Synthesis of aryl fluorides on a solid support and in solution by utilizing a fluorinated solvent

Article abstract of DOI:10.1002/anie.201001507

(Figure Presented) F for fast: The perfluorinated solvent C ₆F₁₄ is the key to a new variant of the BalzSchiemann reaction for the synthesis of fluorinated arenes. Triazenes are converted into fluoroarenes under mild con-ditions on a support and in solution (see scheme). The method is straightforward and inexpensive, and yields previously difficult-to-prepare fluoroarenes in high purity.

Full text of DOI:10.1002/anie.201001507

Communications
DOI: 10.1002/anie.201001507
Aromatic Fluorination
Synthesis of Aryl Fluorides on a Solid Support and in Solution by
Utilizing a Fluorinated Solvent**
Marion Dꢀbele, Sylvia Vanderheiden, Nicole Jung,* and Stefan Brꢁse*
The conversion of diazonium tetrafluoroborate salts[1–3] into
fluorinated arenes[4] was discovered more than 80 years ago
by Balz and Schiemann,[5] and is widely used owing to the
importance of fluorinated compounds in the life sciences[6]
and material science[7] in academic as well as industrial
laboratories.[8,9] This method has also found application for
the synthesis of radioactive-labeled compounds.[10]
The yields of the Balz–Schiemann reaction are moderate
to good, and a few isolated protocols achieve excellent
yields.[11] Therefore many attempts have been made to
increase the yields and to lower the reaction temperatures,
which in general correspond to the melting points of the
tetrafluoroborates, in most cases over 1008C. Some alterna-
tives rely on, for example, the exchange of the counter ion[12]
or the use of other solvents like BF3·Et2O[13] and ionic
liquids.[14] Modified conditions, for example photochemical
methods,[15,16] have also resulted in improved protocols.
Herein we describe a variant of the Balz–Schiemann
reaction which through the utilization of a perfluorinated
solvent leads to very good conversions of diazonium salts and
triazenes to provide the corresponding aryl fluorides under
mild conditions (Scheme 1). In our search for a method that
allows the application of the Balz–Schiemann reaction in
combinatorial chemistry, we tested different sets of condi-
tions. Our leitmotiv was the cleavage of triazenes to give
diazonium ions followed by their conversion in situ into the
corresponding fluoroarenes. This approach, known as Wal-
lach reaction,[17] offers some advantages over conventional
methods. First, triazenes can be stored for extended periods
without decomposition and they constitute safe alternatives
to explosive diazonium salts. For example, our DSC/TG and
DTA/TG measurements (DSC = dynamic difference calorim-
etry, DTA = differential thermoanalysis, TG = thermog-
ravimetry) on triazene 9 (see Scheme 4) gave a decomposition
temperature of 202.28C (beginning at 1368C up to 2668C,
with a loss of mass of 98%), while no reaction with O2 or H2O
takes place. The enthalpy of decomposition for 9 is deter-
mined to be roughly 40 kJgÀ1. In addition, triazene-masked
diazonium ions can be used in reaction sequences in solution
as well as on a solid support, and are thus amenable to
combinatorial methods.[18] All products of the fluorinating
cleavage should first be analyzed in terms of purity, as the
isolation of preferably pure crude products plays a pivotal
role in combinatorial chemistry.
Initial tests were conducted with resin-bound triazenes.
We used different solvents (for example, THF, DMF, MeOH)
and observed the generation of “traceless” by-products (the
reduced cleavage compound). As these compounds account
for most of the impurities in the thermal decomposition of
diazonium salts as well, we tried to suppress the reduction
through the use of a perfluorinated solvent. In perfluorohex-
ane[19] under optimized conditions, cleavage of the aromatic
compounds to give the diazonium tetrafluoroborate salts and
in situ fluorination led to the crude products in very good
purities. A comparative analysis of the yields we obtained
with our substrates with recent results of similar fluorinating
methods is given in the Supporting Information.[13,20]
Scheme 2 summarizes some attempts of the cleavage of
resin-bound aromatic compounds. The fluorinations were
performed with a reaction time of 1 hour in perfluorohexane
at 1008C. In the first step, aniline derivatives were converted
into diazonium salts through diazotization and then immobi-
lized as triazenes on N-benzylaminomethyl-functionalized
polystyrene resin. For the direct evaluation of the fluorinating
cleavage method the immobilized diazonium compounds 2
were directly cleaved from the solid support without further
derivatization. The achieved purities are very good after the
reaction was performed once on the resin. Only ortho-nitro-
und ortho-fluoro-substituted substrates did not deliver the
fluorinated compounds 3. Here either the reduced compound
or the phenol derivatives were formed. For all other
derivatives (also valid for the compounds in Scheme 3) the
side reaction yielding the reduced compound could be
suppressed. Thus, our fluorination reaction in a perfluori-
Scheme 1. Aryl fluorides 3 resulting from diazonium ion 1 and from
triazene-masked diazonium ions 2.
[*] M. Dꢀbele, S. Vanderheiden, Dr. N. Jung, Prof. Dr. S. Brꢁse
Institute of Organic Chemistry, KIT-Campus Sꢂd
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax: (+49)721-608-8581
E-mail: braese@kit.edu
S. Vanderheiden, Dr. N. Jung, Prof. Dr. S. Brꢁse
IOC-ComPlat, KIT-Campus Nord
Hermann von Helmholtz Platz 1
76344 Eggenstein-Leopoldshafen (Germany)
[**] We thank Bekir Bulat for synthetic work and Dr. Wolfgang Ebenbeck
(Saltigo) for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001507.
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step the products were cleaved from the support under
optimized reaction conditions (808C, 12 h). In this way we
could synthesize 17 different fluoroarenes, including hetero-
arenes such as 3-fluoropyridine hydrochloride (3n) and (E)-2-
(4-fluorostyryl)pyridine (3s).
The yields were good to excellent for compounds cleaved
directly from the support without further derivitization, but the
yields were lower for fluorine compounds that had required an
additional cross-coupling reaction. In subsequent experiments
the coupling reaction was performed three times to guarantee
complete conversion of the aryl iodides. The results after
cleavage of the target molecules show that the previous
moderate yields could be improved (for example 3v: one
reaction=34% yield, three reactions: 77% yield). Furthermore,
using the example of 3m we could prove that our approach is
also appropriate for reactions on a larger scale. Reaction of
2.00 g of resin gave the target compound in 81% yield.
Scheme 2. Syntheses of aryl fluorines via resin-bound arenes (GC/MS
purities of the products in brackets). c) For R1 =I: 1. ArB(OH)2,
[Pd(PPh3)4], Na2CO3, DMF, H2O, 1208C, 12 h (1–3 repetitions);
2. alkene, [Pd(PPh3)4], NEt3, DMF, 1208C, 12 h (1–3 repetitions);
3. alkyne, CuICl, [Pd(PPh3)4], NEt3, DMF, 808C, 48 h; for R1 =COCH3:
diethyl cyanomethylphosphonate, KOtBu, DMF, 808C, 12 h.
Fluorinating cleavage was also investigated in the liquid
phase. Because of the low solubility of the starting materials,
the diazonium salts 1 and the diisopropyl triazenes 5–9 were
suspended in perfluorohexane and subsequently reacted for
12 hours at 808C following the optimized protocol for the
solid-phase reaction. The examples in Scheme 4 show good
results also for solution-phase reactions, and upscaling was
nated solvent becomes the preferred method for the auto-
mated synthesis of compound libraries.
The use of a perfluorinated solvent considerably simplifies
the Balz–Schiemann reaction: various compounds can be
generated reliably in good purity, and the formation of the
reduced by-products is suppressed. This method tolerates
traces of water, and it is possible to recycle the solvent since it
can be separated readily from the resin and the supernatant.
For the isolation of a small library of fluorinated
substances we immobilized less-volatile aniline derivatives
and, additionally, resin-bound anilines were further deriva-
tized on a solid support. We chose the Horner–Wadsworth–
Emmons, Heck, Suzuki, and Sonogashira reactions to synthe-
size biaryls, cinnamic acid esters, and other arenes. In the final
[
]
*
successful as well (3ad: 69%). With regard to the planned
application of fluorinating cleavages to automated, solid-
phase synthesis this is the method of choice as no separation
from the residual diisopropyl amine is required.
The good results in perfluorohexane can be explained by
two effects. First, any side reaction of the solvent with reactive
intermediates is prevented; neither the reduced by-products
nor the chlorinated compounds that would arise in the
presence of CH2Cl2,[9] for example, form. A second effect is
Scheme 4. Aromatic fluorination in solution phase. *GC/MS purity of
the crude product. [a] Cleavage of 5–9; [b] Cleavage of 1a: 3-chloro-2-
methylbenzene diazonium salt, 1b: pyridinium-3-diazonium salt.
[*] When the reaction was performed on a 0.7 mmol scale, the yield was
69%; on a 1.8 mmol scale compound 3ad was obtained in 47%
yield; in each case the reaction time was 1 hour. Further upscaling
might require longer reaction times.
Scheme 3. Aryl fluorides isolated after cleavage from immobilized
triazenes 2. [a] Yield over one step. [b] Yield over two steps. [c] For-
mation of the ketone in acidic aqueous media.[21]
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Communications
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Using a perfluorinated solvent we could apply a new
variant of the Balz–Schiemann reaction to generate a small
library of fluorinated substances. Either triazenes that were
resin-bound or in solution could be converted under very mild
conditions, giving the corresponding aryl fluorides in good to
very good yields. This easy and cost-effective procedure
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Experimental Section
Synthesis of 3u:
Standard procedure for solid-phase synthesis according to
Scheme 1: The triazene resin 2u (150 mg, 0.678 mmolgÀ1
,
0.102 mmol) was suspended at room temperature in 4.00 mL perfluor-
ohexane and tetrafluoroboric acid diethyl ether complex (100 mg,
620 mmol) was added. The vial was sealed with a pressure-resistant
crimp top and the suspension was shaken at 808C for 12 h. After the
reaction mixture had cooled down, acetone was added and the mixture
was shaken again. The acetone layer was isolated and concentrated in
vacuo. and the aryl fluoride was purified by column chromatography
(cyclohexane(CH)/ethyl acetate (EA) 99:1–20:1). The target com-
pound 3u was obtained in 80% (16.4 mg, 0.081 mmol) yield.
Standard procedure for the solution-phase synthesis according to
Scheme 4: Triazene 6 (19.0 mg, 6.10 mmol) was suspended in 4.00 mL
perfluorohexane at room temperature and tetrafluoroboric acid diethyl
ether complex (200 mg, 1.24 mmol) was added. The vial was sealed with
a pressure-resistant crimp top, and the suspension was shaken at 808C
for 12 h. After the reaction mixture had cooled down, acetone was added
and the mixture was shaken again. The acetone layer was isolated and
concentrated in vacuo, and the residue was purified by column
chromatography (CH/EA 99:1–20:1). The target compound 3u was
obtained in 67% (8.40 mg, 4.31 mmol) yield.
[16] For an overview of fluorination with different fluorination
agents: Houben-Weyl, Vol. E10a, Thieme, Stuttgart, 1999,
pp. 686 – 740.
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[19] Fluorinert72 (CAS 355-42-0) was purchased from ABCR.
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Synthesis of 3l:
Standard procedure for the solution-phase synthesis according to
Scheme 4: Diazonium salt 1a (68.0 mg, 283 mmol) was suspended in
2.00 mL perfluorohexane at room temperature and tetrafluoroboric
acid diethyl ether complex (100 mg, 620 mmol) was added. The vial
was sealed with a pressure-resistant crimp top, and the suspension was
shaken at 808C for 12 h. After the reaction mixture had cooled down,
acetone was added and the mixture was shaken again. The acetone
layer was isolated and the purity (81%) of the target compound 3l
was determined by GC/MS analysis.
Received: March 12, 2010
Revised: April 17, 2010
[22] C. Galli, Chem. Rev. 1988, 88, 765 – 792.
Published online: July 14, 2010
[23] a) I. Szele, H. Zollinger, J. Am. Chem. Soc. 1978, 100, 2811 –
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Keywords: Balz–Schiemann reaction · combinatorial chemistry ·
.
perfluorinated solvents · solid-phase synthesis · triazenes
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