Palladium-catalyzed intramolecular C–H acylation of indoles with thioester

Article abstract of DOI:10.1016/j.tetlet.2019.151061

A palladium-catalyzed intramolecular C–H acylation of indole with thioester is described, providing a direct and effective approach for the synthesis of the biologically active indole-indolone scaffolds. The method obviates the need for the prefunctionalized starting materials including organometallic reagents, alkyl halides, and NHP esters in previous metal-catalyzed cross-coupling reaction with thioester. Substrates bearing sensitive halo groups are compatible in the reaction, leaving a functional handle for further structural elaborations.

Full text of DOI:10.1016/j.tetlet.2019.151061

Journal Pre-proofs
Palladium-catalyzed Intramolecular C–H Acylation of Indoles with Thioester
Min Liu, Yu-Wen Liu, Hui Xu, Hui-Xiong Dai
PII:
S0040-4039(19)30821-4
DOI:
https://doi.org/10.1016/j.tetlet.2019.151061
TETL 151061
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 July 2019
16 August 2019
19 August 2019
Please cite this article as: Liu, M., Liu, Y-W., Xu, H., Dai, H-X., Palladium-catalyzed Intramolecular C–H Acylation
of Indoles with Thioester, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151061
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will
undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing
this version to give early visibility of the article. Please note that, during the production process, errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2019 Elsevier Ltd. All rights reserved.

Graphical Abstract
Leave this area blank for abstract info.
Palladium-catalyzed Intramolecular C–H Acylation of Indoles with Thioester
Min Liu, Yu-Wen Liu, Hui Xu and Hui-Xiong Dai
H
R
Pd(PPh3)4 (10 mol%)
DPPPe (20 mol%)
O
SEt
R
N
N
O
CuTC, DMSO, 90 o
C
Indole-indolone scaffolds
Gram-scale synthesis
Up to 94% yields
Compatibility with aryl bromide

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Palladium-catalyzed Intramolecular C–H Acylation of Indoles with Thioester
Min Liua,c , Yu-Wen Liua,c, Hui Xua,c  and Hui-Xiong Dai a,b,c

a Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Shanghai 201203, China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China
c University of Chinese Academy of Sciences, Beijing 100049, China
———
ARTICLE INFO
ABSTRACT
 Corresponding author. e-mail: xuhui2018@simm.ac.cn
 Corresponding author. e-mail: hxdai@simm.ac.cn
Article history:
Received
A palladium-catalyzed intramolecular C–H acylation of indole with thioester is described,
providing a direct and effective approach for the synthesis of the biologically active indole-
Received in revised form
Accepted
Available online
indolone scaffolds. The method obviates the need for the prefunctionalized starting materials
including organometallic reagents, alkyl halides, and NHP esters in previous metal-catalyzed
cross-coupling reaction with thioester. Substrates bearing sensitive halo groups are compatible in
the reaction, leaving a functional handle for further structural elaborations.
Keywords:
C–H acylation
2009 Elsevier Ltd. All rights reserved.
Thioester
Liebeskind-Srogl reaction
Indole-indolone scaffolds
Thioesters, as versatile building blocks in organic chemistry, has been successfully applied in the metal-catalyzed ketone synthesis due
to their highly chemoselective activation of C(O)–S bond by oxidative addition to a low-valent transition metal.1 In 1998, Fukuyama
reported a novel ketone synthesis by the palladium-catalyzed coupling reaction of thioesters with nucleophilic organozinc reagent
(Scheme 1a).2 The reaction proceeded via a C–S bond activation/C–C bond formation sequence under the mild condition. Subsequently,
by using air- and moisture-stable, relatively low toxic organoboron reagent as coupling partner, Liebeskind and Srogl reported a
mechanistically unprecedented ketone synthesis with thioester under “baseless” conditions, which is known as Liebeskind-Srogl cross-
coupling reaction.3 Since then, organotin,4 organosilicon,5 and organoindium6 were employed as the nucleophilic metallic reagent in the
palladium-catalyzed ketone synthesis with thioester. Beside these nucleophilic organometallic reagents, Weix group developed novel
ketone synthesis by Ni-catalyzed cross-electrophile coupling of thioester with alkyl halides or N-hydroxyphthalimide (NHP) esters as
alkyl radical donors (Scheme 1a).7 Despite significant progresses have been made, prefunctionalized starting materials are required in
these protocols, which will add costly chemical steps to the ketone construction. Thus, the development of more efficient methodologies
that utilizes the readily available starting material would be highly desirable.
a. Cross coupling reaction with thioester
O
O
Metal catalyst
+
R
X
R1
R1
SR2
R
Previous work
Nucleophiles: R-M ( Zn,2 B,3 Sn,4 Si,5 In6)
Electrophiles: R-I7
Radicals: N-hydroxyphthalimide(NHP) esters7
b. C-H activiation for the ketone synthesis13,14
O
O
Metal catalyst
C
H
R1
+
R1
SR2
C
Challenge
c. Intramolecular C-H acylation of indoles with thioester
O
H
Pd(PPh3)4/DPPPe
SEt
N
N
This work
O
Scheme 1 Metal-catalyzed ketone synthesis with thioester
Recently, transition-metal-catalyzed C–H activation has drawn significant attentions due to the merit of obviation of the halogenation or
stoichiometric metalation of starting materials.8 Pd-catalyzed C–H acylation of arenes by using aldehyde,9 α-oxocarboxylic acids10, acyl

2
chlorides11 or acid anhydrides12 as acylation reagents has been reported in recent years. However, metal-catalyzed C–H acylation of
arenes with thioester is still a challenge problem and rarely reported (Scheme 1b). In 2016, Gu reported a Pd/norbornene/Cu-catalyzed
ortho C−H acylation and ipso thiolation reaction of aryl halides with thioesters.13 Recently, by using dual catalyst system containing Ni
catalyst and Ir photosensitizer, Doyle realized the direct α-C−H acylation of N-phenyl pyrrolidine with thioester.14 To develop an
alternative and improved avenue for the ketone synthesis, we questioned whether we could harness C–H as the starting material in lieu
of organometallic reagents and alkyl halides to couple with thioester. Herein, we report the first example of palladium-catalyzed
intramolecular C–H acylation of indole derivatives with thioester (Scheme 1c).
Considering the high importance of the indole and indolone derivatives in pharmaceuticals and agrochemicals, the development of new
methodologies is an important objective in organic chemistry.15 In this manuscript, we commenced our studies by treating indole-
o
contained thioester 1a with 10 mol% Pd(OAc)2, 20 mol% PPh3, and 0.3 mmol CuTc at 90 C, To our delight, C-2 acylated indole-
indolone scaffolds were obtained exclusively in 26% yields (entry 1, Table 1). Other palladium catalyst were also examined, and
Pd(PPh3)4 could give the desired product in 30% yields (entry 2-4). Phosphine ligands play an important role in palladium-catalyzed C–
H activation. So we screened various phosphine ligands, and found DPPPe gave the desired product in 58% yields (entry 5-10). The
influence of solvent was also examined, and DMSO shown the best results (entry 11-14). Furthermore, we could improve the yield to
77% by increase the concentration of 1a to 0.1 M (entry 15). No desired product 2a was observed in the absence of Pd(PPh3)4 or CuTC
(entry 16, 17). In Liebeskind-Srogl cross-coupling reaction, Cu salts were required to facilitate the transmetalation by forming a
stronger Cu–S bond, or acting as a reactive transmetalation center.3 So we screened some Cu salts, and found that CuOAc and
Cu(OAc)2 could also gave the desired products in 38% and 46% yields, respectively (entry 18-21). Finally, the optimal conditions
involved the following parameters: 10 mol% Pd(PPh3)4, 20 mol% DPPPe, 3 equivalents of CuTc in 0.5 mL DMSO at 90 oC.
Table 1 Optimization of the reaction conditionsa
O
H
Pd, ligand, Cu
solvent
SEt
N
N
O
2a
a
1
Pd
Copper
salt
Yield
(%)
Entry
Ligand
Solvent
catalyst
Pd(OAc)2
Pd2dba3
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
-
PPh3
PPh3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
26
7
1
2
PdCl2
PPh3
15
30
22
16
40
8
3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
-
-
4
PCy3
PtBu3
DPPE
DPPP
DPPB
DPPPe
DPPPe
DPPPe
5
6
7
8
35
58
54
30
17
65
77
9
10
11
12
13
14
15b
16b
17b
18b
19b
20b
21b
THF
DPPPe Cyclohexane
DPPPe
DPPPe
DPPPe
DPPPe
DPPPe
DPPPe
DPPPe
DPPPe
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
0
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
CuCl
CuI
0
0
CuOAc
38
Cu(OAc)2
46
aReaction conditions: 1 (0.05 mmol), Pd catalyst (10 mol%), ligand (20 mol%), CuTC (0.15 mmol), sovent (1 mL). The yield was determined by GC-
MS analysis of crude product using C16H34 as internal standard. DPPE = 1,2-Bis(diphenylphosphino)ethane, DPPP = 1,3-Bis(diphenyl
phosphino)propane, DPPB = 1,4-Bis(diphenylphosphino)butane, DPPPe = 1,5-Bis(diphenylphosphino)pentane. CuTC = Copper(I) thiophene-2-
carboxylate; b0.5 mL DMSO.
With the optimized reaction conditions in hand, we examined the substrates scope for this reaction. As shown in Scheme 2, substrates
bearing electron-donating and electron-withdrawing substituents (-Me, -OMe, -F, -Cl, and -Br) at the 4-, 5-, 6- and 7- position of the
indole fragment were compatible in the reaction, giving the corresponding C-2 selective acylated products in moderate to good yields
(2a-2m). Notably, the bromo-contained substrates could be well tolerant in the present of Pd(0), leaving a functional handle for further
structural elaborations. Substrates bearing bromo and methoxyl substituents on the thioester fragment could be acylated smoothly,
giving the corresponding product 2n and 2o in 40% and 94% respectively.

3
Scheme 2 Substrates scope for the intramolecular C–H acylation with thioester
H
R
Pd(PPh3)4 (10 mol%)
DPPPe (20 mol%)
O
SEt
R
N
N
O
CuTC, DMSO, 90 o
C
1a 1o
-
2a 2o
-
OMe
Me
O
O
O
N
N
N
2a,
79%
N
2b,
2c,
90%
82%
Me
MeO
F
O
O
O
N
N
2e,
91%
2d,
86%
2f,
70%
Cl
Br
O
O
O
N
N
N
Me
2i,
60%
2h,
54%
2g,
57%
O
O
O
N
N
N
MeO
F
Br
2j,
2l,
56%
80%
2k,
47%
O
O
O
N
N
N
Me
OMe
Br
MeO
2m,
54%
2n,
40%
2o,
94%
aReaction conditions:1 (0.1 mmol), Pd(PPh3)4 (10 mol%), DPPPe (20 mol%), CuTC (0.3
mmol), DMSO (1 mL), 90 oC, N2, 13 h.
Finally, we investigated the feasibility of this transformation for gram-scale reaction under the standard condition, and the desired
product could be isolated in 81% yields (Scheme 3).
Scheme 3 Gram-scale synthesis
Pd(PPh3)4 (10 mol%)
H
O
SEt
DPPPe (20 mol%)
N
N
CuTC, DMSO , 90 o
C
O
1a
2a
0.63 g, 81% yield
3.6 mmol, 1.01 g
Based on the previous reports3, a plausible mechanism for the reaction is proposed in scheme 4. First, oxidative addition of Pd(0) into
C(O)–S bond of thiolester generate the Pd(II) complex I. Due to the poor electrophilic ability of the organopalladium intermediate, the
copper salt was needed as an activator to enhance the electrophilicity by forming a stronger Cu-S bond. Subsequently, intramolecular
C–H activation of indoles at the C2-position forms the stable six-membered cyclopalladium species II. Finally, reductive elimination of
complex II give the desired product 2a with the regeneration of Pd(0).
Scheme 4 Proposed mechanism

4
O
O
N
N
SEt
Pd(0)
2a
1a
Regeneration of catalyst
(1) Oxidative
addition
(3) Reductive
elimination
L
(2) Intramolecular
C-H activation
L
Pd
L
O
N
N
O
Pd
S
L
Et
CuSEt + HTC
CuTC
II
I
In summary, we have developed a palladium-catalyzed intramolecular C-2 selective acylation of indoles with thioester. A range of
functional groups are tolerated in this reaction. It provides a direct and effective method for the synthesis of indole fused indolone
scaffolds, which play an important role in bioactive molecules.
Acknowledgments
We gratefully acknowledge Shanghai Institute of Materia Medica, Chinese Academy of Sciences, NSFC (21772211), Youth
Innovation Promotion Association CAS (NO. 2014229 and 2018293), Institutes for Drug Discovery and Development, Chinese
Academy of Sciences (NO.CASIMM0120163006), Science and Technology Commission of Shanghai Municipality (17JC1405000),
Program of Shanghai Academic Research Leader (19XD1424600), National Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program”, China (2018ZX09711002-006), and the State Key Laboratory of Natural and Biomimetic Drugs
for financial support.
References and notes
[1] (a) H. Prokopcová, C.O. Kappe, Angew. Chem. Int. Ed. 48 (2009), 2276-2286;
(b) H. Cheng, H. Chen, Y. Liu, Q. Zhou Asian J. Org. Chem. 7(2018) 490-508;
(c) V. Hirschbeck, P.H. Gehrtz, I. Fleischer Chem. Eur. J. 24 (2018) 7092-7107.
[2] (a) H. Tokuyama, S. Yokoshima, T. Yamashita, T. Fukuyama, Tetrahedron Lett. 39 (1998) 3189-3192.
(b) H. Tokuyama, S. Yokoshima, T. Yamashita, S.C. Lin, L. Li, T. Fukuyama, J. Braz. Chem. Soc. 9 (1998) 381-387;
(c) R. Oost, A. Misale, N. Maulide, Angew. Chem. Int. Ed. 55 (2016) 4587-4590.
[3] (a) L.S. Liebeskind, J. Srogl, J. Am. Chem. Soc. 122 (2000) 11260–11261.
(b) D. G. Musaev, L.S. Liebeskind, Organometallics (28) 2009 4639–4642.
(c) M. Wang, Z. Dai, X, Jiang Nat. Commun. DOI: https://doi.org/10. 1038/s41467-019-10651-w.
[4] H. Li, H. Yang, L.S. Liebeskind, Org. Lett. 10 (2008) 4375–4378.
[5] V.P. Mehta, A. Sharma, E. Van der Eycken, Adv. Synth. Catal. 350 (2008) 2174–2178.
[6] B.W. Fausett, L.S. Liebeskind, J. Org. Chem. 70 (2005) 4851–4853.
[7] (a) A.C. Wotal, D.J. Weix, Org. Lett., 14 (2012) 1476-1479;
(b) J. Wang, B.P. Cary, P.D. Beyer, S.H. Gellman, D.J. Weix, Angew. Chem. Int. Ed. DOI: 10.1002/anie.201906000
[8] (a) W.L. Thomas, M.S. Sanford Chem. Rev. 110 (2010) 1147–1169;
(b) S. Rej, N. Chatani Angew. Chem. Int. Ed. 58 (2019) 8304–8329;
(c) G. Rouquet, N. Chatani, Angew. Chem. Int. Ed. 52 (2013) 11726-117430;
(d) X. Chen, K.M. Engle, D.H. Wang, J.Q. Yu, Angew. Chem., Int. Ed. 48 (2009) 5094−5115;
(e) K.M. Engle, T.S. Mei, M. Wasa, J.Q. Yu, Acc. Chem. Res. 45 (2012) 788−802.
[9] C. Pan, X. Jia, J. Cheng Synthesis 44 (2012) 677–685.
[10] F. Penteado, E.F. Lopes, D. Alves, G. Perin, R.G. Jacob, E.J. Lenardão Chem. Rev. 119 (2019) 7113−7278.
[11] Y. Huang, R. Zhu, K. Zhao, Z. Gu, Angew. Chem. Int. Ed. 54 (2015) 12669-12672.
[12] (a) P. Zhou, Y. Ye, C. Liu, L. Zhao, J. Hou, D. Chen, Q. Tang, A. Wang, J. Zhang, Q. Huang, P. Xu, Y. Liang ACS Catal. 5 (2015) 4927-4931;
(b) P. Mamone, G. Danoun, L.J. Gooβen Angew. Chem. Int. Ed. 52 (2013) 6704-6708.
[13] F. Sun, M.Li, C. He, B. Wang, B. Li, X. Sui, Z. Gu, J. Am. Chem. Soc. 138 (2016) 7456-7459.
[14] C.L. Joe, A.G. Doyle, Angew. Chem. Int. Ed. 55 (2016) 4040-4043.
[15] (a) M.Z. Zhang, Q. Chen, G.F. Yang, Eur. J. Med. Chem. 89 (2015) 421−441;
(b) A.J. Kochanowska-Karamyan, M.T. Hamann, Chem. Rev. 110 (2010) 4489−4497;
(c) G.R. Humphrey, J.T. Kuethe, Chem. Rev. 106 (2006) 2875-2911;
(d) H.F. Motiwala, R.H. Vekariya, J. Aubé, Org. Lett. 17 (2015) 5484-5487;
(e) X. Wang, Z. Li, S. Cao, Adv. Synth. Catal. 358 (2016) 2059-2065.
(f) C. Shao, Z. Wu, X. Ji, B. Zhou, Y. Zhang, Chem. Commun. 53 (2017) 10429-10432.

5
Highlight:




Intramolecular C–H acylation of indoles with thioester
Gram-scale synthesis of indole-indolone scaffolds
Up to 94% yields
Compatibility with aryl bromide
Graphical Abstract
Leave this area blank for abstract info.
Palladium-catalyzed Intramolecular C–H Acylation of Indoles with Thioester
Min Liu, Yu-Wen Liu, Hui Xu and Hui-Xiong Dai
H
R
Pd(PPh3)4 (10 mol%)
DPPPe (20 mol%)
O
SEt
R
N
N
O
CuTC, DMSO, 90 o
C
C-H acylation of indoles with thioester
Gram-scale synthesis
Up to 94% yields
Compatibility with aryl bromide