Aerobic C-H amination of tetrahydrocarbazole derivatives via photochemically generated hydroperoxides

Article abstract of DOI:10.1039/c3ob40919h

A Bronsted acid catalyzed C-H functionalization via Intermediate PeroxideS (CHIPS), generated photochemically, allows the oxidative coupling of indole derivatives with a variety of nitrogen nucleophiles. The reaction can be performed in one pot and requires only visible light, elemental oxygen, a Bronsted acid and a photosensitizer. The method can be applied to an efficient synthesis of some biologically active compounds. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40919h

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Biomolecular Chemistry
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Aerobic C–H amination of tetrahydrocarbazole
derivatives via photochemically generated
hydroperoxides†
Cite this: Org. Biomol. Chem., 2013, 11,
4516
Naeem Gulzar and Martin Klussmann*
A Brønsted acid catalyzed C–H functionalization via Intermediate PeroxideS (CHIPS), generated photo-
chemically, allows the oxidative coupling of indole derivatives with a variety of nitrogen nucleophiles.
The reaction can be performed in one pot and requires only visible light, elemental oxygen, a Brønsted
acid and a photosensitizer. The method can be applied to an efficient synthesis of some biologically
active compounds.
Received 20th March 2013,
Accepted 13th May 2013
DOI: 10.1039/c3ob40919h
www.rsc.org/obc
Introduction
The functionalization of C–H bonds is an important and long
standing goal in organic chemistry.1 Under oxidative con-
ditions, a C–H bond can be activated and coupled with
different molecules to form C–C and C–heteroatom bonds,
respectively.2 Such oxidative coupling reactions help to stream-
line the synthesis by saving steps, time and material and are
thus attractive for green chemistry.3 But often the requirement
for stoichiometric amounts of synthetic oxidants, expensive
reagents or harsh conditions diminishes the overall sustain-
ability of the method.
Autoxidation reactions occur frequently in nature and can
functionalize C–H bonds by introducing a hydroperoxide
moiety.4 These processes can be highly useful, for example
in the industrial oxygenation of hydrocarbons, but are also
perceived as unwanted if they lead to decomposition or if they
generate dangerously explosive compounds like ether per-
oxides. Recently, we discovered an oxidative coupling reaction
that forms new C–C bonds without the need for a redox-active
catalyst, a representative example being the coupling of
xanthene with cyclopentanone (Scheme 1a).5 The product is
formed by simply stirring the substrates under air or oxygen in
the presence of catalytic amounts of methanesulfonic acid.
The reaction is believed to proceed by an autoxidation via
intermediate peroxides like 1. Inspired by this mechanistic
Scheme 1 C–H functionalization via Intermediate PeroxideS (CHIPS): (a) auto-
xidative coupling via suggested intermediate 1 (ref. 5a); (b) C–H amination of
indole derivatives by Brønsted acid catalyzed nucleophilic substitution via photo-
chemically generated hydroperoxides.
rationale, we attempted to intentionally design similar reac-
tions for the C–H functionalisation via Intermediate PeroxideS
(CHIPS),6 which would give access to synthetically valuable
products in a sustainable manner. As in the model reaction
with xanthene, such reactions should optimally require only
oxygen as the reagent and otherwise simply catalysts to facili-
tate the autoxidation and substitution of the peroxide group.7
In general, hydroperoxides are sensitive compounds and
prone to O–O bond cleavage, requiring the right choice of cata-
lyst to prevent these undesired reactions while facilitating the
desired C–O bond cleavage and thus substitution with the
desired reactant. Peroxides are known to rearrange in the pres-
ence of acid, a process that is industrially used in the synthesis
of phenol and acetone via cumyl hydroperoxide, also known as
the Hock phenol synthesis.8 On the other hand, it has been
shown that the selectivity of O–O versus C–O bond cleavage
in reactions with cumyl hydroperoxide can be controlled by
a Lewis acid.9 Similar nucleophilic substitution reactions of
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an
der Ruhr, Germany. E-mail: klusi@mpi-muelheim.mpg.de; Fax: (+49) 208-306-2980;
Tel: (+49) 208-306-2453
†Electronic supplementary information (ESI) available: Further optimisation
studies, detailed experimental methods and product characterisation data
including crystallographic analysis. CCDC 914987, 914988, 915538 and 915539.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob40919h
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peroxides have also been reported for
compounds.6,7,10
a
few other
Indoles constitute a large number of biologically active
compounds11 and they are known to form peroxides by autoxi-
dation in air.12 For synthetic purposes, indole hydroperoxides
can be easily synthesized by reaction with singlet oxygen,
which can be generated by photochemical methods, using a
sensitizer and visible light.13 These hydroperoxides have been
used in organic synthesis for further transformations like
reductions or rearrangements, but apparently never for direct
substitution reactions.14 Based on our previous experiences
with the oxidative C–H functionalization of xanthene men-
tioned above, we investigated various Brønsted acids for the
substitution of the hydroperoxide group in compounds like 3,
derived from indole derivatives 2 by the action of singlet
oxygen (Scheme 1b).
Fig. 1 Reported pharmaceutical activities of compounds synthesized according
to method B (see Table 1 for the conditions). HPV: activity against human papil-
loma virus, see 18a. VEGF: inhibition of vascular endothelial growth factor, see
18c. HCV: activity against hepatitis C virus, see 18b.
Results and discussion
We started with tetrahydrocarbazole 2 as a test substrate,
which can be easily oxidized to the corresponding hydroper-
oxide 3 by irradiation with visible light in the presence of
elemental oxygen and a sensitizer like rose bengal.12a,14j
Amino-derivatives of 2 are interesting synthetic targets due to
their pharmaceutical activity.11a,b,15 We screened various N–H
nucleophiles and acid catalysts to facilitate a substitution reac-
tion of the hydroperoxide moiety in 3. These initial studies
revealed p-nitroaniline to be a suitable nucleophile and
trifluoroacetic acid as the best catalyst (see the ESI† for opti-
mization details). A high yield of 86% of product 4 was achieved
in methanol with a catalyst loading of 10 mol% (Table 1, entry
1, method A). The new C–N bond was selectively formed in
the 1-position of the saturated ring as revealed by NMR
spectroscopy and X-ray crystallography of selected products
(see the ESI† for details) and in accordance with previous
observations of related coupling reactions.14j,16 The reaction
did not require an excess of one reagent and was completed
within two hours at ambient temperature.
Using this method, good yields were obtained with anilines
having strongly electron withdrawing groups, but poor yields
with aniline. The problem could be solved by using acetic acid
as the solvent without any additional catalyst: aniline gave
10% isolated yield of coupling product 6 in methanol with
trifluoroacetic acid, but 60% in acetic acid (Table 1, entry 3).
In general, the use of acetic acid as the solvent (method B) was
found to be most suitable for the reaction with aniline,
halogen substituted anilines and indole derivatives without an
annulated ring (e.g. products 18, 23–26 and 28, see Scheme 4
and Fig. 1 below), while the use of methanol and trifluoro-
acetic acid (method A) was better for the coupling with more
electron poor anilines. Anilines bearing electron donating
groups did not react, nor did amides or aliphatic amines. For
anilines having a cyano, ester or carbonyl group, both methods
work equally well (Table 1, entry 2, see also products 13 and 19
below).
In principle, hydroperoxide 3 can be conveniently prepared
according to literature procedures.12a,14j Irradiating a homo-
geneous solution of 2 in toluene under an atmosphere of
oxygen in the presence of rose bengal with visible light – either
using a lamp or simply sunlight – leads to precipitation of the
pure hydroperoxide. This material can be conveniently isolated
by filtration and be directly employed in the substitution reac-
tion, a procedure that was used for most of our studies
(Scheme 2a). Alternatively, the solvent of the oxidation reaction
can be removed under vacuum and the resulting mixture can
be used in the next step without impairment of the yield in the
final product (Scheme 2b). In order to provide an efficient one-
pot method for the conversion of tetrahydrocarbazole to the
desired coupling products without the need to change
solvents, we also investigated the photooxidation in methanol.
A screening of several photosensitizers revealed phthalo-
cyanine to be suitable, giving hydroperoxide 3 in quantitative
Table 1 Choice of reaction conditions depending on the electronic nature of
the aniline nucleophilea
Entry
R
Product
Method A yield (%)
Method B yield (%)
1
2
3
NO2
CN
H
4
5
6
86
80
10
30
80
60
a Method A: 3 (0.5 mmol), aniline (0.5 mmol), CF3CO2H (0.05 mmol),
MeOH (0.5 ml), r.t., 2 h; Method B: 3 (0.5 mmol), aniline (0.5 mmol),
AcOH (0.5 ml), r.t., 2 h; isolated yields given.
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Scheme 2 Development of one-pot methods without isolation of hydroper-
oxide intermediate 3; (a) a two-step method with isolation of 3; (b) a one-pot
method with solvent exchange; (c)
exchange.
a one-pot method without solvent
yield after a reaction time of 40 hours at −40 °C. Addition
of aniline and acid catalyst to this mixture then provides
the coupling product
(Scheme 2c).
4 in essentially unchanged yield
Accordingly, amination of the indole-derivatives described
below can be performed in a one-pot, two-step method without
the need to change the reaction solvent, except for the cases
where acetic acid is used as the solvent for the coupling step.
In all cases, the reaction does not require any aqueous work-
up. The solvent is directly evaporated after the completion of
the reaction and the crude product is purified by column chromato-
graphy. In many cases, the product precipitates in pure form
during the reaction and no chromatography is needed.
Scheme 3 Product scope of the reaction using method A (see Table 1 for the
conditions). [a] Without the use of CF3CO2H.
The product scope of the reaction between a wide range of
aniline derivatives having electron withdrawing substituents
and tetrahydrocarbazole hydroperoxides is shown in the reaction could also be performed successfully with 2,3-
dialkyl substituted indoles. It was not possible to form the
corresponding hydroperoxide from 2,3-dimethyl indole;
Scheme 3. Substituents in the tetrahydrocarbazole unit were
well tolerated (e.g. products 7–9, 14–16) as were various
anilines, indoline and tetrahydroquinoline nucleophiles (e.g. however, the hydroperoxides from 2-benzyl,3-methylindole and
2-propyl,3-ethylindole could be synthesized at ambient temp-
erature or more reproducibly at −40 °C. The coupling products
products 10–13). Saccharin, being acidic itself, afforded the
coupling product 17 without the need for an additional acid
catalyst. The reaction of 3-methyl- and 3-phenyl-tetrahydrocar- with p-cyanoaniline, 23 and 24, were formed in 67% and 60%
yield, respectively. Indole derivatives with an annulated satu-
rated five membered ring did not yield the desired products,
bazole hydroperoxides with anilines resulted in the formation
of diastereomeric mixtures of products 14–16, with diastereo-
mer ratios ranging from 91 : 9 to 65 : 35. The major diastereo- probably due to the reported instability of the corresponding
hydroperoxide.17
mers for 15 and 16 were purified by column chromatography
Aniline-substituted tetrahydrocarbazole derivatives are
and the relative configuration of the alkyl group and aniline
residue was determined as trans by 1H-NMR spectroscopy effective as antiviral agents or in cancer treatment.15,18 Using
method B, we could directly synthesize compounds 25–28,
(see the ESI†).
which are highly pharmaceutically active against human papil-
Scheme 4 and Fig. 1 show the coupling products with less
electron deficient anilines or with more sensitive indole loma virus18a and hepatitis C virus18b or inhibit the vascular
endothelial growth factor (Fig. 1).18c
derivatives, using method B. Halogenated anilines generally
The exclusive C–H amination in 1-position of the tetra-
ducts 18, 25 and 26. The presence of the annulated saturated hydrocarbazole scaffold can be explained by an acid-catalyzed
gave better yields under these conditions, for example pro-
tautomerization reaction between the imine form of
six membered ring is not necessary for the coupling reaction;
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sustainable chemistry and should be applicable to a variety of
different substrate classes. Further investigation into the reac-
tion mechanism and extension of this method to access other
synthetically interesting products are now the focus of our
ongoing efforts.
Experimental
General
Except where indicated otherwise, all the reagents and solvents
were purchased from commercial sources and used as
received. All reactions and work-up procedures were conducted
under air except where noted otherwise.
Synthesis of starting materials
The different tetrahydrocarbazole and indole derivatives were
synthesized by Fischer Indole Synthesis using standard
procedures.19
Scheme 4 Product scope of the reaction using method B (see Table 1 for the
conditions).
General procedure for the synthesis of hydroperoxides14j
The indole derivative (1 g) was dissolved in toluene (100 ml).
To this solution was added rose bengal (2 mg). The resultant
reaction mixture was irradiated with a 23 watt lamp under an
atmosphere of O2. The progress of the reaction was controlled
1
by H NMR. After full conversion of the substrate, the precipi-
tated solid was filtered to afford the desired product in quanti-
tative yields.
General procedures for the reaction of hydroperoxides with
N–H nucleophiles
Method A (MeOH–CF3CO2H). The hydroperoxide (0.49 mmol,
1.0 equiv.) was dissolved in methanol (0.5 ml). To this reaction
mixture was added the desired nucleophile (0.49 mmol,
1.0 equiv.) followed by the addition of CF3CO2H (3.7 μL,
0.049 mmol, 0.1 equiv.). After 2–4 h, the solvent was reduced
to dryness and the resulting solid was purified by column
chromatography or by recrystallization.
Scheme 5 Proposed mechanism of the C–H amination and regiochemistry of
C–N bond formation by acid catalyzed tautomerization between imine 3 and
enamine 29.
hydroperoxide 3 and its enamine isomer 29 (Scheme 5). Proto-
nation of the hydroperoxide group and loss of hydrogen per-
oxide would result in a stabilized allylic cation 30, which can
be trapped by the N-nucleophile, furnishing exclusively the
thermodynamically preferred rearomatized product 31.
Method
B
(AcOH). The hydroperoxide (0.49 mmol,
1.0 equiv.) was dissolved in acetic acid (0.5 ml). To this reac-
tion mixture was added the desired nucleophile (0.49 mmol,
1.0 equiv.). After 2–4 h, the solvent was reduced to dryness and
the resulting solid was purified by column chromatography
or by recrystallization.
Conclusion
One-pot method with exchange of the solvent. After the syn-
We have developed a practical method for the C–H amination thesis of the peroxide according to the procedure described
of tetrahydrocarbazole derivatives via intermediate hydroper- above, toluene is removed under vacuum and the resulting
oxides with the aid of oxygen, visible light and catalytic amounts mixture is directly employed in the next step.
of a cheap Brønsted acid and a sensitizer. The reaction can
One-pot method without change of the solvent. The indole
be run in two steps or in a one-pot fashion, does not require derivative (0.49 mmol) was dissolved in methanol (10 ml). To
elevated temperatures or protective groups and can afford this solution was added phthalocyanine (2 mg). The resultant
the coupling products in high yields within 5–6 hours. The reaction mixture was irradiated with a 500 watt lamp under an
reaction has been applied to the synthesis of some representa- atmosphere of oxygen for 40 hours at −40 °C. The progress of
1
tive pharmaceutically active compounds. The strategy to func- the reaction was controlled by H NMR. After full conversion
tionalize C–H bonds via substitution of intermediate peroxides of the substrate, the aniline nucleophile (1.0 equiv.) and
formed by the action of oxygen holds great potential for CF3CO2H (10 mol%) were added and the mixture was stirred at
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ambient temperature. After 3 hours, the solvent was reduced
to dryness and the resulting solid was purified by column
chromatography or by recrystallization.
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