Aldehyde as a Traceless Directing Group for Rh(III)-Catalyzed C-H Activation: A Facile Access to Diverse Indolo[1,2- a ]quinolines

Article abstract of DOI:10.1021/acs.orglett.5b01171

The aldehyde group has been developed for the first time as a traceless directing group to promote regioselective Rh(III)-catalyzed C-H activation/cyclization of indolyl aldehydes with alkynes. This protocol streamlines access to a variety of appealing indolo[1,2-a]quinoline structures. As illustrative examples, a concise three-step synthesis of indolo[1,2-a]quinoline-based sensitizers is accomplished that exhibits the potential of C-H activation in the construction of organic optoelectronic materials.

Full text of DOI:10.1021/acs.orglett.5b01171

Letter
pubs.acs.org/OrgLett
Aldehyde as a Traceless Directing Group for Rh(III)-Catalyzed C−H
Activation: A Facile Access to Diverse Indolo[1,2‑a]quinolines
Xingyan Liu,† Xiaoyu Li,† Hu Liu,† Qiang Guo,† Jingbo Lan,*,† Ruilin Wang,‡ and Jingsong You*,†
†Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, and State Key Laboratory of
Biotherapy, West China Medical School, and ‡College of Materials Science and Engineering, Sichuan University, 29 Wangjiang Road,
Chengdu 610064, China
S
* Supporting Information
ABSTRACT: The aldehyde group has been developed for the first time as
a traceless directing group to promote regioselective Rh(III)-catalyzed C−
H activation/cyclization of indolyl aldehydes with alkynes. This protocol
streamlines access to a variety of appealing indolo[1,2-a]quinoline
structures. As illustrative examples, a concise three-step synthesis of
indolo[1,2-a]quinoline-based sensitizers is accomplished that exhibits the
potential of C−H activation in the construction of organic optoelectronic materials.
ransition-metal-catalyzed C−H bond activation has
tigation process, we unexpectedly obtained indolo[1,2-a]-
Temerged as an increasingly important synthetic approach quinoline derivatives as the products of C2−H activation/
cyclization of indolyl aldehydes with alkynes. Notably, cesium
pivalate (CsOPiv) is a critical additive in the control of selective
activation between C2−H and C4−H of indoles (Scheme 1).
for construction of carbon−carbon and carbon−heteroatom
bonds.1 The use of chelation-assisted strategy enables wide
substrate scope, good regioselectivity, structural diversity of
products, and application to total synthesis.2 The traceless
directing C−H activation strategy, in which the C−H bond
functionalization of substrate and the removal of directing
group can be operated in one pot, not only avoids extra steps to
remove the undesired directing group from products but also
offers unusual regioselectivity of transformations such as a
formal meta-selectivity of direct C−H arylation and thus has
emerged as a greatly appealing synthetic protocol in the
construction of organic functional molecules and natural
products.3−5 However, the functional groups that can be
employed as the traceless directing groups remain relatively
rare.3 Due to the easy occurrence of decarboxylation under
transition-metal-mediated conditions, the carboxylic acid has
been developed as a traceless directing group for various
decarboxylative C−H functionalizations.4 In addition, N-oxide,
silanol, and (pinacolato)boron (Bpin) have also been employed
as traceless directing groups to promote direct C−H olefination
and borylation of arenes.5 Although the aldehyde group is
removable under suitable reaction conditions,6 transition-metal-
catalyzed C−H activation reactions by utilizing the aldehyde
group as a traceless directing group still remain unprecedented.
Aldehydes are prevalent in natural and synthetic products
and are also versatile synthetic building blocks. However, the
aldehyde group is rarely used as the directing group for
transition-metal-catalyzed C−H functionalization reactions due
to its weak coordinative affinity and facile oxidation under
strongly oxidizing conditions.7 Recently, we have disclosed
Rh(III)-catalyzed aldehyde-directed regioselective C4−H acti-
vation/cyclization of indolyl aldehydes with alkynes to forge
benzo-fused oxindoles through a probable six-membered
metallocyclic intermediate.8 During the mechanistic inves-
Scheme 1. Rh(III)-Catalyzed Aldehyde-Assisted Site-
Selective (Hetero)aromatic C−H Activation/Cyclization
The aldehyde group herein could act as a traceless directing
group to promote Rh(III)-catalyzed ortho-C−H activation
through a possible five-membered rhodacycle intermediate. To
the best of our knowledge, the aldehyde group has not been
disclosed as a traceless directing group for C−H activation
reactions.
Indolo[1,2-a]quinoline derivatives are a class of privileged
polycyclic heteroaromatic scaffolds frequently found in
bioactive natural products, pharmaceuticals, and organic
functional materials (Scheme 2).9 The development of a new,
efficient method to streamline the synthesis of these scaffolds is
highly desirable.10 Herein, we report the construction of diverse
indolo[1,2-a]quinolines through a Rh(III)-catalyzed C−H
activation/cyclization of indolyl aldehydes with alkynes by
taking advantage of the aldehyde group as a traceless directing
group.
Received: April 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01171
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Selected Natural Products and Organic
Functional Molecules
Scheme 3. Scope of Indole 3-Aldehydes
In an initial attempt, the C2−H activation product 3a was
formed in 26% yield when 1-phenyl-1H-indole-3-carbaldehyde
(1a) reacted with 1,2-diphenylacetylene (2a) in the presence of
[Cp*RhCl2]2 (Cp* = pentamethyl cyclopentadienyl, 5.0 mol
%)/AgSbF6 (20 mol %) as catalyst, Ag2CO3 (2.1 equiv) as
oxidant, and CsOPiv (2.0 equiv) as additive in toluene (2 mL)
at 120 °C under N2 for 24 h (Table S1, entry 1). The structure
1
of 3a was confirmed by H and 13C NMR spectra, mass
spectrometry data, and single-crystal X-ray diffraction analysis
(Figure S3). In the absence of CsOPiv, benzo-fused oxindole as
the C4−H activation product of indolyl aldehyde was
obtained.8 Further optimization demonstrated that the reaction
could also occur in a slightly better yield without AgSbF6
(Table S1, entry 2). Other additives such as CsF, Cs2CO3, and
CsOAc were found to be less effective than CsOPiv (Table S1,
entries 6−8). After screening a variety of oxidants, Cu(OAc)2
turned out to be more effective than others (Table S1, entries
9−11). The yield was improved to 68% when the temperature
was raised to 140 °C (Table S1, entry 12). Among the solvents
investigated, dioxane was the best choice, affording 3a in 82%
yield (Table S1, entry 14). Decreasing the catalyst loading
would lead to a lower yield of 3a (Table S1, entry 17). Overall,
the optimized conditions consisted of [Cp*RhCl2]2 (5.0 mol
%), Cu(OAc)2 (2.1 equiv), and CsOPiv (2.0 equiv) in dioxane
at 140 °C under N2 for 24 h.
a
Reactions were performed in the presence of indole 3-aldehyde 1
(0.375 mmol), alkyne 2a (0.25 mmol), [Cp*RhCl2]2 (5.0 mol %),
Cu(OAc)2 (2.1 equiv), CsOPiv (2.0 equiv), and dioxane (2.0 mL) at
140 °C for 24 h.
a
Scheme 4. Scope for Alkynes
With the optimized conditions in hand, we next examined
the scope of indolyl aldehyde substrates. As depicted in Scheme
3, a series of indolyl aldehydes reacted smoothly with 1,2-
diphenylacetylene to give the corresponding products in good
to excellent yields. Indolyl aldehydes with both electron-
withdrawing and electron-donating groups were suitable
substrates for this transformation. Various functional groups
such as alkoxy, cyano, and ester on both the fused phenyl and
N-aryl of indole were well tolerated (3e−m). However, the
more reactive bromo, iodo, aldehyde, and alcohol function-
alities were incompatible with the current catalytic system. In
addition, indole aldehyde bearing a N-heteroaromatic sub-
stituent could also react with diphenylacetylene to give the
desired product 3p in 61% yield.
Next, the scope of the annulation reaction was further
extended to various substituted acetylenes (Scheme 4). It was
found that diverse diarylacetylenes with functional groups such
as fluoro, chloro, and alkoxy smoothly gave 5,6-diarylindolo-
[1,2-a]quinolines in good yields (4c−e). Gratifyingly, dialky-
lalkynes could enable the desired reaction in good to excellent
yields (4f,g). The unsymmetrical alkyne could also go through
the current transformation in a good yield but with a low
regioselectivity (4h).
Although the product 3a was obtained in 59% yield with 1-
phenyl-1H-indole-3-carboxylic acid as the starting material, 1-
phenyl-1H-indole-3-carboxylic acid was not detected with 1-
phenyl-1H-indole-3-carbaldehyde as the starting material in the
current catalyst system, and only a trace amount of 1-phenyl-
a
Reactions were performed in the presence of indole 3-aldehyde 1a
(0.375 mmol), alkyne 2 (0.25 mmol), [Cp*RhCl2]2 (5.0 mol %),
Cu(OAc)2 (2.1 equiv), CsOPiv (2.0 equiv), and dioxane (2.0 mL) at
140 °C for 24 h.
B
DOI: 10.1021/acs.orglett.5b01171
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1H-indole was observed. Furthermore, the indolecarboxylic
acid was not yet detected in the absence of alkynes except for
the recovery of indole 3-aldehyde (eq 1). Thus, we speculated
Scheme 6. Synthesis of Indolo[1,2-a]quinoline-Based
Sensitizers
that the annulation reaction could undergo a decarbonylative
process. In addition, a small amount of C3-deuterated product
was observed with the deuterated aldehyde (CDO) as a
substrate. The parallel reactions were performed by using
indole 3-aldehyde and 2-deuterioindole 3-aldehyde under the
optimized conditions. A primary kinetic isotopic effect (KIE) of
1.13 was observed, which revealed that the C2−H bond
cleavage of indole might not be involved in the rate-
determining step.14 Accordingly, a plausible mechanism for
annulation is depicted in Scheme 5. First, the coordination of
sunlight. The ground oxidation potentials of 7A (Eox = 0.94 V
vs NHE) and 7B (Eox = 0.79 V vs NHE), estimated from cyclic
voltammograms (CV), are more positive than the iodine/
iodide redox potential value (0.42 V vs NHE), and the excited-
state oxidation potentials of 7A (E*ox = −1.33 V vs NHE) and
7B (Eo*x = −1.46 V vs NHE) are sufficiently negative in
comparison with the conduction band energy level of TiO2
(−0.5 V vs NHE) (Figure S1 and Table S2). The incident
photon-to-current conversion efficiencies (IPCEs) of the DSSC
devices based on 7A and 7B display a broad band in the region
of 300−600 nm (Figure S2). Under simulated AM 1.5G
irradiation, the photocurrent−voltage (J−V) plots exhibit an
overall conversion efficiency (η) of 5.8% for the 7B-based
DSSC (Jsc = 11.64 mA cm−2, Voc = 0.765 V, and FF = 0.650)
Scheme 5. Plausible Catalytic Cycle
and 4.6% for the 7A-based DSSC (Jsc = 9.51 mA cm−2, Voc
=
0.717 V, and FF = 0.676), respectively (Figure S2 and Table
S3), suggesting indolo[1,2-a]quinolines may be ideal π-
conjugated skeletons for applications in DSSCs.
the carbonyl oxygen atom to Rh(III) and sequential pivalate-
assisted C2−H bond activation form a five-membered rhoda-
cycle B.11,12 Insertion of alkyne to the Rh−C bond generates a
seven-membered rhodacycle C. Cleavage of the aldehyde C−H
bond and subsequent rearrangement generate a six-membered
rhodacycle D.13 The decarbonylation next occurs to reproduce
a five-membered rhodacycle E.6 Subsequent protonolysis of the
Rh−C bond of indole and recyclorhodation with the phenyl
ring afford a seven-membered rhodacycle F, which undergoes
reductive elimination to afford the final product and regenerate
the active Rh(III) species.
Considering that the indolo[1,2-a]quinoline skeleton has
multiple substitution sites and an electron-rich π-system similar
to ullazine,15 we conceived that indolo[1,2-a]quinoline would
be a good candidate for the construction of π-conjugated
materials for dye-sensitized solar cells (DSSCs). To elucidate
the usefulness of the method further, the concise synthesis of
indolo[1,2-a]quinoline-based sensitizers 7A and 7B was
performed by the sequential Rh(III)-catalyzed C−H activa-
tion/cyclization of indolyl aldehyde with alkyne, reduction of
cyano, and Knoevenagel condensation with cyanoacetic acid
(Scheme 6).
In summary, we have developed a regioselective Rh(III)-
catalyzed C−H activation/cyclization of indolyl aldehydes with
alkynes via the aldehyde group as a traceless directing group to
construct diverse indolo[1,2-a]quinolines. This protocol is
compatible with various functional groups such as fluoro,
chloro, alkoxy, cyano, and ester, which are very useful for
further synthetic transformations. To elucidate the usefulness of
the method developed herein, a concise three-step synthesis of
indolo[1,2-a]quinoline-based sensitizers is accomplished. The
highly efficient path to polycyclic heteroaromatic scaffolds
described here shows the potential of C−H activation in the
construction of organic optoelectronic materials.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, X-ray crystal
structure (CIF) of 3a (CCDC 1055155), and copies of NMR.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01171.
UV−vis absorption spectra of 7A and 7B in CH2Cl2 solution
and on TiO2 film exhibit broad absorption bands in the range
of 300−550 nm (Figure S2). The molar extinction coefficients
of both 7A and 7B in CH2Cl2 solution are quite high, exceeding
4.0 × 104 M−1 cm−1, which suggests a good absorbance of
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jsyou@scu.edu.cn.
*E-mail: jingbolan@scu.edu.cn.
C
DOI: 10.1021/acs.orglett.5b01171
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
49, 7349. (d) Zhou, B.; Yang, Y.; Shi, J.; Feng, H.; Li, Y. Chem.Eur. J.
2013, 19, 10511. (e) Yang, T.; Zhang, T.; Yang, S.; Chen, S.; Li, X.
Org. Biomol. Chem. 2014, 12, 4290.
Notes
The authors declare no competing financial interest.
(14) A more detailed mechanism study was described in the
Supporting Information.
(15) Delcamp, J. H.; Yella, A.; Holcombe, T. W.; Nazeeruddin, M.
ACKNOWLEDGMENTS
■
This work was supported by grants from the 863 Program
(2013AA031901), the 973 Program (2011CB808601), the
National NSF of China (Nos. 21432005, 21372164, 21172155,
21272160, and 21321061), and the Sichuan Provincial
Foundation (2012JQ0002).
K.; Gratzel, M. Angew. Chem., Int. Ed. 2013, 52, 376.
̈
REFERENCES
■
(1) (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res.
2008, 41, 1013. (b) Bouffard, J.; Itami, K. Top. Curr. Chem. 2010, 292,
231. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(d) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
(e) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588. (f) Kuhl, N.;
Schroder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356, 1443.
̈
(2) (a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res.
2012, 45, 788. (b) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J.
A. Acc. Chem. Res. 2012, 45, 814. (c) Ackermann, L. Acc. Chem. Res.
2014, 47, 281.
(3) Zhang, F.; Spring, D. R. Chem. Soc. Rev. 2014, 43, 6906.
(4) For selected examples of carboxylic acids as traceless directing
groups, see: (a) Cornella, J.; Righi, M.; Larrosa, I. Angew. Chem., Int.
Ed. 2011, 50, 9429. (b) Luo, J.; Preciado, S.; Larrosa, I. J. Am. Chem.
Soc. 2014, 136, 4109. (c) Zhang, Y.; Zhao, H.; Zhang, M.; Su, W.
Angew. Chem., Int. Ed. 2015, 54, 3817.
(5) For selected examples of other functional groups as traceless
directing groups, see: (a) Huang, C.; Chattopadhyay, B.; Gevorgyan,
V. J. Am. Chem. Soc. 2011, 133, 12406. (b) Preshlock, S. M.; Plattner,
D. L.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.; Smith, M. R.,
III. Angew. Chem., Int. Ed. 2013, 52, 12915. (c) Huang, X.; Huang, J.;
Du, C.; Zhang, X.; Song, F.; You, J. Angew. Chem., Int. Ed. 2013, 52,
12970.
(6) (a) Tsuji, J.; Ohno, K. Tetrahedron Lett. 1965, 3969.
(b) Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am. Chem.
Soc. 2002, 124, 3806. (c) Shuai, Q.; Yang, L.; Guo, X.; Basle,
J. J. Am. Chem. Soc. 2010, 132, 12212.
́
O.; Li, C.-
(7) (a) Padala, K.; Jeganmohan, M. Org. Lett. 2012, 14, 1134.
(b) Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 6262. (c) Yang, F.;
Rauch, K.; Kettelhoit, K.; Ackermann, L. Angew. Chem., Int. Ed. 2014,
53, 11285.
(8) Liu, X.; Li, G.; Song, F.; You, J. Nat. Commun. 2014, 5, 5030.
(9) (a) Anderson, W. K.; Heider, A. R.; Raju, N.; Yucht, J. A. J. Med.
Chem. 1988, 31, 2097. (b) Ambros, R.; Schneider, M. R.; von Angerer,
S. J. Med. Chem. 1990, 33, 153. (c) Ahmed, E.; Briseno, A. L.; Xia, Y.;
Jenekhe, S. A. J. Am. Chem. Soc. 2008, 130, 1118. (d) Kemnitzer, W.;
Kuemmerle, J.; Jiang, S.; Sirisoma, N.; Kasibhatla, S.; Crogan-Grundy,
C.; Tseng, B.; Drewe, J.; Cai, S. X. Bioorg. Med. Chem. Lett. 2009, 19,
3481. (e) Verma, A. K.; Jha, R. R.; Chaudhary, R.; Tiwari, R. K.;
Reddy, K. S. K.; Danodia, A. J. Org. Chem. 2012, 77, 8191.
(10) (a) Hulcoop, D. G.; Lautens, M. Org. Lett. 2007, 9, 1761.
(b) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R. C.
Angew. Chem., Int. Ed. 2009, 48, 1138. (c) Yamashita, M.; Horiguchi,
H.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 7481.
(d) Panteleev, J.; Geyer, K.; Aguilar-Aguilar, A.; Wang, L.; Lautens, M.
Org. Lett. 2010, 12, 5092. (e) Shukla, S. P.; Tiwari, R. K.; Verma, A. K.
J. Org. Chem. 2012, 77, 10382.
(11) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(12) (a) Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 2818.
(b) Zhang, L.-Q.; Yang, S.; Huang, X.; You, J.; Song, F. Chem.
Commun. 2013, 49, 8830. (c) Li, B.; Ma, J.; Xie, W.; Song, H.; Xu, S.;
Wang, B. J. Org. Chem. 2013, 78, 9345.
(13) (a) Shimizu, M.; Tsurugi, H.; Satoh, T.; Miura, M. Chem.
Asian J. 2008, 3, 881. (b) Shi, Z.; Schroder, N.; Glorius, F. Angew.
̈
Chem., Int. Ed. 2012, 51, 8092. (c) Jijy, E.; Prakash, P.; Shimi, M.;
Pihko, P. M.; Joseph, N.; Radhakrishnan, K. V. Chem. Commun. 2013,
D
DOI: 10.1021/acs.orglett.5b01171
Org. Lett. XXXX, XXX, XXX−XXX