Ortho-trifluoromethylation of functionalized aromatic triazenes

Article abstract of DOI:10.1002/anie.201107414

A silver key to add CF₃: In presence of in situ generated AgCF₃, it is possible to trifluoromethylate aromatic triazenes in high ortho selectivity and good yields by means of a C-H substitution (see scheme). Owing to the further tran

Full text of DOI:10.1002/anie.201107414

Angewandte
Chemie
DOI: 10.1002/anie.201107414
Trifluoromethylation
Ortho-Trifluoromethylation of Functionalized Aromatic Triazenes**
Andreas Hafner and Stefan Brꢀse*
Fluorine containing organic agents play a crucial role in the
search for new active pharmaceutical and agrochemical
compounds. Owing to their fluorine moieties, these com-
pounds have unique chemical and physical properties. For
example, they can increase the metabolic stability or the
lipophilicity, which can enhance the biological activity of
a drug.[1]
For these reasons, the CF3 group is an essential moiety of
numerous commercially available aromatic and non-aromatic
biological active agents. Therefore, the research on new
excess of the required aromatic compound is needed and only
a low regioselectivity is achieved.[7]
For years, our group has been working on triazenes[8] and
their application in solid-phase synthesis, as well as the
investigation of new efficient cleavage reactions of tria-
zenes.[9] Starting from commercially available aromatic ani-
line derivatives, a variety of functionalized aromatic triazenes
are accessible by a simple one-step procedure.[9] Note that the
toxicity of triazenes can be significantly reduced by using
diisopropyl-substituted triazenes.[10]
During our investigation for a new cleavage method for
triazenes in the presence of Ag2CO3, KF, and TMS-CF3 we did
not obtain the desired product but the ortho-trifluoromethy-
lated triazene 2a in 31% yield. This reaction probably
occurred via in situ generated AgCF3.[11] By optimizing the
reaction conditions we were able to increase the yield to up to
64%. In this case, a second substitution was observed which
led to the di-ortho-substituted triazene 3a in 32% yield
(Scheme 1).
synthetic routes for introducing this group to aromatic
systems is an important field of modern organic chemistry.
Over the last years, numerous synthetic examples for the
direct trifluoromethylation of aromatic compounds were
developed. Most of these routes are based on aromatic
halides (mainly iodides), which are converted into the
corresponding trifluoromethylated compound using a transi-
tion metal (Cu or Pd) and (trifluoromethyl)trimethylsilane
(“Ruppert–Prakash reagent”).[2,3] The substitution of aro-
matic boronic acids is also known.[4]
Scheme 1. Trifluoromethylation of triazenes 1a. Reaction conditions:
1a (0.40 mmol), TMS-CF3 (0.80 mmol), AgF (1.60 mmol), C6F14
(1 mL), 1008C, 4 h.
In contrast to these routes, the direct trifluoromethylation
In addition to our preferred solvent perfluorohexane, the
reaction could be also performed in acetonitrile, but gave
lower yields (48%, 608C, 16 h). Furthermore, when higher
temperatures (1008C) were applied in acetonitrile, byprod-
ucts were obtained, through the formation of difluorocarbene.
This result indicates the in situ generation of AgCF3.
Changing the solvent to dichloroethane, which was used
by the Sanford group, resulted in a conversion of 1a into 2a in
only 20% yield. To investigate the scope of the reaction, we
synthesized further aromatic triazenes and trifluoromethy-
lated these compounds under analogous conditions
(Scheme 2). When para-substituted triazenes were used, we
always obtained a very high ortho selectivity. In all cases only
small amounts (< 4%) of meta substituted byproduct were
detected by GC-MS analysis.
À
by C H substitution has hardly been investigated. To date,
this kind of reaction succeeds only with electrophilic CF3
reagents[5] or on
a
few heteroaromatic compounds.[6]
Recently, independently of our work, Sanford et al. reported
À
a new trifluoromethylation reaction by C H substitution.
However, the synthetic application is limited, because an
[*] Dipl.-Chem. A. Hafner, Prof. Dr. S. Brꢀse
Institute of Organic Chemistry, KIT-Campus South
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
E-mail: braese@kit.edu
[**] We thank the Landesgraduiertenfçrderung Baden-Wꢁrttemberg for
financial support.
In the case of mono-ortho-substituted triazenes, the ortho
trifluoromethylated triazenes 2 f, 2g, and 2h were obtained as
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201107414.
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À
equilibrium between AgCF3 and Ag(CF3)2 occurs and that
À
Ag(CF3)2 is the reactive species in the trifluoromethylation
of mercury(II) chlorides.[13] However, in the aromatic tri-
fluoromethylation reaction, another reactive species seemed
to be involved. On the basis of experiments involving the
addition of radical initiators/inhibitors, the Sanford group
supposed that radical intermediates are involved. Although
a radical mechanism seems unlikely owing to the high ortho
selectivity, similar experiments using radical initiators/inhib-
itors do indicate the existence of radical species. While
a radical initiator such as azobisisobutyronitrile (AIBN) did
not have any influence on the reaction, the addition of
2 equivalents of (2,2,6,6-tetramethylpiperidine-1-yl)oxyl
(TEMPO) decreased the yield of 2a to 30% (determined
by GC-MS). When 5 equivalents of TEMPO were used, no
product could be found at all. As TEMPO is known as
a scavenger of CF3 radicals,[6] this result suggests that the CF3
radicals are the reactive species. Nevertheless, the high ortho
selectivity of triazenes is remarkable.
Triazenes are useful equivalents of protected diazonium
salts and therefore can be easily transformed into various
functional groups. Thus, it is possible to convert the triazene
moiety into different halides,[14] into the corresponding
azide,[15] nitrile,[16] and phenol[17] or back to the starting
amine.[18] A traceless transformation back to the hydrocarbon
was also feasible.[19] Furthermore, cross-coupling reactions
using triazenes are also known (Scheme 3).[20]
Scheme 2. Trifluoromethylation of different functionalized triazenes.
Yields of the isolated ortho-substituted product.
the main products. However, best yields could be obtained
when one ortho as well as the para position were blocked for
À
a C H substitution (2e). Overall, the trifluoromethylation
reaction occurred mostly in good yields.
Noteworthy is the high tolerance of various functional
groups. Thus, the aromatic trifluoromethylation was applica-
ble in presence of iodides, bromides, chlorides, fluorides,
cyanides, as well as in the presence of ester and methoxy
groups (Scheme 2). Interestingly, the conversion of the
halogenated halides 2a–2d, 2 f, and 2g was always almost
quantitative into the corresponding trifluoromethylated prod-
ucts (ortho, di-ortho @ para @ meta), whereas a substitution of
the corresponding halide was never detected. This situation is
remarkable, because most common metal-mediated trifluor-
omethylation reactions substitute halides, especially iodides.
Therefore, the new reaction shows a reaction pathway that is
orthogonal to common routes.[3]
Scheme 3. Transformations of the triazene moiety reported in the
literature.
We believe that this versatility together with the high
selectivity towards trifluoromethylation makes triazenes
useful in the synthesis of new CF3 building units. To
demonstrate this synthetic potential we tested the trans-
formation of the triazene moiety to the corresponding iodide
(5a) and azide (6j). Both reactions succeeded under liter-
ature conditions in good to excellent yields (Scheme 4).
While many applications of AgCF3 in transmetallation
reactions are reported,[11] only a few synthetic examples are
[7,12]
À
known in which AgCF3 is used to form new C CF3 bonds.
Therefore, information on the reaction mechanism of silver-
mediated trifluoromethylation reactions is limited. Naumann
et al. showed by NMR spectroscopy that in aprotic solvents an
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In conclusion, a highly ortho-selective trifluoromethyla-
tion of aromatic triazenes was reported. This reaction
tolerates a broad range of functional groups, especially
iodides and bromides. Our further studies will deal with
investigating the reaction mechanism as well as exploring the
further synthetic scope of AgCF3 mediated trifluoromethyla-
tion reactions.
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[10] In contrast to methyl-substituted triazenes, triazenes such as
1 are not a source of carcinogen alkylation agents. Therefore, the
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Experimental Section
Representative trifluoromethylation of aromatic triazenes: A vial
equipped with a septum and a stirring bar was charged with AgF
(202 mg, 1.60 mmol, 4.00 equiv) and the triazene 1a (133 mg,
0.400 mmol). The reaction vessel was closed and, under argon
atmosphere, perfluorohexane (1 mL) was added by syringe. Then
TMS-CF3 (0.120 mL; 114 mg, 0.800 mmol, 2.00 equiv) was added and
the suspension was heated to 1008C. The suspension was stirred for
4 h. Afterwards, the solution was cooled to room temperature and
ethyl acetate (3 mL) was added. The layers were separated (in
a separating funnel) and the perfluorohexane layer was reextracted
with ethyl acetate twice. The combined organic phases were
concentrated under reduced pressure. The crude product was purified
by flash column chromatography (with cyclohexane on silica gel) and
2a could be obtained as a yellow oil (101 mg, 64%).
Received: October 20, 2011
Published online: February 8, 2012
Keywords: silver · triazene · trifluoromethylation ·
.
(trifluoromethyl)trimethylsilane
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