Copper-Mediated Trifluoroacetylation of Arenediazonium Salts with Ethyl Trifluoropyruvate

Article abstract of DOI:10.1002/chem.201604300

A copper-mediated trifluoroacetylation of various arenediazonium salts with ethyl trifluoropyruvate is reported. The reaction proceeded smoothly under mild conditions at room temperature giving trifluoromethyl aryl ketones in moderate to good yields. A variety of functional groups, including methoxy, hydroxy, ester, ketone, trifluoromethyl, and halide groups, were well tolerated. A possible reaction mechanism involving an aryl radical intermediate was proposed and supported by experimental evidence. This reaction provides a new route to trifluoromethyl aryl ketones, notable synthetic targets, from the corresponding anilines.

Full text of DOI:10.1002/chem.201604300

A Journal of
Accepted Article
Title: Copper-Mediated Trifluoroacetylation of Arenediazonium Salts with Ethyl
Trifluoropyruvate
Authors: Zhiqiang Weng; Wei Wu; Qinli Tian; Taotao Chen
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to post their Accepted Article online prior to editing, proofing, and formal publication
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Copper-Mediated Trifluoroacetylation of Arenediazonium Salts
with Ethyl Trifluoropyruvate
Wei Wu, Qinli Tian, Taotao Chen, and Zhiqiang Weng*
Dedication ((optional))
Abstract:
A
copper-mediated trifluoroacetylation of various
heterocycles are used as histone deacetylase inhibitors[7]
(Figure 1). In addition, TMFKs are widely used as building
blocks for the preparation of trifluoromethylated heterocycles,[8]
medicinal compounds,[9] and fluorinated analogues of natural
products.[10] Consequently, substantial attention has been paid
to develop efficient methods for TMFKs synthesis and, in the
recent past, numerous new synthetic protocols have been
reported (Scheme 1).[11] They rely on traditional reactions
including Friedel–Crafts acylation,[12] Grignard reaction,[13] ortho-
lithiation,[14] oxidation of trifluoromethyl alcohols,[15] nucleophilic
trifluoromethylation of esters or amide with trifluoromethyl
agent,[16] Suzuki–Miyaura cross-coupling reaction,[17] Wittig
reaction with trifluoroacetamides,[18] and other methods.[19]
Although these procedures provide a viable route for the
synthesis of TFMKs, necessary use of toxic and expensive
reagents, multistep reaction sequences, the requirement of
severe experimental conditions, and low yields or lack of
regioselectivity in the formation of trifluoroacetyl group limits
their potential application. Thus, the development of a mild and
operationally simple strategy for the construction of
trifluoromethyl aryl ketones from readily available starting
materials is highly desirable.
arenediazonium salts with ethyl trifluoropyruvate is reported. The
reaction proceeded smoothly under mild conditions at room
temperature giving trifluoromethyl aryl ketones in moderate to good
yields. A variety of functional groups, including methoxy, hydroxy,
ester, ketone, trifluoromethyl, and halide groups, were well tolerated.
A possible reaction mechanism involving an aryl radical intermediate
was proposed and supported by experimental evidence. This
reaction provides a new route to trifluoromethyl aryl ketones, notable
synthetic targets, from the corresponding anilines.
Organofluorine compounds constitute an attractive class of
compounds that continues to grow in importance in our society.
They show a modification of the physicochemical properties,
improved binding affinity, and metabolic stability of the parent
molecules.[1], [2], [3] Although fluorine is among the most abundant
elements in the earth’s crust, the occurrence of organofluorine
compounds in nature is exceedingly rare, with only thirteen
fluorine containing natural products having been isolated and
characterized.[4] Therefore, the development of effective and
reliable methods for the synthesis of organofluorine compound is
of significant interest.
Figure 1. Representative examples of patented trifluoroacetyl-containg
inhibitors.
Among organofluorine compounds, trifluoromethyl ketones
(TFMKs) are especially important. TFMKs are potential inhibitors
of hydrolytic enzymes often observed in a plethora of biologically
significant molecules and pharmaceuticals.[5] This is due to the
strong electron-withdrawing nature and large hydrophobic
domain of the trifluoromethyl group and the propensity of TFMKs
to form stable hydrates and related tetrahedral adducts. For
example, N-(2-trifluoroacetylphenyl)arylamides and analogs, are
herpesvirus protease inhibitors,[6] and trifluoroacetyl-substituted
Scheme 1. Methods for the synthesis of trifluoromethyl ketones.
In the past few years, Sandmeyer-type fluoroalkylation of
diazonium salts with a copper- or silver-fluoroalkyl source
provided an attractive way of introducing fluoroalkyl groups to
[21] [22]
aromatic molecules.[20]
These results, together with our
interest in the copper-mediated synthesis of organofluorine
compounds,[23] led us to explore a copper-mediated Sandmeyer
reaction for the introduction of trifluoroacetyl on aromatic rings.
This would in principle allow the preparation of valuable
trifluoromethyl aryl ketones from inexpensive and broadly
available anilines.
[a]
W. Wu, Q. Tian, T. Chen, Prof. Dr. Z. Weng
State Key Laboratory of Photocatalysis on Energy and Environment
College of Chemistry, Fuzhou University, Fuzhou, 350108, China
E-mail: zweng@fzu.edu.cn
Herein, we report
a
copper-mediated Sandmeyer
trifluoroacetylation of arenediazonium salts with ethyl
trifluoropyruvate at room temperature (Scheme 1); the mild
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reaction conditions enable the functionalization of substrates
displaying sensitive functionality.
CH3CN, THF, or CH2Cl2 led to marked diminished yields (Table
1, entries 11–14). The best result was obtained when the
combining DMSO and CH2Cl2 (1:17) as solvent, where the
trifluoromethyl ketone 3b was generated in 89% yield from 3.0
equiv of ethyl trifluoropyruvate (1b), 1 equiv of arenediazonium
salt 2b, and 25 mol % of Cu2O at r.t. (Table 1, entry 15).
Furthermore, the use of methyl trifluoropyruvate (1a) gave
relatively lower yields of product (77%; Table 1, entry 16).
Table 1. Optimization of trifluoroacetylation of 4-methoxybenzenediazonium
tetrafluoroborate (2f). [a]
Entry
[Cu]
1
Solvent
Yield (%)
(25 mol%)
1
Cu(MeCN)4PF6
CuCN
CuSCN
CuTc
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
DMSO
28
10
7
2
DMSO
3
DMSO
4
DMSO
5
5
CuI
DMSO
15
0
6
Cu(OTf)2
CuSO4
Cu
DMSO
7
DMSO
0
8
DMSO
0
9
Cu2O
-
DMSO
55
0
10
11
12
13
14
15
16
DMSO
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
DMF
2
CH3CN
0
THF
0
CH2Cl2
0
DMSO/CH2Cl2 (1:17)
DMSO/CH2Cl2 (1:17)
89
77
[a] Reaction conditions: [Cu] (0.10 mmol), 1a or 1b (1.2 mmol), 2b (0.40
mmol), solvent (1 mL), 16 h, r.t. [b] Yields were determined by 19F NMR
analysis of the crude reaction mixture with PhOCF3 as an internal standard.
DMSO = dimethyl sulfoxide, DMF = N,N-dimethylformamide.
At the outset, 4-toluenediazonium tetrafluoroborate (2b) and
ethyl trifluoropyruvate (1b) were chosen as model substrates for
the trifluoroacetylation reaction at room temperature (Table 1).
After reaction in DMSO for 16
h using 25 mol % of
Cu(MeCN)4PF6 as a catalyst, the trifluoroacetylated product 3b
was formed in 28% yield (determined by 19F NMR spectroscopy;
Table 1, entry 1). Having observed the trifluoroacetylated
product, an optimization of the reaction conditions was carried
out (Table 1). Among the different copper catalysts tested (Table
1, entries 2–9), Cu2O was found to be optimal (55% yield, Table
1, entry 9). The absence of trifluoroacetylated product in control
experiments clearly shows the importance of the catalyst in this
reaction (Table 1, entry 10). A further screening of the reaction
conditions revealed that replacement of DMSO with DMF,
Scheme 2. Scope of the Sandmeyer trifluoroacetylation. Reaction conditions:
Cu2O (0.20 mmol), 1b (2.4 mmol), 2 (0.80 mmol), DMSO (0.12 mL), CH2Cl2
(2.0 mL), 16 h, N2, room temperature; yield of isolated product.
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Following the identification of the optimized reaction
conditions, we next examined the scope of the reaction by
subjecting various arenediazonium tetrafluoroborates to the
trifluoroacetylation process, the results are summarized in
Scheme 2. Arenediazonium salts 2a–2h bearing either neutral or
electron-donating groups (methyl, phenyl, and methoxy) at
meta- or/and para-positions, gave the corresponding products in
good yields (3a–3h). 3-Hydroxybenzenediazonium salt 2i is
also a suitable substrate for the reaction, affording product 3i in
55%. Arenediazonium tetrafluoroborates 2j–2h, containing
electron-withdrawing groups (ester, ketone, and trifluoromethyl)
at meta- or/and para-positions, also converted smoothly into
trifluoroacetylated products 3j–3h in 39%–70% yields, further
expanding the scope of the reaction. In particular, for the
substrate 2o containing a para-cyano group, the yield of product
3o was only 13%. The trifluoroacetylation reaction also revealed
good tolerance towards fluoro, chloro, bromo, and iodo groups
(3p–3v), which provides opportunities for further functional
manipulations through cross-coupling reactions. However, no
trifluoromethyl ketone formation (3w) was observed with the
ortho-substituted aryl diazonium salt 2w. This may result from
reactions.
Scheme 4. Late-stage trifluoroacetylation of an estradiol derivative.
When 2-(allyloxy)diazonium tetrafluoroborate (2ab) was
used as the substrate, the cyclized product 6, phenyl allyl ether,
and other unidentified side products were formed, whereas the
acyclic product 3ab was not detected in the GC−MS or 19F NMR
analysis (Scheme 6). These results demonstrate that the
reaction may proceed with the intermediacy of an aryl radical
although we could not rule out the possibility that the ortho-
substituted aryl diazonium salt was not suitable substrate for this
transformation.
+
the steric hindrance to the adjacent C–N2 position of the
diazonium. In addition, the polycyclic aromatic diazonium salt,
naphthalene-2-diazonium tetrafluoroborate (2x) was exposed to
the reaction conditions and led to the desired product 3x in good
yield (75%). It is worth noting that hetero-aromatic diazonium
salts (2y–2aa) produced the expected products (3y–3aa) in
54%, 30%, and 46% yields, respectively.
To demonstrate the scalability of the present methodology, a
reaction of [1,1'-biphenyl]-4-diazonium tetrafluoroborate (2e) and
ethyl trifluoropyruvate (1b) was performed on a 1 g scale. The
corresponding product 3e was obtained in 82% isolated yield as
shown in Scheme 3.
Scheme 5. Inhibition experiment with TEMPO.
Scheme 6. Radical clock probe experiment.
Scheme 3. Scalability of the trifluoroacetylation of 2e.
To further explore its applicability we investigated the new
reaction on molecules containing complex architectures.
Accordingly, the trifluoroacetylation reaction of estradiol
derivative 4 with 1b provided 5 in a 41% isolated yield (Scheme
4). This result demonstrates the mild and selective nature of our
copper-catalyzed transformation.
To gain some mechanistic insights into the current
trifluoroacetylation reaction, inhibition experiments were
conducted. A radical scavenger, TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy) was added in the reaction mixture under the
optimized conditions. The reaction produced the desired product
3e in only 9% yield together with a TEMPO-Tol adduct and p-
cresol, as detected by GC-MS (Scheme 5). This observation
implied that an aryl radical intermediate might be involved in the
Scheme 7. Proposed catalytic cycle for the trifluoroacetylation.
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On the basis of the above observations, a mechanistic
proposal involving radical intermediates, is presented in Scheme
7. An initial copper(I)-promoted decarboxylation of ethyl
trifluoropyruvate generates an acyl Cu(I) species A. Subsequent
single electron transfer (SET) from A to the diazonium salt
occurs to form the diazo radical, which then releases nitrogen to
form an aryl radical.[24] Finally, the acyl Cu(II) species B reacts
with the aryl radical to afford the desired product 3 along with
regeneration of the starting copper complex to complete the
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In summary, we have developed a new and versatile route to
trifluoromethyl aryl ketones through the Cu-mediated
trifluoroacetylation of various arenediazonium salts using ethyl
trifluoropyruvate as trifluoroacetylating reagent. The reaction is
functional-group tolerant, and proceeds in moderate to good
yields with a wide range of aromatic diazonium salts. This
method is attractive because simple and inexpensive starting
materials are employed under mild reaction conditions, leading
to the formation of valuable products.
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Financial support from National Natural Science Foundation of
China (21372044), and Fuzhou University (022494) is gratefully
acknowledged.
Keywords: trifluoroacetylation • copper • diazonium salts •
Sandmeyer reaction • decarboxylation
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Entry for the Table of Contents (Please choose one layout)
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Wei Wu, Qinli Tian, Taotao Chen, and
Zhiqiang Weng*
Page No. – Page No.
Copper-Mediated Trifluoroacetylation
of Arenediazonium Salts with Ethyl
Trifluoropyruvate
Trifluoromethyl aryl ketones are obtained directly from arenediazonium salts and
ethyl trifluoropyruvate in the presence of a catalytic amount of Cu2O. This
Sandmeyer-type trifluoroacetylation reaction proceeds smoothly under mild
conditions at room temperature and exhibits good functional group tolerance. It
provides a new approach for the synthesis of trifluoromethyl aryl ketones, notable
synthetic targets, from the corresponding anilines.
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