An efficient and facile strategy for trifluoromethylation and perfluoroalkylation of isoquinolines and heteroarenes

Article abstract of DOI:10.1039/d0cc00963f

An effective and regioselective strategy for trifluoromethylation and perfluoroalkylation of isoquinolines and heteroarenes was developed. By combination of TMSCnF2n+1 (n = 1, 2, 3) with PIFA, the method achieved the corresponding perfluoroalkylated produ

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DOI: 10.1039/D0CC00963F
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An efficient and facile strategy for trifluoromethylation and
perfluoroalkylation of isoquinolines and heteroarenes
Yang Pan,a,b Jiangtao Li,a,b Zhefeng Li,c Feng Huang,a Xiaofeng Ma,a Wei Jiao*a and Huawu Shao*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An effective and regioselective trifluoromethylation and
perfluoroalkylation of isoquinolines and heteroarenes was
developed. By combination of TMSCnF2n+1 (n=1,2,3) with PIFA, the
method achieved the corresponding perfluoroalkylated products
with broad functional groups tolerance.
Owing to unique size and electronic properties of fluorine
atom, the perfluoroalkylation of organic substrates can
remarkably improve the molecular lipophilicity, metabolic
stability and bioavailability. These advantages therefore make
the perfluoroalkylation, especially, trifluoromethylation of
aromatic compounds as hot research topics in the
pharmaceuticals, agrochemicals and materials science.1 Most
of the current strategies for introduction CF3 in these aromatic
motifs require pre-functionalized substrates, such as aryl
halides,2 aromatic diazonium salts (from corresponding
aromatic amines)3 and aromatic boronic derivatives4 catalyzed
by a suitable transition metal catalyst. Though some elegant
strategies have been developed, the cross-coupling reaction
requires multiple steps for the preparation of functional
substrates that would reduce the practicability and efficiency
of such methodologies. Consequently, development of the
methods for regioselective direct C-H trifluoromethylation of
aromatic systems has become increasingly important in the
last few years.
Even though in some cases, poor yield and selectivity
were observed, direct trifluoromethylation of electron-rich
aromatic and heteroaromatic systems now are increasing
prospering via a radical process under photochemical or
oxidation conditions,5 whereas the related direct
trifluoromethylation of electron-deficient systems have not
reached the same level of development. Within this context, in
2014, Kanai et al. revealed a regioselective direct approach for
α-trifluoromethylation of N-heteroaromatic N-oxides (Scheme
Scheme 1 Regioselective direct C-H trifluoromethylation of six-
membered N-heteroaromatic systems.
1a).6 Despite its high regioselectivity, the pre-preparation of N-
oxide−BF2CF3 complex is still required. Larionov and co-
workers, in the same year, also presented a 2-position-
selective C-H trifluoromethylation of six-membered N-
heteroaromatic N-oxides.7 Nevertheless, the cumbersome pre-
activation processes made them less attractive. Until 2018,
Yoichiro and co-workers disclosed a 2-position direct selective
C-H trifluoromethylation and perfluoroalkylation of quinoline
derivatives (Scheme 1b).8 In the protocol, the in situ formed
hydrogen fluoride (HF) from reaction of KHF2 and CF3COOH
(TFA) can activate quinoline and trifluoromethyl
trimethylsilane (TMSCF3) simultaneously, which prompted
trifluoromethyl group nucleophilic attack to activated
quinoline via a six-membered transition state. Apart from this,
there
were
also
some
radicals
based
direct
trifluoromethylation of six-membered N-heteroaromatic
systems, including pyridines, quinoxalines, pyrimidines,
pyridazines and others.9 These methods avoid substrates pre-
functionalization and pre-activation, as well as obtain various
trifluoromethylated nitrogen heterocycles. However, without
ring pre-activation, the regioselectivity of these reactions are
generally difficult to control.
Over the past few years, there were some works revealed
direct single-electron oxidation of TMSCF3 using hypervalent
iodine can generate CF3 radical,10 which was applied to the
a. Natural Products Research Centre, Chengdu Institute of Biology, Chinese Academy
of Sciences, Chengdu, China. E-mail: shaohw@cib.ac.cn, jiaowei@cib.ac.cn.
b. University of Chinese Academy of Sciences, China.
c. School of Chemistry and Chemical Engineering, Chongqing University, Chongqing
400044, China.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Table 1 Optimization of the reaction conditionsa
was only produced in low yields (Table 1, entries 8-10). Besides,
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no desired transformation took place when other oxidants t-
DOI: 10.1039/D0CC00963F
butylhydroperoxide (TBHP) and K2S2O8 were employed (Table
1, entries 11 and 12). Same results were obtained when the
fluoride source was changed from KF to CsF (Table 1, entry 13).
While under the same conditions, TBAF and AgF given no
target product (Table 1, entries 14 and 15). Performing the
reaction at 0 C, the hightest yield was obtained, but with
temperature of reaction decreased to -10 C, the yield reduced
to 66% (Table 1, entries 16 and 17). Thus,
Yieldb
(%)
Temp.
Entry
Oxidant
F-
Solvent
(C)
1
2
3
4
5
6
7
8
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIDA
KF
KF
KF
KF
KF
KF
KF
KF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
CH3CN
dioxane
MeOH
toluene
THF
trace
n.r.
n.r.
n.r.
trace
10
Table 2 Substrate scope of isoquinolines and N-heteroarenes a
DMF
NMP
57
NMP
6
Koser’s
reagent
9
KF
r.t.
NMP
4
10
11
12
13
14
15
16
17
PhIO
TBHP
K2S2O8
PIFA
KF
KF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
7
n.r.
n.r.
52
KF
CsF
TBAF
AgF
KF
PIFA
trace
n.r.
73
PIFA
PIFA
PIFA
KF
-10
66
a Reaction conditions: 1a (0.2 mmol), TMSCF3 (3.0 equiv.), oxidant
(3.0 equiv.), and fluoride source (4.0 equiv.) in 2.0 mL anhydrous
solvent for 24 h under Ar. b Isolated yield, n.r. = no reaction.
direct C-H trifluoromethylation of vinyl azides,10b alkenes,10c-10e
and electron-rich arenes.10f, 10g Due to our continuing interests
in the study of heterocyclic compounds,11 the further research
was inspired by a recent hypervalent iodine induced acylation
of N-heterocycles with aldehydes via an acyl radical.12 We
hence envisioned that a regioselective trifluoromethylation of
the electron-deficient N-heterocycles could be achieved by a
similar radical process. Herein, the direct C-H
trifluoromethylation and perfluoroalkylation of isoquinolines
and other N-heteroaromatic compounds is disclosed.
We initiated our investigation by using isoquinoline as
model substrate. The [Bis(trifluoroacetoxy)iodo]benzene (PIFA)
and TMSCF3 were employed as the source of CF3 radical.
CH3CN was chosen for solvent priority as it is generally a
reliable solvent in this kind of reaction.10b, 10d However, under
the condition, only trace amount of product was detected
(Table 1, entry 1). We then screened a series of solvents, and
delightedly found that the desired product 3a was isolated in
10% yield in DMF (Table 1, entry 6). By switching the solvent to
NMP, the yield of trifluoromethylated product was increased
dramatically to 57% (Table 1, entry 7).
a Reaction conditions: unless otherwise stated, substrate
1 (0.2
mmol), PIFA (3.0 equiv.), KF (4.0 equiv.), TMSCnF2n+1 (3.0 equiv.)
in NMP (2.0 mL) at 0 C for 24 h. b PIFA (4.0 equiv.) was used at
c
room temperature. The number in parentheses is the yield
Due to the hypervalent iodine reagents (HIRs) were
effective for organic transformations as selective oxidants,13
a
based on recovered starting material.
series of HIRs were examined (Table S2, ESI†). However, 3a
2 | J. Name., 2012, 00, 1-3This journal is © The Royal Society of Chemistry 20xx
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the model reaction, which was inhibited dramatically.
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Meanwhile, the TEMPO-CF adduct was detected by LC-MS.
DOI: 10.1039/D0CC00963F
3
Scheme 2 Synthetic application.
PIFA (3.0 equiv.), TMSCF3 (3.0 equiv.), and KF (4.0 equiv.) in

NMP at 0 C was chosen as the optimal reaction condition for
the trifluoromethylation.
Having the optimal conditions in hand, the substrates
scope of isoquinoline and heteroarenes were explored (Table
2). A variety of isoquinoline derivatives bearing electron-
donating and electron-withdrawing groups at the 6-position
were firstly tested. We found that the substrates with
electron-donating groups, such as methyl and methoxy groups
offered corresponding compounds (3b and 3c) in higher yields
(78% and 82% respectively), while electron-withdrawing
groups resulted in lower yields (3d and 3e). Additionally, the
reaction tolerated a broad range of functional groups on
benzene ring part. For example, substrates with alkyne and
aldehyde substituents, which were easily oxidized by
hypervalent iodine,13f were smoothly converted into the
corresponding trifluoromethylated derivatives in 72% and 36%
yield respectively (3f and 3g). The nitro group at 5-position of
isoquinoline was tolerated as well (3h). Placement of a
methoxy or di-methoxy groups on other positions of benzene
unit was also achieved in good yields (3i and 3j). When 4-
position of isoquinoline was substituted with halogen,
methoxy and phenyl groups, the transformation gave desired
products in 52%-65% yields (3k-3n). Different substituted
groups at the 8-position were also acceptable, which achieved
the trifluoromethylated isoquinolines (3o and 3p).
Fig. 1 IRC plot of the key transition state TS with representative
structures. The red curve is the process of the electron transfer,
and the blue curve is dehydrogenation process. green: α
electron, blue: β electron.
To explore the scope of the method, we then turned our
attention to other N-heterocyclic compounds. The pyridines,
quinoline, pyrazine, thienopyridines, 1,6-naphthyridine,
phenanthridine and phenanthroline were explored under the
standard reaction conditions, which delivered the products in
32% to 68% yields (3q-3z). Interestingly, the trifluoromethyl
group reaches the 2-position of quinazoline 1π, which was
different from the regioselectivity of isoquinoline.
Moreover, our direct C-H trifluoromethylation
methodology can also be extended to perfluoroethylation of
isoquinolines and pyridines. As shown in Table 2, exposure of
TMSC2F5 and TMSC3F7 to the same conditions as
trifluoromethylation process, the desired perfluoroethylation
products (4a-4e) were obtained in 67% to 74% yields.
Scheme 3 Plausible mechanistic pathways.
These results suggest a free-radical pathway is probably
involved in this process and the CF3 radical take part in our
system. The generally accepted mechanism for the
hypervalent iodine induced functionalization of electron-rich
arenes was the generation of radicals can occur through a
single electron transfer (SET) oxidation of arenes via a charge-
transfer (CT) complex.15 However, for the electron-deficient
system, because of the high reactivity of intermediates
formed from hypervalent iodine reagents，it is difficult to
At this stage, we have successfully prepared a wide range
of trifluoromethylated products under mild, direct, and metal
free conditions with high regioselectivity and multifunctional
groups toleration. The synthetic utility of the
trifluoromethyltion reaction was further demonstrated by
preparing 6-bromo-1-(trifluoromethyl)isoquinoline 3λ, which is
a pre-requisite intermediate for the synthesis of Valiglurax, a
potential candidate for the treatment of Parkinson’s disease.
Generally, 3λ was synthesized from 6-bromoisoquinoline 1λ
via 2 steps reaction in 37% to 43% total yield.14 In our case, 3λ
was conveniently obtained in 66% yield in one step (Scheme 2).
In order to study the reaction mechanism, several control
experiments were performed (Scheme S3, ESI†). The radical
quenchers such as 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) and butylated hydroxytoluene (BHT) were added to
understand how the hypervalent iodine reagents interact with
electron-deficient heteroarenes in radical reaction through the
conventional experimental protocols. To further understand
the mechanism of the direct C−H trifluoromethylation, DFT
calculations were performed on the reaction of isoquinoline 1a
and PIFA.16, 17
Based on the above experimental results, a plausible
mechanism for direct C-H trifluoromethylation of isoquinoline
and its analogues was proposed, which was shown in Scheme
3. At the initial stage of the reaction, isoquinoline 1a forms a
-
weak complex with PIFA. After the activation of fluoride, CF3
was released from TMSCF3 and then through ligand exchange
with PIFA to form intermediate INT1. Subsequently, homolysis
of INT1 could give rise to CF3 radical. The released CF3 radical
would attack the 1-position of 1a, which is the most reactive
site of isoquinoline.18 The transition state TS went through a
This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 3
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Fluor. Chem., 2010, 131, 98; (i) L. Cui, Y. MatusaVkiie,wNA.rtTicaledOan,linTe.
single electron transfer (SET) and a dehydrogenation process
to give the product 3a, and the intrinsic reaction coordinate
(IRC) shows the detailed process from the transition state to
the generation of trifluoromethylated product 3a (Fig. 1).19
In conclusion, we have developed a direct, mild easily
operated and highly regioselective method for the C−H
trifluoromethylation and perfluoroalkylation of isoquinolines
and heteroarenes with readily available TMSCnF2n+1 and
hypervalent iodine under metal-free conditions. The
advantage of the transformation is the synthetic simplicity and
diversity. The application of this reaction was illustrated by
preparation of useful medicinal molecules.
Miura, B. Uno and A. Itoh, Adv. Synth. Catal., 2013, 355, 2203.
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This work was supported by the National Science
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Conflicts of interest
There are no conflicts to declare.
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DOI: 10.1039/D0CC00963F
An effective and regioselective trifluoromethylation and perfluoroalkylation of
isoquinolines and heteroarenes was developed.