Rhodium-catalyzed C–H functionalization of heteroarenes using indoleBX hypervalent iodine reagents

Article abstract of DOI:10.3762/bjoc.14.102

The C–H indolation of heteroarenes was realized using the benziodoxolone hypervalent iodine reagents indoleBXs. Functionalization of the C–H bond in bipyridinones and quinoline N-oxides catalyzed by a rhodium complex allowed to incorporate indole rings into aza-heteroaromatic compounds. These new transformations displayed complete regioselectivity for the C-6 position of bipyridinones and the C-8 position of quinoline N-oxides and tolerated a broad range of functionalities, such as halogens, ethers, or trifluoromethyl groups.

Full text of DOI:10.3762/bjoc.14.102

Rhodium-catalyzed C–H functionalization of heteroarenes
using indoleBX hypervalent iodine reagents
Erwann Grenet, Ashis Das, Paola Caramenti and Jérôme Waser*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1208–1214.
Laboratory of Catalysis and Organic Synthesis, Institute of Chemical
Sciences and Engineering, Ecole Polytechnique Fedérale de
Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne,
Switzerland
doi:10.3762/bjoc.14.102
Received: 07 March 2018
Accepted: 09 May 2018
Published: 25 May 2018
Email:
Jérôme Waser* - jerome.waser@epfl.ch
This article is part of the Thematic Series "Hypervalent iodine chemistry in
organic synthesis".
* Corresponding author
Guest Editor: T. Wirth
Keywords:
C–H activation; hypervalent iodine; indoleBX; indoles; pyridinones;
rhodium catalysis
© 2018 Grenet et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The C–H indolation of heteroarenes was realized using the benziodoxolone hypervalent iodine reagents indoleBXs. Functionaliza-
tion of the C–H bond in bipyridinones and quinoline N-oxides catalyzed by a rhodium complex allowed to incorporate indole rings
into aza-heteroaromatic compounds. These new transformations displayed complete regioselectivity for the C-6 position of
bipyridinones and the C-8 position of quinoline N-oxides and tolerated a broad range of functionalities, such as halogens, ethers, or
trifluoromethyl groups.
Introduction
Nitrogen-containing heteroaromatic compounds have valuable other heterocycles, such as a dihydropyrazidinone in hamacan-
properties in medicinal chemistry, pharmacology and func- thine A (4) (Figure 1) [3]. Due to their occurrence in biological-
tional materials. Among those, pyridinone, sometimes called ly active compounds, it is therefore attractive to develop new
pyridone, is a key structural motif of well-known active com- methods to functionalize pyridinones. The introduction of
pounds and natural products (Figure 1) [1]. For example, the further heterocyclic rings, such as indoles, is particularly attrac-
2-pyridinone ring is present in milrinone (1), used to treat heart tive.
failure, while a 4-pyridinone is part of mimosine (2), an alka-
loid isolated from Mimosa pudica. A benzene-fused pyridinone Most of the methods for indolylpyridinone synthesis involve a
– a quinolone – can be found in brexpiprazole (3), a drug used condensation cascade process to generate the pyridinone ring
against schizophrenia. In addition, the indole core is also omni- [4-6]. These methods usually require an electron-withdrawing
present in bioactive compounds [2]. It can be directly bound to group (nitrile, nitro, carbonyl), which ends up on the pyridi-
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Beilstein J. Org. Chem. 2018, 14, 1208–1214.
Figure 1: Bioactive compounds with pyridinone, quinolone and indole cores.
none ring. As alternative, a Suzuki–Miyaura coupling between derivatives in particular [21], have found broad application in
3-halogenoindoles and (2-methoxypyridyl)boronic acids fol- synthetic chemistry. Aryl iodonium salts have been used suc-
lowed by a deprotection of the methoxy group [7,8] or transi- cessfully in transition-metal-catalyzed transformations [22], but
tion-metal-catalyzed annulation methods [9] have also been re- only one application of indole iodonium salts in copper cataly-
ported.
sis by You and co-workers had been reported until 2017 [23]. In
this context, indole-based benziodoxole hypervalent iodine
In contrast, several procedures have been described for the reagents, recently introduced by Yoshikai's and our group [24-
modification of pyridinones to introduce other substituents, 27], appeared ideal partners to develop a new C–H heteroaryla-
especially based on highly efficient C–H functionalization tion of pyridinones.
methods [10]. Very recently, several research groups have
selectively functionalized the C-6 C–H bond by using a Herein, we report the selective C–H heteroarylation of the C-6
2-pyridyl directing group on the nitrogen and a transition metal position of bipyridinones by a rhodium-catalyzed reaction with
catalyst (reaction 1, Scheme 1A) [11-19]. In particular, Li and indoleBX (reaction 2, Scheme 1A). In addition, we demon-
co-workers have used ethynylbenziodoxolone (EBX) hyperva- strate that the mild conditions developed allow the heteroaryla-
lent iodine reagents to achieve a regiodivergent alkynylation of tion of the C-8 position of quinoline N-oxides, whereas forma-
the pyridinone core employing either a gold(I) or a rhodium(III) tion of the quinolinone had been observed in our previous work
catalyst for C-5 and C-6 functionalization, respectively [13]. (Scheme 1B). The obtained products combine up to three
Hypervalent iodine reagents in general [20], and benziodoxole classes of privileged heterocycles in medicinal chemistry in a
Scheme 1: C–H functionalization of pyridinones and quinoline N-oxides.
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Beilstein J. Org. Chem. 2018, 14, 1208–1214.
single compound, and are therefore expected to be highly use- and the poorly stable (1H-indol-3-yl)(phenyl)iodonium tetra-
ful building blocks in the search for new bioactive compounds. fluoroborate [23] (10, Table 1, entry 10) did not lead to the for-
mation of 7a, highlighting the unique reactivity of the benzio-
Results and Discussion
We started the studies on C–H indolation with the optimization
doxolone hypervalent iodine reagent.
of the reactions conditions (Table 1) for the coupling of [1,2'- The scope and limitations of the reaction were then studied
bipyridin]-2-one (5a) with Me-indoleBX 6a, easily obtained (Scheme 2). The diversification of the directing group was ex-
from commercially available 1-methylindole and 2-iodoben- amined first. The unsubstituted pyridine group led to the forma-
zoic acid [24]. While the reaction conditions previously de- tion of product 7a in 86% yield. The electron-rich 5-methoxy-
veloped in our group for the C–H functionalization of 2-phenyl- pyridine and the electron-poor 5-trifluoromethylpyridine
pyridine [24] failed for the coupling of 5a with 6a (Table 1, directing groups gave products 7b and 7c in 82% and 72%
entry 1), we were pleased to see that addition of 0.15 equiv yield, respectively. When a nitro group was present on the pyri-
Zn(OTf)2 allowed a full conversion to the desired product 7a in dine (5d), the product was not observed, probably due to a
86% yield (Table 1, entry 2). The Lewis acid is supposed to weaker coordination of the nitrogen on the pyridine. Pyrimi-
weaken the O–I bond by coordination of the carboxy group in dine could not be used as directing group (5e), confirming what
6a. No base was required in this case. The reaction was com- has already been reported by others authors [13]. Quinoline 7f
pletely selective for the C-6 position of the pyridinone ring. was obtained in 79% yield. Concerning the pyridinone core,
Control experiments pointed out that both Lewis acid (Table 1, both an electron-donating methyl group and electron-with-
entry 3) and AgSbF6 as additive (Table 1, entry 4) were neces- drawing trifluoromethyl and fluoro groups (7g–i) were well
sary for an efficient reaction. The transformation was tolerant to tolerated in the C-3 position. However, the strong electron-with-
air (Table 1, entry 5). However, more byproducts were ob- drawing CF3 group resulted in a lower 65% yield (7h). This ob-
served. Decreasing the temperature (Table 1, entry 6) or the servation is also true for the C-4 position. Indeed, products 7j–l
catalyst loading (Table 1, entry 7) resulted in lower yields. were synthesized in 78% yield for a methyl, 66% yield for a tri-
Finally, three control experiments with 1-methylindole (8, fluoromethyl and 84% yield for a benzyloxy substituent. As
Table 1, entry 8), 3-iodo-1-methylindole (9, Table 1, entry 9) previously reported [13], 5-substituted pyridinone 5m could not
Table 1: Optimization of the C–H heteroarylationa,b.
Entry
1
Changes from conditions
Yield (%)
[RhCp*Cl2]2 (2.5 mol %),
AgSbF6 (0.10 equiv),
NaOPiv (0.10 equiv),
DCE, 12 h, 50 °C
no reaction
2
–
86
3
without Zn(OTf)2
without AgSbF6
under air atmosphere
60 °C
no reaction
4
60
5
80
6
48
7
1 mol % of [RhCp*Cl2]2
1-methylindole (8)
3-iodo-1-methylindole (9)
iodonium salt 10
75
8
no reaction
9
0c
0c
10
aReactions conditions: 5 (0.20 mmol), 6 (0.20 mmol), [RhCp*Cl2]2 (3.7 mg, 6.0 µmol, 3 mol %), AgSbF6 (10.3 mg, 30.0 µmol, 0.15 equiv), Zn(OTf)2
(10.9 mg, 30.0 µmol, 0.15 equiv), methanol (2.0 mL) at 80 °C for 12 h. bIsolated yield after preparative TLC. cDecomposition.
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Beilstein J. Org. Chem. 2018, 14, 1208–1214.
Scheme 2: Scope and limitations of the Rh-catalyzed C–H activation of [1,2'-bipyridin]-2-one.
be functionalized. Isoquinolone 7n was prepared in 82% yield. We also applied these conditions to different quinoline N-oxides
The methodology could also be applied to 4-pyridone in a mod- (Scheme 3). This class of substrates had also been used for C–H
erate 57% yield for product 7o. Unfortunately, pyrazin-2-one 5p alkynylation using EBX reagents [28]. During our previous
could not be functionalized. Modification of the hypervalent work, we had attempted the C8-heteroarylation of quinoline
iodine reagent was then investigated with three selected com- N-oxide with Me-indoleBX 6a. However, the transformation re-
pounds only. A bromo substituent on the benzene ring was well quired a temperature of 100 °C, leading to the formation of the
tolerated (7q). The coupling could be also performed with N–H corresponding isoquinolone in only 38% yield [24]. By employ-
unprotected indoleBX reagents to afford products 7r and 7s in ing the milder conditions developed for pyridinones, we were
84% and 77% yield, respectively.
pleased to see that the N-oxide group could be preserved and
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Beilstein J. Org. Chem. 2018, 14, 1208–1214.
Scheme 3: Scope of the Rh-catalyzed peri C–H activation of quinoline N-oxides.
product 12a was obtained in 60% yield. A methyl substitution Zn(OTf)2 as Lewis acid. The reaction could also be applied to
in C-2 position gave the product 12b in 66% yield. In C-6 posi- functionalize one pyridin-4-one in C-6 position, one isoquinoli-
tion both a methoxy and a phenyl group were well tolerated none in C-3 position and quinoline N-oxides in C-8 position.
giving 57% and 73% yield of products 12c and 12d.
After cleavage of the directing group or rearrangement of the
N-oxide function, we were able to access 6-(indol-3-yl)pyridi-
The pyridine directing group could be cleaved by alkylation of none and 8-(indol-3-yl)quinolone. The developed transformat-
the pyridine nitrogen using methyl triflate followed by reduc- ions give access to important heterocyclic building blocks for
tion with sodium cyanoborohydride to deliver the N–H unpro- synthetic and medicinal chemistry and set the stages for the de-
tected pyridinone 13 in 74% yield (Scheme 4) [29]. A rear- velopment of other C–H heteroarylation processes based on
rangement of the N-oxide furnished the corresponding indoleBX reagents.
isoquinolone 14 in 62% yield.
Experimental
Conclusion
General procedure for C–H heteroarylation
In summary, we have developed the C-6 selective C–H In a sealed tube, [RhCp*Cl2]2 (3.7 mg, 6.0 µmol, 3 mol %),
heteroarylation of pyridin-2-ones using indoleBXs as coupling AgSbF6 (10.3 mg, 30.0 µmol, 0.15 equiv), Zn(OTf)2 (10.9 mg,
partners, [RhCp*Cl2]2 as catalyst, AgSbF6 as co-catalyst and 30.0 µmol, 0.15 equiv), the corresponding pyridinone or quino-
Scheme 4: Product modifications.
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hypervalent iodine reagent (0.20 mmol, 1.00 equiv) were solu-
bilized in dry MeOH (2.0 mL, 0.1 M) under N2 atmosphere.
The mixture was stirred at 80 °C for 12 h. The mixture was then
diluted with DCM (5 mL) and quenched with a saturated
aqueous solution of NaHCO3 (5 mL). The two layers were sep-
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(5 mL). The organic layers were combined, dried over magne-
sium sulfate dehydrate, filtered and concentrated under reduced
pressure. The crude residue was purified by preparative TLC
using DCM/MeOH to afford the pure desired compound.
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This work is supported by the ERC starting grant 334840,
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