Rh(III)-Catalyzed C-H Amidation of 2-Arylindoles with Dioxazolones: A Route to Indolo[1,2-c]quinazolines

Article abstract of DOI:10.1021/acs.orglett.9b02615

Rhodium(III)-catalyzed C-H amidation of 2-arylindoles with dioxazolones for the synthesis of indolo[1,2-c]quinazolines is reported. The reaction is compatible with a wide range of electronically diverse 2-arylindoles and dioxazolones, providing indolo[1,2

Full text of DOI:10.1021/acs.orglett.9b02615

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh(III)-Catalyzed C−H Amidation of 2‑Arylindoles with
Dioxazolones: A Route to Indolo[1,2‑c]quinazolines
Xiaogang Wang,†,∥ Jin Zhang,*,†,∥ Di Chen,†,‡ Bo Wang,† Xiufang Yang,† Yangmin Ma,*,†
and Michal Szostak*,†,§
†College of Chemistry and Chemical Engineering, Shaanxi Key Laboratory of Chemical Additives for Industry, Shaanxi University of
Science and Technology, Xi’an 710021, China
‡School of Food and Biological Engineering, Shaanxi University of Science and Technology, Xi’an 710021, China
§Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
S
* Supporting Information
ABSTRACT: Rhodium(III)-catalyzed C−H amidation of 2-
arylindoles with dioxazolones for the synthesis of indolo[1,2-
c]quinazolines is reported. The reaction is compatible with a
wide range of electronically diverse 2-arylindoles and
dioxazolones, providing indolo[1,2-c]quinazolines in high to
excellent yields. Most notably, the combination of this Rh-
catalyzed C−H amidation and intramolecular N−H/N−C(O)
cyclization enables the most straightforward direct route to
indolo[1,2-c]quinazolines to date. Mechanistic studies and
evaluation of antitumor activity of these high value heterocycles are disclosed.
ndolo[1,2-c]quinazolines are an important class of indole-
fused heterocycles that are widely represented in natural
Scheme 1. Previous Studies and This Work
I
products, bioactive compounds, and organic photoluminescent
devices (Figure 1).1,2 A classic method for the synthesis of
Figure 1. Examples of indolo[1,2-c]quinazolines.
indolo[1,2-c]quinazolines involves intramolecular condensa-
tion of 2-ortho-aminoarylindoles with carbonyl equivalents;
however, this approach is inefficient, requires indole
prefunctionalization, and is limited in terms of atom and step
economy (Scheme 1A).3,4 Given our interest in amide
bonds,5,6 we postulated that a direct route to this high value
scaffold should be feasible utilizing C−H amidation of broadly
available 2-arylindoles7 (Scheme 1B). We hypothesized that
the capacity of N−H indoles to form amidorhodium8 species
followed by C−H amidation9,10 together with a proximity
driven electrophilic cyclization of the aromatic amide11 might
enable an expedient route to indolo[1,2-c]quinazolines. If
successful, this would provide the most straightforward
catalytic route to this high value heterocyclic scaffold to
date.12−15
Considering the synthetic importance of indolo[1,2-c]-
quinazolines, methods for the improved synthesis of this
Received: July 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
heterocycle have attracted a great deal of attention. For
example, the studies by Zhang demonstrated that indolo[1,2-
c]quinazolines can be accessed by Cu-catalyzed sequential
amination (X = Br, I)/aerobic oxidative cyclization of 2-(2-
haloaryl)-1H-indoles (Scheme 1C).12 Fan reported Cu-
catalyzed cascade amination/condensation/oxidative cycliza-
tion of 2-(2-bromoaryl)-1H-indoles (Scheme 1C).13 More
recently, a Cu-catalyzed electrophilic amidation of 2-(2-
amidoaryl)-1H-indoles was reported, wherein the Cu-catalyst
acts as an O-coordinating Lewis acid to facilitate the
cyclization.14 However, these methods start from ortho-
substituted 2-arylindoles15 and are limited by atom economy.3
In sharp contrast, a direct synthesis of indolo[1,2-c]-
quinazolines by C−H amidation/N−H to N−C(O) con-
densation of 2-arylindoles would provide an attractive platform
for generating a diversity of this important heterocycle.
In the past decade, group-directed C−H functionalization
has been broadly developed for building valuable C−C and
C−heteroatom bonds.16 Chang17 and Li18 have reported
dioxazolones as electrophilic −NC(O)R sources for direct C−
H amidation reactions.19 These highly reactive amidating
reagents have numerous advantages that permit introducing
valuable amide bonds by leveraging high affinity of the Lewis
basic nitrogen atom with facile nitrenoid formation.20 The
amidation step could be combined with the subsequent
cyclization for the synthesis of heterocycles, such as quinazo-
lines,21 benzimidazoles,22 quinazolinone,23 or quinazoline N-
oxides.24,25 Herein, we report Rh(III)-catalyzed synthesis of
indolo[1,2-c]quinazolines by a direct C−H amidation of 2-
arylindoles with dioxazolones (Scheme 1B). The method
enables the most straightforward diversity generating direct
route to indolo[1,2-c]quinazolines and is characterized by high
atom and step economy with H2O and CO2 formed as
byproducts.
amidation/N−H to N−C(O) cyclization product in 62%
(entry 1). Among other catalytic systems, including
[Cp*RhCl2]2, [Ru(p-cym)Cl2]2/AgSbF6, [Cp*CoCOI2]/
AgSbF6, and Pd(OAc)2 (entries 2−5) only Co(III) afforded
a trace of the desired product (<5%). A solvent screen revealed
that DCE is optimal (entries 6−8). We could further improve
the yield of (3aa) to 85% by using LiOAc as an additive (25
mol %) (entry 9), whereas other additives (NaOAc, KOAc,
Cu(OAc)2) were ineffective (entries 10−12). [Cp*Ir(III)Cl2]2
is not a competent catalyst for the reaction (recovery of the
starting material). The C−H amidation does not proceed at 80
°C (recovery of the starting material).
With the optimized conditions in hand, the scope of the
reaction was next investigated (Scheme 2). As shown, the
scope of 2-aryl-1H-indole substrates is quite broad and
a b
,
Scheme 2. Scope of 2-Aryl-1H-Indole Substrates
We commenced our studies by investigating the reaction
between 2-phenyl-1H-indole (1a) and 3-phenyl-1,4,2-dioxazol-
5-one (2a) to optimize the reaction conditions (Table 1). The
reaction using [Cp*RhCl2]2 (5 mol %) and AgSbF6 (25 mol
%) as the catalytic system and CsOAc (25 mol %) as a basic
additive in DCE at 140 °C afforded the desired C−H
a
Table 1. Optimization of Reaction Conditions
entry
catalyst
additive
solvent
yield (%)
1
2
3
4
5
6
7
8
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2
[Ru(p-cym)Cl2]2/AgSbF6
[Cp*CoCOI2]/AgSbF6
Pd(OAc)2
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
[Cp*RhCl2]2/AgSbF6
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
LiOAc
DCE
DCE
DCE
DCE
DCE
dioxane
toluene
DMF
DCE
DCE
DCE
DCE
62
<5
<5
<5
<5
<5
12
<5
85
44
<5
<5
9
10
11
12
NaOAc
KOAc
Cu(OAc)2
a
Conditions: 1a (1.0 equiv), 2a (1.2 equiv), [Cp*RhCl2]2 (5 mol %),
AgSbF6 (25 mol %), LiOAc (25 mol %), DCE (0.10 M), 140 °C, 24
a
Conditions: 1a (1.0 equiv), 2a (1.2 equiv), catalyst (5 mol %),
additive (25 mol %), solvent (0.10 M), 140 °C, 24 h.
b
h. Isolated yields. See Supporting Information (SI) for details.
B
DOI: 10.1021/acs.orglett.9b02615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
accommodates a broad range of electron-donating (3ba−3da),
electron-withdrawing (3ea−3ga), and halide groups (3ea) at
the para position of the 2-aryl ring; however, 2-aryl-1H-indoles
bearing electron-withdrawing groups gave lower yields (vide
infra). It is noteworthy that a single regioisomer was formed
using a meta-substituted substrate (3ha). Furthermore, the
reaction was equally efficient when sterically hindered ortho-
substituted 2-aryl-1H-indoles were used (3ia−3ja). The scope
could be further extended to a napththyl-substituted indole,
furnishing a conjugated pentacyclic benzo[g]indolo[1,2-c]-
quinazoline (3ka). Importantly, 2-phenyl-1H-indoles bearing
electron-donating (3ma−3na) as well as halide groups (3la,
3oa−3pa) at the 5- or 6-position of the indole ring could also
be used to rapidly generate the indolo[1,2-c]quinazoline
scaffold.
tolerance for an aryl bromide is noteworthy (3aj). Finally, we
delighted to find that the reaction of 3,5-dimethoxyphenyl-
1,4,2-dioxazol-5-one afforded 3ak in 68% yield. This product
shows excellent antibacterial activity, highlighting the practical
utility of the current protocol. Typically, we have not observed
side reactions in this method. At the present stage of reaction
development 4-nitrophenyl dioxazolone has not been tested.
Future work will focus on expanding the scope of C−H
amidation processes.
We conducted experiments to gain insight into the reaction
mechanism (Scheme 4). Intermolecular competition studies
Scheme 4. Mechanistic Studies
To further investigate the substrate scope, we subjected a
range of dioxazolones to the reaction with 2-phenyl-1H-indole
(Scheme 3). Pleasingly, we found that both 3-alkyl and 3-aryl
a b
,
Scheme 3. Scope of 1,4,2-Dioxazol-5-one Substrates
between differently substituted 2-aryl-1H-indoles revealed
electron-rich arenes to be inherently more reactive (Scheme
4A). Furthermore, electron-rich 2-phenyl-1H-indoles are
inherently more reactive than their electron-deficient counter-
parts (Scheme 4B), while electron-deficient arenes are
transferred preferentially from the dioxazolone amidating
reagent (Scheme 4C). Moreover, radical inhibition studies
revealed decreased yields of the amidation product (Scheme
4D). Overall, these studies are consistent with an electrophilic
C−H activation mechanism, with the N−H to C(O)−N
cyclization facilitated by electron-rich indoles.
A plausible reaction mechanism is shown in Scheme 5. The
formation of an amidorhodium N−Rh(III) species and
subsequent C−H activation gives a five-membered rhodacycle
4.9 Coordination of dioxazolone and CO2 extrusion gives a
highly reactive Rh-imido intermediate 5.18 Migratory insertion
and cyclization gives the indolo[1,2-c]quinazoline product 3
and regenerates the catalyst. The electrophilic cyclization onto
a
Conditions: 1a (1.0 equiv), 2a (1.2 equiv), [Cp*RhCl2]2 (5 mol %),
AgSbF6 (25 mol %), LiOAc (25 mol %), DCE (0.10 M), 140 °C, 24
b
h. Isolated yields. See Supporting Information (SI) for details.
substituted 1,4,2-dioxazol-5-one reagents could be used for the
synthesis of indolo[1,2-c]quinazolines. The reactions with alkyl
dioxazolones afforded the products in excellent yields (3ab−
3ac). 3-Aryl-1,4,2-dioxazol-5-ones containing electron-donat-
ing (3ad−3ae), polyaromatic (3af), electron-withdrawing
(3ag), and halide groups (3ah−3aj) worked well to afford
functionalized indolo[1,2-c]quinazolines. The functional group
C
DOI: 10.1021/acs.orglett.9b02615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 5. Proposed Catalytic Cycle
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.9b02615.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhangjin@sust.edu.cn.
*E-mail: mym63@sina.com.
*E-mail: michal.szostak@rutgers.edu.
ORCID
Jin Zhang: 0000-0002-6616-7087
Michal Szostak: 0000-0002-9650-9690
Author Contributions
∥X.W. and J.Z. contributed equally.
the amide is likely facilitated by a N−/O−Rh migration to
increase the amide bond electrophilicity.11
The potential of the present method in the synthesis of
complex indolo[1,2-c]quinazolines is highlighted in cytotoxic
studies (Table 2). Intrigued by the unique capacity of this
Notes
The authors declare no competing financial interest.
a
ACKNOWLEDGMENTS
Table 2. Cytotoxicity of 3aa−3ak in Human Cancer Cells
■
J.Z. thanks the China Scholarship Council (No. 2018086-
10096). Financial support was provided by the Foundation for
Young Scholars of Shaanxi University of Science and
Technology (No. BJ12-26). M.S. thanks Rutgers University
and the NSF (CAREER CHE-1650766).
IC50 (μm)
entry
compound
PC3
A549
MCF-7
1
2
3
4
5
6
3aa
3pa
3ad
3ag
3ak
cisplatin
229.8
88.16
132.2
242.8
158.4
4.97
134.9
63.1
51.4
30.7
87.4
12.2
n/a
n/a
252
n/a
287.9
70.4
REFERENCES
■
(1) (a) Blackman, A. J.; Hambley, T. W.; Picker, K.; Taylor, W. C.;
Thirasasana, N. Hinckdentine-A: a novel alkaloid from the marine
bryozoan Hincksinoflustra denticulate. Tetrahedron Lett. 1987, 28,
5561−5562. (b) Liu, Y.; McWhorter, W. W. Synthesis of 8-
desbromohinckdentine A1. J. Am. Chem. Soc. 2003, 125, 4240−4252.
(2) (a) Rohini, R.; Shanker, K.; Reddy, P. M.; Sekhar, V. C.;
Ravinder, V. 6-substituted indolo[1,2-c]quinazolines as new anti-
microbial agents. Arch. Pharm. 2009, 342, 533−540. (b) Rohini, R.;
Reddy, P. M.; Shanker, K.; Hu, A.; Ravinder, V. Antimicrobial study
of newly synthesized 6-substituted indolo[1,2-c]quinazolines. Eur. J.
Med. Chem. 2010, 45, 1200−1205. (c) Sharma, V.; Kumar, P.; Pathak,
D. Biological importance of the indole nucleus in recent years: a
comprehensive review. J. Heterocycl. Chem. 2010, 47, 491−502.
(d) Sravanthi, T. V.; Manju, S. L. Indoles - A promising scaffold for
drug development. Eur. J. Pharm. Sci. 2016, 91, 1−10. (e) Shin, C.;
Kim, K.; Hoon, D.; Jang, J.; Chun, M. Aromatic compounds as
electroluminescent material and/or semiconductor material for
organic electroluminescent devices. WO2012173371 2012, Dec 20,
2012. (f) Lee, D. U.; Bae, J. S.; Nam, H.; Hong, S. G.; Lee, D. H.;
Jeon, S. Y. Organic electroluminescent material and organic
electroluminescent apparatus utilizing the electroluminescent materi-
al. KR 2010082986 2010, Jul 21, 2010.
(3) Joule, J. A.; Mills, K. Heterocyclic Chemistry; Wiley-Blackwell:
Oxford, 2010.
(4) Li, C. J.; Trost, B. M. Green chemistry for chemical synthesis.
Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 13197−13202.
(5) (a) Shi, S.; Nolan, S. P.; Szostak, M. Well-defined palladium(II)-
NHC (NHC = N-Heterocyclic Carbene) precatalysts for cross-
coupling reactions of amides and esters by selective acyl CO−X (X =
N, O) cleavage. Acc. Chem. Res. 2018, 51, 2589−2599. (b) Liu, C.;
Szostak, M. Decarbonylative cross-coupling of amides. Org. Biomol.
Chem. 2018, 16, 7998−8010. (c) Li, G.; Ji, C. L.; Hong, X.; Szostak,
M. Highly chemoselective, transition-metal-free transamidation of
a
Selected results are shown. See SI for full details.
valuable heterocyclic scaffold to act as a privileged synthon in
drug discovery, we tested the synthesized products against
human prostate cancer cells (PC3), human lung cancer cells
(A549), and human Michigan cancer foundation cells (MCF-
7) (see SI for details).26 As shown, the compounds 3pa, 3ad,
3ag, and 3ak displayed promising growth inhibition of A549
cells (3ag: IC50 = 30.7 uM). The results demonstrate that
indolo[1,2-c]quinazolines could represent a new class of cancer
growth inhibitors.27
In summary, we have reported Rh-catalyzed synthesis of
indolo[1,2-c]quinazolines through direct C−H amidation and
intramolecular N−H/N−C(O) cyclization of broadly available
2-aryl-1H-indoles with dioxazolones. This mild and highly
efficient process permits the most straightforward platform for
the synthesis of indolo[1,2-c]quinazolines developed to date.
The reaction showed broad scope with respect to indole and
dioxazolone. The reaction proceeds with high atom economy
with H2O and CO2 formed as byproducts and avoids any
substrate prefunctionalization. The potential of this method
has been highlighted by the discovery of indolo[1,2-
c]quinazolines that exhibit promising antitumor activity.
Further studies on the formation of amides via C−H
functionalization as well as tandem annulation are underway
in our laboratory.
D
DOI: 10.1021/acs.orglett.9b02615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
unactivated amides and direct amidation of alkyl esters by N-C/O-C
cleavage. J. Am. Chem. Soc. 2019, 141, 11161−11172.
bond cleavage. Angew. Chem., Int. Ed. 2009, 48, 9792−9826.
(h) Gandeepan, P.; Muller, T.; Zell, D.; Cera, G.; Warratz, S.;
̈
(6) For representative studies from our laboratory, see: (a) Zhang,
J.; Hou, Y.; Ma, Y.; Szostak, M. Synthesis of amides by mild
palladium-catalyzed aminocarbonylation of arylsilanes with amines
enabled by copper(II) fluoride. J. Org. Chem. 2019, 84, 338−345.
(b) Nan, J.; Hu, Y.; Chen, P.; Ma, Y. Metal-free synthesis of 2-
fluoroalkylated quinolines using polyfluoroalkanoic acids as direct
fluorine sources. Org. Lett. 2019, 21, 1984−1988. (c) Liu, S.; Gao, W.;
Miao, Y.; Wang, M. Dinuclear zinc-azephenol catalyzed asymmetric
aza-Henry reaction of N-Boc imines and nitroalkanes under ambient
conditions. J. Org. Chem. 2019, 84, 2652−2659.
Ackermann, L. 3d Transition Metals for C−H Activation. Chem. Rev.
2019, 119, 2192−2452. (i) Sambiagio, C.; Schonbauer, D.; Blieck, R.;
Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.;
Wencel-Delord, J.; Besset, T.; Maes, B. U. W.; Schnurch, M. A
̈
̈
comprehensive overview of directing groups applied in metal-
catalysed C−H functionalisation chemistry. Chem. Soc. Rev. 2018,
47, 6603−6743.
(17) (a) Park, Y.; Park, K. T.; Kim, J. G.; Chang, S. Mechanistic
studies on the Rh(III)-mediated amido transfer process leading to
robust C-H amination with a new type of amidating reagent. J. Am.
Chem. Soc. 2015, 137, 4534−4542. (b) Park, J.; Chang, S.
Comparative catalytic activity of group 9 [Cp*MIII] complexes:
cobalt-catalyzed C-H amidation of arenes with dioxazolones as
amidating reagents. Angew. Chem., Int. Ed. 2015, 54, 14103−14107.
(18) Wang, H.; Tang, G. D.; Li, X. W. Rhodium(III)-catalyzed
amidation of unactivated C(sp3)-H bonds. Angew. Chem., Int. Ed.
2015, 54, 13049−13052.
(7) Lal, S.; Snape, T. J. 2-Arylindoles: a privileged molecular scaffold
with potent, broad-ranging pharmacological activity. Curr. Med. Chem.
2012, 19, 4828−4837.
(8) (a) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Rhodium-
catalyzed oxidative coupling/cyclization of 2-phenylindoles with
alkynes via C-H and N-H bond cleavages with air as the oxidant.
Org. Lett. 2010, 12, 2068−2071. (b) Yamauchi, D.; Nishimura, T.;
Yorimitsu, H. Asymmetric hydroarylation of vinyl ethers catalyzed by
a hydroxoiridium complex: azoles as effective directing groups. Chem.
Commun. 2017, 53, 2760−2763.
(9) For an excellent review on C−H amination, see: Park, Y.; Kim,
Y.; Chang, S. Transition metal-catalyzed C-H amination: ccope,
mechanism, and applications. Chem. Rev. 2017, 117, 9247−9301.
(10) For an excellent review on non-classical methods of synthesis of
amides, see: de Figueiredo, R. M.; Suppo, J. S.; Campagne, J. M.
Nonclassical routes for amide bond formation. Chem. Rev. 2016, 116,
12029−12122.
(11) For a review on using as amides as N−C(O) electrophiles, see:
Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide Linkage:
Structural Significance in Chemistry, Biochemistry and Materials Science;
Wiley-VCH: New York, 2003.
(19) For a mechanistic study, see: Park, Y.; Heo, J.; Baik, M. H.;
Chang, S. Why is the Ir(III)-mediated amido transfer much faster
than the Rh(III)-mediated reaction? A combined experimental and
computational study. J. Am. Chem. Soc. 2016, 138, 14020−14029.
(20) For recent elegant intramolecular amidations using dioxazo-
lones, see: (a) Hong, S. Y.; Park, Y.; Hwang, Y.; Kim, Y. B.; Baik, M.
H.; Chang, S. Selective formation of γ-lactams via C-H amidation
enabled by tailored iridium catalysts. Science 2018, 359, 1016−1021.
(b) Park, Y.; Chang, S. Asymmetric formation of γ-lactams via C-H
amidation enabled by chiral hydrogen-bond-donor catalysts. Nat.
Catal. 2019, 2, 219−227.
(21) (a) Wang, F.; Wang, H.; Wang, Q.; Yu, S.; Li, X. Co(III)-
catalyzed synthesis of quinazolines via C-H activation of N-
sulfinylimines and benzimidates. Org. Lett. 2016, 18, 1306−1309.
(b) Wang, J.; Zha, S.; Chen, K.; Zhang, F.; Song, C.; Zhu, J.
Quinazoline synthesis via Rh(III)-catalyzed intermolecular C-H
functionalization of benzimidates with dioxazolones. Org. Lett. 2016,
18, 2062−2065.
(12) Sang, P.; Xie, Y. J.; Zou, J. W.; Zhang, Y. H. Copper-catalyzed
sequential Ullmann N-arylation and aerobic oxidative C-H amination:
a convenient route to indolo[1,2-c]quinazoline derivatives. Org. Lett.
2012, 14, 3894−3897.
(13) Guo, S. H.; Tao, L.; Zhang, W. W.; Zhang, X. Y.; Fan, X. S.
Regioselective synthesis of indolo[1,2-c]quinazolines and 11H-
Indolo[3,2-c]quinolines via copper-catalyzed cascade reactions of 2-
(2-bromoaryl)-1H-indoles with aldehydes and aqueous ammonia. J.
Org. Chem. 2015, 80, 10955−10964.
(14) Guo, S.; Wang, F.; Tao, L.; Zhang, X.; Fan, X. Solvent-
dependent copper-catalyzed indolyl C3-oxygenation and N1-cycliza-
tion reactions: selective synthesis of 3H-indol-3-ones and indolo[1,2-
c]quinazolines. J. Org. Chem. 2018, 83, 3889−3896.
(15) (a) For the classic Kiang−Mann synthesis using acyl halides,
see: Kiang, A. K.; Mann, F. G.; Prior, A. F.; Topham, A. Action of acyl
cyanides on 2- and 1,2-substituted indoles. II. Derivatives of 2-o-
aminophenylindole. J. Chem. Soc. 1956, 1319−1331. (b) For an
oxidative variant using aldehydes followed by oxidation, see refs 2a
and b.
(16) For selected reviews on C−H activation, see: (a) Science of
Synthesis: Catalytic Transformations via C−H Activation; Yu, J. Q., Ed.;
Thieme: Stuttgart, 2015. (b) Davies, H. M. L.; Morton, D. Recent
advances in C−H functionalization. J. Org. Chem. 2016, 81, 343−350.
(c) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Cross-coupling of
heteroarenes by C-H functionalization: Recent progress towards
direct arylation and heteroarylation reactions involving heteroarenes
containing one heteroatom. Adv. Synth. Catal. 2014, 356, 17−117.
(d) Rouquet, G.; Chatani, N. Catalytic functionalization of C(sp2)-H
and C(sp3)-H bonds by using bidentate directing groups. Angew.
Chem., Int. Ed. 2013, 52, 11726−11743. (e) Yeung, C. S.; Dong, V. M.
Catalytic dehydrogenative cross-coupling: forming carbon−carbon
bonds by oxidizing two carbon−hydrogen bonds. Chem. Rev. 2011,
111, 1215−1292. (f) Lyons, T.; Sanford, M. Palladium-catalyzed
ligand-directed C−H functionalization reactions. Chem. Rev. 2010,
110, 1147−1169. (g) Ackermann, L.; Vicente, R.; Kapdi, A. R.
Transition-metal-catalyzed direct arylation of (hetero)arenes by C-H
(22) (a) Xia, J.; Yang, X.; Li, Y.; Li, X. Iridium(III)-catalyzed
synthesis of benzimidazoles via C-H activation and amidation of
aniline derivatives. Org. Lett. 2017, 19, 3243−3246. (b) Chen, Y. Y.;
Zhang, R.; Peng, Q. J.; Xu, L. T.; Pan, X. H. Rhodium(III)-catalyzed
directed C-H amidation of N-nitrosoanilines and subsequent
formation of 1,2-disubstituted benzimidazoles. Chem. - Asian J.
2017, 12, 2804−2808.
(23) Mishra, A.; Mukherjee, U.; Vats, T. K.; Deb, I. Ir(III)/MPAA-
catalyzed mild and selective C-H amidation of N-sulfonyl ketimines:
Access to benzosultam-fused quinazolines/quinazolinones. J. Org.
Chem. 2018, 83, 3756−3767.
(24) Wang, Q.; Wang, F.; Yang, X. F.; Zhou, X. K.; Li, X. W.
Rh(III)- and Zn(II)-catalyzed synthesis of quinazoline N-oxides via
C-H amidation-cyclization of oximes. Org. Lett. 2016, 18, 6144−6147.
(25) For additional representative examples, see: (a) Wang, F.; Jin,
L.; Kong, L.; Li, X. Cobalt(III)- and rhodium(III)-catalyzed C-H
amidation and synthesis of 4-quinolones: C-H activation assisted by
weakly coordinating and functionalizable. Org. Lett. 2017, 19, 1812−
1815. (b) Mei, R.; Loup, J.; Ackermann, L. Oxazolinyl-assisted C-H
amidation by cobalt(III) catalysis. ACS Catal. 2016, 6, 793−797.
(c) Hermann, G. N.; Bolm, C. Mechanochemical rhodium(III)-
catalyzed C-H bond amidation of arenes with dioxazolones under
solventless conditions in a ball mill. ACS Catal. 2017, 7, 4592−4596.
(d) Wang, H.; Lorion, M. M.; Ackermann, L. Overcoming the
limitations of C-H activation with strongly coordinating N-hetero-
cycles by cobalt catalysis. Angew. Chem., Int. Ed. 2016, 55, 10386−
10390. (e) Zhou, Y.; Engl, O. D.; Bandar, J. S.; Chant, E. D.;
Buchwald, S. L. CuH-catalyzed asymmetric hydroamidation of
vinylarenes. Angew. Chem., Int. Ed. 2018, 57, 6672−6675. (f) Halskov,
K. S.; Roth, H. S.; Ellman, J. A. Synthesis of [5,6]-bicyclic heterocycles
with a ring-junction nitrogen atom: Rhodium(III)-catalyzed C-H
functionalization of alkenyl azoles. Angew. Chem., Int. Ed. 2017, 56,
E
DOI: 10.1021/acs.orglett.9b02615
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
9183−9187. For representative direct intramolecular amidations, see:
(g) Wu, X.; Zhao, Y.; Ge, H. Direct aerobic carbonylation of C(sp2)-
H and C(sp3)-H bonds through Ni/Cu synergistic catalysis with DMF
as the carbonyl source. J. Am. Chem. Soc. 2015, 137, 4924−2927.
(h) Wu, X.; Yang, K.; Zhao, Y.; Sun, H.; Li, G.; Ge, H. Cobalt-
catalysed site-selective intra- and intermolecular dehydrogenative
amination of unactivated sp3 carbons. Nat. Commun. 2015, 6, 6462.
(26) Berridge, M. V.; Herst, P. M.; Tan, A. S. Tetrazolium dyes as
tools in cell biology: new insights into their cellular reduction.
Biotechnol. Annu. Rev. 2005, 11, 127−152.
(27) Dadashpour, S.; Emami, S. Indole in the target-based design of
anticancer agents: A versatile scaffold with diverse mechanisms. Eur. J.
Med. Chem. 2018, 150, 9−29.
F
DOI: 10.1021/acs.orglett.9b02615
Org. Lett. XXXX, XXX, XXX−XXX