Syntheses of E- and Z-2- and 4-fluorourocanic acids

Article abstract of DOI:10.1016/S0022-1139(02)00045-3

Horner-Wadsworth-Emmons olefination of ring-fluorinated N-trityl-imidazole carboxaldehydes with dialkyphosphonoacetic acid esters produced ring-fluorinated imidazolyl-E- and Z-acrylate esters. Stereochemistry was controlled by choice of phoshonate. Acid c

Full text of DOI:10.1016/S0022-1139(02)00045-3

Journal of Fluorine Chemistry 115 (2002) 137±142
Syntheses of E- and Z-2- and 4-¯uorourocanic acids
*
Junfa Fan, Bohumil Dolensky, In Ho Kim, Kenneth L.Kirk
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, MD 20982, USA
Received 31 January 2002; accepted 31 January 2002
Abstract
Horner±Wadsworth±Emmons ole®nation of ring-¯uorinated N-trityl-imidazole carboxaldehydes with dialkyphosphonoacetic acid esters
produced ring-¯uorinated imidazolyl-E- and Z-acrylate esters.Stereochemistry was controlled by choice of phoshonate.Acid catalyzed
removal of trityl followed by ester saponi®cation gave the target 2- and 4-¯uoro-E- and Z-urocanic acid derivatives.These are being
investigated as potential mediators of photo-immunosupression. # 2002 Elsevier Science B.V. All rights reserved.
Keywords: Fluoroimidazoles; Horner±Wadsworth±Emmons ole®nation; Urocanic acid; Tritylation
1. Introduction
recently have completed the syntheses of E- and Z-b-¯uor-
ourocanic acids [7].
E-urocanic acid (E-1a) is the product of histidine ammo-
nia lyase catalyzed elimination of ammonia from histidine in
the ®rst step of histidine catabolism (Scheme 1).This
metabolite is further degraded by urocanase to produce
formamino glutamic acid, a source of one carbon units in
subsequent biochemical transformations [1].Absorption of
light by E-urocanic acid present in the epidermis prompted
speculation that it functioned as a naturally-occurring sun
screen [2].In the process, E-urocanic acid is photo-isomer-
ized to the Z-isomer (Z-1a).The discovery that Z-urocanic
acid functions systemically as an immunosupressive agent
has sparked renewed interest in the biology of urocanic acid
[3].
As part of our investigation of ring ¯uorinated imidazoles,
several years ago we studied the behavior of 2- and 4-¯uoro-
L-histidine as substrates for histidine ammonia lyase.Both
isomers were moderate substrates and provided small
amounts of (E)-2-¯uorourocanic acid (E-1b) and (E)-4-¯uor-
ourocanic acid (E-1c), respectively [4].Neither of these was a
substrate for urocanase, but 2-¯uorourocanic acid (E-1b) was
a potent competitive inhibitor of the urocanase [5].We have
extended our studies of ¯uorinated urocanic acids to include
the syntheses of E- and Z-a-¯uorourocanic acids [6]1 and
The current intensi®ed interest in the photochemistry and
biology of urocanic acid has prompted us to develop synth-
eses of ring-¯uorinated analogues of urocanic acid that would
provide both E- and Z-isomers.In particular, a direct synthesis
of the Z-isomers seemed particularly important since these
analogues could be useful tools in the study of the mechanism
of the photo-immunosuppressive activity of Z-urocanic acid
[3].This synthetic work is the subject of this report.
2. Chemistry
The availability of methods to control the stereochemistry
of the Horner±Wittig ole®nation reaction to produce pre-
dominantly either the E- or Z-isomer made this approach
attractive.We previously had prepared 1-trityl-2-¯uoroimi-
dazole-4-carboxaldehyde (2b) as an intermediate for the
synthesis of radiolabelled 2-¯uorohistidine [8].Reaction of
2b with the potassium salt of (diethoxy-phosphoryl)-acetic
acid ethyl ester in the presence of 18-crown-6 [9] was highly
stereoselective and gave (E)-3-(2-¯uoro-1-trityl-1H-imida-
zol-4-yl)-acrylic acid ethyl ester (3b) in good yield.
Removal of the trityl group was accomplished by heating
a solution of 3b in 5% ethanolic acetic acid to give ester 4b.
Saponi®cation of the ester, and isolation of the product by
ion exchange chromatography gave (E)-2-¯uorourocanic
acid (E-1b), identical to material prepared previously by
enzymatic degradation of L-2-¯uorohistidine [4].Reaction
of 2b with [bis-(2,2,2-tri¯uoroethyoxy)-phosphoryl]-acetic
* Corresponding author.Tel:. ‡1-301-496-2619; fax: ‡1-301-402-4182.
E-mail address: kennethk@bdg8.niddk.nih.gov (K.L. Kirk).
1 In this report, the scheme we constructed describing the mechanism of
action of urocanase was over-simplified and contained incorrect structures.
Please see [1] for a thorough discussion of this mechanism.
0022-1139/02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 0 2 ) 0 0 0 4 5 - 3

138
J. Fan et al. / Journal of Fluorine Chemistry 115 (2002) 137±142
Scheme 1.
1
acid methyl ester in the presence of excess 18-crown-6,
according to the procedure developed by Still and Gennari
[10], stereoselectively produced Z-3-(2-¯uoro-1-trityl-1H-
imidazol-4-yl)-acrylic acid methyl ester (5b).Heating a
solution of 5b in 5% methanolic acetic acid in methanol
effected removal of the trityl group to give ester 6b.Sapo-
ni®cation and isolation as described for preparation of E-1b
gave Z-1b (Scheme 2).
Ethyl-4-¯uoroimdazole-5-carboxylate (7) is readily avail-
able by photochemical decomposition of the corresponding
diazonium ¯uoroborate in ¯uoroboric acid (the photoche-
mical Schiemann reaction) [11].
The high resolution mass spectra (HRMS) and H and 13C
NMR indicated that each of these was formed by tritylation of
the imidazole ring.There are three possible sites of tritylation,
corresponding to structures 8±10 (Scheme 3).The structure of
compound 9 was assigned based on the following evidence.
(1) A broad NH signal is present in the 1H NMR spectrum of 9
(9.06 ppm). (2) The chemical shift of the C-2 carbon in the 13
C
NMR spectrum of the imidazole ring of 9 is signi®cantly
different from the corresponding signals of structures 8 and 10
(see Section 4).(3) This C-2 carbon is coupled ( 1JCH) by the
attached proton in 8 and 10 but this coupling is missing in 9.
(4) The benzylic carbon of the trityl group of 9 is at a higher
®eld than in 8 or 10, as predicted if connected to a less
electronegative carbon and not to nitrogen (see Section 4). 1H
and 13C NMR were also be used to differentiate between
We were surprised to ®nd that reaction of 7 with trityl
chloride gave a mixture of three compounds (two were expec-
ted), separated by column chromatography (see Section 4).
Scheme 2.

J. Fan et al. / Journal of Fluorine Chemistry 115 (2002) 137±142
139
Scheme 3.
structure 8 and 10.Thus, 13C±19F coupling through three
bonds is known to be greater than 13C±19F coupling through
four bonds (which is usually zero).The presence of 13C±19F
coupling (3JCF ˆ 1:7 Hz) is strong evidence for assignment
of structure 10.Supporting evidence is also found in the
higher ®eld chemical shift of the ethyl ester group of com-
pound 8 compared to the corresponding signals of the other
two products.This shift to higher ®eld can be ascribed to the
anisotropic effect of phenyl rings of trityl group that is
situated closer to the ethyl group in structure 8 than in
structures 9 and 10.These structural assignments are tentative
but seen consistent with all our data that establish 10 as the
major product.In any event, the trityl group is removed from
10 during the synthesis, so the structural assignments are
purely of academic interest.At this time we have no explana-
tion for the formation of the unusual C-alkylation product 9.
Reduction of the major product 10 with DIBAL gave the
aldehyde 2c. The synthetic sequence described for the
preparation of E-1b and Z-1b was used to prepare E- and
Z-1c (Scheme 2).
Elemental analyses were done by Atlantic microlab Inc.
Silica gel Merck 60 (0.040±0.063 mm) was used for column
chromatography, UniplateTM GF (Analtech) was used for
preparative TLC.All reagents and dry solvents were pur-
chased from Aldrich if not otherwise indicated and used
without additional puri®cation or drying.
4.1. (E)-3-(2-Fluoro-1-trityl-1H-imidazol-4-yl)-acrylic
acid ethyl ester (3b)
A stirred solution of 337 mg (1.5 mmol) of (diethoxy-
phosphoryl)-acetic acid ethyl ester and 396 mg (1.5 mmol)
of 18-crown-6 ether in 10 ml of THF was cooled in a dry ice/
acetone bath.To this was added over 5 min via a syringe
3.0 ml (1.5 mmol) of a 0.5 M solution of potassium bis-
(trimethylsilyl)amide in toluene.After an additional 15 min
stirring, a solution of 358 mg (1.0 mmol) of 2b in 8 ml of
THF was added over 5 min via a syringe.The mixture was
stirred for 30 min while being cooled in a dry ice/acetone
bath, then was allowed to warm to ice-bath temperature, and
was stirred for an additional 90 min.The reaction was then
quenched with aqueous solution NH4Cl, water was added,
and the solution was extracted three times with EtOAc.The
combined organic fractions were washed with water and
brine, and then dried over Na2SO4.After the removal of
volatile solvents by rotary evaporation, the solid residue was
chromatographed (9:1 petroleum ether:EtOAc) to give
355 mg (83%) of 3b as white crystals, mp 151±152 8C (from
The ultraviolet spectra of E-1b,c and Z-1b,c (in methanol)
are consistent with the data reported for E-1a and Z-1a in
that etrans > ecis. E-1b: Lmax ˆ 279, e ˆ 17,800; Z-1b:
Lmax ˆ 282, e ˆ 11,500; E-1c: Lmax ˆ 287:5, e ˆ 16,900;
Z-1c: Lmax ˆ 290, e ˆ 10,700.Literature values [12] for
urocanic acid (E-1a): Lmax ˆ 277, e ˆ 18,800; Z-1a:
Lmax ˆ 277, e ˆ 13,600.
1
EtOAc:petroleum ether). H NMR (CDCl3): d 7.2±7.1 and
3. Summary
7.4±7.3 (multiplets, 16 H, TrH, bH), 6.73 (s, 1H, Im-5H),
6.42 (d, 1H, J ˆ 15:6 Hz, aH), 4.20 (q, 2H, J ˆ 6:9 Hz,
CH2), 1.28 (t, 3H, J ˆ 6:9 Hz, CH3).HRMS: Calcd.for
C27H23FN2O2: 426.1733; Found: 426.1733. Anal. Calcd. for
C27H23FN2O2: C, 76.04; H, 5.44; N, 6.57; Found: C, 75.80;
H, 5.53; N, 6.54.
We have prepared four isomeric ring-¯uorinated urocanic
acids using stereocontrolled Horner±Wadsworth±Emmons
reactions.These compounds, along with side-chain ¯uori-
nated analogues, are being investigated with respect to
photo-immunosupressive activity.The effect of ¯uorine
substitution on the photochemical reactions of urocanic
acids also will be investigated.
4.2. (Z)-3-(2-Fluoro-1-trityl-1H-imidazol-4-yl)-acrylic
acid methyl ester (5b)
A stirred solution of 238 mg (0.75 mmol) of [bis-(2,2,2-
tri¯uoroethyoxy)-phosphoryl]-acetic acid methyl ester and
660 mg (2.5 mmol) of 18-crown-6 ether in 10 ml of THF
was cooled in a dry ice/acetone bath.To this was added via
syringe over a period of 3 min 1.5 ml (0.75 mmol) of a 0.5 M
solution of potassium bis(trimethylsilyl)amide in toluene.
After the mixture was stirred for 10 min, a solution of
179 mg (0.5 mmol) of 2b in 3 ml of THF was added.The
reaction was allowed to stir at for 1 h while being cooled in
4. Experimental details
1
The H and 13C NMR spectra were recorded at frequen-
cies of 300 and 75.5 MHz, respectively. Chemical shifts (d)
are relative to TMS (0 ppm) 19F NMR (282 MHz) chemical
shifts (d) are relative to CF3CO2H as external standard.
Capillary tube melting points (mp) are not corrected.FAB
ionization technique with Xe gas was used to record HRMS.

140
J. Fan et al. / Journal of Fluorine Chemistry 115 (2002) 137±142
the dry ice/acetone bath, at which time TLC (5:1 petroleum
ether:EtOAc) demonstrated the disappearance of 2b.The
reaction was quenched and worked up as described for the
isolation of 3b, to give, after chromatography (9:1 petroleum
ether:EtOAc) 163 mg (79%) of 5b, mp 140±141 8C (from
4.6. (Z)-3-(2-Fluoro-1H-imidazol-4-yl)-acrylic acid
(Z-2-fluorourocanic acid) (Z-1b)
A solution of 35 mg (0.20 mmol) of 6b in 1.0 ml of 1 N
NaOH was stored for 2 days at room temperature.Isolation
using Amberlite ion exchange as described for the preparation
of the E-isomer produced 26 mg (83%) of crystalline Z-1b,
mp 190±197 8C (decomp). 1H NMR (CD3OD): d 6.77 (s, 1H,
Im-4H), 6.47 (dd, 1H, J ˆ 12:9, 3.3 Hz, bH), 5.69 (d, 1H,
J ˆ 12:6 Hz, aH). 13C NMR (CD3OD): d 170.1, 157.6
133.3, 123.5, 116.7 (d, 242) 103.5 ppm. 19F NMR (CD3OD):
1
EtOAc:petroleum ether). H NMR (CDCl3): d 7.99 (s, 1H,
Im-5H ), 7.19±7.17 and 7.34±7.36 (multiplets, 15 H, ArH),
6.75 (d, 1H, J ˆ 12:6 Hz, bH), 5.74 (d, 1H, J ˆ 12:6 Hz,
aH), 3.61(s, 3H, OCH3).HRMS: Calcd.for C 26H21FN2O2:
412.1587; Found: 412.1589. Anal. Calcd. for C26H21FN2O2:
C, 75.71; H, 5.13; N, 6.79; Found: C, 75.53; H, 5.08; N, 6.75.
d À756.ppm.HRMS: Calcd.for C
6H5FN2O2: 156.0335;
4.3. (E)-3-(2-Fluoro-1H-imidazol-4-yl)-acrylic
acid ethyl ester (4b)
Found: 156.0332.
4.7. Tritylation of 5-fluoro-1H-imidazole-4-carboxylic
acid ethyl ester (7)
A solution of 318 mg (0.75 mmol) of 3b in 4 ml of 5% (v/
v) ethanolic acetic acid was re¯uxed for 3.5 h. The solution
was cooled and concentrated by rotary evaporation.The solid
residue was puri®ed by column chromatography (5:1 petro-
luem ether:EtOAc) to give 79 mg (58%) of 4b, mp 180±
183 8C. 1H NMR (CD3OD): d 7.43 (dd, 1H, J ˆ 15, 2.4 Hz,
bH), 6.87 (s, 1H, Im-5H), 6.47 (d, 1H, J ˆ 15:3 Hz, aH), 4.23
(q, 2H, J ˆ 6:9 Hz, CH2), 1.31 (t, 3H, J ˆ 7:2 Hz, CH3).
HRMS: Calcd.for C 8H9FN2O2: 184.0648; Found: 184.0646.
To an ice-cold solution of 158 mg (1.0 mmol) of 5-¯uoro-
1H-imidazole-4-carboxylic acid ethyl ester (7) and 335 mg
(1.2 mmol) of trityl chloride in 3 ml of dry DMF was added
0.2 ml (1.5 mmol) of triethylamine under nitrogen. The
solution was stirred for 20 h at room temperature.The
reaction mixture was diluted with ethyl acetate and the
solution was washed with water and brine.After drying
with sodium sulfate, the solvent was evaporated to give a
solid that was separated by column chromatography (5:1
hexane:EtOAc ! 1:1 hexane:EtOAc).
4.4. (Z)-3-(2-Fluoro-1H-imidazol-4-yl)-acrylic acid
methyl ester (6b)
A solution of 160 mg (0.44 mmol) of 5b in 4 ml of 5%
(v/v) methanolic acetic acid was re¯uxed for 2.5 h. Volatile
solvents were removed by rotary evaporation and the solid
residue was chromatographed (5:1 petroleum ether:EtOAc)
4.7.1. 4-Fluoro-1-trityl-1H-imidazole-5-carboxylic acid
ethyl ester (8)
The ®rst compound eluted (5:1 hexane:EtOAc) was iden-
ti®ed as 8, 60 mg (15%). 1H NMR (CDCl3): 7.34±7.29 and
7.17±7.12 (m, 16 H, TrH, Im-2H), 3.77 (q, 2H, J ˆ 7:2 Hz,
CH2), 0.87 (t, 3H, J ˆ 7:2 Hz, CH3). 13C NMR (CDCl3): d
160.7 (d, J ˆ 252:7 Hz), 157.6 (d, J ˆ 5:6 Hz), 141.4 (3C),
136.7 (d, J ˆ 15:4 Hz), 129.8 (6C), 127.9 (3C), 127.7 (6C),
106.2 (d, J ˆ 26:2 Hz), 78.0, 60.2, 13.7. HRMS: Calcd. for
C25H21FN2O2: 400.1587; Found: 400.1591.
1
to give 35 mg (47%) of 6b, mp 175±190 8C (decomp). H
NMR (CD3OD): d 6.99 (s, 1H, Im-5H), 6.69 (dd, 1H,
J ˆ12:6, 3.3 Hz, bH), 5.65 (d, 1H, J ˆ 12:3 Hz, aH), 3.80
(s, OCH3).HRMS: Calcd.for C H7FN2O2: 170.0492; Found:
7
170.0494.
4.5. (E)-3-(2-Fluoro-1H-imidazol-4-yl)-acrylic acid
(E-2-fluorourocanic acid) (E-1b)
4.7.2. 4 (5)-Fluoro-2-trityl-1H-imidazole-5 (4)-carboxylic
acid ethyl ester (9b)
A solution of 45 mg (0.28 mmol) of 4b in 1.0 ml of 1 N
NaOH was stored at room temperature for 2 days.The
solution was then added to an Amberlite strongly acidic
ion exchange column (5 ml wet volume) and the column was
eluted with water until the eluant was neutral.The column
was eluted with NH4OH (concentrated diluted 1:4 with
distilled water) until TLC indicated all product had been
removed.The fractions containing product (TLC) were
combined and lyophilized to give 31 mg (71%) of crystalline
E-1b, mp 202±214 8C (decomp). 1H NMR (CD3OD): d 7.20
(dd, 1H, J ˆ 15:9, 2.7 Hz, bH), 6.89 (s, 1H, Im-5H), 6.94 (d,
1H, J ˆ 15:9 Hz, aH). 13C NMR (CD3OD): d 169.6, 157.8
133.0, 123.1, 116.6 (d, 246), 102.2 ppm. 19F NMR
(CD3OD): d À78.1 ppm. HRMS: Calcd. for C6H5FN2O2:
156.0335; Found: 156.0341.
The next product eluted (5:1 hexane:EtOAc) was com-
pound 9, 27 mg (7%). 1H NMR (CDCl3): d 9.06 (broad s, 1H,
NH), 7.34±7.29 and 7.15±7.11 (m, 15 H, TrH), 4.31 (q, 2H,
J ˆ 7:2 Hz, CH2), 1.34 (t, 3H, J ˆ 7:2 Hz, CH3). 13C NMR
(CDCl3): d 159.3 (d, J ˆ 4:6 Hz), 157.0 (d, J ˆ 249:3 Hz),
149.1 (d, J ˆ 13:7 Hz), 143.3 (3C), 130.2 (6C), 128.2 (6C),
127.5 (3C), 101.8 (d, J ˆ 31:3 Hz), 61.3, 61.0, 14.3. HRMS:
Calcd.for C 25H21FN2O2: 400.1587; Found: 400.1591.
4.7.3. 5-Fluoro-1-trityl-1H-imidazole-4-carboxylic
acid ethyl ester (10)
The major, most polar fraction, 10, was eluted with 1:1
hexane:EtOAc and obtained as 313 mg (78%) of a white solid,
1
mp 138±139 8C. H NMR (CDCl3): d 7.39±7.34 and 7.17±
7. 14 (m, 15 H, TrH), 7.12 (broad s, 1H, Im-2H), 4.35 (q, 2H,

J. Fan et al. / Journal of Fluorine Chemistry 115 (2002) 137±142
141
J ˆ 7:2 Hz, CH2), 1.35 (t, 3H, J ˆ 7:2 Hz, CH3). 13C NMR
(CDCl3): d 161.0 (d, J ˆ 5:1 Hz), 150.7 (d, J ˆ 289:1 Hz),
139.9 (3C), 130.8 (d, J ˆ 5:7 Hz), 128.9 (6C), 128.0 (9C),
112.8, 75.8 (d, J ˆ 1:7 Hz), 603., 140..HRMS: Calcd.for
C25H21FN2O2: 400.1587; Found: 400.1595.
stirred for 10 min, a solution of 100 mg (0.28 mmol) of 2c
in 2 ml of THF was added.The reaction was allowed to stir
while being cooled in a dry ice/acetone bath for 2 h.The
reaction was quenched and worked up as earlier for the
isolation of 5b to give, after chromatography (9:1 petroleum
ether:EtOAc) 86 mg (72%) of 5c, mp 102±104 8C (from
EtOAc:petroleum ether). 1H NMR (CDCl3): d 7.36±7.16
(multiplets, 16 H, ArH, Im-2H), 6.64 (d, 1H, J ˆ 12:6 Hz,
aH), 5.82 (d, 1H, J ˆ 12:6 Hz, bH), 3.78 (s, 3H, OCH3).
HRMS: Calcd.for C 26H21FN2O2: 412.1605; Found: 412.1587.
4.8. 5-Fluoro-trityl-1H-imidazole-4-carboxaldehyde (2c)
To 400 mg (1 mmol) of 10 in 10 ml of toluene, cooled in a
dry ice/acetone bath, was added dropwise 1.0 ml of a 1.5 M
solution of DIBAL in toluene.The solution was stirred at the
same temperature for 1 h and then quenched with 10 ml of
1 M aqueous potassium tartarate.The aqueous solution was
extracted three times with EtOAc, dried (Na2SO4) and
evaporated to give 333 mg of solid.This was chromato-
graphed (1:1 EtOAc:petroleum ether) to give 191 mg (54%)
of 2c, recrystallized from 1:1 EtOAc:petroleum ether, mp
135±136 8C. 1H NMR (CDCl3): d 9.83 (s, 1H, CHO), 7.39±
7.37 and 7.17±7.14 (m, 15 H, ArH), 7.17 (s, 1H, Im-2H).
4.11. (E)-3-(5-Fluoro-1H-imidazol-4-yl)-acrylic acid
ethyl ester (4c)
A solution of 90 mg (0.21 mmol) of 3c in 2 ml 5% (v/v)
ethanolic acetic acid was heated for 3.5 h at 90 8C.The
solution was cooled and concentrated by rotary evaporation.
The solid residue was puri®ed by column chromatography
(4:1 petroleum ether:EtOAc) to give 19 mg (50%) of 4c, mp
175±180 8C. 1H NMR (CD3OD): d 7.50 (s, 1H, Im-2H), 7.47
(d, 1H, J ˆ 16:2 Hz, aH), 6.16 (d, 1H, J ˆ 16:2 Hz, bH ),
4.23 (q, 2H, J ˆ 7:2 Hz, CH2), 1.30 (t, 3H, J ˆ 7:2 Hz,
4.9. (E)-3-(5-Fluoro-1-1-trityl-1H-imidazol-4-yl)-acrylic
acid ethyl ester (3c)
‡
CH3).HRMS: Calcd.for C 8H10FN2O2 (FAB, MH ):
A stirred solution of 95 mg (0.42 mmol) of (diethoxy-
phosphoryl)-acetic acid ethyl ester and 110 mg (0.42 mmol)
of 18-crown-6 in 8 ml of THF was cooled in a dry ice/
acetone bath.To this was added over 5 min via a syringe
0.84 ml of a 0.5 M solution of potassium bis(trimethyl-
silyl)amide in toluene.After an additional 15 min stirring,
a solution of 100 mg (0.28 mmol) of 2c in 2 ml of THF
added over 5 min via a syringe.The mixture was stirred for
30 min while being cooled in a dry ice/acetone bath, then
was allowed to come to ice-bath temperature, and was stirred
for an additional 90 min.The reaction was then quenched
with aqueous solution NH4Cl, water was added, and the
solution was extracted three times with EtOAc.The com-
bined organic fractions were washed with water and brine,
and then dried with Na2SO4.After removal of volatile
solvents by rotary evaporation, the solid residue was chro-
matographed (1:9 EtOAc:petroleum ether) to give 95 mg
(80%) of 3c as white crystals, mp 118±120 8C (from
EtOAc:petroleum ether). 1H NMR (CDCl3): d 7.48 (d,
1H, J ˆ 15:9 Hz, aH), 7.37±7.45 (multiplets, 16 H, ArH,
Im-2H), 6.43 (d, 1H, J ˆ 15:6 Hz, bH), 4.21 (q, 2H,
J ˆ 7:2 Hz, CH2), 1.29 (t, 3H, J ˆ 7:2 Hz, CH3).HRMS:
Calcd.for C 27H23FN2O2: 426.1744; Found: 426.1748.
185.0726; Found: 185.0735.
4.12. (Z)-3-(5-Fluoro-1H-imidazol-4-yl)-acrylic acid
methyl ester (6c)
A solution of 80 mg (0.19 mmol) of 5c in 2 ml 5% (v/v)
methanolic acetic acid was heated for 3.5 h at 90 8C.The
solution was cooled and concentrated by rotary evaporation.
The solid residue was puri®ed by column chromatography
(1:4 EtOAc:petroleum ether) to give 27 mg (85%) of 6c, mp
154±160 8C. 1H NMR (CD3OD): d 7.34 (s, 1H, Im-2H), 6.81
(d, 1H, J ˆ 12:6 Hz, aH), 5.65 (d, 1H, J ˆ 12:6 Hz, bH),
3.79 (s, 3H, OCH3).HRMS: Calcd.for C 7H7FN2O2:
170.0492; Found: 170.0498.
4.12.1. (E)-3-(4-Fluoro-1H-imidazol-5-yl)-acrylic acid
(E-4-fluorourocanic acid) (E-1c)
A solution of 15 mg (0.08 mmol) of 4c in 1.0 ml of 1 N
NaOH was stored for 2 days at room temperature.Isolation
using Amberlite ion exchange as described for the prepara-
tion of E-1b produced 10 mg (80%) of crystalline E-1c, mp
1
210±218 8C (decomp). H NMR (CD3OD): d 7.43 (s, 1H,
Im-2H), 7.30 (d, 1H, J ˆ 15:9 Hz, bH), 6.17 (d, 1H,
J ˆ 15:9 Hz, aH). 13C NMR (CD3OD): d 193.4, 157.9
(d, 244), 133.5 (d, 16.4), 129.4, 128.4 (d, 5.15), 117.8
ppm. 19F NMR (CD3OD): d À56.9 ppm. HRMS: Calcd.
for C6H5FN2O2: 156.0335; Found: 156.0340.
4.10. (Z)-3-(5-Fluoro-1-trityl-1H-imidazol-4-yl)-acrylic
acid methyl ester (5c)
A stirred solution of 140 mg (0.42 mmol) of [bis-(2,2,2-
tri¯uoroethyoxy)-phosphoryl]-acetic acid methyl ester and
552 mg (2.1 mmol) of 18-crown-6 in 8 ml of THF was cooled
in a dry ice/acetone bath.To this was added via syringe over a
period of 3 min 0.84 ml of a 0.5 M solution of potassium
bis(trimethylsilyl)amide in toluene.After the mixture was
4.13. (Z)-3-(4-Fluoro-1H-imidazol-5-yl)-acrylic acid
(Z-4-fluorourocanic acid) (Z-1c)
A solution of 20 mg (0.12 mmol) of 6c in 1.0 ml of 1 N
NaOH was stored for 2 days at room temperature.Isolation

142
J. Fan et al. / Journal of Fluorine Chemistry 115 (2002) 137±142
F.Noonan, EC. .DeFabo, Immunol.Today 13 (1992) 250±254;
J.Garssen, M.Norval, J.Crosby, P.Dortant, H.Van Loveren,
Immunology 96 (1999) 298±306.
using Amberlite ion exchange as described for the prepara-
tion of the E-isomer produced 12 mg (64%) of crystalline
Z-1c, mp 193±205 8C (decomp). 1H NMR (CD3OD): d 7.09
(s, 1H, ImH), 6.19 (d, 1H, J ˆ 12:6 Hz, bH), 5.34 (d, 1H,
J ˆ 12:6 Hz, aH). 13C NMR (CD3OD): d 173.4, 158.1
(d, 246), 131.2 (d, 16.3) 124.3 (d, 5.16), 117.9, 110.3
ppm. 19F NMR (CD3OD): d À58.9 ppm. HRMS: Calcd.
for C6H5FN2O2: 156.0333; Found: 156.0329.
and references therein.
[4] K.L. Kirk, L.A. Cohen, in: R. Filler (Ed.), Biochemistry of the
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[7] B.Dolensky, KL. .Kirk, in preparation.
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XXIII (1986) 1±8.
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