Efficient copper-catalyzed trifluoromethylation of aromatic and heteroaromatic iodides: The beneficial anchoring effect of borates

Article abstract of DOI:10.1021/ol501967c

Efficient copper-catalyzed trifluoromethylation of aromatic iodides was achieved with TMSCF₃ in the presence of trimethylborate. The Lewis acid was used to anchor the in situ generated trifluoromethyl anion and suppress its rapid decomposition. Broad applicability of the new trifluoromethylating reaction was demonstrated in the functionalization of different aromatic and heteroaromatic iodides.

Full text of DOI:10.1021/ol501967c

Letter
pubs.acs.org/OrgLett
Efficient Copper-Catalyzed Trifluoromethylation of Aromatic and
Heteroaromatic Iodides: The Beneficial Anchoring Effect of Borates
Zsombor Gonda,† Szabolcs Kovacs,† Csaba Weber,‡ Tamas Gati,‡ Attila Meszaros,† Andras Kotschy,*,‡
́
́
́
́
́
́
́
and Zoltan Novak*,†
́
́
†MTA-ELTE “Lendulet” Catalysis and Organic Synthesis Research Group, Institute of Chemistry, Eotvos Loran
er stny. 1/a, H-1117 Budapest, Hungary
‡Servier Research Institute of Medicinal Chemistry, Zah
́
ony utca 7, H-1031 Budapest, Hungary
́
d University,
̈
̈
̈
Paz
́
man
́
y Pet
́
S
* Supporting Information
ABSTRACT: Efficient copper-catalyzed trifluoromethylation
of aromatic iodides was achieved with TMSCF3 in the
presence of trimethylborate. The Lewis acid was used to
anchor the in situ generated trifluoromethyl anion and
suppress its rapid decomposition. Broad applicability of the new trifluoromethylating reaction was demonstrated in the
functionalization of different aromatic and heteroaromatic iodides.
ecause of their unique physical and biological properties,
Bcompounds bearing the trifluoromethyl functional group
have attracted significant attention in medicinal research,
agrochemistry and materials science.1 While the importance
of this group is unquestionable, the introduction of the
trifluoromethyl group into organic molecules in most cases is
very challenging. The most important issues faced by
trifluoromethylation reactions are the application of cheap,
stable and readily available reagents, and the development of
efficient, scalable, and selective processes. Trifluoromethylation
has been achieved via transition metal-catalyzed oxidative
couplings,2 radical functionalizations,3 and in cross-coupling
reactions. Besides the palladium-catalyzed directed functional-
ization of aryl halides,4 several copper-based stoichiometric5
and catalytic methods6 were developed recently for the
introduction of the trifluoromethyl group onto the aromatic
core. The first copper-catalyzed trifluoromethylation of iodides
in the presence of a CuI/phenanthroline catalyst was reported
by Amii and co-workers.6a Though this catalytic reaction works
efficiently, the use of expensive and relatively inaccessible
TESCF3 as the trifluoromethyl source makes this process less
economic, especially for large scale syntheses. Later, Goossen
utilized K[CF3B(OMe)3] for copper-catalyzed trifluoromethy-
lation.6b While this salt works efficiently, its sensitivity and
instability limit its application.7
methyl anion and release it only slowly (Scheme 1).8 A good
buffer system should be stable enough to stabilize the CF3 ion,
while still labile enough to transfer CF3 to the copper cycle.
Scheme 1. Lewis Acid-Buffered Copper-Catalyzed
Trifluoromethylation
As a starting point we examined the trifluoromethylation of
1-iodonaphthalene with 3 equiv TMSCF3 and 3 equiv KF in the
presence of 20% CuI and 20% phenanthroline ligand. The
Lewis acid free reaction gave only 15% conversion in 2 h (Table
1, entry 1) that remained the same after 24 h. This finding is in
agreement with the rapid KF triggered formation and
decomposition of the CF3 anion.9 When we used 1 equiv of
TMSCF3, KF, and B(OMe)3 the conversion increased to 36%
after 2 h at 60 °C (entry 2), but the reaction stopped again.
When we increased the amount of TMSCF3 and KF to 3 equiv
while maintaining B(OMe)3 at 1 equiv (entry 3) the conversion
rose to 70%, clearly demonstrating the buffering ability of the
borate.
To circumvent the drawbacks of trifluoromethylborate salts
and TESCF3, we aimed to develop a new procedure in which
the relatively cheap and readily available TMSCF3 is used as the
trifluoromethyl source. The major problem with the application
of TMSCF3 in combination with a fluoride source is the rapid
−
generation of large amounts of the CF3 anion. Since the
To our delight, when TMSCF3:KF:B(OMe)3 were applied in
3:3:3 equiv ratio the reaction reached 92% conversion in 2 h
catalytic transformation is relatively slow, a significant amount
−
of active CF3 is lost before entering the catalytic cycle. A
potential solution to this problem would be the reversible
−
quenching of the CF3 anion by the addition of a Lewis acid
Received: July 8, 2014
Published: July 28, 2014
species, which would protect the rapidly produced trifluoro-
© 2014 American Chemical Society
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Letter
a
trifluoromethylation by preparing a diverse set of trifluoro-
methylated compounds, including heterocyclic derivatives
(Scheme 2). To demonstrate the applicability of the method
Table 1. Optimization Studies
Scheme 2. Synthesis of Trifluoromethylated Compounds in
a
Copper-Catalyzed Trifluoromethylation
2:3:4
ratio
conv
b
entry solvent
ligand
borate
[%]
1
2
3
4
5
6
DMSO Phen
−
3:3:0
1:1:1
3:3:1
3:3:3
3:3:3
3:3:3
15
36
70
92
81
0
DMSO Phen
DMSO Phen
DMSO Phen
B(OMe)3
B(OMe)3
B(OMe)3
B(OMe)3
B(OMe)3
DMSO Me4-Phen
DMSO 8-OH-
Quinoline
7
DMSO sparteine
DMSO Phen
DMSO Phen
DMSO Phen
DMSO Phen
DMSO Phen
DMSO Phen
B(OMe)3
B(OEt)3
3:3:3
3:3:3
3:3:3
3:3:3
3:3:3
3:3:3
3:3:3
13
85
2
8
9
B(OCH2CF3)3
B(OPr)3
B(OiPr)3
B(OBu)3
B(OtBu)3
10
11
12
13
64
10
48
37
a
CuI (0.07 mmol), 1,10-phenanthroline (0.07 mmol), aryl iodide
b
(0.35 mmol) in 1 mL of anhydrous solvent at 60 °C. % conversions
of 1-iodonaphthalene were determined by GC−MS.
(entry 4).10 Next, we examined the effect of the ligand and the
Lewis acid on the reaction. Only the phenanthroline based
ligand proved to be applicable for the transformation (entries
4−7). Variation of the Lewis acid showed that the bulkier the
alkyl group on the borate the less able it is to stabilize the CF3
anion, resulting in a lower conversion. Changing the methyl
group to ethyl resulted in 81% conversion (entry 8), while the
use of propyl, isopropyl, butyl and tert-butyl borates led to 64,
10, 48 and 37% conversion, respectively (entries 10−13).
Replacement of ethyl group with 1,1,1-trifluoroethyl group, the
borate become completely ineffective in the coupling due
probably to its increased electron deficiency (entry 9).11 To
identify the optimal conditions for the trifluoromethylation of
1-iodonaphthalene, the temperature, copper loading, fluoride
source and the solvent were also varied. As a result of this
multidimension parameter screening we found that the use of
20 mol % CuI as copper source, 20 mol % 1,10-phenanthroline
as ligand,12 KF as fluoride source, and anhydrous DMSO as
solvent are optimal for the coupling that is best run under
argon at 60 °C. With these conditions in hand we explored the
scope and limitations of the Lewis-acid enabled copper-
catalyzed trifluoromethylation.
a
CuI (0.4 mmol), 1,10-phenanthroline (0.4 mmol), KF (6 mmol), aryl
The functional group tolerance of the transformation was
established on a set of 21 aromatic and heteroaromatic iodides
having different electronic and steric properties, as well as
protecting groups. In the first round the reactions were
analyzed by GC−MS.13 On the basis of these studies we
established that the trifluoromethylation can be achieved with
aryl iodides containing both electron donating and electron
withdrawing groups. However, in the latter case the reactions
were faster. The presence of bulky substituents in the ortho
position was also tolerated. However, longer reaction times
were necessary to reach complete conversion. We have also
established that for the successful coupling free hydroxyl and
amino groups (including indoles) should be protected.
iodide (2.00 mmol), DMSO (anh., 4.0 mL) B(OMe)3 (6 mmol),
TMSCF3 (6 mmol), Ar, 60 °C, % isolated yield.
for the trifluoromethylation of functionalized aromatic iodides
we performed successfully the trifluoromethylation of a
protected phenol and two protected anilines, and isolated the
appropriate products 4a, 4b, and 4c in 67, 68 and 35% yield,
respectively. Ester and amide derivatives of aromatic carboxylic
acids also proved to be excellent substrates, and their
trifluoromethyl substituted derivatives (4d, 4e) were obtained
in moderate to good yield (34, 81%).
The application of pyridine derivatives bearing ester-,
protected alcohol- and halogen functions beyond the iodo
group afforded the desired products 4f, 4g and 4h in good to
excellent yield (59, 92 and 71%). The reaction was also
Having established the functional group tolerance we aimed
to prove the synthetic utility of the Lewis-acid enabled
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Letter
successful with 6-iodo-4-methyl-2-(methylthio)-pyrimidine and
the trifluoromethylated compound was isolated in 90% yield
(4i). In the case of 1-benzyl-4-iodopyrazole and sterically
hindered 1-benzyl-3,5-diphenyl-4-iodopyrazole the reactions
were not complete (87 and 68% conversion) but the desired
trifluoromethylated products 4j, 4k were isolated in 60 and 34%
yield. Functionalization of 1-iodoisoquinoline and 6-iodoquino-
line gave the desired trifluoromethylated isoquinoline (4l) and
quinoline (4m) in 82 and 64% yields. We also prepared the
quinoline 4n bearing a bromo substituent next to the
trifluoromethyl group (32%). The analogous chloro-iodo-
quinoline derivatives gave the appropriate trifluoromethylated
products 4o, 4p and 4q in good yields (95, 74 and 80%).The
coupling of benzyl protected indole derivatives, 5-iodoindole, 7-
iodoindole and 5-methoxy-3-iodoindole afforded the appro-
priate products (4r, 4s, 4t) in 72, 88 and 30% isolated yields,
respectively.
The reaction of N-benzyl protected derivatives of N-
heterocycles such as 3-iodo-7-azaindole, 4-iodoindazole, 6-
chloro-7-iodo-7-deazapurine and 4-iodocarbazole provided the
appropriate heterocycles 4u, 4v, 4w and 4x in good yields (94,
87, 27 and 87%). Iodo derivatives of benzofuran and
dibenzofuran reacted smoothly under the optimized conditions.
Trifluoromethylation of 2-methyl-5-iodobenzofuran gave the
appropriate product (4y) in 62% isolated yield, while in an
analogous reaction 2-(trifluoromethyl)-dibenzofuran (4z) was
isolated in 86% yield. Replacement of the oxygen in the
heterocyclic compound by sulfur did not cause significant
changes in reactivity, and 2-ethyl-5-trifluoromethyl benzothio-
phene (4aa) was obtained in 69% yield. For comparison we
have also performed the trifluoromethylation on the carbacyclic
compound 2-iodofluorene, and we isolated the trifluoromethy-
lated product (4ab) only in 21% yield.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data and NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: andras.kotschy@hu.netgrs.com.
*E-mail: novakz@elte.hu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The financial support of Servier, as well as the contribution of
the Hungarian Academy of Sciences (“Lendulet” Research
Scholarship), and OTKA-NKTH (CK 80763) is gratefully
acknowledged. The authors also thank Prof. Tim Peelen
(Lebanon Valley College) for the proofreading of this
manuscript.
■
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In conclusion, we have developed a Lewis-base enabled
approach for the copper-catalyzed trifluoromethylation of
aromatic and heteroaromatic iodides. The transformation
utilizes TMSCF3 as a readily available CF3 source and trialkyl
−
borates as Lewis acid for the temporary trapping of the CF3
anion generated by KF from the trifluoromethylating agent.
The transformation has good functional group tolerance, and
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several trifluoromethylated aromatic and heteroaromatic
molecules. The advantage of the procedure is that it eliminates
the use of expensive TESCF3 and unstable trifluoromethylbo-
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catalyzed trifluoromethylation. Moreover, the developed
conditions offer an efficient synthetic tool for the introduction
of trifluoromethyl group into aromatic and heteroaromatic
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was necessary to obtain full conversion.
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goal of these experiments was to establish the functional group
tolerance of the transformation. We intended to identify functional
groups that allow for high (or low) conversion in the coupling. To
achieve this we used GC−MS analysis to predict the steric and
electronic influence of functional groups on the reaction and the
necessity of protecting groups. Being aware of the limitations of the
applied analytical methodology, we believe that the data provided is
still solid enough to make the appropriate conclusions as is exemplified
in the preparation of the compounds summarized in Scheme 2, where
yields of isolated products were provided.
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