Modular Synthesis of 9,10-Dihydroacridines through an ortho-C Alkenylation/Hydroarylation Sequence between Anilines and Aryl Alkynes in Hexafluoroisopropanol

Article abstract of DOI:10.1021/acs.orglett.1c00487

9,10-Dihydroacridines are frequently encountered as key scaffolds in OLEDs. However, accessing those compounds from feedstock precursors typically requires multiple steps. Herein, a modular one-pot synthesis of 9,10-dihydroacridine frameworks is achieved through a reaction sequence featuring a selective ortho-C alkenylation of diarylamines with aryl alkynes followed by an intramolecular hydroarylation of the olefin formed as an intermediate. This transformation was accomplished by virtue of the combination of hexafluoroisopropanol and triflimide as a catalyst that triggers the whole process.

Full text of DOI:10.1021/acs.orglett.1c00487

pubs.acs.org/OrgLett
Letter
Modular Synthesis of 9,10-Dihydroacridines through an ortho-C
Alkenylation/Hydroarylation Sequence between Anilines and Aryl
Alkynes in Hexafluoroisopropanol
Shengdong Wang, Guillaume Force, Jean-Franco
Vincent Gandon,* and David Lebœuf*
̧
is Carpentier, Yann Sarazin, Christophe Bour,
Cite This: Org. Lett. 2021, 23, 2565−2570
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: 9,10-Dihydroacridines are frequently encountered as
key scaffolds in OLEDs. However, accessing those compounds from
feedstock precursors typically requires multiple steps. Herein, a
modular one-pot synthesis of 9,10-dihydroacridine frameworks is
achieved through a reaction sequence featuring a selective ortho-C
alkenylation of diarylamines with aryl alkynes followed by an
intramolecular hydroarylation of the olefin formed as an intermediate. This transformation was accomplished by virtue of the
combination of hexafluoroisopropanol and triflimide as a catalyst that triggers the whole process.
n the past decade, 9,10-dihydroacridines have emerged as
privileged structural motifs in chemistry owing to their
sequence proved to be limited. In this context, we questioned
whether we could address the limitations of this transformation
by employing hexafluoroisopropanol (HFIP) as a solvent.10 In
the past years, HFIP has become a prominent solvent in
organic synthesis due to its combination of atypical properties,
including strong H-bond donating ability, low nucleophilicity,
redox stability, and mild acidity.11 It allowed us to achieve
reactions that were unlikely to take place in traditional organic
solvents,8k,10d,12 emphasizing that, when HFIP was associated
with a Lewis acid or a Brønsted acid, the acidity of the
corresponding combination could be considerably boosted to
even activate unreactive substrates such as highly deactivated
styrenes. Recently, we applied this principle to the ortho-C
alkylation of anilines with alkenes,8k which relies on a
concerted-like mechanism that is fostered by the presence of
HFIP and prevents common regioselectivity issues associated
with this type of process (Scheme 1c). While rather efficient
and general, this transformation is still fraught with a few
limitations in terms of reactivity. For instance, electron-rich
styrenes or triarylamines preferentially led to para-adducts due
to a facile protonation of the olefin moiety under the reaction
conditions. Following this work, we assumed that this strategy
could be transposed to aryl alkynes to afford the target 9,10-
dihydroacridines. We hypothesized that, since the protonated
alkynes (vinyl carbocations) are less reactive than protonated
I
remarkable electronic properties. They are now extensively
used in the field of materials science as electron-donor units,
notably for organic light-emitting diode (OLED) devices.
Hence, they have been employed as an integral part of
fluorescent emitters, thermally activated delayed fluorescence
(TADF) materials, or hole-transport materials.1 Moreover,
they have recently proven particularly effective in other areas
such as photocatalysis,2 detection of explosives,3 and medicinal
chemistry.4 However, despite the wealth of reports regarding
their utilization, the development of efficient and versatile
synthetic methods to access those building blocks from readily
available precursors remain strikingly sparse,5 representing a
serious impediment to broadening their range of applications.
Currently, their preparation usually requires multistep syn-
thesis from anilines, which are furthermore not always
commercially available (Scheme 1a).1j On this basis, most of
the applications reported tend to be limited to simple 9,10-
dimethyl and -diphenylacridines. As an alternative, the group
of Stephan described, in 2017, an elegant approach to access
9,10-dihydroacridines following a one-pot sequence featuring
an ortho-C alkenylation of an aniline with an aryl alkyne and a
subsequent hydroarylation of the styrene intermediate in the
presence of a phosphonium dication catalyst (Scheme 1b).5c
The selective ortho-C alkenylation of the aniline with the
alkyne is the key part of the process;6,7 however, the
applicability of this type of reactivity is still underdeveloped
when compared to the ortho-C alkylation of anilines with
olefins.8 It might be explained by the formation of an sp
hybridized carbenium center, which is a sluggish electrophile
compared to its sp2 carbenium counterpart generated from
alkenes.9 As a result, the scope exhibited by this reaction
Received: February 9, 2021
Published: March 16, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00487
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2565−2570
2565

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. Strategies to Access 9,10-Dihydroacridines
a
[P]+ = [(PhO)P(2(N-Mepy))Ph2]2+.
alkenes, a concerted mechanism pathway would be predom-
inant, bypassing the above-mentioned limitations. This strategy
would thus enable a straightforward and modular synthesis of
9,10-dihydroacridines so that the properties of the correspond-
ing organic materials could be easily tuned, enabling new
applications for this class of compounds. Herein, we disclose
our findings regarding this reaction sequence to produce an
array of structurally varied 9,10-dihydroacridines in good to
high yields and with an excellent functional group compat-
ibility. Moreover, we show that the developed conditions also
allow the preparation of xanthenes and thioxanthenes.
because of its low boiling point, it can be easily recovered by
distillation,15 counterbalancing this issue.
We started our investigations by examining the reaction
between 1-ethynyl-4-(trifluoromethyl)benzene 1a (highly
deactivated aryl alkyne) and diphenylamine 2a in HFIP (see
the Supporting Information for more details). We established
We next examined the scope of this transformation (Scheme
2), first evaluating a variety of terminal aryl alkynes (1aa−1ua)
in reactions with diphenylamine 2a. In this respect, the tested
aryl alkynes bearing moderate and strong electron-donating
and -withdrawing groups at the para-position were all tolerated
and provided the corresponding 9,10-dihydroacridines 3aa−
3ka in high yields, ranging from 73 to 98%. Of note, in the case
of strong electron-withdrawing groups such as nitrile and nitro
(1c and 1d), the reaction had to be conducted at 120 °C to
reach complete conversion of the alkyne starting materials. In
the case of strong electron-donating groups such as methoxy
and amine (1j and 1k), the reaction proceeded faster than the
previous examples (6 vs 16 h), providing the target products
3ja and 3ka in 86 and 79% yield, respectively. The use of
highly electron-poor alkynes such as the 3,5-bis(trifluoro-
13
that using Brønsted acid HNTf2 as catalyst proved to be
optimal to deliver the target 9,10-dihydroacridine 3aa in 86%
yield after 16 h at 80 °C (eq 1).14 A survey of the reaction
optimization revealed that HFIP is crucial for the reaction
outcome, as another fluorinated solvent such as trifluoroetha-
nol (TFE) yielded the product 3aa in a low yield (5%); only
traces of 3aa were observed in common solvents such as 1,2-
DCE, toluene, and nitromethane. Gratifyingly, the reaction
worked smoothly on a larger scale (5 mmol), furnishing 3aa in
81% yield (1.37 g). An issue regularly mentioned with the
utilization of HFIP is its cost, but it is important to stress that,
2566
https://dx.doi.org/10.1021/acs.orglett.1c00487
Org. Lett. 2021, 23, 2565−2570

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 2. Scope of 9,10-Dihydroacridines and Other Heterocycles
methyl)phenyl derivative required an increase in the catalyst
loading to 10 mol % to afford 9,10-dihydroacridine 3la in 83%
yield. The presence of an ortho-substituent was also well
tolerated (3ma, 87%). The reaction sequence was not limited
to a phenyl group but could also be extended to a naphthyl or
thienyl group, delivering both 3na and 3oa in 80% yield. More
2567
https://dx.doi.org/10.1021/acs.orglett.1c00487
Org. Lett. 2021, 23, 2565−2570

Organic Letters
pubs.acs.org/OrgLett
Letter
importantly, the transformation occurred also for internal
alkynes incorporating alkyl substituents (e.g., adducts 3pa and
3qa were generated in 73 and 70% yield), albeit at a slower
rate than the reactions involving terminal alkynes. Gratifyingly,
dialkynes 1s−1t and trialkyne 1u were readily accommodated
in the reactions to provide multiple-9,10-dihydroacridine-
bearing compounds in high yields (71−89%). On the other
hand, bis-alkyl alkynes proved to not be competent precursors
for the reaction, essentially leading to decomposition of the
substrate with only traces of the target product 3ra detected.
We then explored the scope with respect to the diarylamine
component (2b−2n), using representative aryl alkynes 1c (R =
CN) and 1g (R = H) as benchmark precursors. In the case of
2,7-substituted 9,10-dihydroacridines (3cb−3cj, 3gd, 3gf, and
3gi), the reaction demonstrated a broad functional group
compatibility from both symmetrical and dissymmetrical
diarylamines to provide the products in medium to high yields
(57−95%). Both electron-donating and -withdrawing sub-
stituents were amenable to the reaction; notably, bromide
substituents were easily introduced to generate products 3ce,
3ci, and 3gi (57−68%), which constitute useful platforms for
further derivatizations. In addition, 4,5-substituted 9,10-
dihydroacridines such as 3ck could be generated in 73%
yield. N-Alkyl diarylamines such as 1l also underwent the
reaction process in high yields (up to 85%), employing both
terminal and internal alkynes (3al, 3cl, 3gl, and 3pl). By
incorporating a naphthyl moiety, we could prepare complex
polycyclic structures (3 cm, 3cn, and 3gn) in yields ranging
from 61 to 87%.
Triarylamines, notably triphenylamine 2o, displayed a
satisfying reactivity with respect to this process to form the
products in medium to high yields (41−93%), regardless of the
electronic demand of the aryl alkyne and its nature (terminal
or internal). Another key feature of this method is that the
reaction of diphenyl sulfide 2r in place of 2a yielded the
corresponding thioxanthene 3cr in 83% yield. In the same vein,
the reaction with diphenyl ether 2s underwent the diarylation
to give xanthene 3gs in 67% yield. However, it should be
stressed that diphenyl ether is less reactive than diarylamines
and diphenyl sulfide, as it was ineffective with highly
deactivated aryl alkyne such as 1c (10% yield after 1 week at
120 °C). Regarding the limitations of this approach, we
noticed that the use of meta-substituted diarylamines (2s and
2t) and triarylamines with nonidentical aryl groups led to the
formation of a mixture of 2 regioisomers that could not be
separated in some cases by flash column chromatography.
To further illustrate the synthetic utility of this method, we
carried out a few postfunctionalizations. As stated above, the
reaction sequence with dissymmetrical diarylamines occurred
with ease to return the corresponding products in high yields.
Those results could be used to our advantage to generate
densely functionalized 9,10-dihydroacridines such as 4
incorporating four different aryl units, following a Ullmann
C−N cross-coupling.16 It also represents a simple way to
circumvent the reactivity issue mentioned with triarylamines.
Additionally, we executed a Pd(II)-catalyzed C−H activation
to convert 3ma into pentacyclic compound 5 in 94% yield.17,18
In summary, we have developed an efficient protocol for the
assembly of 9,10-dihydroacridines and related heterocycles
from inexpensive precursors through the cooperation of HFIP
and a Brønsted acid catalyst. The wide array of substrates
tolerated validates the utility of this transformation as a means
to provide a rapid access to molecules that could find
applications in the field of materials science and photocatalysis.
In addition, the viability at scale of this method was also
demonstrated.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00487.
Experimental procedures, characterization data, and
NMR spectra of all new compounds (PDF)
FAIR data, including the primary NMR FID files, for
compounds 3aa−3′gv, 4, and 5 (ZIP)
AUTHOR INFORMATION
Corresponding Authors
■
Vincent Gandon − Institut de Chimie Moléculaire et des
Matériaux d’Orsay (ICMMO), 91405 Orsay, France;
Laboratoire de Chimie Moléculaire (LCM), Institut
Polytechnique de Paris, 91128 Palaiseau Cedex, France;
orcid.org/0000-0003-1108-9410;
Email: vincent.gandon@universite-paris-saclay.fr
David Lebœuf − Institut de Science et d’Ingénierie
Supramoléculaires (ISIS), Université de Strasbourg, 67000
Strasbourg, France; orcid.org/0000-0001-5720-7609;
Email: dleboeuf@unistra.fr
Authors
Shengdong Wang − Institut de Chimie Moléculaire et des
Matériaux d’Orsay (ICMMO), 91405 Orsay, France; The
Fifth Affiliated Hospital, Key Laboratory of Molecular Target
& Clinical Pharmacology and the State Key Laboratory of
Respiratory Disease, School of Pharmaceutical Sciences,
Guangzhou Medical University, Guangzhou, Guangdong
511436, China
Guillaume Force − Institut de Chimie Moléculaire et des
Matériaux d’Orsay (ICMMO), 91405 Orsay, France
Jean-Franco̧ is Carpentier − Université Rennes, Institut des
Sciences Chimiques de Rennes (ISCR), 35000 Rennes, France
Yann Sarazin − Université Rennes, Institut des Sciences
Chimiques de Rennes (ISCR), 35000 Rennes, France;
orcid.org/0000-0003-1121-0292
Christophe Bour − Institut de Chimie Moléculaire et des
Matériaux d’Orsay (ICMMO), 91405 Orsay, France;
orcid.org/0000-0001-6733-5284
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00487
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully thank the ANR (ANR-17-CE07-0003 funding
for S.W. and ANR-16-CE07-0022 funding for G.F.), the
CNRS, Ecole Polytechnique, and Université Paris-Saclay for
the support of this work. We used the OCCIGEN high
performance cluster of the CINES.
REFERENCES
■
(1) For selected applications, see: (a) Park, M. S.; Lee, J. Y. Indolo
Acridine-Based Hole-Transport Materials for Phosphorescent OLEDs
with Over 20% External Quantum Efficiency in Deep Blue and Green.
2568
https://dx.doi.org/10.1021/acs.orglett.1c00487
Org. Lett. 2021, 23, 2565−2570

Organic Letters
pubs.acs.org/OrgLett
Letter
Chem. Mater. 2011, 23, 4338−4343. (b) Méhes, G.; Nomura, H.;
Zhang, Q.; Nakagawa, T.; Adachi, C. Enhanced Electroluminescence
Efficiency in a Spiro-Acridine Derivative through Thermally Activated
Delayed Fluorescence. Angew. Chem., Int. Ed. 2012, 51, 11311−
11315. (c) Kim, M.; Lee, J. Y. Improved Power Efficiency in Deep
Blue Phosphorescent Organic Light-Emitting Diodes Using an
Acridine Core Based Hole Transport Material. Org. Electron. 2012,
13, 1245−1249. (d) Zhang, Q.; Li, B.; Huang, S.; Nomura, H.;
Tanaka, H.; Adachi, C. Efficient Blue Organic Light-Emitting Diodes
Employing Thermally Activated Delayed Fluorescence. Nat. Photonics
2014, 8, 326−332. (e) Zhang, Y.-X.; Zhang, L.; Cui, L.-S.; Gao, C.-H.;
Chen, H.; Li, Q.; Jiang, Z.-Q.; Liao, L.-S. Control of Conjugation
Degree via Position Engineering to Highly Efficient Phosphorescent
Host Materials. Org. Lett. 2014, 16, 3748−3751. (f) Liu, X.-Y.; Liang,
F.; Yuan, Y.; Jiang, Z.-Q.; Liao, L.-S. Utilizing 9,10-Dihydroacridine
and Pyrazine-Containing Donor-Acceptor Host Materials for Highly
Efficient Red Phosphorescent Organic Light-Emitting Diodes. J.
Mater. Chem. C 2016, 4, 7869−7874. (g) Zhang, L.; Zhang, Y.-X.; Hu,
Y.; Shi, X.-B.; Jiang, Z.-Q.; Wang, Z.-K.; Liao, L. S. Highly Efficient
Blue Phosphorescent Organic Light-Emitting Diodes Employing a
Host Material with Small Bandgap. ACS Appl. Mater. Interfaces 2016,
8, 16186−16191. (h) Zeng, W.; Lai, H.-Y.; Lee, W.-K.; Jiao, M.; Shiu,
Y.-J.; Zhong, C.; Gong, S.; Zhou, T.; Xie, G.; Sarma, M.; Wong, K.-T.;
Wu, C.-C.; Yang, C. Achieving Nearly 30% External Quantum
Efficiency for Orange-Red Organic Light Emitting Diodes by
Employing Thermally Activated Delayed Fluorescence Emitters
Composed of 1,8-Naphthalimide-Acridine Hybrids. Adv. Mater.
2017, 29, 1704961. (i) Yu, L.; Wu, Z.; Xie, G.; Zeng, W.; Ma, D.;
Yang, C. Molecular Design to Regulate the Photophysical Properties
of Multifunctional TADF Emitters Towards High-Performance
TADF-Based OLEDs with EQES up to 22.4% and Small Efficiency
Roll-Offs. Chem. Sci. 2018, 9, 1385−1391. (j) Liu, X.-Y.; Ma, Y.-Y.;
Zhang, W.; Song, B.; Ding, L.; Fung, M.-K.; Fan, J. A Novel Linking
Strategy of Using 9,10-Dihydroacridines to Construct Efficient Host
Materials for Red Phosphorescent Organic Light-Emitting Diodes.
Chem. - Eur. J. 2018, 24, 11755−11762. (k) Wada, Y.; Kubo, S.; Kaji,
H. Adamantyl Substitution Strategy for Realizing Solution-Process-
able Thermally Stable Deep-Blue Thermally Activated Delayed
Fluorescence Materials. Adv. Mater. 2018, 30, 1705641. (l) Yang,
Y.; Wang, S.; Zhu, Y.; Wang, Y.; Zhan, H.; Cheng, Y. Thermally
Activated Delayed Fluorescence Conjugated Polymers with Back-
bone-Donor/Pendant-Acceptor Architecture for Nondoped OLEDs
with High External Quantum Efficiency and Low Roll-Off. Adv. Funct.
Mater. 2018, 28, 1706916. (m) He, X.; Ren, S.; Liu, H.; Zhao, S.; Liu,
F.; Du, C.; Min, J.; Zhang, H.; Lu, P. Efficient Nondoped Pure Blue
Organic Light-Emitting Diodes Based on an Anthracene and 9,9-
Diphenyl-9,10-dihydroacridine Derivative. Chem. - Asian J. 2020, 15,
163−168.
(2) (a) Buss, B. L.; Lim, C.-H.; Miyake, G. M. Dimethyl
Dihydroacridines as Photocatalysts in Organocatalyzed Atom Trans-
fer Radical Polymerization of Acrylate Monomers. Angew. Chem., Int.
Ed. 2020, 59, 3209−3217. (b) Liu, Y.; Chen, Q.; Tong, Y.; Ma, Y. 9,9-
Dimethyl Dihydroacridine-Based Organic Photocatalyst for Atom
Transfer Radical Polymerization from Modifying “Unstable” Electron
Donor. Macromolecules 2020, 53, 7053−7062.
(3) Andrew, T. L.; Swager, T. M. Detection of Explosives via
Photocatalytic Cleavage of Nitroesters and Nitramines. J. Org. Chem.
2011, 76, 2976−2993.
(4) Bagriantsev, S. N.; Ang, K.-H.; Gallardo-Godoy, A.; Clark, K. A.;
Arkin, M. R.; Renslo, A. R.; Minor, D. L., Jr. A High-Throughput
Functional Screen Identifies Small Molecule Regulators of Temper-
ature- and Mechano-Sensitive K2P Channels. ACS Chem. Biol. 2013, 8,
1841−1851.
(5) For selected examples, see: (a) Mahendar, L.; Satyanarayana, G.
Copper Catalyzed Coupling of Protecting Group Free and Sterically
Hindered 2-Bromobenzyl Tertiary Alcohols with Phenols and
Anilines: Facile Synthesis of Xanthenes and Dihydroacridines. RSC
Adv. 2016, 6, 20588−20597. (b) Yoshida, H.; Kuriki, H.; Fujii, S.; Ito,
Y.; Osaka, I.; Takaki, K. Aryne-Imine-Aryne Coupling Reaction via [4
+ 2] Cycloaddition between Aza-o-Quinone Methides and Arynes.
Asian J. Org. Chem. 2017, 6, 973−976. (c) LaFortune, J. H. W.;
Bayne, J. M.; Johnstone, T. C.; Fan, L.; Stephan, D. W. Catalytic
Double Hydroarylation of Alkynes to 9,9-Disubstituted 9,10-
Dihydroacridine Derivatives by an Electrophilic Phenoxyphospho-
nium Dication. Chem. Commun. 2017, 53, 13312−13315. (d) LaFor-
tune, J. H. W.; Szkop, K. M.; Farinha, F. E.; Johnstone, T. C.; Postle,
S.; Stephan, D. W. Probing Steric Influences on Electrophilic
Phosphonium Cations: A Comparison of [(3,5-(CF3)2C6H3)3PF]+
and [(C6F5)3PF]+. Dalton Trans 2018, 47, 11411−11419. (e) Smith,
A. J.; Dimitrova, D.; Arokianathar, J. N.; Kolodziejczak, K.; Young, A.;
Allison, M.; Poole, D. L.; Leach, S. G.; Parkinson, J. A.; Tuttle, T.;
Murphy, J. A. New Reductive Rearrangement of N-Arylindoles
Triggered by the Grubbs-Stoltz Reagent Et3SiH/KOtBu. Chem. Sci.
2020, 11, 3719−3726.
(6) (a) Arienti, A.; Bigi, F.; Maggi, R.; Marzi, E.; Moggi, P.; Rastelli,
M.; Sartori, G.; Tarantola, F. Regioselective Electrophilic Alkylation of
Anilines with Phenylacetylene in the Presence of Montmorillonite
KSF. Tetrahedron 1997, 53, 3795−3804. (b) Fedushkin, I. L.;
Nikipelov, A. S.; Morozov, A. G.; Skatova, A. A.; Cherkasov, A. V.;
Abakumov, G. A. Addition of Alkynes to a Gallium Bis-Amido
Complex: Imitation of Transition-Metal-Based Catalytic Systems.
Chem. - Eur. J. 2012, 18, 255−266. (c) Fedushkin, I. L.; Moskalev, M.
V.; Baranov, E. V.; Abakumov, G. A. Addition of Diphenylacetylene
and Methylvinylketone to Aluminum Complex of Redox-Active
Diimine Ligand. J. Organomet. Chem. 2013, 747, 235−240.
(d) Mameda, N.; Peraka, S.; Kodumuri, S.; Chevella, D.; Marri, M.
R.; Nama, N. Ortho-Alkenylation of Anilines with Aromatic Terminal
Alkynes over Nanosized Zeolite Beta. RSC Adv. 2015, 5, 78374−
78378. (e) Chatupheeraphat, A.; Rueping, M.; Magre, M. Chemo-
and Regioselective Magnesium-Catalyzed ortho-Alkenylation of Ani-
lines. Org. Lett. 2019, 21, 9153−9157.
(7) For the synthesis of related compounds starting from olefins, see:
Cooper, P.; Crisenza, G. E. M.; Feron, L. F.; Bower, J. F. Iridium-
Catalyzed α-Selective Arylation of Styrenes by Dual C−H Activation.
Angew. Chem., Int. Ed. 2018, 57, 14198−14202.
(8) For selected examples of ortho-C alkylation of anilines with
olefins, see: (a) Beller, M.; Thiel, O. R.; Trauthwein, H. Catalytic
Alkylation of Aromatic Amines with Styrene in the Presence of
Cationic Rhodium Complexes and Acid. Synlett 1999, 1999, 243−
245. (b) Kaspar, L. T.; Fingerhut, B.; Ackermann, L. Titanium-
Catalyzed Intermolecular Hydroamination of Vinylarenes. Angew.
Chem., Int. Ed. 2005, 44, 5972−5974. (c) Cherian, A. E.; Domski, G.
J.; Rose, J. M.; Lobkovsky, E. B.; Coates, G. W. Acid-Catalyzed ortho-
Alkylation of Anilines with Styrenes: An Improved Route to Chiral
Anilines with Bulky Substitutents. Org. Lett. 2005, 7, 5135−5137.
(d) Anderson, L. L.; Arnold, J.; Bergman, R. G. Proton-Catalyzed
Hydroamination and Hydroarylation Reactions of Anilines and
Alkenes: A Dramatic Effect of Counteranions on Reaction Efficiency.
J. Am. Chem. Soc. 2005, 127, 14542−14543. (e) Crisenza, G. E. M.;
Sokolova, O. O.; Bower, J. F. Branch-Selective Alkene Hydroarylation
by Cooperative Destabilization: Iridium-Catalyzed ortho-Alkylation of
Acetanilides. Angew. Chem., Int. Ed. 2015, 54, 14866−14870. (f) Song,
G.; Luo, G.; Oyamada, J.; Luo, Y.; Hou, Z. ortho-Selective C−H
Addition of N,N-Dimethyl Anilines to Alkenes by a Yttrium Catalyst.
Chem. Sci. 2016, 7, 5265−5270. (g) Zhu, W.; Sun, Q.; Wang, Y.;
Yuan, D.; Yao, Y. Chemo- and Regioselective Hydroarylation of
Alkenes with Aromatic Amines Catalyzed by [Ph3C][B(C6H5)4]. Org.
Lett. 2018, 20, 3101−3104. (h) Schroeter, F.; Lerch, S.; Kaliner, M.;
Strassner, T. Cobalt-Catalyzed Hydroarylations and Hydroaminations
of Alkenes in Tunable Aryl Alkyl Ionic Liquids. Org. Lett. 2018, 20,
6215−6219. (i) Grélaud, S.; Cooper, P.; Feron, L. J.; Bower, J. F.
Branch-Selective and Enantioselective Iridium-Catalyzed Alkene
Hydroarylation via Anilide-Directed C−H Oxidative Addition. J.
̈
Am. Chem. Soc. 2018, 140, 9351−9356. (j) Rank, C. K.; Ozkaya, B.;
Patureau, F. W. HBF4- and AgBF4-Catalyzed ortho-Alkylation of
Diarylamines and Phenols. Org. Lett. 2019, 21, 6830−6834.
(k) Wang, S.; Force, G.; Guillot, R.; Carpentier, J.-F.; Sarazin, Y.;
Bour, C.; Gandon, V.; Lebœuf, D. Lewis Acid/Hexafluoroisopropa-
2569
https://dx.doi.org/10.1021/acs.orglett.1c00487
Org. Lett. 2021, 23, 2565−2570

Organic Letters
pubs.acs.org/OrgLett
Letter
nol: A Promoter System for Selective ortho-C-Alkylation of Anilines
with Deactivated Styrene Derivatives and Unactivated Alkenes. ACS
Catal. 2020, 10, 10794−10802.
(16) Sambiagio, C.; Marsden, S. P.; Blacker, A. J.; McGowan, P. C.
Copper Catalysed Ullmann Type Chemistry: From Mechanistic
Aspects to Modern Development. Chem. Soc. Rev. 2014, 43, 3525−
3550.
(17) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. Catalytic
Direct Arylation with Aryl Chlorides, Bromides, and Iodides:
Intramolecular Studies Leading to New Intermolecular Reactions. J.
Am. Chem. Soc. 2006, 128, 581−590.
(9) Byrne, P. A.; Kobayashi, S.; Wurthwein, E.-U.; Ammer, J.; Mayr,
̈
H. Why Are Vinyl Cations Sluggish Electrophiles? J. Am. Chem. Soc.
2017, 139, 1499−1511.
(10) For examples of hydroarylation processes in HFIP, see:
́
(a) Richmond, E.; Vukovic, V. D.; Moran, J. Nucleophilic Ring
(18) For another approach to synthesize this type of compounds,
see: Gu, Z.-Y.; Liu, C.-G.; Wang, S.-Y.; Ji, S.-J. Pd-Catalyzed
Intramolecular Heck Reaction, C(sp2)−H Activation, 1,4-Pd
Migration, and Aminopalladation: Chemoselective Synthesis of
Dihydroindeno[1,2,3-kl]acridines and 3-Arylindoles. Org. Lett. 2016,
18, 2379−2382.
Opening of Donor-Acceptor Cyclopropanes Catalyzed by a Brønsted
Acid in Hexafluoroisopropanol. Org. Lett. 2018, 20, 574−577.
(b) Roy, S.; Motiwala, H. F.; Koshlap, K. M.; Aubé, J.
Hexafluoroisopropanol and Acetyl Chloride Promoted Catalytic
Hydroarylation with Phenols. Eur. J. Org. Chem. 2018, 2018, 306−
́
315. (c) Richmond, E.; Yi, J.; Vukovic, V. D.; Sajadi, F.; Rowley, C.
N.; Moran, J. Ring-Opening Hydroarylation of Monosubstituted
Cyclopropanes Enabled by Hexafluoroisopropanol. Chem. Sci. 2018,
9, 6411−6416. (d) Qi, C.; Gandon, V.; Lebœuf, D. Calcium(II)-
Catalyzed Intermolecular Hydroarylation of Deactivated Styrenes in
Hexafluoroisopropanol. Angew. Chem., Int. Ed. 2018, 57, 14245−
14249. (e) Takahashi, I.; Fujita, T.; Shoji, N.; Ichikawa, J. Brønsted
Acid-Catalysed Hydroarylation of Unactivated Alkynes in a
Fluoroalcohol−Hydrocarbon Biphasic System: Construction of
Phenanthrene Frameworks. Chem. Commun. 2019, 55, 9267−9270.
(f) Nielsen, C. D.-T.; White, A. J. P.; Sale, D.; Bures, J.; Spivey, A. C.
Hydroarylation of Alkenes by Protonation/Friedel-Crafts Trapping:
HFIP-Mediated Access to Per-aryl Quaternary Stereocenters. J. Org.
Chem. 2019, 84, 14965−14973. (g) Colomer, I. Hydroarylation of
Alkenes Using Anilines in Hexafluoroisopropanol. ACS Catal. 2020,
10, 6023−6029.
(11) For reviews on HFIP, see: (a) Bégué, J.-P.; Bonnet-Delpon, D.;
Crousse, B. Fluorinated Alcohols: A New Medium for Selective and
Clean Reaction. Synlett 2004, 18−29. (b) Shuklov, I. A.; Dubrovina,
N. V.; Börner, A. Fluorinated Alcohols as Solvents, Cosolvents and
Additives in Homogeneous Catalysis. Synthesis 2007, 2007, 2925−
2943. (c) Sugiishi, T.; Matsugi, M.; Hamamoto, H.; Amii, H.
Enhancement of Stereoselectivities in Asymmetric Synthesis Using
Fluorinated Solvents, Auxiliaries, and Catalysts. RSC Adv. 2015, 5,
17269−17282. (d) Wencel-Delord, J.; Colobert, F. A Remarkable
Solvent Effect of Fluorinated Alcohols on Transition Metal Catalysed
C-H Functionalizations. Org. Chem. Front. 2016, 3, 394−400.
(e) Colomer, I.; Chamberlain, A. E. R.; Haughey, M. B.; Donohoe,
T. J. Hexafluoroisopropanol as a Highly Versatile Solvent. Nat. Rev.
Chem. 2017, 1, 0088. (f) Sinha, S. K.; Bhattacharya, T.; Maiti, D. Role
of Hexafluoroisopropanol in C−H Activation. React. Chem. Engl.
2019, 4, 244−253. (g) Yu, C.; Sanjosé-Orduna, J.; Patureau, F.;
Pérez-Temprano, M. Chem. Soc. Rev. 2020, 49, 1643−1652.
(h) Pozhydaiev, V.; Power, M.; Gandon, V.; Moran, J.; Lebœuf, D.
Exploiting Hexafluoroisopropanol (HFIP) in Lewis and Brønsted
Acid-Catalyzed Reactions. Chem. Commun. 2020, 56, 11548−11564.
(12) (a) Lebœuf, D.; Marin, L.; Michelet, B.; Perez-Luna, A.;
Guillot, R.; Schulz, E.; Gandon, V. Harnessing the Lewis Acidity of
HFIP Through its Cooperation with a Calcium(II) Salt: Application
to the Aza-Piancatelli Reaction. Chem. - Eur. J. 2016, 22, 16165−
16171. (b) Qi, C.; Hasenmaile, F.; Gandon, V.; Lebœuf, D.
Calcium(II)-Catalyzed Intra- and Intermolecular Hydroamidation of
Unactivated Alkenes in Hexafluoroisopropanol. ACS Catal. 2018, 8,
1734−1739. (c) Qi, C.; Yang, S.; Gandon, V.; Lebœuf, D.
Calcium(II)- and Triflimide-Catalyzed Intramolecular Hydroacylox-
ylation of Unactivated Alkenes in Hexafluoroisopropanol. Org. Lett.
2019, 21, 7405−7409.
(13) Zhao, W.; Sun, S. Triflimide (HNTf2) in Organic Synthesis.
Chem. Rev. 2018, 118, 10349−10392.
(14) For preliminary investigations regarding the mechanism of the
reaction, notably the key ortho-C alkenylation step, see the Supporting
Information for details.
(15) Vekariya, R. H.; Aubé, J. Hexafluoro-2-propanol-Promoted
Intermolecular Friedel-Crafts Acylation Reaction. Org. Lett. 2016, 18,
3534−3537.
2570
https://dx.doi.org/10.1021/acs.orglett.1c00487
Org. Lett. 2021, 23, 2565−2570