Cp*IrIII-Catalyzed [3+2] Annulations of N-Aryl-2-aminopyrimidines with Sulfoxonium Ylides to Access 2-Alkyl Indoles Through C–H Bond Activation

Article abstract of DOI:10.1002/ejoc.201900495

The iridium-catalyzed aromatic C–H alkylation followed by intramolecular annulation reactions between N-aryl-2-aminopyridines and sulfoxonium ylides for the synthesis of 2-alkyl indoles is described. This highly efficient and step-economical cyclization r

Full text of DOI:10.1002/ejoc.201900495

A Journal of
Accepted Article
Title: Cp*Ir(III)-Catalyzed [3+2] Annulations of N-Aryl-2-
aminopyrimidines With Sulfoxonium Ylides to Access 2-Alkyl
Indoles through C-H Bond Activation
Authors: Yi Luo, Lingmei Guo, Xinling Yu, Haosheng Ding, Huijing
Wang, and Yong Wu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900495
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10.1002/ejoc.201900495
European Journal of Organic Chemistry
COMMUNICATION
Cp*Ir(III)-Catalyzed [3+2] Annulations of N-Aryl-2-
aminopyrimidines With Sulfoxonium Ylides to Access 2-Alkyl
Indoles through C-H Bond Activation
Yi Luo,[a] Lingmei Guo,[a] Xinling Yu,[a] Haosheng Ding,[a] Huijing Wang,*[b]and Yong Wu*[a]
Dedication ((optional))
Abstract: The iridium-catalyzed aromatic C-H alkylation followed by
intramolecular annulation reactions between N-aryl-2-aminopyridines
and sulfoxonium ylides for the synthesis of 2-alkyl indoles is
described. This highly efficient and step-economical cyclization
reaction displays excellent functional group compatibility and
regioselectivity. Afterwards, the directing group in C-H alkylation can
be readily removed to obtain the free N-H indoles. Thus, the
sulfoxonium ylide, a carbene precursor, is proved as a useful
surrogate of diazo compounds in C-H activation chemistry.
as the atomic and step economy.[5] In 2008, Fagnou and.
coworkers reported a novel rhodium-catalyzed oxidative reaction
to synthesize substituted indoles from acetanilides and internal
alkynes via C-H activation.[6] Inspired by this work, various
elegant strategies have been reported for constuctiong the
indole skeleton. Untill now, besides alkynes,[7] alkenes,[8] and
diazo[9] compounds have also been reported as efficient
coupling partners (Scheme 1). However, most of synthetic
approaches require oxidants to induce catalytic turnovers. Thus,
development of oxidant-free and mild methods to prepare 2-alkyl
indole framework efficiently is still desirable.
Introduction
2-Alkyl indoles are important structural motifs because of their
abundance in natural products and drugs,[1,2] such as
Umifenovirl and Efipladib (Figure 1), which have attractive
pharmacological and biological activities.[3] Consequently, the
synthesis of 2-alkyl indole nucleus have been intensively
investigated.The synthesis of indoles are well studied.[4]
However, due to the non-commercial starting materials used in
these previously developed reactions, the application of these
methodologies are limited .
Scheme 1. Indoles synthesis on C-H activation
Figure 1.Examples of indole derivatives in bioactive drugs.
In recent years, sulfoxonium ylides have been sutdied as
alternative carbenoid precursors for C-H activation.[10] In contrast
with diazo compounds, sulfoxonium ylides are safer to handle
and generate non-volatile DMSO as byproduct within mental-
carbenoid insertion reaction.[11] In 2017, Li and coworkers
reported sulfoxonium ylide as carbene precursor in Rh(III)-
Catalyzed C−H acylmethylation of arene.[12] Subsequently, using
sulfoxonium ylides as C2 or C1 synthon with homogeneous
rhodium, iridium or ruthenium as the catalysts, a number of
In the past few years, transition metal-catalyzed C-H activation
has been well explored, because of its outstanding merits such
[a]
Y. Luo, L. Guo, Dr. X. Yu, H. Ding and Prof. Dr. Y. Wu.
Key Laboratory of Drug-Targeting of Education Ministry and
Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan University, Chengdu, 610041, P. R. of China.
E-mail: wyong@scu.edu.cn
condensed
heterocycles
such
as
isoquinolones,10
isocoumarins,[13] naphthols,[14] indazoles[15] and indoles[16] were
achieved via ortho C-H activation/annulation. Yet, to the best of
our knowledge, the use of sulfoxonium ylides for the synthesis of
2-alkyl indoles remains is underdeveloped and Cp*Ir(III) catalysts
have not been used. Inspired by previous works in our group,[17]
we disclose a novel methodology for efficient synthesis of indole
[b]
Dr. H. Wang
Skaggs School of Pharmacy and Pharmaceutical Sciences,
University of California, San Diego, 9500 Gilman Drive, La Jolla,
California 92093-0934, United States.
Email: huw026@ucsd.edu
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10.1002/ejoc.201900495
European Journal of Organic Chemistry
COMMUNICATION
derivatives from N-aryl-2-aminopyrimidines and sulfoxonium
ylides via Cp*Ir(III)-catalyzed direct C-H activation/annulation.
(Table 1, entry 7) was found to improve the yield from 30% to
71%, while other tested solvent, such as H2O, THF and HFIP
provided inferior results (Table 1, entries 6-9). Also, The
addition of HOAc led to much higher yield (see ESI, Table S1,
entries 16-19), indicating that additive played a crucial role to
this reaction. To our delight, the combination solevnts EtOH and
HOAc (3:1 v/v) were found to producea satisfying result (85%
yield of 3aa, Table 1, entry 12).
Subsequently, we examined the substrate scope of arylamines
in the C-H alkylation reaction using the optimized reaction
condition. As shown in Table 2, N-aryl-2-aminopyridines
derivatives with various electron-donating (1b, 1c, 1g, 1h, 1k, 1l)
andelectron-withdrawing (1d-1f, 1i, 1j, 1m, 1n) groups at
different positions of the phenyl ring generated the desired 2-
alkyl indoles in moderate to high yields (from 74% to 86%). For
instance, methyl, methoxy at the meta- or ortho- of the benzene
ring performed well under standard condition and offered the
corresponding indole products 3ga-3la in 78%-82% yields.
Furthermore, a wide spectrum of functional groups, including Cl-
(1d, 1i, 1m), Br- (1e, 1j, 1n), trifluoromethyl (1f), 2.3-dimethyl
(1o), and 2.4-dimethyl (1p) were well tolerated, offering valuable
synthetic handles for further derivatization. Besides pyrimidine,
other N-containing heterocycles, such as pyrazine (1q),
pyridazine (1r), and pyridine (1s) could also act as chelating
group in this C-H activation/annulation reaction, providing the
corresponding products in good yields.
Results and Discussion
With N-(2-pyrimidyl)aniline and tert-butyl sulfoxonium ylides as
precursor, we investigated the aromatic C-H alkylation reaction,
employing 1a and 2a, as model reaction. The initial experiment
using Cp*Rh(MeCN)3(SbF6)2 (5 mol%) as catalyst under Ar
atmosphere, at 100 °C in DCE for 24 h gave the desired product
3aa in 18% yield (Table 1, entry 1). After experiments with
different catalysts such as [Cp*RhCl2]2, [Cp*CoI2]2, Ru(p-
cymene)Cl2 and [IrCp*Cl2]2, an improved yield (30%) was
achieved when [IrCp*Cl2]2 was used as the catalyst (Table 1,
entries 2-5). Encouraged by this outcome, we investigated the
effect of various Ag salts. AgNTf2 was identified as the most
effective among great set of representative silver(I) additives (SI,
Table S1, entries 5-8). Further condition screening revealed
that solvent had a remarkable influence on the conversion. EtOH
Table 1. Optimization for Reaction Conditions.[a]
Table 2. Scopes of arylamines and directing groups.[a][b]
entry
cat.
solvent
DCE
Yield [b]
1
Cp*Rh(MeCN)3(SbF6)2
18%
2
3
4
[Cp*RhCl2]2
DCE
DCE
DCE
trace
N.R
N.R
[Cp*CoI2]2
Ru(p-cymene)Cl2
5
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
DCE
THF
30%
60%
71%
58%
52%
77%
81%
85%
80%
6
7
EtOH
H2O
8
9
HFIP
EtOH
EtOH
EtOH
EtOH
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.45 mmol), [IrCp*Cl2]2 (5 mol%),
AgNTf2 (20.0 mol%) in 2 mL EtOH/HOAc (3/1, v/v) at 100 °C for 24 h under the
argon. [b] Isolated yield.
10 [c]
11 [d]
12 [e]
13 [f]
[a]
We then investigated the scope of the sulfoxonium ylides in this
coupling reation (Table 3). Sulfoxonium ylides bearing alkyl
substituents such as isopropy, ethyl, propyl and butyl (2b-2e),
gave moderate to high yields of corresponding products 3ab-3ae
respectively. Meanwhile, sulfoxonium ylides with benzyl
substituents also performed successfully, with 65% to 70%
yields (3af-3ah). Finally, we also tried aryl-substituted
sulfoxonium ylides in this reaction under the standard conditions.
And we got corresponding products in a low yield (3ai).
Reaction conditions: 1a (0.25mmol), 2a (0.45 mmol, 1.8 equiv.),
[IrCp*Cl2]2 (5 mol%), Ag Salt (20 mol%), in solvent (2 mL). [b] Isolated
[c]
[d]
[e]
yield.
EtOH:HOAc = 10:1 (v/v).
EtOH:HOAc = 5:1 (v/v).
EtOH:HOAc = 3:1 (v/v). [f] EtOH:HOAc = 2:1 (v/v).
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10.1002/ejoc.201900495
European Journal of Organic Chemistry
COMMUNICATION
coordination of sulfoxonium ylides generates intermediate B,
which undergoes the α-elimination of DMSO to give a reactive
carbene species C. The subsequent migratory insertion provides
the corresponding six-membered intermediate D, followed by the
protonolysis of Ir-alkyl bond by HOAc to release the intermediate
E and regenerates active catalyst to participate the next catalytic
Table 3. Scopes of sulfoxonium ylides.[a][b]
cycle. Enol intermediate
F is formed through ketoenol
tautomerization, and the final product 3aa was furnished by a
dehydration process.
[a]
Reaction conditions: 1a (0.25 mmol), 2a (0.45 mmol), [IrCp*Cl2]2 (5
mol%), AgNTf2 (20.0 mol%) in 2 mL EtOH/HOAc (3/1, v/v) at 100 °C for 24
h under the argon. [b] Isolated yield.
After the exploration of Cp*Ir(III)-catalyzed [3+2] annulation to
generate 2-alkyl indoles 3, we investigated its usefulness in
preparing N-H free indole. The directing in the product 3aa could
be readily removed by treatment of t-BuOK in DMSO at 110 °C
for 24h, obtaining the N-H free indole (4a) in 82% yield
( scheme 2).
Scheme 4. Proposed mechanism.
Conclusions
In conclusion, the Cp*Ir(III)-catalyzed [3+2] annulations of N-
aryl-2-aminopyrimidines and sulfoxonium ylides to access 2-
alkyl indoles via C-H bond activation was successfully
developed for the first time. This highly efficient and step-
economical cyclization reaction features excellent functional
group compatibility and regioselectivity. The sulfoxonium ylides
are served as carbene precursors, but also useful surrogates of
the well explored diazo compounds in C-H activation chemistry.
In addition, free N-H indoles could be easily obtained by removel
of the pyridyl directing group. We believe this synthetic
methodology to efficiently produce 2-alkyl indoles with multiple
handles for further derivation has strong potential to be applied
in the synthetic and pharmaceutical industry.
Scheme 2. Deprotection of directing group to synthesize free N-H
functionalized indoles.
To gain insight into the reaction mechanism, a kinetic
isotope effect experiment was carried out. KIE value was
determined to be 1.6 (Scheme 3), which indicated that the
cleavage of the C-H bond is likely not involved in the
turnover-limiting step.
Experimental Section
Scheme 3. KIE experiment
General procedure for the synthesis of 3aa
A sealed tube was charged with [IrCp*Cl2]2 (5mol% , 6.98 mg), AgNTf2
(0.2 eq, 13.6 mg), N-(2-pyrimidyl)aniline 1a (0.25 mmol), sulfoxonium
ylide 2a (0.45 mmol),argon and EtOH/HOAc (3/1, v/v, 2mL). The reaction
mixture was stirred at 100 °C for 24 h under the argon. After that, the
solvent was removed under reduced pressure and the residue was
Based on these results and previous related studies,[18] the
mechanism outlines the formation of compound 3aa (Scheme 4).
First, the iridium complex is activated by AgNTf2 to generate
electrophilic cationic complex Cp*Ir(III), which participates in the
C-H cleavage to obtain intermediate A. Subsequently, the
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10.1002/ejoc.201900495
European Journal of Organic Chemistry
COMMUNICATION
purified by silica gel chromatography by using PE/EA (100:1) to afford
the product 3aa (yield: 85%).
[13] Y. Xu, G. Zheng, X. Yang, X. Li, Chem. Commun. 2018, 54, 670-673.
[14] a) P. Hu, Y. Zhang; Y. Xu, S. Yang; B. Liu, X. Li, Org. Lett. 2018, 20,
2160-2163. (b) C. Zhou, F. Fang, Y. Cheng, Y. Li, H. Liu, Y. Zhou, Adv.
Synth. Catal. 2018, 360, 2546-2551.
[15] H. Oh, S. Han, A. K. Pandey, S. H. Han,N. K. Mishra, S. Kim, R.; Kim,
H. S. Chun, J. Park, I. S. Kim, J. Org. Chem. 2018, 83, 4070-4077.
[16] a) Z. Shen, C. Pi, X. Cui, Y. Wu, Chin. Chem. Lett. DOI:
10.1016/j.cclet.2019.01.033. b). X. Cui, Z. Ban, W. Tian, F. Hu, X. Zhou,
H. Ma, Z. Zhan, G. Huang, Org. Biomol. Chem., 2019, 17, 240–243.
[17] R. Lai, X. Wu, S. Lv, C. Zhang, M. He, Y. Chen, Q. Wang, L. Hai, Y. Wu,
Chem. Common., 2019, 55, 4039-4042.
Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (NSFC) (grant number 81573286,
81773577).
[18] C. Liu, M. Liu, L. Dong, J. Org. Chem. 2019, 84, 409-416.
Keywords: Indole Derivates • C-H activation • [3+2] Annulations
• sulfoxonium ylides • Ir-Catalyzed
[1]
a) T. J. Maimone, Y. Ishihara, P.S. Baran, Tetrahedron 2015, 71, 3652-
3665. b) S. M. Allin, C. I. Thomas, J. E. Allard, K. Doyle, M. R. J.
Elsegood, Tetrahedron Letters 2004, 45, 7103-7105.
[2]
a) X. Chen, L. Si, D. Liu, P. Proksch, L. Zhang, D. Zhou, W. Lin, Eur. J.
Med. Chem 2015, 93, 182-195. b) E. -M. Karg, S. Luderer, C. Pergola,
U. Bühring, A. Rossi, H. Northoff, L. Sautebin,R. Troschütz, O. Werz, J.
Med. Chem. 2009, 52, 3474-3483. c) I. Kumar, R. Kuamr, U. Sharma,
Synthesis 2018, 50, 2655-2677.
[3]
[4]
a) J. Gonda, M. Široký, M. Martinková, S. Homolya, M. Vilková, M. B. Pil
átová, S. Sesták, Tetrahedron 2019, 75, 398-408. b) C. J. Trabbic, H. M.
Dietsch, E. M. Alexander, P. I. Nagy, M. W. Robinson, J. H. Overmeyer,
W. A. Maltese, P. W. Erhardt, ACS Med. Chem. Lett. 2014, 5, 73-77.
a) E. L. Noey, Z. Yang, Y. Li, H. Yu, R. N. Richey, J. M. Merritt, D. P.
Kjell, K. N. Houk, J. Org. Chem. 2017, 82, 5904-5909. b) S. A. D.
Ghumro, R. D. Alharthy, M. al-Rashida, S. Ahmed, M. I. M. Malik, A.
Hameed, ACS Omega 2017, 2, 2891-2900. c) G. Bartoli, R. Dalpozzo,
M. Nardi, Chem. Soc. Rev. 2014, 43, 4728-4750. d) M. M. Heravi, S.
Rohani, V. Zadsirijan, N. Zahedi, RSC Adv. 2017, 7, 52852-52887. e) H.
Vuong, S. D. A. Duarte,Topics in Catalysis 2018, 61, 685-688.
a) J. He, M. Wasa, K, S. L. Chan, Q. Shao, J. Yu, Chem. Rev. 2017,
117, 8754-8786. b) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017, 117,
9247-9301. c) R. Vicente, A. R. Kapdi, L. Ackermann, Angew. Chem.
Int. Ed. 2009, 48, 9792-9826. d) L. McMurray, F. O’Hara, M. J. Gaunt,
Chem. Soc. Rev. 2011, 40,1885-1898. e) W. Ma, P. Gandeepan, J. Li,
L. Ackermann, Org. Chem. Front. 2017, 4, 1435-1467. f) J. Wencel-
Delord, F. Glorius, Nat. Chem. 2013, 5, 369-375.
[5]
[6]
[7]
D. R. Stuart, M. Bertrand-Laperle, K. M. N. Burgess, K. Fagnou, J. Am.
Chem. Soc. 2008, 130, 16474-16475.
G. N. Hermann, C. L. Jung, C. Bolm, Green Chem. 2017, 19, 2520-
2523. b) B. Liu, C. Song, C. Sun, S. Zhou, J. Zhu, J. Am. Chem. Soc.
2013, 135, 16625-16631. c) A. Lerchen, S. Vásquez‐Céspedes, F.
Glorius, Angew. Chem. Int. Ed. 2016, 55, 3208-3211. d) A. V. Lygin, L.
Ackermann, Org. Lett. 2012, 14, 764-767. e) J. Chen, G. Song, C. Pan,
X. Li, Org. Lett. 2010, 12, 5426-5429. f) C. Wang, H. Sun, Y. Fang, Y.
Huang, Angew. Chem. Int. Ed. 2013, 52, 5795-5798. g) D. Zhao, Z. Shi,
F. Glorius, Angew. Chem. Int. Ed. 2013, 52, 12426-12429.
[8]
[9]
a) S. Cai, S. Lin, X. Yi, C. Xi, J. Org. Chem. 2017, 82, 512-520. b) M. K.
Manna, G. Bairy, R. Jana, J. Org. Chem. 2018, 83, 8390-8400.
a) X. Guo, J. Han, Y. Liu, M. Qin, X. Zhang, B. Chen, J. Org. Chem.
2017, 82, 11505-11511. b) Z. Qi, S. Yu, X. Li, Org. Lett. 2016, 18, 700-
703. c) H. Lv, J. Shi, B. Wu, Y. Guo, J. Huang, W. Yi, Org. Biomol.
Chem. 2017, 15, 8054-8058. d) H. Jiang, S. Gao, J. Xu, X. Wu, A. Lin,
H. Yao, Adv. Synth. Catal. 2016, 358,188-194.
[10] (a) R. M. Dias, A. C. B. Burtoloso, Org. Lett. 2016, 18, 3034-3037. b) G.
Zheng, M. Tian, Y. Xu, X. Chen, X. Li, Org. Chem. Front. 2018, 5, 998-
1002.
[11] a) L. Lu, T. Li, Q. Wang, W. Xiao, Chem. Soc. Rev. 2017, 46, 4135-
4149. b) I. A. Leonarczyk, R. M. P. Dias, A. C. B. Burtoloso, Eur. J. Org.
Chem. 2013, 5005-5016.
[12] Y. W. Xu, X. Zhou, G. Zheng, X. Li; Org. Lett. 2017, 19, 5256-5259.
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COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Indole Derivates • C-H activation •
[3+2] Annulations • sulfoxonium
ylides • Ir-Catalyzed
Yi Luo, Lingmei Guo, Xinling Yu,
Haosheng Ding, Huijing Wang,*and
Yong Wu*
We have developed a novel synthesis of 2-alkyl indoles that used N-aryl-2-
aminopyrimidines and sulfoxonium ylides. It was an efficient, mild method for the
synthesis of 2-alkyl indoles. We used cleaner solvent, effcient alternative carbenoid
precursors and novel catalyst system to complete this reaction. Many different
directing groups can be used in this process, and the reaction tolerates a variety of
functional groups. We believe this synthetic methodology to efficiently produce 2-
alkyl indoles with multiple handles for further derivation has strong potential to be
applied in the synthetic and pharmaceutical industry
Page No. – Page No.
Cp*Ir(III)-Catalyzed [3+2] Annulations
of N-Aryl-2-aminopyrimidines With
Sulfoxonium Ylides to Acess 2-Alkyl
Indoles through C-H Bond Activation
*C-H activaon/annulation
[a]
[b]
Key Laboratory of Drug-Targeting of Education Ministry and
Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan University, Chengdu, 610041, P. R. of
E-mail: wyong@scu.edu.cn
Skaggs School of Pharmacy and Pharmaceutical Sciences,
University of California, San Diego, 9500 Gilman Drive, La J
California 92093-0934, United States.
Email: huw026@ucsd.edu
Supporting information for this article is given via a link at th
the document.((Please delete this text if not appropriate))
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