Cascade Reaction to Selectively Synthesize Multifunctional Indole Derivatives by IrIII-Catalyzed C?H Activation

Article abstract of DOI:10.1002/chem.202101602

An effective and condition-controlled way to synthesize with high selectivity a variety of functionalized indoles with potent biological properties has been developed. Notably, 2,4-dialkynyl indole products were obtained by direct double C?H bond alkynylation, whereas alkynyl at the C4 position could convert to carbonyl to generate 2-alkynyl-3,4-diacetyl indoles fast and effectively. Additionally, a one-pot relay catalytic reaction led to 2,5-di-alkynyl-3,4-diacetyl indoles when using a carbonyl group as the directing group and by controlling the type and quantity of additives. A possible mechanism was proposed based on many studies including deuterium-exchange experiments, the necessary conditions of product conversion, and the effect of water on the reaction.

Full text of DOI:10.1002/chem.202101602

Communication
doi.org/10.1002/chem.202101602
Chemistry—A European Journal
Cascade Reaction to Selectively Synthesize Multifunctional
Indole Derivatives by IrIII-Catalyzed CÀ H Activation
Xin-Yue Chai,[a] Hui-Bei Xu,[a] and Lin Dong*[a]
Abstract: An effective and condition-controlled way to
synthesize with high selectivity a variety of functionalized
indoles with potent biological properties has been devel-
oped. Notably, 2,4-dialkynyl indole products were obtained
by direct double CÀ H bond alkynylation, whereas alkynyl at
the C4 position could convert to carbonyl to generate 2-
alkynyl-3,4-diacetyl indoles fast and effectively. Additionally,
a one-pot relay catalytic reaction led to 2,5-di-alkynyl-3,4-
diacetyl indoles when using a carbonyl group as the
directing group and by controlling the type and quantity of
additives. A possible mechanism was proposed based on
many studies including deuterium-exchange experiments,
the necessary conditions of product conversion, and the
effect of water on the reaction.
Figure 1. Representative examples of derivatives.
Indole units are widely spread in natural products, pharmaceut-
icals, and functional materials owing to their versatile properties
of biological activities and high reactivities.[1] In particular,
functional indoles such as alkynyl- and carbonyl-indoles have
attracted widespread attention (Figure 1).[2] For example, the
PARP enzyme is responsible for repair of damaged DNA. PARP
inhibitors containing a carbonyl-indole structure co-adminis-
tered with a standard chemotherapeutic agent were more
effective than the standard treatment alone, which was an
exciting new mechanism for the treatment of cancer.[2] With the
rapid development of transition metal-catalyzed direct CÀ H
functionalization in the past few decades, these efficient
methods have been broadly used to introduce function groups
into indole units.[3]
Scheme 1. Functionalization of indoles from alkynes through CÀ H activation.
Owing to their strong reactivities in synthetic chemistry,[4]
haloalkynes have found various applications in the modification
of chemical substances through CÀ H functionalization in recent
years,[5,6] such as selective alkynylation at C2, C3 (pyrrole rings)[7]
or C4, C7 (benzenoid rings)[8] of indoles [Scheme 1, Eq. (1)].
Although some achievements have been made, only mono-
alkynylated indoles have been reported in these approaches. To
our knowledge, bis- or multiply substituted, even highly
decorated, indoles forming in one pot has never been
mentioned. In addition, the preparation of carbonylated indoles
from haloalkynes has never been reported.[9] Whereas common
methods to create carbonylated or multiply substituted indoles
usually involve multistep conversion and harsh conditions,[10]
herein, we report a condition-controlled approach to highly
selectively synthesize a variety of highly decorated indole
derivatives from haloalkynes and 3-acetyl indoles [Eq. (2)]. First,
2,4-dialkynyl indole products were formed successfully by
double CÀ H bond alkynylation. Then, 2,4-dialkynyl indoles as
intermediates could be quickly converted to 2-alkynyl-3,4-
diacetyl indoles by changing the reaction conditions. Signifi-
cantly, complex 2,5-dialkynyl-3,4-diacetyl indoles were gener-
[a] X.-Y. Chai, Dr. H.-B. Xu, Prof. L. Dong
Key Laboratory of Drug-Targeting and
Drug Delivery System of the Education Ministry
Sichuan Research Center for Drug Precision Industrial Technology
West China School of Pharmacy
Sichuan University
Chengdu 610041 (P. R. China)
E-mail: dongl@scu.edu.cn
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202101602
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ated in one pot through a domino induction effect by using an
in situ carbonyl group as the relay directing group.
With the best conditions in hand, we extended the
substrate applicability of indoles. As shown in Scheme 2, 2a
could react with 5- and 6-substituted indole substrates, and all
these substrates could give good yields (3ba–3ha) no matter
with the electron-withdrawing or -donating groups. Interest-
ingly, using 7-methoxy and 7-methyl indoles as substrates,
monoalkynylation products (3ia’ and 3ja’) at C4-position were
obtained in lower temperature and shorter reaction time. When
C2 or C4 was block, monoalkynylation products 3la (70%) and
3ka (93%) were obtained, respectively. From the above results,
we had reason to believe that the activity of alkynylation at the
4-position of indole was higher than the 2-position in this
system. In order to exclude background electrophilic aromatic
substitution, we did study for the substrate 1i and 1j in the
absence of the Ir catalyst, but no products were obtained.
Reactions with different carbonyl substituents all led to
excellent yields (3ma–3qa). While some electron-deficient
groups were not tolerated in the coupling reaction.[11] In
addition, various N-substituted indoles, including alkenyl, long-
chain alkyl, even phenyl-substituted groups showed good
reactivity, giving products in 80–99% yields (3ra–3ua).
In the beginning, 1-benzyl-3-acetylindole 1a was selected
to react with 2a as a model reaction (Table 1). To our delight,
2,4-dialkynyl indole 3aa was detected as a main product in
moderate yield (entry 1). The influence of different bases on this
kind of reaction could not be ignored, and KOAc slightly
improved the yield of 3aa (entries 2–4). From the effect of
different additives on the reaction point of view, mixture of
Ag2CO3 and AgOAc as co-additives exhibited better reactivity
than other combinations (entries 5 and 6).[11] Solvents were
essential to the reaction, the yield of 3aa was increased to 98%
in MTBE (entries 7–9). However, reducing the amount of silver
salts could decrease the yield of 3aa (entry 10). And the effect
of other copper salts was not outstanding. When Zn(OAc)2 and
AgOAc were used as co-additives, improving the equivalence of
KOAc and AgNTf2, carbonylated-substituted product 4aa could
be obtained in 80% yield, and the structure of 4aa was
characterized by X-ray crystallography (entries 11–17).[12] In-
creasing the temperature and the amount of additives (Ag2CO3
and AgOAc), highly decorated product 5aa was isolated in 45%
yield in one-pot (entries 18–20). When the reaction directly
started from 4aa, 5aa was formed in 95% yield (entry 21).
Similarly, the applicability of 4-carbonylation substrates was
also investigated, and the results were shown in Scheme 3.
Table 1. Optimization of reaction conditions.[a]
Additive/equiv
Base
Solvent
Yield [%][b]
3aa
4aa
5aa
1
2
3
4
5
6
7
8
AgOAc/2
AgOAc/2
AgOAc/2
AgOAc/2
NaOAc
KOAc
PivONa
K2CO3
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
LiOAc
LiOAc
DCE
DCE
DCE
DCE
DCE
DCE
1,4-dioxane
THF
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
43
56
47
trace
42
65
75
trace
98/60[h]
90
22
0
0
56
trace
<10
ND
0
10
0
0
0
0
0
0
0
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
trace
23
Ag2CO3/2
AgOAc/2+Ag2CO3/2
AgOAc/2+Ag2CO3/2
AgOAc/2+Ag2CO3/2
AgOAc/2+Ag2CO3/2
AgOAc/0.5+Ag2CO3/2
AgOAc/2+Cu(OAc)2·H2O/1
AgOAc/2+Cu(acac)2 /1
AgOAc/2+CuCl /1
AgOAc/2+Cu(OAc)2·H2O/2
AgOAc/2+Cu(OAc)2·H2O/1
AgOAc/3
AgOAc/2+Zn(OAc)2/1
AgOAc/3+Ag2CO3/2
AgOAc/3+Ag2CO3/2
AgOAc/3+Ag2CO3/2
AgOAc/1+Ag2CO3/1
9[c]
10
11
12
13
14
15[d]
16
17[c,d]
18[d]
19[d,e]
20[d,f]
21[c,g]
ND
30
0
0
20
74
75
80/75[h]
45
40
15
–
trace
20
–
45
trace
95
Reaction conditions unless otherwise specified: [a] 0.1 mmol of 1a, 4 equiv. of 2a, 5 mol% of [Cp*IrCl2]2, 0.3 equiv. of AgNTf2, 0.3 equiv. of base, 1 mL of
°
°
°
solvent, 100 C, 12 h, air atmosphere. [b] Isolated yield. [c] 6 h. [d] 0.7 equiv. of AgNTf2, 0.5 equiv. of base. [e] 120 C, 12 h. [f]130 C, 12 h. [g] Using 4aa as
substrate, 1 equiv. of Ag2CO3, 1 equiv. of AgOAc, 0.2 equiv. of AgNTf2, 0.3 equiv. of LiOAc and 2 equiv. of 2a. [h] scale-up: 1 mmol of 1a. MTBE=methyl tert-
butyl ether.
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Scheme 3. Substrate scope of synthesis of 4.[a] Reaction conditions: 0.1 mmol
of 1, 4 equiv. of 2a, 5 mol% of [Cp*IrCl2]2, 0.7 equiv. of AgNTf2, 2 equiv. of
AgOAc, 1 equiv. of Zn(OAc)2, 0.5 equiv. of KOAc, 1 mL of commercial MTBE,
°
100 C, 6 h, air atmosphere.
Scheme 2. Substrate scope of the synthesis of 3.[a] Reaction conditions unless
otherwise specified: [a] 0.1 mmol of 1, 4 equiv. of 2a, 5 mol% of [Cp*IrCl2]2,
0.3 equiv. of AgNTf2, 2 equiv. of AgOAc, 2 equiv. of Ag2CO3, 0.3 equiv. of
°
°
KOAc, 1 mL of commercial MTBE, 100 C, 6 h, air atmosphere. [b] 80 C, 2 h.
Indole derivatives with different substituents, including elec-
tron-rich and -poor group, gave good yields (4ba–4ja). Addi-
tionally, the use of 5-F and 5-Cl substituted indoles as substrates
could generate the TIPS removal products (4ka’–4la’). This was
probably due to the strong electron-withdrawing effect of
halogen. We also explored the applicability of N-substituted
substrates, and the compatibility was very good (4ma–4oa). In
addition, different carbonyls as directing groups also proceeded
smoothly (4pa–4ra).
Scheme 4. Substrate scope of synthesis of 5.[a] Reaction conditions unless
otherwise specified: [a] 0.1 mmol of 1, 5 equiv. of 2a, 5 mol% of [Cp*IrCl2]2,
Next, we explored the substrate applicability of 2,5-di-
°
0.6 equiv. of AgNTf2, 1 equiv. of LiOAc, 1 mL of commercial MTBE, 120 C, 6 h,
air atmosphere. [b] Using 4 as substrate, 1 equiv. of Ag2CO3, 1 equiv. of
AgOAc, 0.2 equiv. of AgNTf2, 0.3 equiv. of LiOAc and 2 equiv. of 2a.
alkynyl-3,4-diacetyl
multifunctional
indole
derivatives
(Scheme 4). The indole units with various substitutions were all
tolerated in the domino coupling reaction, giving the corre-
sponding aimed products in mild yields (5ba–5ga). Moreover,
when 2-alkynyl-3,4-diacetyl indoles 4 were directly employed as
the substrates, excellent yields were obtained. These results
fully showed that the intramolecular relay catalysis could be
carried out in this system.
Functionalized indole 4aa could give further transformation
to more complex molecules (Scheme 5). Deprotection TIPS of
4aa with AgF gave terminal alkyne 6, which was subjected Click
reaction to prepare triazole 7. Intramolecular condensation of
4aa generated novel tricyclic product 8 [Eq. (1)]. However, 5aa
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Scheme 5. Synthetic applications.
could not be further transformed to tri-carbonyl compound
5aa’’, and only gave the 4-TIPS deprotection product 5aa’ in a
low yield [Eq. (2)].
Then, we did some experiments to explore the mechanism
(Scheme 6). In the H/D exchange experiment, the deuteriation
rate of 4-position (75%) and 2-position (40%) could be
obtained (equation 1). In contrast, no deuterium was detected
at C2 or C4 in the absence of [Cp*IrCl2]2, which showed that the
reaction underwent Ir-catalyzed CÀ H bond activation (equa-
tion 2). Control experiment revealed that activity of the CÀ H
bond at C4 prevailed over its at C2 (equation 3).[11] Besides, 3aa
could construct 4aa in 83% yield under the combined action of
AcOH and AgNTf2 (equation 4), while the 2-position alkynyl
group cannot be converted to carbonyl group, which indicated
that carbonylation is more likely to occur on the benzene ring
rather than pyrrole ring probably due to electronic effect.[13]
From the result, it was obvious that 3aa was an intermediate
for the formation of 4aa, and LC–MS analysis could also prove
the formation of 4aa needs to go through the intermediate
3aa during the reaction.[11] To better analyze the source of
carbonyl oxygen atom, the isotope labeling reaction was
studied in the presence of H218O, and the data verified that the
source of oxygen might come from water in the wet solvent of
reaction system (eqs 5 and 6). In addition, when commercial
wet MTBE as solvent was directly used without additional water
in the original conditions, products with similar high yields
were obtained, while different amount of water could only
slightly influent the reaction.[11] Competition experiment con-
firmed that withdrawing- or donating-substituted substituents
had little effect on this reaction [Eq. (7)].
We could give a preliminary possible reaction mechanism in
Scheme 7. The carbonyl group in the substrate as the guide
group coordinated with iridium giving the intermediate I
through CÀ H bond activation at C4. Subsequently, bromo-
alkyne oxidant addition generated the intermediate II (path a),
which could undergo reductive elimination forming the inter-
mediate III. The second CÀ H bond activation at C2 and alkyne
insertion generated Ir complex IV. Then reduction elimination
provided the product 3aa. And the other alternative pathway
might involve alkyne insertion to produce intermediate II’ and
AgOAc-assisted bromide elimination to give intermediate III
Scheme 6. Preliminary mechanistic investigation.
(path b).[3i] Changing the conditions, 3aa could transform to
4aa. Notably, the newly formed carbonyl group in 4aa could
play the role of chelation assistance, constructing domino
product 5aa by the third CÀ H activation.
In conclusion, we have reported an IrIII-catalyzed cascade
approach to selectively synthesize various decorated indole
derivatives: 2,4-di-alkynyl indoles by direct double CÀ H activa-
tion, 2-alkynyl-3,4-diacetyl indoles through intramolecular con-
version from C4 alkyne groups, and 2,5-di-alkynyl-3,4-diacetyl
indoles through a carbonyl group formed in situ as the relay
directing group. At the same time, the synthetic application of
the products was proved effectively.
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Zhang, R. C. Su, X. Y. Chen, B. Y. Feng, Y. D. Yang, J. S. You, ACS Catal.
2019, 9, 6372–6379; f) H. Lu, T. T. Zhao, J. H. Bai, D. Ye, P. F. Xu, Angew.
Chem. Int. Ed. 2020, 59, 23345–23898; Angew. Chem. 2020, 132, 23549–
23549; g) W. J. Kong, X. R. Chen, M. M. Wang, H. X. Dai, J. Q. Yu, Org.
Lett. 2018, 20, 1–3; h) Z. l. Wang, C. Y. Wang, Green Synth. Catal. 2021, 2,
66–69; i) J. Wen, Z. Z. Shi, Acc. Chem. Res. 2021, 54, 1723–1736.
[4] a) D. Petko, S. Koh, W. Tam, Curr. Org. Synth. 2019, 16, 546–582; b) X. J.
Zeng, S. W. Liu, G. B. Hammond, B. Xu, ACS Catal. 2018, 8, 904–909;
c) W. Q. Wu, H. F. Jiang, Acc. Chem. Res. 2014, 47, 2483–2504; d) V.
Cadierno, Eur. J. Inorg. Chem. 2020, 886–898; e) W. Shi, Y. D. Luo, X. C.
Luo, L. Chao, H. Zhang, J. Wang, A. Lei, J. Am. Chem. Soc. 2008, 130, 44–
45; f) P. D. G. Fernández, J. I. Sigüenza, P. S. R. Jerez, E. Díez, E. G.
Bengoa, R. Fernández, J. M. Lassaletta, J. Am. Chem. Soc. 2020, 142,
16082–16089.
[5] a) V. G. Landge, G. Jaiswal, E. Balaraman, Org. Lett. 2016, 18, 812–815;
b) V. G. Landge, A. Parveen, Chem. Commun. 2018, 54, 7483–7486;
c) Z. X. Ruan, N. Sauermann, E. Manoni, L. Ackermann, Angew. Chem. Int.
Ed. 2017, 56, 3172–3176; Angew. Chem. 2017, 129, 3220–3224; d) T. Liu,
J. X. Qiao, M. A. Poss, J. Q. Yu, Angew. Chem. Int. Ed. 2017, 56, 10924–
10927; Angew. Chem. Int. Ed. 2017, 56, 3172–3176
[6] a) S. K. Mahato, N. Chatani, ACS Catal. 2020, 10, 5173–5178; b) H. M. F.
Viart, A. Bachmann, W. Kayitare, R. Sarpong, J. Am. Chem. Soc. 2017, 139,
1325–1329; c) E. Tan, O. Quinonero, M. E. Orbe, A. M. Echavarren, ACS
Catal. 2018, 8, 2166–2172; d) E. Tan, A. I. Konovalov, G. A. Fernandez, R.
Dorel, A. M. Echavarren, Org. Lett. 2017, 19, 5561–5564; e) S. Porey, X. L.
Zhang, S. Bhowmick, V. K. Singh, S. Guin, R. S. Paton, D. Maiti, J. Am.
Chem. Soc. 2020, 142, 3762–3774.
Scheme 7. Plausible reaction mechanism.
[7] a) G. N. Hermann, M. T. Unruh, S. H. Jung, M. Krings, C. Bolm, Angew.
Chem. Int. Ed. 2018, 57, 10723–10727; Angew. Chem. 2018, 130, 10883–
10887; b) Z. Z. Zhang, B. Liu, C. Y. Wang, B. F. Shi, Org. Lett. 2015, 17,
4094–4097; c) W. Q. Wu, S. J. Fang, G. B. Jiang, M. Li, H. F. Jiang, Org.
Chem. Front. 2019, 6, 2200–2204; d) Y. H. Gu, X. M. Wang, Tetrahedron
Lett. 2009, 50, 763–766; e) J. P. Brand, J. Charpentier, J. Waser, Angew.
Chem. Int. Ed. 2009, 48, 9346–9349; Angew. Chem. 2009, 121, 9510–
9513; f) N. Sauermann, M. J. González, L. Ackermann, Org. Lett. 2015, 17,
5316–5319.
[8] a) C. N. Kona, Y. Nishii, M. Miura, Angew. Chem. Int. Ed. 2019, 58, 9856–
9860; Angew. Chem. 2019, 131, 9961–9965; b) G. Wu, W. Ouyang, Q.
Chen, Y. Huo, X. W. Li, Org. Chem. Front. 2019, 6, 284–289; c) S. J. Fang,
G. B. Jiang, M. Li, Z. Y. Liu, H. F. Jiang, W. Q. Wu, Chem. Commun. 2019,
55, 13769–13772.
[9] a) J. Q. Liu, X. Chen, A. Shatskiy, M. D. Kärkäs, X. S. Wang, J. Org. Chem.
2019, 84, 14–41; b) G. Xie, Y. Zhao, C. Cai, G. J. Deng, H. Gong, Org. Lett.
2021, 23, 410–415; c) J. Zhang, M. Wu, J. Fan, Q. Q. Xu, M. H. Xie, Chem.
Commun. 2019, 55, 8102–8105; d) C. N. Kona, Y. Nishii, M. Miura, Org.
Lett. 2020, 22, 4806–4811; e) J. L. Bras, J. Muzart, Synthesis. 2019, 15,
2871–2890.
[10] a) A. T. Gillmore, M. Badland, C. L. Crook, N. M. Castro, D. J. Critcher, S. J.
Fussell, K. J. Jones, M. C. Jones, E. Kougoulos, J. S. Mathew, L. McMillan,
J. E. Pearce, F. L. Rawlinson, A. E. Sherlock, R. Walton, Org. Process Res.
Dev. 2012, 16, 1897–1904; b) F. Ito, K. Yamaguchi, Tetrahedron Lett.
2012, 68, 3708–3716; c) Y. F. Li, J. Waser, Angew. Chem. Int. Ed. 2015, 54,
5438–5442; Angew. Chem. 2015, 127, 5528–5532.
Acknowledgements
We are grateful for financial support from “111 Project B18035”
and “the Fundamental Research Funds for the Central Uni-
versities“.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Alkynylation · cascade reactions · carbonylation ·
iridium · multifunctional indole derivatives · multistep CÀ H
activation
[1] a) A. J. Kochanowska-Karamyan, M. T. Hamann, Chem. Rev. 2010, 110,
4489–4497; b) S. Lancianesi, A. Palmieri, M. Petrini, Chem. Rev. 2014,
114, 7108–7149; c) I. Ali, S. D. Mukhtar, M. F. Hsieh, Z. A. Alothmand, A.
Alwarthan, RSC Adv. 2018, 8, 37905–37914; d) G. R. Humphrey, J. T.
Kuethe, Chem. Rev. 2006, 106, 2875–2911; e) A. Unzue, H. Zhao, G. Lolli,
J. Dong, J. Zhu, M. Zechner, A. Dolbois, A. Caflisch, C. Nevado, J. Med.
Chem. 2016, 59, 3087–3097; f) G. Bartoli, R. Dalpozzo, M. Nardi, Chem.
Soc. Rev. 2014, 43, 4728–4750.
[2] a) A. T. Gillmore, M. Badland, C. L. Crook, N. M. Castro, D. J. Critcher, S. J.
Fussell, K. J. Jones, M. C. Jones, E. Kougoulos, J. S. Mathew, L. McMillan,
J. E. Pearce, F. L. Rawlinson, A. E. Sherlock, R. Walton, Org. Process Res.
Dev. 2012, 16, 1897–1904; b) Y. Y. Syed, Drugs. 2017, 77, 585–592; c) M.
Elkady, R. Nieß, A. M. Schaible, J. Bauer, S. Luderer, G. Ambrosi, O. Werz,
S. A. Laufer, J. Med. Chem. 2012, 55, 8958–8962; d) A. Scopton, T. R.
Kelly, J. Org. Chem. 2005, 70, 10004–10012.
[11] For more information, please see the Supporting Information.
[12] Deposition Number 2091591 (4aa) contains the supplementary crystal-
lographic data for this paper. These data are provided free of charge by
the joint Cambridge Crystallographic Data Centre and Fachinforma-
tionszentrum Karlsruhe Access Structures service. Crystallographic data
̄
for 4aa: C39H57NO2Si2, M=628.06 g/mol, space group P1, unit cell: a=
°
12.3455 (8) Å, b=12.7730 (10) Å, c=131801 (8) Å, α=77.588(2) , β=
3
°
°
65.199(2) , γ=83.821(3) , T=150.0 K, calcd density=1.159 g/cm .
[13] a) Z. W. Chen, D. N. Ye, Y. P. Qian, M. Ye, L. X. Liu, Tetrahedron. 2013, 69,
6116–6120; b) M. B. T. Thuong, A. Mann, A. Wagner, Chem. Commun.
2012, 48, 434–436; c) X. Y. Xu, S. H. Kim, X. Zhang, A. K. Das, H. Hirao,
S. H. Hong, Organometallics. 2013, 32, 164–171.
[3] a) Y. Q. Yang, Z. Z. Shi, Chem. Commun. 2018, 54, 1676–1685; b) H. Zhu,
S. Zhao, Y. Zhou, C. Li, H. Liu, Catalysts. 2020, 10, 1253–1280; c) Y. Q. Xia,
L. Dong, Org. Lett. 2017, 19, 2258–2261; d) B. Liu, J. Li, P. J. Hu, X. K.
Zhou, D. C. Bai, X. W. Li, ACS Catal. 2018, 8, 9463–9470; e) S. Y. Chen, M.
Manuscript received: May 5, 2021
Version of record online: ■■■, ■■■■
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COMMUNICATION
CÀ H activation cascade reaction: An
effective way to synthesize a variety
of functionalized indoles with potent
biological properties has been
X.-Y. Chai, Dr. H.-B. Xu, Prof. L. Dong*
1 – 6
Cascade Reaction to Selectively Syn-
thesize Multifunctional Indole Deriv-
atives by IrIII-Catalyzed CÀ H Activa-
tion
developed. Notably, 2,4-dialkynyl
indole products were obtained by
direct double alkynylation of CÀ H
bonds, whereas alkynyl on C4 position
might convert to carbonyl to generate
2-alkynyl-3,4-diacetyl indoles. Addi-
tionally, relay catalysis allowed the
synthesis of 2,5-di-alkynyl-3,4-diacetyl
indoles by using an in situ carbonyl
group as the directing group.