Silver-mediated trifluoromethylation of aryldiazonium salts: Conversion of amino group into trifluoromethyl group

Article abstract of DOI:10.1021/ja4056239

A novel strategy for aromatic trifluoromethylation by converting aromatic amino group into CF₃ group is reported herein. This method, which can be considered as trifluoromethylation variation of the classic Sandmeyer reaction, uses readily available aromatic amines as starting materials and is performed under mild conditions.

Full text of DOI:10.1021/ja4056239

Communication
pubs.acs.org/JACS
Silver-Mediated Trifluoromethylation of Aryldiazonium Salts:
Conversion of Amino Group into Trifluoromethyl Group
Xi Wang, Yan Xu, Fanyang Mo, Guojing Ji, Di Qiu, Jiajie Feng, Yuxuan Ye, Songnan Zhang, Yan Zhang,
and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry, Peking University, Beijing 100871, China
S
* Supporting Information
is becoming increasingly important in drug development. To
ABSTRACT: A novel strategy for aromatic trifluorome-
thylation by converting aromatic amino group into CF3
group is reported herein. This method, which can be
considered as trifluoromethylation variation of the classic
Sandmeyer reaction, uses readily available aromatic amines
as starting materials and is performed under mild
conditions.
tackle such a problem, methodologies for the direct
trifluoromethylation of arenes have been developed. A
commonly applied approach is the conversion of halogen
substituents into CF3 groups through transition-metal-mediated
or -catalyzed reactions (Scheme 1b). Since the first discovery by
McLoughlin and Thrower in 1969,4 CuCF3 reagents have been
extensively studied and widely used in the stoichiometric
trifluoromethylation of aryl halides.2e More recently, Cu- or Pd-
catalyzed trifluoromethylation has attracted great attention
from the synthetic community. Accordingly, significant
progress in this field has been achieved.5−7 Closely related
methods, the Cu-catalyzed or -mediated conversion of a boron
group into a CF3 group, have also been developed (Scheme
1c).8 In addition to the transition-metal-catalyzed or -promoted
methods, a distinct approach to introducing a CF3 group is the
facile trifluoromethylation of an aromatic C−H bond through a
radical process (Scheme 1, d).9,10
Although numerous efforts have been devoted to aromatic
trifluoromethylation and remarkable progress has been made,
the problem is far from being solved. Most current methods
suffer from at least one of the following drawbacks: harsh
reaction conditions, limited substrate scope, low regioselectiv-
ity, and expensive reagents or catalysts/ligands. Therefore,
further developments are needed to enable the use of cheap
and abundantly available starting materials as well as mild
trifluoromethylation conditions. To this end, we report herein a
novel approach to aromatic trifluoromethylation through direct
conversion of an aromatic amino group into CF3 group
(Scheme 1e).
rifluoromethylated arenes have become increasingly
Tprevalent in numerous fields, ranging from pharmaceut-
icals, agrochemicals, to functional materials.1 However, CF3-
containing compounds are absent in nature, which accounts for
the vital importance of developing general and practical
methods to introduce a CF3 group onto aromatic structures.
In recent years, the scientific community has witnessed a rapid
development of methods for trifluoromethylation of arenes.2
The traditional means for introducing a CF3 group onto an
aromatic ring relies on a Swarts-type reaction, pioneered by
Swarts in 1892.3 The Swarts-type reaction involves exhaustive
chlorination at the benzylic position, followed by chlorine/
fluorine exchange with HF under harsh conditions (Scheme
1a). Although relatively practical for large-scale industrial
production of CF3-containing aromatic building blocks and
intermediates, this process is not appropriate for late-stage
introduction of a CF3 group onto an aromatic structure, which
Scheme 1. Methods for Aryl Trifluoromethylation
Categorized by the Groups Being Converted
Aromatic amines are commonly used chemicals and easily
available. The aromatic amino group serves as a versatile motif,
which can be converted into various functional groups. These
transformations mostly proceed through arene diazonium salts,
which are important intermediates in organic chemistry. Since
their first discovery in 1858,11,12 several named reactions related
to arene diazonium salts have been established as classic
methods for functional group transformations. Undoubtedly,
the most prominent one is the Sandmeyer reaction, which can
replace aromatic amino groups with halides or pseudohalides.13
Another important reaction is Balz−Schiemann reaction, which
can convert an amino group into a fluoro group.14 These classic
Received: June 5, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja4056239 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
transformations are not only routinely practised in research
laboratories but also widely applied in industry.
Table 1. Optimization of Trifluoromethylation Conditions
Based on the oxidizing properties of aryl diazonium salts and
the strong σ-donor nature of the trifluoromethyl group in the
[AgCF3] complex2e and also inspired by Ritter’s recent reports
on reductive elimination from bimetallic high-valent silver
complex to form Caryl−F bonds,15 we proposed that oxidative
addition of diazonium salt A would be favored at an electron-
rich silver center to afford intermediate B (Scheme 2).
b
entry
X
[MCF3]
temp
solvent
3, yield
Scheme 2. Proposed Strategy for Trifluoromethylation of
Aromatic Amines
c
1
2
3
4
5
6
7
Cl
Cl
AgCF3
0 °C-rt
MeCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
41%
95% (80%)
trace
d
AgCF3
AgCF3
AgCF3
AgCF3
AgCF3
CuCF3
−78 °C-rt
−78 °C-rt
−78 °C-rt
−78 °C-rt
−78 °C-rt
−60 °C-rt
OtBu
BF4
46%
Br
93%
CF3CO2
Cl
93%
37%
a
Reaction conditions: preparation of the diazonium salt: 1 (0.3
mmol), aq HX (0.6 mmol), t-BuONO (0.33 mmol), solvent, 0 °C, 15
min; preparation of [AgCF3]: AgF (1.05 mmol), TMSCF3 (1.05
mmol), EtCN (3 mL), room temperature, 15 min; preparation of
[CuCF3]: CuCl (1.05 mmol), CsF (1.05 mmol), TMSCF3 (1.05
mmol), DMF (3 mL), room temperature, 30 min. The [MCF3]
solution was added dropwise to the solution of 2 (0.30 mmol) over a
period of 1 h. The solution was stirred for another 3 h and then
Subsequently, intermediate B undergoes reductive elimination
to form a Caryl−CF3 bond and a AgCl precipitate. According to
this hypothesis, we envisioned that conversion of aromatic
amines into the corresponding trifluoromethyl arenes (trifluor-
omethylation variation of the classic Sandmeyer reaction)
would be feasible.
b
warmed to room temperature. Unless otherwise noted, the yields are
based on 19F NMR with 4-CF3OC6H4OMe as internal standard.
c
d
[AgCF3] was prepared in MeCN (3 mL). Value in parentheses
Initially, we imitated the classic Sandmeyer reaction
conditions by slowly adding a solution of [AgCF3] in MeCN,
freshly prepared from AgF and Me3SiCF3 (Ruppert−Prakash
reagent),16,17 into the diazonium chloride 2 (X = Cl) at 0 °C,
prepared in MeCN from ethyl 4-aminobenzoate 1 through
diazotization with t-BuONO/aq HCl (Table 1).18 To our
delight, the expected trifluoromethylated product 3 was formed
in 41% yield based on 19F NMR analysis (entry 1). It was found
that the reaction was favored at low temperature. When the
solvent was switched to EtCN (mp −93 °C) and the addition
of [AgCF3] was carried out at −78 °C, we observed a dramatic
increase in the yield (entry 2). It was noted that 3.5 equiv of
[AgCF3] was necessary to maintain the high yield. Further
study indicates that the counterions of diazonium salt impose
refers to isolated yield.
29 are due to the sublimation of the trifluoromethylated
naphthalene products under reduced pressure during purifica-
tion.
For the substrate bearing pyridine moiety, the reaction gave
only a low yield of the product 30, presumably due to the
protonation of the pyridine nitrogen. In the case of
heteroaromatic amines, such as indoles and benzofurans, the
desired products 31−34 could be formed in moderate yields.
Besides, various di- and multi-substituted CF3-bearing arenes
could be accessed through this transformation in generally good
yields (35−46). Finally, to demonstrate the applicability of this
method in more complex molecules, we smoothly converted
the amino groups embedded in the estrone and tocopherol
framework into the trifluoromethyl groups (47 and 48).
The reaction with ethyl 4-aminobenzoate 1 was also
conducted on a gram scale to generate the desired product 3
in comparable yields as the small-scale experiment (eq 1).
significant affect on the reaction. Br− and CF3CO2 afforded
−
similar results as Cl−, whereas BF4 gave diminished yield and
−
t-BuO− gave only a trace amount of the product (entries 3−6).
It is noteworthy that using [CuCF3] as the CF3 source, freshly
prepared from CuCl, CsF, and Me3SiCF3 in DMF, the
trifluoromethylation also proceeded, albeit with lower yield
(entry 7).19 Finally, other solvents, such as DMF, DCE, MeOH,
and EtOH, were all found to give poor results.
With the optimal reaction conditions (Table 1, entry 2), the
substrate scope was then surveyed with a series of aromatic
amine derivatives (Scheme 3). In general, the aniline derivatives
bearing either electron-withdrawing or -donating groups react
smoothly to afford the corresponding trifluoromethylation
products in moderate to excellent yields. 4-Aminoazobenzene is
also a suitable substrate for the reaction, affording product 14.
Trifluoromethylation of unprotected alcohol and benzoic acid
affords the desired products 15 and 16 in good yields,
respectively. Remarkably, oxidation sensitive groups, such as
vinyl, alkynyl, Bpin, and TMS groups, also tolerate the reaction
conditions (17−22). The anilines bearing ortho-substitutents,
including ester and bulky isopropyl groups, also worked well to
give 23 and 24, respectively. The diminished yields of 28 and
Moreover, by employing our previously established metal-free
borylation method,20 we could smoothly convert the two
amino groups of benzene-1,4-diamine 49 into Bpin and CF3
groups successively, with similar Sandmeyer-type reaction for
both steps (eq 2). This transformation shows the oxidation
sensitive Bpin group tolerates the Sandmeyer-type trifluor-
omethylation (also see 20 in Scheme 3).
Preliminary mechanistic investigations have been carried out
on this reaction. For the Sandmeyer-type transformations, it
was proposed that the reaction may involve aryl radical
B
dx.doi.org/10.1021/ja4056239 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
probe was introduced by using 2-(but-3-en-1-yl)aniline 52 as
the substrate in the reaction (Scheme 4a). The normal
Scheme 3. Trifluoromethylation of Various Aromatic Amine
Substrates
a
Scheme 4. (a) Radical Clock Probe Experiment. (b)
Trapping Experiment for Possible Radical Intermediates. (c)
Background Reaction of [AgCF3]
trifluoromethylation product 54 was formed in 41% yield
(19F NMR), whereas cyclization product 55 could not be
detected.22 The diminished yield of the trifluoromethylation
product 54 was due to the decomposition of the substrate and
the product under the reaction conditions. These results are
not in favor of the possible involvement of aryl radical species.
Next, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a well-
known free radical scavenger, was introduced as the additive in
the standard reaction (Scheme 4b). The yield of 3 was
diminished to 42% and TEMPO-CF3 56 was formed in 17%
yield when 1.0 equiv of TEMPO was added under standard
condition. The yield of 3 was further dropped to 34%, and 73%
of TEMPO-CF3 56 was observed when 3.5 equiv of TEMPO
was added. However, TEMPO-Ar adducts were not observed,
as judged by both NMR and GC-MS analysis of the crude
product. Nitrobenzene, which has been shown to be the
inhibitor of SET steps in free radical aryl C−H trifluorome-
thylation,24,9c has essentially no effect on the reaction.
a
b
Yields refer to the isolated products if not otherwise noted. These
yields are based on 19F NMR with 4-CF3O−C6H4OMe as internal
standard.
We speculate that the formation of CF3 radical is due to the
background reaction of [AgCF3] (Scheme 4c).9c,10c Thus, in
the absence of aryl diazonium salt, [AgCF3] was added to the
TEMPO in EtCN. We observed the formation of TEMPO-CF3
56 in 18% yield. Moreover, in the trifluoromethylation reaction,
we found that most silver remains as Ag(I) salt, rather than
Ag(0). Collectively, these results indicate that CF3 radical is
unlikely involved in the trifluoromethylation pathway. An
oxidative addition−reductive elimination mechanism involving
high-valent silver species, as shown in Scheme 2, may be
species.21 To validate whether aryl radical species are generated
in the current trifluoromethylation process, a radical clock
C
dx.doi.org/10.1021/ja4056239 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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In summary, the conversion of an amino group into a CF3
group is a valuable complement to the previously established
trifluoromethylation methods.25 The reaction proceeds at low
temperature and tolerates various functional groups. Moreover,
the amino group can be readily protected and deprotected,
rendering this method suitable for late-stage introduction of a
CF3 group onto an aromatic structure.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure, characterization data, and copies of 1H
and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
wangjb@pku.edu.cn
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(19) For detailed screening of reaction conditions, see Supporting
Information.
We thank Ms. Xiu Zhang and Ms. Hui Fu for NMR analysis,
Mr. Guojiao Wu (Peking University) for helpful discussions,
and Mr. John Thompson (University of Texas at Austin) for
correcting the manuscript. Support of this work by 973
Program (no. 2012CB821600) and NSFC (no. 21272010) is
gratefully acknowledged.
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C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.-J.; Lu, X.; Liu, L.; Fu, Y. J. Am. Chem.
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