Copper-Catalyzed Functionalization of Aza-Aromatic Rings with Fluoroalcohols via Direct C(sp2)-H/C(sp3)-H Coupling Reactions

Article abstract of DOI:10.1021/acs.orglett.0c00797

An efficient copper-catalyzed direct C(sp²)-H/C(sp³)-H coupling reaction of aza-aromatic rings with fluoroalcohols is developed. A variety of useful building blocks including hydroxyfluoroalkylated aniline, pyrrole, and indole derivatives bearing a quaternary carbon center could be constructed with high regioselectivity and good to excellent yields under very mild reaction conditions. The reaction is believed to undergo a fluoroalcohol oxidation and to follow an electronic addition reaction pathway.

Full text of DOI:10.1021/acs.orglett.0c00797

pubs.acs.org/OrgLett
Letter
Copper-Catalyzed Functionalization of Aza-Aromatic Rings with
Fluoroalcohols via Direct C(sp2)−H/C(sp3)−H Coupling Reactions
Jie Chen, Meng Li, Jinli Zhang, Wangbin Sun,* and Yaojia Jiang*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00797
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: An efficient copper-catalyzed direct C(sp2)−H/
C(sp3)−H coupling reaction of aza-aromatic rings with fluoroalco-
hols is developed. A variety of useful building blocks including
hydroxyfluoroalkylated aniline, pyrrole, and indole derivatives
bearing a quaternary carbon center could be constructed with
high regioselectivity and good to excellent yields under very mild
reaction conditions. The reaction is believed to undergo a
fluoroalcohol oxidation and to follow an electronic addition
reaction pathway.
irect coupling reactions have been recognized as some of
the most useful synthetic strategies in modern organic
D
chemistry1 because of their atom economy, easy handling, and
lack of halogenic or sensitive metal reagent requirements.2
Compared to well-developed C(sp2)−H/C(sp2)−H coupling
reactions,3 C(sp2)−H/C(sp3)−H direct coupling to construct
a new C−C bond is still limited to two major strategies: (1)
transition metal-catalyzed C−H activation and consequently
reductive eliminations4 and (2) a radical initiator-promoted
single-electron transfer (SET) process.5 Despite these develop-
ments, they still suffered from a variety of limitations such as
the introduction of additional directing groups, harsh reaction
conditions, well-polished substrate structures, and a complex
catalytic system. Hence, designing simpler and more practical
procedures for realizing C(sp2)−H/C(sp3)−H coupling from
general available substrates is highly desirable. We envisioned
that electrophilic addition reactions6 might be applied in this
area by employing alcohol oxidation in situ to generate
carbonyl compounds, which were attacked by electron-rich
aza-aromatic rings (Figure 1).
Figure 1. C(sp2)−H/C(sp3)−H cross-dehydrogenative coupling
reactions involving fluoroalcohols.
pounds.13 Liu’s group reported an elegant radical-triggered
hydrogen-atom transfer (HAT) strategy for realizing the
C(sp2)−H/C(sp3)−H coupling of trifluoroethanol (TFE)
and indoles, though the substrate scope was largely limited
to primary fluoroalcohols and needed a stoichiometric amount
of radical initiators.14 Due to the importance of the C3
position of fluorine-containing indoles, the development of
practical and facile synthetic methods for their incorporation is
still of great interest and highly desirable. Herein, we describe a
Organofluorine compounds are widely found in medicinal,
agricultural, and material sciences.7 The organic community
has devoted a great deal of effort to the selective introduction
of fluorine-containing skeletons into organic molecules.8
Furthermore, various organofluorine reagents have been
designed for this purpose.9 Fluoroalcohols as some of the
most general solvents are normally acknowledged to be stable,
easy to handle, and inexpensive.10 However, using fluoroalco-
hols as C(sp3)−H coupling counterparts to perform direct
C(sp2)−H/C(sp3)−H coupling reactions has rarely been
explored.11 3-Substituted indoles are unique structural
skeletons in drugs, natural products, and biological mole-
cules.12 Direct coupling of the C(sp2)−H bond of indoles with
other C−H bonds is one of the most effective and
straightforward methods for expanding this class of com-
Received: March 2, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00797
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
novel method for constructing hydroxyfluoroalkylated com-
pounds through copper-catalyzed direct C(sp2)−H/C(sp3)−H
coupling reactions of aza-aromatic rings with fluoroalcohols
under very mild conditions without any additional radical
initiators.
With the optimized reaction conditions in hand, we further
investigated the substrate scope of the reaction (Scheme 1). In
a b
,
Scheme 1. Substrate Scope
At the outset, 1-methyl-1H-indole 1a was examined as the
model substrate for reaction with hexafluoroisopropanol
(HFIP) 2 in the presence of different metal catalysts under
an air atmosphere at 90 °C (Table 1). A trace amount of the
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
FeCl3
Co(OAc)2
Cu(OAc)
Cu(OH)2
CuCl2
ligand
atmosphere
yield
1
2
3
4
5
6
7
8
−
−
−
−
−
−
−
air
air
air
air
air
air
air
air
air
air
air
air
O2
N2
air
air
air
air
0
0
5
8
12
10
15
0
CuBr2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
PPh3
DPPP
9
7
10
11
12
13
14
2,2′-Bipy
1,10-phen
DTBBPY
DTBBPY
DTBBPY
DTBBPY
DTBBPY
DTBBPY
DTBBPY
25
41
92
93
9
75
82
90
57
c
15
16
d
e
17
f
18
a
Unless otherwise noted, reactions were carried out using 1a (0.20
mmol), catalyst (10 mol %), and ligand (20 mmol %) in HFIP (0.1
M, 2 mL) at 90 °C for 24 h under an air atmosphere. Abbreviations:
DPPP, 1,3-bis(diphenylphosphino)propane; DTBBPY, 4,4′-di-tert-
b
butyl-2,2′-bipyridine; HFIP, hexafluoroisopropanol. Isolated yields.
c
d
With 5 mmol % catalyst and 10 mmol % ligand. With 7.5 mmol %
e
catalyst and 10 mmol % ligand. With 10 mmol % catalyst and 15
mmol % ligand. The reaction temperature is 70 °C.
f
desired coupling product 3a could be obtained with copper
catalysts (Table 1, entries 3−7), while other cheap metal
catalysts, including iron and cobalt, failed to promote the
reaction (Table 1, entries 1 and 2, respectively). The reaction
efficiency could be improved more obviously when nitrogen-
containing ligands were employed compared to phosphine
ligands (Table 1, entries 8−12). To our delight, when 4,4′-di-
tert-butyl-2,2′-bipyridine (DTBBPY) was added, the desired
product 3a was isolated in 92% yield (Table 1, entry 12).
Further optimization found that the reaction was almost
suppressed under nitrogen protection while an oxygen
atmosphere did not influence the reaction obviously (Table
1, entries 13 and 14, respectively). After careful evaluation of
the ratio of the copper catalyst and ligand, the final optimized
reaction conditions were carried out using 1a (0.20 mmol),
Cu(OAc)2 (10 mol %), and DTBBPY (15 mmol %) in HFIP
(0.1 M, 2 mL) at 90 °C under an air atmosphere for 24 h
(Table 1, entry 17). The yield decreased significantly at a lower
temperature (Table 1, entry 18).
a
Unless otherwise noted, reactions were carried out using 1 (0.20
mmol), Cu(OAc)2 (10 mol %), and DTBBPY (15 mmol %) in HFIP
(0.1 M, 2 mL) at 90 °C for 24 h. Isolated yields. On a 5.0 mmol
scale. With trifluoroethnol as the solvent.
b
c
d
general, an array of substituted indoles could be successfully
reacted with fluoroalcohols to generate the C3 hydroxyfluor-
oalkylated indoles in good to excellent yields. Indoles bearing
methyl groups at different positions of phenyl rings were
studied under standard reaction conditions, and the reactions
proceeded smoothly to afford the desired products in 80−91%
yields (3b−3e). Halogenic substituents (Cl, Br, and I) were
then investigated, and the results showed that 4-substituted
halogenic indoles (3f and 3h) gave yields that were obviously
lower than the yields of others (3g and 3i−3k). These
B
https://dx.doi.org/10.1021/acs.orglett.0c00797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
halogenic products are potentially applied in coupling reactions
like Suzuki reactions (4i).15 Electronic effects were observed as
different indoles bearing electron-rich groups (-OMe and
-OPh) gave excellent yields while electron-withdrawing groups
(-CN and -CO2Me) failed to react (3l−3o). Then, we also
investigated different N substituents of indoles. Phenyl, benzyl,
alkynl, and alkenyl functional groups all survived well under the
standard reaction conditions (3p−3s). Furthermore, free N−H
of indoles also reacted successfully and exhibited reactivities
that were similar to those of N-methylindole derivatives (3t−
3w). Then we turned our attention to other N-containing
compounds. N,N-Dimethylaniline could react with HFIP to
generate a p-fluoro functional product in 47% yield (3x).
Pyrrole could also participate in a cross-dehydrogenative
coupling reaction with HFIP at position 3 of pyrrole in 98%
yield (3y). Finally, other fluorinated alcohols were also
examined under the same reaction conditions with trifluor-
oethnol (TFE) as the solvent instead of HFIP. Overall, the
reactions proceeded smoothly to afford the corresponding
products in good to excellent yields (3z−3D).
hexafluoroacetone by 19F NMR spectroscopy (Scheme 3).
During the 8 h reaction, two peaks, those for HFIP 2 (δ −76.0
Scheme 3. 19F NMR Spectroscopy Experiment
Then, a series of controlled experiments were carried out to
study the possible reaction pathways. We conducted the
reaction with different free radical trapping reagents, including
butylated hydroxytoluene (BHT), 1,1-diphenylethylene
(DPE), and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
(Scheme 2, a), and the desired product was obtained in good
Scheme 2. Control Experiments
ppm) and product 3i (δ −76.8 ppm), were detected; however,
there was no hexafluoroacetone (δ −82.8 ppm) observed. The
19F NMR result seems to be contradicted by control
experiment b (Scheme 2). Therefore, we suspected that a
HFIP−copper complex might be involved. On the other hand,
it is also possible that the reaction of hexafluoroacetone with
indole is much faster than oxidation of HFIP to hexafluor-
oacetone.
We proposed possible reaction pathways according to the
obtained results as depicted in Scheme 4. First, hexafluor-
oisopropanol 2 may coordinate with a copper catalyst to give
complex A. The copper complex then oxidizes the α-H to
generate the four-membered ring intermediate B. Intermediate
Scheme 4. Proposed Reaction Pathways
yields (80%, 90%, and 93%, respectively). This may rule out
the possible radical pathway. Furthermore, the same product 3i
could be obtained in high yield when hexafluoroacetone 2i′
was employed instead of HFIP either with or without a copper
catalyst (Scheme 2, b and c). It should be noted the reactions
proceeded very quickly in 1 h compared to 24 h for the model
reaction. The direct C−H bond activation process also could
be excluded because there was no deuterium product detected
at position 3 of indole (Scheme 2, d).
These results suggested that the reaction mechanism
probably included a catalytic electrophilic substitution process
involving hexafluoroacetone as the key intermediate. We
further designed a liner tracking experiment to analyze the
C
https://dx.doi.org/10.1021/acs.orglett.0c00797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
B might be attacked directly by indole through pathway B, or it
was further oxidized to hexafluoroacetone copper complex C
and then attacked by indole through pathway A. Both of these
pathways included the HFIP α-H oxidation step to generate
the intermediate D, which was further isomerized to E. After
protonation of complex E, the reaction finally afforded the
desired product and released the copper catalyst.
In summary, we have developed a copper-catalyzed highly
regioselective functionalization of aniline, pyrrole, and indole
derivatives with fluoroalcohols to construct a variety of useful
fluorine-containing building blocks. The reaction involves a
simple and easy handling protocol in the presence of catalytic
copper in an open flask without radical initiators. The reaction
mechanism is believed to involve the fluoroalcohol oxidation
step followed by an electronic addition reaction pathway. A
series of parallel and control experiments were examined to
support the proposed mechanism.
REFERENCES
■
(1) (a) Yeung, C. S.; Dong, V. M. Catalytic Dehydrogenative Cross-
Coupling: Forming Carbon-Carbon Bonds by Oxidizing Two
Carbon-Hydrogen Bonds. Chem. Rev. 2011, 111, 1215. (b) Yang,
Q.; Zhang, L.; Ye, C.; Luo, S.; Wu, L.-Z.; Tung, C.-H. Visible-Light-
Promoted Asymmetric Cross-Dehydrogenative Coupling of Tertiary
Amines to Ketones by Synergistic Multiple Catalysis. Angew. Chem.,
Int. Ed. 2017, 56, 3694. (c) Lee, A.; Betori, R. C.; Crane, E. A.;
Scheidt, K. A. An Enantioselective Cross-Dehydrogenative Coupling
Catalysis Approach to Substituted Tetrahydropyrans. J. Am. Chem.
Soc. 2018, 140, 6212. (d) Zhu, C.; Zhu, R.; Zeng, H.; Chen, F.; Liu,
C.; Wu, W.; Jiang, H.-F. Copper-Catalyzed C(sp3)-H/C(sp3)-H
Cross-Dehydrogenative Coupling with Internal Oxidants: Synthesis of
2-Trifluoromethyl-Substituted Dihydropyrrol-2-ols. Angew. Chem., Int.
Ed. 2017, 56, 13324.
(2) (a) Xu, W.; Huang, Z.; Ji, X.; Lumb, J.-P. Catalytic Aerobic
Cross-Dehydrogenative Coupling of Phenols and Catechols. ACS
Catal. 2019, 9, 3800. (b) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Bond
Formations Between Two Nucleophiles: Transition Metal Catalyzed
Oxidative Cross-Coupling Reactions. Chem. Rev. 2011, 111, 1780.
(c) Guo, C.; Song, J.; Luo, S.-W.; Gong, L.-Z. Enantioselective
Oxidative Cross-Coupling Reaction of 3-Indolylmethyl C-H Bonds
with 1,3-Dicarbonyls Using a Chiral Lewis Acid-Bonded Nucleophile
to Control Stereochemistry. Angew. Chem., Int. Ed. 2010, 49, 5558.
(d) Girard, S. A.; Knauber, T.; Li, C.-J. The Cross-Dehydrogenative
Coupling of Csp3-H Bonds: A Versatile Strategy for C-C Bond
Formations. Angew. Chem., Int. Ed. 2014, 53, 74.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00797.
Experimental procedures and characterization data for
new compounds (PDF)
(3) (a) Masui, K.; Ikegami, H.; Mori, A. Palladium-Catalyzed C-H
Homocoupling of Thiophenes: Facile Construction of Bithiophene
Structure. J. Am. Chem. Soc. 2004, 126, 5074. (b) Do, H.-Q.; Daugulis,
O. An Aromatic Glaser-Hay Reaction. J. Am. Chem. Soc. 2009, 131,
17052. (c) Fan, S.; Chen, Z.; Zhang, X. Copper-Catalyzed
Dehydrogenative Cross-Coupling of Benzothiazoles with Thiazoles
and Polyfluoroarene. Org. Lett. 2012, 14, 4950. (d) Li, C.-J. Cross-
Dehydrogenative Coupling (CDC): Exploring C-C Bond Formations
beyond Functional Group Transformations. Acc. Chem. Res. 2009, 42,
335. (e) Liu, C.; Yuan, J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A.
Oxidative Coupling between Two Hydrocarbons: An Update of
Recent C−H Functionalizations. Chem. Rev. 2015, 115, 12138. (f) Li,
Y.; Qian, F.; Ge, X.; Liu, T.; Jalani, H. B.; Lu, H.; Li, G. Copper and
Cobalt Co-Catalyzed Aerobic Oxidative Cross-Dehydrogenative
Coupling Reaction of (Benzo)azoles. Green Chem. 2019, 21, 5797.
(4) (a) Xie, Z.; Cai, Y.; Hu, H.; Lin, C.; Jiang, J.; Chen, Z.; Wang, L.;
Pan, Y. Cu-Catalyzed Cross-Dehydrogenative Coupling Reactions of
(Benzo)thiazoles with Cyclic Ethers. Org. Lett. 2013, 15, 4600.
(b) Banerjee, A.; Santra, S. K.; Mishra, A.; Khatun, N.; Patel, B. K.
Copper(I)-Promoted Cycloalkylation-Peroxidation of Unactivated
Alkenes via sp3 C-H Functionalisation. Org. Biomol. Chem. 2015,
13, 1307. (c) Yang, J.-C.; Zhang, J.-J.; Guo, L.-N. Copper-Catalyzed
Oxidative Cyclization of Vinyl Azides with Benzylic Csp3-H Bonds for
the Synthesis of Substituted Phenanthridines. Org. Biomol. Chem.
2016, 14, 9806. (d) Kim, H.; Chang, S. Transition-Metal-Mediated
Direct C-H Amination of Hydrocarbons with Amine Reactants: The
Most Desirable but Challenging C-N Bond-Formation Approach.
ACS Catal. 2016, 6, 2341. (e) Jiang, Y.; Deng, G.; Zhang, S.; Loh, T.-
P. Directing Group Participated Benzylic C(sp3)-H/C(sp2)-H Cross-
Dehydrogenative Coupling (CDC): Synthesis of Azapolycycles. Org.
Lett. 2018, 20, 652. (f) Deng, G.; Chen, J.; Sun, W.; Bian, K.; Jiang,
Y.; Loh, T.-P. Bioinspired Deamination of alpha-Amino Acid
Derivatives by a Palladium/Nickel Complex. Adv. Synth. Catal.
2018, 360, 3900. (g) Li, C.; Shin, K.; Liu, R. L.; Buchwald, S. L.
Engaging Aldehydes in CuH-Catalyzed Reductive Coupling Reac-
tions: Stereoselective Allylation with Unactivated 1,3-Diene Pronu-
cleophiles. Angew. Chem., Int. Ed. 2019, 58, 17074.
AUTHOR INFORMATION
■
Corresponding Authors
Wangbin Sun − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China; Email: ias-wbsun@njtech.edu.cn
Yaojia Jiang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China; orcid.org/0000-0003-0695-0069;
Email: iamyjjiang@njtech.edu.cn
Authors
Jie Chen − Institute of Advanced Synthesis, School of Chemistry
and Molecular Engineering, Nanjing Tech University, Nanjing
211816, China
Meng Li − Institute of Advanced Synthesis, School of Chemistry
and Molecular Engineering, Nanjing Tech University, Nanjing
211816, China
Jinli Zhang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech
University, Nanjing 211816, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00797
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge funding from the National
Natural Science Foundation of China (21971112) and the
Starting Funding of Research (39837107) from Nanjing Tech
University. Y.J. is also thankful for the financial support of the
Chinese Scholarship Council and thanks Dr. Laszlo Ku
at Rice University (Houston, TX).
(5) (a) Jakubowski, W.; Matyjaszewski, K. Activator Generated by
Electron Transfer for Atom Transfer Radical Polymerization.
Macromolecules 2005, 38, 4139. (b) Giedyk, M.; Narobe, R.; Weiß,
S.; Touraud, D.; Kunz, W.; Konig, B. Photocatalytic Activation of
Alkyl Chlorides by Assembly-Promoted Single Electron Transfer in
́
́
̈
rti’s lab
D
https://dx.doi.org/10.1021/acs.orglett.0c00797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Microheterogeneous Solutions. Nat. Catal. 2020, 3, 40. (c) Xiao, P.;
Ni, C.-F.; Miao, W.-J.; Zhou, M.; Hu, J.-Y.; Chen, D.-B.; Hu, J.-B.
Fluoroalkylation of Various Nucleophiles with Fluoroalkyl Sulfones
Through a Single Electron Transfer Process. J. Org. Chem. 2019, 84,
8345. (d) Vacas, T.; Alvarez, E.; Chiara, J. L. Phthalimides as
Exceptionally Efficient Single Electron Transfer Acceptorsn in
Reductive Coupling Reactions Promoted by Samarium Diiodide.
Org. Lett. 2007, 9, 5445. (e) Plesniak, M. P.; Huang, H.-M.; Procter,
D. J. Radical Cascade Reactions Triggered by Single Electron
Transfer. Nat. Rev. Chem. 2017, 1, 0077.
(6) (a) Ma, S. Electrophilic Addition and Cyclization Reactions of
Allenes. Acc. Chem. Res. 2009, 42, 1679. (b) Conrad, W. E.; Fukazawa,
R.; Haddadin, M. J.; Kurth, M. J. The Davis-Beirut Reaction: N1, N2-
Disubstituted-1H-Indazolones via 1,6-Electrophilic Addition to 3-
Alkoxy-2H-Indazoles. Org. Lett. 2011, 13, 3138. (c) Zottig, V. E.;
Todd, M. A.; Nichols-Nielander, A. C.; Harrison, D. P.; Sabat, M.;
Myers, W. H.; Harman, W. D. Epoxidation, Cyclopropanation, and
Electrophilic Addition Reactions at the meta Position of Phenol and
meta-Cresol. Organometallics 2010, 29, 4793.
Trifluoromethylation of (Hetero)Arenes with CF3Br. Angew. Chem.,
Int. Ed. 2016, 55, 2782. (g) Yang, X.; Tsui, G. C. Copper-Mediated
Trifluoromethylation-Allylation of Arynes. Org. Lett. 2018, 20, 1179.
(h) Chachignon, H.; Maeno, M.; Kondo, H.; Shibata, N.; Cahard, D.
Novel Use of CF3SO2Cl for the Metal-Free Electrophilic Trifluor-
omethylthiolation. Org. Lett. 2016, 18, 2467. (i) Xu, C.; Song, X.;
Guo, J.; Chen, S.; Gao, J.; Jiang, J.; Gao, F.; Li, Y.; Wang, M. Synthesis
of Chloro(phenyl)trifluoromethyliodane and Catalyst-Free Electro-
philic Trifluoromethylations. Org. Lett. 2018, 20, 3933.
(10) (a) Li, Y.; Xia, G.; Guo, Q.; Wu, L.; Chen, S.; Yang, Z.; Wang,
W.; Zhang, Z.-Y.; Zhou, X.; Jiang, Z.-X. Design, Synthesis and
Evaluation of Novel 19F Magnetic Resonance Sensitive Protein
Tyrosine Phosphatase Inhibitors. MedChemComm 2016, 7, 1672.
(b) Domino, K.; Veryser, C.; Wahlqvist, B. A.; Gaardbo, C.;
Neumann, K. T.; Daasbjerg, K.; De Borggraeve, W. M.; Skrydstrup,
T. Direct Access to Aryl Bis(trifluoromethyl)carbinols from Aryl
Bromides or Fluorosulfates: Palladium-Catalyzed Carbonylation.
Angew. Chem., Int. Ed. 2018, 57, 6858. (c) Zhou, L.; Shen, Y.-B.;
An, X.-D.; Li, X.-J.; Li, S.-S.; Liu, Q.; Xiao, J. Redox-Neutral β-
C(sp3)−H Functionalization of Cyclic Amines via Intermolecular
Hydride Transfer. Org. Lett. 2019, 21, 8543.
(11) (a) Sugimori, A.; Yamada, T.; Ishida, H.; Nose, M.; Terashima,
K.; Oohata, N. Radiation-Induced Alkylation of Quinoline Derivatives
with Alcohol. Bull. Chem. Soc. Jpn. 1986, 59, 3905. (b) Kamitanaka,
T.; Hikida, T.; Hayashi, S.; Kishida, N.; Matsuda, T.; Harada, T.
Direct Addition of Supercritical Alcohols, Acetone or Acetonitrile to
the Alkenes without Catalysts. Tetrahedron Lett. 2007, 48, 8460.
(c) Sam, B.; Luong, T.; Krische, M. J. Ruthenium-Catalyzed C-C
Coupling of Fluorinated Alcohols with Allenes: Dehydrogenation at
the Energetic Limit of β-Hydride Elimination. Angew. Chem., Int. Ed.
2015, 54, 5465. (d) Zhang, Y.; Yan, W.; Wang, Y.; Weng, Z. Copper-
Catalyzed Synthesis of Indol-3-yl α-(Difluoromethyl)-α-
(trifluoromethyl)carbinols: Construction of Difluoromethylated sp3
Carbon Centers. Org. Lett. 2017, 19, 5478. (e) Zhao, H.; Zhao, S.; Li,
X.; Deng, Y.; Jiang, H.; Zhang, M. Cobalt-Catalyzed Selective
Functionalization of Aniline Derivatives with Hexafluoroisopropanol.
Org. Lett. 2019, 21, 218.
(12) For selected leading reviews, see: (a) Kochanowska-Karamyan,
A. J.; Hamann, M. T. Marine Indole Alkaloids: Potential New Drug
Leads for the Control of Depression and Anxiety. Chem. Rev. 2010,
110, 4489. (b) Taber, D. F.; Tirunahari, P. K. Indole Synthesis: A
Review and Proposed Classification. Tetrahedron 2011, 67, 7195.
(c) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. Rings in Drugs. J.
Med. Chem. 2014, 57, 5845. (d) Stempel, E.; Gaich, T. Cyclohepta-
[b]indoles: A Privileged Structure Motif in Natural Products and
Drug Design. Acc. Chem. Res. 2016, 49, 2390. (e) Li, L.; Chen, Z.;
Zhang, X.; Jia, Y. Divergent Strategy in Natural Product Total
Synthesis. Chem. Rev. 2018, 118, 3752.
(7) (a) Cametti, M.; Crousse, B.; Metrangolo, P.; Milani, R.;
Resnati, G. The Fluorous Effect in Biomolecular Applications. Chem.
Soc. Rev. 2012, 41, 31. (b) O’Hagan, D. Organofluorine Chemistry:
Synthesis and Conformation of Vicinal Fluoromethylene Motifs. J.
Org. Chem. 2012, 77, 3689. (c) Tsui, G. C.; Hu, J.-B. Organofluorine
Chemistry. Asian J. Org. Chem. 2019, 8, 566. (d) Hunter, L.;
O’Hagan, D. Multi-Vicinal Fluoroalkanes: a New Class of Organo-
fluorine Compounds. Org. Biomol. Chem. 2008, 6, 2843. (e) Reddy, V.
P.; Vadapalli, A.; Sinn, E.; Hosmane, N. N-Heterocyclic Carbenes in
Organofluorine Chemistry. J. Organomet. Chem. 2013, 747, 43.
(8) (a) Nagib, D. A.; MacMillan, D. W. C. Trifluoromethylation of
Arenes and Heteroarenes by Means of Photoredox Catalysis. Nature
2011, 480, 224. (b) Chu, L.; Qing, F.-L. Copper-Catalyzed Direct C-
H Oxidative Trifluoromethylation of Heteroarenes. J. Am. Chem. Soc.
2012, 134, 1298. (c) Xu, C.; Liu, J.; Ming, W.; Liu, J.; Liu, J.; Wang,
M.; Liu, Q. In Situ Generation of PhI+CF3 and Transition-Metal-Free
Oxidative sp2 C-H Trifluoromethylation. Chem. - Eur. J. 2013, 19,
9104. (d) Rey-Rodriguez, R.; Retailleau, P.; Bonnet, P.; Gillaizeau, I.
Iron-Catalyzed Trifluoromethylation of Enamide. Chem. - Eur. J.
2015, 21, 3572. (e) Jacquet, J.; Blanchard, S.; Derat, E.; Desage-El
Murr, M.; Fensterbank, L. Redox-Ligand Sustains Controlled
Generation of CF3 Radicals by Well-Defined Copper Complex.
Chem. Sci. 2016, 7, 2030. (f) Hanakawa, T.; Isa, K.; Isobe, S.;
Hoshino, Y.; Zhou, B.; Kawatsura, M. Intramolecular Construction of
Trifluoromethyl Group by the Palladium-Catalyzed Alkylation of
2,3,3-Trifluoroallylic Carbonates with Indoles. J. Org. Chem. 2017, 82,
2281. (g) Mestre, J.; Lishchynskyi, A.; Castillon, S.; Boutureira, O.
Trifluoromethylation of Electron-Rich Alkenyl Iodides with Fluoro-
form-Derived “Ligandless” CuCF3. J. Org. Chem. 2018, 83, 8150.
(h) Cai, S.-H.; Ye, L.; Wang, D.-X.; Wang, Y.-Q.; Lai, L.-J.; Zhu, C.;
Feng, C.; Loh, T.-P. Manganese-Catalyzed Synthesis of Monofluor-
oalkenes via C−H Activation and C−F Cleavage. Chem. Commun.
2017, 53, 8731.
(9) (a) Xu, X.-H.; Liu, G.-K.; Azuma, A.; Tokunaga, E.; Shibata, N.
Synthesis of Indole and Biindolyl Triflones: Trifluoromethanesulfo-
nylation of Indoles with Tf2O/TTBP (2,4,6-tri-tert-butylpyridine)
System. Org. Lett. 2011, 13, 4854. (b) Zhang, C.-P.; Wang, Z.-L.;
Chen, Q.-Y.; Zhang, C.-T.; Gu, Y.-C.; Xiao, J.-C. Copper-Mediated
Trifluoromethylation of Heteroaromatic Compounds by Trifluor-
omethyl Sulfonium Salts. Angew. Chem., Int. Ed. 2011, 50, 1896.
(c) Mejia, E.; Togni, A. Rhenium-Catalyzed Trifluoromethylation of
Arenes and Heteroarenes by Hypervalent Iodine Reagents. ACS Catal.
2012, 2, 521. (d) Pitre, S. P.; McTiernan, C. D.; Ismaili, H.; Scaiano,
J. C. Metal-Free Photocatalytic Radical Trifluoromethylation Utilizing
Methylene Blue and Visible Light Irradiation. ACS Catal. 2014, 4,
2530. (e) Zhang, X.; Wang, J.; Wan, Z. New Reagent for Highly
Efficient Synthesis of Trifluoromethyl-Substituted Arenes and
Heteroarenes. Org. Lett. 2015, 17, 2086. (f) Natte, K.; Jagadeesh, R.
V.; He, L.; Rabeah, J.; Chen, J.; Taeschler, C.; Ellinger, S.; Zaragoza,
(13) (a) Cacchi, S.; Fabrizi, G. Synthesis and Functionalization of
Indoles through Palladium-Catalyzed Reactions. Chem. Rev. 2005,
105, 2873. (b) Ackermann, L. Catalytic Arylations with Challenging
Substrates: from Air-stable HASPO Preligands to Indole Syntheses
and C-H Bond Functionalizations. Synlett 2007, 2007, 0507.
(c) Bandini, M.; Eichholzer, A. Catalytic Functionalization of Indoles
in A New Dimension. Angew. Chem., Int. Ed. 2009, 48, 9608. (d) Shiri,
M. Indoles in Multicomponent Processes (MCPs). Chem. Rev. 2012,
112, 3508. (e) Palmer, W. N.; Obligacion, J. V.; Pappas, I.; Chirik, P.
J. Cobalt-Catalyzed Benzylic Borylation: Enabling Polyborylation and
Functionalization of Remote, Unactivated C(sp3)−H Bonds. J. Am.
Chem. Soc. 2016, 138, 766. (f) Leitch, J. A.; Bhonoah, Y.; Frost, C. G.
Beyond C2 and C3: Transition-Metal-Catalyzed C−H Functionaliza-
tion of Indole. ACS Catal. 2017, 7, 5618. (g) Soni, V.; Khake, S. M.;
Punji, B. Nickel-Catalyzed C(sp2)−H/C(sp3)−H Oxidative Coupling
of Indoles with Toluene Derivatives. ACS Catal. 2017, 7, 4202.
(h) Yang, Y.; Shi, Z. Regioselective Direct Arylation of Indoles on the
Benzenoid Moiety. Chem. Commun. 2018, 54, 1676.
(14) Xu, Z.; Hang, Z.; Chai, L.; Liu, Z.-Q. A Free-Radical-Promoted
Site-Specific Cross-Dehydrogenative-Coupling of N-Heterocycles
with Fluorinated Alcohols. Org. Lett. 2016, 18, 4662.
F.; Neumann, H.; Bruckner, A.; Beller, M. Palladium-Catalyzed
̈
E
https://dx.doi.org/10.1021/acs.orglett.0c00797
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(15) Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A.;
Snieckus, V.; Josephy, P. D. Sequential Directed Ortho Metalation-
Boronic Acid Cross-Coupling Reactions. A General Regiospecific
Route to Xxygenated Dibenzo[b,d]Pyran-6-Ones Related to Ellagic
Acid. J. Org. Chem. 1991, 56, 3763.
F
https://dx.doi.org/10.1021/acs.orglett.0c00797
Org. Lett. XXXX, XXX, XXX−XXX