Expeditious Synthesis of 6-Fluoroalkyl-Phenanthridines via Palladium-Catalyzed Norbornene-Mediated Dehydrogenative Annulation

Article abstract of DOI:10.1021/acs.orglett.8b02588

A novel palladium-catalyzed, norbornene-mediated intermolecular dehydrogenative annulation approach for the synthesis of 6-fluoroalkyl-phenanthridines from aryl iodides and fluorinated imidoyl chlorides, which are important structural motifs for bioactive molecules, is reported. Fluorinated imidoyl chlorides served as a new type of electrophilic reagent in the Catellani-type reaction, which, in turn, could be readily prepared from various anilines and fluorinated carboxylic acids. Control experiments were carried out to study the mechanism of the reaction. This transformation is scalable and tolerates a broad range of functional groups.

Full text of DOI:10.1021/acs.orglett.8b02588

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Expeditious Synthesis of 6‑Fluoroalkyl-Phenanthridines via
Palladium-Catalyzed Norbornene-Mediated Dehydrogenative
Annulation
Zhuo Wang, Tongyu Li, Jinghui Zhao, Xiaonan Shi, Dequan Jiao, Han Zheng, Chen Chen,*
and Bolin Zhu*
Tianjin Key Laboratory of Structure and Performance for Functional Molecules; Key Laboratory of Inorganic−Organic Hybrid
Functional Materials Chemistry (Tianjin Normal University), Ministry of Education; College of Chemistry, Tianjin Normal
University, Tianjin 300387, People’s Republic of China
S
* Supporting Information
ABSTRACT: A novel palladium-catalyzed, norbornene-medi-
ated intermolecular dehydrogenative annulation approach for
the synthesis of 6-fluoroalkyl-phenanthridines from aryl iodides
and fluorinated imidoyl chlorides, which are important structural
motifs for bioactive molecules, is reported. Fluorinated imidoyl
chlorides served as a new type of electrophilic reagent in the
Catellani-type reaction, which, in turn, could be readily prepared from various anilines and fluorinated carboxylic acids. Control
experiments were carried out to study the mechanism of the reaction. This transformation is scalable and tolerates a broad range
of functional groups.
henanthridines represent a class of fused heteroaromatic
motifs found universally in many natural products,1
Scheme 1. Approaches To Access 6-Fluoroalkyl-
phenanthridines
P
biologically active molecules,2 and in optoelectronic materials.3
Well known members include trisphaeridine,4 fagaronine,5 and
ethidium6 (Figure 1). Moreover, the incorporation of a
Figure 1. Biologically active phenanthridines.
fluoroalkyl group into phenanthridines often alters its physical
and chemical properties, leading to improved biological
functions, due to increased lipophilicity and metabolic stability.
Therefore, the development of efficient methodologies to
synthesize 6-fluoroalkyl-phenanthridines and their derivatives
has become a subject of great interest during the past few years
and many useful synthetic procedures have been explored. In
one such transformation, trifluoromethylation of 2-arylisocy-
nides was carried out using radical trifluoromethylating
reagents, such as Togni’s reagent,7 Umemoto’s reagent,8
Langlois’ reagent,9 CF3I,10 CF3SO2Cl,11 TMSCF3,12 and
others (Scheme 1a). In recent years, fluorinated imidoyl
chlorides have proven to be good building blocks for the
synthesis of 6-fluoroalkyl-phenanthridines using transition
metal catalysts. For example, Zhang and co-workers13 prepared
6-trifluoromethyl-phenanthridines through palladium-catalyzed
tandem Suzuki/C−H arylation reactions of N-aryltrifluoro-
acetimidoyl chlorides with arylboronic acids (Scheme 1b).
Later, Fu14 achieved the intramolecular cyclization of N-
biaryltrifluoroacetimidoyl chloride to obtain 6-trifluoromethyl-
Received: August 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
phenanthridines (Scheme 1c). Although many methods are
available, the requirement of specific prefunctionalized starting
materials and their low efficiencies limit the scope of these
methods. Therefore, the development of expeditious ap-
proaches for the synthesis of 6-fluoroalkyl-phenanthridines
from readily available starting materials is necessary.
Table 1. Optimization of Reaction Conditions
b
entry
1
[Pd]
ligand
base
yield (%)
Pd/norbornene (NBE) chemistry represents a powerful
strategy that allows the efficient construction of polyfunctional
aromatic and heteroaromatic compounds,15 which was
pioneered by Catellani and co-workers in 1997.16 Further
explorations by Catellani’s group,17 Lautens’ group,18 and
others19 have enriched and expanded the scope of this method.
Taking advantage of the palladium/NBE catalysis, ortho and
ipso bis-functionalization products can be obtained by coupling
with an electrophile and a nucleophile simultaneously. In
recent years, different types of electrophilic reagents have been
found to react with a key aryl-NBE palladacycle intermediate in
reactions, such as amination,19e,g,20 arylation,21 alkylation,16,22
and acylation,23 which result in ortho-functionalized products.
In order to broaden the scope of this reaction, it becomes
crucial to explore new electrophilic reagents for the synthesis
of divergent polysubstituted arenes.
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(cod)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOH
40%
15%
trace
trace
22%
36%
52%
50%
45%
43%
23%
42%
32%
45%
87%
50%
45%
c
2
3
4
d
e
5
6
7
8
S-Phos
P(2-furyl)3
P(4-F-C6H4)3
P(4-CF3-C6H4)3
dppe
f
9
f
10
11
dppf
f
DPE-Phos
12
13
14
15
P(4-F-C6H4)3
P(4-F-C6H4)3
P(4-F-C6H4)3
P(4-F-C6H4)3
P(4-F-C6H4)3
P(4-F-C6H4)3
K3PO4
K3PO4
K3PO4
In 2016, Jiao and co-workers24 developed an efficient
approach to synthesize phenanthridinone derivatives by
employing palladium/NBE cooperative catalysis. This protocol
was easy to handle, and aryl carbamic chloride served as the
electrophilic reagent to realize ortho-acylation. As part of our
continued interest in the development of practical method-
ologies for highly efficient construction of heterocyclic
molecules from readily available building blocks25 and inspired
by Jiao’s work,24 we surmised that biologically relevant 6-
fluoroalkyl-phenanthridines could be obtained from aryl
iodides and fluorinated imidoyl chlorides through a palla-
dium-catalyzed Catellani-type one-pot dehydrogenative annu-
lation reaction. Scheme 1d depicts a convergent synthetic
route to the aforementioned scaffolds. We hypothesize that the
reaction is initiated by Pd(0), which undergoes oxidative
addition with aryl iodide, followed by insertion of the
norbornene and ortho C−H activation to form the key Pd(II)
intermediate A. Subsequent oxidative addition of the
fluorinated imidoyl chlorides with A provides the Pd(IV)
complex B, which undergoes reductive elimination to afford
Pd(II) intermediate C. The target 6-fluoroalkyl-phenanthri-
dines and Pd(0) are obtained by elimination of the β-C with
the removal of norbornene along with activation of the C−H
bond to afford Pd(II) intermediate D, which finally undergoes
another reductive elimination, thereby completing the Pd
cycle. To the best of our knowledge, synthesis of 6-fluoroalkyl-
phenanthridines by using this strategy is still unknown and is
challenging due to two adjacent C−C bond formations via C−
H bond cleavage.26 Recently, Pd/NBE chemistry has proven to
be an important protocol that allows activation of both the
ipso- and ortho-positions of arenes.27−32 These results
encouraged us to test our dehydrogenative protocol.
g
16
17
h
a
Reaction conditions: the reactions were carried out with 1a (0.2
mmol), 2a (0.24 mmol), [Pd] (0.02 mmol), ligand (0.04 mmol),
norbornene (0.2 mmol), base (0.8 mmol), toluene (2.0 mL), nitrogen
atmosphere, 12 h. Isolated yield. Xylene 2.0 mL. PhCF3 2.0 mL.
b
c
d
e
f
g
h
MeCN 2.0 mL. Ligand (0.02 mmol). Norbornene (0.1 mmol). 5
mol % Pd(OAc)2.
4). A subsequent survey of a series of ligands indicated that
P(4-F-C6H4)3 was the most efficient ligand, giving a 52% yield
of the product. In contrast to P(4-F-C6H4)3, other ligands
including diphosphines and monophosphines failed to show
better catalytic reactivities (Table 1, entries 5−11). Among the
catalysts investigated, Pd(OAc)2 was found to be the most
efficient one (Table 1, entries 12 and 13). To further improve
the yield, various bases were examined, and to our delight,
K3PO4 exhibited the best performance and afforded the
product in 87% yield (Table 1, entries 14 and 15).
Additionally, when the loading of norbornene was decreased
to 50 mol %, the yield was only 50% (Table 1, entry 16).
Moreover, use of 5 mol % Pd(OAc)2 decreased the yield to
45%, due to the low conversion of starting materials (Table 1,
entry 17). Finally, the reaction of 1a (1.0 equiv) with 2a (1.2
equiv) in the presence of Pd(OAc)2 (10 mol %), P(4-F-C6H4)3
(20 mol %), norbornene (1.0 equiv), and K3PO4 (4.0 equiv) in
toluene (2.0 mL) under nitrogen atmosphere at 100 °C for 12
h was considered to be the most optimal.
With optimal reaction conditions in hand, the scope of this
methodology with respect to substituted aryl iodides was first
examined. As shown in Scheme 2, a variety of iodoarenes were
tested, all of which proved to be competent substrates for
reaction with 2a. In addition, regarding 1a, a variety of ortho-
substituents on the iodoarenes were tolerated in the reaction,
which included isopropyl, methoxyl, fluoro, chloro, trifluor-
omethyl, trifluoromethoxyl, and phenyl groups, and the
corresponding products 3aa−3ha were isolated in moderate
to excellent yields. Both electron-withdrawing and -donating
groups on iodoarenes were tolerated, although substrates with
electron-withdrawing groups gave products with relatively
lower yields. Furthermore, multisubstituted aryl iodides with
To test our hypothesis as shown in Scheme 1d, compounds
1a and 2a were initially chosen as the model substrates, which
were reacted in the presence of Pd(OAc)2 (10 mol %), PPh3
(20 mol %), norbornene (1.0 equiv), and Cs2CO3 (4.0 equiv)
in toluene (2.0 mL) at 100 °C under a nitrogen atmosphere.
Gratifyingly, after 12 h, the expected product 3aa was indeed
obtained in 40% isolated yield (Table 1, entry 1). Inspired by
this result, first, a range of solvents were tested, of which
toluene was found to be the most efficient (Table 1, entries 2−
B
DOI: 10.1021/acs.orglett.8b02588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Variation of Aryl Iodides
Scheme 3. Variation of Fluorinated Imidoyl Chlorides
a
Reaction conditions: the reactions were carried out with 1 (0.2
mmol), 2a (0.24 mmol), Pd(OAc)2 (0.02 mmol), P(4-F-C6H4)3
(0.04 mmol), norbornene (0.2 mmol), K3PO4 (0.8 mmol) in toluene
(2.0 mL) under a nitrogen atmosphere for 12 h.
a
Reaction conditions: the reactions were carried out with 1a (0.2
mmol), 2 (0.24 mmol), Pd(OAc)2 (0.02 mmol), P(4-F-C6H4)3 (0.04
mmol), norbornene (0.2 mmol), K3PO4 (0.8 mmol) in toluene (2.0
mL) under a nitrogen atmosphere for 12 h. Regioselectivity ratio
(the major isomer is substituted at the 3-position as indicated).
versatile groups reacted smoothly to give the corresponding
products in 65%−78% yields (3ia−3ma). Meanwhile the
molecular structure of 3ka was unambiguously confirmed by
X-ray crystallographic analysis (CCDC 1859470; for other
details, see the Supporting Information). Reaction with 1-
iodonaphthalene provided 3na in 82% yield. Notably,
heteroaryl iodide 1o was also found to be a suitable substrate,
which reacted with 2a to afford 3oa in 83% yield.
b
To gain insight into the mechanism, several control
experiments were carried out. In order to understand the
role of each component, when the reactions were carried out
by excluding either norbornene or the Pd catalyst, desired
dehydrogenative annulation product 3aa was not obtained
(Scheme 4a). Competing reactions with fluorinated imidoyl
chloride substrates bearing different electronic properties were
investigated. 1H NMR analysis indicated that the more
electron-rich substrate 2e had a higher reaction rate
(3ae:3ah = 1:0.74) probably due to the fact that the C−H
activation process occurs easily (Scheme 4b). Next, an
equimolar mixture of 1i and 1k that differed in electronic
effects was also examined. The 1H NMR analysis of this
product mixture revealed a slight preference for more electron-
rich iodoarenes (3ia:3ka = 1:0.71) (Scheme 4c). Then, to
study the kinetic isotope effects (KIE) in the reactions,
intermolecular competition experiments were performed under
standard conditions for 3 h. The reaction of 1a with 2a and 2a-
D provided a mixture of the products 3aa and 3aa-D in 20%
combined yield, and the ratio of 3aa: 3aa-D was 1.5.
Furthermore, a parallel experiment was also performed under
standard conditions for 1 h. The KIE was 1.33 (for details, see
the Supporting Information). The KIE values suggested that
the C−H bond activation step is not the rate-determining step
of this reaction (Scheme 4d). It is noteworthy that the
cyclization product was not detected with styrene derivative 4
as the substrate under the standard conditions, which
The catalytic dehydrogenative annulation methodology was
then extended to other fluorinated imidoyl chlorides, which
could be easily prepared from the corresponding aniline and
fluorinated carboxylic acids. As shown in Scheme 3, p-, m-, and
o-methyl substituents on the aryl ring of 2 were well tolerated
and the desired products 3ab−3ad were obtained in 80−85%
yields. Among them, meta-substituted substrate 2c with 1a
resulted in a mixture of the products 3ac with moderate
regioselectivity (3:1). Different derivatives of 2 with electron-
withdrawing and -donating groups on the phenyl ring were
tested, which showed good performance, affording the
corresponding products in moderate yields (3ae−3al). More-
over, multisubstituted fluorinated imidoyl chlorides were also
compatible under these reaction conditions (3am and 3an).
Likewise, other fluorinated substrates 2p−2u were also tested,
wherein the corresponding 6-fluoroalkyl-phenanthridines
3ap−3au were formed smoothly in moderate to excellent
yields. Different CF2X (X = Cl, Br, H, CF3) groups could also
be introduced into phenanthridines through these reactions.
Notably, this transformation could very well introduce the
CF2Br group, which is potentially useful for the further
elaboration of more valuable molecules through cross-coupling
reactions.33
C
DOI: 10.1021/acs.orglett.8b02588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02588.
Experimental procedures and full spectroscopic data for
all new compounds (PDF)
Accession Codes
CCDC 1859470 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tjnuchenchen@163.com (C.C.).
*E-mail: hxxyzbl@gmail.com (B.Z.).
ORCID
Chen Chen: 0000-0002-5388-9611
Bolin Zhu: 0000-0002-6846-566X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported jointly by the Doctoral Program
Foundation of Tianjin Normal University (043135202-
XB1703), NSFC (21572160), and the Foundation of the
Development Program of Future Expert in Tianjin Normal
University (WLQR201706; WLQR201811). We are also
grateful to the Tianjin Key Laboratory of Structure and
Performance for Functional Molecules, Key Laboratory of
Inorganic−Organic Hybrid Functional Materials Chemistry
(Tianjin Normal University), Ministry of Education, and the
Program for Innovative Research Team in University of
Tianjin (TD13-5074) for financial support.
REFERENCES
■
(1) (a) Viladomat, F.; Selles, M.; Cordina, C.; Bastida, J. Planta Med.
1997, 63, 583. (b) Ali, A. A.; El Saved, H. M.; Abdalliah, O. M.;
Steglich, W. Phytochemistry 1986, 25, 2399. (c) Krane, B. D.; Fagbule,
M. O.; Shamma, M.; Gozler, B. J. Nat. Prod. 1984, 47, 1.
demonstrated that the imine group probably played a key role
in this transformation (Scheme 4e). Moreover, scale-up of 1a
to 4 mmol (872 mg) with 4.8 mmol (996 mg) of 2a provided
the corresponding 6-trifluoromethyl-phenanthridines 3aa in
84% yield (878 mg).34
In conclusion, we developed a useful strategy to synthesize
6-fluoroalkyl-phenanthridines from simple aryl iodides and
fluorinated imidoyl chlorides, through dual C−H bond
activations. Fluorinated imidoyl chlorides served as a new
type of electrophilic reagent in Pd/NBE catalysis, which, in
turn, could be readily prepared from various anilines and
fluorinated carboxylic acids. The good tolerance for functional
groups on fluorinated imidoyl chlorides and aryl iodides
indicated its high potential for constructing biologically active
fluorinated phenanthridine heterocycles. Further applications
of this method to synthesize various other heterocycles are
underway in our laboratory.
(2) (a) Bernardo, P. H.; Wan, K.-F.; Sivaraman, T.; Xu, J.; Moore, F.
K.; Hung, A. W.; Mok, H. Y. K.; Yu, V. C.; Chai, C. L. L. J. Med.
Chem. 2008, 51, 6699. (b) Merz, K.-H.; Muller, T.; Vanderheiden, S.;
̈
Eisenbrand, G.; Marko, D.; Brase, S. Synlett 2006, 2006, 3461.
(c) Zhu, S.; Ruchelman, A. L.; Zhou, N.; Liu, A. A.; Liu, L. F.; LaVoie,
E. J. Bioorg. Med. Chem. 2005, 13, 6782. (d) Lewis, W. G.; Green, L.
G.; Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 1053. (e) Lynch, M.
A.; Duval, O.; Sukhanova, A.; Devy, J.; MacKay, S. P.; Waigh, R. D.;
Nabiev, I. Bioorg. Med. Chem. Lett. 2001, 11, 2643.
(3) (a) Stevens, N.; O’Connor, N.; Vishwasrao, H.; Samaroo, D.;
Kandel, E. R.; Akins, D. L.; Drain, C. M.; Turro, N. J. J. Am. Chem.
Soc. 2008, 130, 7182. (b) Bondarev, S. L.; Knyukshto, V. N.;
Tikhomirov, S. A.; Pyrko, A. N. Opt. Spectrosc. 2006, 100, 386.
(c) Zhang, J.; Lakowicz, J. R. J. Phys. Chem. B 2005, 109, 8701.
(4) Abdel-Halim, O. B.; Morikawa, T.; Ando, S.; Matsuda, H.;
Yoshikawa, M. J. Nat. Prod. 2004, 67, 1119.
(5) Phillips, S. D.; Castle, R. N. J. Heterocycl. Chem. 1981, 18, 223.
D
DOI: 10.1021/acs.orglett.8b02588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) Sripada, L.; Teske, J. A.; Deiters, A. Org. Biomol. Chem. 2008, 6,
Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 1849. (l) Gericke, K. M.;
Chai, D. I.; Bieler, N.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48,
1447. (m) Martins, A.; Lautens, M. Org. Lett. 2008, 10, 5095.
(n) Mariampillai, B.; Alliot, J.; Li, M.; Lautens, M. J. Am. Chem. Soc.
2007, 129, 15372. (o) Rudolph, A.; Rackelmann, N.; Lautens, M.
Angew. Chem., Int. Ed. 2007, 46, 1485. (p) Hulcoop, D. G.; Lautens,
M. Org. Lett. 2007, 9, 1761. (q) Bressy, C.; Alberico, D.; Lautens, M.
J. Am. Chem. Soc. 2005, 127, 13148. (r) Lautens, M.; Piguel, S. Angew.
Chem., Int. Ed. 2000, 39, 1045.
263.
(7) (a) Lubbesmeyer, M.; Leifert, D.; Schafer, H.; Studer, A. Chem.
̈
̈
Commun. 2018, 54, 2240. (b) Gorbanev, Y.; Leifert, D.; Studer, A.;
O’Connell, D.; Chechik, V. Chem. Commun. 2017, 53, 3685.
(c) Zhang, B.; Muck-Lichtenfeld, C.; Daniliuc, C. G.; Studer, A.
̈
Angew. Chem., Int. Ed. 2013, 52, 10792.
(8) (a) Wang, R.; Jiang, H.; Cheng, Y.; Kadi, A. A.; Fun, H.-K.;
Zhang, Y.; Yu, S. Synthesis 2014, 46, 2711. (b) Cheng, Y.; Jiang, H.;
Zhang, Y.; Yu, S. Org. Lett. 2013, 15, 5520.
(19) For some typical reports, see: (a) Zuo, Z.; Wang, H.; Fan, L.;
Liu, J.; Wang, Y.; Luan, X. Angew. Chem., Int. Ed. 2017, 56, 2767.
(b) Zhang, B.-S.; Hua, H.-L.; Gao, L.-Y.; Liu, C.; Qiu, Y.-F.; Zhou, P.-
X.; Zhou, Z.-Z.; Zhao, J.-H.; Liang, Y.-M. Org. Chem. Front. 2017, 4,
1376. (c) Fan, L.; Liu, J.; Bai, L.; Wang, Y.; Luan, X. Angew. Chem.,
Int. Ed. 2017, 56, 14257. (d) Sui, X.; Ding, L.; Gu, Z. Chem. Commun.
2016, 52, 13999. (e) Pan, S.-F.; Ma, X.-J.; Zhong, D.-N.; Chen, W.-Z.;
Liu, M.-C.; Wu, H.-Y. Adv. Synth. Catal. 2015, 357, 3052. (f) Lei, C.;
Jin, X.; Zhou, J. Angew. Chem., Int. Ed. 2015, 54, 13397. (g) Shi, H.;
Babinski, D. J.; Ritter, T. J. Am. Chem. Soc. 2015, 137, 3775.
(h) Dong, Z.; Wang, J.; Ren, Z.; Dong, G. Angew. Chem., Int. Ed.
2015, 54, 12664. (i) Huang, Y.; Zhu, R.; Zhao, K.; Gu, Z. Angew.
Chem., Int. Ed. 2015, 54, 12669. (j) Zhou, P.-X.; Ye, Y.-Y.; Liu, C.;
Zhao, L.-B.; Hou, J.-Y.; Chen, D.-Q.; Tang, Q.; Wang, A.-Q.; Zhang,
J.-Y.; Huang, Q.-X.; Xu, P.-F.; Liang, Y.-M. ACS Catal. 2015, 5, 4927.
(k) Wu, X.-X.; Shen, Y.; Chen, W.-L.; Chen, S.; Xu, P.-F.; Liang, Y.-
M. Chem. Commun. 2015, 51, 16798. (l) Zhang, H.; Chen, P.; Liu, G.
Angew. Chem., Int. Ed. 2014, 53, 10174. (m) Narbonne, V.; Retailleau,
P.; Maestri, G.; Malacria, M. Org. Lett. 2014, 16, 628. (n) Jiao, L.;
Bach, T. J. Am. Chem. Soc. 2011, 133, 12990.
(20) For some typical reports of amination, see: (a) Dong, Z.; Dong,
G. J. Am. Chem. Soc. 2013, 135, 18350. (b) Sun, F.; Gu, Z. Org. Lett.
2015, 17, 2222. (c) Chen, Z.-Y.; Ye, C.-Q.; Zhu, H.; Zeng, X.-P.;
Yuan, J.-J. Chem. - Eur. J. 2014, 20, 4237. (d) Zhou, P.-X.; Ye, Y.-Y.;
Ma, J.-W.; Zheng, L.; Tang, Q.; Qiu, Y.-F.; Song, B.; Qiu, Z.-H.; Xu,
P.-F.; Liang, Y.-M. J. Org. Chem. 2014, 79, 6627.
(21) For some typical reports of arylation, see: (a) Catellani, M.;
Motti, E.; Baratta, S. Org. Lett. 2001, 3, 3611. (b) Dong, Z.; Wang, J.;
Dong, G. J. Am. Chem. Soc. 2015, 137, 5887. (c) Wang, X.-C.; Gong,
W.; Fang, L.-Z.; Zhu, R.-Y.; Li, S.; Engle, K. M.; Yu, J.-Q. Nature
2015, 519, 334.
(9) (a) Li, J.; Caiuby, C. A. D.; Paixao, M. W.; Li, C.-J. Eur. J. Org.
Chem. 2018, 2018, 2498. (b) Fang, J.; Shen, W.-G.; Ao, G.-Z.; Liu, F.
Org. Chem. Front. 2017, 4, 2049. (c) Sakamoto, R.; Kashiwagi, H.;
Selvakumar, S.; Moteki, S. A.; Maruoka, K. Org. Biomol. Chem. 2016,
14, 6417. (d) Liu, Y.-R.; Tu, H.-Y.; Zhang, X.-G. Synthesis 2015, 47,
3460.
(10) (a) Wang, Y.; Wang, J.; Li, G.-X.; He, G.; Chen, G. Org. Lett.
2017, 19, 1442. (b) Zhang, B.; Studer, A. Org. Lett. 2014, 16, 3990.
(11) Tang, X.; Song, S.; Liu, C.; Zhu, R.; Zhang, B. RSC Adv. 2015,
5, 76363.
(12) (a) Stephens, D. E.; Chavez, G.; Valdes, M.; Dovalina, M.;
Arman, H.; Larionov, O. V. Org. Biomol. Chem. 2014, 12, 6190.
(b) Wang, Q.; Dong, X.; Xiao, T.; Zhou, L. Org. Lett. 2013, 15, 4846.
(13) Wang, W.-Y.; Feng, X.; Hu, B.-L.; Deng, C.-L.; Zhang, X.-G. J.
Org. Chem. 2013, 78, 6025.
(14) (a) Fu, W.; Zhu, M.; Xu, F.; Fu, Y.; Xu, C.; Zou, D. RSC Adv.
2014, 4, 17226. (b) Zhu, M.; Fu, W.; Zou, G.; Xu, C.; Wang, Z. J.
Fluorine Chem. 2014, 163, 23.
(15) (a) Zhou, Q.; Liu, Z.-S.; Gao, Q.; Cheng, H.-G. Chem. - Eur. J.
2018, DOI: 10.1002/chem.201802818. (b) Kim, D.-S.; Park, W.-J.;
Jun, C.-H. Chem. Rev. 2017, 117, 8977. (c) Della Ca’, N.; Fontana,
M.; Motti, E.; Catellani, M. Acc. Chem. Res. 2016, 49, 1389. (d) Ye, J.;
Lautens, M. Nat. Chem. 2015, 7, 863. (e) Zhu, H.; Ye, C.; Chen, Z.
Youji Huaxue 2015, 35, 2291. (f) Ferraccioli, R. Synthesis 2013, 45,
581. (g) Martins, A.; Mariampillai, B.; Lautens, M. Top. Curr. Chem.
2009, 292, 1. (h) Catellani, M.; Motti, E.; Della Ca’, N. Acc. Chem.
Res. 2008, 41, 1512.
(16) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed.
Engl. 1997, 36, 119.
(17) (a) Xu, D.; Dai, L.; Catellani, M.; Motti, E.; Della Ca’, N.;
Zhou, Z. Org. Biomol. Chem. 2015, 13, 2260. (b) Motti, E.; Della Ca’,
N.; Xu, D.; Piersimoni, A.; Bedogni, E.; Zhou, Z.-M.; Catellani, M.
Org. Lett. 2012, 14, 5792. (c) Maestri, G.; Motti, E.; Della Ca’, N.;
Malacria, M.; Derat, E.; Catellani, M. J. Am. Chem. Soc. 2011, 133,
8574. (d) Della Ca’, N.; Maestri, G.; Malacria, M.; Derat, E.;
Catellani, M. Angew. Chem., Int. Ed. 2011, 50, 12257. (e) Larraufie,
(22) For some typical reports of alkylation, see: (a) Lei, C.; Jin, X.;
Zhou, J. ACS Catal. 2016, 6, 1635. (b) Sui, X.; Zhu, R.; Li, G.; Ma, X.;
Gu, Z. J. Am. Chem. Soc. 2013, 135, 9318.
(23) For some typical reports of acylation, see: (a) Fan, X.; Gu, Z.
Org. Lett. 2018, 20, 1187. (b) Wang, J.; Zhang, L.; Dong, Z.; Dong, G.
Chem. 2016, 1, 581. (c) Sun, F.; Li, M.; He, C.; Wang, B.; Li, B.; Sui,
X.; Gu, Z. J. Am. Chem. Soc. 2016, 138, 7456.
́
M.-H.; Maestri, G.; Beaume, A.; Derat, E.; Ollivier, C.; Fensterbank,
̂
L.; Courillon, C.; Lacote, E.; Catellani, M.; Malacria, M. Angew.
(24) Li, X.; Pan, J.; Song, S.; Jiao, N. Chem. Sci. 2016, 7, 5384.
(25) (a) Han, F.; Yang, W.; Zhao, A.; Zheng, R.; Ji, C.; Liu, X.; Liu,
G.; Chen, C. Asian J. Org. Chem. 2018, 7, 1124. (b) Chen, C.; Hou,
L.; Cheng, M.; Su, J.; Tong, X. Angew. Chem., Int. Ed. 2015, 54, 3092.
(c) Chen, C.; Hu, J.; Su, J.; Tong, X. Tetrahedron Lett. 2014, 55, 3229.
(d) Chen, C.; Su, J.; Tong, X. Chem. - Eur. J. 2013, 19, 5014.
(26) (a) Zhang, J.; Ugrinov, A.; Zhao, P. Angew. Chem., Int. Ed.
2013, 52, 6681. (b) Li, B.-J.; Wang, H.-Y.; Zhu, Q.-L.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2012, 51, 3948. (c) Patureau, F. W.; Besset, T.;
Kuhl, N.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154. (d) Umeda,
N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2008, 47,
4019.
(27) Whyte, A.; Olson, M. E.; Lautens, M. Org. Lett. 2018, 20, 345.
(28) (a) Ding, L.; Sui, X.; Gu, Z. ACS Catal. 2018, 8, 5630. (b) Xu,
S.; Jiang, J.; Ding, L.; Fu, Y.; Gu, Z. Org. Lett. 2018, 20, 325.
(29) (a) Liu, C.; Liang, Yu.; Zheng, N.; Zhang, B.-S.; Feng, Y.; Bi, S.;
Liang, Y.-M. Chem. Commun. 2018, 54, 3407. (b) Shen, Y.; Wu, X.-X.;
Chen, S.; Xia, Y.; Liang, Y.-M. Chem. Commun. 2018, 54, 2256.
(30) (a) Qian, G.; Bai, M.; Gao, S.; Chen, H.; Zhou, S.; Cheng, H.-
G.; Yan, W.; Zhou, Q. Angew. Chem., Int. Ed. 2018, 57, 10980.
(b) Wu, C.; Cheng, H.-G.; Chen, R.; Chen, H.; Liu, Z.-S.; Zhang, J.;
Zhang, Y.; Zhu, Y.; Geng, Z.; Zhou, Q. Org. Chem. Front. 2018, 5,
Chem., Int. Ed. 2011, 50, 12253. (f) Motti, E.; Della Ca’, N.; Deledda,
S.; Fava, E.; Panciroli, F.; Catellani, M. Chem. Commun. 2010, 46,
4291. (g) Maestri, G.; Della Ca’, N.; Catellani, M. Chem. Commun.
2009, 32, 4892. (h) Della Ca’, N.; Sassi, G.; Catellani, M. Adv. Synth.
Catal. 2008, 350, 2179. (i) Motti, E.; Faccini, F.; Ferrari, I.; Catellani,
M.; Ferraccioli, R. Org. Lett. 2006, 8, 3967. (j) Faccini, F.; Motti, E.;
Catellani, M. J. Am. Chem. Soc. 2004, 126, 78. (k) Ferraccioli, R.;
Carenzi, D.; Rombola, O.; Catellani, M. Org. Lett. 2004, 6, 4759.
̀
(18) (a) Luo, B.; Gao, J.-M.; Lautens, M. Org. Lett. 2016, 18, 4166.
(b) Qureshi, Z.; Schlundt, W.; Lautens, M. Synthesis 2015, 47, 2446.
(c) Qureshi, Z.; Weinstabl, H.; Suhartono, M.; Liu, H.; Thesmar, P.;
Lautens, M. Eur. J. Org. Chem. 2014, 2014, 4053. (d) Sickert, M.;
Weinstabl, H.; Peters, B.; Hou, X.; Lautens, M. Angew. Chem., Int. Ed.
2014, 53, 5147. (e) Weinstabl, H.; Suhartono, M.; Qureshi, Z.;
Lautens, M. Angew. Chem., Int. Ed. 2013, 52, 5305. (f) Liu, H.; El-
Salfiti, M.; Lautens, M. Angew. Chem., Int. Ed. 2012, 51, 9846.
(g) Chai, D. I.; Thansandote, P.; Lautens, M. Chem. - Eur. J. 2011, 17,
8175. (h) Candito, D. A.; Lautens, M. Org. Lett. 2010, 12, 3312.
(i) Martins, A.; Candito, D. A.; Lautens, M. Org. Lett. 2010, 12, 5186.
(j) Candito, D. A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 6713.
(k) Zhao, Y.-B.; Mariampillai, B.; Candito, D. A.; Laleu, B.; Li, M.;
E
DOI: 10.1021/acs.orglett.8b02588
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2533. (c) Cheng, H.-G.; Wu, C.; Chen, H.; Chen, R.; Qian, G.; Geng,
Z.; Wei, Q.; Xia, Y.; Zhang, J.; Zhang, Y.; Zhou, Q. Angew. Chem., Int.
Ed. 2018, 57, 3444. (d) Chen, S.; Liu, Z.-S.; Yang, T.; Hua, Y.; Zhou,
Z.; Cheng, H.-G.; Zhou, Q. Angew. Chem., Int. Ed. 2018, 57, 7161.
(e) Liu, Z.-S.; Qian, G.; Gao, Q.; Wang, P.; Cheng, H.-G.; Wei, Q.;
Liu, Q.; Zhou, Q. ACS Catal. 2018, 8, 4783.
(31) (a) Dong, Z.; Lu, G.; Wang, J.; Liu, P.; Dong, G. J. Am. Chem.
Soc. 2018, 140, 8551. (b) Wang, J.; Li, R.; Dong, Z.; Liu, P.; Dong, G.
Nat. Chem. 2018, 10, 866. (c) Yoon, K.-Y.; Dong, G. Angew. Chem.,
Int. Ed. 2018, 57, 8592. (d) Li, R.; Dong, G. Angew. Chem., Int. Ed.
2018, 57, 1697.
(32) (a) Elsayed, M. S. A.; Griggs, B.; Cushman, M. Org. Lett. 2018,
20, 5228. (b) Bai, L.; Liu, J.; Hu, W.; Li, K.; Wang, Y.; Luan, X.
Angew. Chem., Int. Ed. 2018, 57, 5151.
(33) (a) Gu, J.-W.; Zhang, X. Org. Lett. 2015, 17, 5384. (b) Jiang,
H.; Lu, W.; Yang, K.; Ma, G.; Xu, M.; Li, J.; Yao, J.; Wan, W.; Deng,
H.; Wu, S.; Zhu, S.; Hao, J. Chem. - Eur. J. 2014, 20, 10084. (c) Wu,
Y.-M.; Li, Y.; Deng, J. J. Fluorine Chem. 2006, 127, 223.
(34) Scalability of 6-trifluoromethyl-phenanthridines 3aa was
described in the Supporting Information.
F
DOI: 10.1021/acs.orglett.8b02588
Org. Lett. XXXX, XXX, XXX−XXX