Copper-promoted sandmeyer trifluoromethylation reaction

Article abstract of DOI:10.1021/ja404217t

A copper-promoted trifluoromethylation reaction of aromatic amines is described. This transformation proceeds smoothly under mild conditions and exhibits good tolerance of many synthetically relevant functional groups. It provides an alternative approach for the synthesis of trifluoromethylated arenes and heteroarenes. It also constitutes a new example of the Sandmeyer reaction.

Full text of DOI:10.1021/ja404217t

Communication
pubs.acs.org/JACS
Copper-Promoted Sandmeyer Trifluoromethylation Reaction
Jian-Jun Dai,† Chi Fang,† Bin Xiao,‡ Jun Yi,† Jun Xu,† Zhao-Jing Liu,† Xi Lu,† Lei Liu,‡ and Yao Fu*,†
†Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
‡Department of Chemistry, Tsinghua University, Beijing 100084, China, and State Key Laboratory for Oxo Synthesis and Selective
Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, 730000 Lanzhou, China
S
* Supporting Information
conversion of ArNH2 amine group into numerous functional
ABSTRACT: A copper-promoted trifluoromethylation
reaction of aromatic amines is described. This trans-
formation proceeds smoothly under mild conditions and
exhibits good tolerance of many synthetically relevant
functional groups. It provides an alternative approach for
the synthesis of trifluoromethylated arenes and hetero-
arenes. It also constitutes a new example of the Sandmeyer
reaction.
groups such as halogen, hydrogen, hydroxyl, cyano, azido, and
boronate groups,8−13 our study adds an unprecedented yet
synthetically important example to this century-old trans-
formation.
We began the study by examining the reaction between 4-
phenoxyaniline (1a) and Umemoto’s reagent (2a) in the
presence of different metals and alkyl nitrites (Table 1). It was
interesting to find that when Cu powder was used as the
promoter, the desired product 3a was obtained in 30% yield in
CH3CN at room temperature under air (entry 1). We then
rifluoromethylated arenes (ArCF3) have been recognized
T
as important structural motifs in many bioactive com-
pounds.1 The CF3 group can enhance the metabolic stability,
lipophilicity, and bioavailability of the parent molecule.
Considerable interest has been paid to the development of
methods for the synthesis of ArCF3.2 Earlier methods such as the
conversion of toluene and benzoic acid derivatives to ArCF3
usually suffer from harsh reaction conditions and limited
functional group tolerance.3 To overcome these problems,
recent research has been directed to transition-metal-promoted
trifluoromethylation reactions that usually employ aryl halides,4
boronic acid derivatives,5 and even arenes6 as substrates (Scheme
1a). For further improvement of the flexibility and selectivity of
a
Table 1. Optimization of the Reaction Conditions
b
entry
metal
RONO
solvent
T (°C)
yield (%)
1
2
Cu
Zn
Mn
Fe
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
n-BuONO
i-BuONO
i-AmONO
n-AmONO
i-AmONO
i-AmONO
i-AmONO
i-AmONO
i-AmONO
i-AmONO
i-AmONO
i-AmONO
i-AmONO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
PhCN
23
30
23
trace
trace
trace
trace
trace
46
3
23
4
23
5
Mg
Ni
23
6
23
Scheme 1. Aromatic Trifluoromethylation
7
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
none
23
8
23
48
9
23
51
10
11
12
13
14
15
16
17
18
19
23
49
23
19
PhCF3
23
0
DCE
23
0
DMAc
23
trace
28
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
50
0 to 15
0 to 15
0 to 15
0 to 15
62
the trifluoromethylation process, it remains important to explore
the conversion of other functional groups to CF3.
c
74
cd
,
68
0
In this context, we explored the conversion of ArNH2 to ArCF3
because aromatic amines are cheap and readily available
substrates. We were surprised to find that when Umemoto’s
reagent is used as the trifluoromethylation agent, ArCF3 can be
easily synthesized under Sandmeyer reaction conditions
(Scheme 1b). It is significant that this Sandmeyer-type
trifluoromethylation reaction enjoys operational simplicity with
a good functional group tolerance. Thus, the new reaction
provides a useful alternative method for the synthesis of
trifluoromethylated arenes as well as heteroarenes. Moreover,
although the Sandmeyer reaction7 has been used for the
a
Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.3 mmol, 1.5
equiv), metal (0.6 mmol, 3 equiv), and RONO (0.6 mmol, 3 equiv) in
the solvent (1.0 mL) for 8 h under an air atmosphere, unless otherwise
noted. GC yields with biphenyl as an internal standard added after
the reaction. Under an Ar atmosphere. The reaction was performed
b
c
d
with 2b instead of 2a.
Received: January 28, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
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a
examined whether or not Cu could be replaced by an even
cheaper metal such as Zn, Mn, Fe, Mg, or Ni (entries 2−6).
Unfortunately, only trace amounts of the desired product were
detected. Next, we tested different alkyl nitrites (entries 7−10).
The use of isoamyl nitrite (i-AmONO) increased the yield of 3a
to 51% (entry 9). Furthermore, the reaction efficiency was found
to be affected by the solvent system (entries 11−14). CH3CN
was the optimal medium for the reaction, whereas in PhCF3, 1,2-
dichloroethane (DCE), and N,N-dimethylacetamide (DMAc)
we observed a considerable amount of deamination/protonation
product [see the Supporting Information (SI)]. In regard to the
influence of temperature on the reaction, it was found that the
yield of 3a increased to 62% at 0 to 15 °C (entry 16), whereas a
low yield of 28% was obtained when the reaction was conducted
at 50 °C (entry 15). Finally, by changing the reaction atmosphere
from air to argon, we further increased the yield of 3a to 74%
(entry 17). When the triflate salt 2b was used instead of 2a, the
reaction also proceeded smoothly with a yield of 68% (entry 18).
It is important to mention that no product was detected when no
metal promoter was employed (entry 19).
Table 2. Substrate Scope for Aryl Amines
With the optimized conditions in hand, we investigated the
scope of the new reaction with diverse aryl amines (Table 2). It
was found that a variety of aryl amines can be successfully
trifluoromethylated to the desired product in modest to good
yields. The reaction can tolerate well electron-donating groups
such as ether (3k, 3q), thioether (3m), and amide (3d, 3f, 3g, 3l)
as well as electron-withdrawing groups such as ketone (3b, 3e, 3j,
3q), nitro (3m), ester (3i), and azo (3p). Unsaturated CC
double bonds (3c) and CC triple bonds (3s, 3t, 3u) are also
compatible with the process. It is interesting to note that the
present reaction can even tolerate an unprotected OH group
(3n). In some recent studies, Umemoto’s reagent was shown to
be capable of trifluoromethylating the ortho C−H bond of some
functional groups (e.g., amide) under Pd or Cu catalysis.6 Under
the present conditions, all of the C−H bonds are compatible with
the trifluoromethylation process (3d, 3f−h, 3k, 3r). Further-
more, aryl halide (3f, 3g, 3o) as well as alkyl halide (3t) groups
were also found to be compatible with the new transformation.
The above features indicate that the present method is
complementary to the previous transition-metal-catalyzed
trifluoromethylation processes.14 These features also make
additional functionalization reactions possible at the ortho C−
H bonds or halogenated positions.
a
The reactions were carried out for 8 h on a 0.2 mmol scale. Isolated
b
yields are shown. See the SI for more details. Shown in parentheses
are the isolated yields for reactions performed on a 1.0 mmol scale.
c
The X-ray crystal structure of 3u is shown with the thermal ellipsoids
set at 35% probability.
a
Table 3. Substrate Scope for Heteroaromatic Amines
In regard to the trifluoromethylation of heteroaromatic
amines, our tests showed that six- or five-membered ring
heterocycles (including pyridines and pyrazoles) can be
converted to the corresponding trifluoromethylated products
in modest yields (Table 3). These transformations can tolerate
electron-donating groups such as amide (5b) as well as sterically
hindered substrates (5c). It should be noted that the C−H bonds
of the heterocycle were not affected by the present
trifluoromethylation process. Thus, the present method enables
site-selective trifluoromethylation of heteroaromatic amines.
To understand the mechanism of the copper-promoted
Sandmeyer trifluoromethylation reaction, we examined the
trifluoromethylation of 2-(allyloxy)aniline (6a).4k,15 Interest-
ingly, we obtained only the cyclized product 7a in 68% yield,
whereas the acyclic product 8 was not detected in the GC−MS or
19F NMR analysis (Scheme 2). This observation indicated that
the reaction should proceed with the intermediacy of an aryl
radical, which is presumably generated from the aryldiazonium
intermediate. It is worth noting that the above cyclization/
trifluoromethylation sequence also provides an interesting new
a
The reactions were carried out for 8 h on a 0.2 mmol scale. Isolated
b
yields are shown. Shown in parentheses is the isolated yield for a
reaction performed on a 1.0 mmol scale.
approach for the synthesis of CF3-substituted heterocycles.
Indeed, similar reactions of 6b−d gave trifluoromethylated 2,3-
dihydrobenzofuran, chroman, and indoline derivatives in modest
isolated yields.
B
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a
Scheme 2. Formation of CF3-Substituted Heterocycles
Scheme 4. Proposed Mechanism
To test the synthetic utility of the copper-promoted
Sandmeyer trifluoromethylation reaction, we examined a new
route for the preparation of leflunomide (12), a disease-
modifying antirheumatic drug that can be used to treat moderate
to severe rheumatoid arthritis and psoriatic arthritis.17 As shown
in Scheme 5, 1,4-benzenediamine (10) was easily acylated to
afford 11 in 81% yield. With the new reaction described in the
present study, 11 can be converted to 12 in 58% yield (Scheme
5).
a
The reactions were carried out for 8 h on a 0.2 mmol scale. Isolated
b
yields are shown. Yield determined by 19F NMR spectroscopy with
1,3,5-trifluorobenzene as an internal standard.
Scheme 5. New Synthesis of Leflunomide
Scheme 3. Trapping of CF3 Radical by TEMPO
Moreover, site-selective C−H trifluoromethylation remains an
important challenge for the synthesis of CF3-containing
compounds.6,18 While aromatic nitration is a traditional
transformation, it remains synthetically useful for the function-
alization of aromatic C−H bonds. Because the nitro group can be
readily reduced to an amino group, the copper-promoted
Sandmeyer trifluoromethylation reaction provides an effective
new approach for the conversion of an aromatic C−H bond to a
C−CF3 bond. This approach is expected to be useful for the rapid
generation of trifluoromethylated derivatives of biologically
active molecules. As shown in Scheme 6, we can selectively
introduce an NO2 group onto 5,6-dimethoxy-1-indanone (13)
and then reduce the intermediate to 14 through catalytic
hydrogenation. Using the new reaction developed in the present
Furthermore, we tested the reaction of Umemoto’s reagent
with 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) under the
promotion of copper (Scheme 3). When either copper or
Umemoto’s reagent was not added, the solution of TEMPO
exhibited a characteristic electron spin resonance (ESR)
spectrum. On the other hand, when both Umemoto’s reagent
and copper were added, the ESR signal of TEMPO decreased
significantly, presumably due to the formation of 9 (whose
identity was also confirmed by GC−MS analysis). Thus, the
above experiment implies the generation of CF3 radical when
Umemoto’s reagent is treated with copper powder. In addition,
we examined the reaction of Umemoto’s reagent with copper
(see the SI). This reaction generated a product with an 19F NMR
chemical shift of −34.72 ppm, matching that previously reported
for CuCF3.4b,i
Scheme 6. C−H Trifluoromethylation of Bioactive
Compounds
On the basis of the above experimental observations (i.e., the
intermediacy of an aryl radical and the generation of CF3Cu), we
propose that the Cu-promoted Sandmeyer trifluoromethylation
reaction may proceed through the mechanism shown in Scheme
4. First, copper-mediated single electron transfer (SET) in
Umemoto’s reagent generates the CF3 radical, which then reacts
with copper to produce CF3Cu. Second, CF3Cu reacts with the
aryl radical generated from the aryldiazonium ion (produced in
situ from the aryl amine and alkyl nitrite) to afford the desired
product.16
C
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Journal of the American Chemical Society
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E.; Benet-Buchholz, J.; Grushin, V. V. J. Am. Chem. Soc. 2011, 133,
20901.
study, we can easily convert 14 to 15 in 62% yield. Notably,
compound 15 is a trifluoromethylated derivative of an
Alzheimer’s drug (Aricept) precursor19 that was previously
made by Nagib and MacMillan6e through photoredox catalysis.
In summary, we have developed a copper-promoted
Sandmeyer trifluoromethylation reaction for the conversion of
aromatic amines to trifluoromethylated arenes and heteroarenes.
This new reaction is operationally simple and can be conducted
under very mild conditions. A variety of synthetically important
functional groups are well-tolerated. Thus, we expect that the
new reaction can be used for the rapid generation of
trifluoromethylated derivatives of biologically active molecules.
To reduce the cost of the reaction further, our next challenge will
be the search for less expensive trifluoromethylating agents for
the Sandmeyer process.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
fuyao@ustc.edu.cn
Notes
The authors declare no competing financial interest.
(9) Dugave, C. J. Org. Chem. 1995, 60, 601.
ACKNOWLEDGMENTS
■
(10) (a) Hanson, P.; Jones, J. R.; Taylor, A. B.; Walton, P. H.; Timms,
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P.; Rowell, S. C.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem.
Soc., Perkin Trans. 2 2002, 1126.
We thank the National Basic Research Program of China (973
Program) (2012CB215306), the “863” Program of the Ministry
of Science and Technology (2012AA02A700), the NNSFC
(20972148), CAS (KJCX2-EW-J02), and the China Postdoc-
toral Science Foundation (2011M500289, 2012T50078) for
support.
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(15) The aryl radical derived from 6a cyclizes with a rate constant of
1010 s−1. Thus, if the Sandmeyer trifluoromethylation reaction occurs
through an aryl radical, then cyclized product 7a should be observed.
See: Annunziata, A.; Galli, C.; Marinelli, M.; Pau, T. Eur. J. Org. Chem.
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