Regioselective Synthesis of 2-Substituted Indoles from Benzotriazoles and Alkynes by Photoinitiated Denitrogenation

Article abstract of DOI:10.1021/acscatal.7b01025

Herein, we describe a photoinitiated and regioselective synthesis of 2-substituted indoles under mild reaction conditions. This biologically privileged scaffold was accessed in good yields from N-aroylbenzotriazoles, a quencher class previously identified using our mechanism-based luminescence screening, and terminal alkynes in the presence of a photocatalyst and blue light irradiation. This straightforward protocol displays a broad substrate scope and functional group tolerance. Furthermore, the mildness and robustness of the reaction were assessed by the application of an additive-based robustness screen. The determination of the reaction quantum yield and Stern-Volmer studies support the proposed photoinitiated radical chain mechanism.

Full text of DOI:10.1021/acscatal.7b01025

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Letter
Regioselective Synthesis of 2-Substituted Indoles from
Benzotriazoles and Alkynes by Photoinitiated Denitrogenation
Michael Teders, Lena Pitzer, Stefan Buss, and Frank Glorius
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Regioselective Synthesis of 2-Substituted Indoles from Ben-
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Michael Teders, Lena Pitzer, Stefan Buss, and Frank Glorius*
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany
ABSTRACT: Herein, we describe a photoinitiated and regioselective synthesis of 2-substituted indoles under mild reac-
tion conditions. This biologically privileged scaffold was accessed in good yields from N-aroylbenzotriazoles — a quench-
er class previously identified using our mechanism-based luminescence screening — and terminal alkynes in the presence
of a photocatalyst and blue light irradiation. This straightforward protocol displays a broad substrate scope and functional
group tolerance. Furthermore, the mildness and robustness of the reaction were assessed by the application of an addi-
tive-based robustness screen. The determination of the reaction quantum yield and Stern-Volmer studies support the
proposed photoinitiated radical chain mechanism.
KEYWORDS: photocatalysis, robustness screen, regioselective, indoles, benzotriazoles, mechanism-based screening
The discovery of new transformations and reactivity modes is
the overall aim of organic chemists. To this end, chemists
have a wide range of tools at their disposal, from rational
design based on chemical understanding to the application
of screening methodologies.1 We recently published a mech-
anism-based screening method,2 which focuses on accelerat-
ing discoveries in the field of photocatalysis.3 This screening
approach focusses on a single key mechanistic step, the in-
teraction of an excited photocatalyst with a substrate. By
narrowing one’s sight and focusing only on one fundamental
step of the overall catalytic cycle, the obtained insights are
helpful for the development and optimization of a reaction.
Application of this screening approach led to the discovery of
N-aroylbenzotriazoles (1) as a new quencher substrate class
for photocatalytic reactions. Using this new oxidative
quencher, four novel visible light-promoted functionaliza-
tions delivering ortho-thiolated, -borylated, -alkylated and
hydrodenitrogenated N-arylbenzamides were developed
(Scheme 1, b).4 We sought to move beyond ortho-
functionalizations and envisaged transformations in which
the remaining nitrogen atom is used for the construction of
Scheme 1. a) Examples for the synthesis of substituted
indoles. b) This work: Utilizing benzotriazoles for the
regioselective synthesis of 2-substituted indoles.
heterocyclic systems. Inspired by König and coworkers’ re-
port on a photoinitiated synthesis of benzothiophenes from
ortho-methylthioarene diazonium salts,5 we recognized that
benzotriazoles as synthetically otherwise non-accessible
ortho-aminodiazonium precursors might be cheap, easy-to-
handle and stable starting materials for the synthesis of in-
dole scaffolds.6
Consequently, several synthetic strategies have been devel-
oped over the years.10 Most of these strategies employ aniline
derivatives as starting materials, like in the classical Bischler-
Möhlau11 or Larock indole synthesis (Scheme 1, a).12 Alterna-
tively, Terada and coworkers’ have shown that benzotriazoles
could be used as synthetic aniline equivalents in combina-
tion with terminal alkynes for the synthesis of 2,3-diarylated
indoles.13 This denitrogenative approach, however, suffers
from harsh reaction conditions limiting the scope to internal
alkynes.
Indoles are important structural motifs which are embedded
in many natural and synthetic molecules, and are often de-
scribed as privileged in terms of biological activity.7 2- Ar-
ylindoles have recently been shown to possess significant
antibacterial and fungicidal activity,8 and represent im-
portant intermediates in the synthesis of complex mole-
cules.9 Therefore, the need for synthetic routes to indoles
and 2-arylindoles is of great interest for organic and medici-
nal chemists.
Building on our strategy to use N-aroylbenzotriazoles as
masked ortho-aminodiazonium compounds,6e we sought to
access 2-substituted indoles under mild conditions.
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Table 1. Optimization of reaction conditionsa.
5a in 61% yield.17 Alternatively, 1a could be generated in situ,
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6
7
8
from 1H-benzotriazole and 7, affording 5a in a slightly lower
yield (66%), however, saving one synthetic step. Next, we
studied the influence of electronic effects on the benzotria-
zole ring. The use of 5-methyl or 5-chloro substituted N-
aroylbenzotriazoles afforded the corresponding 2-arylated
indoles in 52% (5b) and 85% (5c) yield, respectively. Due to
Dimroth rearrangement of the starting materials, mixtures of
5- and 6-substituted products were obtained.18 5,6-
Dimethylbenzotriazole was successfully transformed to the
corresponding product 5d in good yield (74%). Gratifyingly,
the insertion of a p-methoxy substituent on the protecting
group was also well tolerated under the reaction conditions
delivering 5e in 79% isolated yield.
Equiv
4
Additive
(equiv)
Yield
5ab
Entry
Ratio 1a : 2
1
2
1 : 10
1 : 10
1 : 10
1 : 20
1 : 20
1 : 20
1 : 20
1 : 20
1 : 20
3
3
3
3
3
3
3
3
/
/
32
47
60
73
75
69
3
nBu4NBr (1.0)
nBu4NCl (1.0)
nBu4NCl (1.0)
nBu4NCl (1.0)
nBu4NCl (2.0)
nBu4NCl (2.0)
nBu4NCl (2.0)
nBu4NCl (2.0)
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3
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4
5c
6d,e
7d, e, f
8d, e, g
9d,e
/
/
aReaction conditions: N-(benzoyl)benzotriazole (1a, 1.0 equiv),
[Ir(ppy)2(dtbbpy)]PF6 (3, 2.5 mol%), benzoic anhydride (7, 2.0 equiv),
DMSO (0.2 M), r.t., 15 h, 455 nm irradiation. bGC-FID yield. cneat; no
DMSO. d1.0 mol% [Ir]-photocatalyst used. e0.5 equiv benzoic anhy-
dride used. no photocatalyst. gno light. BA = benzoic anhydride,
f
DIPEA = N,N-diisopropylethylamine. Bz = benzoyl.
The addition of an o-aminated aryl radical, obtained after
denitrogenation from 1, to a terminal alkyne and subsequent
cyclization might result in the formation of the desired in-
dole nucleus (Scheme 1, b).
Our earlier work on the o-functionalization of N-
aroylbenzotriazoles suggested that higher yields were ob-
tained when an indirect reductive quenching manifold was
employed.4 Furthermore, the addition of benzoic anhydride
(7) ensured the crucial protection of the benzotriazole in
terms of quenching, leading to increased product yields.
Therefore, initially, N-benzoylbenzotriazole (1a), phenyla-
cetylene (2), DIPEA (4), benzoic anhydride (7) and
[Ir(ppy)2(dtbbpy)](PF6) (3, 2.5 mol%, ppy = 2-phenylpyridine,
dtbbpy = 4,4ʹ-di-tert-butyl-2,2ʹ-bipyridine) were irradiated
with blue LEDs (λmax = 455 nm) in DMSO (0.1 M) for 15 h at
room temperature.14 We were delighted to observe the for-
mation of the desired product N-benzoyl-2-phenylindole (5a)
in 32% GC-yield (table 1, entry 1). We hypothesized that the
use of soluble organic salts might result in the stabilization of
the postulated ionic intermediates, thus increasing the yield
of the reaction.15 Indeed, by adding tetrabutylammonium
bromide (nBu4Br), 5a was obtained in 47% yield (entry 2).
Further optimization of the counter anion (entry 3) and the
equivalents of phenylacetylene, afforded 5a in 73% yield
(entry 4). Interestingly, the reaction also worked when it was
performed in the absence of solvent (75% yield, entry 5).
Gratifyingly, the catalyst loading could be reduced to 1.0
mol% affording the product in a slightly decreased yield of
69% (entry 6). Control experiments showed that only traces
of the product were observed in the absence of a photocata-
lyst (entry 7),16 and that the reaction did not proceed in the
absence of light or DIPEA (entry 8 and 9).
Reactions were performed on a 0.3 mmol scale; isolated yields are
given. For more detailed reaction conditions, see the supporting
a
information. In situ formation of N-benzoylbenzotriazole (1a) from
1H-benzotriazole (1.0 equiv) and benzoic anhydride (2.0 equiv). See
supporting information for experimental details and reference [4]. b
c
1H-NMR-yield using CH2Br2. Using 4-methoxybenzoic anhydride.
dReaction was performed on a 0.1 mmol scale. Bz = benzoyl,
pOMeBz = p-methoxybenzoyl. See the supporting information for
experimental details and results of the additive-based robustness
screen.
With the optimized reaction conditions in hand we next
investigated the scope and limitations of this regioselective
synthesis of 2-substituted indoles (Scheme 2, a). N-benzoyl-
2-phenylindole (5a) was isolated in 70% yield. Pleasingly, the
reaction also proceeded well on a 3.0 mmol scale delivering
Scheme 2. Scope (a) and robustness screen (b).
We next examined the effect of modifying the alkyne. The
reaction tolerates a wide range of p-substituted phenylacety-
lene derivatives, affording the corresponding products in 48-
92% yield (5h-5p).
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major product. The robustness and functional group preser-
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vation of this denitrogenative indole synthesis was addition-
ally investigated by conducting an additive-based robustness
screen. The results are summarized in histograms (Scheme 2,
b).19 We were delighted to see that in most cases the yield of
the product was not affected by the presence of an additive,
indicating a high robustness of the overall transformation.
Furthermore, the reaction is characterized by a high func-
tional group preservation, since the additives were recovered
in an average yield of 80%.
The deprotection of the N-benzoyl-2-substituted indole
products can be easily achieved by basic treatment with
potassium hydroxide in an ethanol/water mixture, delivering
the free indoles in high yields (see SI).20 Alternatively, we
observed during our scope investigations that a strongly
withdrawing trifluoromethyl group incorporated on the
benzoyl fragment leads to the formation of the correspond-
ing deprotected indoles 5Ha-5He in moderate yields
(Scheme 3, 35-62%). This strategy represents a valuable ap-
proach for the synthesis of 2-phenyl substituted indoles
without the need for additional deprotection steps.
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Scheme
3.
Scope
using
N-(4-
trifluoromethyl)benzoylbenzotriazoles to obtain depro-
tected indoles.
Electron-withdrawing substituents, such as trifluoromethyl
or chloro, and electron-donating substituents, e.g. methoxy
t
or Bu, were well tolerated. In addition, terminal deuterated
alkynes could also be employed, which represents a general
method for the preparation of 2-arylated indoles with a deu-
terium atom in the C3 position (5f, 67%).Pleasingly, the use
of 2-ethynylpyridine gave the corresponding product 5q in
79% yield and in 61% yield on a 3.0 mmol scale. Unfortunate-
ly, no product formation was observed when internal alkynes
were used (5r, 5s and 5t). N-phenylbenzamide (13) was ob-
tained in those cases, thus suggesting that the addition of the
aryl radical to the alkyne might not be taking place. Finally,
we evaluated whether terminal aliphatic alkynes could also
be used to access 2-alkylated indoles under our reaction
conditions. Proof of principle experiments were carried out
using 1-hexyne and 2-ethynylcyclopropane, affording the
corresponding products 5u and 5v in diminished yields com-
pared to the arylalkyne derivatives (21% and 31%, respective-
ly). Moreover, the synthesis of 2-silylated indoles was also
possible, as shown by the isolation of 5w in 40% yield. In the
latter three experiments, benzanilide 13 was identified as the
Scheme 4. Chemodivergent functionalizations of N-
benzoylbenzotriazole (1a).
During the optimization studies, we observed a chemodiver-
gent switch when the solvent was changed from DMSO to
MeCN (Scheme 4). When the latter was used, (Z)-
stilbene derivative 8 was obtained in an isolated
yield of 55%. These products might be useful for
enantioselective halocyclizations using chiral
anion phase-transfer catalysis resulting in the
formation of halogenated 4H-3,1-benzoxazines.21
Once the scope and limitations of our methodolo-
gy were stablished, we began to probe the reac-
tion mechanism. Stern-Volmer analysis, quantum
yield determination and other mechanistic exper-
iments were carried out to support the proposed
reaction mechanism (Scheme 5).22 Initially, the
excited state photocatalyst, obtained upon blue
LED irradiation, is reduced by a single electron
transfer (SET) to the reductive quencher 4,23 af-
fording the amine radical cation 9 and a highly
reducing IrII photocatalyst. The latter will interact
with benzotriazole 1 via a SET, thus regenerating
the IrIII photocatalyst and the radical anion 10.
Subsequent nitrogen extrusion from 10 will afford
the aryl radical 11, which can either add to the
Scheme 5. Proposed mechanism for the photoinitiated deni-
trogenative synthesis of 2-substituted indoles.
alkyne 2 to give the stabilized radical intermediate
12 or picks up a hydrogen atom from the solvent
3
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resulting in the formation of the undesired side product 13.4
Radical intermediate 12 is then predominantly oxidized by
another molecule of 1, as suggested by a reaction quantum
yield of 16.3, which indicates a radical chain mechanism. The
zwitterionic intermediate 14 cyclizes to give the desired
product 5.24
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In conclusion, we have successfully developed a protocol for
the mild and regioselective construction of biologically im-
portant 2-substituted indoles using cheap and stable ben-
zotriazoles. This synthetic strategy displays broad substrate
scope, a high functional group tolerance and represents a
valuable complement to the synthesis of 2-substituted in-
doles. The reaction proceeds via a radical chain mechanism
as indicated by the determined reaction quantum yield and
Stern-Volmer analysis. We have successfully shown that
benzotriazoles as quenchers, discovered by our mechanism-
based screening technique, can be used as synthetic equiva-
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of
otherwise
non-accessible
ortho-amino-
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arenediazonium salts in a variety of new photocatalytic reac-
tions.
ASSOCIATED CONTENT
(10) For reviews on indole syntheses, see: (a) Cacchi, S.; Fabrizi,
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(14) The photocatalyst was selected aided by data obtained from
mechanism-based luminescence screening, see (4).
(15) Tetrabutylammonium salts have been used in our group
before as additives to increase the product yield: Honeker, R.;
Garza-Sanchez, R. A.; Hopkinson, M. N.; Glorius, F. Chem. Eur. J.
2016, 22, 4395-4399.
Supporting Information. Experimental details, characteri-
zation data, mechanistic experiments and copies of NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: glorius@uni-muenster.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Generous financial support by the DFG (Leibniz Award) is
gratefully acknowledged. M. T. thanks SusChemSys2.0 for
support. We thank Dr. A. Gómez-Suárez, F. Klauck and Dr.
L. Candish (all WWU Münster) for helpful discussions.
REFERENCES
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(17) 18.5 equiv of phenylacetylene were recovered after the reac-
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(22) See the supporting information for further details.
(23) Stern-Volmer luminescence quenching studies identified
1
diisopropylethylamine (4) as the only quenching species, see SI.
(24) Based on additionally performed experiments, a cascade
mechanism seems unlikely, see SI for further details.
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
ACS Paragon Plus Environment