Metal-free synthesis of 2-fluoroalkylated quinolines using polyfluoroalkanoic acids as direct fluorine sources

Article abstract of DOI:10.1021/acs.orglett.9b00039

A novel [5 + 1] cyclization of 2-vinylanilines with polyfluoroalkanoic acids under catalyst- A nd additive-free conditions was successfully implemented. The approach directly employs very low-cost and readily available polyfluoroalkanoic acids as both C1 synthons and fluoroalkyl building blocks. This method provides concise access to diverse 2-fluoroalkylated (CF₃, C₂F₅, C₃F₇, CF₂H, CF₂Cl, and CF₂Br) quinolines in good yields with excellent functional group tolerance in high yield on a gram scale.

Full text of DOI:10.1021/acs.orglett.9b00039

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free Synthesis of 2‑Fluoroalkylated Quinolines Using
Polyfluoroalkanoic Acids as Direct Fluorine Sources
Jiang Nan,* Yan Hu, Pu Chen, and Yangmin Ma*
Shaanxi Key Laboratory of Chemical Additives for Industry, College of Chemistry and Chemical Engineering, Shaanxi University of
Science and Technology, Xi’an 710021, China
S
* Supporting Information
ABSTRACT: A novel [5 + 1] cyclization of 2-vinylanilines with
polyfluoroalkanoic acids under catalyst- and additive-free conditions
was successfully implemented. The approach directly employs very
low-cost and readily available polyfluoroalkanoic acids as both C1
synthons and fluoroalkyl building blocks. This method provides
concise access to diverse 2-fluoroalkylated (CF3, C2F5, C3F7, CF2H,
CF2Cl, and CF2Br) quinolines in good yields with excellent functional
group tolerance in high yield on a gram scale.
he continual discoveries of organofluorine compounds
In this context, several straightforward fluorination methods
for accessing 2-fluoroalkylated (CnFm or CF2H) quinolines
have been established.5−11 For example, the groups of
Grushin,5 Weng,6 and Amii7 independently reported the
preparation of 2-perfluoroalkylated quinolines by C−X
cleavage relying on metal-containing fluorinating reagents
(Figure 2a). Soon after, Kanai,8 Larionov9 and Kuninobu10
T
have been, inarguably, an important research topic to
chemists and pharmacologists.1 In this aspect, 2-fluoroalkylated
quinolines are prominent and valuable structural subunits that
are frequently encountered in bioactive pharmaceuticals
(Figure 1). For instance, compound I, named mefloquine, is
Figure 1. Selected examples of biologically active fluorinated
quinolines.
a well-recognized clinically used drug for treating resistant
Plasmodium falciparum malaria.2a Compounds II−VI were
investigated as antituberculosis agents,2b PDE4 inhibitors,2c
cardiovascular agents,2d VR1 receptor antagonists,2e and anti-
infective agents,2f respectively. In addition, 2-trifluoromethyl
quinolines are also excellent ligands for metal-catalyzed
reactions.3 The documented methods for accessing these
intriguing motifs mainly focus on the cyclization of highly
decorated starting materials that often require multistep
preparations as well as preinstalled fluorine groups.4 From
the viewpoint of synthetic efficiency, the development of a
step-economical and direct fluorination strategy for accessing
2-fluoroalkylated quinolines is of great importance.
Figure 2. Synthesis of 2-fluoroalkylated quinolines.
skillfully developed cutting-edge C−H trifluoromethylations of
quinolines employing the Ruppert−Prakash reagent
(TMSCF3) (Figure 2a). In addition, the assembly of 2-
difluoromethylated quinolines was reported using (CF2H)Ag-
(SIPr) or CF2HCOOH as the fluorine source in a metal-
catalyzed manner;11 however, only two substrates provided the
Received: January 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00039
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Organic Letters
Letter
target molecules (Figure 2b). Despite these tremendous
achievements, most of the aforementioned fluorinating
reagents are not practical for use on a large scale because of
their high cost,12 limited availability, and poor atom
economy,13 which significantly restrict their applicability.
Furthermore, no methodologies providing the other CF3-
derived 2-fluoroalkylated (CF2Cl and CF2Br) quinolines have
been reported. As such, the pursuit of versatile approaches
toward preparing diverse 2-fluoroalkylated quinolines from a
low cost and more readily available starting material is of
utmost importance.
reaction performance was significantly enhanced by increasing
the reaction temperature (entries 10 and 11), delivering 3a in
92% yield under 140 °C. However, the higher temperature still
gave the product with low yield in the presence of solvent
(entries 12).
Having effective reaction conditions in hand, we first
investigated the generality of this process by employing a
variety of 2-vinylaniline substrates in the reaction with TFA. As
revealed in Scheme 1, the reaction proceeded smoothly to
Scheme 1. Substrate Scope of 2-Vinylanilines
On the other hand, trifluoroacetic acid (TFA) is clearly an
ideal fluorine building block in terms of its price and
commercial availability.14 Along with general studies on
introducing trifluoromethyl moieties from TFA to produce
important substances typically via multistep transformations,15
a few recent reports by the groups of Tortoioli,16 Li,17 and
Zhang18 have demonstrated that TFA can be used to directly
install trifluoromethyl units into organic molecules by either
radical or ionic methods in one step. Despite these remarkable
examples, the development of additional types of reactions
using very low-cost TFA as a direct trifluoromethyl source is
necessary. Herein, we disclose a very practical and versatile
method for synthesizing a variety of 2-fluoroalkylated (CF3,
C2F5, C3F7, CF2H, CF2Cl, and CF2Br) quinolines from useful
2-vinylanilines19 and easily accessible polyfluoroalkanoic acids
(Figure 2c). The new process proceeds smoothly under
catalyst- and additive-free conditions.
We commenced this study by reacting 2-vinylamine 1a with
TFA (2a) to explore suitable reaction conditions (Table 1).
a
Table 1. Optimization of the Reaction Conditions
deliver a wide range of desired 2-trifluoromethylated quino-
lines in 61−95% yields. Various substituents at different
positions of the aromatic ring were well tolerated in this
transformation, including methyl (1b), methoxy (1c,l),
thiomethyl (1d), phenyl (1e), methylenedioxy (1m), and
cyclohexyl (1o) groups, as well as electron-withdrawing groups
(EWGs) such as fluoro (1f), trifluoromethoxy (1h), nitro (1i),
and ester (1j) groups. Potentially labile halogen functionalities
(1g,k) were also tolerated in the reaction, and these groups are
valuable handles for further elaboration. In addition, further
studies revealed that naphthylated substrates underwent the
cyclization quite smoothly, giving rise to products (3n,p)
possessing polycyclic π-conjugated systems in excellent yields.
Given the high value of 2-fluoroalkylated quinolines, we
evaluated the performance of ortho α- or β-substituted anilines.
The results showed that 2-vinylanilines bearing diverse vinyl
substituents fragments could undergo this transformation and
provide products in moderate to high yields (Scheme 2). The
R2 substituents could be various aryl groups (1q−t) with
diverse electronic and steric properties, and these substrates
led to corresponding 2-trifluoromethylated quinolines 3q−t in
64−94% yields under the same reaction conditions. Hetero-
cyclic substituents such as thiophene were also tolerated,
although they provided moderate yields. Moreover, a series of
monoalkyl- and dialkyl-substituted substrates with methyl
(1v), cyclohexyl (1w), or cycloheptyl (1x) moieties were
found to be suitable for this process. Finally, it should be
mentioned that substrate 1y underwent this cyclization and
gave structurally more crowed 2,3,4-trisubstituded quinoline
3y in 76% yield instead of formation of expected 4-ethyl-2-
b
entry
solvent
MeCN
DMF
1,4-dioxane
CHCl3
toluene
toluene
toluene
2a (mmol)
T (°C)
yield (%)
1
2
3
4
5
6
0.4
0.4
0.4
0.4
0.4
1.0
1.0
5.0
10.0
10.0
10.0
1.0
100
100
100
100
100
100
100
100
100
120
140
140
<5
<5
<5
<5
8
15
13
36
49
78
92
21
c
7
8
9
10
11
12
toluene
a
All reactions were carried out using 1a (0.2 mmol), 2a, and solvent
(0.8 mL) and stirred for 24 h under air. Isolated yields. 4 Å MS
(30.0 mg) was added.
b
c
Screening of various solvents was found to be completely
ineffective for accessing compound 3a (entries 1−4), although
toluene solvent gave the target molecule in 8% yield (entry 5).
Further attempts with increased amounts of TFA and
employing activated 4 Å molecular sieves also failed to
improve this progress (entries 6 and 7). Notably, treating the
reaction with excess amount of TFA obviously showed the
superior results at the absence of solvent (entries 8 and 9, and
Table 1 in the Supporting Information). Furthermore, the
B
DOI: 10.1021/acs.orglett.9b00039
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Organic Letters
Letter
Scheme 2. Substrate Scope of 2-Vinylanilines
Scheme 4. Large-Scale Reaction and Further Applications
(trifluoromethyl)quinoline, which could be explained by the
migration of the alkene under the acidic conditions.
To prepare additional types of fluoroalkylated quinolines, we
sought to expand the scope of the acid partner. Overall, a series
of commercially available polyfluoroalkanoic acids were
successfully introduced, furnishing diversely fluoroalkyl-sub-
stituted quinolines 3a′−t′ in 44−86% yields (Scheme 3). With
Scheme 3. Scope of Polyfluoroalkanoic Acids
over Pd/C, the pyridine fragment of 3a was selectively reduced
via hydrogenation to give 5 as a single diastereomer in 64%
yield (Scheme 4c). Gratifyingly, fluoroalkylated quinoline 3z
was also obtained from 1z, in 76% yield, satisfactorily allowing
the rapid assembly of an appealing class of tetracyclic
compounds 6 through a Pd(0)-catalyzed, highly regioselective
C−H activation by forming a C−C bond in 79% isolated yield
(Scheme 4d).
To elucidate the mechanism, several exploratory experi-
ments were performed. A control experiment with 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO, 2.0 equiv) as a radical
scavenger still efficiently delivered desired product 3a,
excluding the involvement of a radical intermediate (Scheme
5a). The reaction with acetic acid (7) provided amide species 9
Scheme 5. Control Experiments
regard to the RF groups, chloro (2b), bromo (2c),
trifluoromethyl (2d), and pentafluoroethyl (2e) units were
well tolerated. In particular, the difluoromethyl (CF2H)
functionality was efficiently installed when using difluoroacetic
acid (2f) as a substrate, and this moiety often functions as a
lipophilic hydrogen-bonding donor and can be employed as a
bioisostere of alcohols and thiols.20 To further shed light upon
the conformation of desired products, the structures of selected
fluoroalkylated (R = CF3, Br, Cl, and H) quinolines were
unambiguously elucidated by X-ray diffraction analyses on 3d′,
3h′, 3l′, and 3p′.
Subsequently, we turned our attention to the scalability and
potential utility of this method. First, a larger scale experiment
with 10.0 mmol of 1a was carried out, and the reaction
afforded target 3a (2.46 g) with a comparable yield and
efficiency (Scheme 4a); gram-scale syntheses involving the
introduction of a trifluoromethyl group are quite rare.
Moreover, trifluoroacetic anhydride (TFAA), another rarely
reported trifluoromethylating reagent,21 was able to undergo
the same transformation in place of TFA to efficiently furnish
the desired product (Scheme 4b). Upon treatment with H2
as main product instead of desired 2-methyl-4-phenylquinoline
(8), which suggested the necessity of the strong acids for this
methodology (Scheme 5b). With 2-phenylaniline 10 as the
substrate, none of anticipated compound 11 was observed, but
corresponding trifluoroacetamide 12 was generated in 90%
yield (Scheme 5c). These results indicated that the
corresponding amide species is most likely involved in the
process.22
C
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Organic Letters
Letter
According to the above results, together with previous
reports,23 a tentative pathway for the generation of 2-
trifluoroalkylated quinolines was proposed as depicted in
Scheme 6. Initially, trifluoroacetamide 13 was generated in situ
Education Department of Shaanxi Province (18JK0110). We
thank Dr. Yifan Kang at Shaanxi University of Science and
Technology for X-ray crystallographic assistance.
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currently underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00039.
Experimental procedures and spectral data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: nanjiang@sust.edu.cn.
*E-mail: mym63@sina.com.
ORCID
Jiang Nan: 0000-0001-5570-6834
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This work was supported by the NSFC (21801159), the China
Postdoctoral Science Foundation (2018M640944), and the
■
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