Syntheses of (trifluoromethyl)imidazoles with additional electronegative substituents, an approach to receptor-activated affinity labels

Article abstract of DOI:10.1021/jo9814952

Electrophilic substitution in 2- and 4-(trifluoromethyl)imidazoles provides derivatives containing one or two nitro, chloro, bromo, or iodo groups. Fluoro and chloro derivatives were also prepared by photochemical trifluoromethylation of the respective haloimidazole. The results demonstrate that (trifluoromethyl)imidazoles behave fairly typically under the conditions of electrophilic nitration and halogenation. Of the alternative routes to the desired bifunctional and trifunctional imidazoles, electrophilic substitution on the preformed (trifluoromethyl)imidazole appears to be the method of choice in most cases. A large number of the products show herbicidal or insecticidal activity.

Full text of DOI:10.1021/jo9814952

9448
J . Org. Chem. 1998, 63, 9448-9454
Syn th eses of (Tr iflu or om eth yl)im id a zoles w ith Ad d ition a l
Electr on ega tive Su bstitu en ts. An Ap p r oa ch to Recep tor -Activa ted
Affin ity La bels
Yoshio Hayakawa,† Hiroshi Kimoto,† Louis A. Cohen,‡,1 and Kenneth L. Kirk*,‡
National Industrial Research Institute of Nagoya, Hirate-cho, Kita-ku, Nagoya 462, J apan, and
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, Maryland 20892
Received J uly 28, 1998
Electrophilic substitution in 2- and 4-(trifluoromethyl)imidazoles provides derivatives containing
one or two nitro, chloro, bromo, or iodo groups. Fluoro and chloro derivatives were also prepared
by photochemical trifluoromethylation of the respective haloimidazole. The results demonstrate
that (trifluoromethyl)imidazoles behave fairly typically under the conditions of electrophilic nitration
and halogenation. Of the alternative routes to the desired bifunctional and trifunctional imidazoles,
electrophilic substitution on the preformed (trifluoromethyl)imidazole appears to be the method of
choice in most cases. A large number of the products show herbicidal or insecticidal activity.
Sch em e 1
In tr od u ction
Imidazoles bearing a trifluoromethyl group at C-2 or
C-42 undergo rapid elimination of hydrogen fluoride
under alkaline conditions to form transient difluorodi-
azafulvenes (Scheme 1).3 These intermediates combine
readily with water or other nucleophiles and ultimately
form carboxylic acids or their derivatives. (Perfluoroalkyl)-
imidazoles, in general, show parallel behavior by under-
going hydrolysis to (perfluoroalkyl)ketones; the latter
species are slowly converted to imidazolecarboxylic acids
via the fluoroform reaction.3c This behavior suggests that
the controlled generation of fulvene intermediates at
specific sites in biological systems should provide a novel
class of irreversible affinity ligands. Since the process is
initiated simply by loss of the NH proton from the
imidazole ring, affinity labeling with (trifluoromethyl)-
imidazoles may be applicable to receptors and antibodies,
as well as to enzymes.
Titration data and kinetic studies provide pK2 values
of 10.0 for 2-(trifluoromethyl)imidazole (1) and 11.4 for
4-(trifluoromethyl)imidazole (6).3a At mildly alkaline pH
(8-9), the rate of fulvene formation thus is severely
limited by the small fraction of imidazolate anion present.
Fulvene formation is the rate-limiting step in all cases
examined, and kinetic measurements are based on the
rate of appearance of the carboxylate chromophore in UV
spectra. Thus, at pH 8 (30 °C), t1/2 ) 730 h for 1 and 2000
h for 6; at pH 9, t1/2 is reduced to 80 h for 1 and 200 h for
6. In order for a more significant concentration of
imidazolate ion to be generated within range of physi-
ological pH (7.4), an additional electronegative substitu-
ent on a ring carbon would be required to reduce pK2.
Our preliminary studies had shown, however, that a
strongly electronegative substituent, while increasing NH
acidity as expected, simultaneously retards elimination
of fluoride ion (as measured by formation of carboxylate
ion). To identify the substituents most suitable to achieve
a balance between these opposing effects, we required a
detailed study of electronic effects on both pK2 and krate
.
We report here the preparation of a series of (trifluoro-
methyl)imidazoles to be used in this study.
The variety of (trifluoromethyl)imidazoles needed for
such study is accessible either (a) by photochemical
trifluoromethylation of an appropriately substituted imi-
dazole4,5 or (b) by electrophilic substitution in the pre-
formed (trifluoromethyl)imidazole. These methods are not
† National Industrial Research Institute of Nagoya.
‡ National Institutes of Health.
(1) Deceased, September 12, 1996.
(2) For the sake of simplicity, the imidazole ring is numbered
arbitrarily according to one NH tautomer. No tautomer preference is
implied by such numbering.
(3) (a) Kimoto, H.; Cohen, L. A. J . Org. Chem. 1979, 44, 2902. (b)
Kimoto, H.; Cohen, L. A. J . Org. Chem. 1980, 45, 3831. (c) Fujii, S.;
Maki, Y.; Kimoto, H.; Cohen, L. A. J . Fluorine Chem. 1987, 35, 437.
(4) (a) Kimoto, H.; Fujii, S.; Cohen, L. A. J . Org. Chem. 1982, 47,
2867. (b) Kimoto, H.; Fujii, S.; Cohen, L. A. J . Org. Chem. 1984, 49,
1060.
10.1021/jo9814952 CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/19/1998

(Trifluoromethyl)imidazoles
J . Org. Chem., Vol. 63, No. 25, 1998 9449
Sch em e 2
necessarily interchangeable. For example, we had already
found that photochemical trifluoromethylation of ni-
troimidazoles gives unimpressive yields, and we were also
concerned that certain substituents (especially the higher
halogens) would not survive lengthy irradiation. On the
other hand, the strongly electronegative trifluoromethyl
group was expected to deactivate the imidazole ring
toward electrophilic substitution. In this report, we
describe the use of both methods in the syntheses of a
variety of (trifluoromethyl)imidazoles with additional
electronegative substituents.
Electronegatively substituted imidazoles, in general,
have attracted considerable attention because of their
special activities in biological systems. For example, both
2- and 4-nitroimidazoles show antimicrobial6a and radia-
tion sensitizer6b properties, while 2-fluoro- and 2-iodohis-
tidine have potent antimalarial activity.7 Imidazoles
substituted by halogen, cyano, and nitro groups are
known to have herbicidal activity.8 Some halogenated
(trifluoromethyl)imidazoles also have activity as herbi-
cides9,10 and as pesticides. Thus, apart from our interest
in enhancing the reactivity of the trifluoromethyl group
in compounds intended to serve as models for more
complex bioimidazoles, we expect these polysubstituted
imidazoles to be worthy of examination as antimetabo-
lites in their own right.
Resu lts a n d Discu ssion
Nitr o Der iva tives. Nitration of 2-(trifluoromethyl)-
imidazole (1) (Scheme 2) with a mixture of fuming nitric
and concentrated sulfuric acids occurs rapidly at reflux
(10 min) and provides a mixture of the mononitro (2, 46%)
and dinitro (3, 39%) derivatives. The very strong acidity
of 3 (pK2 ) -1.9) leads to unusual properties, e.g., an
ether-soluble sodium salt (see Experimental Section).
Efforts to limit the degree of nitration were unsuccessful.
Thus, the use of concentrated nitric acid (d ) 1.38) at 80
°C gave no nitration while, at 100 °C, 2 and 3 were again
formed in approximately equal amounts. Since 2 is
converted completely to 3 under the first set of conditions,
dinitration appears to occur sequentially. Nitration of
4-methyl-2-(trifluoromethyl)imidazole (4) provides 4-meth-
yl-5-nitro-2-(trifluoromethyl)imidazole (5) in only 21%
yield, possibly because of further oxidative degradation
of the activated methyl group in 5.11 Nitration at C-5 is
more strongly retarded by a proximate electronegative
trifluoromethyl group at C-4 than by a more distant
group at C-2 and requires much longer reaction time even
with the use of fuming nitric acid. Thus, 4-(trifluoro-
methyl)imidazole (6, Scheme 3) gave less than 20%
nitration in 10 min, and 86% of the 5-nitro derivative
(7) only after 24 h at reflux, but 2-methyl-4-(trifluoro-
methyl)imidazole (8) gave 76% of 2-methyl-5-nitro-4-
(trifluoromethyl)imidazole (9) after 4 h at reflux. Appar-
ently, the 2-methyl group in 8 partially counteracts the
deactivating effect of the trifluoromethyl substituent but
is itself not sufficiently activated by the 5-nitro group in
9 to undergo oxidative destruction.11 As expected, 7 does
not undergo further nitration at C-2, nor does 6 produce
the isomeric 2-nitro derivative.12
Since the nitro group (σp ) 0.79) should destabilize an
adjacent carbocation somewhat more strongly than will
the trifluoromethyl group (σp ) 0.61), it is surprising that
further nitration of 2 occurs so much more readily than
does nitration of 6. While we considered the possibility
that 3 is formed by simultaneous radical addition of the
elements of N2O4 to C-4 and C-5, the facile conversion of
2 to 3 appears to rule out the need for an alternative
mechanism. Electrophilic nitration of imidazole has been
shown to involve the predominant imidazolium ion in
(5) Some trifluoromethyl and (perfluoroalkyl)imidazoles are also
accessible via electrolytic generation of the corresponding radical:
Medebielle, M.; Pinson, J .; Saveant, J . M. Tetrahedron Lett. 1990, 31,
1279; J . Am. Chem. Soc. 1991, 113, 6872. Whether this method lends
itself to large-scale synthesis has not been established. Introduction
of the trifluoromethyl group via transition-metal-mediated intermedi-
ates usually requires temperatures too severe for most bioimidazoles
and histidine peptides, cf.: Labroo, V. M.; Labroo, R. B.; Cohen, L. A.
Tetrahedron Lett. 1990, 31, 5705. For a review of metal-mediated
syntheses, cf. ref 4a. We and others have also described methods
involving ring closure of acyclic precursors: Kimoto, H.; Kirk, K. L.;
Cohen, L. A. J . Org. Chem. 1978, 43, 3403. Baldwin, J . J .; Kisinger,
P. A.; Novello, F. C.; Sprague, J . M. J . Med. Chem. 1975, 18, 895.
Lombardini, J . G.; Wiseman, E. H. J . Med. Chem. 1974, 17, 1182. Such
methods are generally restricted to the preparation of (trifluoromethyl)-
imidazoles with alkyl or aryl substituents. Only the photochemical and
electrolytic methods have been explored for the synthesis of electrone-
gatively substituted (trifluoromethyl)imidazoles.
(6) (a) Nair, M. D.; Nagarajan, K. In Progress in Drug Research;
J ucker, E., Ed.; Birkhauser Verlag: Basel, 1983; Vol. 27, pp 163-252.
(b) For example: J enkins, T. C.; Naylor, M. A.; O’Neill, P.; Threadgill,
M. D.; Cole, S.; Stratford, I. J .; Adams, G. E.; Fielden, E. M.; Suto, M.
J .; Stier, M. A. J . Med. Chem. 1990, 33, 2603. Adams, G. E.; Stratford,
I. J . Biochem. Pharmacol. 1986, 35, 71.
(7) (a) Howard, R. J .; Andrutis, A. T.; Leech, J . H.; Ellis, W. Y.;
Cohen, L. A.; Kirk, K. L. Biochem. Pharmacol. 1986, 35, 1589. (b)
Panton, L. J .; Rossan, R. N.; Escajadillo, A.; Matsumoto, Y.; Lee, A.
T.; Labroo, V. M.; Kirk, K. L.; Cohen, L. A.; Aikawa, M.; Howard, R. J .
Antimicrob. Agents Chemother. 1988, 32, 1655.
(8) Draber, W.; Falbe, J . F.; Buchell, F. W. A.; Korte, G. K. U.S.
Pat. 3 501 286, 1970; Chem. Abstr. 1970, 72, 120339.
(9) Seng, F.; Sasse, K.; Beck, G.; Eue, L.; Schmidt, R. R. Ger. Pat.
2 646 142, 1978; Chem. Abstr. 1978, 89, 24310.
(10) Swithenbank, C.; Fujimoto, T. T. U.S. Pat. 4 314 844, 1982;
Chem. Abstr. 1982, 96, 181287.
(11) Rav-Acha, C.; Cohen, L. A. J . Org. Chem. 1981, 46, 4717.
(12) (a) Takeuchi, Y.; Kirk, K. L.; Cohen, L. A. J . Org. Chem. 1979,
44, 4240. (b) Hofmann, K. Imidazole and Its Derivatives; Interscience:
New York, 1953; p 128.

9450 J . Org. Chem., Vol. 63, No. 25, 1998
Hayakawa et al.
Sch em e 3
F lu or o Der iva tives. Early and extensive efforts to
achieve direct or classical fluorination of the imidazole
ring proved fruitless and led to our development of the
photochemical Balz-Schiemann reaction.16 The complex-
ity of the reaction and the consistently low yields,
however, first discouraged us from attempting the con-
version of nitro to fluorine in the presence of the trifluo-
romethyl group. The alternative route, photochemical
trifluoromethylation, seemed equally unpromising since
strongly electronegative substituents (NO2, CF3, etc.) had
been found to deactivate the imidazole ring toward attack
by the electrophilic trifluoromethyl radical. Despite its
high electronegativity, however, the fluoro substituent
was thought capable of stabilizing an intermediate radi-
cal adduct (A) (Scheme 3) by lone pair overlap, in parallel
to its ability to stabilize a carbocation (σp ) -0.07).
Indeed, photochemical trifluoromethylation of 4-fluor-
oimidazole (10, Scheme 3) gave a mixture which, accord-
ing to 19F NMR, contained the isomers 11 and 12 in the
ratio 27:73. These isomers were readily separated on a
silica gel column to give 11 (14%) and 12 (23%).
For comparison, the photochemical Balz-Schiemann
reaction was applied to 7 (Scheme 3), and 12 was
obtained in 8% yield. While the latter route was useful
in confirming the structure assigned to 12, it appears to
be less favorable than the first route starting with 10.
Upon consideration, however, of the limitation in yield
in the synthesis of 6 (47%)4a (the precursor of 7) or of 10
(20-30%),16 the routes from these alternative starting
materials overall are actually quite competitive. Ironi-
cally, both routes make use of consecutive photochemical
syntheses and differ only in the order of events. Photo-
chemical trifluoromethylation of 4-fluoro-5-methylimi-
dazole (13) gave the trifluoromethyl derivative (14) in
53% yield and that of 4-fluoro-2-methylimidazole (15)
gave 4-fluoro-2-methyl-5-(trifluoromethyl)imidazole (16)
in 26% yield. None of these fluoro(trifluoromethyl)-
imidazoles showed herbicidal or pesticidal activity. In
view of the high degree of reactivity of 2-fluoroimidazole,16c
trifluoromethylation in this series was postponed for a
separate study.
strongly acidic media,13 although the neutral imidazole
is expected to be much more reactive. While the trifluo-
romethyl group reduces ring basicity sufficiently to
provide a more significant fraction of free base in strongly
acidic media, it simultaneously destabilizes the carbo-
cation intermediate. We estimate the (trifluoromethyl)-
imidazoles to be somewhat comparable to the corre-
sponding imidazoles in overall ease of nitration, and thus,
these opposing factors apparently offset one another. We
have previously noted the remarkable facilitation of
nitration when a substituent (e.g., fluorine) can simul-
taneously reduce ring basicity and stabilize a carbocation
intermediate by resonance.12a
Ch lor o Der iva t ives. The photochemical trifluoro-
methylation of 4-chloroimidazole (17) forms the isomers,
18 and 19, in a ratio of 25:75 according to 19F NMR
(Scheme 4), almost identical with that observed for
4-fluoroimidazole. The isolated yields of 18 and 19 were
14% and 39%, respectively. Photochemical trifluorom-
ethylation of 4,5-dichloroimidazole (20) gave 21 in 32%
yield. Compound 21 had been obtained previously by
fluoride exchange of the trichloromethyl analogue.9
An alternative and preferable route to 21 involved the
perchlorination of 1 with N-chlorosuccinimide at reflux
to give the intermediate trichloro[2H]imidazole (22)
(Scheme 4). This was reduced to 21 with hydrogen
sulfide, with an overall yield from 1 of 76%. That 22 has
the structure shown was demonstrated by a sequential
methanolysis and hydrolysis to give 23. The symmetry
of 23 was confirmed by its IR and 13C NMR spectra, and
the 19F NMR spectrum shows a CF3 signal on the sp3
carbon. The structure assigned to 23 was confirmed by
Photochemical trifluoromethylation of 4-nitroimidazole
was not achieved in our initial attempts because of its
very low solubility, while 2-methyl-4-nitroimidazole gave
36% of 9.14 Thus, nitration of the preformed (trifluoro-
methyl)imidazole may be the preferred route in most
cases.5 All of the nitro(trifluoromethyl)imidazoles that
were prepared exhibit strong herbicidal activity, and
several also show toxicity to the housefly.15
(13) Austin, M. W.; Blackborow, J . R.; Ridd, J . H.; Smith, B. V. J .
Chem. Soc. 1965, 1051.
(14) The yield of 8% given in ref 4a is the result of an error in
calculation.
(15) Kimoto, H.; Fujii, S.; Muramatsu, H.; Hirata, N.; Oshio, H.;
Kamoshita, K. J pn. Pat. 61 109 702, 1986; Chem. Abstr. 1986, 105,
185869.
(16) Kirk, K. L.; Cohen, L. A. J . Am. Chem. Soc. 1971, 93, 3060. (b)
Kirk, K. L.; Cohen, L. A. J . Am. Chem. Soc. 1973, 95, 4619. (c) Kirk,
K. L.; Nagai, W.; Cohen, L. A. J . Am. Chem. Soc. 1973, 95, 8389. (d)
Kirk, K. L.; Cohen, L. A. J . Org. Chem. 1973, 38, 3647.

(Trifluoromethyl)imidazoles
Sch em e 4
J . Org. Chem., Vol. 63, No. 25, 1998 9451
Sch em e 5
Sch em e 6
half of the starting material, almost no monobrominated
product could be detected by GC-MS or by 19F NMR.
Photoreduction of 28 in 2-propanol led to the monobro-
minated products, 29 and 30, in almost equal amounts.
Iodination of 1 did not occur under a variety of mild
conditions but was achieved with a mixture of iodine and
periodic acid to give 31 in 54% yield (Scheme 6). Iodina-
tion of 6 using similar conditions gave the diiodo deriva-
tive, 32, in 82% yield. In either case, no more than a trace
of monoiodinated product could be detected. We had
previously observed that removal of one halogen atom
from the highly photosensitive diiodoimidazoles by pho-
toreduction was difficult to control, and preparation of
the monoiodo derivatives was not pursued further. All
the monobromo, dibromo, and diiodo derivatives of the
(trifluoromethyl)imidazoles show strong herbicidal activ-
ity.15
These results demonstrate that (trifluoromethyl)imi-
dazoles behave fairly typically under the conditions of
electrophilic nitration and halogenation. Of the alterna-
tive routes to the desired bifunctional and trifunctional
imidazoles, we believe electrophilic substitution on the
preformed (trifluoromethyl)imidazole to be the method
of choice in most cases. The halogenation of trifluoro-
methylated bioimidazoles and histidine peptides is an
extension of this work that we are pursuing.
X-ray crystallography.17 Small amounts of additional
methanolysis product were obtained, the structures of
which could not be assigned unambiguously.
4-(Trifluoromethyl)imidazole (6) is less reactive than
1 toward N-chlorosuccinimide and produces an insepa-
rable mixture of perchloro[4H]imidazoles (five new tri-
fluoromethyl signals are observed by 19F NMR), of which
24 may be a representative component (Scheme 4).
Reduction of the mixture of chlorinated isoimidazoles,
containing 24, gave 25 in 38% yield from 6. The literature
method for perchlorination of imidazole18a and of some
2-substituted imidazoles18b by the action of excess chlo-
rine on the imidazole hydrochloride, failed with 1 or 6.
Both 21 and 25 show strong herbicidal activity, whereas
18 and 19 are only weakly active.
Br om o a n d Iod o Der iva tives. In contrast to the
results with chlorination, bromination of 1 with excess
bromine and triethylamine occurred readily and smoothly
to give 26 in 82% yield, whereas the monobromo deriva-
tive, 27, was not detected (Scheme 5). The latter com-
pound, however, was readily obtained in 87% yield by
photoreduction of 26 in 2-propanol. In view of the
reactivity of the trifluoromethyl group in imidazoles,
removal of one bromine atom from 26 by sodium sulfite
at reflux19 was not considered. Isomer 6 was significantly
less reactive than was 1 toward dibromination, and 28
was obtained in 41% yield. Despite the recovery of nearly
Exp er im en ta l Section
Ma ter ia ls. The precursor (trifluoromethyl)imidazoles (1, 4,
6, 8) were prepared by photochemical trifluoromethylation of
the corresponding imidazoles.4a 4-Fluoroimidazoles (10, 13, 15)
were prepared from the corresponding nitroimidazoles by the
photochemical Balz-Schiemann reaction.12a,16d
(17) Morikawa, H.; Kato, K.; Kimoto, H.; Cohen, L. A. Anal. Sci.
1995, 11, 465.
(18) (a) Buchel, K. H.; Erdmann, H. Chem. Ber. 1976, 109, 1625.
(b) Buchel, K. H.; Erdmann, H. Chem. Ber. 1976, 109, 1638.
(19) Balaban, I. E.; Pyman, F. L. J . Chem. Soc. 1922, 121, 947.
An alytical Meth ods an d In str u m en tation . Melting points
are uncorrected. 1H NMR spectra were recorded at 90 MHz

9452 J . Org. Chem., Vol. 63, No. 25, 1998
Hayakawa et al.
with TMS as internal reference. 19F NMR spectra were
recorded at 84.7 MHz; positive δ values are downfield from
the external reference, trifluoroacetic acid. 13C NMR spectra
were recorded at 125 MHz. All NMR spectra were measured
in acetone-d6 unless otherwise noted. Mass spectra were
measured by electron-impact ionization at 70 eV. GC-MS
separations were performed at 100-180 °C with helium carrier
gas and using a glass column (3 mm × 300 cm) packed with
1.5% OV-17 Chromosorb WAW DMCS (80-100 mesh). El-
emental analyses were performed by the Takarazuka Research
Center of Sumitomo Chemical Co., Ltd. and by Atlantic
Microlab, Inc., Norcross, GA. The homogeneity and identity
of each product were verified by NMR, IR, MS, GLC, and TLC.
collected by filtration. The filtrate was extracted with ethyl
acetate (3 × 50 mL), and the combined extracts were dried
and evaporated. The residual material and the white solid
were combined and crystallized from ethyl acetate-ether to
give 0.78 g (86%) of 7 as colorless plates: mp 190-192 °C; IR
(KBr) 1555 cm-1 (NO2); MS m/e 181 (M+), 165, 108, 96, 69; 1H
NMR δ 8.04 (s, 2-H); 19F NMR δ 17.1 (s, 4-CF3). Anal. Calcd
for C4H2F3N3O2: C, 26.53; H, 1.11; N, 23.21. Found: C, 26.58;
H, 1.06; N, 23.27.
2-Meth yl-5-n itr o-4-(tr iflu or om eth yl)im id a zole (9). A
solution of 2-methyl-4-(trifluoromethyl)imidazole (8, 0.90 g, 6
mmol) in a mixture of 10 mL of fuming nitric acid and 10 mL
of concentrated sulfuric acid was heated at reflux for 4 h.
Workup as above gave 0.89 g (76%) of 9 as colorless needles
from ethanol: mp 182-183.5 °C (lit.4a mp 181-183 °C); MS
m/e 195 (M+), 176 (M+ - F), 165 (M+ - NO).
4-Nitr o-2-(tr iflu or om eth yl)im id a zole (2) a n d 4,5-Din i-
tr o-2-(tr iflu or om eth yl)im id a zole (3). A solution of 2-(tri-
fluoromethyl)imidazole (1, 1.09 g, 8 mmol) in a mixture of
fuming nitric acid (5 mL, d 1.50) and concentrated sulfuric
acid (5 mL) was heated at gentle reflux for 10 min. The cooled
solution was poured into ice-water, neutralized (pH 5-6) with
20% sodium hydroxide and extracted with ethyl acetate (3 ×
200 mL). The combined extracts were dried (Na2SO4) and
evaporated. The residual material was fractionated on 100 mL
of silica gel with ether as eluent. Initial fractions gave 0.67 g
(46%) of 2 as colorless needles from ether-benzene: mp 210-
4-F lu or o-2-(tr iflu or om eth yl)im id a zole (11) a n d 4-F lu -
or o-5-(tr iflu or om eth yl)im id a zole (12). Trifluoromethyl io-
dide was bubbled into a solution of 4-fluoroimidazole (10, 0.86
g, 10 mmol) in 10 mL of methanol containing triethylamine
(0.51 g, 5 mmol)21 until the gain in weight (0.98 g) cor-
responded to 5 mmol of the iodide. The solution was placed in
a quartz tube (1 × 20 cm, 16 mL) and was irradiated by a 60
W low-pressure mercury lamp with a Vycor filter22 for 3 days
at ambient temperature. The reaction mixture was analyzed
directly by 19F NMR; integration of peak areas for the
trifluoromethyl group gave a ratio of 27% for the 2-CF3 isomer
(11) and 73% for the 4-isomer (12). The reaction mixture was
evaporated to dryness under reduced pressure, the residual
material was applied to a column of 120 mL of silica gel, and
the column was eluted with ether. The initial fractions gave
0.11 g (14%) of 11 as a colorless powder after sublimation: mp
132-134 °C; MS m/e 154 (M+), 134 (M+ - HF), 107, 86; 1H
NMR δ 7.00 (d, J ) 8 Hz, 5-H); 19F NMR δ 13.6 (d, 3, J ) 1
Hz, 2-CF3) and -59.7 (d-q, 1, J ) 8 and 1 Hz, 4-F); HRMS
calcd for C4H2F4N2 154.0154, found: 154.0150. Anal. Calcd for
C4H2F4N2: C, 31.18; H, 1.31; N, 18.18. Found: C, 31.24; H,
1.28; N, 18.27. Continued elution of the column gave 0.18 g
(23%) of 12 as colorless plates from benzene: mp 108-110 °C;
MS m/e 154 (M+), 135 (M+ - F), 134 (M+ - HF), 107, 96, 86,
69; 1H NMR δ 7.62 (br s, 2-H); 19F NMR δ 19.2 (d-d, 3, J ) 10
and 0.3 Hz, 5-CF3) and -54.1 (q, 1, J ) 10 Hz, 4-F); HRMS
calcd for C4H2F4N2 154.0154, found 154.0157. Anal. Calcd for
C4H2F4N2: C, 31.18; H, 1.31; N, 18.18. Found: C, 31.13; H,
1.25; N, 18.31. Further elution of the column allowed recovery
of unreacted 10, which compound is not easily accessible.
Alter n a te Syn th esis of 12. A sample of 7 (1.81 g, 10 mmol)
was reduced with zinc dust to the amine, the amine was
diazotized with nitrous acid, and the diazonium salt was
subjected to photochemical fluorination via the Balz-Schi-
emann reaction, as described below for the synthesis of 15.
Following adjustment of the reaction mixture to pH 5-6, the
product was recovered by extraction with 3 × 200 mL of ether.
Ether was used as the eluent for silica gel chromatography.
The product was purified by sublimation (10 mmHg, 100-150
°C) and then recrystallized from benzene to give 0.12 g (7.8%)
of 12 as colorless plates, mp 108-110 °C.
1
211.5 °C; IR (KBr) 1540 cm-1 (NO2); H NMR δ 8.38 (s, H-5);
19F NMR δ 13.3 (s, 2-CF3); MS m/e 181 (M+), 162 (M+ - F),
108, 96, 69. Anal. Calcd for C4H2F3N3O2: C, 26.53; H, 1.11; N,
23.23. Found: C, 26.76; H, 1.21; N, 22.99.
Continued elution of the column gave 0.89 g (39%)20 of the
sodium salt of 3 (positive flame test) as pale yellow needles or
plates from ethyl acetate-benzene: mp 283-286 °C dec; IR
(KBr) 1550 cm-1 (NO2); 19F NMR δ 13.2 (s, 2-CF3); 13C NMR δ
121.0 (q, J ) 3.5 Hz, CF3), 138.2 (q, J ) 0.5 Hz, C-2), 140.5 (s,
C-4 and C-5); EI MS of this material gave no signal under a
variety of conditions; CI MS (NH3) 249 (M+ + Na +1).
Evidently, the sodium salt of 3 not only is soluble in ethyl
acetate and ether but also is volatilized as the salt in MS. Anal.
Calcd for C4F3N4O4Na‚2H2O: C, 16.91; H, 1.42; N, 19.72.
Found: C, 16.80; H, 1.44; N, 19.49. Water of hydration was
not lost by drying in vacuo at 100 °C. No residual ash was
found during combustion analysis, possibly because the com-
pound explodes on burning. Crystal structure analysis of this
interesting sodium salt was unsuccessful because of its
instability under X-ray irradiation.
The free acid (3) was obtained by solution of the salt in
concentrated hydrochloric acid, evaporation of the solution to
dryness, and repeated extraction of the residual material with
ethyl acetate. The extract was dried (Na2SO4) and evaporated
to give colorless plates: mp 92-93 °C; 19F NMR δ 13.2 (s,
2-CF3); 13C NMR δ 118.4 (q, J ) 3.6 Hz, CF3), 133.3 (q, J )
0.6 Hz, C-2), 136.6 (s, C-4 and C-5); MS m/e 226 (M+), 207
(M+ - F); HRMS calcd for C4HF3N4O4 225.9950 (M+), 206.9965
(M+ - F), found 225.9986 (M+), 206.9966 (M+ - F). In 12 N
HCl or 50% H2SO4, λmax 288 nm (log ꢀ 3.80); in H2O or 1 N
NaOH, λmax 330 nm (log ꢀ 3.76). Spectroscopic determination
of pKa (based on varying dilutions of HCl) provided an
approximate value of -1.9.
5-Meth yl-4-n itr o-2-(tr iflu or om eth yl)im id a zole (5). Ni-
tration of 4-methyl-2-(trifluoromethyl)imidazole (4, 0.45 g, 3
mmol) under the same conditions as for 1 gave 0.12 g (21%) of
5 as colorless needles from ether-benzene: mp 193-196 °C;
IR (KBr) 1545 cm-1 (NO2); MS m/e 195 (M+), 176 (M+ - F);
1H NMR δ 2.70 (s, 5-CH3); 19F NMR σ 13.2 (s, 2-CF3). Anal.
Calcd for C5H4F3N3O2: C, 30.78; H, 2.07; N, 21.54. Found: C,
30.53; H, 2.07; N, 21.39.
5-Nitr o-4-(tr iflu or om eth yl)im id a zole (7). A solution of
4-(trifluoromethyl)imidazole (6, 0.68 g, 5 mmol) in a mixture
of 10 mL of fuming nitric acid and 10 mL of concentrated
sulfuric acid was heated at reflux for 24 h. The cooled solution
was poured into ice-water and was neutralized (pH 5-6) with
20% sodium hydroxide. A white solid separated and was
4-F lu or o-5-m eth yl-2-(tr iflu or om eth yl)im id a zole (14).
Photochemical trifluoromethylation of 4-fluoro-5-methylimi-
dazole (13, 0.50 g, 5 mmol) was performed as described for 10
and gave 0.224 g (53%) of 14 as colorless plates from ether:
mp 149-150 °C; MS m/e 168 (M+), 167 (M+ - H), 149 (M+
-
1
F), 147; H NMR δ 2.21 (dq, J ) 1.0 Hz, 5-CH3); 19F NMR δ
14.0 (m, 3, CF3) and -65.7 (q, 1, J ) 1.0 Hz, 4-F); HRMS calcd
for C5H4F4N2 168.0311, found 168.0315. Anal. Calcd for
C5H4F4N2: C, 35.73; H, 2.40; N, 16.67. Found: C, 35.62; H,
2.33; N, 16.64.
(21) The addition of excess triethylamine had been found to reduce
yields in photochemical perfluoroalkylation. Apparently, the perfluo-
roalkyl radical is diverted from the desired reaction by abstracting a
hydrogen atom from the amine to form the corresponding H-perfluo-
roalkane.
(22) A Vycor filter was used to cut off light below 200 nm; short-
wavelength radiation was found to promote side reactions and polym-
erization.
(20) Reflux of the original reaction mixture for 30 min increases the
yield of 3 (as its sodium salt) to 65%.

(Trifluoromethyl)imidazoles
J . Org. Chem., Vol. 63, No. 25, 1998 9453
1
4-F lu or o-2-m eth ylim id a zole (15). The following proce-
dure is patterned after the syntheses of other fluoroimida-
zoles12a,16d with some modifications. A solution of 2-methyl-4-
nitroimidazole (5.08 g, 40 mmol) in tetrafluoroboric acid (42%,
200 mL) was cooled to -10 °C, and zinc dust (5.08 g, 130 mmol)
was added in portions of ca. 0.1 g with rapid stirring. Each
addition was made only after the prior portion had dissolved
and the temperature had fallen to at least -5 °C. The addition
required ca. 1 h. Small aliquots were removed, diluted with
water, and examined by UV. Total loss of the chromophore at
310 nm was taken to indicate complete reduction. A solution
of sodium nitrite (2.04 g, 44 mmol) in 10 mL of water was then
added dropwise. The resulting solution of the diazonium
compound was diluted to 380 mL with cold 42% tetrafluoro-
boric acid and was irradiated under argon in a Pyrex immer-
sion-well photoreactor using a 400 W high-pressure mercury
lamp (Riko 400-HA).23 After 90 min, the diazonium chro-
mophore at 280 nm had disappeared. The solution was cooled
to -10 °C with dry ice, neutralized slowly with 25% aqueous
sodium hydroxide to pH 5-6, and extracted with 5 × 200 mL
of ethyl acetate. The combined extracts were dried (Na2SO4)
and evaporated. The residual material was purified on 100 mL
of silica gel with ethyl acetate as eluent to give 1.06 g (27%)
of 15 as a colorless powder: mp 142-144 °C (lit.12a mp 142-
143 °C); MS m/e 100 (M+), 99, 86, 72, 58.
and 170 (M+), 152 and 150 (M+ - HF), 125, 123; H NMR δ
7.37 (s, 5-H); 19F NMR δ 13.6 (s, 2-CF3). Anal. Calcd for C4H2-
ClF3N2: C, 28.17; H, 1.18; N, 16.43. Found: C, 28.29; H, 1.17;
N, 16.39. Continued elution gave 19 (0.66 g, 39%) as colorless
needles from ether: mp 158-159 °C; MS m/e 172 and 170 (M+),
153 and 151 (M+ - F), 152 and 150 (M+ - HF), 145, 143, 115;
1H NMR δ 7.82 (s, 2-H); 19F NMR δ 17.3 (s, 5-CF3). Anal. Calcd
for C5H4F4N2: C, 28.17; H, 1.18; N, 16.43. Found: C, 28.25;
H, 1.20; N, 16.49.
4,5-Dich lor o-2-(tr iflu or om eth yl)im id a zole (21). Similar
photochemical trifluoromethylation of 4,5-dichloroimidazole
(20, 1.10 g, 8 mmol) gave 0.26 g (32%) of 21 as colorless plates
from benzene: mp 188-189 °C (lit.9 mp 186-188 °C); MS m/e
208, 206, and 204 (M+), 186, 184, 176, 123; 19F NMR δ 13.2 (s,
2-CF3).
4,5-Dich lor o-2-(tr iflu or om eth yl)im idazole (21) by Ch lo-
r in a tion . To a suspension of 1 (0.544 g, 4 mmol) in 200 mL of
tetrachloromethane was added N-chlorosuccinimide (5.34 g,
40 mmol), and the mixture was heated at reflux with stirring
for 10 h. The solution was cooled to ambient temperature and
was aerated with argon for 1 h. A white solid (consisting of
succinimide and N-chlorosuccinimide) was removed by filtra-
tion. The filtrate was evaporated to dryness, and the residual
material was dissolved in acetonitrile (200 mL). Passage of
hydrogen sulfide through the solution for 2 h resulted in the
separation of a pale yellow solid (sulfur), which was removed
by filtration. The filtrate was evaporated, and the residual
material was purified on 100 mL of silica gel, with dichlo-
romethane-hexane (1:1) as eluent. Pale yellow crystals were
obtained, which were recrystallized from benzene to give 0.62
g (76%) of 21 as colorless plates, mp 188-189 °C.
2,5-Dich lor o-4-(tr iflu or om eth yl)im id a zole (25). Chlo-
rination of 6 (1.36 g, 10 mmol) with 13.4 g (100 mmol) of
N-chlorosuccinimide and subsequent reduction with H2S,
following the procedure described for 21, gave 0.78 g (38%) of
25 as pale yellow needles from chloroform-cyclohexane: mp
135-139 °C: MS m/e 208, 206 and 204 (M+), 189, 187, and
185 (M+ - F), 188, 186, and 184 (M+ - HF), 151 and 149 (M+
- HF - Cl); 19F NMR δ 16.7 (s, 4-CF3). Anal. Calcd for C4-
HCl2F4N2: C, 23.44; H, 0.49; N, 13.67. Found: C, 23.55; H,
0.45; N, 13.74.
4-F lu or o-2-m eth yl-5-(tr iflu or om eth yl)im id a zole (16).
Photochemical trifluoromethylation of 4-fluoro-2-methylimi-
dazole (15, 1.00 g, 10 mmol) was performed as described above
for 10 and gave 0.22 g (26%) of 16 as colorless plates from
ethyl acetate-benzene: mp 179-181 °C; MS m/e 168 (M+),
149 (M+ - F), 148 (M+ - HF), 147, 121, 86, 72; 1H NMR δ
2.33 (q, J ) 0.8 Hz, 2-CH3); 19F NMR σ 19.4 (dq, 3, J ) 11 and
0.8 Hz, 5-CF3) and -63.6 (q, 1, J ) 11 Hz, 4-F). Anal. Calcd
for C5H4F4N2: C, 35.73; H, 2.40; N, 16.67. Found: C, 35.82;
H, 2.41; N, 16.73.
Ch lor in a tion of Im id a zole. To a solution of imidazole (34
g, 0.5 mol) in 300 mL of chloroform was added slowly a solution
of chlorine (7.1 g, 0.1 mol) in 100 mL of chloroform. An
exothermic reaction occurred, and a white precipitate was
generated. The reaction mixture was stirred for 1 h, stored
overnight at ambient temperature, and then poured into
aqueous sodium bisulfite. The organic layer was separated,
and the water layer was extracted with ethyl acetate (3 × 150
mL). The combined organic layers were dried (Na2SO4) and
evaporated. The residual material was fractionated on 180 mL
of silica gel with ether as eluent. Initial fractions gave 1.33 g
(19%) of 4,5-dichloroimidazole (20) as colorless plates from
benzene, mp 181-182 °C (lit.24 mp 179-180 °C, lit.25 mp 180-
181 °C).26 Further elution gave 2.58 g (25%) of 4-chloroimida-
zole (17) as colorless plates from ethyl acetate-ether, mp 119-
119.5 °C (lit.24 mp 117-118 °C, lit.25 mp 115-117 °C).
4-Ch lor o-2-(tr iflu or om eth yl)im id a zole (18) a n d 4-Ch lo-
r o-5-(tr iflu or om eth yl)im id a zole (19). Into a solution of 17
(2.05 g, 20 mmol) and triethylamine (1.01 g, 10 mmol) in
methanol (20 mL) was bubbled trifluoromethyl iodide until
1.96 g (10 mmol) had been absorbed. The solution, in a quartz
tube, was irradiated for 3 days by a low-pressure, 60 W
mercury lamp. The reaction mixture was analyzed directly by
19F NMR; integration of peak areas gave the ratio of com-
pounds 18 and 19 as 1:3, respectively. The reaction mixture
was evaporated to dryness, and the residual material was
fractionated on 180 mL of silica gel with ether-ethyl acetate
(1:1) as eluent. The first fractions gave 0.24 g (14%) of 18 as
colorless plates from benzene: mp 142-144 °C; MS m/e 172
Isola t ion a n d Met h a n olysis/H yd r olysis of 2,4,5-Tr i-
ch lor o-2-(tr iflu or om eth yl)[2H]im id a zole (22). To a sus-
pension of 1 (1.36 g, 10 mmol) in 150 mL of ethanol-free
chloroform27 was added N-chlorosuccinimide (4.01 g, 30 mmol),
and the mixture was heated at reflux for 4 h. The reaction
mixture was evaporated to dryness, and the residual material
was purified on 180 mL of silica gel with ether as eluent. There
was obtained 1.98 g (containing solvent) of 22 as a colorless
oil with a penetrating chlorine-like odor: IR (neat) 1568 and
1595 cm-1 (CdN); MS m/e 244, 242, 240, and 238 (M+), 207,
205, and 203 (M+ - Cl), 186, 184, 179, 177, 123, 85, 83, 69;
19F NMR δ 1.3 (s, 2-CF3). Continued elution of the column gave
0.40 g (20%) of 21, which was followed by recovery of 0.26 g
(19%) of 1.
The crude 22 was added to 20 mL of methanol; the solution
was stirred, and an exothermic reaction occurred. After the
solution had reacted for 10 min, an effort was made to isolate
a
characterizable reaction product, without success. The
solution was then evaporated and the residual material was
dissolved in 10 mL of water. The solution was neutralized with
sodium hydroxide and evaporated to dryness. The residual
material was fractionated on 120 mL of silica gel with ether
as eluent to give 1.24 g (63% based on 1) of 2-methyl-2-
(trifluoromethyl)tetrahydroimidazole-4,5-dione (23) as colorless
plates from chloroform: mp 193-195 °C; IR (KBr) 1775 cm-1
(CdO); MS m/e 198 (M+), 167 (M+ - OCH3), 155, 139, 129 (M+
(23) The earlier synthesis made use of a medium-pressure mercury
lamp and a quartz photoreactor. If a high-pressure mercury lamp is
used, a more readily available Pyrex reaction vessel is acceptable
because sufficient energy is transmitted in the absorption range of the
diazonium salt beyond 300 nm.
(24) Lutz, A. W.; DeLorenzo, S. J . Heterocycl. Chem. 1967, 4, 399.
(25) Imbach, J . L.; J acquier, R.; Romane, A. J . Heterocycl. Chem.
1967, 4, 451.
- CF3), 127, 107, 98, 96, 69; H NMR δ 3.36 (s, 2-OCH3); 19F
1
NMR δ -7.1 (s, 2-CF3); 13C NMR (CD3OD) δ 125.0 (q, J ) 3.6
Hz, CF3), 163.7 (s, OCH3), 94.0 (s, CdO’s). Anal. Calcd for
C5H5F3N2O3: C, 30.32; H, 2.54; N, 14.14. Found: C, 30.36; H,
2.56; N, 14.06.
(26) Although chlorination of imidazole with N-chlorosuccinimide
in chloroform was also achieved, separation of the product from
succinimide proved extremely tedious, even on a small scale.
(27) Commercial chloroform was washed three times with water,
dried over MgSO4, distilled, and stored over molecular sieves (4A).

9454 J . Org. Chem., Vol. 63, No. 25, 1998
Hayakawa et al.
4,5-Dibr om o-2-(tr iflu or om eth yl)im id a zole (26). To a
solution of 1 (272 mg, 2 mmol) in 40 mL of chloroform and 10
mL of methanol were added triethylamine (404 mg, 4 mmol)
and a solution of bromine (400 mg, 5 mmol) in 10 mL of
chloroform. The reaction mixture was left at ambient temper-
ature for 30 min and then was poured into 50 mL of cold, 10%
aqueous sodium bisulfite. The organic layer was separated,
and the water layer was extracted with ethyl acetate (2 × 50
mL). The combined organic layers were dried and evaporated.
The residual material was purified on 100 mL of silica gel by
elution with dichloromethane. Recrystallization from cyclo-
hexane gave 480 mg (82%) of 26 as colorless prisms: mp
190.5-191.5 °C (lit.10 mp 174-179 °C): MS m/e 296, 294, and
5-Br om o-4-(tr iflu or om eth yl)im id a zole (29) a n d 2-Br o-
m o-4-(tr iflu or om eth yl)im id a zole (30). A solution of 28
(1.47 g, 5 mmol) in 5 mL of 2-propanol was irradiated for 3
days in a quartz tube (10 × 200 mm). Direct analysis by 19F
NMR showed the ratio of 28:29:30 to be 31:36:33. The mixture
was fractionated on 120 mL of silica gel, eluting first with ether
and then with ether-ethyl acetate (1:1). The first compound
eluted was unreacted 28. Continued elution gave 30, which
was recrystallized as colorless plates from benzene (0.31 g,
29%): mp 185-187 °C; MS m/e 216 and 214 (M+), 197 and
1
195 (M+ - F), 196 and 194 (M+ - HF), 108; H NMR δ 7.72
(q, J ) 1.3 Hz, 4-H); 19F NMR δ 14.8 (q, J ) 1.3 Hz, 5-CF3).
Anal. Calcd for C4H2BrF3N2: C, 22.35; H, 0.94; N, 13.03.
Found: C, 22.48; H, 1.09; N, 13.02.
292 (M+), 276, 274, and 272 (M+ - HF), 195 and 193 (M+
HF-Br), 120, 118, 69; 19F NMR δ 13.1 (s, 2-CF3).
-
The third compound eluted was 29, recrystallized from
ether-benzene as colorless plates (0.33 g, 31%): mp 196-198
°C; MS m/e 216 and 214 (M+), 197 and 195 (M+ - F), 196 and
194 (M+ - HF), 135, 115, 108; 1H NMR δ 7.95 (s, 2-H); 19F
NMR δ 17.2 (s, 5-CF3). Anal. Calcd for C4H2BrF3N2: C, 22.35;
H, 0.94; N, 13.03. Found: C, 22.40; H, 1.02; N, 12.85.
2,5-Dibr om o-4-(tr iflu or om eth yl)im id a zole (28). Reac-
tion of 6 (680 mg, 5 mmol) with bromine (1.92 g, 12 mmol)
was performed as for 1, but the reaction mixture was left at
ambient temperature for 20 h. Workup gave 600 mg (41%) of
28 as colorless prisms from cyclohexane: mp 166-168 °C (lit.10
mp 162-164 °C); MS m/e 296, 294, and 292 (M+), 276, 274
and, 272 (M+ - HF), 215 and 213 (M+ - Br), 195 and 193 (M+
- HF-Br), 134, 133; 19F NMR δ 16.5 (s, 4-CF3). Continued
elution of the silica gel column gave 320 mg of recovered 6.
Bromination of 6 was also performed in acetic acid in the
absence of a base: to a solution of 6 (680 mg, 5 mmol) in 20
mL of acetic acid was added a solution of 3.2 g bromine (20
mmol) in 2 mL of chloroform. The solution was heated at reflux
for 8 h. The cooled reaction mixture was poured into 100 mL
of 10% aqueous sodium bisulfite containing ice, and the
mixture was extracted with 3 × 100 mL of ethyl acetate. The
combined extracts were dried (Na2SO4) and evaporated. Re-
sidual acetic acid was largely removed by several evaporations
with hexane at aspirator pressure. The residual material was
fractionated on 100 mL of silica gel with dichloromethane as
eluent, to give 750 mg (51%) of 28 and 41% of recovered 6.
4-Br om o-2-(tr iflu or om eth yl)im id a zole (27). A solution
of 26 (588 mg, 2 mmol) in 2 mL of 2-propanol was divided into
two quartz NMR tubes, and the solutions were irradiated for
2 days with a low-pressure mercury lamp (60 W with a Vycor
filter). The reaction mixture was analyzed directly by 19F
NMR: integration showed the ratio of 26:27 to be 12:88. The
solvent was evaporated and the residual material was purified
on 100 mL of silica gel with ether as eluent. Recrystallization
from benzene gave 374 mg (87%) of 27 as colorless needles:
mp 139-140 °C; MS m/e 216 and 214 (M+), 196 and 194 (M+
- HF), 169, 167, 115 (M+ - HF - Br), 108, 69; 1H NMR δ
7.48 (s, 5-H); 19F NMR δ 13.9 (s, 2-CF3). Anal. Calcd for C4H2-
BrF3N2: C, 22.35; H, 0.94; N, 13.03. Found: C, 22.30; H, 0.97;
N, 12.93.
4,5-Diiod o-2-(tr iflu or om eth yl)im id a zole (31). To a solu-
tion of 1 (0.68 g, 5 mmol) in 15 mL of acetic acid were added
iodine (3.81 g, 15 mmol), periodic acid dihydrate (2.28 g, 10
mmol), and chloroform (5 mL). The mixture was heated at
reflux with stirring for 3 h. The cooled reaction mixture was
poured into 10% aqueous sodium bisulfite containing ice, and
the mixture was extracted with 3 × 50 mL of ethyl acetate.
The combined extracts were dried (Na2SO4) and evaporated.
The residual material was purified on 100 mL of silica gel with
10% ether in dichloromethane as eluent. The eluate was
recrystallized from chloroform-ether to give 1.04 g (54%) of
31 as colorless grains: mp 238-240 °C dec; MS m/e 388 (M+),
261 (M+ - I); 19F NMR δ 13.6 (s, 2-CF3). HRMS m/e calcd for
C4HF3I2N2 387.8183 (M+), 368.8199 (M+ - F), 260.9137 (M+
- I), found 387.8149 (M+), 368.8213 (M+ - F), 260.9088 (M+
- I). Anal. Calcd for C4HF3I2N2: C, 12.39; H, 0.26; N, 7.22.
Found: C, 12.61; H, 0.22; N, 7.42.
2,5-Diiod o-4-(t r iflu or om et h yl)im id a zole (32). Com-
pound 6 (0.68 g, 5 mmol) was iodinated as for 1 with reflux
for 8 h to give 1.58 g (82%) of 32 as colorless plates from
chloroform: mp 191-194 °C dec; MS m/e 388 (M+), 261 (M+
- I), 134 (M+ - I2); 19F NMR δ 16.8 (s, 5-CF3). HRMS m/e
calcd for C4HF3I2N2 387.8183 (M+), 368.8199 (M+ - F),
260.9137 (M+ - I), found 387.8139 (M+), 368.8204 (M+ - F),
260.9096 (M+ - I). Anal. Calcd for C4HF3I2N2: C, 12.39; H,
0.26; N, 7.22. Found: C, 12.69; H, 0.16; N, 7.44.
J O9814952