Acyl azolium fluorides for room temperature nucleophilic aromatic fluorination of chloro- and nitroarenes

Article abstract of DOI:10.1021/acs.orglett.5b00538

The reaction of acid fluorides with N-heterocyclic carbenes (NHCs) produces anhydrous acyl azolium fluorides. With appropriate selection of acid fluoride and NHC, these salts can be used for the room temperature S_NAr fluorination of a variety of aryl chlorides and nitroarenes.

Full text of DOI:10.1021/acs.orglett.5b00538

Letter
pubs.acs.org/OrgLett
Acyl Azolium Fluorides for Room Temperature Nucleophilic Aromatic
Fluorination of Chloro- and Nitroarenes
Sarah J. Ryan,† Sydonie D. Schimler,† Douglas C. Bland,‡ and Melanie S. Sanford*,†
†Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
‡Process Science, Dow Chemical Company, 1710 Building, Midland, Michigan 48674, United States
S
* Supporting Information
ABSTRACT: The reaction of acid fluorides with N-heterocyclic carbenes
(NHCs) produces anhydrous acyl azolium fluorides. With appropriate
selection of acid fluoride and NHC, these salts can be used for the room
temperature SNAr fluorination of a variety of aryl chlorides and nitroarenes.
Scheme 1. Soluble Anhydrous Fluoride Sources for SNAr
Fluorination
he incorporation of fluorine atoms into biologically active
Tmolecules can significantly improve properties such as
bioavailability, lipophilicity, and metabolic stability.1 As a result,
fluorinated molecules, particularly fluorinated aromatics and
heteroaromatics, are common features of both pharmaceuticals
and agrochemicals.1,2 Nucleophilic aromatic fluorination
(SNAr) is a common method for the large-scale preparation
of fluorinated aromatics/heteroaromatics.3 SNAr fluorination is
typically achieved via the reaction of an electron-deficient aryl
chloride or nitroarene with an anhydrous alkali metal fluoride
salt. These reactions often require elevated temperatures (>130
°C) and long reaction times (>12 h) due to the low solubility
and trace water content of the metal fluoride salts. These
forcing conditions limit functional group tolerance and can lead
to undesired side reactions. In principle, the use of a more
soluble, anhydrous fluoride reagent, such as a tetraalkylammo-
nium fluoride, should enable milder reaction conditions.
However, such salts are generally only available as hydrates
and often decompose upon dehydration in the solid state.4
In 2005, Sun and DiMagno reported an elegant strategy for
the in situ generation of tetrabutylammonium fluoride from
hexafluorobenzene (C6F6) and tetrabutylammonium cyanide
(Scheme 1a).5 This procedure forms a highly soluble and
rigorously anhydrous source of fluoride (TBAFanh) that
participates in many SNAr reactions at room temperature.6 Our
group has subsequently applied TBAFanh for the room
temperature SNAr fluorination of a variety of biologically
relevant 3- and 5-fluoropyridines (Scheme 1).7 This trans-
formation enables SNAr fluorination within 10 min under mild
conditions in several process-chemistry friendly solvents.
However, despite these advantages, the high cost of C6F6 and
toxicity associated with cyanide limits the potential for process
chemistry applications. In addition, the inaccessibility of 18F
labeled C6F6 precludes translation to radiolabeling applica-
tions.8
To start addressing these limitations, we have focused on
developing alternative approaches to soluble, anhydrous
fluoride for low temperature SNAr reactions. The reaction of
acid fluorides with N-heterocyclic carbenes (NHCs) is known
to produce acyl azolium fluoride salts (Scheme 1b).9 In this
report, we demonstrate that these acyl azolium fluorides can be
used as anhydrous fluoride sources for the room temperature
SNAr fluorination of a variety of aryl chlorides and nitro-
arenes.10 Furthermore, we demonstrate that the reactivity of the
acyl azolium fluorides is strongly dependent on the structure of
both the NHC and the acid fluoride used in this reaction.
Several recent reports have demonstrated that N-heterocyclic
carbenes and acid fluorides react rapidly at room temperature
to afford acyl azolium fluorides (AAFs).9 We hypothesized that
Received: February 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00538
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
these AAFs should serve as soluble, anhydrous fluoride sources
that could be exploited for room temperature SNAr reactions.
Importantly, acid fluorides are available from inexpensive
carboxylic acid chlorides and HF or KF,11 making them
relatively affordable fluoride sources.12 In addition, a
straightforward route to 18F-labeled acyl fluorides has recently
been reported,13 which could ultimately enable the translation
of this chemistry to PET tracer synthesis.
Our initial studies focused on the use of AAFs for the SNAr
fluorination of 4,5-dichloropicolinate 1. For comparison, we
have previously shown that 1 reacts with 4 equiv of TBAFanh to
form the difluorinated product 3 in 79% yield within 24 h at 25
°C in DMF.7 We first examined the reaction of 1 with the AAF
generated from the combination of benzoyl fluoride and
carbene A9 (eq 1). Benzoyl fluoride, A, and 1 were combined in
We reasoned that the nitrogen substituents of the NHC
might also impact the reaction, possibly by modulating the
solubility and/or stability of the AAF intermediate. Indeed,
changing from 2,6-di-iPr phenyl substituents (in A) to iPr
substituents (in C) led to a substantial increase in the yield of 2
(from 5% to 44%). The best results were obtained with carbene
D, which bears methyl groups on the imidazolium ring and iPr
substituents on the nitrogens. With D, the starting material 1
was completely consumed, and the difluorinated product 3 was
formed in 57% yield, along with 10% of 2.
Further optimization was carried out using the 5-
chloropicolinate 4. Substrate 4 is considerably less reactive
than 1 toward SNAr fluorination. For example, 4 does not react
at all with carbenes A−C/benzoyl fluoride over 16 h at room
temperature. However, the reaction of 1 equiv of 4 with 3 equiv
of D and 3 equiv of benzoyl fluoride afforded a 75% yield of the
fluorinated product 5 after 16 h at 25 °C in DMF (Table 1,
Table 1. Effect of Acid Fluoride Structure on Conversion of
4 to 5
a
entry
R
equiv of D
equiv ArC(O)F
yield of 5
1
2
3
4
5
H
3
3
3
2
1
3
3
3
2
1
75%
9%
CF3
anhydrous DMF, and the resulting deep red solution was
stirred for 16 h at room temperature. Analysis of the crude
reaction mixture by 19F NMR spectroscopy showed the
formation of the monofluorinated product 2 in 5% yield as
an approximately 1:1 mixture of isomers. The difluorinated
product 3 was not detected. The experiment suggests that
AAFs can participate in room temperature SNAr reactions.
We hypothesized that reactivity could be enhanced by
changing the structure of the NHC. Several literature reports
have shown that the hydrogens on the imidazolium ring (H1 in
Figure 1) can serve as hydrogen bond donors.10,14 A hydrogen
OMe
OMe
OMe
99%
89%
81%
a
Yields determined by 19F NMR analysis of the crude reaction
mixtures.
entry 1). Analysis of the reaction mixture by GCMS showed
that the mass balance is unreacted 4. Changing the acid fluoride
to the more electrophilic p-trifluoromethylbenzoyl fluoride led
to a dramatic decrease in the yield of 5 (to 9%, entry 2). In
contrast, the use of the more electron-rich p-methoxybenzoyl
fluoride resulted in quantitative conversion and the formation
of 5 in 99% yield as determined by 19F NMR spectroscopy
(entry 3). Using the combination of D and p-methoxybenzoyl
fluoride, the loading of carbene and acid fluoride could be
reduced to 2 equiv or even 1 equiv relative to 4 with minimal
drop-off in yield (89% and 81%, respectively). For comparison,
the SNAr fluorination of 4 with NBu4Cl/KF (2 equiv/2 equiv)
affords an 86% yield after 24 h at 130 °C.15 Using NBu4CN/
C6F6 (2 equiv/0.33 equiv), 4 is converted to 5 in 86% yield in
30 min at room temperature.7
With optimal conditions in hand, we next explored the
combination of carbene D and p-methoxybenzoyl fluoride as an
anhydrous fluoride source for the SNAr fluorination of different
substrates. As summarized in Figure 2, a variety of 5- and 4,5-
substituted chloropicolinate derivatives underwent fluorination
to form products 3 and 5−9 in modest to excellent isolated
yields. The modest yields with 4,5-dichloropicolinate substrates
are due to the formation of byproduct 21 (Figure 3).16
Methoxy, cyano, and trifluoromethyl substituents were
compatible with the reaction conditions (see products 7, 9,
12, 15, 17, and 20). In addition, other aryl halide substituents
(Cl, Br, and I) were well tolerated at less activated sites in the
molecule (see products 6, 8, 10, 14, 18, and 19). Ethyl 3,6-
Figure 1. Impact of NHC structure on the SNAr fluorination of 1 to
form 2 and 3. Conditions: 3 equiv of NHC, 3 equiv of benzoyl
fluoride, 1 equiv of 1, 16 h, 25 °C in DMF (0.2 M). Yields and product
ratios determined by 19F NMR analysis of the crude reaction mixtures.
bonding interaction with fluoride would be expected to
significantly lower its nucleophilicity. Thus, we next examined
carbene B, in which the backbone hydrogens are replaced with
methyl groups. Under otherwise identical conditions, B
provided an enhancement in the yield of the monofluorinated
product 2 (21%, Figure 1).
B
DOI: 10.1021/acs.orglett.5b00538
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Figure 4. Fluorodenitration with D and p-methoxybenzoyl fluoride.a
a General conditions: 1 equiv of nitroarene, 4 equiv of acid fluoride in
DMF (0.2 M in nitroarene), then 3 equiv of D and stir for 16 h at 25
°C. b Yield determined by 19F NMR spectroscopy.
In summary, this report demonstrates that the combination
of N-heterocyclic carbenes and acid fluorides can react to form
a fluoride source that participates in room temperature SNAr
fluorination reactions. We anticipate that this strategy will prove
more broadly applicable to methods that require anhydrous
fluoride reagents.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures and H and 13C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Figure 2. Substrate scope for conversion of aryl/heteroaryl chlorides
to fluorides with D and p-methoxybenzoyl fluoride.a a General
conditions: 1 equiv of aryl chloride, 3 equiv of D in DMF (0.2 M in
aryl chloride), then 3 equiv of acid fluoride and stir for 16 h at 25 °C.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mssanfor@umich.edu.
Notes
c
b 3 equiv of D and 4 equiv of acid fluoride, with D added last. Yield
determined by 19F NMR spectroscopy.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge Dow Chemical for support of this research.
■
REFERENCES
■
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D
DOI: 10.1021/acs.orglett.5b00538
Org. Lett. XXXX, XXX, XXX−XXX