The trifluoromethylating sandmeyer reaction: A method for transforming C-N into C-CF3

Article abstract of DOI:10.1002/anie.201308997

A means to trifluoromethylate: The beneficial properties imparted by the trifluoromethylation of aromatic compounds continue to drive the discovery of novel reagents and reactions for the late-stage introduction of such moieties. Highlighted here is the recently discovered Sandmeyer trifluoromethylation approach, which now permits aromatic amines to be substrates in a direct trifluoromethylation strategy. Copyright

Full text of DOI:10.1002/anie.201308997

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Angewandte
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DOI: 10.1002/anie.201308997
Synthetic Methods
The Trifluoromethylating Sandmeyer Reaction: A
À
À
Method for Transforming C N into C CF **
3
Duncan L. Browne*
arenes · copper · fluorine · reaction mechanisms ·
synthetic methods
T
he presence of fluorine-containing substituents can impart
favorable properties to organic molecules. On one hand they
increase the metabolic stability of important pharmaceutical
[
1]
compounds, thus reducing dosing rates in patients. On the
other hand, they can improve switching times and broaden
the working temperature ranges in LCD devices. Perhaps
even more critical to supporting the basic needs of an ever-
growing population, is the use of fluorine substituents to
tune the rates and selectivities in agrochemical products,
[
2]
[3]
[4]
Scheme 1. Sandmeyer-type trifluoromethylation approach as reported
[7]
thus leading to both reduced quantities of material required
and increasing the reliability and yield of the desired crop per
by Wang and co-workers. TMS=trimethylsilyl.
[
5]
unit area of precious arable land. Owing to these desirable
benefits there has been a recent surge in interest to improve
the range of methods available for introducing monofluor-
omethyl, difluoromethyl, and trifluoromethyl appendages to
C, O, N, and S atoms, typically through a late-stage coupling
or alkylation, and this has also necessitated the development
3.5 equivalents of an in situ generated solution of [AgCF ],
derived from mixing AgF with the Ruppert–Prakash reagent
3
(TMSCF ) at À788C (Scheme 1). Low temperatures were
3
necessary to ensure good conversions and yields, which is
likely a result of the relative instability of diazonium chloride
salts, however diazo tetrafluoroborate salts, which are con-
sidered more stable (and typically isolable) were less reactive
[6]
of new reagents for permitting mild transformations. With
regard to coupling approaches to achieve trifluoromethyla-
tion, it has been demonstrated that CÀX (halide), CÀB, CÀSn,
[10]
under these low-temperature conditions.
The reaction
[
6]
and even CÀH bonds make suitable substrates. Still
a number of issues remain to be solved to further improve
the methods, and they include reducing the cost of the
fluorine reagent, reducing precious metal/ligand loadings, and
increasing the generality of the processes. Towards this goal,
recently, the scope of potential starting materials has been
procedure tolerates electron-withdrawing and electron-do-
nating groups, vinyl and alkynyl substituents, as well as
boronic esters and silyl moieties. Perhaps the most impressive
result, however, which proceeds in 83% yield, is the
installation of CF , ortho to an iPr group, especially when
3
one considers the appropriate steric A values: CF = 2.1 kcal
3
[
7]
[8]
À1
À1
dramatically increased. The groups of Wang, Gooßen, and
mol and iPr= 2.15 kcalmol (for reference Me = 1.7 kcal
[
9]
À1
À1 [11]
Fu have reported the CÀN to CÀCF transformation using
mol and Et = 1.75 kcalmol ).
With regards to hetero-
3
a trifluoromethylating Sandmeyer reaction, as outlined here-
in.
cycles, 3-aminopyridine is converted in 10% yield whereas
three examples of indole and one of a benzofuran are
converted in moderate to good yields (45–72%). Mechanistic
studies were conducted and strongly suggest that the reaction
does not operate by a radical mechanism. The authors
hypothesize instead that high-valent silver species mediate
an oxidative addition, reductive elimination pathway.
The general approach seeks to convert an aromatic amine
into the requisite diazonium salt before treatment with
a suitable metal and trifluoromethyl source. Wang and co-
workers reported a protocol that was successfully applied to
4
8 substrates. The optimized method employs tert-butyl nitrite
(
tBuONO) and aqueous hydrochloric acid to generate the
Gooßen and colleagues report a copper-mediated tri-
fluoromethylating Sandmeyer reaction. In their case however,
the more stable diazonium tetrafluoroborate salts are pre-
formed and isolated before being subjected to the trifluor-
omethylating conditions. The Ruppert–Prakash reagent is
aryl diazonium intermediates as chloride salts (as a solution in
ethanonitrile). This salt was subsequently treated with
[*] Dr. D. L. Browne
again used as the CF source, and is premixed with copper(I)
3
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
E-mail: db543@cam.ac.uk
thiocyanate and cesium carbonate for 10 minutes before
addition of the diazonium salt (Scheme 2). Similarly, the
reaction conditions are tolerant of electron-rich, electron-
poor, ester, amino, keto, carboxylate, cyano, and even iodo
[**] D.L.B. gratefully acknowledges support from the EPSRC (award no.
EP/K009494/1) and Prof. Steven V. Ley.
2
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Angew. Chem. Int. Ed. 2013, 52, 2 – 5
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Scheme 2. Sandmeyer-type trifluoromethylation approach as reported
[
8]
by Gooßen and co-workers.
substituents. The latter being particularly interesting as it
demonstrates the true complimentarity of this process to
existing CÀX trifluoromethylation cross-coupling methods.
Four heterocyclic examples are reported, three of which are
quinoline and one indole, and these provide the trifluoro-
methyl derivatives in moderate to good yield (46–74%). It is
presumed by Gooßen et al. that the reaction proceeds by
a radical process, which is in line with other Sandmeyer
halogenation reactions.
Scheme 4. Sandmeyer-type radical cyclization/trifluoromethylation and
preparation of leflunomide as reported by Fu and co-workers.
The group of Fu report a copper-powder-mediated
version of the reaction, thus employing Umemotoꢀs reagent
[9]
as the CF source. Here isoamyl nitrite (iAmONO) was used
3
to effect the in situ diazotization reaction (Scheme 3). The
even effective in sterically demanding instances, thus high-
lighting them as a useful tool for late-stage trifluoromethy-
lation. The reported methods offer excellent complementar-
ity to existing carbon–halide functionalization processes and
are likely to permit access to compounds that were not
previously available. Of the three methods, the protocol
described by Fu and colleagues appears to be the most
straightforward, as a one-pot operation employing reagents
and solvents straight from commercial suppliers. Improve-
ments for the future could be made both in the amount of the
metal loading and the nature of the CF -containing reagent.
3
Received: October 15, 2013
Revised: November 4, 2013
Scheme 3. Sandmeyer-type trifluoromethylation approach as reported
by Fu and co-workers.
[
9]
Published online: && &&
,
&&&&
scope of this newly discovered process is good, and tolerates
electron-donating (ether, thioether and amide), electron-
withdrawing (nitro, ester, ketone, and azo), alkenyl, alkynyl,
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Ar
bonds into pendant C ÀCF bonds was demonstrated suc-
Ar
3
cessfully for quinolines, pyridines, and pyrazoles (a total of
eight heterocyclic examples). Across the 31 (hetero)aromatic
examples, reaction yields ranged from 32 to 89%.
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Interestingly, mechanistic studies, such as observation of
the intramolecular trapping of a pendant alkene, ESR
1
9
phenomena, and F NMR data highlighting a CuCF species,
3
all support a radical pathway. This information was used to
access a number of interesting trifluoromethylated bicyclic
scaffolds by an intramolecular radical cyclization with sub-
sequent intermolecular radical combination of trifluorometh-
yl and exo-methylene radicals (Scheme 4). Lastly, the method
was applied to a new preparation of leflunomide, an
antirheumatic drug (Scheme 4).
In conclusion, the presented methods permit a significant-
ly broadened scope of starting substrates which can be used to
introduce a CF3 substituent. The methods show good
tolerance to a range of appended functionalities and are
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[
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[
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 2 – 5
These are not the final page numbers!

Angewandte
Chemie
Highlights
Synthetic Methods
D. L. Browne*
A means to trifluoromethylate: The ben-
eficial properties imparted by the tri-
fluoromethylation of aromatic com-
pounds continue to drive the discovery of
novel reagents and reactions for the late-
stage introduction of such moieties.
Highlighted here is the recently discov-
ered Sandmeyer trifluoromethylation
approach, which now permits aromatic
amines to be substrates in a direct tri-
fluoromethylation strategy.
&&&& — &&&&
The Trifluoromethylating Sandmeyer
Reaction: A Method for Transforming CÀ
N into CÀCF3
Angew. Chem. Int. Ed. 2013, 52, 2 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!