Metal-free direct intramolecular carbotrifluoromethylation of alkenes to functionalized trifluoromethyl azaheterocycles

Article abstract of DOI:10.1021/ol403391v

The first example of a metal-free direct carbotrifluoromethylation of alkenes using inexpensive TMSCF3 as the CF3 source is described. The methodology not only exhibits high chemoselectivity for this transformation but also expands the substrate scope tha

Full text of DOI:10.1021/ol403391v

Letter
pubs.acs.org/OrgLett
Metal-Free Direct Intramolecular Carbotrifluoromethylation of
Alkenes to Functionalized Trifluoromethyl Azaheterocycles
Lei Li, Min Deng, Sheng-Cai Zheng, Ya-Ping Xiong, Bin Tan,* and Xin-Yuan Liu*
Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518055, P. R. China
S
* Supporting Information
ABSTRACT: The first example of a metal-free direct carbotri-
fluoromethylation of alkenes using inexpensive TMSCF3 as the
CF3 source is described. The methodology not only exhibits high
chemoselectivity for this transformation but also expands the
substrate scope that is difficult to access by known transition-
metal-catalyzed methods.
he increasing importance of trifluoromethyl aza-hetero-
the metal center and the bidentate ligand with five-membered
T
cycles1 for the synthesis of anticholinergic, antiemetic, and
ring chelation,8 to render insufficient activation of the reactive
functional group of the substrate. To address some of these
limitations, the development of a promising and mechanistically
distinct strategy for expanding the carbotrifluoromethylation of
alkenes method, especially for the reaction of precursors
bearing strong coordinating functional substituents under
metal-free conditions with inexpensive CF3 reagents, is still
an urgent need.
antispastic drugs as well as enzyme inhibitors has spurred
vigorous research for the development of new methods for C−
CF3 bond formation with intriguing selectivity and high atom
economy.2,3 More recently, direct difunctionalization of
alkenes, such as oxytrifluoromethylation,4 aminotrifluorome-
thylation,5 and carbotrifluoromethylation,6 has attracted con-
siderable attention, providing the most attractive strategy for
the simultaneous formation of two vicinal chemical bonds, with
concomitant formation of a C−CF3 bond and rings. For
example, transition-metal-catalyzed aryltrifluoromethylation
offers a convenient and step-economical synthesis of trifluor-
omethyl azaheterocycles from the respective acyclic starting
materials (Scheme 1a).6 Although significant progress has been
Over the past two decades, hypervalent iodine(III) reagents
have been widely used to promote a variety of organic
transformations under metal-free conditions.9 In contrast, the
potential of iodine(III) reagents with the combination of an
inexpensive CF3 source such as TMSCF37 in oxidative carbon−
CF3 bond formation under metal-free conditions remains
widely unexplored, and examples of trifluoromethylation
reactions have only recently emerged.3f,10 In these reported
reactions, the transformation might be realized using iodine-
(III) reagents for the generation of an electrophilic CF3 radical.
These results10 and the recent advance in radical-involved
aryltrifluoromethylation6 of alkenes have prompted us to
envision that the direct aryltrifluoromethylation of alkenes
might be performed under metal-free conditions via a single-
electron-transfer (SET) process11 triggered by an electrophilic
CF3 radical generated from iodine(III) reagents.10 Further-
more, we reasoned that the judicious combination of the
appropriate hypervalent iodine reagents and TMSCF3 without
any metal catalysis could tolerate many different coordinating
functional groups, as it would obviate the need for metal
catalysis to avoid the strong coordination8 between the metal
center and the functional groups and yet still render the CF3
radical electrophilic.10 In connection with our continuous
efforts devoted to the synthesis of CF3-azaheterocycles,5d
herein, we describe the first example of the development of a
remarkably mild and general PhI(OAc)2-mediated direct
Scheme 1. Intramolecular Aryltrifluoromethylation
made with high yields and a reasonable substrate scope, some
crucial issues have remained fairly unaddressed. First, these
reactions generally involve an expensive and highly toxic metal
catalyst and the requirement for very expensive electrophilic
CF3 reagents,7 making the process less applicable to large-scale
synthesis especially at a late stage. Furthermore, substrates in
these transformations6 are inherently limited to those bearing
only alkyl or single carbonyl linkers lacking functionality.
However, substrates bearing imide groups next to the alkene
remain a formidable challenge for this reaction with metal
catalysis, owing to the rapid and strong coordination between
Received: November 22, 2013
Published: December 18, 2013
© 2013 American Chemical Society
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Letter
carbotrifluoromethylation of alkenes using inexpensive
TMSCF3 under alternative metal-free conditions.12
KF, and Na2CO3 in EtOAc at 50 °C (Scheme 3). Additional
comparisons were run to evaluate the performance of Togni’s
To validate the feasibility of the proposed metal-free
processes, we selected N-arylacrylamides 1a as the model
substrate for the optimization of reaction conditions, based on
recent reports that such a substrate can undergo aryltrifluor-
omethylation in the presence of transition-metal catalysis.6 As
such, we initially examined the reaction of 1a by using TMSCF3
as the CF3 source and PhI(OAc)2 as the oxidant in the presence
of KF. We found that such a system could activate this reaction
in 1,4-dioxane at 50 °C to form the desired product 2a in 34%
yield (Table S1 in the Supporting Information). Encouraged by
this result, we then screened different organic solvents revealing
EtOAc as being optimal to give 2a in 74% yield, suggesting a
significant solvent effect for this reaction. Among the reaction
temperatures examined, the reaction at 50 °C gave the best
results. Subsequently, two more substituted oxidants, such as
PhI(OPiv)2 or PhI(OCOCF3)2, were examined and found to
result in sluggish reactions. We then investigated the effect of
changing additives and found that the use of inorganic bases13
such as CsF, Cs2CO3, or KF with 4 Å MS can activate the
reaction, but gave the desired product in relatively low yields
compared with the use of KF.
Scheme 3. Trifluoromethylation of α,β-Unsaturated Imide
Alkenes under Metal-Free Conditions
reagent with the CuI catalyst in this process, under the
conditions identical to those of copper-catalyzed aryltrifluor-
omethylation.6 However, no desired product was obtained at
different reaction temperatures from 40 to 70 °C for different
reaction times in all cases, demonstrating that the catalytic
activity of copper may be possibly suppressed by the strong
coordination between the metal center and imide groups. It is
important to note that this methodology under metal-free
conditions allows us to easily realize transformation, which can
serve as an attractive complementary approach to the more
conventional transition-metal-catalyzed trifluoromethylation
reactions.6 We next investigated the scope of the reaction
using different types of substituted α,β-unsaturated imides. A
range of diversely functionalized imides, including those having
electron-withdrawing and -donating groups at different
positions of the phenyl ring, gave the corresponding products
4a−4e in moderate to good yields.
With optimized reaction conditions for the metal-free
carbotrifluoromethylation reaction in hand, we evaluated this
methodology with a wide range of substituted N-arylacryla-
mides. Several substituents, such as Me, MeO, Ph, NO2, F, or
Br, on the para- or ortho-position of the N-aryl moiety were
consistent with the optimized conditions, and the correspond-
ing oxindoles 2b−2g were obtained in good yields (Scheme 2).
Scheme 2. Trifluoromethylation of Activated N-
Arylacrylamide Alkenes under Metal-Free Conditions
To further expand the application of such a reaction system,
we also extended the substrates to conjugated tosyl amides,
which underwent a cascade transformation to give trifluor-
omethylated oxindoles using Togni’s reagent with the copper
catalyst recently reported by Nevado and co-workers.6h To our
delight, the results show that, under the standard conditions, N-
tosyl substrates bearing different substituents at the N-atoms or
having electron-withdrawing and -donating groups at the para-
position of the phenyl ring were good for this transformation,
producing desired products 6a−6h in moderate to good yields
(Scheme 4). It is worth mentioning that when substrates 5g
Scheme 4. Trifluoromethylation of α,β-Unsaturated Imide
Alkenes under Metal-Free Conditions
Substrate 1h having two substituents on the phenyl ring also
provided the product 2h in 56% yield. This reaction shows
excellent compatibility with different N-substitution of the
amides, including N-aryl and N-alkyl groups to form different
trifluoromethyl heterocyclic compounds 2i−2k in good yields.
In addition, a functional group, such as ester (1l), at the 2-
position of the acrylamide moiety was compatible with this
metal-free system to form 2l in good yield.
Encouraged by the aforementioned aryltrifluoromethylation
reaction of N-arylacrylamides, we next turned our attention
toward expanding the substrate scope to α,β-unsaturated
imides. Much to our surprise, after optimization of the reaction
conditions, the reaction of α,β-unsaturated imides 3a gave the
desired product 4a in 65% yield by using TMSCF3, PhI(OAc)2,
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Letter
and 5h with N-benzyl groups were employed, the reaction
proceeded selectively and afforded the cyclized products 6g and
6h in good yields exclusively, which is in sharp contrast to a
copper-catalyzed reaction with poor chemoselectivity.6h
In order to gain more insight into the reaction mechanism,
several control experiments were performed. The reaction of 1a
with TMSCF3, PhI(OAc)2, and KF in the presence of 2,6-di-
tert-butyl-4-methylphenol (BHT) or 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) under the standard conditions
produced the desired products only in very little yields (eqs
1 and 3), while the TEMPO−CF3 adduct was formed in 94%
inexpensive TMSCF3 as the CF3 source and PhI(OAc)2 as the
oxidant. The methodology furnishes a diverse collection of
synthetically valuable trifluoromethylated heterocycles under
metal-free and mild conditions. Furthermore, in comparison
with reported methods for carbotrifluoromethylation of
alkenes, this approach not only exhibits high chemoselectivity
for this transformation but also expands the substrate scope
that is difficult to access by known transition-metal-catalyzed
methods, thus reflecting the synthetic utility of this method.
Efforts toward an asymmetric variant of this transformation are
currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterizations, and Table
S1. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liuxy3@sustc.edu.cn.
*E-mail: tanb@sustc.edu.cn.
Notes
yield as estimated by 19F NMR analysis. In addition, the
TEMPO−CF3 adduct was obtained in 63% yield when
TEMPO was reacted with TMSCF3, PhI(OAc)2, and KF
under the standard conditions (eq 2). These results reveal that
the CF3 radical is likely involved as the reactive species under
the current conditions.
Based on the control experimental results and the previous
investigation on aryltrifluoromethylation of alkenes,6 a plausible
mechanism for our methodology is depicted in Scheme 5. A
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for the financial support from the National
Natural Science Foundation of China (Nos. 21302088,
21302087), Shenzhen special funds for the development of
biomedicine, Internet, new energy, and new material industries
(JCYJ20130401144532131, JCYJ20130401144532137), and
South University of Science and Technology of China.
Scheme 5. Proposed Mechanism for the
Aryltrifluoromethylation Reaction of Alkenes
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