Indole- and Pyrrole-BX: Bench-Stable Hypervalent Iodine Reagents for Heterocycle Umpolung

Article abstract of DOI:10.1002/chem.201703723

The one-step synthesis of the bench-stable hypervalent iodine reagents IndoleBX and PyrroleBX using mild Lewis acid catalyzed conditions is reported. The new reagents are stable up to 150 °C and were applied in the C?H arylation of unactivated arenes using either rhodium or ruthenium catalysts. A broad range of heterocyclic systems of high interest for synthetic and medicinal chemistry was accessed in high yields. The developed C?H functionalization could not be achieved using reported reagents or methods, highlighting the unique reactivity of Indole- and Pyrrole-BX.

Full text of DOI:10.1002/chem.201703723

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Accepted Article
Title: Indole- and Pyrrole-BX: Bench-Stable Hypervalent Iodine
Reagents for Heterocycle Umpolung
Authors: Paola Caramenti, Stefano Nicolai, and Jerome Waser
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To be cited as: Chem. Eur. J. 10.1002/chem.201703723
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10.1002/chem.201703723
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Indole- and Pyrrole-BX: Bench-Stable Hypervalent Iodine
Reagents for Heterocycle Umpolung
Paola Caramenti, Stefano Nicolai and JeromeWaser*
Abstract: The one-step synthesis of the bench-stable hypervalent
iodine reagents IndoleBX and PyrroleBX using mild Lewis acid
catalyzed conditions is reported. The new reagents are stable up to
150 °C and were applied in the C-H arylation of unactivated arenes
using either rhodium or ruthenium catalysts. A broad range of
heterocyclic systems of high interest for synthetic and medicinal
chemistry was accessed in high yields. The developed C-H
functionalization could not be achieved using reported reagents or
methods, highlighting the unique reactivity of Indole- and Pyrrole-BX.
Recently, more stable indole and pyrrole iodonium salts were
reported by Moriyama and co-workers[8] and Kita and co-
workers[9] respectively, based on the introduction of an electron-
withdrawing group on the nitrogen. The electrophilic character of
these reagents was used for direct reactions with nucleophiles,
such as alkyl lithium reagents,[7c] azides,[10a] amines[10b] and
electron-rich arenes.[9] There is only one report on the use of
indole iodonium salts involving a transition metal: the copper-
catalyzed de-aromatization of indoles reported by You and co-
workers.[11] This stands in stark contrast with the hundreds of
transformations reported for other aryl iodonium salts,[6] and is
probably due to the lower stability of indole and pyrrole iodonium
salts in presence of metals and/or at higher temperature.
Pyrrole and indole heterocycles are omnipresent in natural and
synthetic biologically active compounds and have found countless
applications in the pharmaceutical and agrochemical industries.[1]
Therefore, synthetic chemists have invested unceasing efforts
towards their synthesis and functionalization.[2] As indoles and
pyrroles are highly nucleophilic, the broad majority of
functionalization methods is based on reactions with electrophiles,
which limits the structural diversity of compounds in medicinal
chemistry studies. In order to allow indoles and pyrroles to react
with nucleophiles and discover new chemical space, an
Umpolung of the innate reactivity of the heterocycles would be
highly useful. However, accessing electrophilic indole and pyrrole
synthons constitutes a formidable challenge. Most approaches
rely on the substitution of the heterocycles with one or several
electron-withdrawing groups or on reactive electrophilic indolyl
intermediates generated in situ.[3] More stable halogenated
indoles have been used only in cross-coupling reactions with
activated partners.[4] Clearly, the development of better indole and
pyrrole electrophilic synthons combining high reactivity with
enhanced stability is needed.
In this context, hypervalent iodine reagents are recognized
for their high reactivity, which can lead to the formal Umpolung of
functional groups.[5] The introduction of reactive yet stable aryl
iodonium salts (Scheme 1A) has led to the development of
broadly applicable arylation reactions.[6] Nevertheless, there are
only few reports on indole and pyrrole-based iodonium salts.
Pioneering works by Neiland, Kost, Moriarty and co-workers
required a multi-step procedure via a potentially explosive betaine
intermediate to access NH unprotected indole iodonium salts.[7]
Scheme 1. Aryliodonium salts, benziodoxolones and Indole/Pyrrole-BX
reagents.
The enhanced stability of cyclic hypervalent iodine reagents,
in particular those obtained from 2-iodobenzoic acid and its
derivatives – the benzidoxol(on)es - has been established since
several decades (Scheme 1B).[12] The use of reagents such as
benziodoxolones
1-3
in
group-transfer
reactions
(trifluoromethylation, alkynylation and azidation) has been
investigated only more recently.[13] In the short time since their
introduction, they have already had a strong impact in the fields
of synthetic and medicinal chemistry. Aryl benziodoxolones 4
have also displayed enhanced stability and are easily accessible,
but they have not found broad application in synthesis.[14] Indeed,
in most reactions with nucleophiles, the benzoic acid group is
transferred, limiting the scope of those transformations.[14c,15]
There is no report on indole or pyrrole based benziodoxol(on)e
[a]
Paola Caramenti, Dr. Stefano Nicolai and Prof. Dr. Jerome Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fédérale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (CH)
Fax: (+)41 21 693 97 00
E-mail: jerome.waser@epfl.ch
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201703723
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reagents, however, and the strongly acidic or oxidizing methods
used for the introduction of other aryl groups cannot be used for
these more sensitive heterocycles.
Free NH IndoleBX 9b could be also synthesized in 78%
yield starting from N-silylated indole (Figure 1). The hypervalent
structure of this compound was confirmed by X-ray analysis.[18]
Different alkyl groups on the nitrogen were well tolerated (9c-e).
Herein, we report the first synthesis of pyrrole- and indole-
based benziodoxolone reagents in one step from the heterocycles, Reagent 9f bearing a C2-substituted indole was also obtained in
based on a mild zinc-catalyzed direct iodonium transfer from
acetoxy benziodoxolone (5) (Scheme 1C). The new reagents are
air- moisture- and thermally stable. They were applied in the
directed ortho C-H functionalization of arenes using rhodium and
ruthenium catalysts, resulting in bond formations that could not be
achieved using reported methods and reagents.
good yield, but no conversion was observed with C3-substitution.
Arenes bearing ethers (9g), halogens (9h-j) and a sensitive
boronic ester (9k) could also be used. Reagent 9l derived from a
less reactive azaindole was still isolated in 30% yield. PyrroleBX
9m-q were also successfully synthesized. When starting from N-
silylated pyrrole, a complete C3 regioselectivity was achieved
(9m). When methyl-and benzyl-pyrrole where used as substrates,
mixtures of separable C2:C3 functionalized reagents were
obtained. The availability of both isomers in pure form opened the
way for the selective synthesis of C2- or C3- functionalized
pyrroles by reaction with nucleophiles. The synthesis of new
pyrrole and indole electrophilic synthons is especially important,
as none of the currently available reagents can be used in C-H
functionalization reactions, in contrast to other classes of
heterocycles. Nevertheless, the use of other electron-rich
aromatic compounds could also be envisaged. Indeed, carbazole-
BX 9r, thiophene-BX 9s and furan-BX 9t were also obtained in
low to moderate yields without further optimization.
To access the targeted Indole- and Pyrrole-BX reagents, we
first applied recently reported methods for aryl benziodoxolone
synthesis based on the oxidation of iodobenzoic acid (6) followed
by reaction with N-methyl indole (8a) in presence of triflic or
sulfuric acid (Table 1, entries 1-2).[14] However, only
decomposition of the indole was observed. To avoid the use of
oxidants, iodine(III) precursors were then examined. Starting from
hydroxy benziodoxolone 7 with trimethylsilyl triflate (TMSOTf) as
activating agent,[16] decomposition was still occurring (entry 3). If
a lower amount of TMSOTf was used, no conversion was
observed (entry 4). A promising result was obtained with acetoxy
benziodoxolone 5 as precursor: the desired indole-BX could be
obtained in 16% yield using 20 mol% of TMSOTf (entries 5 and
6).[17] This compound could be purified by silica gel column
chromatography and was thermally stable up to 150 °C.[18] No
conversion was observed in absence of TMSOTf (entry 7). Better
results were obtained with Zn(OTf)2 and Cu(OTf)2 as Lewis acids
(entries 8 and 9), giving 9a in 36% yield. Changing to
dichloromethane as solvent with Zn(OTf)2 as catalyst, 9a was
obtained in 97% yield with complete C3 selectivity (entry 10). This
synthesis could be easily scaled up to give 9a in 87% yield on the
10 mmol scale (entry 11).
Table 1. Optimization of the synthesis of Indole-BX 9a.
Entry Iodine precursor
Reaction Conditions[a]
Yield[b] (%)
[14b]
1
2
6
6
7
7
5
5
5
5
5
5
5
mCPBA, TfOH, CH2Cl2, then NH3
<5[c]
<5[c]
<5[c]
<5[d]
<5[c]
16
[14c]
Figure 1. Scope of heteroaromatic benziodoxole reagents. Reaction conditions:
1.00 mmol heterocycle, 1.10 mmol 5, 0.200 mmol Zn(OTf)2, 0.05 M in DCM, RT,
open air. Isolated yields. [a] Sc(OTf)3 was used starting from N-TBS heterocycle.
[b] Sc(OTf)3 was used. [c] In(OTf)3 was used.
Oxone, H2SO4, CH2Cl2, then NaHCO3
3
1 equiv TMSOTf, CH3CN, then pyridine
20 mol% TMSOTf, CH3CN
1 equiv TMSOTf, Et2O
20 mol% TMSOTf, Et2O
Et2O
4
5
6
7
<5[d]
Preliminary investigations showed that the reactivity of indole-BX
9a differed from the one of both aryliodonium salts and EBX
reagents (Scheme 2). The reaction of EBX reagents and
aryliodonium salts with thiols, alcohols and stabilized carbon
nucleophiles in presence of base is well established,[19] but no
reaction occurred with 9a. In the case of thiol 10, a moderate yield
of thiol indolation product 11 could be obtained in presence of a
copper catalyst (Scheme 2A). Palladium-catalyzed C-H bond
arylation,[6a,20] was also unsuccessful. In contrast, highly efficient
C-H functionalizations could be developed using either rhodium-
8
20 mol% Zn(OTf)2, Et2O
20 mol% Cu(OTf)2, Et2O
20 mol% Zn(OTf)2, CH2Cl2
20 mol% Zn(OTf)2, CH2Cl2
36
9
36[c]
97
87[e]
10
11
[a] Reactions were performed on 0.10 mmol scale with 1.1 equiv of iodine
precursor. [b] Isolated yield after purification by column chromatography. [c]
Decomposition of N-methylindole (8a) was observed. [d] No conversion of 7 or
8a. [e] Reaction performed on 10 mmol scale.
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or ruthenium catalysts.[21] Importantly, complete and selective
transfer of the indole was obtained to give 13a and 15a, with no
coupling of benzoic acid.
Scheme 2. Preliminary studies of the reactivity of Indole-BX 9a. Reaction
conditions: a) 10, 20 mol% CuOTf•C6H6, CH2Cl2, RT; b) 12, 2.5 mol%
[Rh(Cp*Cl2)]2, 10 mol% NaOPiv, 10 mol% AgSbF6, DCE, 0.1 M, 50 °C; c) 14,
10 mol% Ru[p-cymene(AdCOO)2],[22] trifluoroethanol, 0.1 M, 60 °C. [a] See
supporting Information for detailed reaction conditions.
The latter results are especially interesting, as the introduction of
an indole on a benzene C-H bond in ortho position to a pyridine
or a benzamide has never been reported. This is surprising, as
ortho C-H bond functionalization in arenes is now considered as
a mature field.[23] When considering the high importance of indole
and pyrrole heterocycles in synthetic and medicinal chemistry,
realizing such
a transformation would be an important
breakthrough in the field. We wondered therefore if established
methods for the introduction of indoles onto other types of C-H
bonds could be used to access products 13a and 15a. However,
when reported methods for C-H indolation based on oxidative C-
H/C-H couplings[24-26] with indole 8a or C-H functionalization with
electrophilic indoles 16, 17 and 18,[18] were examined,
compounds 13a and 15a could not be obtained (Scheme 2B).
Therefore, the discovery of Indole-BX reagents allowed new C-H
functionalizations which were not possible before.
The scope of the rhodium-catalyzed C-H functionalization was
then examined (Scheme 3A). Indoles 13b and 13c bearing either
a free NH group or an alkyl chain were obtained in good yield.
Ethers, halogens and a sensitive boronic ester were well tolerated
on the benzene ring of the indole reagent (13d-h). The
regioselective synthesis of both C2 and C3 substituted pyrroles
was possible (13i-m).[27] Methoxy, halogens, esters and cyanides
functional groups could be present on the arene substrate (13n-
r). Diarylation was also possible using an excess of reagent 8a to
give product 19. Good results were also obtained with other
heterocyclic directing groups such as pyrimidine (20) or pyrazole
(21). Benzoquinoline 22 and pyrimidine-substituted indole 23
were also formed in good yield. When quinoline N-oxide was used
as the starting material, quinolone 24 was obtained in 38% yield.
The developed C-H arylation could also be applied to a purine-
based nucleoside to give product 25.
Scheme 3. Scope of the Rh- and Ru- catalyzed C-H Functionalizations.
Reactions were performed on 0.30 mmol scale. [a] 0.1 M in DCE:MeOH (1:1
ratio). [b] at 80 °C. [c] Using 0.660 mmol 8a. [d] at 100 °C.
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[8] K. Ishida, H. Togo, K. Moriyama, Chem. Asian J. 2016, 11, 3583.
The thermal stability of the developed reagents was essential to
achieve a broad scope, as several substrates required higher
temperature to reach useful conversion (80 °C for products
13c,k,l,r, 20 and 21, and 100 °C for compound 24). Preliminary
investigations of the scope of the ruthenium-catalyzed C-H
functionalization were then conducted (Scheme 3B). The
benzamide directing group is attractive, as it can be easily
modified or removed. Alkyl groups, ethers, trifluoromethyl groups
and halogens were all well tolerated both in para and meta
position to the amide (15a-i). Tetrasubstituted arene 15j and
naphthyl derivatives 15k were also obtained in good yields.
[9] K. Morimoto, Y. Ohnishi, D. Koseki, A. Nakamura, T. Dohi, Y. Kita, Org.
Biomol. Chem. 2016, 14, 8947.
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D. P. Hari, M. V. Vita, J. Waser, Angew. Chem., Int. Ed. 2016, 55, 4436.
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B. Olofsson, Eur. J. Org. Chem. 2011, 3690; c) M. S. Yusubov, R. Y. Yusubova,
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Org. Chem. 1996, 61, 6547.
In conclusion, we have reported the first synthesis of indole- and
pyrrole substituted benziodoxolone reagents. Indole- and Pyrrole-
BX were synthesized in one-step from the heterocycles under
mild Lewis acid catalyzed conditions and are thermally stable up
to 150 °C. These new reagents can be used for the Rh- and Ru-
ortho C-H functionalization of arenes using heterocyclic and
benzamide directing groups, a transformation that could not be
realized using previously reported methods. Many of the obtained
products are new combinations of privileged (hetero)arenes,
covering interesting chemical space for medicinal chemistry. The
availability of stable electrophilic indole and pyrrole synthons is
expected to lead to broad applications in synthetic and medicinal
chemistry.
[17] Diethyl ether was used as solvent due to the low solubility of 5 in acetonitrile.
[18] See Supporting Information.
[19] Selected examples: a) R. Frei, M. D. Wodrich, D. P. Hari, P. A. Borin, C.
Chauvier, J. Waser, J. Am. Chem. Soc. 2014, 136, 16563; b) R. Ghosh, E.
Lindstedt, N. Jalalian, B. Olofsson, ChemistryOpen 2014, 3, 54; c) D. Fernandez
Gonzalez, J. P. Brand, J. Waser, Chem. Eur. J. 2010, 16, 9457.
[20] Selected examples: a) D. Kalyani, N. R. Deprez, L. V. Desai, M. S. Sanford,
J. Am. Chem. Soc. 2005, 127, 7330; b) O. Daugulis, V. G. Zaitsev, Angew.
Chem., Int. Ed. 2005, 44, 4046.
[21] Selected examples: a) C. Feng, T.-P. Loh, Angew. Chem., Int. Ed. 2014,
53, 2722; b) F. Xie, Z. Qi, S. Yu, X. Li, J. Am. Chem. Soc. 2014, 136, 4780; c)
K. D. Collins, F. Lied, F. Glorius, Chem. Commun. 2014, 50, 4459; d) R.
Boobalan, P. Gandeepan, C.-H. Cheng, Org. Lett. 2016, 18, 3314. Nevertheless,
extensive optimization of the reaction conditions was still needed to obtain good
yields with Indole-BX 9a, see the Supporting Information for details.
[22] Z. Ruan, S.-K. Zhang, C. Zhu, P. N. Ruth, D. Stalke, L. Ackermann, Angew.
Chem., Int. Ed. 2017, 56, 2045.
Acknowledgements
This work is supported by the Swiss National Science Foundation
(No. 200021_159920), the European Research Council (ERC
Starting Grant 334840) and the COST action CA15106 (C-H
Activation in Organic Synthesis, CHAOS). We thank Dr R.
Scopelliti and Dr F. F. Tirani from ISIC at EPFL for X-ray analysis,
and Dr. Fides Benfatti and Ms. Marylene Stempien from Syngenta
Crop Science for DSC experiments. Mr. Elliott Le Du from EPFL
is thanked for performing the thiol indolation experiment.
[23] J. Q. Yu, in Topics in Current Chemistry: C-H Activation; Springer, 2010;
Vol. 292.
[24] Review: a) Y. Yang, J. Lan, J. You, Chem. Rev. 2017, 117, 8787; Selected
examples of C-H indolation: b) D. R. Stuart, K. Fagnou, Science 2007, 316,
1172; c) D. R. Stuart, E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007, 129,
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Chem. Soc. 2009, 131, 1668; f) J. Wencel-Delord, C. Nimphius, H. Wang, F.
Glorius, Angew. Chem., Int. Ed. 2012, 51, 13001.
Keywords:
Indoles • Hypervalent Iodine • Umpolung • C-H
Functionalization • Heterocycles
[25] Selected examples for coupling of indoles with fluorinated arenes: a) C. Y.
He, Q. Q. Min, X. G. Zhang, Organometallics 2012, 31, 1335; b) X. C. Cambeiro,
N. Ahlsten, I. Larrosa, J. Am. Chem. Soc. 2015, 137, 15636.
[1] G. W. Gribble, Indole Ring Synthesis: From Natural Products to Drug
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[26] Selected examples for coupling of indoles with electron-poor heterocycles:
a) X. Gong, G. Y. Song, H. Zhang, X. W. Li, Org. Lett. 2011, 13, 1766; b) M.
Nishino, K. Hirano, T. Satoh, M. Miura, Angew. Chem., Int. Ed. 2012, 51, 6993;
c) N. Kuhl, M. N. Hopkinson, F. Glorius, Angew. Chem., Int. Ed. 2012, 51, 8230;
d) Z. Wang, F. J. Song, Y. S. Zhao, Y. M. Huang, L. Yang, D. B. Zhao, J. B. Lan,
J. S. You, Chem. Eur. J. 2012, 18, 16616; e) X. R. Qin, H. Liu, D. K. Qin, Q. Wu,
J. S. You, D. B. Zhao, Q. Guo, X. L. Huang, J. B. Lan, Chem. Sci. 2013, 4, 1964;
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2163; g) K. Morimoto, K. Sakamoto, T. Ohshika, T. Dohi, Y. Kita, Angew. Chem.,
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[2] G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875.
[3] M. Bandini, Org. Biomol. Chem. 2013, 11, 5206.
[4] Selected example: G. Li, E. Wang, H. Chen, H. Li, Y. Liu, P. G. Wang,
Tetrahedron 2008, 64, 9033.
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Chem. Heterocycl. Compd. 1974, 10, 189. b) V. A. Budylin, M. S. Ermolenko, F.
A. Chugtai, P. A. Sharbatyan, A. N. Kost, Chem. Heterocycl. Compd. 1981, 17,
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28, 3071.
[27] The rhodium-catalyzed C-H functionalization was not successful with
reagents 9r-t.
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Paola Caramenti, Stefano Nicolai,
Jerome Waser*
Page No. – Page No.
Indole- and Pyrrole-BX: Bench-Stable
Hypervalent Iodine Reagent for
Heterocycle Umpolung
Electrophilic Indoles/Pyrroles: The first synthesis of indole and pyrrole-derived
benziodoxole reagents in one step from the heterocycles is reported. The new Indole-
and Pyrrole- BX reagents are stable up to 150 °C and can be used for selective
heterocycle transfer onto the C-H bonds of arenes ortho to directing groups by using
rhodium or ruthenium catalysts.
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