s). IR (KBr,
thin film) 3050, 3000, 2960,1612, 1583, 1547, 1510, 1492, 1484, 1261,
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H.-J.; Elsliger, M.-A.; Grittini, C.; Grzechnik, S. K.; DiDonato, M.; Hale, J.;
Hampton, E.; Han, G. W.; Haugen, J.; Hornsby, M. I.; Jaroszewski, L.; Klock, H. E.;
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.
Acknowledgements
We are grateful for partial support of this project from the
American Chemical Society-Petroleum Research Fund. We thank
Dr. D. Powell for determining the crystal structures of 10 and 18.
Helpful discussions with Dr. Robert Houser are also acknowledged.
Supplementary data
1H and 13C NMR spectra of all new compounds and X-ray data
collection and structure determination information about metal
complexes 10 and 18. Supplementary data associated with this
article can be found, in the online version, at doi:10.1016/
j.tet.2012.02.042.
17. Policar, C.; Durot, S.; Lambert, F.; Cesario, M.; Ramiandrasoa, F.; Morgenstern-
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