Catalytic Reductive Synthesis and Direct Derivatization of Unprotected Aminoindoles, Aminopyrroles, and Iminoindolines

Article abstract of DOI:10.1002/anie.201702310

A titanium(III)-catalyzed radical cyclization to unprotected 3-aminoindoles, 3-aminopyrroles, or 3-iminoindolines is reported. The reaction is non-hazardous, scalable, and allows facile isolation of the free products by extraction. The method is demonstrated on a large substrate scope and it further allows the direct installation of various nitrogen protecting groups or the synthesis of building blocks for peptide chemistry in a single sequence. Fused bisindoles can be directly accessed from the cyclization products.

Full text of DOI:10.1002/anie.201702310

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201702310
German Edition: DOI: 10.1002/ange.201702310
Synthetic Methods
Catalytic Reductive Synthesis and Direct Derivatization of
Unprotected Aminoindoles, Aminopyrroles, and Iminoindolines
Leonardus H. Leijendekker, Jens Weweler, Tobias M. Leuther, and Jan Streuff*
Abstract: A titanium(III)-catalyzed radical cyclization to
unprotected 3-aminoindoles, 3-aminopyrroles, or 3-iminoindo-
lines is reported. The reaction is non-hazardous, scalable, and
allows facile isolation of the free products by extraction. The
method is demonstrated on a large substrate scope and it
further allows the direct installation of various nitrogen
protecting groups or the synthesis of building blocks for
peptide chemistry in a single sequence. Fused bisindoles can be
directly accessed from the cyclization products.
Aminated five-membered heterocycles are important build-
ing blocks in organic synthesis and indispensable to medicinal
chemistry.[1] In particular, 3-aminoindoles, 3-aminopyrroles,
and related heterocycles mark structural motifs of molecules
with striking biological activities.[2] Hence, there is a need for
efficient approaches to the corresponding synthetic precur-
sors. Modern catalytic methods, however, usually furnish
electronically deactivated and N-protected derivatives that
lead to undesired functional-group modifications in the
ensuing synthetic applications.[3] This problem also applies
to conventional anionic cyclizations to nitriles.[4] The develop-
ment of new synthetic approaches to electron-rich, unpro-
tected aminoindoles and aminopyrroles was impeded by the
low stability of the products in solution and in the solid
form.[5] As a consequence, nitration-reduction or azidation-
reduction sequences that present significant hazards still
constitute the main synthetic routes.[5–7] To overcome these
issues, we herein report an operationally convenient and
broadly applicable titanium(III)-catalyzed synthesis of unpro-
tected 3-aminated indoles, pyrroles, and iminoindoline prod-
ucts, which further allows a facile derivatization.
Scheme 1. Concept of a titanium(III)-catalyzed synthesis of unpro-
tected aminated heterocycles.
mentary to Fꢀrstnerꢁs low-valent Ti-promoted and catalyzed
syntheses of indoles or pyrroles in terms of mechanism,
functional-group tolerance, and oxidation-state distribution
at the carbon centers involved.[14]
The cyclization of aldimine 1a to 3-aminoindole 2a served
as the starting point for the development of the new indole
synthesis [Eq. (1)]. Several parameters including the catalyst
We contemplated that an in situ formed titanium(III)
catalyst would undergo a single-electron transfer to an
N-cyanoarylated or N-cyanoalkenylated imine, forming a sta-
bilized aminoalkyl radical (Scheme 1).[8] In accordance with
previous reports on TiIII-catalyzed cyclizations to nitriles,[9,10]
this would trigger a catalyst-controlled radical attack to the
nitrile,[11,12] and depending on the nature of the imine an
aminoindole, aminopyrrole, or iminoindoline product is
ultimately received. The overall sequence would constitute
a catalytic reductive umpolung reaction,[13] that is comple-
type, reducing agent, and additives were optimized in a series
of screening experiments.[15] Importantly, no reaction was
observed in the absence of the catalyst. As expected, product
2a and related unprotected aminoindoles were found to be
unstable, which prevented standard chromatographic purifi-
cation. Crystallization from benzene or toluene–hexanes
mixtures under exclusion of light and oxygen was found to
be a viable way to enhance the product purity,[5c] but the yield
was be diminished. Gratifyingly, an acid–base extraction was
found to allow the isolation of 2a. Using these conditions and
only 5 mol% of titanocene dichloride, the desired product
was isolated in a yield of 92% from a 2.5 mmol reaction.
A number of unprotected 3-aminoindoles was then
synthesized using this method to demonstrate the scope of
the titanium(III)-catalyzed cyclization (Scheme 2). Electron-
[*] L. H. Leijendekker, J. Weweler, T. M. Leuther, Dr. J. Streuff
Institut fꢀr Organische Chemie
Albert-Ludwigs-Universitꢁt Freiburg
Albertstrasse 21, 79104 Freiburg im Breisgau (Germany)
E-mail: jan.streuff@ocbc.uni-freiburg.de
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702310.
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The titanium(III)-catalyzed cyclization was then tested in
the synthesis of 3-aminopyrroles. Corresponding pyrrolo-
amides play a unique role in the molecular recognition of
DNA,[2d,e] but the ways of preparing unprotected amino-
pyrrole building blocks are limited, in particular with regard
to fully substituted pyrroles. Only recently was 3-amino-
pyrrole itself prepared and characterized in solution.[5a] For
these reasons, we were delighted to find that the unprotected
aminopyrrole 4a was formed in good yield from readily
accessible aldimine 3a under standard reaction conditions
(Scheme 3).[15] The product was isolated in analogy to the
aminoindoles 2a–p by extraction in 88% yield. In a similar
fashion but with 10 mol% catalyst and 1.5 equivalents of
chlorotrimethylsilane, 2-(o-bromophenyl)-substituted 4b was
obtained in 78% yield.[16]
Scheme 3. Catalytic reductive synthesis of unprotected 3-aminopyr-
roles. [a] Reaction in presence of 10 mol% Cp2TiCl2 and 1.5 equiv
TMSCl.
In a parallel series of experiments we sought to investigate
whether N-cyanoarylated ketimines could be cyclized in
a similar fashion to the corresponding 3-iminoindolines
(Scheme 4). This transformation would be of interest, since
indoxyls, which can be obtained by hydrolysis of iminoindo-
lines,[17] occur in the skeleton of biologically active natural
products, such as brevianamide A or several duocarmy-
cins.[17b,18] Using ketimine 5a, a brief survey of the cyclization
conditions then showed that the reaction can indeed be
achieved,[15] and a combination of rac-(ebthi)TiCl2 as catalyst
and manganese as reductant at 808C gave the best results,
minimizing the formation of unidentifiable byproducts. Fol-
lowing these conditions, the products 6a–c were furnished in
43–66% yield. To our delight, even an ester-substituted imine
Scheme 2. Scope of the cyclization to unprotected aminoindole prod-
ucts. [a] 2.5 mmol scale, identical to Equation (1). [b] 5 mmol scale.
[c] 0.2 mmol scale.
rich and electron-poor substituents were tolerated in the para
and meta positions of a 2-aryl substituent and the correspond-
ing products 2b–2j were obtained in good to very good yields
(63–87%). Of particular interest were the smooth reactions
that were observed with the ortho-bromo or ortho-methyl
benzaldehyde-derived imines 1k and 1l (83% and 92% yield,
respectively). Ortho-substitution was previously found to be
problematic for a number of titanium(III)-catalyzed reduc-
tive couplings.[10] Along these lines, the cyclization to
1-naphthyl-substituted 2m proceeded without problems in
85% yield. The method was further applied to the construc-
tion of thienyl- and benzodioxole-derived products 2n and
2o. Even a free 3-aminoindole containing two mildly elec-
tron-donating methyl groups in the backbone (2p) could be
accessed in a very good yield of 90%.
All products shown in Scheme 2 were received after
extraction, either in analytically pure form or in > 95% purity
as judged by NMR spectroscopy. Analysis had to be carried
out quickly because of the rapid decomposition of the free
products in solution. A number of the free aminoindoles
could be precipitated,[15] and limited storage (1–5 days) of the
neat products was possible at ꢀ208C under argon in the dark.
Scheme 4. Catalytic reductive cyclization to iminoindolines. ebthi=
ethylenebis(tetrahydroindenyl).
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Scheme 6. Expansion of the substrate scope. The overall yield with
respect to the imine precursor is reported. [a] Gram scale. [b] Isolated
by filtration.
Scheme 5. Direct sequential N-functionalization. Overall yields are
given with respect to 1a. a) Boc2O, ZrCl4 (10 mol%), THF, 238C, 24 h,
79%; b) Ac2O, Et3N, CH2Cl2, 08C ! 238C, 14 h, 71%; c) TsCl, Et3N,
CH2Cl2, 08C ! 238C, 14 h, 58%; d) Phthalic anhydride, [bmim][PF6],
808C, 24 h, 42%; e) Boc-Ala-OH, T3P (1.43m in DMF), Et3N, CH2Cl2,
08C ! 238C, 24 h, 73%.
2-alkylated products currently represents a limitation of the
method, but 2-alkylated aminoindoles, such as 18, can be
conveniently obtained by hydrogenation of the corresponding
2-alkenyl derivative [Eq. (2)].
5d that was prepared from methyl phenylglyoxylate under-
went the cyclization to iminoindoline 6d in 55% yield.[19]
Then, it was probed whether the cyclization products 2
could be directly submitted after the extraction to sequential
modifications and couplings. Starting from imine 1a, a direct
Boc-protection of the 3-amino group of the crude cyclization
product was conveniently achieved with catalytic amounts of
ZrCl4 in 79% overall yield (7, Scheme 5).[20] In a similar
manner, an N-acetylation with Ac2O, a tosylation with tosyl
chloride, and a phthalimide formation using phthalic anhy-
dride were achieved in good yields in a single reaction
sequence (8–10). The strategy could also be applied to
a peptide coupling with Boc-Ala-OH and T3P (11). The
reaction proceeded smoothly and the 3-(2-phenyl)indolyl-
protected amino acid derivative was isolated in 73% yield.
This could become particularly useful for the introduction of
indoles into peptides.
To show the value of our approach to other fields, we
applied it to the synthesis of fused bisindoles, which are
a family of organic semiconductors with increasing applica-
tion in the development of novel organic field-effect tran-
sistors (OFETs).[23] The access to such compounds, in
particular to unsymmetric ones, has been very limited until
recently. To this end, product 14b was submitted to copper-
promoted coupling conditions and the corresponding selec-
tively monoprotected building block 19 was received in 78%
yield [Eq. (3)].
With a direct cyclization-functionalization strategy at
hand, the scope of the titanium(III)-catalysis was further
expanded (Scheme 6). 3-Aminoindoles having a bromo- or
chloro-substituted backbone (12, 13) were isolated after
a sequential Boc protection in 84% and 52% overall yield.
N-Acyl and N-Boc 2-(o-bromophenyl)-3-aminoindoles 14a
and 14b and a corresponding N-Boc pyrrole 15 were prepared
in analogy on gram scale. The sequence also enabled the
isolation of aminoheterocycles that were difficult to isolate
otherwise, such as 2-styryl derivative 16, of which the
structure was confirmed by X-ray analysis.[21] 7-azaindoles,
which represent important structural motifs in medicinal
chemistry,[22] could be accessed as well if imines derived from
2-aminonicotinnitrile were employed (17, 72%). The product
could be conveniently isolated by filtration. The synthesis of
In conclusion, an expedient titanium-catalyzed synthesis
of unprotected 3-aminoindoles, 3-aminopyrroles, and 3-imi-
noindolines was developed that excels in functional-group
compatibility and synthetic practicality. It further enables the
direct derivatization of the crude 3-aminoheterocycles, which
makes the overall sequence a valuable transformation for
medicinal chemistry, peptide chemistry, or organic functional-
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Conflict of interest
The authors declare no conflict of interest.
Keywords: heterocycles · homogeneous catalysis · radicals ·
reductive coupling · titanium
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Manuscript received: March 3, 2017
Final Article published: && &&, &&&&
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Communications
Synthetic Methods
L. H. Leijendekker, J. Weweler,
T. M. Leuther, J. Streuff*
&&&& — &&&&
Catalytic Reductive Synthesis and Direct
Derivatization of Unprotected
Aminoindoles, Aminopyrroles, and
Iminoindolines
Free at last: A titanium(III)-catalyzed
reductive cyclization allows the safe and
convenient synthesis of unprotected
aminoindoles, aminopyrroles, and other
aminated heterocycles. The novel cycli-
zation approach further enables the direct
functionalization at the nitrogen atom via
various coupling methods in a single
sequence.
Angew. Chem. Int. Ed. 2017, 56, 1 – 5
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!