Fluorinated imidazoles as 19F probes for biomimetic studies of heme a3 - Cub site in cytochrome c oxidase

Article abstract of DOI:10.1016/S0022-1139(00)00328-6

A series of 4,5-imidazole carboxylic acids bearing fluorinated substituents is synthesized from simple commercially available fluorinated substrates utilizing several different approaches to modify the imidazole core. These imidazole derivatives are speci

Full text of DOI:10.1016/S0022-1139(00)00328-6

Journal of Fluorine Chemistry 106 (2000) 189±197
19
Fluorinated imidazoles as F probes for biomimetic studies of
heme a3 Ð Cub site in cytochrome c oxidase
James P. Collman*, Roman Boulatov, Christopher J. Sunderland, Min Zhong
Department of Chemistry, Stanford University, Stanford, CA 94305, USA
Received 1 May 2000; accepted 26 July 2000
Abstract
A series of 4,5-imidazole carboxylic acids bearing ¯uorinated substituents is synthesized from simple commercially available ¯uorinated
substrates utilizing several different approaches to modify the imidazole core. These imidazole derivatives are speci®cally designed to be
sensitive probes for physicochemical studies of processes in the coordination environments of metals employing 19F-NMR techniques,
particularly in the context of our ongoing biomimetic work on imidazole-derivatized porphyrins. # 2000 Elsevier Science S.A. All rights
reserved.
Keywords: Imidazoles; Fluorine compounds; Carboxylic acids derivatives; 19F-NMR
1. Introduction
criteria (Fig. 1). Proximity of the 19F nuclei to the metal of
interest increases their sensitivity as analytical probes. This
must be balanced against any detrimental effects that such
additional substituents may have on the metal±ligand inter-
action, both sterically and electronically. For example, in
order for the proximal imidazole to serve as a high-af®nity
axial ligand to the metalloporphyrin, its derivatization has to
be limited to the C-4 position. Substituents at any other site
create unfavorable steric interactions with the macrocycle in
the metalloporphyrin-proximal imidazole adduct, thus,
facilitating its dissociation. The latter deleteriously affects
the reactivity of the model compound towards dioxygen.
Similar steric considerations limit the substitution pattern of
the distal imidazoles to the C-2 and/or N-1 positions. On the
other hand, the strong electron-withdrawing effect of ¯uor-
ine makes 2-, and 4-¯uoroimidazoles such poor ligands, as
to render them inappropriate for the present studies, even
though ¯uorine atoms in the close proximity to the metal-
coordinating site are particularly sensitive analytical probes.
The unfavorable electronic in¯uence of ¯uorine can be
mitigated by the use of a hydrocarbon link, but the link's
length needs to be optimized experimentally, so that the
probe retains suf®cient analytical sensitivity. As the ®rst step
towards designing the ideal 19F-marker for our biomimetic
studies, we have prepared a series of imidazole-4,5-car-
boxylic acids bearing ¯uorine atoms at different separations
from the metal-coordinating nitrogen. Such precursors for
the distal-site superstructure include 2-tri¯uoro- (1, no link),
N-(2,2,2-tri¯uoroethyl)- (2, CH2 link), and 2-(o,o-di¯uoro-
In metalloproteins, the imidazole moiety of histidine is a
common constituent in the coordination environment of
metal ions. Among the enzymes that bind and activate O2
and NO, such as cytochrome c oxidase and NO reductase,
this heterocycle mediates the important tasks of providing
axial ligation to the heme iron, coordination to nearby metal
ion centers, and stabilization of dioxygen complexes [1,2].
We recently reported [3] a general method for preparing
imidazole-appended aminophenylporphyrins which leads to
the synthesis of biomimetic heme models of unprecedented
complexity. For example, one series of our model com-
pounds possesses great structural similarity to the catalytic
site of cytochrome c oxidase, thus, permitting detailed
biomimetic studies of the possible mechanisms of O2 reduc-
tion by this important enzyme. Such work relies heavily on
our ability to perform multinuclear NMR spectroscopy on
these complex ligand systems, for both their original char-
acterization, and the subsequent course of physicochemical
experiments. Among the common NMR active nuclei, such
as 13C, 2H and 19F, we chose 19F due to the high sensitivity
and the wide range of chemical shifts characteristic of 19F-
NMR spectroscopy.
An appropriate 19F-marker, in terms of its chemical nature
and placement on a ligand system, has to satisfy several
* Corresponding author.
E-mail address: jpc@chem.stanford.edu (J.P. Collman).
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 3 2 8 - 6

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J.P. Collman et al. / Journal of Fluorine Chemistry 106 (2000) 189±197
with SF4 [5]. C-2 substituted 4-(tri¯uoromethyl)imidazoles
are available via condensation of an aldehyde with tri¯uor-
odibromoacetone in the presence of ammonia [6], whereas
2-(tri¯uoromethyl)imidazole derivatives can be obtained by
a ring closure of 1-substituted cis-1,2-dibenzoamido-1-
alkenes in the presence of tri¯uoroacetic anhydride [7].
None of these methods, however, provided a practical
synthesis of 1. Free-radical tri¯uoromethylation is often
useful, but requires lengthy irradiation times, gives mixtures
of isomers, and is incompatible with the presence of several
functional groups. Similarly, SF4-based ¯uorination cannot
be used for a selective conversion of one carboxylic group in
the presence of another. Condensation of dibenzoamidoalk-
enes with tri¯uoroacetic anhydride was reported to give high
yields only for relatively bulky substituents at C-1. In our
opinion, oxidative cleavage [5] of commercially available 2-
tri¯uorobenzimidazole followed by N-methylation and
selective decarboxylation of the resulting diacid constitutes
a more effective route to 1 (Scheme 1).
The standard methods for N-alkylation of imidazoles,
such as reaction between N-imidazolate anion and an alkyl
halide, cannot be used in the case of tri¯uoromethylimida-
zoles due to the susceptibility of the CF3 group towards basic
hydrolysis. In the only reported example of successful N-
alkylation of a (tri¯uoromethyl)imidazole, N-methyl-2-(tri-
¯uoromethyl)imidazole was obtained via corresponding
poorly-soluble silver 2-(tri¯uoromethyl)imidazolate [5].
We have found that a much simpler and more successful
procedure is N-methylation with trimethyl-ortho-acetate [8].
Thus, treatment of diacid 5 with (MeO)3CCH3 affords, after
chromatography, N-methyl-imidazolecarboxylate 7 in 80%
yield, whereas N-methylation of the more soluble diester 6
proceeds at lower temperature, and produces pure 7 in 76%
overall yield.
Fig. 1. A general structure of cytochrome c oxidase model compound. Rf,
R0f and R0f0 indicate the possible position of substituents bearing 19F-
markers.
phenyl)-(3a, three bond link), 2-(p-¯uorophenyl)- (3b, phe-
nyl link) and 2-(p-tri¯uoromethylphenyl)-(3c) derivatives.
Finally, attempts to prepare 4-(2,2,2-tri¯uoroethyl)imida-
zole, with the goal of using it as a precursor for the
proximal-site ligand, yielded a derivative of 4-(2,2,2-tri-
¯uoro-1-hydroxoethyl)imidazole (4).
2. Results and discussion
2.1. 2-Trifluoromethyl-1-methyl-4-carboxylic acid (1)
Selective transformations of non-symmetric imidazoles
have been studied extensively in order to ®nd both condi-
tions that would favor one regioisomer and simple analytical
techniques that would unambiguously distinguish between
them [9]. For example, N-methylimidazoledicarboxylic acid
yields predominantly 1-methylimidazole-5-carboxylic acid
Several synthetic routes to tri¯uoromethylimidazoles
have been reported. One or more CF3 groups can be intro-
duced onto an imidazole ring via free radical tri¯uoromethy-
lation [4] or ¯uorination of carboxylic acids functionalities
Scheme 1. Synthetic route to acid 1.

J.P. Collman et al. / Journal of Fluorine Chemistry 106 (2000) 189±197
191
Scheme 2. Synthetic route to acid 2.
upon heating at 1008C in acetic anhydride [10,11]. The
reaction was proposed to proceed via N-acylation which
determines the site of decarboxylation [11]. If the transfor-
mation is carried out in a solvent that does not undergo an
electrophilic attack on the imidazole nitrogen, the other
regioisomer predominates. In contrast, regioselectivity of
decarboxylation of diacid 8 is dependent on the reaction
temperature, but not on the solvent. For example, if the
reaction is conducted at 1708C in either DMSO, or ethylene
glycol only the C-4-isomer, 1, is produced. The other isomer,
2-tri¯uoromethyl-1-methylimidazole-5-carboxylic acid, can
be obtained only as a mixture with at least 70% of 1, by
carrying out decarboxylation at 1208C in either DMSO or
acetic anhydride1. This result suggests that diacid 8 does not
undergo acylation, re¯ecting the deactivation of the hetero-
cycle by the strongly electron-withdrawing CF3 group. The
CF3 functionality also imparts signi®cant stability towards
decarboxylation: for example, N-methylimidazole-4,5-
dicarboxylic acid undergoes complete decarboxylation in
DMSO at 1808C within 10 min [12], whereas the reaction
time for diacid 8 under identical conditions is 2 h. The
assigned regiochemistry of 1 is supported by observation
of NOE enhancement of the N-CH3 signals upon irradiation
of the imidazole HC-5 resonance. Such enhancement is not
expected between the HC-4 and N-CH3 groups. Indeed, of
the two regioisomers of structurally related 1-methyl-2-
propylimidazolecarboxylic acid, only 1-methyl-2-propyli-
midazole-4-carboxylic acid demonstrates the NOE enhance-
ment of the N-CH3 group [12].
obtained via a nucleophilic alkylation of the appropriate
imidazole derivative with CF3CH2OTf (Scheme 2). The poor
reactivity of the CF3CH2 moiety towards nucleophilic attack
is well-known, however, the origin of this inertness is still a
matter of controversy. An intuitive notion [13] that the CF3
group destabilizes partial positive charge developing on the
ˆ
C-1 carbon in the transition state, ‰2CF3 CH2XYŠ has been
1
criticized [14]. More recently, both inductive effects and
``shielding'' of the C-1 by F atoms have been invoked [15].
Alkylation of the dicyanoimidazolate-anion is further com-
plicated by its diminished nucleophilicity and poor solubi-
lity in THF: for example, no reaction is observed between
this weak nucleophile and CH3I over a week in THF at RT.
N9-alkylation of an adenine derivative with CF3CH2I pro-
ceeds satisfactorily in a more polar solvent, DMF [16].
However, dicyanoimidazolate-anion undergoes extensive
self-condensation in DMF, probably via an intermolecular
nucleophilic attack of the anion on a CN group. The use of
18-crown-6 (18C6) ether allowed us to achieve quantitative
N-alkylation of dicyanoimidazole 9 with CF3CH2OTf in
THF at RT. The role of the crown ether is not only to
increase the solubility of the N-imidazolate salt, but also to
break up the potassium-imidazolate ion pair. Removal of the
solvent followed by extraction with Et2O yields 10 as a
mixture with excess of 18C6, which is used directly in the
subsequent step; if desired, 10 can be puri®ed chromato-
graphically. This method is superior to a previous attempt
[17] to prepare N-(tri¯uoroethyl)imidazole in both simpli-
city and yield.
As expected, the CF3CH2 group in 10 is susceptible to
base hydrolysis (Scheme 3). Treatment of 10 with 2 M
aqueous NaOH for 2 h leads to loss of the 19F-NMR signals
corresponding to the CF3 group and yields several polar
products, as a result of additional partial or complete
hydrolysis of the CN groups. The ease of hydrolysis re¯ects
the increased acidity of the methylene hydrogens, as a
consequence of the inductive effects of both the CF3 group
and the heterocycle. The tri¯uoroethyl functionality also
2.2. 1-(2,2,2-Trifluoroethyl)imidazole-5-carboxylic acid
(2)
The next compound in the series, in which the 19F-marker
is separated from the heterocycle by a two-carbon chain was
1 NMR data for 2-trifluoromethyl-1-methylimidazole-5-carboxylic acid
(DMSO-d6) 1H: 8.29 (s), 3.85 (s); 19F: 61.42 (q, JHF ˆ 1 Hz).
5

192
J.P. Collman et al. / Journal of Fluorine Chemistry 106 (2000) 189±197
Scheme 3. Possible mechanism of hydrolysis of 10 in aqueous base.
greatly inhibits the acid hydrolysis of the cyano groups, such
that diacid 13 is obtained only after heating dicyanoimida-
zole 10 at re¯ux for a week in concentrated HCl. Under less
forcing conditions, only the cyano group farthest from the
CF3CH2 moiety is hydrolyzed, yielding 11. Neither the 4-
cyano-5-carboxylic acid isomer nor diacid 13 are observed.
This outcome, which de®nes the regiochemistry of the ®nal
product, is probably due to the ®eld effect of the CF3CH2
substituent [18]. The assigned regiochemistry of 11 is also
supported by comparison of its 13C spectrum with the
previously reported spectra [19] of authentic 5-cyano-1-
methyl imidazole-4-carboxylate and 4-cyano-1-methylimi-
dazole-5-carboxylate. Finally, the crown ether impurity
introduced with the starting material 10 is easily removed
on this stage via recrystallization of 11.
condensation of an appropriately labeled aldehyde with
dibromoacetone in the presence of ammonia [6]; or
with diaminomaleonitrile (DAMN), followed by chemical
oxidation of the resulting Schiff base [20]. Whereas the
corresponding diacid, was readily available via basic hydro-
lysis of 4,5-dicyano-2-(p-tri¯uoromethylphenyl)imidazole
obtained by the latter method, the respective monoacid
could not have been obtained in synthetically useful yields.
On the other hand, a variety of 2-substituted imidazole-4-
carboxylic acids (3a±c) were obtained by basic hydrolysis of
the CF3 group in corresponding 4-tri¯uoromethylimidazole
derivatives (14a±c) (Scheme 4). These derivatives are
synthesized in good yields via condensation of ¯uorinated
benzaldehydes with tri¯uorodibromoacetone [6].
It has been reported that an attempt to decarboxylate 5-
cyano-1-methylimidazole-4-carboxylic acid failed since the
acid sublimed without change [19]. At temperatures above
1808C, acid 11 demonstrates similar behavior in the solid
state; however, clean decarboxylation is achieved under
milder conditions. The product, 5-cyanoimidazole 12, sub-
limes as colorless needles, which requires no subsequent
work-up or puri®cation, and the method can be scaled up
very easily. Alternatively, heating a solution of acid 11 in
DMSO at 1508C for 1.5 h yields 5-cyanoimidazole 12
quantitatively. The product is not isolated, but used in the
subsequent hydrolysis as a DMSO±hydrochloric acid solu-
tion. This synthetic route is faster and more suitable for
small-scale preparations. Finally, hydrolysis of 12 in an
acidic medium, followed by recrystallization, gives color-
less plates of (tri¯uoroethyl)imidazole-5-carboxylic acid 2
in 55% overall yield.
2.4. 4-(2,2,2-Trifluoro-1-hydroxyethyl)imidazole derivative
(4)
As mentioned above (Fig. 1), placement of a 19F-marker
on the proximal imidazole is restricted to the C-4 position.
We attempted to introduce the CF3CH2 group into this
position by an Sn2 reaction of the appropriate imidazole
carbanion with CF3CH2OTf. The C-4/5 hydrogen in imida-
zoles is least acidic, and the corresponding anion can be
generated only if the nitrogen and C-2 positions are suitably
protected. N-protection was achieved with either sulfomoyl
(SO2NMe2) or ortho-amide (CH(OEt)2) groups and tert-
butyldimethylsilyl (TBDMS) moiety was used for the pro-
tection at the C-2 position [21,22]. This particular choice of
the protective groups was determined by their stability
towards strong bases (such as BuLi) necessary for the 5-
lithiation, and the ability to remove them under relatively
mild, acidic conditions (to prevent hydrolysis of the CF3
functionality). The corresponding 5-lithio derivatives, 16a
and 16b (Scheme 5) can be generated in THF within 10 min
at 788C upon addition of 1.1 eq. of BuLi and they are
stable up to 208C. Quenching of the reaction mixture with
D2O proves the completeness and regioselectivity of depro-
tonation, and the corresponding 5-methyl derivatives can be
2.3. 2-Fluoroarylimidazole-4-carboxylic acids (3a±c)
The ®nal set of ¯uorinated distal imidazoles for our
studies contains the 19F-marker attached to the imidazole
ring via a phenyl link. The most effective synthetic
approaches consist of assembling an imidazole ring, through

J.P. Collman et al. / Journal of Fluorine Chemistry 106 (2000) 189±197
193
Scheme 4. General synthetic route for acids 3a±c.
‡
prepared by addition of CH3I. However, 16b is much less
reactive, owing to its poor solubility in THF. The reaction of
16a and 16b with CF3CH2OTf and CF3CH2OTs is remark-
able: whereas both fail to react with the tosylate, 16a reacts
rapidly with the tri¯ate to yield the starting material, 15a
and 2-(tert-butyldimethylsilyl)-5-(1-hydroxo-2,2,2-tri¯uor-
ethyl)-1-sulfomoylimidazole, 4 in 1:1 molar ratio. Quench-
ing the reaction mixture with D2O immediately after
addition of CF3CH2OTf at 788C yields no detectable 5-
deutero derivative, indicating that the reaction is complete in
<2 min under those conditions.
the CF3CH2 group serves as a source of H for such
protonation. An increased acidity of the CH2 hydrogens
in CF3CH2OTf is expected and is evident by the facile base
hydrolysis of the CF3 group in 10. Interestingly, 5-lithio
derivative 16b is neither protonated, nor alkylated by
CF3CH2OTf despite the higher basicity expected of 16b.
This result most likely is due to the low solubility of 16b in
THF.
3. Experimental
The outcome of this reaction is qualitatively identical to
the nucleophilic attack of the 5-imidazolate carbanion on
tri¯uoroacetaldehyde, and (for examples of related trans-
formations, see [23]). The mechanism, however, is not clear.
Addition of more than an equivalent of CF3CH2OTf led to a
decrease in the molar ratio of (tri¯uorohydroxyethyl)imi-
dazole derivative 4 to starting material 15a, indicating
depletion of 5-imidazolate anion, 16a. It is very likely that
Acetic anhydride was shaken with anhydrous K2CO3
and dried with molecular sieves. Tert-butyldimethylsi-
lylchloride was distilled twice immediately prior to use;
all other reagents were used as received. Compounds 5 [7],
14a±c [8], 15a, 1-(diethoxymethyl)imidazole and 1-(N,N-
dimethylsulfomoyl)imidazole [20] were obtained as pre-
viously described. NMR and IR spectra were recorded on
Scheme 5. Reactivity of lethoderivatives 16a±b towards some substrates.

194
J.P. Collman et al. / Journal of Fluorine Chemistry 106 (2000) 189±197
Unitylnova-500 and Mattson In®nity 60AR spectrometers,
respectively; melting points were measured on a Mel-temp
apparatus, and are uncorrected. High-resolution mass spec-
tra (HRMS) were taken at the Mass Spectrometry Facility,
precipitate 1 is allowed to form at 48C overnight (yield:
60%).
3.5. 4,5-Dicyano-1-(2,2,2-trifluoroethyl)imidazole (10)
1
University of California at San Francisco. H-, 13C-, 19F-
NMR, HRMS and melting points data are given in Table 1.
To
a
suspension of dicyanoimidazole (300 mg,
2.54 mmol) and KH (110 mg, 2.75 mmol, 1.1 eq.) in anhy-
drous THF (10 ml) under N2, 18C6 (730 mg, 1.1 eq.) is
added, the mixture is stirred until solids dissolve and
CF3CH2OTf (770 mg, 1.3 eq) is added dropwise. The solu-
tion is stirred under N2 for 24 h during which time a
precipitate of K(18C6)Tf appears. THF is removed under
vacuum, a mixture of the product and unreacted 18C6 is
extracted in Et2O (3 Â 20 ml). This mixture can be used
directly in the subsequent steps; chromatography (silica/
CH2Cl2) yields pure 10 as yellowish oil which subsequently
solidi®es (400 mg, 2 mmol, 80% yield). IR (KBr, cm 1):
2234 (NC), 1182 (CF); TLC (2% MeOH/CH2Cl2) Rf ˆ
0:51. The compound is somewhat light sensitive, and should
be stored in the dark.
3.1. Dimethyl 2-trifluoromethylimidazole-4,5-
dicarboxylate (6)
Under N2 crude 5 (300 mg, 1.34 mmol) is suspended in
anhydrous MeOH (20 ml), dry HCl gas is bubbled through
the suspension for 25 min and the mixture is brought to
re¯ux. After 48 h, the solvent is removed in vacuo, the
yellowish residue redissolved in H2O (15 ml) and the solu-
tion is acidi®ed with concentrated hydrochloric acid to
pH ˆ 2. The product appears as a white microcrystalline
powder after 12 h at 48C. 280 mg (80%) after drying for 24 h
at 508C in vacuo. TLC (10% MeOH/CH2Cl2) Rf ˆ 0:30.
3.2. Dimethyl 2-trfluoromethyl-1-methyl-4,5-dicarboxylate
(7)
3.6. 5-Cyano-1-(2,2,2-trifluoroethyl)imidazole-4-
carboxylic acid (11)
Compounds 5 (300 mg, 1.34 mmol) or 6 (360 mg,
1.43 mmol) are added to (MeO)3CCH3 (3 ml, 20 mmol,
14 eq.) and the mixture is heated to 1208C (5, in an apparatus
for short-path distillation) or 858C (6) for 2 h. The excess of
ortho-acetate is removed in vacuo to give a yellowish oil.
Compound 7 obtained directly from 5 was subjected to
chromatography (¯ash silica/CH2Cl2). Yield: 280 mg (from
5, 80%); 360 mg (from 6, 95%). TLC (CH2Cl2) Rf ˆ 0:46.
A suspension of 10 (100 mg, 0.50 mmol) in concentrated
hydrochloric acid (2 ml) is heated at re¯ux under N2 for 2 h.
The solution is allowed to cool slowly to RT, H2O (1 ml) is
added; a white microcrystalline precipitate of 11 appears
after overnight at 48C is washed with H2O (2 ml) and Et2O
(2 Â 10 ml). Yield: 100 mg (90%). IR (KBr, cm 1): 3141
(OH), 2246 (NC), 1192 (CF).
3.3. 2-Trifluoromethyl-1-methyl-4,5-dicarboxylic acid (8)
3.7. 5-Cyano-1-(2,2,2-trifluoroethyl)imidazole (12)
NaOH (5 ml 1 M solution in H2O) is added to 7 (300 mg,
1.13 mmol), the dispersion is stirred at RT for 2 h; during
this time, the oil completely dissolves. The solution is
carefully acidi®ed to pH ˆ 2 with concentrated hydrochlo-
ric acid; the white crystalline precipitate appears after 2 h at
48C. Yield: 280 mg (90%) after drying in vacuo at 508C for
24 h.
Method A: Compound 11 (100 mg, 0.46 mmol) is dis-
solved in DMSO-d6 (1 ml) and heated at 1508C for 2 h; the
solution concentrated three-fold and is used directly in
subsequent steps; complete removal of DMSO is unneces-
sary for further step, and is not recommended due to
appreciable volatility of 12. Conversion is quantitative, as
1
judged by H-NMR.
Method B: Compound 11 (100 mg, 0.46 mmol) is heated
at 1708C in a sublimation apparatus for 48 h; the product
sublimes as colorless needless: 55 mg (70% yield). IR (KBr,
cm 1): 2234 (NC), 1160 (CF).
3.4. 2-Trifluoromethyl-1-methyl-4-carboxylic acid (1)
Under N2, 8 (100 mg, 0.36 mmol) is dissolved in 2 ml
DMSO and the mixture is heated to 1708C for 2 h. The
solvent is removed in vacuo (508C, 48 h, 0.5 mTorr) to give
white powder of 1 (80 mg, 95%). The product can be
recrystallized by dissolving it in boiling H2O (ca. 5 ml),
acidifying the hot solution with ca. 5 M HCl to pH ˆ 2 and
letting the precipitate form at 48C for 24 h. Similarly, the
decarboxylation can be conducted in HOCH2CH2OH as
described above. After removing the solvent (808C, 48 h,
0.5 mTorr), the oily residue is dissolved in 1 M aqueous
NaOH (ca. 3 ml) with heating, the solution is stirred for 2 h
at 608C, acidi®ed with concentrated HCl while hot, and
3.8. 1-(2,2,2-Trifluoroethyl)imidazole-5-carboxylic acid
(2)
Compound 12 (100 mg, 0.57 mmol) is suspended in
concentrated HCl (5 ml) and the mixture is heated at re¯ux
for 4 h. The solution is concentrated three-fold, and the
product is obtained as colorless plates after overnight at 48C,
washed with concentrated hydrochloric acid (2 Â 1 ml),
acetone (2 Â 1 ml) and dried at 508C in vacuo. Yield:
100 mg (85% yield).

Table 1
1H-, 13C-, 19F-NMR, HRMS and melting points data
a
‡
Compound 1H (500 MHz)a
19F (470 MHz) vs. CFCl3
13C (126 MHz)a
HRMS, M : calculated (found)
mp (8C)
3
5
7.52 (NH), 3.69 (CH3)
164.0 (MeO2C), 143.2 (C-2, q, JCF ˆ 35:1 Hz) 134.2 (C-4/5),
1
121.0 (CF3, q, JCF ˆ 275 Hz), 50.60 (CH3O2C)
7b
3.87 (CH3O2C), 3.84 (NCH3, br),
3.81 (CH3O2C)
67.4 (br)
161.5 (MeO2C), 159.6 (MeO2C), 137.0 (C-2, q, JCF ˆ 46 Hz),
C9H9N2F3O4: 266.0514 (266.0517)
c
±
3
1
134.2, 128.9 (C-4/5), 117.8 (CF3, q, JCF ˆ 270 Hz), 52.96,
4
52.36 (CH3O2C), 33.24 (NCH3, q, JCF ˆ 2:8 Hz)
5
8
10.1 (HO2C, br), 4.03 (NCH3, q)
61.45 (q, JHF ˆ 1 Hz)
162.6 (HO2C), 160.6 (HO2C), 135.4 (C-2, C-4, br), 131.7 (C-5),
1
C7H5N2O4F3: 238.0201 (238.0204)
C6H5F3O2N2: 194.0303 (194.0305)
C7H3N4F3: 200.03009 (200.0301)
180±181 (dec.)
>190 (dec.)
81±82
118.4 (CF3, q, JCF ˆ 271 Hz), 33.51 (NCH3)
1
8.13 (HC-5), 3.82 (NCH3, q,
5JHF ˆ 1 Hz)
61.42 (q)
162.52 (HO2C), 134.80 (C-2, br), 132.04 (C-4), 131.53 (C-5),
1
118.52 (CF3, q, JCF ˆ 270 Hz), 35.10 (NCH3)
10b
7.82 (HC-2), 4.73 (CH2CF3, q)
70.2 (t, JHF ˆ 8:5 Hz)
143.4 (C-2), 123.4 (C-4), 122.0 (CF3, q, JCF ˆ 283 Hz),
3
1
113.3 (C-5), 111.4 (NC), 107.2 (NC), 47.54 (CH2CF3,
2
q, JCF ˆ 36:4 Hz)
3
11
12
13.6 (HO2C), 8.26 (HC-2),
5.30 (CH2CF3, q)
70.4 (t, JHF ˆ 8:5 Hz)
160.9 (HO2C), 143.0 (C-4), 142.0 (C-2), 122.8 (CF3, q,
1JCF ˆ 278 Hz), 109.4 (NC), 108.9 (C-5), 46.48 (CH2CF3, q,
2JCF ˆ 35:4 Hz)
C7H4N3O2F3: 219.0256 (219.0312)
204±206 (dec.)
3
1
8.18 (HC-2), 7.98 (HC-4, d,
4JHH ˆ 1:5 Hz) (in CDCl3: 7.73,
7.71, 4.64 (q); in CD3OD: 8.11,
7.83, 5.07 (q)), 5.24 (CH2CF3, q)
12.12 (HO2C, br), 9.00 (HC-2),
8.12 (HC-4), 5.49 (CH2CF3, q)
(in CD3OD: 9.45, 8.35, 5.60 (q))
70.6 (t, JHF ˆ 8:9 Hz)
143.4 (C-2), 140.7 (C-4), 123.0 (CF3, q, JCF ˆ 281 Hz),
C6H4N3F3: 175.035732 (175.035733) 68±69
2
110.5 (C-5), 109.1 (NC), 46.08 (CH2CF3, q, JCF ˆ 38:0 Hz)
3
2
70.5 (t, JHF ˆ 9:5 Hz)
159.6 (HO2C), 142.1, 130.5, 124.0, 123.0 (CF3,
1
C6H5N2F3O2: 194.03031 (194.03034) >209 (dec.)
2
q, JCF ˆ 280 Hz), 46.12 (CH2CF3, q, JCF ˆ 35:3 Hz)
‡
3
13
13.4 (HO2C, HN , br), 8.89 (HC-2),
70.3 (t, JHF ˆ 8:8 Hz)
161.4 (5-HO2C), 159.3 (4-HO2C), 140.6, 133.4, 126.6,
1
C7H5N2O4F3: 238.0201 (238.0207)
C10H5N2F5: 248.0373 (248.0364)
204 (dec.)
164±165
5.58 (CH2CF3, q)
123.0 (CF3, q, JCF ˆ 279 Hz), 46.43 (CH2CF3,
2
q, JCF ˆ 34:3 Hz)
14ad
12.4 (NH, br, s), 7.88 (HC-5, d,
4JHF ˆ 1 Hz), 7.53 (C-30 F2Ph, tt,
8.5 Hz, 6.5 Hz), 7.13 (C-40 F2Ph,
112.56 (F2Ph, m),
3
161.47 (C-20 F2Ph, dd, JCF ˆ 252:1 Hz, JCF ˆ 6:2 Hz),
1
3
62.30 (F3C, d, JHF ˆ 1 Hz) 138.33 (C-2), 133.21 (C-4), 132.85 (C-10 F2Ph, t, 10.7 Hz),
123.33 (CF3, q, JCF ˆ 266 Hz), 119.65 (C-5, br, s), 113.05 (C-30
1
4
2
3
t, JHF ˆ 8:5 Hz)
F2Ph, dd, JCF ˆ 20:2 Hz, JCF ˆ 4:3 Hz), 109.17 (C-40 F2Ph,
3
t, JCF ˆ 18:2 Hz)
l4bd
14cd
3a
12.3 (NH, br, s), 8.04 (FPh, m),
7.75 (HC-5, br, s), 7.23 (FPh,
t, 9 Hz)
112.97 (Ph, m),
164.27 (C-40 FPh, d, JCF ˆ 247 Hz), 148.04 (C-2), 134.01 (C-4,
C10H5N2F: 230.0467 (230.0467)
199±200 (dec.)
1
2
2
62.56 (F3C, d, 1.5 Hz)
q, JCF ˆ 38:0 Hz), 128.75 (C-30 FPh, d, JCF ˆ 8:8 Hz),
127.34 (C-10 FPh, d, JCF ˆ 3:1 Hz), 123.4 (CF3, q,
4
1JCF ˆ 265 Hz), 119.11 (C-5, q, JCF ˆ 3:7 Hz),
3
116.76 (C-20 FPh, d, JCF ˆ 22:7 Hz)
3
12.5 (NH, br, s), 8.54 (CF3Ph,
d, 8 Hz), 8.25 (CF3Ph, d, 8 Hz),
7.86 (HC-5, br, s)
62.86 (CF3Ph, br, s),
62.73 (CF3Im, d,
3JHF ˆ 1:5 Hz)
147.59 (C-2), 134.36 (C-10 CF3Ph), 133.51 (C-4, q,
2JCF ˆ 39 Hz), 131.17 (C-40 CF3Ph, q, JCF ˆ 32 Hz),
2
127.06 (C-5, br, s), 126.91 (C-20 CF3Ph, q, 4.3 Hz),
1
125.33 (CF3Ph, q, JCF ˆ 272 Hz), 123.26 (CF3Im, q,
1JCF ˆ 268 Hz), 119.95 (C-30 CF3Ph, q, JCF ˆ 4:3 Hz)
3
8.13 (HC-5), 7.67 (F2Ph, m),
7.33 (F2Ph, t, 8.5 Hz)
111.25 (br, s)
161.46 (CO2H), 159.86 (C-20 F2Ph, dd,
C10H6N2F2O2: 224.0397 (224.0387) 230±231
1JCF ˆ 252 Hz, JCF ˆ 6:1 Hz), 135.94 (C-2), 133.54 (C-10 F2Ph,
3
br, s), 129.75 (C-4), 126.96 (C-5), 112.38 (C-30 F2Ph, dd, 24 Hz,
4 Hz), 106.0 (F2Ph, br, s)

Table 1 (Continued )
Compound 1H (500 MHz)a
19F (470 MHz) vs. CFCl3
110.40 (br, s)
13C (126 MHz)a
HRMS, M : calculated (found)
mp (8C)
a
‡
1
3b
3c
4b
13.4 (NH, CO2H, br, s),
163.13 (C-40 FPh, d, JCF ˆ 248 Hz), 161.77 (CO2H),
C10H7FN2O2: 206.0491 (206.0496)
197±199
4
8.15 (FPh, m), 8.03 (HC-5),
7.37 (FPh, t, 9 Hz)
146.23 (C-2), 128.84 (C-10 FPh, d, JCF ˆ 8:5 Hz),
127.82 (C-5, br, s), 127.76 (C-20 FPh, d, JCF ˆ 8:5 Hz),
3
124.15 (C-4), 116.10 (C-30 FPh, d, JCF ˆ 22:4 Hz)
2
12.8 (NH, CO2H, br, s),
3
61.23
162.43 (CO2H), 145.59 (C-2), 132.50 (C-4), 129.20 (C-10 CF3Ph, C11H7F3N2O2: 256.0459 (256.0421) 229±230 (dec.)
5
8.33 (CF3Ph, d, JHH ˆ 8:5 Hz),
q, JCF ˆ 32 Hz), 127.40 (C-5), 126.39 (CF3Ph, q, 101 Hz),
7.96 (HC-5), 7.86 (CF3Ph,
d, 8.5 Hz)
126.23 (CF3Ph, q, 95.8 Hz), 126.09 (CF3Ph, q, 92.2 Hz),
1
124.11 (CF3Ph, q, JCF ˆ 272 Hz)
‡
‡
c
±
7.37 (HC-5, br, s), 5.42 (CHOH,
quint., 6.5 Hz), 3.90 (OH, br, s),
2.84 (SO2N(CH3)2),
81.54 (dd, 6.6 Hz, 1.4 Hz) 157.59 (C-2), 132.31 (C-5), 128.10 (C-4),
1
M ±CH3: 372.1025 (372.1028),
123.63 (CF3, q, JCF ˆ 309:1 Hz), 63.93 (CHOH, q,
M ±tert-Bu: 330.0555 (330.0566)
2JCF ˆ 34 Hz), 37.56 (SO2N(CH3)2), 27.17 (C(CH3)3),
0.965 (tert-Bu), 0.375 (Si-Me),
0.367 (Si-Me)
18.40 (CMe3), 3.70 (Si-Me), 3.74 (Si-Me)
a NMR solvent Ð DMSO-d6, unless stated otherwise; multiplicities, when not stated, are 1; sign of the 1H±19F and 13C±19F coupling constants was not determined; 13C assignments were made by examining
the pattern of 13C±1H and 13C±19F couplings and/or by comparison with previously assigned spectra of structurally similar compounds.
b In CDCl3.
c Oil/wax.
d In acetone-d6.

J.P. Collman et al. / Journal of Fluorine Chemistry 106 (2000) 189±197
197
3.9. 1-(2,2,2-Trifluoroethyl)imidazole-4,5-dicarboxylic
acid (13)
10 min; the solution immediately turns yellow. The reaction
is quenched with D2O (2 ml) after 5 min at 788C, the THF
separated, the aqueous layer extracted with CH2Cl2
(2 Â 10 ml), the organic fractions are combined, dried over
K2CO3, the solvents are removed and the mixture is sub-
jected to chromatography (silica, CH2Cl2) to give pure 4 is
yellow wax (100 mg, 45%); TLC (CH2Cl2): Rf ˆ 0:22.
Compound 15a (65 mg, 40%) is recovered as a yellowish
oil (1H-NMR (CDCl3): 7.28 (HC), 7.37 (HC), 2.90 (sulfo-
moyl), 1.00 (tert-Bu), 0.43 (Si-Me)).
Compound 10 (100 mg, 0.50 mmol) is added to concen-
trated HCl (5 ml) and the mixture is heated at re¯ux under
N2 for 7 days. The solution was concentrated three-fold,
diluted with H2O (1 ml) and the product obtained as color-
less crystals after 24 h at 48C (95 mg, 80% yield).
3.10. Acids 3a±3c
Suspensions of 14a±c (1.2 mmol) in NaOH (10 ml, 3 M
aqueous solution) are stirred at room temperature for 2 h.
The resulting solutions are acidi®ed with concentrated HCl
to pH ˆ 2. The product collected is a white solid after
cooling the solution to 48C for 12 h; yields: 95%.
Acknowledgements
We thank the NIH (Grant GM 17880), NSF (Grant CHE-
9612725) and Stanford University Fellowship (R. Boulatov)
for ®nancial support. The Mass Spectrometry Facility at
University of California, San Francisco is supported by NIH
(grants RR 04112 and RR 01614).
3.11. 2-(Tert-butyldimethylsilyl)-1-
(diethoxymethyl)imidazole (15b)
Under N2, 1-(diethoxymethyl)imidazole (100 mg,
0.6 mmol) is dissolved in anhydrous THF (5 ml) the solution
cooled to 408C and BuLi (270 ml of 2.5 M solution in
hexanes; 0.7 mmol, 1.2 eq.) is added dropwise. The reaction
is stirred for 10 min and TBDMS-chloride (110 mg,
0.7 mmol as a solution in 200 ml of anhydrous THF) is
added, the solution is allowed to warm to RTover a period of
1 h and stirred at RT for 1.5 h. The reaction is quenched with
H2O (2 ml), the organic layer separated and the aqueous
fraction is extracted with CH2Cl2 (2 Â 5 ml). The organic
portions are combined, dried with K2CO3 and the solvent
removed in vacuo to give 15b as a yellow oil (160 mg, 95%).
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solution in hexanes; 0.60 mmol, 1.05 eq.) is added dropwise;
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