Halogen exchange (Halex) reaction of 5-iodo-1,2,3-triazoles: Synthesis and applications of 5-fluorotriazoles

Article abstract of DOI:10.1002/anie.201204979

A good exchange: 5-Iodo-1,2,3-triazoles undergo facile substitution reactions with fluoride salts, thus providing ready access to 5-fluorotriazoles (see scheme). The latter can be further elaborated with various nucleophiles to furnish fully substituted 1,2,3-triazole compounds. Copyright

Full text of DOI:10.1002/anie.201204979

Angewandte
Chemie
DOI: 10.1002/anie.201204979
Heterocycles
Halogen Exchange (Halex) Reaction of 5-Iodo-1,2,3-triazoles:
Synthesis and Applications of 5-Fluorotriazoles**
Brady T. Worrell, Jason E. Hein, and Valery V. Fokin*
Fluorinated molecules are omnipresent in pharmaceuticals
and agrochemicals,[1] materials,[2] and as imaging agents for
positron emission tomography (PET) scanning.[3] PET imag-
ing has become a widely used technique in medical diagnos-
tics in recent years. This method requires the use of a fluorine-
containing agent enriched with the 18F nucleus. This fluorine
isotope has a notoriously short half-life of 109 minutes, thus
imposing strict requirements for the speed and operational
simplicity of reactions used for its introduction into imaging
probes. Considerations of cost and practicality demand that
the fluorine is derived from simple fluoride salts (such as KF
and NaF). While methods for the late-stage introduction of
fluorine into complex molecules have been reported,[4] a new
robust process would be a useful addition to the developing
field of medical imaging, especially in light of the growing use
of the CuAAC (see below).
of methods for their postsynthetic functionalization
(Scheme 2),[12] specifically the introduction of other halides
by a halogen exchange (Halex) reaction.[13] To this end, when
Scheme 2. Postsynthetic functionalization of 5-iodotriazoles.
the iodotriazole 1 was heated in a brine solution at 1008C over
a two-day period, the complete conversion of the starting
material into a mixture of the chlorotriazole 2 and the 5-H-
1,2,3-triazole (ca. 1:3) was observed. Encouraged by this
result, we examined the exchange of different halides under
microwave-assisted conditions. We were pleased to discover
that 5-chloro- (2) and, most interestingly, 5-fluorotriazoles (3)
could be obtained in synthetically useful yields by this
method. While several other syntheses of 5-chloro-substituted
triazoles exist,[14] we found no reports describing fluorinated
(neither 4- nor 5- substituted) triazoles.[15] As a result of their
conspicuous absence in the chemical literature and the
distinct value of sp2-hybridized fluorine compounds (see
below), we focused our studies on this process. Reported
herein is a general, rapid, and operationally simple approach
for the synthesis of 5-fluoro-1,4,5-trisubstituted-1,2,3-triazoles
from the corresponding 5-iodotriazoles and the synthetic
application of this unique scaffold to regiospecifically gen-
erate previously inaccessible fully substituted triazoles.
Initial survey of the reaction conditions proved that both
basic potassium fluoride (KF) and the acidic potassium
bifluoride (KHF2) were effective as the nucleophilic fluoride
source (Scheme 3). We were pleased to discover that only
5 equivalents of KFand 7 equivalents of KHF2 were necessary
for this reaction to reach completion. In consideration of both
cost and practicality, other fluoride sources were omitted
from this study and we instead concentrated on these
inexpensive and commercial salts.
The copper(I)-catalyzed azide–alkyne cycloaddition reac-
tion[5] (CuAAC; Scheme 1a) has emerged as a powerful
method for the creation of covalent links between diverse
Scheme 1. Routes to various substituted 1,2,3-triazoles.
building blocks. The experimental simplicity and robust
nature of 1,2,3-triazole products have enabled numerous
applications of this process in synthetic and medicinal
chemistry,[6] bioconjugations,[7] materials science,[8] and poly-
mer chemistry.[9] Medical imaging has also benefited from this
process, and a number of probes containing 1,2,3-triazoles
have been described.[10] However, none of them rely on the
introduction of the fluorine atom directly appended to the
triazole heterocycle.
Recently, our group has reported the use of 1-iodoalkynes
as active cycloaddition partners with organic azides for the
regiospecific synthesis of 5-iodo-1,2,3-triazoles (Sche-
me 1b).[11] With a simple route to these halogenated hetero-
cycles in hand, we were interested in expanding the repertoire
The temperature required for this reaction was found to
be less forgiving, requiring a minimum of 1408C for the
reaction to be initiated and 1808C to drive it to completion. A
[*] B. T. Worrell, Dr. J. E. Hein, Prof. Dr. V. V. Fokin
Department of Chemistry, The Scripps Research Institute
La Jolla, CA 92037 (USA)
E-mail: fokin@scripps.edu
Homepage: http://www.scripps.edu/chem/fokin
[**] The financial support of this work by the National Science
Foundation (CHE-0848982) is gratefully acknowledged.
Scheme 3. Halogen exchange reaction of 1 to give various halogenated
1,2,3-triazoles. [a] Used KCl. [b] Used KF. Values in parentheses repre-
sent yields of isolated products. Bn=benzyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204979.
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biphasic solvent mixture of water/acetonitrile (1:1, v/v) was
effective and did not require further optimization. The use of
various cryptands, crown ethers, and polar aprotic solvents did
not accelerate or affect the efficiency of this reaction; the best
results were observed utilizing the above biphasic condi-
tions.[16] Short reaction times, only 10 minutes to reach
complete conversion, were most effective, while prolonged
heating led to decomposition of the product.
Under these optimized reaction conditions, we screened
a large variety of 5-iodo-l,2,3-triazoles for substitution with
the fluoride anion. The basic fluoride nucleophile (KF)
demonstrated good functional group compatibility: 5-iodo-
triazoles containing heterocycles (4 and 5), chloride (7), acetal
(8), N1-aryl (11) and alcohol (12) groups were smoothly
converted into the corresponding fluorinated products in
excellent yield (Scheme 4a). Utilization of the acidic fluoride
salt (KHF2) further expanded compatibility with other func-
tional groups: free amides (13 and 18), nitrile (14), ketone
(15), N-toluenesulfonyl (17), and bis(bromo)triazole (20)
moieties readily underwent this substitution reaction (Sche-
me 4b). Both of these complementary procedures produced
5-fluorotriazoles in moderate to excellent yields, and in all
cases the starting material was completely consumed. It
should be noted that an aromatic group at the 4-position of
the triazole is required for an effective transformation to the
5-fluorotriazole product, as aliphatic substituents resulted in
complex mixtures of products.[17] Alternatively, triazoles with
an aromatic substituent at N1 gave the corresponding 5-
fluorotriazole products, albeit in lower yields (e.g., 11).[18]
With a general method for the synthesis of 5-fluorotria-
zoles in hand, we examined their reactivity in SNAr-type
reactions to yield fully substituted 1,2,3-triazoles. Indeed, we
found that the sodium salts of the amide 20, alcohols 21 and
23, azole 22, and thiols 24 and 25 gave good yields of the 5-
substituted triazoles under mild reaction conditions (708C) in
THF (Scheme 5a). Although SNAr reactions of S, O, and
Scheme 5. a) SNAr reactions of 5-fluorotriazoles. [a] General reaction
conditions with NaH: 3 (1 equiv), NuH (1.5 equiv), NaH (1.5 equiv),
THF, RT to 708C, 15 h. [a] Commercial NaOMe (1.5 equiv) was used
instead. b) Unsuccessful SNAr reactions of 5-iodo-, 5-bromo-, and 5-
chlorotriazole analogues of fluorotriazole 3. [b] No reaction under the
general reaction conditions was observed (see the Supporting Informa-
tion for details). Values in parentheses represent yields of isolated
products.
N nucleophiles with 5-chlorotriazoles have been described,
they require electron-withdrawing substituents at the 4-
position (esters, amides, etc.) and do not proceed with non-
activated triazoles (e.g. 1, 2).[19] Indeed, when 5-iodo- (1), 5-
bromo- (26), and 5-chlorotriazole (2) analogues of the
fluorotriazole 3 were reacted under the general SNAr
conditions, only starting materials were recovered (Sche-
me 5b).
Scheme 4. a) Substrate scope for the halogen exchange reaction of 5-
iodotriazoles with KF. General reaction conditions with KF: 5-iodotria-
zole (1 equiv), KF (5 equiv), MeCN/H2O, 1808C, 10 min. Values in
parentheses represent yields of isolated products. b) Substrate scope
for the halogen exchange reaction of 5-iodotriazoles with KHF2.
General reaction conditions with KHF2: 5-iodotriazole (1 equiv), KHF2
(7 equiv), MeCN/H2O, 1808C, 10 min. Values in parentheses represent
yields of isolated products. Ac=acetyl, Ar=3,5-bistrifluoromethyl
benzene, Bz=benzoyl, Ts=tosyl.
To demonstrate the generality of this method, we used it
for the moderate scale synthesis of a complex molecule
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Scheme 6. Large-scale synthesis of the 5-fluorotriazole 28 and the subsequent SNAr reaction to produce the fully substituted triazole 29. Values in
parentheses represent yields of isolated products. Ar=4-tBuC6H4.
containing multiple functional groups and several stereogenic
centers. To this end, we synthesized the 5-iodotriazole 27, in
high yield and submitted it to the newly developed fluorina-
tion reaction with KHF2 (Scheme 6). The fluorinated product
28 was formed in 81% yield on a gram scale. Furthermore,
when the flurotriazole 28 was reacted under our reaction
conditions for SNAr with the sodium salt of pyrazole, the fully
substituted triazole 29 was obtained in acceptable yield. Thus,
this fluorination/substitution sequence could be employed not
only as a method for the synthesis of PET tracer molecules,
but also as a general route to various previously inaccessible
fully substituted triazoles with absolute control of regioiso-
meric purity.[20]
Interestingly, when different isomers of the triazole 1 (30
and 31) were submitted to our general halogen exchange
conditions, no fluorinated products were obtained; only
starting materials were fully recovered (Scheme 7a). We
hypothesize that the observed reactivity of only the 1,4-
substituted-5-iodotriazoles (32) in this process is its ability to
undergo ring-chain isomerization, thus resulting in the
formation of a diazo/imidoyl halide tautomer at elevated
temperature (33). Indeed, imidoyl halides (i.e. 33) are well
known to undergo halogen exchange reactions under similar
experimental conditions, specifically for the formation of
imidoyl fluorides.[21] Therefore, we postulate that the open
diazo form 33 is the intermediate reacting with the fluoride
anion. Thus, the reaction proceeds by the reversible opening
of the triazole 32 to the diazo/imidoyl iodide tautomer 33,
reversible addition of the nucleophile (FÀ) to give putative
intermediate 34, extrusion of the iodide anion giving the
intermediate 35, and final ring closure yielding the 5-
fluorotriazole product 36 (Scheme 7b). Similar to other
reactions of 1-sulfonyl-1,2,3-triazoles,[22] an aromatic group
at C4 of the triazole is necessary for the stabilization of the
open diazo form of the heterocycle (33–35). An alternative,
more familiar SNAr mechanism, proceeding through an
intermediate such as 37 (Scheme 7c), cannot be discounted
as a viable pathway at this time.
This work demonstrates that 5-iodotriazoles (e.g., 1)
efficiently engage in the halogen exchange reaction with
simple fluoride salts to produce 5-fluorotriazoles (e.g., 3).
This reaction proceeds quickly (10 min), gives bench-stable
fluorinated products, and exhibits excellent functional-group
tolerance. This previously unreported fluorinated heterocycle
is reactive in SNAr-type transformations under mild reaction
conditions and gives the corresponding fully substituted
products in excellent yields. In addition to the synthetic
utility of these heterocycles, fluorination of iodotriazoles with
hot fluoride sources (18F salts) should prove useful in the
synthesis of PET imaging probes.
Received: June 26, 2012
Revised: August 24, 2012
Published online: October 11, 2012
Keywords: click chemistry · fluorine · heterocycles ·
.
imaging agents · nucleophilic substitution
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