Benzylic C(sp3)-H Perfluoroalkylation of Six-Membered Heteroaromatic Compounds

Article abstract of DOI:10.1002/anie.201505335

Successful benzylic C(sp³)-H trifluoromethylation, pentafluoroethylation, and heptafluoropropylation of six-membered heteroaromatic compounds were achieved as the first examples of a practical benzylic C(sp³)-H perfluoroalkylation. I

Full text of DOI:10.1002/anie.201505335

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201505335
German Edition: DOI: 10.1002/ange.201505335
Heterocycle Synthesis
3
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Benzylic C(sp ) H Perfluoroalkylation of Six-Membered
Heteroaromatic Compounds
Yoichiro Kuninobu,* Masahiro Nagase, and Motomu Kanai*
3
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Abstract: Successful benzylic C(sp ) H trifluoromethylation,
as follows: 1) using N-heteroaromatic N-oxide/BF2CnF2n+1
(n = 1–3) complexes as substrates; the boranes BF2CnF2n+1
pentafluoroethylation, and heptafluoropropylation of six-
membered heteroaromatic compounds were achieved as the
work as both Lewis acids and perfluoroalkylation reagents;
3
3
À
À
first examples of a practical benzylic C(sp ) H perfluoroalkyl-
2) this is a rare example of a C(sp ) CnF2n+1 bond-formation
3
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ation. In these reactions, BF2CnF2n+1 (n = 1–3) functioned as
both a Lewis acid to activate the benzylic position and
a CnF2n+1 (n = 1–3) source. The perfluoroalkylation proceeded
at both terminal and internal positions of the alkyl chains.
Perfluoroalkylated products were obtained in moderate to
excellent yields, even on gram scale, and in a sequential
procedure without isolation of the intermediates. By using this
method, trifluoromethylation of a bioactive compound, as well
as introduction of a CF3 group into a bioactive molecular
skeleton, proceeded regioselectively.
reaction by C(sp ) H perfluoroalkylation; and 3) the
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C(sp ) CnF2n+1 bond formation can be achieved without
using a transition-metal catalyst. In C(sp ) H perfluoroalkyl-
ation, reductive elimination to form the C CF3 bond is
generally difficult, therefore, the use of an oxidant is
necessary to generate a higher oxidation state of the catalytic
center to achieve reductive elimination.[4a]
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À
We previously reported that BF2CF3 complexes of heter-
oaromatic N-oxides are stable, yet very strongly activated
electrophilic aromatic compounds, thus allowing C2-selective
2
À
aromatic C(sp ) H trifluoromethylation with a very weak CF3
F
luorinated functional groups, including a trifluoromethyl
nucleophile.[4f] Applying these reaction conditions [Me3SiCF3
(3.0 equiv) and CsF (3.0 equiv) in ethyl acetate at 258C for
3 h] to the 2-methylquinoline N-oxide/BF2CF3 complex 1a
gave 2-(2,2,2-trifluoroethyl)quinoline (2a) in 9% yield. To
improve the yield of 2a, we screened several bases other
than CsF. Tetramethylammonium fluoride tetrahydrate
(TMAF·4H2O) proved to be a better base, and 2a was
obtained in 38% yield. Interestingly, the trifluoromethylation
reaction also proceeded without the use of Me3SiCF3, thus
giving 2a in 30% yield. This finding indicated that the BF2CF3
group, play important roles in many drugs, agrochemicals, and
organic functional materials,[1] and generally improve the
bioactivity, metabolic stability, lipophilicity, and physical
properties of organic functional molecules. Thus, the develop-
ment of highly efficient and practical methods to introduce
fluorinated functional groups is highly desirable. Together
2
[2–4]
À
with C(sp ) CF3 bond-forming reactions,
there are many
3
À
examples of reactions to construct a C(sp ) CF3 bond, such as
the addition of anionic CF3 species to carbonyl groups,[5]
trifluoromethylation at the a-position of carbonyl com-
group acted as both a Lewis acid and a trifluoromethylation
pounds,[6] addition of a CF3 radical to alkenes,[7] and cross-
reagent, and is in sharp contrast to our previous C(sp ) H
2
À
coupling reactions.[8] However, the examples of C(sp ) CF3
trifluoromethylation in which the BF2CF3 group did not
function as a CF3 source and Me3SiCF3 was essential as an
external trifluoromethylation reagent.[4f] Optimization of the
reaction conditions dramatically improved the yield of 2a.
Treatment of 1a with TMAF·4H2O in acetonitrile/ethyl
acetate (1:2) at 658C for 10 minutes gave 2a in 80% yield
[94% yield (NMR); Eq. (1); M.S. = molecular sieves].[13] The
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3
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bond-formation reactions by C(sp ) H trifluoromethylation
are still rare.[9,10]
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Herein we successfully developed a new C(sp ) CF3,
3
3
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À
C(sp ) C2F5, and C(sp ) C3F7 bond-forming reactions
through benzylic C(sp ) H trifluoromethylation, pentafluor-
3
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oethylation, and heptafluoropropylation, respectively, of six-
membered heteroaromatic compounds. This reaction can
efficiently provide pyridine and quinoline derivatives with
either a trifluoroethyl,[11,12] pentafluoropropyl, or heptafluor-
obutyl group. The characteristic features of this reaction are
[*] Prof. Dr. Y. Kuninobu, M. Nagase, Prof. Dr. M. Kanai
Graduate School of Pharmaceutical Sciences
The University of Tokyo
reaction even proceeded at 258C and 2a was obtained in 80%
yield (NMR) after 11 hours. In some cases, an acetonitrile
adduct [3-(quinolin-2-yl)propanenitrile] was formed in ace-
tonitrile. Therefore, a mixed solvent (acetonitrile and ethyl
acetate) was used to suppress the formation of the adduct.
The trifluoromethylation of the quinoline ring did not occur
at all.
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
E-mail: kuninobu@mol.f.u-tokyo.ac.jp
kanai@mol.f.u-tokyo.ac.jp
Prof. Dr. Y. Kuninobu, Prof. Dr. M. Kanai
ERATO (Japan) Science and Technology Agency (JST)
Kanai Life Science Catalysis Project, Tokyo 113-0033 (Japan)
Under the optimized reaction conditions, we investigated
the substrate scope of six-membered heteroaromatic com-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505335.
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Table 1: Benzylic trifluoromethylation of six-membered heteroaromatic
reaction did not proceed using N-oxide-BF2CF3 complexes
of 2-(chloromethyl)quinoline, 6-methylnicotinonitrile, 2-
methyl-4-nitropyridine, 2-bromo-6-methylpyridine, (5-ace-
toxy-6-methylpyridine-3,4-diyl)bis(methylene) diacetate, 4,6-
dimethylpyrimidine, and 2,3-dimethylquinoxaline as sub-
strates.
compounds.[a]
Other fluorinated alkyl groups were also investigated
[Eq. (2)]. Pentafluoroethylated and heptafluoropropylated
products, 4 and 6, respectively, were obtained in good yields
when the corresponding 2-methylquinoline N-oxide/BF2C2F5
3 and 2-methylquinoline N-oxide/BF2C3F7 complex 5 were
used as substrates. The desired reaction did not proceed in the
case of 2-methylquinoline N-oxide/BF2C6F5 complex.
The trifluoromethylation reaction of 1a was not inhibited
by the radical scavenger galvinoxyl (see the Supporting
Information), thus indicating that it does not proceed by
a radical pathway. A plausible reaction mechanism is
described in Scheme 1. 1) Formation of the enamine-type
[a] Yield of isolated product is given. Value within parenthesis represents
the yield as determined by 19F NMR analysis of the crude reaction
mixture using 1,4-difluorobenzene as an internal standard. [b] CH3CN,
258C, 24 h. [c] 1 h. [d] CH3CN, 1 h.
3
pounds (Table 1). The trifluoromethylation reaction pro-
ceeded in moderate to excellent yields using quinoline
substrates. Quinoline N-oxide/BF2CF3 complexes (1b–d)
bearing either an electron-donating or electron-withdrawing
group gave the corresponding trifluoromethylated products
(2b–d) without loss of the functional groups. The trifluor-
omethylation reaction also occurred at the internal benzylic
positions and produced the trifluoromethylated quinolines
2e–g. Interestingly, the trifluoromethylation reaction also
proceeded at the 4-methyl group of the quinoline N-oxide/
BF2CF3 complex 1h, and produced the corresponding tri-
fluoromethylated product 2h without generating any C2-
trifluoromethylated product. In contrast, the yields of the
trifluoromethylated products 2j–m were lower when using
the pyridine substrates 1j–m. The yields of 2i and 2n were
higher when using the complexes 1i and 1n, respectively, as
substrates. The trifluoromethylated products 2o and 2p were
also obtained using other heteroaromatic substrates, such as
À
Scheme 1. Proposed mechanism for benzylic C(sp ) H trifluoro-
methylation.
intermediate A by deprotonation of the N-oxide/BF2CF3
complex 1 with TMAF;[15] and 2) nucleophilic attack of the
CF3 group on the enamine moiety to give 2 along with the
elimination of Me4NOBF2. For 1, the acidity of the benzylic
proton is significantly enhanced by the strong Lewis acid,
BF2CF3, and electron-withdrawing substituents, thus leading
to facile deprotonation by TMAF. In addition, A must be
stabilized by p-conjugated systems because the trend with
respect to the yields of the trifluoromethylated products is as
follows: quinoline derivatives > pyridine derivatives; 5-(phe-
nylethynyl)-2-(2,2,2-trifluoroethyl)pyridine
(2k,
49%
yield) > 2-(2,2,2-trifluoroethyl)pyridine (24% yield); and 2-
(2,2,2-trifluoro-1-phenylethyl)pyridine (2n, 58% yield) > 2-
(2,2,2-trifluoroethyl)pyridine (24% yield). Formation of an
acetonitrile adduct in acetonitrile also supported the forma-
tion of A.
The reaction proceeded in excellent yield, even on gram
scale. Treatment of 4.83 grams of 1a with TMAF·4H2O in
acetonitrile/ethyl acetate gave 3.12 grams of 2a in 85% yield,
isoquinoline and quinazoline derivatives. The trifluorome-
3
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thylation reaction also took place at the tertiary C(sp ) H
bond of 2-isopropylquinoline, but the yield of the product was
low (17%). This reaction is a rare example of the construction
of tertiary carbon–CF3 bond.[14] The trifluoromethylation
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Scheme 2. Synthesis of trifluoromethylated product 2a from 2-methyl-
quinoline (7) by sequential reactions. mCPBA=m-chloroperbenzoic
acid.
Scheme 3. Synthesis of trifluoromethylated analogue of ICI D8731.
Reagents and conditions: a) mCPBA (1.1 equiv), CHCl3, 258C, 6 h,
95%; b) NaNO3 (5.0 equiv), CF3CO2H, 508C, 0.5 h, 82%; c) P(OMe)3
(1.5 equiv), white LED irradiation, CH2Cl2, 258C, 5 h, 89% (11);
d) 1.0m H2SO4 (6.2 equiv), CF3CO2H, 608C, 2 h, 92% (12); e) 13
(1.5 equiv), Cs2CO3 (1.5 equiv), acetone, reflux, 3 h, 80%; f) 1.0m HCl,
MeOH/1,4-dioxane (1:2), 258C, 2 h, 89% (14). Tr =trityl.
which was comparable to the yield of 2a on a smaller scale
[Eq. (1): 80%, 1a: 169 mg].
A trifluoromethylated product could be obtained from 2-
methylquinoline (7) by sequential reactions without isolating
the quinoline N-oxide 8 and 1a (Scheme 2). Oxidation of
2.80 grams of 7 with mCPBA, and treatment of a mixture of
KBF3CF3 and BF3·OEt2 with the formed quinoline N-oxide 8
led to 1a, which was treated with TMAF·4H2O to give the
desired trifluoromethylated product 2a in 67% overall yield
(2.84 g).
The method was applied to benzylic trifluoromethylation
of a more complex molecule. Papaverine is an antispasmodic
drug which contains an isoquinoline moiety with a benzylic
substituent at the 1-position.[16] Treatment of the papaverine
N-oxide/BF2CF3 complex 9 with TMAF·4H2O produced the
trifluoromethylated papaverine 10 in 51% yield [Eq. (3)].
This result reveals that the present reaction enables late-stage
the perfluoroalkylation reaction, even on gram scale, and the
ability to perform sequential reactions without isolating the
intermediates. Trifluoromethylation of a bioactive compound
(papaverine) proceeded regioselectively by using this
method. Moreover, a CF3-containing drug lead, an analogue
of ICI D8731, was synthesized. This method will be useful for
the efficient and practical introduction of fluorinated alkyl
groups into the benzylic position of six-membered hetero-
aromatic compounds.
trifluoromethylation of bioactive molecules with N-hetero- Experimental Section
aromatic ring(s) and functional groups.
Gram-scale synthesis of 2-(2,2,2-trifluoroethyl)quinoline (2a): 4 Š
Finally, a unique analogue (14) of an angiotensin II
M.S. (3.48 g, 200 mgmmolÀ1) were added to a three necked 1 L round
bottom flask, and then flame-dried under vacuum. After cooling to
room temperature, TMAF·4H2O (8.62 g, 52.2 mmol), difluoro((2-
methylquinolin-1-ium-1-yl)oxy)(trifluoromethyl)borate (1a; 4.82 g,
17.4 mmol), AcOEt (348 mL), and MeCN (174 mL) were added.
The mixture was heated at 658C and stirred at the same temperature
for 10 min. After cooling to room temperature, an insoluble solid in
the reaction mixture was filtered off through a pad of Celite, washed
with CH2Cl2, and then the solvent was removed under reduced
pressure. AcOEt (150 mL), n-hexane (150 mL), and H2O (100 mL)
were added to the crude reaction mixture, and the mixture was
extracted two times. The combined organic phases were dried over
MgSO4, and then the solvent was removed under reduced pressure.
The crude product was purified by column chromatography on silica
gel (n-hexane/AcOEt = 10:1) to give 2-(2,2,2-trifluoroethyl)quinoline
(2a, 3.12 g, 85% yield).
receptor antagonist, ICI D8731,[17] was synthesized for the
first time to demonstrate the utility of the present benzylic
trifluoromethylation (Scheme 3; see the Supporting Informa-
tion). Starting from 2a, introduction of a nitro group at the 4-
position, hydrolysis, and O-alkylation with 13 produced 14,
after deprotection, in high overall yield.
3
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In summary, we developed selective C(sp ) H trifluoro-
methylation, pentafluoroethylation, and heptafluoropropyla-
tion at the benzylic positions of 2-alkylpyridines, 2-alkylqui-
nolines, and their related compounds. This protocol is the first
Acknowledgements
This work was supported in part by ERATO from JST, Grant-
in-Aid for Scientific Research (B) from the Ministry of
Education, Culture, Sports, Science, and Technology of Japan
and the Astellas Foundation for Research on Metabolic
Disorders. We thank Dr. Tomoaki Nishida for his contribution
at the initial stage of this project.
example of regioselective perfluoroalkylation at the benzylic
3
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C(sp ) H bond of six-membered heteroaromatic compounds.
In this reaction, boranes, BF2CnF2n+1 (n = 1–3), function as
both a Lewis acid, to activate the benzylic position of six-
membered heteroaromatic compounds, and a CnF2n+1 (n = 1–
3) source. The reaction proceeds at both the terminal and
internal positions of the alkyl chains. The practicality of the
reaction was demonstrated by the good to excellent yields of
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[12] For several examples for the synthesis of heteroaromatic func-
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Lewis acids
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