Synthesis of (E)- and (Z)-α,β-difluorourocanic acid

Article abstract of DOI:10.1016/j.jfluchem.2007.09.006

Horner-Emmons fluoroolefination of an aryl aldehyde followed by introduction of a second fluorine via FBr addition provides an original approach to the preparation of 1-alkyl-2-aryl-1,2-difluoroethenes. The utility of this procedure is demonstrated by the preparation of (E and Z)-α,β-difluorourocanic acid.

Full text of DOI:10.1016/j.jfluchem.2007.09.006

Available online at www.sciencedirect.com
Journal of Fluorine Chemistry 129 (2008) 112–118
www.elsevier.com/locate/fluor
Synthesis of (E)- and (Z)-a,b-difluorourocanic acid
*
´
Jan Hajduch, Bohumil Dolensky, Shinichi Yoshida, Junfa Fan, Kenneth L. Kirk
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, MD 20892, United States
Received 9 August 2007; received in revised form 11 September 2007; accepted 12 September 2007
Available online 15 September 2007
Abstract
Horner–Emmons fluoroolefination of an aryl aldehyde followed by introduction of a second fluorine via ‘‘FBr’’ addition provides an original
approach to the preparation of 1-alkyl-2-aryl-1,2-difluoroethenes. The utility of this procedure is demonstrated by the preparation of (E and Z)-a,b-
difluorourocanic acid.
Published by Elsevier B.V.
Keywords: Fluoroimidazole; Urocanic acid; Fluoroolefins; FBr addition; Regiochemistry
1. Introduction
and biological behavior by virtue of the difluoroacrylate
functionality.
(E)-Urocanic acid 1a is elaborated in vivo by histidine
ammonia lyase-catalyzed loss of ammonia from histidine. The
photochemistry and biological properties of urocanic acid
continue to receive attention, in part because of evidence that
(Z)-urocanic acid (1b), formed in the body by photo-
isomerization of the E isomer, is a mediator of photo-
immunosuppression [1]. As part of our program to prepare
fluorinated analogues of biologically important imidazoles, we
have reported the synthesis of (E)- and (Z)-2- and 4-
fluorourocanic acid (2a,b and 3a,b, respectively) [2], (E)-
and (Z)-a-fluorourocanic acid (4a,b) [3] and (E)- and (Z-b)-
fluorourocanic acid (5a,b) [4]. Ring-fluorinated analogues 2
and 3 were prepared from ring-fluorinated aldehyde precursors
using a Horner–Emmons olefination with triethyl phospho-
noacetate [2]. A similar olefination of 1-trityl-(1H)imidazole-4-
carboxaldehyde with triethyl flourophosphonoacetate was the
key step in the synthesis of 4a,b [3]. To access the b-
fluoroanalogues 5a,b, addition of ‘‘FBr’’ to a vinyl imidazole
derivative to place fluorine adjacent to the imidazole ring was
the key step [4]. Missing from the inventory of side-chain
fluorinated analogues of urocanic acid is a,b-difluorourocanic
acids (6a,6b), compounds that should have interesting chemical
Published routes to compounds of the general structure Aryl-
CF CF-Alkyl would not seem readily applicable to the
synthesis of 6a and 6b. One approach based on reaction of
CF2 CF2 or R–CF CFX (where X is H or halogen) with ArLi
has been applied to heteroaryl compounds [5]. However, in
general, this method would not readily tolerate functional
groups. A second approach that involves elimination of ‘‘X–X’’
from R–CFX–CFX–R [6] requires lengthy and, in our case,
problematic preparation of precursors. A third approach would
be direct addition of F2 diluted with N2 to a triple bond. In one
example, addition of F2 to a series of tolanes give mixtures of
products, including a,a0-difluorostilbenes [7]. We did not
consider this approach because of the complex reaction
products and requirement for special equipment.
* Corresponding author.
E-mail address: kennethk@intra.niddk.nih.gov (K.L. Kirk).
0022-1139/$ – see front matter. Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2007.09.006

J. Hajduch et al. / Journal of Fluorine Chemistry 129 (2008) 112–118
113
Table 1
We have approached the synthesis of 6a,b by combining
Results of addition of ‘‘FBr’’ on 6a or 6b
chemistry we used for the preparation of 4 and 5. In a key
reaction in our synthesis of a-fluorourocanic acids, Horner–
Emmons olefination of 1-trityl-(1H)imidazole-4-carboxalde-
hyde with triethyl fluorophosphonoacetate produces a-fluor-
opropenoates 7 [3]. In our synthesis of b-fluorourocanic acids,
we took advantage of regiospecific ‘‘FBr’’ addition to a vinyl
imidazole derivative followed by HBr elimination to install
fluorine in the b-position [4]. In contemplating a combination
of these two approaches in order to place fluorine at both the a-
and b-positions, a critical question involves regioselectivity of
the ‘‘FBr’’ addition to 1-alkyl-2-aryl-1-fluoroalkenes. If the
directive effect of fluorine (resulting in stabilization of an a-
carbonium ion) is strong enough to take precedence over aryl
carbonium ion stabilization, ‘‘FBr’’ addition would be
predicted to lead to the geminal instead of the desired vicinal
difluoro compounds. Indeed, this is the observed product of
addition of FBr to vinyl fluorides where an aryl group is not
present [8] or when the aryl group and fluorine are on the same
carbon [9]. To our surprise, we have found no examples of
electrophilic additions to 1-alkyl-2-aryl-1-fluoroalkenes.
Having found no precedent wherein addition of ‘‘FBr’’ to a
vinyl monofluoride produces the vicinal difluoride, we were
pleased to find that addition of ‘‘FBr’’ to 3-(1-trityl-1(H)-
imidazol-4-yl)-1-hydroxymethyl-2-fluoro-2-propene (8) in fact
proceeds with regioselectivity to produce the vicinal difluoride.
This somewhat unexpected direction of addition provides a
convenient route to a,b-difluorourocanic acids. In addition, this
discovery should make possible the synthesis of other 1-aryl-
1,2-difluoroalkenes by the same route.
Starting isomer
Reaction conditionsa
Products molar ratio (%)
‘‘HF’’
NBS
Time
9a
9b
10a
10b
8b
(a) 8a
(b) 8a
(c) 8b
(d) 8b
(e) 8b
1.5
1.5
1.5
2.5
3.2
1.1
1.1
1.1
1.8
2.2
2
5
41
51
3
17
18
24
41
59
13
6
13
6
16
19
48
27
0
14
44
19
12
11
15
13
15
18
6
8
a
Content of columns is as follows: equivalents of Et3Nꢀ3HF, equivalents of
NBS, reaction time in hours.
b
Starting isomer 8a or 8b.
100%. Under the usual conditions, the conversion of 2-
fluoropropenols to products 9a and 9b was only 84% of 8a and
52% of 8b. As is usual in the cases of poorly reactive olefins, in
addition to the desired FBr adducts, the dibromo adducts 10
were also formed in about 25% yield. Thus the reactivity is
similar to trityl urocanic methyl ester (conversion 62%) [4]. As
in that case, the conversion of 8 can be increased by increasing
the reagent amounts (see Table 1). We found no evidence (1H
and 19F NMR) of reversed regioselectivity with formation of
geminal difluoro compound.
It is well documented that in these reactions, trans alkenes
give mainly the product of anti addition, but cis alkenes give
mixture of anti and syn addition [4]. However, there are few
precedents for reactions of alkenes having a halogen substituent
in place of hydrogen on the double bond. We found that isomer
8b, where the carbon substituents are trans to each other, gives
diastereoisomeric adducts in a ratio of 88:12, tentatively
assigned as products from anti (9b, 2R*,3S*-configuration) and
syn (9a, 2R*,3R*-configuration) additions, respectively. This is
slightly lower diastereoselectivity than found with the
nonfluorinated analog (95:5) [4]. Isomer 8a, where the carbon
substituents are in a cis orientation, gives a diastereoisomeric
mixture in a ratio of 75:25, tentatively assigned as products
from anti (9a) and syn (9b) additions. This is significantly
higher anti diastereoselectivity than found with the cis-
configured nonfluorinated analog, which gave an anti/syn
addition ratio of 20:80 [4]. It is interesting to note that
byproduct Br2-adducts, two diastereoisomers 10a and 10b are
formed in ratio of about 1:1 in both cases. These results are
summarized in Table 1.
2. Chemistry
(E)- and (Z)-Ethyl 2-fluoro-3-(1-trityl-1-H-imidazol-4-yl)-
prop-2-enoate (7a,b) were prepared as described [4]. Based on
our experience with the preparation of 5, we were aware that
reduction of the ester to alcohol was necessary to achieve the
desired chemoselectivity of halide elimination (bromide vs.
fluoride) in the sequence [4]. Previously, we also found that the
carboxyl function of urocanic acid deactivates the double bond
to the extent that ‘‘FBr’’ addition via Et3Nꢀ3HF and NBS
becomes a sluggish process [4]. In a related example, we were
unable to effect ‘‘FBr’’ addition to ethoxycabonylalkynylimi-
dazole [10]. Consistent with these results, we found that no
FBr-adducts are formed from a-bromourocanate or a-
fluorourocanate 7 using our usual conditions. Therefore, we
reduced the deactivating ester function to the hydroxymethyl
electron donating group to obtain 2-fluoropropenols 8a and 8b.
These were then used as substrates to study FBr adduct
formation. In subsequent reactions, since addition of ‘‘FBr’’ to
either olefin produced diasteromeric mixtures of products that
were extremely difficult to separate, it was convenient to carry
out addition of ‘‘FBr’’ and elimination of HBr on mixtures of
8a/8b.
Dehydrobromination of mixture 9a and 9b gives corre-
sponding difluoropropenols 11a and 11b in the usual yields of
60–70%. Double bond configuration was readily assigned to the
two geometrical isomers based on 19F NMR data. The (E)-
isomer 11a has a significantly higher F–F coupling constant
(126 Hz) than does the (Z)-isomer 11b (21 Hz). The oxidation
to aldehyde 12a and 12b by MnO2 surprisingly proceeds with
formation of byproduct 13, the yield of which increases with
longer reaction times or increased reaction temperature. The
isomer 11b is significantly less reactive than 11a and compound
13 becomes the main product of the oxidation (see Section 4.8).
We have found no precedent for this conversion and any
mechanistic proposals would be entirely speculative. For
acceptable yield of the aldehydes 12 (30–50%), it is necessary
The reactivity of the 2-fluoropropenols 8a,b proved to be
lower in comparison to their nonfluorinated analogs [4] or
isomeric 3-fluoropropenols [9], where the conversion is about

114
J. Hajduch et al. / Journal of Fluorine Chemistry 129 (2008) 112–118
Scheme 1. (a) DIBAL-H, CH2Cl2, 74% 8a, 72% 8b; (b) Et3Nꢀ3HF, NBS, CH2Cl2, 58% 9a,b; (c) Et3N, DMSO, 47% 11a, 29% 11b; (d) MnO2, CH2Cl2, 53% 12a, 33%
12b; (e) NaHPO4, NaClO2, t-BuOH/H2O; (f) HCl, CH3CO2H, 96% 6a, 37% 6b.
to use a large excess of MnO2 and to monitor the reaction by
TLC in order to stop the reaction immediately after full
conversion of the starting material.
the internal standard; 13C NMR chemical shifts: CDCl3,
d = 77.23; DMSO-d6, d = 39.51 ppm. For 19F NMR, fluoro-
trichloromethane was used as the internal standard. HRMS
spectra were recorded on a Waters LCT Premier TOF
mass spectrometer. Flash chromatography was performed
on Biotage SP4. LC/MS was performed on Agilent 1100
system.
4.2. (E)-Ethyl 2-fluoro-3-(1-trityl-1H-imidazol-4-yl)-prop-
2-enoate (7a)
Subsequent one pot oxidation and deprotection of aldehydes
12 afforded the desired a,b-difluorourocanic acids 6a and 6b.
We did not purify and characterize the immediate products of
the oxidation due to complications with their purification that
led to decomposition. This was especially true for the product
of oxidation of aldehyde 12b. By this one pot procedure, we
obtained (E)-a,b-difluorourocanic acid (6a) in high yield
(96%) and (Z)-a,b-difluorourocanic acid (6b) in moderate yield
(37%) (Scheme 1).
Compound 7a was prepared as published in ref. [4]. We
report here the additional spectral data. 13C NMR (CDCl3):
2
160.68 (d, JCF = 34.1, CO), 144.76 (d, JCF = 250.2, CF),
1
3
142.01 (3C, Tr), 138.78 (s, C2Imi), 131.56 (d, JCF = 11.2,
C4Imi), 129.63 (6CH, Tr), 128.06 (3CH, Tr), 128.03 (6CH, Tr),
125.75 (d, 4JCF = 5.4, C5Imi), 117.23 (d, 2JCF = 30.8; CH CF),
75.70 (s, 1C, Tr), 61.07 (s, CH2), 13.96 (s, CH3). 19F NMR
3
(CDCl3): ꢁ124.3 (d, JHF = 24.0).
3. Conclusion
4.3. (Z)-Ethyl 2-fluoro-3-(1-trityl-1H-imidazol-4-yl)-prop-
2-enoate (7b)
We report here the synthesis of new fluorinated analogues of
urocanic acid. The methodology developed includes a
procedure for the preparation of functionalized 1-alkyl-2-
aryl-1,2-difluoroethenes from readily available starting materi-
als. For this synthesis, there was no requirement for hydroxyl
group protection. This procedure should be applicable to other
aryl and heteroaryl systems as borne out by our preliminary
successful experiments with benzaldehydes. Studies on the
biology and photochemistry of fluorinated urocanic acids are a
subject of continued research. Neither 6a nor 6b was an
inhibitor of urocanase.
Compound 7b was prepared as published in ref. [4]. We
report here the additional spectral data. 13C NMR (CDCl3):
2
161.09 (d, JCF = 33.8, CO), 145.83 (dd, JCF = 259.7, CF),
1
3
141.88 (3C, Tr), 139.47 (s, C2Imi), 132.43 (d, JCF = 3.32,
C4Imi), 129.66 (6CH, Tr), 128.25 (3CH, Tr), 128.16 (6CH, Tr),
125.13 (d, 4JCF = 13.4, C5Imi), 112.73 (d, 2JCF = 8.2, CH CF),
75.88 (s, 1C, Tr), 61.45 (s, CH2), 14.15 (s, CH3). 19F NMR
3
5
(CDCl3): ꢁ123.9 (dd, JHF = 36.2, JHF = 1.6).
4.4. (E)- and (Z)-2-Fluoro-3-(1-trityl-1H-imidazol-4-yl)-
prop-2-en-1-ol (8a,b)
4. Experimental
4.1. General
To a stirred solution of propenoates 7 (6.37 g, 14.9 mmol,
7a:7b 5:9) in 370 mL of dry CH2Cl2 was slowly added 33 mL
of DIBAL-H (1 M in CH2Cl2, 33 mmol) at ꢁ65 8C. The
mixture was allowed to warm to room temperature and was
stirred overnight. After addition of 30 mL of water, the
mixture was partitioned between CH2Cl2 and water/brine.
The NMR spectra were recorded at 22 8C on a Varian
Mercury-300 instrument at frequencies of 300.1 for H, 75.5
for 13C and 282.2 MHz for 19F spectra. All 13C NMR spectra
are proton-decoupled. Tetramethylsilane (TMS) was used as
1

J. Hajduch et al. / Journal of Fluorine Chemistry 129 (2008) 112–118
115
The organic part was dried over MgSO4 and evaporated to
dryness. The resulting solid was separated by column
chromatography (250 g, CH2Cl2:Et2O, 9:1) to give pure 8a
(1.51 g, 74% based on 7a). Isomer 8b was eluted with
CH2Cl2:CH3OH (9:1) and purified by column chromatogra-
phy (100 g, CH2Cl2:EtOAc 1:1) to give pure 8b (2.65 g, 72%
based on 7b).
HRMS (CI+): for M + H, i.e. C25H22BrF2N2O calculated:
483.0884; found: 483.0833.
4.5.1. (2R*,3R*)-2-Bromo-2,3-difluoro-3-(1-trityl-1H-
imidazol-4-yl)-propan-1-ol (9a)
1H NMR (CDCl3): 7.47 (1H, d, J = 1.4, Imi), 7.35 (9H, m, Tr),
7.11 (6H, m, Tr), 7.07 (1H, dd, J = 3.2, 1.4, Imi), 6.24 (1H, bs,
2
3
OH), 5.77 (1H, dd, JHF = 45.9, JHF = 10.6), 4.44 (1H, ddd,
2JHH = 13.0, 3JHF = 5.4, 4JHF = 1.4), 3.94 (1H, dm, 2JHH = 14.2).
13C NMR (CDCl3): 141.63 (3C, Tr), 139.15 (s, C2Imi), 133.23
4.4.1. (E)-2-Fluoro-3-(1-trityl-1H-imidazol-4-yl)-prop-2-
en-1-ol (8a)
1H NMR (CDCl3): 7.42 (1H, d, J = 1.5, Imi), 7.38–7.32 (9H,
m, Tr), 7.17–7.09 (6H, m, Tr), 7.04 (1H, bs, Tr), 6.74 (1H, d,
(dd, JCF = 22.6, JCF = 7.1, C4Imi), 129.66 (6CH, Tr), 128.43
(3CH, Tr), 128.27 (6CH, Tr), 123.79 (dd, 3JCF = 5.9, 4JCF = 1.2,
C5Imi), 109.68 (dd, 1JCF = 260.0, 2JCF = 26.4, CFBr), 89.86 (dd,
2
3
3
J = 1.5, Imi), 6.05 (1H, d, JHF = 20.8, CH CF), 4.44 (2H, d,
3JHF = 14.8, CH2). 13C NMR (CDCl3): 162.09 (d, 1JCF = 259.3,
CF), 141.87 (3C, Tr), 138.77 (s, C2Imi), 134.30 (d, 3JCF = 15.1,
C4imi), 129.64 (6CH, Tr), 128.21 (3CH, Tr), 128.13 (6CH, Tr),
120.24 (d, 4JCF = 8.1, C5Imi), 101.69 (d, 2JCF = 30.8, CH CF),
1JCF = 183.9, JCF = 26.5, CHF), 76.03 (s, 1C, Tr), 65.08 (dd,
2
3JCF = 31.0, 4JCF = 2.2, CH2). 19F NMR (CDCl3): ꢁ120 (1F, m),
ꢁ169.4 (1F, dd, 2JHF = 45.8, 3JFF = 22.2).
2
75.57 (s, 1C, Tr), 59.97 (d, JCF = 37.9, CH2). 19F NMR
4.5.2. (2R*,3S*)-2-Bromo-2,3-difluoro-3-(1-trityl-1H-
imidazol-4-yl)-propan-1-ol (9b)
3
3
(CDCl3): ꢁ102.7 (dt, JHF = 20.7, JHF = 15.0). mp: 194.5–
195.5 8C (CH2Cl2/Et2O). HRMS: for M + H, i.e. C25H22FN2O
calculated: 385.1716; found: 385.1729. Elemental analysis for
C25H21FN2O calculated: 78.10%C, 5.51%H, 7.29%N, found:
77.99%C, 5.51%H, 7.32%N.
1H NMR (CDCl3): 7.46 (1H, t, J = 1.5, Imi), 7.35 (9H, m,
Tr), 7.11 (6H, m, Tr), 7.05 (1H, dt, J = 2.3, 1.0, Imi), 6.24 (1H,
2
bs, OH), 5.87 (1H, ddd, JHF = 45.0, JHF = 9.5, JHH = 1.0),
3
4
2
3
4.17 (1H, dd, JHH = 13.4, JHF = 3.5), 4.04 (1H, dd,
2
3JHF = 26.9, JHH = 13.4). 13C NMR (CDCl3): 141.74 (3C,
2
Tr), 138.75 (s, C2Imi), 134.12 (dd, JCF = 25.8, JCF = 7.3,
3
4.4.2. (Z)-2-Fluoro-3-(1-trityl-1H-imidazol-4-yl)-prop-2-
en-1-ol (8b)
C4Imi), 129.66 (6CH, Tr), 128.36 (3CH, Tr), 128.23 (6CH, Tr),
1H NMR (CDCl3): 7.39 (1H, d, J = 1.4, Imi), 7.34–7.28 (9H,
m, Tr), 7.16–7.10 (6H, m, Tr), 7.09 (1H, t, J = 1.6, Imi), 6.01
(1H, d, 3JHF = 40.1, CH CF), 5.24 (1H, bs, OH), 4.16 (2H, d,
3JHF = 12.6, CH2). 13C NMR (CDCl3): 158.86 (d, 1JCF = 264.2,
3
121.81 (dd, JCF = 5.0, JCF = 3.3, C5Imi), 110.64 (dd,
4
2
1
1JCF = 263.7, JCF = 22.6, CFBr), 90.18 (dd, JCF = 182.2,
2JCF = 26.9, CHF), 76.01 (s, 1C, Tr), 67.81 (dd, JCF = 23.7,
3
4JCF = 2.5, CH2). 19F NMR (CDCl3): ꢁ120 (1F, m), ꢁ189.1
3
2
(1F, dd, JHF = 45.3, JFF = 21.6).
3
CF), 142.07 (3C, Tr), 138.04 (s, C2Imi), 133.50 (d, JCF = 1.0,
C4imi), 129.71 (6CH, Tr), 128.09 (3CH, Tr), 128.07 (6CH, Tr),
121.31 (d, 4JCF = 11.7, C5Imi), 101.07 (d, 2JCF = 9.7, CH CF),
4.5.3. 2,3-Dibromo-2-fluoro-3-(1-trityl-1H-imidazol-4-yl)-
propan-1-ol (10a)
2
75.58 (s, 1C, Tr), 60.30 (d, JCF = 32.2, CH2). 19F NMR
3
3
(CDCl3): ꢁ109.7 (dt, JHF = 40.1, JHF = 12.6). mp: 194–
195 8C (ethyl acetate). Elemental analysis for C25H21FN2O
calculated: 78.10%C, 5.51%H, 7.29%N, found: 77.98%C,
5.53%H, 7.32%N.
1H NMR (CDCl3): 7.46 (1H, dd, J = 1.4, 0.4, Imi), 7.37–
7.32 (9H, m, Tr), 7.15–7.09 (6H, m, Tr), 6.98 (1H, d, J = 1.4,
Imi), 6.36 (1H, bs, OH), 5.63 (1H, dd, 3JHF = 8.1, 4JHH = 0.9),
2
3
4.63 (1H, dd, JHH = 13.0, JHF = 4.5), 3.94 (1H, ddd,
3
4
2JHH = 13.0, JHF = 12.2, JHH = 1.0). 13C NMR (CDCl3):
141.48 (3C, Tr), 139.04 (s, C2Imi), 135.88 (d, 3JCF = 7.0, C4Imi),
129.60 (6CH, Tr), 128.40 (3CH, Tr), 128.22 (6CH, Tr), 122.05
4.5. 2-Bromo-2,3-difluoro-3-(1-trityl-1H-imidazol-4-yl)-
propan-1-ol (9a,b)
4
1
(d, JCF = 1.9, C5Imi), 110.85 (d, JCF = 269.9, CF), 76.05 (s,
2
2
To a solution of compound 8a,b (3.11 g, 8.1 mmol) in
40 mL of anhydrous dichloromethane was slowly added
Et3Nꢀ3HF (1.94 g, 12.0 mmol) at 0 8C. After the solution
was stirred for 10 min, 1.59 g of NBS (8.9 mmol) was added.
The cooling bath was removed and the reaction was stirred
for 2 days at which time TLC indicated that almost all the
starting material had disappeared. The solvent was evapo-
rated and 150 mL of ethyl acetate was added. The resulting
solution was washed with water (2 ꢂ 20 mL), brine
(2 ꢂ 20 mL) and dried over anhydrous Na2SO4. Evaporation
of the solvent and purification of the residue by chromato-
graphy on silica gel (hexane/ethyl acetate 2:1) afforded
2.27 g (58%) of a mixture of compound 9a and compound 9b
as a white solid. 1HNMR indicated the ratio of the two
compounds to be 40:60.
1C, Tr), 66.55 (d, JCF = 30.9, CHBr), 51.49 (d, JCF = 28.1,
CH2). 19F NMR (CDCl3): ꢁ105.28 (1F, bs).
4.5.4. 2,3-Dibromo-2-fluoro-3-(1-trityl-1H-imidazol-4-yl)-
propan-1-ol (10b)
1H NMR (CDCl3): 7.44 (1H, d, J = 1.5, Imi), 7.37–7.32 (9H,
m, Tr), 7.15–7.09 (6H, m, Tr), 7.08 (1H, m, Imi), 6.36 (1H, bs,
3
4
OH), 5.61 (1H, dd, JHF = 11.2, JHH = 0.7), 4.22 (1H, dd,
3
3
2JHH = 13.1, JHF = 11.5), 4.07 (1H, dd, JHF = 23.5,
2JHH = 13.1). 13C NMR (CDCl3): 141.62 (3C, Tr), 139.10 (s,
C2Imi), 136.39 (d, 3JCF = 4.5, C4Imi), 129.60 (6CH, Tr), 128.32
4
(3CH, Tr), 128.18 (6CH, Tr), 123.17 (d, JCF = 3.4, C5Imi),
1
112.57 (d, JCF = 265.5, CF), 76.05 (s, 1C, Tr), 68.34 (d,
2JCF = 24.9, CHBr), 49.68 (d, JCF = 26.2, CH2). 19F NMR
2
(CDCl3): ꢁ111.73 (1F, bs).

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J. Hajduch et al. / Journal of Fluorine Chemistry 129 (2008) 112–118
4.5.5. Reaction of ‘‘FBr’’ with pure (E)-2-fluoro-3-(1-
trityl-1H-imidazol-4-yl)-prop-2-en-1-ol (8a)
2JCF = 46.8, CF), 141.86 (3C, Tr), 139.33 (s, C2Imi), 130.23 (dd,
2JCF = 29.0, 3JCF = 6.1, C4Imi), 129.66 (6CH, Tr), 128.26 (3CH,
3
4
To a solution of compound 8a (1.44 g, 3.7 mmol) in 40 mL
of anhydrous dichloromethane was slowly added Et3Nꢀ3HF
(0.94 g, 5.8 mmol) at 0 8C. After the solution was stirred for
30 min, 0.73 g of NBS (4.1 mmol) was added. The cooling bath
was removed after 60 min and the reaction was stirred for an
additional 4 h at which time TLC indicated that almost all the
starting material had disappeared. The solvent was evaporated
and 70 mL of ethyl acetate was added. The resulting solution
was washed with water (2 ꢂ 10 mL), brine (2 ꢂ 10 mL) and
dried over anhydrous Na2SO4. Evaporation of the solvent and
purification of the residue by chromatography on silica gel
(dichloromethane/ethyl acetate 9:1) afforded 1.00 g (55%) of a
mixture of compound 9a and compound 9b as a white solid. 1H
NMR indicated the ratio of the two compounds to be 75:25.
Tr), 128.18 (6CH, Tr), 121.39 (dd, JCF = 11.1, JCF = 5.6,
C5Imi), 75.85 (s, 1C, Tr), 55.88 (d, 2JCF = 24.3, CH2). 19F NMR
(CDCl3): ꢁ156.0 (1F, dt, 3JFF = 125.5, 3JHF = 22.9), ꢁ161.6 (1F,
3
2
dt, JFF = 125.5, JHF = 5.3). HRMS (FAB+): for MH, i.e.
C25H21F2N2O calculated: 403.1622; found: 403.1623; mp: 157–
158 8C (ethylacetate). Elemental analysis for C25H20F2N2O
calculated: 74.61%C, 5.01%H, 6.96%N, found: 74.50%C,
5.14%H, 6.91%N.
4.6.2. (Z)-2,3-Difluoro-3-(1-trityl-1H-imidazol-4-yl)-prop-
2-en-1-ol (11b)
1H NMR (CDCl3): 7.47 (1H, dd, J = 2.8, 1.5, Imi), 7.38–
7.33 (9H, m, Tr), 7.16–7.70 (6H, m, Tr), 7.06 (1H, bs, Imi), 5.25
(1H, bs, OH), 4.51 (2H, dd, 3JHF = 20.8, 4JHF = 4.1, CH2). 13
C
NMR (CDCl3): 146.84 (dd, JCF = 258.1, JCF = 13.3, CF),
1
2
1
142.30 (dd, JCF = 237.7, JCF = 19.8, CF), 141.71 (3C, Tr),
2
4.5.6. Reaction of ‘‘FBr’’ with pure (Z)-2-fluoro-3-(1-trityl-
1H-imidazol-4-yl)-prop-2-en-1-ol (8b)
4
2
139.44 (d, JCF = 1.7, C2Imi), 131.60 (dd, JCF = 33.7,
3JCF = 1.4, C4Imi), 129.65 (6CH, Tr), 128.41 (3CH), 128.28
(6CH), 119.95 (dd, 3JCF = 9.3, 4JCF = 1.0, C5Imi), 76.03 (s, 1C,
To a solution of compound 8b (870 mg, 2.26 mmol) in 40 mL
of anhydrous dichloromethane was slowly added Et3Nꢀ3HF
(547 mg, 3.39 mmol) at 0 8C. After the solution was stirred
for 30 min, 445 mg of NBS (2.50 mmol) was added. The
cooling bath was removed after 60 min and the reaction was
stirred for an additional 2 days at which time TLC indicated
that almost all the starting material had disappeared. The solvent
was evaporated and 70 mL of ethyl acetate was added. The
resulting solution was washed with water (2 ꢂ 10 mL), brine
(2 ꢂ 10 mL) and dried over anhydrous Na2SO4. Evaporation of
the solvent and purification of the residue by chromatography on
silica gel (dichloromethane/ethyl acetate 1:1) afforded 226 mg
(18%) of a mixture of compound 9b and compound 9a as a white
solid. 1H NMR indicated the ratio of the two compounds to be
88:12.
2
3
Tr), 58.27 (dd, JCF = 29.0, JCF = 2.2, CH2). 19F NMR
3
3
(CDCl3): ꢁ136.1 (1F, td, JHF = 20.7, JFF = 10.3), ꢁ147.6
(1F, dtd, JFF = 10.3, JHF = 3.8, JHF = 3.2). HRMS (FAB+):
for MH, i.e. C25H21F2N2O calculated: 403.1622; found:
403.1630; mp: 140–141 8C (ethylacetate). Elemental analysis
for C25H20F2N2O, calculated: 74.61%C, 5.01%H, 6.96%N;
found: 74.44%C, 4.90%H, 6.90%N.
3
4
4
4.7. (E)-a,b-Difluoro-3-(1-trityl-1H-imidazol-4-yl)-
propenal (12a)
To a solution of compound 11a (380 mg, 0.95 mmol) in
10 mL of anhydrous dichloromethane (20 mL) was added
activated MnO2 (804 mg, 9.25 mmol). The mixture was
stirred at room temperature for 12 h until TLC indicated
complete disappearance of starting material. The mixture was
filtered and solvent was evaporated. The crude product was
purified by column chromatography (hexane/ethyl acetate
1:1). Purification afforded 200 mg (53%) of the desired
product 12a in yield along with 52 mg (15%) of byproduct 13.
The ratio 12a/13 was 80:20 (calculated from LC and 19F
NMR of the crude product).
4.6. (E)- and (Z)-2,3-Difluoro-3-(1-trityl-1-H-imidazol-4-
yl)-prop-2-en-1-ol (11a and 11b)
In a 100 mL flask, 1.51 g of a mixture of compounds 9a and
9b (3.13 mmol) was dissolved in 50 mL of anhydrous DMF and
5 mL of triethylamine (ꢃ36 mmol) at room temperature. The
mixture was heated to 100 8C and stirred overnight. After
evaporation of the solvent, the residue was dissolved in 200 ml
of ethyl acetate. The resulting mixture was washed with water
(2 ꢂ 30 mL), brine (2 ꢂ 30 mL) and dried over Na2SO4. The
solvent was evaporated and the residue was purified by
chromatography on silica gel (hexane/ethyl acetate 2:1) to give
585 mg of compound 11a (47%) and 365 mg of compound 11b
(29%) as white solids. The ratio 11a:11b in the crude mixture
was 60:40 (calculated from LC and 19F NMR).
3
4
1H NMR (CDCl3): 9.86 (1H, ddd, JHF = 18.9, JHF = 2.5,
6JHH = 0.6, CHO), 7.64 (1H, dq, J = 1.4, 0.7, Imi), 7.52 (1H, td,
J = 1.4, 0.6, Imi), 7.41–7.34 (9H, m, Tr), 7.18–7.11 (6H, m, Tr).
13C NMR (CDCl3): 178.63 (dd, 2JCF = 17.0, 3JCF = 4.2, CHO),
1
2
157.62 (dd, JCF = 256.5, JCF = 39.9, CF), 144.94 (dd,
2
1JCF = 244.7, JCF = 35.6, CF), 141.31 (3C, Tr), 140.98 (bs,
C2Imi), 129.49 (6CH, Tr), 128.51 (3CH, Tr), 128.31 (6CH, Tr),
3
4
126.53 (dd, JCF = 13.9, JCF = 7.2, C5Imi), 76.44 (s, 1C, Tr),
C4Imi is covered by signals of trityl group. 19F NMR (CDCl3):
ꢁ152.4 (1F, dd, 120.8, 2.5), ꢁ168.4 (1F, dddt, 120.8, 18.9, 1.4,
0.7). HRMS (DCI): for C25H18F2N2O (M), calculated:
400.1387, found: 400.1389; mp: 139–141 8C (ethylacetate).
Elemental analysis for C25H18F2N2O, calculated: 74.99%C,
4.53%H, 7.00%N; found: 74.91%C, 4.48%H, 7.02%N.
4.6.1. (E)-2,3-Difluoro-3-(1-trityl-1H-imidazol-4-yl)-prop-
2-en-1-ol (11a)
1H NMR (CDCl3): 7.51 (1H, bs, Imi), 7.36–7.31 (9H, m, Tr),
3
7.16–7.10 (7H, m, Tr, Imi), 4.46 (2H, dd, JHF = 22.9,
4JHF = 5.5), 3.21 (1H, bs, OH). 13C NMR (CDCl3): 148.65
1
2
(dd, JCF = 244.9, JCF = 50.0, CF), 144.44 (dd, JCF = 228.7,
1

J. Hajduch et al. / Journal of Fluorine Chemistry 129 (2008) 112–118
117
4.8. (Z)-a,b-Difluoro-3-(1-trityl-1H-imidazol-4-yl)-
propenal (12b)
ethylacetate (2 ꢂ 5 ml) and 2 mL of H2O. The residue was then
dried on vacuum and 45 mg (96%) of the final product 6a was
obtained as a white solid.
To a solution of compound 11b (232 mg, 0.58 mmol) in
anhydrous dichloromethane (10 mL) was added activated
MnO2 (501 mg, 5.77 mmol). The mixture was stirred at room
temperature for 6 days until TLC indicated complete
disappearance of starting material. The mixture was filtered,
solvent was evaporated and crude product was purified by
column chromatography. The crude product was purified by
column chromatography (hexane/ethyl acetate 4/1) to give
76 mg (33%) of the desired product 12b and 90 mg (42%) of
byproduct 13. The ratio 12b/13 was 40:60 (calculated from LC
and 19F NMR of the crude product).
1H NMR (DMSO-d6): 7.91 (bs, 1H), 7.69 (bs, 1H). 13C NMR
(DMSO-d6): 160.73 (dd, 2JCF = 46.4, 3JCF = 29.3, CO), 152.32
(dd, 1JCF = 254.2, 2JCF = 46.4, CF), 137.63 (bs, C2Imi), 137.47
1
2
2
(dd, JCF = 237.8, JCF = 39.5, CF), 127.56 (d, JCF = 31.9,
3
4
C4Imi), 121.89 (dd, JCF = 13.7, JCF = 6.0, C5Imi). 19F NMR
3
(DMSO-d6): ꢁ138.90 (d, 1F, JFF = 125.0), ꢁ160.88 (d, 1F,
3JCF = 128.1). HRMS (ESI): for M ꢁ H, i.e. C6H3F2N2O2
calculated: 173.0163; found: 173.0164; mp: decomposition
between 250 and 270 8C. Elemental analysis for C6H4F2N2O2,
calculated: 41.39% C, 2.35% H, 16.09% N; found 40.98% C,
2.33% H, 15.76% N.
1H NMR (CDCl3): 10.58 (1H, dd, JHF = 19.1, JHF = 2.3,
CHO), 7.53 (1H, dd, J = 2.9, 1.4, Imi), 7.42–7.34 (9H, m, Tr),
7.18–7.10 (7H, m, Tr, Imi). 13C NMR (CDCl3): 184.71 (dd,
2JCF = 15.4, 3JCF = 7.7), 156.12 (dd, 1JCF = 262.8, 2JCF = 16.2),
143.26 (dd, 1JCF = 254.6, 2JCF = 12.7), 141.46 (3C, Tr), 141.08
3
4
4.11. (Z)-a,b-Difluorourocanic acid (6b)
Compound 12b (70 mg, 0.18 mmol) was dissolved in 8 mL
of t-BuOH and 3 mL of 2-methyl-2-butene. The solution
was then cooled to 0 8C and a solution of NaClO2 (160 mg,
1.78 mmol) and NaH2PO4 (214 mg, 1.78 mmol) in 4.0 mL of
H2O was added. The mixture was stirred at room temperature
until TLC indicated the complete disappearance of aldehyde.
Dichloromethane (80 mL) was added and the mixture was
washed with water (2 ꢂ 10 mL), brine (2 ꢂ 10 mL) and dried
over anhydrous Na2SO4. The mixture was filtered and
evaporated. The residue was washed with water (2 ꢂ 5 mL)
and dissolved in 10 mL of CH3COOH and 1.0 mL of
concentrated HCl. After the mixture was stirred at room
temperature for 3 h, the solvent was evaporated and the residue
was washed with ethyl acetate (2 ꢂ 5 ml) and 2 mL of H2O.
Vacuum drying of the residue gave 11 mg (37%) of the final
product 6b as a white solid.
4
2
(d, JCF = 1.8, C2Imi), 139.56 (d, JCF = 23.9, C4Imi), 129.56
(6CH, Tr), 128.55 (3CH, Tr), 128.37 (6CH, Tr), 124.37 (dd,
4
3JCF = 8.9, JCF = 3.3, C5Imi), 76.32 (s, 1C, Tr). 19F NMR
3
(CDCl3): ꢁ123.6 (1F, d, JFF = 12.0), ꢁ159.4 (1F, dd,
3
3JHF = 19.1, JFF = 12.0). HRMS (DCI): for C25H18N2F2O
(M), calculated: 400.1387; found: 400.1389. mp: 136–137 8C
(ethylacetate).
4.9. 2-Fluoro-1-(1-trityl-1H-imidazol-4-yl)-ethanone (13)
1H NMR (CDCl3): 7.70 (1H, d, J = 1.4, Imi), 7.44 (1H, d,
J = 1.4, Imi), 7.39–7.33 (9H, m, Tr), 7.14–7.08 (6H, m, Tr),
5.29 (2H, d, 2JHF = 47.4, CH2F). 13C NMR (CDCl3): 189.28 (d,
2JCF = 15.8, CO), 141.45 (3C, Tr), 139.62 (s, C2Imi), 137.46 (s,
C4Imi), 129.58 (6CH, Tr), 128.50 (3CH, Tr), 128.35 (6CH, Tr),
4
2
4
126.16 (d, JCF = 4.2, C5Imi), 83.55 (d, JCF = 179.1, CH2F),
2
1H NMR (DMSO-d6): 8.42 (d, 1H, JHF = 1.5), 7.99 (bs,
76.31 (s, 1C, Tr). 19F NMR (CDCl3): ꢁ235.7 (t, JHF = 47.5).
1H). 13C NMR (DMSO-d6): 164.65 (dd, JCF = 26.1,
2
mp: 193–194 8C (ethylacetate). HRMS (FAB+): for MH, i.e.
C24H20FN2O calculated: 371.1560; found: 371.1553. Elemen-
tal analysis for C24H19FN2O, calculated: 77.82% C, 5.17% H,
7.56% N; found: 77.78% C, 5.09% H, 7.75% N.
3JCF = 6.0, CO), 154.92 (dd, JCF = 250.8, JCF = 21.8, CF),
1
2
1
2
141.81 (s, C2Imi), 142.33 (dd, JCF = 245.9, JCF = 14.6, CF),
131.49 (d, 2JCF = 35.3, C4Imi), 125.10 (d, 3JCF = 8.6, C5Imi). 19
F
NMR (DMSO-d6): ꢁ132.95 (bs, 1F), ꢁ141.99 (bs, 1F). HRMS
(ESI): for M ꢁ H, i.e. C6H3F2N2O2 calculated: 173.0163;
found: 173.0166; mp: decomposition between 250 and 270 8C.
Elemental analysis for C6H4F2N2O2, calculated: 41.39% C,
2.35% H, 16.09% N; found: 41.16% C, 2.35% H, 15.81% N.
4.10. (E)-a,b-Difluorourocanic acid (6a)
Compound 12a (108 mg, 0.27 mmol) was dissolved in
8.0 mL of t-BuOH and 3.2 mL of 2-methyl-2-butene. Then the
mixture was cooled to 0 8C and a solution of NaClO2 (162 mg,
1.79 mmol) and NaH2PO4 (218 mg, 1.82 mmol) in 4.0 mL of
H2O was added. The resulting mixture was stirred at room
temperature until TLC indicated complete disappearance of
the aldehyde. Dichloromethane (80 mL) was added and
the mixture was washed with water (2 ꢂ 10 mL), brine
(2 ꢂ 10 mL) and dried over anhydrous Na2SO4. The mixture
was filtered and evaporated. The residue was then washed with
water (2 ꢂ 5 mL) and dissolved in 10 mL of CH3COOH and
1.0 mL of concentrated HCl. The mixture was stirred at room
temperature for 3 h. After this period, the solvent was
evaporated and the residue was washed subsequently with
Acknowledgement
This research was supported by the intramural research
funds of NIDDK.
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