4-Position-Selective C-H Perfluoroalkylation and Perfluoroarylation of Six-Membered Heteroaromatic Compounds

Article abstract of DOI:10.1021/jacs.6b01753

The first 4-position-selective C-H perfluoroalkylation and perfluoroarylation of six-membered heteroaromatic compounds were achieved using nucleophilic perfluoroalkylation and perfluoroarylation reagents. The regioselectivity was controlled by electrophilically activating the heteroaromatic rings, while sterically hindering the 2-position, with a sterically bulky borane Lewis acid. The reaction proceeded in good yield, even in gram scale, and by a sequential reaction without isolating the intermediates. This reaction could be applied to late-stage trifluoromethylation of a bioactive compound.

Full text of DOI:10.1021/jacs.6b01753

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Communication
4-Position-selective C-H Perfluoroalkylation and
Perfluoroarylation of 6-Membered Heteroaromatic Compounds
Masahiro Nagase, Yoichiro Kuninobu, and Motomu Kanai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01753 • Publication Date (Web): 02 May 2016
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4-Position-selective C-H Perfluoroalkylation and Perfluoroarylation
of 6-Membered Heteroaromatic Compounds
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Masahiro Nagase,† Yoichiro Kuninobu,*†,‡ Motomu Kanai*†,‡
† Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-
0033, Japan
‡ ERATO, Japan Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Supporting Information Placeholder
lectivity was controlled using a bulky borane Lewis acid
(Figure 1d).
ABSTRACT: The first 4-position-selective C-H perfluoro-
alkylation and perfluoroarylation of 6-membered heteroaro-
matic compounds were achieved using nucleophilic per-
fluoroalkylation and perfluoroarylation reagents. The regio-
selectivity was controlled by electrophilically activating the
heteroaromatic rings, while sterically hindering the 2-
position, with a sterically bulky borane Lewis acid. The reac-
tion proceeded in good yield, even in gram scale, and by a
sequential reaction without isolating the intermediates. This
reaction could be applied to late-stage trifluoromethylation
of a bioactive compound.
Perfluoroalkyl and perfluoroaryl groups that include a tri-
fluoromethyl group play an important role in many drugs,1
agrochemicals,2 and organic functional materials.3 There-
fore, the development of regioselective and efficient reac-
tions to introduce such functional groups is very important.4
One of the most direct and efficient methods is direct C-H
perfluoroalkylation and perfluoroarylation, but until recently,
it was quite difficult to promote regioselective C-H per-
fluoroalkylation and perfluoroarylation of 6-membered het-
eroaromatic compounds. In many cases, a mixture of regi-
oisomers is formed because highly reactive perfluoroalkyl
radicals are used as perfluoroalkylation reagents.5 Recently,
our group succeeded in 2-position-selective C-H trifluoro-
methylation of 6-membered heteroaromatic compounds.6,7
The key to our success was the use of a less reactive tri-
fluoromethyl anion as the trifluoromethylation source. There
are no reports, however, of 4-position-selective C-H per-
fluoroalkylation and perfluoroarylation of 6-membered het-
Figure 1. Synthesis of 4-trifluoromethyl pyridines and quino-
lines by C-H transformations.
To achieve 4-position-selective C-H trifluoromethylation,
we designed a new reaction system, in which a bulky Lewis
acid electronically activates 6-membered heteroaromatic
compounds and sterically protects the 2-position of the het-
eroaromatic rings. As described above, we recently
achieved 2-position-selective C-H trifluoromethylation of 6-
membered heteroaromatic compounds using 6-membered
heteroaromatic-N-oxide-BF2CF3 complexes as substrates.
We used a more bulky Lewis acid B(C6F5)3 instead of
BF2CF3 to protect the 2-position of the heteroaromatic rings
(Scheme 1a). Unfortunately, quinoline N-oxide-B(C6F5)3
complex 2 was unstable during silica gel purification, thus
the trifluoromethylation reaction was conducted without iso-
lating the complex. The desired trifluoromethylation, howev-
er, did not proceed at all. Next, we used a stronger Lewis
acid B(C6F4-4-CF3)3 to stabilize the corresponding quinoline
eroaromatic
compounds.
Syntheses
of
4-
(trifluoromethyl)pyridines from 4-halopyridines (or 4-pyridyl
boronic acids or 4-diazoquinolines) and CF3-copper rea-
gents have been reported (Figure 1a).8 In some cases, the
CF3-copper reagents are prepared in situ. Catalytic versions
of such reactions (cross-coupling reactions) are also report-
ed (Figure 1b).9,10 In 2012, Hartwig and Shen independently
reported the synthesis of 4-trifluoromethylated pyridine de-
rivatives by 4-position selective iridium-catalyzed C-H
borylation of a 2,6-disubstituted pyridine derivative and suc-
cessive trifluoromethylation by converting the boryl groups
(Figure 1c).11 The substrate scope of 6-membered het-
eroaromatic compounds, however, is quite limited. We re-
port herein the first 4-position-selective C-H perfluoroalkyla-
tion of 6-membered heteroaromatic compounds. Regiose-
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N-oxide-borane complex 3 (Scheme 1b). In this case,
case of quinoline derivatives, the 4-position selective C-H
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quinoline N-oxide-B(C6F4-4-CF3)3 complex 3 remained sta-
ble during silica gel purification, and the trifluoromethylation
was investigated using the isolated complex 3. A mixture of
trifluoromethylated dihydroquinoline N-oxide-B(C6F4-4-CF3)3
complexes 4 and 5 was formed with low C4/C2 selectivity.
In addition, it was difficult to rearomatize the formed hetero-
cyclic rings. The reason for the low regioselectivity was as-
sumed to be the lower steric hindrance from the borane
moiety due to the presence of an oxygen atom. Therefore,
we investigated the direct activation of quinoline with
B(C6F4-4-CF3)3 using quinoline-tris(2,3,5,6-tetrafluoro-4-
(trifluoromethyl)phenyl)borane complex 6a, which was also
stable during silica gel purification. By the reaction of com-
plex 6a with trifluoromethyltrimethylsilane (7a) and tetrabu-
tylammonium difluorotriphenylsilicate (TBAT) with succes-
sive oxidation of the formed intermediate 8a by phenyl-3-
iodanediyl bis(2,2,2-trifluoroacetate), the desired 4-
(trifluoromethyl)quinoline 9a was obtained in 82% yield
(Scheme 1). Other oxidants, such as pyridinium dichromate
(PDC), 2,3-dichrolo-4,5-dicyano-p-benzoquinone (DDQ),
tritylium tetrafluoroborate (TrBF4), were effective for re-
aromatization (See the Supporting Information, Scheme
S2). It also turned out that the two-step sequence, trifluoro-
methylation and rearomatization, was necessary because
the desired reaction did not proceed and complex 6a was
recovered when trifluoromethylation was conducted in the
presence of the oxidant.
trifluoromethylation generally proceeded in good to excel-
lent yields. We obtained the trifluoromethylated products
9b-9e in moderate to good yields from 3-, 5-, 6, or 7-
methylated quinolines 6b-6e. On the other hand, in the case
of 2- or 8-methylquinolines, the corresponding quinoline-
borane complexes were not formed, which was probably
due to steric hindrance. The trifluoromethylation reaction
proceeded with high functional group tolerance, such as
alkenyl, alkynyl, amide, ester, amino, and methoxy groups
and halogen atoms, and gave the desired trifluoromethylat-
ed quinoline derivatives 9f-9r in moderate to excellent
yields. The reaction was also applicable for pyridine deriva-
tives, and products 9s-9z and 9A-9C were obtained, despite
slightly lower yields than those of trifluoromethylquinolines
9a-9r. The trifluoromethylation reaction proceeded regiose-
lectively using other 6-membered heteroaromatic com-
pounds 6D-6G with two heteroatoms, and gave the corre-
sponding trifluoromethylated products 9D-9G.
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Scheme 2. Investigation of 6-Membered Heteroaromatic
Compounds 6a
Scheme 1. 4-Position-selective C-H Trifluoromethyla-
tion of 6-Membered Heteroaromatic Compound
We then investigated the substrate scope of 6-
membered heteroaromatic compounds (Scheme 2).12 In the
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Scheme 2. (continued) Investigation of 6-Membered
Scheme 4. Proposed Mechanism for 4-Position-
selective C-H Perfluoroalkylation and Perfluoroarylation
Heteroaromatic Compoundsa
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b
a7a (2.0 equiv). After the reaction, MeOH was added and the mix-
ture was heated at 65 °C for 2 h to cleave the boron complex. c19F
NMR Yield of C-2 (or C-6) regioisomer is shown in parenthesis.
dIsolated yield of C-2 (or C-6) regioisomer is shown in parenthesis.
The 4-position-selective C-H trifluoromethylation pro-
ceeded in excellent yield, even in gram scale (Scheme 5).
eTrifluoromethylation reaction was carried out at 0 °C. After the
f
reaction, MeOH was added and the mixture was heated at 65 °C
for 4 h. After the reaction, MeOH was added and the mixture was
heated at 65 °C for 10 h.
Treatment
of
6-iodoquinoline-tris(2,3,5,6-tetrafluoro-4-
g
(trifluoromethyl)phenyl)-borane complex 6r (5.00 mmol) with
trifluoromethyltrimethylsilane (7a) and TBAT, and succes-
sive
oxidation
by
phenyl-3-iodanediyl
bis(2,2,2-
trifluoroacetate) produced 1.31 g (4.07 mmol) of 6-iodo-4-
(trifluoromethyl)quinoline 9r in 81% yield. The gram scale
yield of 9r was comparable to that in a smaller scale (78%
yield, 127 mg) in Scheme 1c.
We then investigated the substrate scope of the intro-
duced perfluoroalkyl and perfluoroaryl groups (Scheme 3).
Perfluoroalkylation reactions, such as pentafluoroethylation
and heptafluoropropylation, proceeded well, and we ob-
tained the corresponding 4-(pentafluoroethyl)quinoline (10)
and 4-(heptafluoropropyl)quinoline (11) in 90% and 89%
yields, respectively. The reactivity of Me3SiCF2H was lower
than that of Me3SiC2F5 and Me3SiC3F7, probably due to the
stronger bond energy of the C-Si bond of Me3SiCF2H.13 The
reaction of Me3SiCF2H was conducted using CsF as the
base and DMF as the solvent to produce 4-
(difluoromethyl)quinoline (12) in 56% yield. The perfluoro-
arylation reaction also proceeded, affording the correspond-
ing 4-(pentafluorophenyl)quinoline (13) in 74% yield.
Scheme 5. Gram-scale Reaction
The 4-position-selective trifluoromethylated product 9r
was obtained from quinoline 14 without isolating the inter-
mediates 6r and 8r (Scheme 6). 6-Iodoquinoline-
tris(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)borane
complex 6r was prepared by the reaction between 14 and in
Scheme 3. Investigation of Fluoroalkylation and Per-
fluoroarylation Reagents 7a
situ-prepared
tris(2,3,5,6-tetrafluoro-4-
(trifluoromethyl)phenyl)borane in diethyl ether at 25 °C for
10 h. The solvent was then replaced with ethyl acetate and
the mixture was treated with trifluoromethyltrimethylsilane
(7a) and TBAT. Successive oxidation by phenyl-3-
iodanediyl
bis(2,2,2-trifluoroacetate)
gave
4-
(trifluoromethyl)quinoline 9r in 63% overall yield.
a7 (2.0 equiv). b19F NMR yield of C-2 regioisomer is shown in paren-
thesis. cMe3SiCF2H (3.0 equiv), CsF (3.0 equiv) and DMF were
used instead of TBAT and ethyl acetate, respectively. See the Sup-
porting Information for the details. dAfter the reaction, MeOH was
added and the mixture was heated at 60 °C for 2 h.
Scheme 6. Sequential Reaction without Isolation of In-
termediates
We propose the following reaction mechanism (Scheme
4): (1) formation of nucleophilically activated CmFn species
from Me3SiCmFn 7 and TBAT; (2) nucleophilic attack of the
CmFn species at the 4-position of pyridine, quinoline, or their
related compound-B(C6F4-4-CF3)3 complex 6, to avoid the
steric repulsion between the borane and CmFn anion; and
(3) aromatization of intermediate 8 by oxidation to give the
desired 4-perfluoroalkyl-pyridine, -quinoline, or their related
compound 9-13.
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The 4-position selective trifluoromethylation could be
Education, Culture, Sports, Science, and Technology of
Japan.
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applied to a late-stage reaction (Scheme 7). Abiraterone
acetate is an anti-prostate cancer drug with a pyridyl group
on the steroid skeleton.14 Treatment of abiraterone acetate-
B(C6F4(4-CF3)3 complex 15 with a mixture of 7a and TBAT,
successive oxidation with a hypervalent iodine compound,
and elimination of the borane from the product with MeOH
gave trifluoromethylated abiraterone acetate 16 in 39%
yield.
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (b) Wang, J.; Sánchez-Roselló,
M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.;
Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432.
(2) (a) Jeschke, P. Chem. Bio. Chem. 2004, 5, 570. (b) Giornal,
F.; Pazenok, S.; Rodefeldb, L.; Lui, N.; Vors, J. P.; Leroux, F. R. J.
Fluorine Chem. 2013, 152, 2.
Scheme 7. 4-Position-selective C-H Trifluoromethyla-
tion of Drug Molecule
9
(3) Schlosser, M. Angew. Chem. Int. Ed. 2006, 45, 5432.
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48
49
50
51
52
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54
55
56
57
58
59
60
(4) (a) Lundgren, R. J.; Stradiotto, M. Angew. Chem. Int. Ed.
2010, 49, 9322. (b) Furuya, T.; Kamler, A. S.; Ritter, T. Nature
2011, 473, 470. (c) Qing, F.-L.; Zheng, F. Synlett 2011, 1052. (d)
Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, V. D.; Roy, S. Tetrahe-
dron 2011, 67, 2161. (e) Tomashenko, O. A.; Grushin, V. V. Chem.
Rev. 2011, 111, 4475. (f) Wu, X.-F.; Neumann, H.; Beller, M.
Chem. Asian J. 2012, 7, 1744.(g) Ye, Y.; Sanford, M. S. Synlett
2012, 23, 2005. (h) Besset, T., Schneider, C.; Cahard, D. Angew.
Chem. Int. Ed. 2012, 51, 5048. (i) Chen, P.; Liu, G. Synthesis 2013,
45, 2919. (j) Liu, H.; Gu, Z.; Jiang, X. Adv. Synth. Catal. 2013, 355,
617. (k) Egami, H.; Sodeoka, M. Angew. Chem. Int. Ed. 2014, 53,
8294. (l) Barata-Vallejo, S.; Lantano, B.; Postigo, A. Chem. Eur. J.
̃
2014, 20, 16806. (m) Alonso, C.; de Marigorta, E. M.; Rubiales, G.;
Palacios, F. Chem. Rev. 2015, 115, 1847. (n) Yang, X.; Wu, T.;
Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826. (o) Char-
pentier, J.; Fruh, N.; Togni, A. Chem. Rev. 2015, 115, 650. (p) Liu,
̈
X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683.
(5) (a) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.;
Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U. S.
A. 2011, 108, 14411. (b) Nagib, D. A.; MacMillan, D. W. C. Nature
2011, 480, 224. (c) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder,
E. D.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herlé, B.; Sach,
N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95.
(6) Nishida, T.; Ida, H.; Kuninobu, Y.; Kanai, M. Nat. Commun.
2014, 5, 3387.
In summary, we successfully achieved a 4-position-
selective C-H trifluoromethylation, pentafluoroethylation,
heptafluoropropylation, difluoromethylation, and pentafluor-
ophenylation of 6-membered aromatic compounds. This is
the first example of a 4-position-selective C-H fluoroalkyla-
tion and perfluoroarylation of 6-membered heteroaromatic
compounds. The 4-position-selective C-H fluoroalkylation
and perfluoroarylation were realized by electronically acti-
vating 6-membered heteroaromatic rings and sterically pro-
tecting the 2-position of the substrates by a bulky borane,
B(C6F4-4-CF3)3. The reaction proceeded in good yield, even
in gram scale, and by sequential reactions without isolating
the intermediates. This reaction could be applied to late
stage trifluoromethylation of a drug, abiraterone acetate. We
expect that this will become a useful reaction for synthesiz-
ing 4-position-fluoroalkylated and perfluoroarylated 6-
membered heteroaromatic compounds.
(7) We also reported benzylic position-selective C(sp3)-H per-
fluoroalkylation of 6-membered heteroaromatic compounds as a
regioselective C-H perfluoroalkylation: Kuninobu, Y.; Nagase, M.;
Kanai, M. Angew. Chem. Int. Ed. 2015, 54, 10263.
(8) (a) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem.
Soc. 2008, 130, 8600. (b) Zhang, C.-P.; Wang, Z.-L.; Chen, Q.-Y.;
Zhang, C.-T.; Gu, Y.-C.; Xiao, J.-C. Angew. Chem. Int. Ed. 2011,
50, 1896. (c) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J.
F. Angew. Chem. Int. Ed. 2011, 50, 3793. (d) Novák, P.; Lishchyn-
skyi, A.; Grushin, V. V. Angew. Chem. Int. Ed. 2012, 51, 7767. (e)
Dai, J.-J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.-J.; Lu, X.; Liu, L.;
Fu, Y. J. Am. Chem. Soc. 2013, 135, 8436. (f) Mormino, M. G.;
Fier, P. S.; Hartwig, J. F. Org. Lett. 2014, 16, 1744.
(9) (a) Ye, Yingda, Sanford, M. S. J. Am. Chem. Soc. 2012, 134,
9034. (b) Chen, M.; Buchwald, S. L. Angew. Chem. Int. Ed. 2013,
52, 11628.
(10) For copper-catalyzed or mediated-trifluoromethylation of io-
dobenzenes using ClCF2CO2SiMe3 (or ClCF2CO2Me) and AgF as a
CF3 reagent, see: (a) Huiban, M.; Tredwell, M.; Mizuta, S.; Wan, Z.;
Zhang, X.; Collier, T. L.; Gouverneur, V.; Passchier, J. Nature
Chem. 2013, 5, 941. (b) Zhang, X.; Wang, J.; Wan, Z. Org. Lett.
2015, 17, 2086.
(11) (a) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem.
Int. Ed. 2012, 51, 536. (b) Liu, T.; Shao, X.; Wu, Y.; Shen, Q. An-
gew. Chem. Int. Ed. 2012, 51, 540.
(12) In some cases, it was necessary to work up the reaction
mixture with methanol to dissociate the borane B(C6F4-4-CF3)3 from
4-trifluoromethylated 6-membered heteroaromatic-B(C6F4-4-CF3)3
complexes. For the details, see the footnotes of Scheme 2.
(13) Zhao, Y.; Huang, W.; Zheng, J.; Hu, J. Org. Lett. 2011, 13,
5342.
(14) Attard, G.; Reid, M. A. H.; Yap, T. A.; Raynaud, F.; Dowsett,
M.; Settatree, S.; Barrett, M.; Parker, C.; Martins, V.; Folkerd, E.;
Clark, J.; Cooper, C. S.; Kaye, S. B.; Dearnaley, D.; Lee, G.; de
Bono, J. S. J. Clin. Oncol. 2008, 26, 4563.
Supporting Information
General experimental procedure and characterization data
for 6-membered heteroaromatic compound-borane com-
plexes, and perfluoroalkylated and perfluoroarylated prod-
ucts. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
Corresponding Author
kuninobu@mol.f.u-tokyo.ac.jp; kanai@mol.f.u-tokyo.ac.jp
Notes
The authors declare no competing financial interests.
This work was supported in part by ERATO from JST and
Grant-in-Aid for Scientific Research (B) from the Ministry of
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