New building blocks for fluorinated imidazole derivatives: Preparation of β-fluoro- and β,β-difluorohistamine

Article abstract of DOI:10.1021/jo0102415

We demonstrate that "FBr" addition to 1-trityl-4-vinyl-1H-imidazole (7) provides a convenient route to side-chain-fluorinated histamines. Thus, addition of "FBr" to the double bond of 7 occurs with Markovnikov regioselectivity to produce 4-(2-bromo-1-fluoroethyl)-1-trityl-1H-imidazole (8). Substitution with azide, reduction, and removal of the trityl group provide β-fluorohistamine (1) as the dihydrochloride. Elimination of HBr from 8 followed by a second addition of "FBr" gives 4-(2-bromo-1,1-difluoroethyl)-1-trityl-1H-imidazole (15). This was similarly converted to β,β-difluorohistamine (2) as the dihydrochloride.

Full text of DOI:10.1021/jo0102415

J . Org. Chem. 2001, 66, 4687-4691
4687
New Bu ild in g Block s for F lu or in a ted Im id a zole Der iva tives:
P r ep a r a tion of â-F lu or o- a n d â,â-Diflu or oh ista m in e
Bohumil Dolensky and Kenneth L. Kirk*
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, Maryland 20892
Kennethk@bdg8.niddk.nih.gov
Received March 6, 2001
We demonstrate that “FBr” addition to 1-trityl-4-vinyl-1H-imidazole (7) provides a convenient route
to side-chain-fluorinated histamines. Thus, addition of “FBr” to the double bond of 7 occurs with
Markovnikov regioselectivity to produce 4-(2-bromo-1-fluoroethyl)-1-trityl-1H-imidazole (8). Sub-
stitution with azide, reduction, and removal of the trityl group provide â-fluorohistamine (1) as
the dihydrochloride. Elimination of HBr from 8 followed by a second addition of “FBr” gives 4-(2-
bromo-1,1-difluoroethyl)-1-trityl-1H-imidazole (15). This was similarly converted to â,â-difluoro-
histamine (2) as the dihydrochloride.
Sch em e 1
In tr od u ction
In biotransformations of biologically important imid-
azoles such as histidine and histamine, the imidazole side
chain is usually the site of enzyme action. Whereas
substitution of fluorine on the imidazole ring has been
shown to affect the interactions of imidazole derivatives
with many biological recognition sites,1,2 fluorine on the
side chain could be expected to have different and
possibly dramatic effects. Despite this, â-fluorohistamine3
(1) is the only example of a side-chain-fluorinated ana-
logue of either histidine or histamine that we are aware
of that has fluorine attached to the methylene group
adjacent to the imidazole role. Examples of biologically
important imidazoles with more distal side chain fluorine
substitution include such compounds as R-fluoromethyl
histidine, an inhibitor of histidine decarboxylase,4 and
E- and Z-R-fluorourocanic acid.5
starting hydroxy or oxo derivative (for a similar prepara-
tion of the difluoro compound) could be problematic.
The availability of stable reagents for fluorodeoxygen-
ation (e.g. DAST, FAR) could provide alternative proce-
dures that would be more convenient, eliminating the
first concern. To examine fluorodeoxygenation as a route
to additional side chain substituted imidazoles, we
explored routes to hydroxy precursors. However, our first
attempts, based on reaction of 1-trityl-1H-imidazole-4-
carboxaldehyde (3) with a C1-synthon and subsequent
functional group manipulation, were unsuccessful (Scheme
1). For example, additions of nitromethane to the alde-
hyde 3 in attempts to prepare adduct 4 proved to be very
complicated. Under varied experimental conditions we
obtained either no reaction, complex mixtures, or the
predominate formation of the bis-adduct of nitromethane
5. Approaches based on deoxyfluorination6 of the tri-
methylsilyl cyanohydrin derived from 3 gave disappoint-
ing initial results in that only trace amounts 6 could be
detected by MS.
We recently have initiated research to develop general
methods for the synthesis of side-chain-fluorinated ana-
logues of biologically important imidazoles. In this report,
we describe one such approach and illustrate the ap-
plication thereof to the synthesis of â-fluorohistamine (1)
and â,â-difluorohistamine (2).
Ch em istr y
â-Fluorohistamine (1) was prepared previously by
reaction of â-hydroxyhistamine with SF4 in HF.3 This
straightforward method has two potential problems. In
the first place, hazardous materials such as SF4 and/or
liquid HF must be used. Second, the availability of
(1) Kirk, K. L.; Cohen, L. A. In Biochemistry involving carbon-
fluorine bonds; R. Filler, Ed., ACS Symposium Series 28, American
Chemical Society: Washington, D.C., 1976, pp 23-36.
(2) De Clercq, E.; Luczak, M.; Reepmeyer, J . C.; Kirk, K. L.; Cohen,
L. A. Life Sci. 1975, 17, 187.
(3) Kollonitsch, J .; Marburg, S.; Perkins, L. M. J . Org. Chem. 1979,
44, 771.
(4) Kollonitsch, J . In Biomedicinal Aspects of Fluorine Chemistry;
Filler, R., Kobayashi, Y., Eds.; Elsevier Biomedical: New York, 1982;
pp 93-122.
(5) a) Percy, E.; Singh, M.; Takahashi, T.; Takeuchi, Y.; Kirk, K. L.
J . Fluorine Chem. 1998, 91, 5. (b) Pirrung, M. C.; Rowley, E. G.;
Holmes, C. P. J . Org. Chem. 1993, 58, 5683.
In a different approach, we explored functionallization
of the double bond of 4-vinyl-1H-imidazoles based an
efficient procedure for the electrophilic addition of a
stoichiometric equivalent of FBr to a double bond. This
is achieved by treatment of an olefin with a source of
electrophilic Br+, usually an N-bromo amide, and nu-
(6) LeTourneau, M. E.; McCarthy, J . R. Tetrahedron Lett. 1984, 25,
5227.
10.1021/jo0102415 This article not subject to U.S. Copyright. Published 2001 by the American Chemical Society
Published on Web 06/06/2001

4688 J . Org. Chem., Vol. 66, No. 13, 2001
Dolensky and Kirk
Sch em e 2a
a
(a) NBS, 3HF‚Et3N; (b) NIS, 3HF‚Et3N; (c) K2CO3; (d) silica.
cleophilic F-, usually an (HF)x‚amine complex. The
addition proceeds predominantly with Markovnikov re-
gioselectivity. This method is the subject of recent
reviews.7 A particularly useful procedure using a com-
bination of the unagressive Et3N‚3HF and N-bromosuc-
cinamide (NBS) has been exploited extensively by Haufe
and co-workers.8 Adding utility to the method is the fact
that the resulting bromofluoro product could be used as
building blocks for subsequent syntheses of difluoro
derivatives.9 Thus, elimination of HBr9,10 followed by a
second “FBr” addition leads to bromodifluoro adducts.9,11
Although the utility of this method for introduction of
fluorine has been amply demonstrated, a limitation to
its generality would be the presence of other groups that
might be susceptible to electrophilic attack or to the
action of Et3N‚3HF. Indeed, we were particularly aware
that NBS is an effective reagent for ring-bromination of
imidazole.12 In fact, we determined that the attempted
addition of “FBr” to the double bond of 4-vinyl-1H-
imidazole led to a complex mixture, the 19F NMR
spectrum of which indicated the complete absence of any
organoflourine compound.
brominated product in our intended substitution reac-
tions. The expected fluoroiodo adduct 11 is formed, also
with complete Markovnikov selectivity and in high yield.
However, we found that the adduct 11 loses the fluorine
atom during chromatography and hydroxyiodo compound
12 is obtained. In view of the stability of 8 under these
conditions, and the fact that the substitution reaction of
11 with potassium phthalimide results in displacement
of iodine, this apparent “substitution” of fluorine is
surprising.
To introduce a second fluorine atom into the side chain,
we envisioned a repeat of the “FBr” addition to the fluoro
olefin 13 prepared by dehydrobromination of 8. Using
K2CO3 as base, the expected olefin 13 was isolated in 50%
yield as the major product accompanied by bromoolefin
14 isolated in 2% yield, the product of dehydrofluorina-
tion. The assignment of the E configuration to 14 was
based on the presence of a new band in the IR spectrum
at 940 cm-1 that indicates15 a trans relationship of the
hydrogen atoms on the double bond. We have consistently
found that competing formation of olefins 13 and 14
accompanies all substitution reactions of 8 that we have
performed.
A repeat of the “FBr” addition to 13 gave 4-(2-bromo-
1,1-difluoroethyl)-1H-tritylimidazole (15) in 71% yield.
Difluoroimidazole 15 is accompanied by traces of
Z-fluorobromoolefin 16 (The E isomer has16 a smaller
3J HF; 29.1 vs 15.6 Hz). This presumably is a result of the
addition of Br2 to 13 followed by elimination of HBr
(Scheme 3). Dibromo adducts such as 17 frequently have
been reported as byproducts of “FBr” additions in these
reactions.7 Another possible origin of bromofluoroolefin
16 would be the addition of “FBr” to bromoolefin 14, a
possible contaminant of starting olefin 13, and subse-
quent elimination of HBr from the resulting dibromo-
fluoro compound 18. This possibility was ruled out by
examination of the chemical behavior of 17 and 18. Thus,
we found that 18 is relatively stable in the presence of
Et3N. In contrast, under the same conditions, dibromo-
fluoro compound 17 readily eliminates HBr and is
completely converted (1H NMR) to bromofluoroolefin 16
(Scheme 3).
In contrast, we found that reaction of 1-trityl-4-vinyl-
1H-imidazole (7) with NBS and Et3N‚3HF (Scheme 2)
occurred cleanly to give the desired bromofluoro deriva-
1
tive 8 in 74-80% yield. From H NMR data, it appears
that the addition takes place with total Markovnikov
regioselectivity. We assume that the bulky trityl group
impedes electrophilic bromination at the adjacent imid-
azole 2- and 5-positions, permitting efficient reaction at
the exocyclic double bond. As byproducts we isolated
triphenylcarbinol (10%), a result of partial detritylation,
and hydroxybromide 9 (6%), apparently due to the
presence of water.13 Smaller amounts (2%) of the adduct
10 were isolated (Scheme 2).14
An alternative to addition of “FBr” is addition of “FI”,
where N-iodosuccinamide (NIS) is used7 as source of I+.
The iodinated product should be more reactive than the
(7) Boguslavskaya, L. S. Russian Chem. Rev. 1972, 41, 740. (b)
Boguslavskaya, L. S. Russian Chemical Reviews 1984, 53, 1178. (c)
Yoneda, N. Tetrahedron 1991, 47, 5329.
(8) Haufe, G.; Alvernhe, G.; Laurent, A.; Ernet, T.; Goj, O.; Kro¨ger,
S.; Sattler, A. Org. Synth. 1999, 76, 159.
(9) Suga, H.; Hamatani, T.; Guggisberg, Y.; Schlosser, M. Tetrahe-
dron 1990, 46, 4255.
(10) Eckes, L.; Hanack, M. Synthesis 1978, 217.
(11) Oldendorf, J .; Haufe, G. J . Prakt. Chem. 2000, 342, 52.
(12) a) J ain, R.; Avramovitch, B.; Cohen, L. A. Tetrahedron 1998,
54, 3235; b) Palmer, B. D.; Denny, W. A. J . Chem. Soc., Perkin Trans.
1 1989, 95.
Compounds 8 and 15 possess functionality that can be
used to prepare imidazole derivatives having, respec-
tively, one or two fluorine substituents on the side chain.
(14) Olah, G. A.; Li, X.-Y.; Wang, Q.; Prakash, G. K. S. Synthesis
1993, 693.
(15) Bellamy, L. J . The Infrared Spectra of Complex Molecules, 2nd
ed.; J ohn Wiley & Sons: New York, 1958; p 46.
(16) Dolensky, B.; Kirk, K. L., manuscript in preparation.
(13) Chi, D. Y.; Kiesewetter, D. O.; Katzenellenbogen, J . A. J .
Fluorine Chem. 1986, 31, 99.

Preparation of â-Fluoro- and â,â-Difluorohistamine
J . Org. Chem., Vol. 66, No. 13, 2001 4689
Sch em e 3
Sch em e 5a
a
(a) NaN3; (b) H2/Pd; (c) aq HCl.
of 8 with sodium azide cleanly produced the azide 22 in
87% yield, accompanied by a mixture of olefins 13 and
14, isolated in 7% yield (13 + 14). Difluoro derivative 15
similarly was converted to the azide 23 in 89% yield.
Catalytic reductions of azides 22 and 23 proceeded
cleanly at atmospheric pressure to give the corresponding
amines 21 and 24. However, hydrogenation of azide 22
at 276 kPa (40 psi) overnight led to reductive loss of
fluorine and tritylated histamine was obtained.
Sch em e 4a
The hydrolysis of tritylated â,â-difluorohistamine (24)
takes place without any problem and the target com-
pound â,â-difluorohistamine (2) was obtained in 87%
yield as the dihydrochloride. Hydrolysis of trityl â-fluo-
rohistamine (21) likewise produced the dihydrochloride
of the target â-fluorohistamine (1), readily identified in
the crude product mixture by NMR and mass spectral
data. However, attempts to purify the dihydrochloride
of 1 have consistently led to substantial material loss
accompanied by formation of intractable material. To
date we have been unable achieve satisfactory purifica-
tion, a disappointing result in light of the previous report3
on the isolation and facile purification of this compound.
The pKa1 and pKa2 values for difluorohistamine 2 were
determined by titration of a solution of the dihydrochlo-
ride of 2 with aqueous NaOH at 25 °C. Analysis of the
titration curve gave estimated values of pKa1 ) 2.9 and
pKa2 ) 6.8. In comparison with pKa values of histamine
(at 30 °C, pKa1 ) 5.9, pKa2 ) 9.7)18 it seems that the two
fluorine substituents in the â-position have similar effects
on both the aromatic amino group (∆pKa1 ) 3.0) and the
aliphatic amino group (∆pKa2 ) 2.9).
a
(a) Potassium phthalimide; (b) aq HCl; (c) NH2NH2.
As initial targets, we chose side-chain-fluorinated hist-
amines that would result from successful application of
the Gabriel synthesis. However, the reaction of compound
8 with potassium phthalimide gave not only substitution
product 19, but also elimination products 13 and 14. The
ratio of substitution vs elimination was found to be quite
independent of the reaction temperature (rt, 80 °C or 110
°C), and furthermore the reaction with iodide 11 gave a
similar ratio.
The trityl group of 19 was removed readily by treat-
ment with aq HCl to give the protected amine 20.
Attempts to first remove the phthaloyl group using
hydrazine produced the tritylated amine 21 (Scheme 4)
along with an unidentified byproduct, possibly resulting
from partial substitution of fluorine (1H NMR). Consis-
tent with the expected lower reactivity17 of the difluoro
derivative 15, reaction with potassium phthalimide in
DMF, even at 150 °C, gave only 5% conversion (1H NMR)
after 24 h.
Con clu sion
The preparation of â-fluoro- and â,â-difluorohistamine
demonstrates the applicability of this approach to side-
chain-fluorinated imidazoles. The prepared histamines
1 and 2 are now subjects of biological studies. We are
continuing this work and are developing routes to other
key imidazole derivatives, including fluorourocanic
acids,16 fluorohistidinols, and fluorohistidines.
Exp er im en ta l Section
We next considered azide substitution as an alternative
(Scheme 5). The azide anion should be a better nucleo-
phile and weaker base than the phthalimide anion, and
the resulting azide should be converted readily to the
amine under mild catalytic reduction conditions. Reaction
The NMR spectra were recorded at frequencies of 300.1 for
1H, 75.5 for 13C, and 282.2 MHz for 19F spectra. Chemical shifts
(δ) of protons and carbons are relative to TMS, the fluorine
shifts are relative to CFCl3, all in ppm. Coupling constants
1
are presented in Hz. The H and 19F signals are presented as
δ (intensity, multiplicity, coupling constants). The 13C signals
(17) Bordwell, F. G.; Brannen, W., J r. J . Am. Chem. Soc. 1964, 86,
4645.
(18) Channing, N. W., Conrad, F. W. J . Phys. Chem. 1961, 65, 1047

4690 J . Org. Chem., Vol. 66, No. 13, 2001
Dolensky and Kirk
are written as δ (number of carbons if not one, multiplicity if
not singlet, coupling constants, assignment); after a marker
“off:” are given the signal characteristics obtained without
decoupling of 1H. The solvent is CDCl3 unless otherwise
specified. Melting points (mp) are not corrected. The low
resolution MS (LRMS) were done with chemical ionization
using ammonia gas. The high-resolution MS (HRMS) were
done with FAB ionization with Xe gas. Elemental analyses
were done by Atlantic Microlab, Inc. Silica gel Merck 60
(0.040-0.063 mm) was used for column chromatography,
Uniplate GF (Analtech) was used for preparative TLC, Merck
TLC plates Silica gel 60 F254 were used for analytical TLC;
UV at 254 nm was used for detection. All reagents and dry
solvents were purchased from Aldrich if not otherwise indi-
cated and used without additional purification or drying.
4-Vinyl-1H-imidazole was prepared as described19 previously
by thermal decarboxylation (distillation in vacuo) of urocanic
acid (Fluka) in yields of 35 to 65%. We found that rapid
distillation is necessary to achieve optimum yield. 1-Trityl-4-
vinyl-1H-imidazole (7) was prepared by tritylation of 4-(hy-
droxymethyl)-1H-imidazole, followed by oxidation to give the
aldehyde (3),20 and subsequent Wittig olefination21 or by direct
tritylation of 4-vinyl-1H-imidazole.
fractions consisting of uncharacterized impurities and a polar
fraction of pure (1H NMR) compound 12 (659 mg, 71%).
Compound 12 was further purified by preparative TLC (ether/
CH2Cl2 9/1) to give an analytical sample.
4-(1-F lu or ovin yl)-1-tr ityl-1H-im id a zole (13). To a solu-
tion of 2.05 g (4.71 mmol) of 8 in 65 mL of dry DMF was added
2.02 g (14.62 mmol) of K2CO3, and the mixture was stirred at
100 °C for 48 h. The mixture was then evaporated to dryness
and partitioned between 100 mL of CH2Cl2 and 100 mL of
brine. The organic layer was washed with 2 × 100 mL of brine,
dried over MgSO4, and evaporated. Separation by silica gel
chromatography (100 g, petroleum ether/acetone, 9/1) gave 867
mg of a 20:1 mixture of the olefins 13 (50%) and 14 (2%) and
402 mg (20%) of starting compound 8. Most of the bromoolefin
14 could be removed by crystallization of the mixture from
cyclohexane, during which process 14 separates as the initially
formed crystals. Attempts to carry out chromatographic sepa-
ration were unsuccessful. Data for 13: 1H NMR: 7.45 (1H, dd,
3.2, 1.5), 7.35-7.29 (9H, m), 7.18-7.12 (6H, m), 7.00 (1H, m,
ΣJ 3.5), 5.16 (1H, dd, 50.9, 3.0), 4.68 (1H, dd, 18.1, 3.0). 13C
NMR: 158.86 (d, 241.2, CF), 141.98 (3C, Tr), 139.67 (d, 1.7,
C2imi), 134.18 (d, 40.1, C4imi), 129.63 (6CH, Tr), 128.15 (3CH,
Tr), 128.09 (6CH, Tr), 118.87 (d, 1.0, C5imi), 87.43 (d, 17.3,
CH2), 75.56 (1C, Tr). 19F NMR: -112.75 (ddd, 50.8, 18.0, 3.3).
Mp 130.5-133.5 °C (cyclohexane, white crystals). Anal. Calcd
for C24H19FN2: C, 81.33; H, 5.40; N, 7.90. Found: C, 80.44;
H, 5.44; N, 7.71. HRMS calcd for C24H19FN2: 354.1532.
Found: 354.1535.
4-(2-Br om o-1-flu or oeth yl)-1-tr ityl-1H-im id a zole (8). To
a cooled (0 °C) and stirred solution of imidazole 7 (12.93 g,
38.4 mmol) dissolved in 370 mL of CH2Cl2 was added 9.9 mL
(60.7 mmol) of Et3N‚3HF. Any undissolved starting imidazole
7 went into solution after the addition of Et3N‚3HF. After 15
min, 7.50 g (42.1 mmol) of NBS was added in portions. The
mixture was allowed to warm to room temperature over 1-2
h and was stirred an additional 10 h. The mixture was then
poured into a mixture of 200 mL of water, 200 mL of brine,
and 20 mL of concentrated aqueous ammonia. The aqueous
solution was extracted with 2 × 200 mL and then 2 × 50 mL
of CH2Cl2, and the combined extracts were washed twice with
200 mL of brine. The organic layer was dried with MgSO4 and
evaporated to give 17.46 g of an oil. This was separated by
column chromatography (100 g silica, CH2Cl2/ether 99/1 f 95/5
f 0/100) to give triphenylcarbinol (1.00 g, 10%) and the
4-(2-Br om o-1,1-diflu or oeth yl)-1-tr ityl-1H-im idazole (15).
Using the procedure as described for the reaction with 7, 858
mg (2.42 mmol) of olefin 13 was subjected to bromofluorination
with 0.6 mL (3.68 mmol) of Et3N‚3HF and 472 mg (2.65 mmol)
of NBS. Separation of the crude product (1.13 g) by column
chromatography on silica gel (100 g, petroleum ether/acetone
9/1) gave 779 mg (71%) of bromide 15 and 42 mg (4%) of olefin
1
16. Data for 15: H NMR: 7.46 (1H, dt, 1.5, 1.2), 7.37-7.32
(9H, m), 7.16-7.09 (7H, m), 3.95 (2H, t, 13.4). 13C NMR:
141.80 (3C, Tr), 139.51 (C2imi), 134.72 (t, 31.7, C4imi), 129.69
(6CH, Tr), 128.31 (3CH, Tr), 128.19 (6CH, Tr), 120.96 (t, 2.8,
C5imi), 116.70 (t, 238.5, CF2), 75.88 (Tr), 32.39 (t, 33.8, CH2).
19F NMR: -96.5 (t, 13.4). Mp 140.0-142.5 °C (cyclohexane,
white crystals). Anal. Calcd for C24H19BrF2N2: C, 63.59; H,
4.22; N, 6.18. Found: C, 63.65; H, 4.33; N, 6.17.
1
fluorobromo derivate 8 (12.40 g, 74%). H NMR: 7.44 (1H, d,
1.2), 7.34-7.30 (9H, m), 7.16-7.09 (6H, m), 6.95 (1H, dd, 2.4,
1.2), 5.60 (1H, dt, 47.4, 6.0), 3.91-3.77 (2H, m). 13C NMR:
142.05 (3C, Tr), 139.30 (C2imi), 136.97 (d, 23.8, C4imi), 129.71
(6CH, Tr), 128.21 (3CH, Tr), 128.14 (6CH, Tr), 120.64 (d, 5.7,
C5imi), 87.94 (d, 172.6, CHF), 75.62 (Tr), 32.83 (d, 29.1, CH2-
Br). 19F NMR: -196.1 (dddd, 47.5, 20.3, 17.2, 2.4). Mp 127.5-
2-[2-Flu or o-2-(1-tr ityl-1H-im idazol-4-yl)-eth yl]isoin dole-
2,5-d ion e (19). A solution of 645 mg (1.48 mmol) of bromide
8 and 323 mg (1.74 mmol) of potassium phthalimide in 9 mL
of dry DMF was stirred at 100 °C for 24 h. The reaction
mixture then was evaporated to dryness and partitioned
between 100 mL of CH2Cl2 and 50 mL of brine. The organic
layer was extracted with 2 × 50 mL of brine, dried over MgSO4,
and evaporated to give 858 mg of crude product. Separation
by column chromatography (40 g, CH2Cl2/ether 100/0 f 95/5
f 9/1) afforded 186 mg of mixture olefins 13 and 14 (molar
ration 92:8 equal to yields 32% 13, 3% 14), 119 mg (46.3%) of
phthalimide, and 364 mg (49%) of substitution product 19. 1H
NMR: 7.87-7.80 (2H, m), 7.74-7.67 (2H, m), 7.46 (1H, d, 1.4),
7.35-7.27 (9H, m), 7.15-7.08 (6H, m), 7.01 (1H, dd, 1.4, 3.1),
5.78 (1H, ddd, 49.5, 8.9, 3.8), 4.49 (1H, ddd, 14.3, 12.0, 9.0),
4.09 (1H, ddd, 27.9, 14.4, 3.8). 13C NMR: 167.76 (2CO), 141.95
(3C, Tr), 139.24 (C2imi), 136.40 (d, 21.7, C4imi), 133.85 (2CH,
Ph), 131.83 (2C, Ph), 129.56 (6CH, Tr), 128.02 (3CH, Tr),
127.97 (6CH, Tr), 123.20 (2CH, Ph), 120.45 (d, 6.3, C5imi), 85.60
(d, 171.8, CHF), 75.44 (Tr), 41.11 (d, 26.9, CH2). 19F NMR:
-175.6 (dddd, 49.6, 27.9, 11.7, 3.2). Mp 190-192 °C (ethanol,
light yellow crystals). Anal. Calcd for C32H24FN3O2: C, 76.63;
H 4,82; N, 8.38. Found: C, 76.34; H; 5.06, N, 8.35. HRMS calcd
for C33H24FN3O2: 502.1931. Found: 502.1924.
130.0 °C (decomp. above 175 °C). HRMS calcd for C24H21
-
BrFN2: 435.0872, 437.0852. Found: 435.0872, 437.0846. Polar
fractions (3.47 g) isolated from this column were subjected to
a second chromatographic separation (60 g silica, CH2Cl2/ether
8/2) to give bromides 9 (1.02 g, 6%) and 10 (0.46 g, 2%).
4-(1-F lu or o-2-iod oeth yl)-1-tr ityl-1H-im id a zole (11). Us-
ing conditions similar to those used for bromofluorination, 674
mg (2.00 mmol) of 7, 0.5 mL (3.07 mmol) of Et3N‚3HF, and
497 mg (2.21 mmol) of NIS in 10 mL of CH2Cl2 was stirred for
15 h under protection from light. As above, the reaction
mixture was extracted with brine, to which had been added a
small amount of Na2S2O3 to remove iodine. After extraction
there was obtained 1.04 g of 11 estimated to be ca. 80-90%
pure by 1H NMR. 1H NMR: 7.42 (1H, br s), 7.35-7.29 (9H,
m), 7.15-7.06 (6H, m), 6.93 (1H, m, ΣJ 6), 5.49 (1H, dt, 47.3,
6.1), 3.71 (1H, ddd, 19.4, 10.5, 5.8), 3.63 (1H, ddd, 16.3, 10.4,
6.5). 13C NMR: 141.99 (3C, Tr), 139.13 (C2imi), 137.54 (d, 23.8,
C4imi), 129.67 (6CH, Tr), 128.14 (3CH, Tr), 128.07 (6CH, Tr),
120.49 (d, 5.6, C5imi), 88.09 (d, 172.3, CHF), 75.53 (Tr), 6.35
(d, 28.6, CH2I). 19F NMR: -161.4 (dt, 47.3, 17.7). HRMS calcd
for C24H21FIN2: 483.0734. Found: 483.0716.
Attempted purification by column chromatography on silica
gel (60 g, CH2Cl2/ether 100/0 f 95/5 f 2/8) gave nonpolar
2-[2-F lu or o-2-(1H-im id a zol-4-yl)-eth yl]isoin d ole-1,3-d i-
on e (20). A mixture of 156 mg (311 µmol) of 19 was stirred in
7 mL of methanol and 0.8 mL of concentrated HCl at 50 °C
for 2 h. The mixture was cooled to room temperature and, after
addition of 10 mL of water, was evaporated to dryness. The
resulting solid was partitioned between 5 mL of water and 5
mL of CH2Cl2. The aqueous phase was extracted with 2 × 2
mL CH2Cl2 and evaporated to dryness. There was obtained
(19) Overberger, C. G.; Vorchheimer, N. J . Am. Chem. Soc. 1963,
85, 951.
(20) Kelly, J . L.; Miller, C. A.; McLean, E. W. J . Med. Chem. 1977,
20, 721.
(21) Kokosa, J . M.; Szafasz, R. A.; Tagupa, E. J . Org. Chem. 1983,
48, 3605.

Preparation of â-Fluoro- and â,â-Difluorohistamine
J . Org. Chem., Vol. 66, No. 13, 2001 4691
55 mg (68%) of compound 20 as the solid hydrochloride with
a pad of Celite, and the Celite pad was washed with additional
methanol. Evaporation of the combined filtrate and methanol
wash gave 319 mg of 24. Purification by column chromatog-
raphy (20 g, CH2Cl2 f CH2Cl2/CH3OH 9/1) produced 304 mg
1
a purity of ca. 80% (1H NMR). H NMR in CD3OD: 9.06 (1H,
d, 1.5), 7.90-7.79 (5H, m), 6.00 (1H, ddd, 45.9, 6.9, 5.4), 4.37
(1H, td, 14.4, 6.9), 4.24 (1H, ddd, 20.1, 14.4, 5.4). 13C NMR in
CD3OD: 169.30 (2C, CdO), 137.13 (C2imi), 135.91 (2CH, Ph),
133.23 (2C, Ph), 130.74 (d, 23.5, C4imi), 124.60 (2CH, Ph),
120.06 (d, 6.2, C5imi), 83.62 (d, 174.6, CHF), 41.53 (d, 28.8,
CH2). 19F NMR in CD3OD: -179.7 (dddd, 46.2, 20.2, 14.1, 3.1).
HRMS calcd for C13H11FN3O2: 260.0835. Found: 260.0845.
2-F lu or o-2-(1-tr ityl-1H-im id a zol-4-yl)eth yla m in e (21).
To 150 mg (299 µmol) of 19 suspended in 10 mL of ethanol
contained in a pressure ampule was added 20 µL (516 µmol)
of 80% aqueous hydrazine hydrate. The tube was closed and
the mixture was stirred at 85 °C at which time the mixture
became homogeneous. After 1.5 h there remained starting 19
so an additional 60 µL (1.55 mmol) of hydrazine hydrate was
added. After an additional 2 h, a solid was formed, and the
reaction was allowed to cool to room temperature. The mixture
was evaporated to dryness and extracted with 3 × 15 mL of
CH2Cl2. The extracts were combined and evaporated to give
96 mg of solid amine 21 in a purity of ca. 80% (1H NMR).
4-(2-Azido-1,1-diflu or oeth yl)-1-tr ityl-1H-im id a zole (23).
The procedure was similar to that used for the reaction with
potassium phthalimide. A mixture of 441 mg (0.97 mmol) of
bromide 15 and 252 mg (3.88 mmol) of NaN3 was stirred in 6
mL of dry DMSO and 0.12 mL of water.23 After 3 days at 80
°C there was 50% conversion as determined by 1H NMR.
Further reaction for 3 days at 110 °C resulted in 95%
conversion. The mixture was partitioned between 50 mL of
CH2Cl2 and 200 mL of brine. The aqueous phase was extracted
with 50 mL of CH2Cl2, and the combined organic phases were
extracted with 2 × 100 mL of brine, dried over MgSO4, and
evaporated to dryness. The obtained crude product (499 mg)
was purified by preparative TLC (petroleum ether/acetone 75/
1
(99%) of pure amine 24 as a white solid. H NMR: 7.44 (1H,
q, 1.2), 7.38-7.33 (9H, m), 7.15-7.09 (7H, m), 3.34 (2H, t, 14.3),
1.88 (2H, br s). 13C NMR: 141.85 (3C, Tr), 139.40 (C2imi),
135.98 (t, 32.2, C4imi), 129.61 (6CH, Tr), 128.25 (3CH, Tr),
128.15 (6CH, Tr), 120.39 (t, 4.3, C5imi), 119.30 (t, 236.7, CF2),
75.76 (Tr), 47.39 (t, 29.3, CH2). 19F NMR: -102.7 (t, 14.1). Mp
124-125 °C. HRMS calcd for C24H22F2N3: 390.1782. Found:
390.1782.
2-F lu or o-2-(1-tr ityl-1H-im id a zol-4-yl)eth yla m in e (21).
Using an analogous procedure as above for 24, 884 mg of azide
22 in 120 mL of methanol was reduced over 450 mg Pd/C for
2 h. Crude product (830 mg, white solid) was purified by
column chromatography (54 g, CH2Cl2/CH3OH 17/3) to give
826 mg (97%) of amine 21 as a colorless oil. 1H NMR: 7.43
(1H, d, 1.5), 7.36-7.30 (9H, m), 7.16-7.09 (6H, m), 6.91 (1H,
ddd, 2.1, 1.5, 0.9), 5.39 (1H, ddd, 48.9, 6.6, 4.2), 3.26 (1H, ddd,
19.5, 14.1, 6.6), 3.16 (1H, ddd, 24.3, 14.1, 4.2), 1.81 (2H, bs).
13C NMR: 141.91 (3C, Tr), 138.93 (C2imi), 137.76 (d, 23.5,
C4imi), 129.42 (6CH, Tr), 127.89 (3CH, Tr), 127.84 (6CH, Tr),
119.87 (d, 5.9, C5imi), 90.32 (d, 166.4, CHF), 75.23 (Tr), 45.43
(d, 24.8). 19F NMR: -179.1 (dddd, 49.0, 24.4, 19.7, 2.6). HRMS
calcd for C24H23FN3: 372.1876. Found: 372.1881. If higher
pressure is used (276 kPa, overnight) the product of the
reaction is 2-(1-tr ityl-1H-im id a zol-4-yl)eth yla m in e (tr ity-
la ted h ista m in e). 1H NMR: 7.35-7.26 (9H, m), 7.15-7.07
(6H, m), 7.02 (1H, s), 6.62 (1H, s), 3.12 (2H, t, 7.2), 2.85 (2H,
t, 7.2). HRMS calcd for C24H24N3: 354.1970. Found: 354.1975.
2,2-Diflu or o-2-(1H-im id a zol-4-yl)eth yla m in e (2) a s d i-
h yd r och lor id e. A solution of 303 mg (778 µmol) of amine 24
in 20 mL of methanol was cooled to 0 °C and treated with 1
mL of hydrochloric acid (12 N diluted 1:5 with water). After
stirring 1 h at 0 °C and 6 h at room temperature, TLC
(CH2Cl2/CH3OH 9/1) indicated no starting material remained.
The mixture was evaporated to dryness at room temperature,
and the resulting solid was partitioned between 15 mL of water
and 10 mL of CH2Cl2. The aqueous layer was extracted with
2 × 10 mL of CH2Cl2 and then lyophilized. After additional
drying in high vacuum at room temperature and there was
obtained 149 mg (87%) dihydrochloride of difluorohistamine
1
15). There was obtained 360 mg (89%) of azide 23. H NMR:
7.48 (1H, dd, 2.7, 1.2), 7.36-7.31 (9H, m), 7.19 (1H, dd, 3.0,
1.5), 7.15-7.10 (6H, m), 3.88 (2H, t, 13.1). 13C NMR: 141.71
(s, 3C, off: m, ΣJ 17.5, Tr), 139.62 (s, off: dd, 212.1, 7.3, C2imi),
134.59 (t, 31.2, off: tddt, 31.2, 11.1, 8.0, 1.6, C4imi), 129.56 (s,
6CH, off: dm, 161, ΣJ 14.5, Tr), 128.25 (s, 3CH, off: dt, 161.5,
7.5, Tr), 128.12 (s, 6CH, off: dm, 162, ΣJ 10.5, Tr), 120.81 (t,
4.3, off: dq, 194.5, 4.0, C5imi), 117.97 (t, 239.6, off: ttd, 239.6,
3.9, 0.9, CF2), 75.88 (s, off: m), 53.85 (t, 31.0, off: tt, 144.9,
31.0, CH2). 19F NMR -99.7 (t, 12.8). Mp 120.5-122.0 °C
(methanol, white crystals). Anal. Calcd for C24H19F2N5: C,
69.39; H, 4.61; N, 16.86. Found: C, 69.48; H, 4.60; N, 16.69.
4-(2-Azid o-1-flu or oeth yl)-1-tr ityl-1H-im id a zole (22). A
solution of 2.00 g (4.59 mmol) of 8 and 900 mg (13.8 mmol) of
NaN3 in 60 mL of dry DMF was stirred at 100 °C for 24 h.
Workup as for 23 gave 1.84 g of crude product that was
separated on column chromatography (100 g, petroleum ether/
acetone 9/1) to give 125 mg of mixture olefins 13 and 14 (molar
ratio 56:44, 4% 13, 3% 14) and 1.59 g (87%) of azide 22. 1H
NMR: 7.47 (1H, d, 1.5), 7.33-7.25 (9H, m), 7.17-7.10 (6H,
m), 7.01 (1H, dd, 2.7, 1.5), 5.54 (1H, ddd, 48.6, 7.5, 3.9), 3.84
(1H, ddd, 17.1, 13.5, 7.5), 3.67 (1H, ddd, 26.0, 13.4, 3.8). 13C
NMR: 141.77 (3C, Tr), 139.10 (C2imi), 136.23 (d, 22.9, C4imi),
129.40 (6CH, Tr), 127.93 (3CH, Tr), 127.86 (6CH, Tr), 120.37
(d, 5.9, C5imi), 87.67 (d, 171.3, CHF), 75.34 (Tr), 53.27 (d, 25.4,
CH2). 19F NMR: -175.3 (dddd, 48.5, 25.9, 17.4, 2.6). Mp 107-
1
2 as an off white solid. H NMR in CD3OD: 9.09 (1H, d, 1.3),
8.12 (1H, td, 1.8, 1.3), 4.01 (2H, dd, 15.7, 15.2). 13C NMR in
CD3OD: 138.58 (C2imi), 127.49 (t, 32.2, C4imi), 121.48 (t, 6.1,
C4imi), 115.95 (t, 241.1, CF2), 44.44 (t, 26.3, CH2). 19F NMR in
CD3OD: -97.8 (td, 15.4, 1.7). Mp 175-200 °C (with slow
decomposition). HRMS: calcd for C5H8F2N3: 148.0686. Found
148.0691. Anal. Calcd for C5H9Cl2F2N3: C, 27.29; H, 4.23; N,
19.10. Found: C, 27.53; H, 4.12; N, 18.71.
2-F lu or o-2-(1H-im id a zol-4-yl)eth yla m in e (1) a s Dih y-
d r och lor id e. The same conditions as described for 2 above
were used. In addition, hydrolyses were carried out in HCl
(12 N or diluted 1:5 with water) without using methanol as a
cosolvent. Under all conditions examined there was obtained
a mixture of compounds that contained as a major component
(60-80%) dihydrochloride of 1. All atempts at further purifica-
1
tion led to material of lower purity. H NMR in CD3OD: 9.12
(1H, d, 1.2), 7.95 (1H, ddd, 2.7, 1.5, 0.6), 6.15 (1H, ddd, 48.3,
9.5, 3.0), 3.76 (1H, td, 14.1, 9.4), 3.63 (1H, ddd, 31.1, 14.1, 3.5).
13C NMR in CD3OD: 137.67 (C2imi), 129.35 (d, 22.7, C4imi),
120.81 (d, 5.9, C5imi), 83.61 (d, 172.7, CHF), 43.26 (d, 23.6,
CH2). 19F NMR in CD3OD: -179.6 (m, ΣJ 110). HRMS calcd
for C5H9N3F: 130.0781. Found 130.0781.
108 °C (cyclohexane, white crystals). Anal. Calcd for C24H20
-
FN5: C, 72.53; H, 5.07; N, 17.62. Found: C, 72.62; H, 5.16; N,
17.65.
2,2-Diflu or o-2-(1-t r it yl-1H -im id a zol-4-yl)-et h yla m in e
(24). To a solution of 329 mg (0.792 mmol) of the azide 23 in
60 mL of methanol under a nitrogen atmosphere was added
152 mg of Pd/C (10%). The flask was attached to a hydrogen-
filled balloon and the reaction was vigorously stirred for 2 h.
After this time, TLC (CH2Cl2/ether 9/1) indicated the absence
of starting material. The reaction mixture was filtered through
Su p p or tin g In for m a tion Ava ila ble: Details for the
preparation of compound 5, 1H, 13C, 19F and mass spectral data
for 16, and 1H, 13C, and mass spectral data for 5, 9, 10, 12,
and 17: details for examination of the reactivities of 17 and
18 toward Et3N. This information is available free of charge
via the Internet at http://pubs.acs.org.
(22) Bałczewski, P.; Mallon, M. K. J .; Street, J . D.; J oule, J . A. J .
Chem. Soc., Perkin Trans. 1 1990, 3193.
(23) Malik, A. A.; Tzeng, D.; Cheng, P.; Baum, K. J . Org. Chem.
1991, 56, 304.
J O0102415