Oxazolidine Formation, or Loss of Acid, from Attempted Fluorination of Amide Side-Chain in 2-Nitroimidazoles

Article abstract of DOI:10.1002/jhet.3183

Reaction of Etanidazole (a 2-nitroimidazole derivative with an amide side-chain containing a hydroxyethyl group) with triflic anhydride gives, depending on conditions, a trifluoromethyl(sulfonyl)oxazolidine via a cyclization reaction, or a fluorine-free formate derivative; reaction with tosyl chloride gives only a chloroethyl derivative. An attempt to replace a Br-atom in a related propyl-containing amide side-chain by a F-atom forms instead a propylene derivative via loss of HBr. The studies stem from interest in use of 2-nitroimidazoles with fluorine-containing amide side-chains as hypoxia markers.

Full text of DOI:10.1002/jhet.3183

Month 2018
Oxazolidine Formation, or Loss of Acid, from Attempted Fluorination of
Amide Side-Chain in 2-Nitroimidazoles
a
a
b
a
*
Ian R. Baird, Brian O. Patrick, Kirsten A. Skov, and Brian R. James
aDepartment of Chemistry, University of British Columbia, Vancouver, BC V6T 1Z1, Canada
bAdvanced Therapeutics, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada
*
E-mail: brj@chem.ubc.ca
Received December 30, 2017
DOI 10.1002/jhet.3183
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
Reaction of Etanidazole (a 2-nitroimidazole derivative with an amide side-chain containing a
hydroxyethyl group) with triflic anhydride gives, depending on conditions, a trifluoromethyl(sulfonyl)oxa-
zolidine via a cyclization reaction, or a fluorine-free formate derivative; reaction with tosyl chloride gives
only a chloroethyl derivative. An attempt to replace a Br-atom in a related propyl-containing amide side-
chain by a F-atom forms instead a propylene derivative via loss of HBr. The studies stem from interest in
use of 2-nitroimidazoles with fluorine-containing amide side-chains as hypoxia markers.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
another 2-nitroimidazole, exchange of the Br of EBr1 by
reaction with K222/KF (potassium Kryptofax 222
fluoride) does yield EF1 (Chart 1), but only in 2% yield;
other products included poorly characterized 2-
nitroimidazole derivatives [8]. Conversion of an alcohol
to a sulfonate ester such as a triflate is also an established
method for labelling compounds with fluorine [4,9,10],
as exemplified by 18F-labelled sugars such as
fluorodeoxyglucose (3-[18F]FDG) [10], a frequently used
radiolabelled imaging compound.
We have studied several halogen exchange type
reactions, and this current paper describes data from
attempted syntheses of the triflate and tosylate derivatives
of Etanidazole, as considered previously by Tewson’s
group [4]; also studied is synthesis and characterization
of EF2Br (Chart 1), and an attempt to make EF3 via
bromine exchange with a fluorine. The findings clarify
some problems with the halogen exchange reactions.
We published recently the syntheses of derivatives of
2-nitroimidazole (2NO2Im), 2-methyl-5-nitroimidazole,
and 2-methyl-4-nitroimidazole [1]. The derivatives all
have an amide side-chain at the N1-atom of the
imidazole, and most of them contain halogen atoms in
this side-chain; the 2-nitroimidazoles are of the type
shown as the products in Chart 1 and are analogous to
the currently used hypoxia marker [18F]EF5 (Chart 1)
used to detect cancerous tumors [1,2]. The E-labelling
derives from the related, so-called Etanidazole (Chart 1),
followed by the numbers of halogen atoms. The
syntheses of EF5 (and EF3) derivatives [1,3] involve
reaction of a fluorine-containing amino side-chain with a
carboxylic acid derivative of 2NO2Im (1) (Chart 1). An
alternative route to incorporate fluorine is use of simple
halogen (or hydrogen) exchange via a fluoride salt, and
such a process to incorporate 18F in compounds for use
in nuclear imaging techniques such as PET is attractive in
terms of overall time needed to make the 18F compound,
the half-life of 18F being only 110 min [4–7]. The most
obvious choice to test for fluorination is Etanidazole as it
contains a primary OH-group (Chart 1), and synthesis of
18F-etanidazole was reported by Tewson in 1997 but
using reaction of 1 with 18F-ethylamine [4]. Within
RESULTS AND DISCUSSION
Attempted syntheses of the triflate analogue of
Etanidazole by its reaction with triflic anhydride (TfO2)
were unsuccessful, but surprisingly, and of interest,
products 2 and 3 were isolated.
© 2018 Wiley Periodicals, Inc.

I. R. Baird, B. O. Patrick, K. A. Skov, and B. R. James
Vol 000
Chart 1. The overall synthesis of the E-labelled imidazoles from the precursor 1 [2-(2-nitro-1H-imidazole-1-yl)acetic acid]; note, Etanidazole has one
less C-atom in the R group.
was shown by crystallography (Fig. 1) to be a 2NO2Im
species containing a cyclic, oxazolidine side-chain.
The bond lengths and angles for the nitroimidazole
component are very similar to those of EF5 [1,3] with
the ring being completely planar, no atoms deviating by
more than 0.006 Å from the mean plane. The C(4)–C(5)
bond length of 1.317 Å is consistent with the exocyclic
methylene functionality. Within the oxazolidine ring, C6
and O1 deviate the most (À0.160 and 0.156 Å,
respectively) from the mean plane, although the N-atom
on this ring is disordered and, within the minor fragment,
C6 and N3A deviate from the mean plane by 0.249 and
À0.215 Å, respectively. X-ray data in recent papers on
The formate ester 2 [(2-(2-nitro-1H-imidazol-1-yl)-N-
substituted oxazolidines that do have biological properties
have noted planar [12], twisted [13], and envelope-type
[14] rings. The synthetic methodology in these and other
oxazolidine systems varies considerably [14–18], the
closest to formation of 3 being one reported by Ye’s
group [14]; Scheme 2 shows both reactions that involve
incorporation of a carbonyl oxygen and an amine
nitrogen into the oxazolidine ring, although the
process for 3 is intramolecular, whereas the other is
intermolecular. Such an intramolecular cyclization within
a triflate derivative of Etanidazole has been suggested
previously [4,5], but no evidence was presented in
either report.
(ethylformate)acetamide)], a white powder, was the main
product (67% yield) when DMF was added to solubilize
the Etanidazole in CH2Cl2 in the Tf2O reaction where
conditions were made basic by the addition of pyridine.
The 19F{1H} NMR spectrum of 2 showed no triflate,
while 1H NMR data unveiled a new signal at δ 8.13 and a
shifted signal for the original CH2–O protons of
Etanidazole (from δ 3.34 to 4.21), consistent with the
presence of a terminal formate proton. IR bands at 1716
and 1655 cmÀ1 correspond to νCO of the formate and
amide, respectively. The findings imply that the
Etanidazole OH group reacts preferentially with DMF
versus Tf2O; presumably, the higher concentration of the
DMF determines reactivity of its carbonyl C-atom
(Scheme 1) versus the more electrophilic S-atoms of Tf2O
with its strongly electron-withdrawing CF3 groups [11].
Using the same conditions used for synthesis of 2,
but omitting the DMF, led to isolation of the yellow
product 3 [(Z)-2-((2-nitro-1H-imidazole-1-yl)methylene-
3-trifluoromethyl(sulfonyl)oxazolidine] in 36% yield that
NMR data of 3 in acetone solution are consistent with
the solid state structure. The 19F{1H} singlet of the triflyl
1
group is seen at δ 0.88, and the H NMR spectrum shows
shifts downfield from those of the precursor Etanidazole
side-chain. The δ 5.21 singlet of the CH2 attached to the
Etanidazole imidazole ring is replaced by one at δ 6.78
for the single olefinic proton that is also involved in weak
Scheme 1. Plausible mechanism for reaction of Etanidazole with DMF to form 2.
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Figure 1. ORTEP diagram of 3. Selected bond lengths and angles. Bond lengths (Å): N4ÀO2/3, 1.218(2); N1ÀC3, 1.367(3); N1ÀC4, 1.418(3); N2ÀC1,
1.303; N1ÀC1, 1.367(2); C4ÀC5, 1.317(3); N3ÀC5, 1.463(4); N3ÀC6, 1.497(5); O1ÀC5, 1.329(3); O1ÀC7, 1.437(2); C6ÀC7, 1.491(3); S1ÀN3,
2.097(5); S1ÀO4, 1.426(18); C8ÀF3, 1.282(9); C8ÀF1, 1.321(9). Bond angles (°): O3ÀN4ÀO2, 123.4(2); C1ÀN4ÀO3, 117.58(19); C1ÀN4ÀO2,
119.01(18); C1ÀN1ÀC3, 104.30(16); C3ÀN1ÀC4, 128.18(18); C4ÀC5ÀN3, 126.2(3); N1ÀC1ÀN4, 124.47(18); N2ÀC1ÀN1, 113.93(18);
N1ÀC4ÀC5, 122.4(2); C5ÀO1ÀC7, 110.43(16); C6ÀC7ÀO1,105.32(18); N3ÀC6ÀC7, 103.6(2); C5ÀN3ÀC6, 106.3(3); C5ÀN3ÀS1, 106.3(3);
N3ÀS1ÀO4, 118.1(4); S1ÀC8ÀF1, 108.3(5); F1ÀC8ÀF2, 105.3(9); F3ÀC8ÀF1, 112.6(7). [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 2. Formation of oxazolidine compounds: (a) Our work to form 3;
Scheme 3. Replacement of OH of Etanidazole by Cl using TsCl.
(b) Literature work [14].
Tewson later reported that reaction of fluoride (18F or 19F)
with the tosylate gave no fluorinated product [4]. We have
synthesized EF1(À1) by reaction of 1 with an amine side-
chain (cf. synthesis of EF2Br—see below) [1]. Johnstrom
and Stone-Elander have reported the synthesis of 2,2,2-
trifluoroethyl triflate [20], which in theory could be
coupled to a nitroimidazolacetamide (e.g. that shown in
Scheme 4) to yield the known, trifluoro derivative
EF3(À1), made previously from 1 [1]. Such coupling
would avoid unwanted side-reactions, such as NO2
displacement (see below) and the cyclization chemistry,
incurred by doing chemistry on the nitroimidazole itself.
Related to possible methods for addition of fluorine to
the nitroimidazole side-chain, attempts to replace the Br-
atom of EBr1 (Chart 1) by a F-atom (and subsequently a
18F-atom for PET imaging [8]) by reaction with
Bu4NF•H2O were unsuccessful; indeed, IR and NMR
data support nucleophilic replacement of the NO2-group
by a F-atom [21], consistent with other reports describing
facile nucleophilic displacement of an imidazole NO2-
group [22,23]. These findings encouraged us to
synthesize EF2Br (Chart 1) in an effort to increase the
electrophilicity of the C–Br carbon with the aim of
generating EF3 by replacing the Br-atom (rather than the
NO2 group) by F. The EF2Br synthesis followed an
H-bonding interactions with the O(2) of the NO2, and O(4)
of the SO2CF3, the respective H..O distances being 2.65
and 2.62 Å. The H signals of the two other Etanidazole
CH2 groups are shifted downfield (δ 3.59 to 4.36, and
3.34 to 4.64, for N–CH2 and CH2–O, respectively) due to
the cyclization; weak H-bonding (2.58 Å) between a C6–
H and O5 is also noted.
Attempts to synthesize the tosylate derivative of
Etanidazole using p-toluenesulfonyl chloride (TsCl)
1
produced, presumably via
a
tosylate intermediate
(Scheme 3), the known ECl1(À1), previously made from
1 and H2N(CH2)2Cl [1]. [The (À1) in ECl1(À1) implies
one C-atom less than in the E-compounds of Chart 1].
The findings suggest that formation of an Etanidazole
sulfonate ester is not a viable route for the incorporation
of fluorine into the side-chain using an active F-
containing species. Lim and Berridge did report at a
conference [19] isolation of the tosylate via another route
and a subsequent reaction with fluoride to give the
corresponding fluorine analogue, EF1(À1); however,
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Scheme 4. Synthesis of EF3(À1) using a triflate.
established methodology [1] using reaction of 1 with the
H2N(CH2)2CF2Br side-chain and X-ray quality crystals
were also made. The solution 1H NMR shifts and
multiplicities are consistent with the solid state structure
(see below); the shifts for the Im protons, the CH2CO
protons, the NH proton, and N-(CH2)2 protons are in the
ranges found for the corresponding protons in other 2-
nitroimidazoles with halogen-containing side-chains—see
examples in Chart 1 [1]. However, the δF 32.71 singlet is
surprisingly downfield of that for EF3 (δF 10.84) [1], the
difference in structures being displacement of the Br by a
F-atom, where the higher electronegativity of the F would
have predicted a more downfield shift for EF3.
F-atoms [1], was treated with fluoride but was unreactive,
the Br not being replaced even at high [FÀ] and high
temperatures. EF3 shows no sign of eliminating the
weaker acid HF. These results suggest that the chemistry
of the side-chain needs further investigation before a high
yield exchange reaction can be accomplished.
Worth noting is the one-electron reduction potential for
the NO2 group of EF2Br, because this is an important
factor in the efficacy of nitroimidazoles as hypoxia-
selective, bioreductive agents (see Introduction) [1]; the
value is À1022 mv (vs. SCE), essentially the same as
that of EF3 (À1024 mv). The corresponding potential for
EF5 is À977 mv, the most positive of a wide range of
nitroimidazoles containing a halogen-containing side-
chain, and hence supports its clinical use [1].
The structure of EF2Br (Fig. 2) shows that the C8ÀBr1
bond (1.939 Å) is, as expected, longer than the two C(8)À
F bonds (average = 1.360 Å); other bond lengths and
angles are similar to those found for analogous E-
derivatives [1]. However, the fluorine atoms of EF2Br
apparently increase the acidity of the CH2CF2Br protons,
and the compound readily eliminates HBr (e.g. even on
treating with Bu4NF•H2O) to form the difluoroalkene
species E═F2 (Chart 1, where R is CH2CH═CF2); this
was isolated as a white solid and well characterized by
CONCLUSIONS
From an attempt to make a triflate derivative of
Etanidazole,
a
(hydroxyethyl)acetamide of
a
2-
nitroimidazole, cyclization via a net loss of H2O generates
a trifluoromethyl(sulfonyl)oxazolidine derivative of the
2-nitroiimidzole; in the presence of DMF, no cyclization
occurs and a formate derivative is produced. In an attempt
to form a tosylate derivative using tosyl chloride, the
Etanidazole-OH group is replaced only by Cl. In an effort
to make EF3 from reaction of EF2Br (see Chart 1) by
displacement of the Br by F, the EF2Br was synthesized
and reacted with Bu4NF•H2O, but instead a net loss of
HBr generates E═F2 containing a 3,3-difluoropropylene
moiety. The chemistry of the side-chains within the
biologically important 2-nitroimidazole derivatives
continues to bring surprises.
1
elemental analysis (EA), IR, and H and 19F{1H} NMR
data. 19F{1H} NMR analysis of the oil from which E═F2
was isolated indicated some NO2-group displacement
[21], but no signals of EF3 [1] were observed. In efforts
to prevent HBr elimination, the known EF4Br, in which
the H-atoms of the CH2CF2Br of EF2Br are replaced by
EXPERIMENTAL
Figure 2. ORTEP diagram of EF2Br; an H2O molecule and a minor dis-
ordered fragment are not shown. Selected bond lengths and angles. Bond
lengths (Å): N4ÀO3, 1.231(4); N1ÀC4, 1.458(4); C4ÀC5, 1.531(3);
N3ÀC5, 1.332(4); N3ÀC6, 1.454(4); C7ÀC8, 1.483(3); C7ÀC6,
1.525(3); C8ÀF1, 1.361(3); C(8)ÀF(2), 1.358(4); C8ÀBr1, 1.939(2).
Bond angles (°):O3ÀN4ÀO2, 124.74(17); C1ÀN4ÀO3, 117.67(17);
C1ÀN4ÀO2, 117.56(17); C3ÀN1ÀC1, 104.69(17); C3ÀN1ÀC4,
124.74(3); C5ÀN3ÀC6, 120.95(19); N3ÀC6ÀC7, 113.24(16);
F1ÀC8ÀF2, 106.2(5); C7ÀC8ÀF2, 111.2(6); F2ÀC8ÀBr1, 106.9(3);
Br1ÀC8ÀC7, 113.01(15). [Color figure can be viewed at
wileyonlinelibrary.com]
General.
Etanidazole (N-2-hydroxyethyl)-2-(2-nitro-
1H-imidazol-1-yl)acetamide) and H2N(CH2)2CF2Br•HBr
were kindly donated by Dr. C. Koch (University of
Pennsylvania) and Prof. W. Dolbier (University of
Florida), respectively, and were used as received. The
precursor imidazole 1 was synthesized as a powder from
Etanidazole via cleavage of the amide bond using
MeOH/HCl to yield the methyl ester that was then
hydrolyzed using NaOH [1,24]. The syntheses described
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below were all carried out under N2 at room temperature (r.
t. ~20°C).
reduced in volume to ~2 mL prior to column
chromatography (CH2Cl2 → CH2Cl2:acetone, 4:1). The
first eluted yellow band (Rf = 0.85) yielded 3 as a yellow
powder (135 mg, 36%), and X-ray quality crystals were
grown from slow evaporation of a 1:1 CH2Cl2:acetone
solution of the compound. Anal. Calcd. for
C8H7N4O5SF3: C, 29.28; H, 2.15; N, 17.07; found: C,
29.15; H, 2.22; N, 17.42. LR-MS [DCI(+)]: 329 (M++H).
IR: 3155 (C–Halkene); 2980 (C–HIm); 2918 (C–H); 1710
(C–O); 1485 (N–Oasym); 1362 (N–Osym); 1203 (S═O).
UV-Vis (MeOH): 314 (4.3). 1H NMR: δ 7.58 (d, 1H,
Im–H5), 7.17 (d, 1H, Im–H4), 6.78 (s, CH═C), 4.64 (t,
2H, CH2O), 4.36 (t, 2H, NCH2). 13C{1H} NMR: δ 146.5
(CH═C), 128.6 and 127.8 (Im–C4 and 5), 120.9 (q, CF3),
89.0 (CH═C), 68.8 (CH2O), 49.9 (NCH2). 19F{1H}
NMR: δ 0.88 (s, CF3).
Commercial chemicals used and other general
experimental details have been recorded recently [1] and
describe the solvents used and their drying agents; the
TLC methodology; and instrumentation used for
measuring EA, UV-Vis, IR, and mass spectra, and
electrochemistry (CV) measurements. UV-Vis spectra are
recorded as λmax (nm), [εmax × 10À3 (MÀ1 cmÀ1)]; IR
1
spectra are listed as cmÀ1. The H (300 MHz), 13C{1H}
(75.4 MHz), and 19F{1H} (188 MHz) NMR spectra were
all recorded at r.t. in d6-acetone solution on a Varian
1
XL300 spectrometer; H and 13C shifts are referenced to
those of the Me groups of residual Me2CO solvent (δH
2.20 and δC 2.50), and the 19F{1H} shift is referenced to
that of external CF3CO2H in D2O; peak multiplicities are
reported as s = singlet; d = doublet; t = triplet;
q = quartet; br = broad; where overlapping peaks mask
multiplicity, the expected multiplicity is given in italics
(e.g. for NHCH2CH2, an observed q for an expected dt is
recorded as q,dt); J values are reported in Hz.
Reaction of Etanidazole with TsCl to form 2-(2-Nitro-1-H-
imidazol-1-yl)-N-(2 chloroethyl)acetamide [ECl1(À1)]. In a
flask equipped with a reflux condenser, CHCl3 (10 mL)
was added to Etanidazole (403 mg, 1.88 mmol) at 0°C to
yield a white slurry; addition of DMF (3 mL) gave a
colorless solution to which TsCl (553 mg, 2.90 mmol)
and py (350 μL, 4.34 mmol) were added, and the
reaction mixture was stirred for 0.5 h, before being left to
warm to r.t. Addition of Et2O (~30 mL) produced a white
precipitate that was filtered off (and identified as a
mixture of pyridinium hydrochloride and pyridinium
tosylate). The filtrate was taken to dryness and the
residue was dissolved in minimal acetone before being
loaded onto a TLC column. Elution using 5% acetone in
CH2Cl2 generated two major bands, the first yielding
unreacted TsCl, and the second band giving the known
ECl1(À1) (207 mg, 47%) [1].
Reaction of Etanidazole with Tf2O to form 2-(2-nitro-1H-
imidazol-1-yl)-N-(ethylformate)acetamide (2), and (Z)-2-((2-
nitro-1H-imidazole-1-yl)methylene-3 trifluoromethyl)sulfonyl)
oxazolidine (3). Addition of CH2Cl2 (15 mL) and DMF
(3 mL) to Etanidazole (303 mg, 1.41 mmol) in a Schlenk
tube gave a colorless solution; this was stirred at 0°C for
30 min when py (320 μL, 3.95 mmol) and then
(CF3SO2)2O (342 μL, 3.95 mmol) were added dropwise.
The resulting orange mixture was stirred for 3 h at r.t.,
when TLC analysis (using THF) revealed three products:
a bright yellow band (Rf = 0.95), and colorless bands at
Rf = 0.65 and 0.10. The solvent was removed under high
vacuum, and 2 was isolated from the 0.65 band using
column chromatography (THF); further purification via
sublimation (at 130°C under vacuum) yielded a white
solid (230 mg, 67%). Anal. Calcd. for C8H10N4O5: C,
39.67; H, 4.16; N, 23.13; found: C, 39.90; H, 4.15; N,
23.03. LR-MS [EI(+)]: 243 (M+), 196 (M+ÀNO2). IR:
3275 (N–H); 3096 (C–HIm); 2940 (C–H); 1716 (C═Oald);
Synthesis of 2-(2-Nitro-1-H-imidazol-1-yl)-N-(3-bromo-3,3-
difluoropropyl)acetamide [EF2Br].
N-Methylmorpholine
(131 μL, 1.20 mmol) and iso-butylchloroformate
(172 μL, 1.32 mmol) were added to a THF solution
(20 mL) of 1 (206 mg, 1.20 mmol), and to the resulting
orange slurry were added H2N(CH2)2CF2Br•HBr
(273 mg, 1.30 mmol) and further N-methylmorpholine
(142 μL, 1.30 mmol). The mixture was then stirred at r.t.
for 6 h, when the white solid that formed was filtered off
and washed with THF (3 × 5 mL). The filtrate was taken
to dryness to give an orange oil that was purified using a
Chromatotron (a rotating disc TLC) with Et2O:acetone
mixtures of 10:0 → 10:3. An orange band eluted from
the plate first using Et2O; the product band was then
eluted using acetone, and the solution, when taken to
dryness, yielded an off-white solid (242 mg, 62%). X-ray
quality crystals were obtained from slow evaporation of a
concentrated MeOH solution. Anal. Calcd. for
C8H9N4O3F2Br: C, 29.38; H, 2.77; N, 17.13; found C,
29.35; H, 2.87; N, 17.22. LR-MS [DCI(+)]: 346, 344
(M+ + NH+4), 329, 327 (M+ + H), 299, 297 (M+ÀNO),
1
1655 (C═Oamide); 1487 (N–Oasym); 1362 (N–Osym). H
NMR: δ 8.13 (s, 1H, CHO), 7.80 (br s, 1H, NH), 7.50 (s,
1H, Im–H5), 7.14 (s, 1H, Im–H4), 5.25 (s, 2H, CH2CO),
4.21 (t, 2H, CH2O), 3.55 (q, dt), 2H, NHCH2CH2).
13C{1H} NMR: δ 166.7 (CONH), 161.8 (CHO), 128.7
and 128.2 (Im–C4 and 5), 62.8 (CH2CO), 52.5 (NHCH2),
39.0 (CH2O).
Under conditions similar to those used above for 2, but
with no DMF, addition of (CF3SO2)2O formed an initial
slurry that initially became a bright yellow solution, but
stirring for ~2 h at r.t. produced a yellow slurry. The
mixture was filtered and the filtrate reduced in volume to
~5 mL; addition of Et2O (25 mL) yielded a white
precipitate that was filtered off. The yellow filtrate was
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282, 280 (M+ÀNO2), 247 (M+ÀBr). HR-MS [DCI(+)]
REFERENCES AND NOTES
Calcd. for C8H10O3N841Br (C8H10O3N749Br): 328.98838
(326.99047); found 328.98733 (326.99038). IR: 3287
(N–H); 3120 (C–HIm); 3062, 2963 (C–H); 1671 (C═O);
1494 (N–Oasym); 1371 (N–Osym). UV-Vis (MeCN): 328
(6.6). 1H NMR: δ 7.86 (br s, 1H, NH), 7.50 (s, 1H,
Im–H5), 7.14 (s, 1H, Im–H4), 5.25 (s, 2H, CH2CO), 3.55
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3
(q, 2H, NHCH2), 2.73 (tt, 2H, JHF = 17, CH2CF2Br).
19F{1H} NMR:
δ
32.71 (s, CF2Br). E1/2 (in
MeCN) = À1022 mV (vs. SCE).
2-(2-Nitro-1-H-imidazol-1-yl)-N-(3,3-difluoropropylene)
acetamide [E═F2].
Addition of EF2Br (40.1 mg,
0.122 mmol) to Bu4NF•H2O (68.4 mg, 0.245 mmol) in
2 mL MeCN gave a yellow solution that was stirred at r.t.
for 10 h; the solvent was then removed and the major
product isolated as a yellow oil via preparative TLC
(CH2Cl2:MeOH, 25:1). The oil was dissolved in EtOAc
(5 mL), and hexanes were added to give a white
precipitate that was filtered off and dried in vacuo
(13.2 mg, 44%). Anal. Calcd. for C8H8N4O3F2: C, 39.03;
H, 3.28; N, 22.76; found C, 39.12; H, 3.20; N, 22.55. IR:
3311 (N–H); 3104 (C–HIm); 2923, 2851 (C–H); 1668
(C═O); 1487 (N–Oasym); 1375 (N–Osym). UV-Vis
(MeCN): 320 (3.9). 1H NMR: δ 7.75 (br s, 1H, NH),
7.50 (s, 1H, Im–H5), 7.12 (s, 1H, Im–H4), 5.22 (s, 2H,
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3
3
CH2CO), 4.55 (dtd, 1H, JHF(trans) = 25, JHH = 7.7,
2
3JHF(cis) = 2.2, CH═CF2), 3.85 (dddd, 2H, JHH = 9.2,
4
4
3JHH = 7.1, JHF(trans) = 2.1, JHF(cis) = 1.4, CH2CH═).
19F{1H} NMR: δ À12.78 (d, JFF = 26.3, ═CFcis),
2
2
À13.82 (d, JFF = 26.3, ═CFtrans).
Crystallographic analyses. The X-ray analyses of 3 and
EF2Br were carried out at 295 K on a Rigaku AFC6S
CCD diffractometer with graphite-monochromated CuKa
radiation (1.54178 Å); the structures were solved by
direct methods [25], with refinements being done using a
SHELXL program [26] via the Olex2 interface [27]. All
non H-atoms were refined anisotropically, and all other
H-atoms were generally placed in calculated positions.
The ORTEP plots and selected bond lengths and angles
are shown in Figures 1 and 2. Full experimental
parameters and structure details are given in CIF format
in the Supplementary Information.
SUPPORTING INFORMATION
Acknowledgments. We thank the Natural Sciences and Engineering
Council of Canada (NSERC), the Medical Research Council of
Canada for financial support, and Drs. C. Koch (University of
Pennsylvania) and W. Dolbier (University of Florida) for the
donated Etanidazole and H2N(CH2)2CF2Br•HBr, respectively.
Additional Supporting Information may be found online
in the supporting information tab for this article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet