2-Position-Selective C-H Perfluoroalkylation of Quinoline Derivatives

Article abstract of DOI:10.1021/acs.orglett.8b00339

We developed 2-position-selective, direct C-H trifluoromethylation, pentafluoroethylation, and heptafluoropropylation of quinoline derivatives. Regioselective transformation was achieved without derivatization of the quinolines. The reaction proceeded at room temperature with high functional group tolerance, even in gram scale. Notably, the reaction was applicable to substrates containing a functional group sensitive to oxidation and a drug molecule.

Full text of DOI:10.1021/acs.orglett.8b00339

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
2‑Position-Selective C−H Perfluoroalkylation of Quinoline
Derivatives
Takahiro Shirai,† Motomu Kanai,*,†,§ and Yoichiro Kuninobu*,‡,§
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
‡Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan
§ERATO, Japan Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-0033, Japan
S
* Supporting Information
ABSTRACT: We developed 2-position-selective, direct C−H trifluoro-
methylation, pentafluoroethylation, and heptafluoropropylation of quinoline
derivatives. Regioselective transformation was achieved without derivatiza-
tion of the quinolines. The reaction proceeded at room temperature with
high functional group tolerance, even in gram scale. Notably, the reaction
was applicable to substrates containing a functional group sensitive to
oxidation and a drug molecule.
fluoride (HF) through the formation of a six-membered
he introduction of perfluoroalkyl groups can significantly
Timprove the functions of organic molecules, such as transition state (Figure 1e). Herein, we report 2-position-
drugs,1 agrochemicals,2 and organic functional materials,3 due
selective direct C−H trifluoromethylation, pentafluoro-
ethylation, and heptafluoropropylation of quinoline derivatives
(Figure 1e).
to their special properties, including strong electron-with-
drawing ability and stability. An ideal method of introducing
perfluoroalkyl groups is direct C−H perfluoroalkylation. For
example, C−H trifluoromethylation reactions with trifluor-
omethyl radical species proceed under mild conditions with a
broad substrate scope.4 Regioselective C−H trifluoromethyla-
tion of six-membered N-heteroaromatic compounds such as
pyridine and quinoline derivatives under radical trifluorome-
thylation conditions is quite difficult, however, mainly due to
the high reactivity of the CF3 radical (Figure 1a).4
On the other hand, several examples of 2-position-selective
C−H trifluoromethylation of six-membered N-heteroaromatic
compounds using a less reactive CF3 anionic species are
reported. In 2007, Makosza and co-workers reported a method
involving the preparation of N-(4-methoxybenzyl)azinium salts:
treatment of the salts with a CF3 anion and successive oxidation
(Figure 1b).5 In 2014, we reported a method involving N-oxide
formation, activation of N-oxides with a BF2CF3 Lewis acid, and
treatment of the BF2CF3 complex with a CF3 anion (Figure
1c).6,7 Subsequently, Larionov revealed a 2-position-selective
C−H trifluoromethylation of six-membered heteroaromatic N-
oxides (Figure 1d).8
Those reactions, however, have the following drawbacks: (1)
several steps to the trifluoromethylated products; (2) increased
production costs due to the need for a BF2CF3 source (Figure
1c); and (3) difficult applications to N-heteroaromatic
compounds containing oxidation-sensitive functional group(s),
such as a formyl group. To address these points, we envisioned
that 2-position-selective C−H trifluoromethylation would be
possible through dual activation of both N-heteroaromatic
substrates and trifluoromethyltrimethylsilane by hydrogen
Treatment of quinoline (1a) with trifluoromethyltrimethyl-
silane (2a) in the presence of trifluoroacetic acid and cesium
fluoride as a potential HF source in dimethylformamide (DMF)
did not afford the desired product (Scheme 1, entry 1). When
toluene was used as the solvent, a mixture of 2-trifluoromethyl-
dihydroquinoline (3a) and 2-trifluoromethylquinoline (4a)
formed in 10% yield (3a + 4a, Scheme 1, entry 2). In this
reaction, no other regioisomers formed. The total yield of 3a +
4a was improved to 38% by replacing the fluoride source with
potassium hydrogen fluoride (KHF2) and adding 3.0 equiv of
DMF (Scheme 1, entry 3). The reaction temperature was
decreased to 25 °C by changing the solvent to dioxane, but the
yield of 3a + 4a was still unsatisfactory (42%: Scheme 1, entry
4). The additive was crucial for this reaction (Scheme 1, entries
5−7), and the best results (73% yield of 3a + 4a) were achieved
by adding 3 equiv of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU) (Scheme 1, entry 7). We speculated
that DMPU acts as a Lewis base to form hypervalent silicon9
and increase the reactivity of Me3SiCF3 (see the proposed
mechanism section). Aromatized 4a should be obtained by
involuntary oxidation of 3a with aerobic oxygen during either
the reaction or workup.
Next, we investigated the substrate scope of six-membered
N-heteroaromatic compounds under the optimized conditions
(Scheme 2). To simplify product isolation, we added
PhI(OAc)2 to the reaction mixture before workup to converge
Received: January 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00339
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope of 2-Position-Selective
Trifluoromethylation of Quinoline Derivatives 1
Figure 1. C−H trifluoromethylation reactions of six-membered N-
heteroaromatic compounds.
Scheme 1. Optimization of the Reaction Conditions for 2-
Position-Selective Trifluoromethylation of Quinoline (1a)
methoxy, formyl, carbonyl, methoxycarbonyl, acetyloxy, amide,
alkenyl, and alkynyl groups and fluorine, chlorine, bromine, and
iodine atoms, remained unchanged. Specifically, an oxidation-
sensitive formyl group was tolerated under the reaction
conditions, albeit with a moderate product yield (33%: 4m).
Moreover, trifluoromethylation of the formyl group hardly
proceeded in this case. The reaction also proceeded using other
quinoline derivatives, such as phenanthroline derivatives and
1,5-naphthyridine (products: 4x−4z). Ditrifluoromethylated
products of 1x and 1z were not formed. In all entries, only
single regioisomers were formed, and almost all starting
substrates were recovered except the formation of the
a
b
Me3SiCF3 (6.0 equiv). 1H NMR yield of 4a after oxidation with
PhI(OAc)2.
the products to 4a. In the case of quinoline derivatives 1a−1g
having a methyl substituent at the 3-, 4-, 5-, 6-, 7-, or 8-position,
the product was obtained in 56%−67% yield. Based on the
results using 3-methylquinoline (1b) and 8-methylquinoline
(1g), the reaction was not affected by steric hindrance around
the nitrogen atom of the substrates. The reaction proceeded
with high functional group tolerance: functional groups, such as
B
DOI: 10.1021/acs.orglett.8b00339
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
trifluoromethylated products. Pyridine derivatives, however,
produced a low yield (e.g., 4,4′-di-tert-butyl-2,2′-dipyridyl:
10%).10,11
Scheme 5. Gram-Scale Experiment
We then expanded the scope of the nucleophiles to other
perfluoroalkylation reactions using 6-methylquinoline (1e) as a
substrate (Scheme 3). 6-Methyl-2-pentafluoroethylquinoline
Scheme 3. Perfluoroalkylation Reactions
Scheme 6. Trifluoromethylation of Quinine
(5) and 6-methyl-2-heptafluoropropylquinoline (6) were
obtained in 83% and 85% yields, respectively, when penta-
fluoroethyltrimethylsilane (2b) and heptafluoropropyl-
trimethylsilane (2c) were used as perfluoroalkylation reagents.
A working hypothesis for the reaction mechanism is
proposed in Scheme 4. After the formation of HF from
substrate containing an sp3 nitrogen atom with higher Brønsted
basicity than that of N-heteroaromatics even though the
reaction is supposed to be promoted by HF. Other functional
groups also remained unchanged during the reaction.
In summary, we developed 2-position-selective, direct C−H
trifluoromethylation, pentafluoroethylation, and heptafluoro-
propylation of quinoline derivatives using perfluoroalkyl-
trimethylsilane, trifluoroacetic acid, KHF2, and DMPU. The
reaction proceeded with high functional group tolerance,
including an oxidation-sensitive formyl group, which might
not be tolerated under the previous conditions. Because the
present reaction does not require the preparation of activated
substrates, it is more practical than previously reported
reactions with regard to the number of steps, time, and cost
required to synthesize 2-perfluoroalkylated quinoline deriva-
tives.
Scheme 4. Proposed Mechanism for 2-Position-Selective
Trifluoromethylation
ASSOCIATED CONTENT
■
CF3COOH and KHF2,12 2-position-selective trifluoromethyla-
tion proceeds through a six-membered transition state A
comprising a hexavalent silicon center derived by the assembly
of substrate 1, HF, Me3SiCnF2n+1 (2), and DMPU.13−16 The
transfer ability of a perfluoroalkyl group on a silicon atom
increases by the coordination of DMPU which coordinates to a
hypervalent silicon atom.13 Then, the nucleophilic attack of the
perfluoroalkyl group to a 2-position of the quinoline derivative,
where it is electrophilically activated by HF, occurs to give
intermediate 3. The resulting dihydroquinoline 3 is converted
to 2-trifluoromethylated quinoline 4 via oxidation of 3 with
PhI(OAc)2.
The trifluoromethylation reaction proceeded even in gram
scale (Scheme 5). Thus, starting from 1.43 g of 6-methylquino-
line (1e), 0.96 g of 6-methyl-2-trifluoromethylquinoline (4e)
was obtained in 45% yield.
The method was applied to the late-stage trifluoromethyla-
tion of a drug molecule, quinine (7), affording trifluoromethy-
lated quinine (8) in 24% yield (Scheme 6). Although the yield
was low, it is noteworthy that the reaction proceeded from a
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00339.
General experimental procedure and characterization
data for trifluoromethylated products (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: kanai@mol.f.u-tokyo.ac.jp.
*E-mail: kuninobu@cm.kyushu-u.ac.jp.
ORCID
Motomu Kanai: 0000-0003-1977-7648
Yoichiro Kuninobu: 0000-0002-8679-9487
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.8b00339
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(16) The trifluoromethylation of quinoline (1a) proceeded using
DMPU-HF reagent (3.0 equiv) instead of CF3COOH, KHF2, and
DMPU, and the desired product 4a was obtained in 28% yield. This
result will support the proposed mechanism.
ACKNOWLEDGMENTS
■
This work was supported in part by ERATO from JST (grant
number: JPMJER1103), JSPS KAKENHI Grant Number JP
16K13946, and Yakugaku Shinkoukai.
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D
DOI: 10.1021/acs.orglett.8b00339
Org. Lett. XXXX, XXX, XXX−XXX