Diaryl-substituted (Dihydro)pyrrolo[3,2,1- hi ]indoles, a class of potent COX-2 inhibitors with tricyclic core structure

Article abstract of DOI:10.1021/acs.joc.5b00537

A new compound class of diaryl-substituted heterocycles with tricyclic dihydropyrrolo[3,2,1-hi]indole and pyrrolo[3,2,1-hi]indole core structures has been designed and was synthesized by a modular sequence of Friedel-Crafts acylation, amide formation, and

Full text of DOI:10.1021/acs.joc.5b00537

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Article
Diaryl-substituted (dihydro)pyrrolo[3,2,1-hi]indoles, a class
of potent COX-2 inhibitors with tricyclic core structure
Markus Laube, Cemena Gassner, Sai Kiran Sharma, Robert Günther, Arne Pigorsch,
Jonas König, Martin Köckerling, Frank Wuest, Jens Pietzsch, and Torsten Kniess
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00537 • Publication Date (Web): 24 Apr 2015
Downloaded from http://pubs.acs.org on April 27, 2015
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Title
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Diarylꢀsubstituted (dihydro)pyrrolo[3,2,1ꢀhi]indoles, a class of
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potent COXꢀ2 inhibitors with tricyclic core structure
Authors
Markus Laube†,‡*, Cemena Gassner†,‡, Sai Kiran Sharma§, Robert Güntherǁ, Arne Pigorsch○,
Jonas König○, Martin Köckerling○, Frank Wuest§, Jens Pietzsch†,‡, Torsten Kniess†*
Affiliations
†HelmholtzꢀZentrum DresdenꢀRossendorf, Institute of Radiopharmaceutical Cancer
Research, Department Radiopharmaceutical and Chemical Biology, Bautzner Landstr. 400,
01328 Dresden, Germany
‡Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062
Dresden, Germany
§Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta,
Canada T6G 1Z2
ǁHelmholtzꢀZentrum DresdenꢀRossendorf, Institute of Radiopharmaceutical Cancer
Research, Research Site Leipzig, Department of Neuroradiopharmaceuticals,
Permoserstraße 15, 04318 Leipzig, Germany
○Department of Inorganic Solid State Chemistry, Institute of Chemistry, University of Rostock,
AlbertꢀEinsteinꢀStr. 3a, 18059 Rostock, Germany
*Corresponding authors: m.laube@hzdr.de and t.kniess@hzdr.de
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TiCl4, Zn
DDQ
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56ꢀ85%
NH
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41ꢀ100%
N
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Y
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dihydropyrrolo[3,2,1ꢀhi]indoles
pyrrolo[3,2,1ꢀhi]indoles
modular & regioselective sequence comprising McMurry cyclization
identification of COXꢀ2 inhibitors with tricyclic core structure
A new compound class of diarylꢀsubstituted heterocycles with tricyclic dihydropyrrolo[3,2,1ꢀ
hi]indole and pyrrolo[3,2,1ꢀhi]indole core structures has been designed and was synthesized
by a modular sequence of FriedelꢀCrafts acylation, amide formation, and McMurry
cyclization. This synthesis route represents a novel and versatile access towards
dihydropyrrolo[3,2,1ꢀhi]indoles and is characterized by good chemical yields and high
modularity. From a set of nineteen derivatives, eleven candidates were selected for
determination of their COX inhibition potency and were found to be selective inhibitors with
high affinity to COXꢀ2 (IC50 ranging from 20 – 2500 nM and negligible inhibition of COXꢀ1).
The binding mode of the novel inhibitors in the active side of COXꢀ2 was calculated in silico
using the proteinꢀligand docking program GOLD by application of the molecular structures of
two compounds derived from Xꢀray crystallography. Two novel compounds with high affinity
to COXꢀ2 (6k = 70 nM, 8e = 60 nM) have got a fluoroꢀsubstituent making them to promising
candidates for the development of 18Fꢀradiolabeled COXꢀ2 inhibitors for imaging purposes
with positron emission tomography (PET).
Key words
pyrrolo[3,2,1ꢀhi]indoles, selective COXꢀ2 inhibitors, McMurry cyclization, GOLD, docking
studies, radiotracer
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Introduction
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The enzyme cyclooxygenaseꢀ2 (COXꢀ2 or prostaglandin H synthaseꢀ2, PGHSꢀ2) mediates
the rateꢀlimiting step in the biosynthesis of prostanoids, a class of autocrine and paracrine
acting lipidꢀmediators responsible for the regulation of physiological as well as
pathophysiological processes.1, 2 COXꢀ2 is involved in the pathogenesis of acute and chronic
inflammatory diseases and its expression is inducible by proinflammatory and proliferative
stimuli. The fact that inhibition of COXꢀ2 exerts antiꢀinflammatory, analgesic and antipyretic
actions but concurrent inhibition of COXꢀ1 causes unwanted gastrointestinal side effects
stimulated the initial search for selective COXꢀ2 inhibitors (COXIBs) in the late 1990’s.3
Meanwhile, COXꢀ2 overexpression was also identified in a variety of cancer entities
implicating the possibility to prevent and treat these diseases with COXIBs, e.g., in
combination with chemotherapy and/ or radiation therapy.4ꢀ6 Due to this and the fact that the
longꢀterm use of COXIBs like celecoxib and etoricoxib is limited because of adverse
cardiovascular effects, the search for novel compounds with improved pharmacological
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profile is an ongoing challenge in medicinal and pharmaceutical chemistry.7, COXꢀ2 is
considered as a biological marker in a number of diseases for that imaging agents targeting
COXꢀ2, e.g., radiolabeled COXꢀ2 inhibitors for positron emission tomography (PET), are
highly desirable.9ꢀ12
In general, most of the synthetic COXIBs can be assigned to the class of diaryl substituted
heterocycles bearing a methylsulfonyl or aminosulfonyl group at one of the phenyl rings.13, 14
Within this class, the inhibitors can possess a monocyclic and bicyclic core structure (figure
1).15 While for example celecoxib has a pyrazole (monocyclic) core, some diarylꢀsubstituted
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indoles represent potent inhibitors of COXꢀ2 with a bicyclic core.16,
In the search for
radiolabeled COXꢀ2 inhibitors a variety of compounds had been evaluated but none of them
has been transferred as radiotracer into the clinic showing the need for further efforts in this
field.9ꢀ12 In our previous work to develop a 18Fꢀlabeled COXꢀ2 inhibitor based on the 2,3ꢀ
diarylꢀ1Hꢀindole scaffold18 we recognized QSAR studies postulating for 2,3ꢀdiarylindoles a
positive influence on the inhibitory potency by an increase in the van der Waals volume of
the inhibitor.19 In this regard we hypothesized that novel potent leads for COXꢀ2 inhibitors
would be accessible by bridging the indole heterocycle between N1 and C7 using formally an
ethylene and ethenyl moiety (figure 1). The resulting heterocycle, the pyrrolo[3,2,1ꢀhi]indole,
is an aromatic, tricyclic 6,5,5ꢀmembered system containing one nitrogen atom. Although the
synthesis of some pyrrolo[3,2,1ꢀhi]indoles has been described before20, 21, for this compound
class no pharmacological effects have been reported yet. In contrast, the 1,2ꢀ
dihydropyrrolo[3,2,1ꢀhi]indole heterocycle can be found in some pharmacologically
interesting molecules, as CB2ꢀreceptor antagonists and inhibitors of cꢀMet expression.22ꢀ24
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COXꢀ2 inhibitors with a dihydropyrrolo[3,2,1ꢀhi]indole and pyrrolo[3,2,1ꢀhi]indole core have
not been described so far. This prompted us to synthesize a comprehensive set of
compounds of this new family and to evaluate their potency as COX inhibitors.
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Figure 1. General structure of COXꢀ2 inhibitors and target compounds of this work
Here we describe the synthesis of diarylꢀsubstituted dihydropyrrolo[3,2,1ꢀhi]indoles starting
from indoline and paraꢀsubstituted benzonitriles via FriedelꢀCrafts acylation and McMurry
cyclization and their conversion to the respective pyrrolo[3,2,1ꢀhi]indoles by
dehydrogenation. This represents a novel route towards 1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indoles
that is characterized by modularity, regioselectivity and a straightforward synthetic route.
COXꢀ1/COXꢀ2 inhibition activity of eleven candidates was determined where compounds of
both classes turned out to be highly potent and selective COXꢀ2 inhibitors. These findings
were supported in silico by proteinꢀligand docking studies with GOLD.
Results and Discussion
Chemical Synthesis
Primarily, 4ꢀ(methylsulfonyl)benzonitrile 2a, one of the starting materials for the main
synthesis sequence, was synthesized in two steps starting from 4ꢀ(methylthio)benzaldehyde
(scheme 1). In brief, 4ꢀ(methylthio)benzaldehyde was allowed to react with hydroxylamine
hydrochloride in DMSO to afford the 4ꢀ(methylthio)benzonitrile 1 in 84% yield via aldehyde
oxime formation and spontaneous dehydratization at a temperature of 100°C as described by
Chill and Mebane for other nitriles.25 The oxidation with metaꢀchloroperbenzoic acid formed
2a in a yield of 77%. Xꢀray structure analysis unambiguously confirmed the molecular
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structure of compounds 1 and 2a (figure 2). For details of the Xꢀray structure analyses, the
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reader is referred to the supporting information.
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Scheme 1. Synthesis of 4ꢀ(methylsulfonyl)benzonitrile (2a)a
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CHO
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a
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aReagents and conditions: (a) NH2OHꢁHCl, DMSO, 100°C; (b) MCPBA, DCM, r.t.
Figure 2. Molecular structure of compounds 1 (left) and 2a (right) in the crystal (ORTEP plot:
displacement thermal ellipsoids are drawn at 50% probability level)
The modular synthesis sequence to form pyrrolo[3,2,1ꢀhi]indoles is based on the Nꢀbenzoylꢀ
substituted 7ꢀbenzoylꢀindolines (5aꢀi) as main building block. The synthetic route starting
from paraꢀsubstituted benzonitriles 2aꢀe is outlined in scheme 2. The first step in this
sequence is the selective benzoylation of indoline in 7ꢀposition that was achieved starting
from the benzonitriles 2aꢀe by a BCl3ꢀmediated FriedelꢀCrafts reaction.26 The reaction with
the fluoroꢀ, chloroꢀ, methylꢀ or unsubstituted (2bꢀe) nitriles afforded the desired 7ꢀ
benzoylindolines 3bꢀe in 78ꢀ98% yield and high purity according to TLC, HPLC and NMR
analysis. In contrast, the reaction of indoline with the methylsulfonylꢀsubstituted benzonitrile
2a under the same conditions gave the 7ꢀ[4ꢀ(methylsulfonyl)benzoyl]ꢀ1Hꢀindoline 3a not in a
1
pure form and HꢀNMR analysis indicated the presence of 11ꢀ35% (m/m) 2a in the mixture.
Despite all efforts we were unable to purify 3a by column chromatography; hence the crude
product was used for the following step.
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Scheme 2. Modular synthesis sequence for
N
ꢀbenzoylꢀ7ꢀbenzoylindolines 5aꢀia
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aReagents and conditions: (a) i: BCl3, AlCl3, toluene, reflux, ii: 2 M HCl, reflux; (b) NEt3, THF, r.t.
Then, the 7ꢀbenzoylꢀsubstituted indolines 3aꢀe were converted by Nꢀacylation with the paraꢀ
substituted benzoyl chlorides 4aꢀf to the corresponding N,7ꢀdibenzoylꢀsubstituted indolines
5aꢀi. By combination of the five 7ꢀbenzoylꢀindolines 3aꢀe and the six benzoyl chlorides 4aꢀf, a
potential library of thirty compounds can be obtained what demonstrates nicely the
modularity of the experimental setup. However, we focused on compounds containing a
methylsulfonyl group at one of the aromatic rings because this structural motif is important for
the selective binding to COXꢀ2.15 By that, Nꢀacylation of the crude methylsufonylꢀsubstituted
7ꢀbenzoylindoline 3a afforded the building blocks 5aꢀd and 5i in 41ꢀ57% yield starting from
indoline. Analogously, the compounds 5eꢀh were prepared in 56ꢀ66% yield starting from the
7ꢀbenzoylindolines 3bꢀe and 4ꢀ(methylsulfonyl)benzoic acid chloride 4e which was
synthesized from the corresponding acid using SOCl2. The successful substitution in 7ꢀ
position of the indoline was unambiguously confirmed by Xꢀray crystal structure analysis of
5c as a representative (figure 3). Of note, an alternative modular synthetic route towards N,7ꢀ
dibenzoylꢀsubstituted indolines comprising Nꢀacylation in the first followed by Pdꢀcatalyzed 7ꢀ
acylation in the second step has been presented recently by Kim et al. which could be useful
if this route fails.27
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Figure 3. Molecular structure of compound 5c in the crystal (the figure shows one of the two independent
molecules in the asymmetric; ORTEP plot: displacement thermal ellipsoids are drawn at 50% probability
level).
To build the 6,5,5ꢀmembered heterocyclic core of the dihydropyrrolo[3,2,1ꢀhi]indoles,
McMurry cyclization was conducted using the “Instantꢀmethod”.28ꢀ30 Briefly, each N,7ꢀ
dibenzoylꢀsubstituted indoline 5aꢀi was allowed to react with TiCl4 and Zn in THF under reflux
affording the dihydropyrrolo[3,2,1ꢀhi]indoles 6aꢀi in yields of 56ꢀ85% (scheme 3).
Scheme 3. Synthesis of dihydropyrrolo[3,2,1ꢀhi]indoles 6aꢀia
N
a
N
O O
R2
R1
5aꢀi
R2
R1
6aꢀi
5aꢀi/ 6aꢀi
5a 6a
/
5f 6f
/ :
: R1/ R2= SO2Me / F
R1/ R2= Cl / SO2Me
5b/6b: R1/ R2= SO2Me / Cl 5g/6g: R1/ R2= H / SO2Me
5c 6c 5h 6h
: R1/ R2= Me / SO2Me
/
: R1/ R2= SO2Me / H
5d/6d: R1/ R2= SO2Me / Me 5i/6i: R1/ R2= SO2Me / OMe
5e 6e
/
/
: R1/ R2= F / SO2Me
aReagents and conditions: (a) TiCl4, Zn, THF, 70°C.
This strategy represents to the best of our knowledge a novel synthetic route towards
dihydropyrrolo[3,2,1ꢀhi]indoles. In the past, the synthesis of dihydropyrrolo[3,2,1ꢀhi]indoles
has been generally described by Fischer indole synthesis.31ꢀ33 Although this reaction is useful
due to its regioselectivity, the low modularity and, in some cases, the laborious access to
appropriate starting materials may be disadvantageous for its utilization, especially for the
library synthesized in this work. Another access to dihydropyrrolo[3,2,1ꢀhi]indoles is the
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synthesis by transition metal catalyzed methods34ꢀ37, dehydrogenation21, radical cyclization38,
as well as photochemical rearrangements39 (scheme 4). However, steric restrictions for the
starting materials, low regioselectivity or the need for special catalysts make these
approaches unsuitable for a general use. Advantageously, with the synthetic route presented
by us differently substituted indolines, nitriles as well as benzoyl chlorides may be combined
because the BCl3ꢀmediated FriedelꢀCrafts acylation is yielding 7ꢀsubstituted indolines
selectively and the McMurry cyclization has a high compatibility for different functional
groups. Hence, our synthetic route gives a highly modular and convenient access to
dihydropyrrolo[3,2,1ꢀhi]indoles.
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Scheme 4. Synthetic route towards dihydropyrrolo[3,2,1ꢀhi]indoles followed in this work and examples
from the literature
For compounds 6a and 6e, Xꢀray crystal structure analyses were performed what
unambiguously confirmed the identity of both regioisomers (figure 4). Interestingly, the
ethylene bridge obviously causes a high ring strain in the 1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole
system, such that the bond between the carbon atoms C1 and C2 (accordingly C7 and C8 in
the numbering in figure 4) is stretched. Although the ethylene bridge is not part of the
aromatic system, the dihydropyrrolo[3,2,1ꢀhi]indole system is almost planar. In both
compounds, the methylsulfonylꢀsubstituted phenyl ring is less twisted out of the plane of the
dihydropyrrolo[3,2,1ꢀhi]indole moiety than the fluoroꢀsubstituted phenyl ring. This indicates
the preferred interaction of the electronꢀdeficient methylsulfonylꢀsubstituted phenyl ring with
the indoleꢀlike πꢀsystem of the electronꢀrich dihydropyrrolo[3,2,1ꢀhi]indole compared to the
fluoroꢀsubstituted phenyl ring.
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Figure 4. Molecular structure of compound 6a (left) and 6e (right) in the crystal (the figure of 6a shows
one of the two independent molecules in the asymmetric unit; ORTEP plot: displacement thermal
ellipsoids are drawn at 50% probability level)
With the aim to synthesize an appropriate precursor for PET radiotracer development, that
means in this case a compound suitable for [18F]fluoroethylation, additionally a hydroxyl
derivative was prepared (scheme 5). Therefore, 6i was demethylated using BBr3 in DCM to
give the 4ꢀhydroxyphenylꢀsubstituted dihydropyrrolo[3,2,1ꢀhi]indole 6j in 91% yield. Then, 2ꢀ
fluoroethylꢀ4ꢀnitrobenzenesulfonate 7, prepared by the reaction of 4ꢀnitrobenzenesulfonyl
chloride and 2ꢀfluoroethanol in THF with KOSiMe3, was allowed to react with 6j in THF using
KOtBu as a base. This gave the 2ꢀfluoroethoxyꢀsubstituted dihydropyrrolo[3,2,1ꢀhi]indole 6k
in 55% yield, a compound that can serve as reference for the radiosynthesis of the
corresponding 18Fꢀradiolabeled PETꢀtracer.
Scheme 5. Synthesis of dihydropyrrolo[3,2,1ꢀhi]indole 6ka
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aReagents and conditions: (a) BBr3, DCM, r.t.; (b) 4ꢀnitrobenzenesulfonyl chloride, KOSiMe3, THF, 0°C; (c)
KOtBu, THF, 70°C.
Finally, from the 1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indoles 6aꢀh the corresponding pyrrolo[3,2,1ꢀ
hi]indoles 8aꢀh were generated by dehydrogenation using DDQ in benzene (scheme 6). With
exception of 8b for that the yield was only moderate (41%), all other pyrrolo[3,2,1ꢀhi]indoles
were formed in high yields of 75ꢀ100%. Noteworthy, according to the structural similarity of
starting materials and products the column chromatographic purification required eluents with
high retention on silica gel (Rf of 0.1ꢀ0.2). Only few synthetic approaches for the synthesis of
pyrrolo[3,2,1ꢀhi]indoles have been reported which are i.e. intramolecular Aldolꢀcyclization20,
21, dehydrogenation of 1,2ꢀdihydroꢀ and 1,2,4,5ꢀtetrahydropyrrolo[3,2,1ꢀhi]indoles by Pd/C21,
40
and a polyphosphoric acid catalyzed reaction41. In this context, dehydrogenation by DDQ
in benzene represents a suitable system for the synthesis of this highly strained ring system
as well.
Scheme 6. Synthesis of pyrrolo[3,2,1ꢀhi]indoles 8aꢀha
aReagents and conditions: (a) DDQ, benzene, 100°C.
COX inhibitory activity
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From the pool of nineteen synthesized dihydropyrrolo[3,2,1ꢀhi]indoles 6 and pyrrolo[3,2,1ꢀ
hi]indoles 8, eleven candidates were selected for determination of the COX inhibition potency
in order to find suitable candidates for labeling with fluorineꢀ18 or carbonꢀ11 and, on the
other hand, to get deeper insights into structure activity relationships. The COX inhibition
potency of the selected dihydropyrrolo[3,2,1ꢀhi]indoles and pyrrolo[3,2,1ꢀhi]indoles as well as
celecoxib as a reference was determined in vitro using a commercial COX assay (“COX
Fluorescent Inhibitor Screening Assay Kit”, Item No. 700100, Cayman Chemical, Ann Arbor,
USA). The results are shown in table 1.
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Table 1. COXꢀinhibitory selected dihydropyrrolo[3,2,1ꢀhi]indoles and pyrrolo[3,2,1ꢀhi]indoles
IC50 (COXꢀ1) IC50 (COXꢀ2)
No. (R1 / R2)
[ꢁM]
[ꢁM]
SI*
6a (SO2CH3 / F)
>100
2.50
> 40
6c (SO2CH3 / H)
6e (F / SO2CH3)
6h (CH3 / SO2CH3)
>100
>100
>100
0.40
0.15
0.10
> 250
> 666
> 1000
6k (SO2CH3 / OEtF)
8a (SO2CH3 / F)
8b (SO2CH3 / Cl)
8c (SO2CH3 / H)
8d (SO2CH3 / CH3)
8e (F / SO2CH3)
8h (CH3 / SO2CH3)
Celecoxib
>100
>100
>100
>100
>100
>100
>100
115
0.07
0.60
0.05
0.20
0.02
0.04
0.50
0.06
> 1428
> 166
> 2000
> 500
> 5000
> 2500
> 200
1917
*SIꢂ Selectivity index, SI = IC50 (COXꢀ1) / IC50 (COXꢀ2)
At the first view it became obvious that all tested compounds with exception of 6a inhibit
COXꢀ2 in the nanomolar level and, noteworthy, do not substantially inhibit COXꢀ1 at all. This
demonstrates that the compound class of dihydropyrroloꢀ and pyrrolo[3,2,1ꢀhi]indoles are
COX inhibitors with exceptional selectivity for COXꢀ2, with four compounds (6k, 8b, 8d and
8e) showing a selectivity index comparable with that of celecoxib. Within the evaluated
series, the fluoroꢀsubstituted dihydropyrrolo[3,2,1ꢀhi]indole 6a shows the weakest COXꢀ2
inhibition potency with an IC50 for COXꢀ2 about 2.5 ꢃM. Compounds 6c, 6e, 6h, 8a, 8c and
8h were identified as selective COXꢀ2 inhibitors with an IC50 ranging in the 0.5 ꢀ 0.1 ꢃM level
whereas compounds 6k, 8b, 8d and 8e turned out to inhibit COXꢀ2 with an IC50 between 20
and 70 nM. By a direct comparison, the pyrrolo[3,2,1ꢀhi]indoles are more potent than their
analogous dihydropyrrolo[3,2,1ꢀhi]indole derivatives. In three of four pairs the affinity to COXꢀ
2 was improved by a magnitude of ten comparing the dihydroꢀcompound with the oxidized
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species (6a vs. 8a, 6c vs. 8c, 6e vs. 8e). This indicates not only a steric but also electronic
influence resulting from the extended πꢀsystem. However, for one pair the
dihydropyrrolo[3,2,1ꢀhi]indole is slightly more potent (6h vs. 8h). It is obvious that bulkier
substituents cause higher inhibition potency because a replacement of a fluoroꢀ by a chloro
atom results in an improvement by factor 10 (8a vs. 8b). A similar effect was observed by
substitution of hydrogen by a methyl group (8c vs. 8d). Regarding the regioisomers there are
no clear tendencies to conclude; in the case of dihydropyrrolo[3,2,1ꢀhi]indoles 6a and 6e the
inhibition potency was increased by shifting the methylsulfonyl substituent from the 4ꢀphenyl
ring to the 5ꢀphenyl ring. The same tendency was found by shifting the methylsulfonyl group
in the corresponding pyrrolo[3,2,1ꢀhi]indoles 8a and 8e. In contrast, the analogous
displacement within the pair 8d and 8h leads to a decrease of affinity for COXꢀ2.
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Recently, we investigated the COX inhibition potency of a number of fluoroꢀ and methoxyꢀ
substituted 2,3ꢀdiarylꢀ1Hꢀindole derivatives and found with the same assay 5ꢀ42% inhibition
of COXꢀ2 in the 0.1 ꢃM level indicating IC50ꢀvalues in the upper nanomolar or even
micromolar range.42 By a direct comparison of the indole derivatives with the
dihydropyrrolo[3,2,1ꢀhi]indoles as well as the pyrrolo[3,2,1ꢀhi]indoles, the last two
demonstrate a noteworthy higher affinity as well as increased selectivity towards COXꢀ2.
Hence, the enlargement of the bicyclic indole core by either an ethenyl or an ethylene bridge
has a positive impact on the COXꢀ2 inhibition potency. This is in agreement with previous
QSAR studies for 2,3ꢀdiarylꢀ1Hꢀindoles postulating a positive impact on COX inhibition
potency by increasing the van der Waals volume of the indole core.19
Thus, we have identified a class of vicinal substituted diarylheterocycles with a tricyclic core
that act as potent COXꢀ2 inhibitors. This is much more surprising since, to the best of our
knowledge, this type of compounds has not been described yet as COX inhibitors at all in
prominent reports and reviews regarding COX.13ꢀ15, 43ꢀ46 As much as we know, there exist a
few reports for COXꢀ2 inhibitors with tricyclic core but only having none or one phenyl
substituent, some of them were designed as conformational restricted derivatives of
monocyclic COXIBs.47ꢀ54 Since the elegant scheme presented by Singh & Mittal15 to classify
COXꢀ2 inhibitors lacks this class of inhibitors, herewith we present an updated scheme
(figure 5) with the aim to stimulate synthetic approaches for the synthesis of novel COXꢀ2
inhibitors with tricyclic core.
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central core
ꢀ substituted with two phenyl rings or other substituents ꢀ
5
6
7
carbocyclic
acyclic
heterocyclic
8
9
monocyclic
bicyclic
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O
O
NH2
O
O
tricyclic
O
S
S
S
R
S
O
O
O
O
N
N
O
N
O
N
F3C
N
S
R
O
O
[52]
[47]
[49]
Figure 5. Update of the structural classification of COXꢀ2 inhibitors according to Singh & Mittal15
with further examples from the literature
Molecular docking studies
As mentioned above, the diarylꢀsubstituted (dihydro)pyrrolo[3,2,1ꢀhi]indoles 6 and 8
represent potent inhibitors of COXꢀ2. We performed in silico studies using the protein ligand
55
docking program GOLD
using the elucidated molecular structure of 6a and 6e to get
information about the binding mode of the novel inhibitors in the active side of COXꢀ2. For
this, the crystal structure of COXꢀ2 (PDBꢀentry 3LN1, numbering based on ovine COXꢀ156)
was prepared for docking using MOE. The center of the active side was defined at the
position of the coꢀcrystallized molecule of celecoxib. Docking studies taking the whole protein
as docking side (n = 10, r = 50 Å) revealed that the most preferred docking position is located
within the active side of the enzyme. When docking in the active side of COXꢀ2 (n = 100,
r = 10 Å) was performed as shown in figure 6, the proposed binding mode of 6a and 6e was
found to be very similar to that of celecoxib. That is consistent with the ability of both
compounds to inhibit COXꢀ2 with high affinity. The methylsulfonylꢀsubstituted phenyl ring of
6a sticks into the side pocket of COXꢀ2 and forms hydrogen bonds to Argꢀ513 (6a: d(Nꢀ
HꢁꢁꢁO) = 1.926 Å, 6e: d(NꢀHꢁꢁꢁO) = 1.997 Å) and Hisꢀ90 (6a: d(NꢀHꢁꢁꢁO) = 2.243 Å, 6e: d(Nꢀ
HꢁꢁꢁO) = 2.321 Å) as well as CꢀHꢁꢁꢁπꢀinteractions between the phenyl ring and Serꢀ353 as
well as Valꢀ523 (6a: d = 2.702ꢀ2.790 Å, 6e: d = 2.699ꢀ2.773 Å,). The fluoroꢀsubstituted
phenyl ring interacts by donorꢀacceptor interactions (6a: d(CindoleꢀHꢁꢁꢁF) = 1.561 Å, 6e:
d(CindoleꢀHꢁꢁꢁF) = 1.538 Å) with Trpꢀ387. In 6a, the indoleꢀmoiety of the central
dihydropyrrolo[3,2,1ꢀhi]indoleꢀcore interacts by CꢀHꢁꢁꢁπꢀinteractions to Valꢀ349 (D(Cꢀ
HꢁꢁꢁCentroidphenyl) = 3.219 Å) and Alaꢀ527 (D(CꢀHꢁꢁꢁCentroidpyrrol) = 3.919 Å) as well as weak
hydrogen bonds with Serꢀ530 (6a: d(CꢀHꢁꢁꢁO) = 2.737 Å). In 6e, the indoleꢀmoiety of the
central dihydropyrrolo[3,2,1ꢀhi]indoleꢀcore interacts by CꢀHꢁꢁꢁπꢀinteractions also with Valꢀ349
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(D(CꢀHꢁꢁꢁCentroidphenyl) = 3.345 Å)
and
Alaꢀ527
(D(CꢀHꢁꢁꢁCentroidpyrrol) = 3.432 Å).
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8
9
Furthermore, 6e forms weak hydrogen bonds with Tyrꢀ355 (6a: d(CꢀHꢁꢁꢁO) = 2.725 Å). Of
note, the GOLD score, a dimensionless value giving a guide how good the docking pose is,
was determined to be 107.2 for 6a, 105.5 for 6e, and 97.5 for docking of celecoxib what
reflects the ability of both compounds to inhibit COXꢀ2 but is not matching the order of
potency observed experimentally.
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Figure 6. Docking of 6a (left) and 6e (right) in the active side of COXꢀ2. The ten best docking results from
100 runs are shown as superimposed structures (black Cꢀatoms) together with the coꢀcrystallized
celecoxib molecule (red Cꢀatoms) as a reference.
Identification of candidates for radiotracer development
Several highly potent COXꢀ2 inhibitors were identified within the (dihydro)pyrrolo[3,2,1ꢀ
hi]indole series, among them compound 8d as the most potent one having an IC50 for COXꢀ2
of 20 nM. Thus, 8d represents a promising candidate for radiolabeling with carbonꢀ11 by
introduction of a 11Cꢀmethylsulfonyl group, e.g. starting from the respective sulfinate
precursor as described by de Vries et al.57 8e shows high COXꢀ2 inhibition potency with an
IC50(COXꢀ2) of 40 nM and is hence a suitable compound for the development of a fluorineꢀ18
labeled radiotracer via McMurry cyclization as described by us.18 Furthermore, 6k represents
a promising candidate for labeling with fluorineꢀ18 by means of [18F]fluoroethylation starting
from the corresponding hydroxylꢀprecursor.
Summary and Conclusion
A set of diarylꢀsubstituted heterocycles with the tricyclic dihydropyrrolo[3,2,1ꢀhi]indole and
pyrrolo[3,2,1ꢀhi]indole ring core was successfully synthesized by a sequence of Friedelꢀ
Crafts acylation, amide formation, McMurry cyclization, and dehydrogenation. This synthesis
route represents a novel and versatile access towards dihydropyrrolo[3,2,1ꢀhi]indoles and is
characterized by good chemical yields and high modularity. The molecular structure of the
substituted dihydropyrrolo[3,2,1ꢀhi]indoles 6a and 6e beside other intermediates was
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analyzed by Xꢀray diffraction analyses. For evaluation of the COX affinity of this compound
class, a set of eleven compounds was selected and subjected to a COXꢀinhibition assay.
Within this series the dihydropyrrolo[3,2,1ꢀhi]indole 6k, and the pyrrolo[3,2,1ꢀhi]indoles 8d
and 8e were identified as COXꢀ2 inhibitors having an affinity similar or higher than celecoxib.
In regard to PET radiotracer development, the methylꢀsubstituted compound 8d with an
IC50(COXꢀ2) of 20 nM is the most potent inhibitor of both classes and a promising candidate
for radiolabeling with carbonꢀ11. The fluoroethoxyꢀsubstituted compounds 6k and the fluoroꢀ
substituted derivative 8e were identified as worthy candidates for 18Fꢀradiotracer
development, particularly accessible by either [18F]fluoroethylation or 18Fꢀfluorination with
subsequent McMurry cyclization.
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In summary, the dihydropyrrolo[3,2,1ꢀhi]indoles and pyrrolo[3,2,1ꢀhi]indoles were found to be
suitable as tricyclic core structures for the development of inhibitors with high affinity and
selectivity towards COXꢀ2. Within this new class of COXꢀ2 inhibitors with tricyclic core, three
compounds, 6k, 8d, and 8e, were identified to have a considerable potential for the
development of radiolabeled COXꢀ2 inhibitors for functional imaging of COXꢀ2 activity by
PET.
Experimental Section
All commercial reagents and solvents were used without further purification unless otherwise
specified. Flash chromatography was conducted using Silica Gel (mesh size 40ꢀ63 ꢃm).
DCVC indicates the use of “Dry Column Vacuum Chromatography” as reported by Pedersen
and Rosenbaum.58 Thinꢀlayer chromatography (TLC) was performed on silica gel Fꢀ254
aluminum plates. Visualization was carried out using UV (254 nm/366 nm). Analytical HPLC
analysis were carried out with a C18 column (250
× 4.6 mm, 5 ꢃm) using an isocratic eluent
(acetonitrile/ water+0.1% TFA 70/30) by a gradient pump with a flow rate of 1 mL/min. The
products were monitored by an UV detector at 254 nm. Purity of all compounds exceeded
95% as determined by analytical HPLC analysis unless otherwise stated. Low resolution
mass spectra were obtained using ASAP ionization (Atmospheric Solids Analysis ProbeTM).
High resolution mass spectra were obtained on a QꢀTOF MS using electrospray ionization.
Elemental analyses were performed using an Elemental Analyzer. Melting points were
determined on a melting points apparatus and are uncorrected. Nuclear magnetic resonance
spectra were recorded on a 400 MHz spectrometer. NMR spectra were referenced to the
1
residual solvent shifts for H and 13C, and to CFCl3 for 19F spectra as internal standard. δꢀ
Values are given in ppm. For compounds 3a and 6j, isotope effects on 13CꢀNMR chemical
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shifts59 were observed in acetoneꢀd6 which were caused by hydrogen/deuterium exchange
while measurement. The signals with deuterium isotope shifts are indicated and the range
from minimal to maximal value is given.
6
7
8
9
Spectroscopic and fluorescent properties were determined using an multiꢀmode microplate
reader. The samples were dissolved in an appropriate amount of DMSO to give a 10 mM
stock solution. To 20 ꢃL of this stock solution was added 80 ꢃL DMSO, 100 ꢃL TWEEN 20
and 9800 ꢃL PBS to yield a 20 ꢃM test solution for the measurement of the extinction
coefficient. Using 1 cm quartz vessels, the extinction coefficients at λ > 280 nm were
determined from the absorption spectra. The extinction coefficients are given in ε/dm3 molꢀ1
cmꢀ1 at the specified wavelength in nm. The fluorescence excitation and emission spectra
were determined using a 100 ꢃM solution of the test compound in a solution of 1% DMSO
and 1% TWEEN 20 in PBS. In both experiments, baseline correction was done using a
solution of 1% DMSO and 1% TWEEN 20 in PBS.
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Chemical Synthesis
4ꢀ(Methylthio)benzonitrile (1). 4ꢀ(Methylthio)benzaldehyde (8.57 mL, 10 g, 65 mmol) was
added at room temperature to a solution of hydroxylamine hydrochloride (8.41 g, 0.121 mol)
in anhydrous DMSO (130 mL). The mixture was heated at 100°C for 1 h. After cooling to
room temperature, the mixture was poured into water (300 mL) and the resulting precipitate
was separated by filtration and washed with a small amount of water. After drying the solid in
vacuum, 1 was obtained as pale beige solid (8.19 g, 84%). mp 60ꢀ62°C (Lit. 60: 62ꢀ63°C);
1
Rf = 0.62 (petroleum ether/ ethyl acetate 50:50); H NMR (acetoneꢀd6, 400 MHz): δ 2.57 (s,
3
3
3H), 7.42 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H); 13C {1H} NMR (acetoneꢀd6, 101
MHz): δ 14.5, 108.4, 119.4, 126.5, 133.1, 147.2. Crystals suitable for Xꢀray analysis were
obtained by slow evaporation of a solution of 1 in DCM layered with petroleum ether.
4ꢀ(Methylsulfonyl)benzonitrile (2a). The synthesis was performed as described by Creary
et al.60 Instead of separation in water and ether, a mixture of water (150 mL) and ethyl
acetate (200 mL) was used. Instead of crystallization from hexane/ether, the crude product
was purified by column chromatography (DCVC, petroleum ether/ ethyl acetate
100:0
ꢀ85:15
ꢀ50:50ꢀ0:100). Starting from
1
(8.18 g, 55 mmol) and 77% mꢀ
chloroperbenzoic acid (27.85 g, 124 mmol), 2a was obtained as colorless, crystalline solid
(7.62 g, 77%). mp 144ꢀ146°C (Lit. 60: 142ꢀ143°C); Rf = 0.32 (petroleum ether/ ethyl acetate
1
3
50:50); H NMR (acetoneꢀd6, 400 MHz,): δ 3.23 (s, 3H); 8.10 (d, J = 8.7 Hz, 2H), 8.17 (d,
3J = 8.7 Hz, 2H); 13C {1H} NMR (acetoneꢀd6,101 MHz): δ 43.9, 117.8, 118.1, 129.1, 134.2,
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146.1. Crystals suitable for Xꢀray analysis were obtained by slow evaporation of a solution of
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2a in DCM layered with petroleum ether.
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General Procedure A for the synthesis of 7ꢀbenzoylꢀ1Hꢀindolines (3aꢀe). The synthesis
9
followed the procedure described by Lo et al.26 and Walsh et al.61 Under nitrogen
atmosphere, to a solution of a 1 M BCl3 solution in toluene (4.4 mL. 4.4 mmol) was added in
this order indoline (449 ꢃL, 4 mmol) in 1.8 mL toluene, the appropriate nitrile (as given below)
and anhydrous AlCl3 (608 mg, 4.4 mmol). The mixture was heated to reflux for 12ꢀ18 h. After
that, water (0.25 mL) and 10% HCl (4.5 mL) was added at a temperature of 0°C and the
mixture was heated to reflux for 2 h. The mixture was cooled to 0°C and the resulting
precipitate was filtered off by vacuum filtration. Afterwards, the solid was suspended in 2.5%
NaOH (10 mL) and stirred for 1 h at room temperature. Filtration and drying in vacuo yields
the desired product.
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7ꢀ[4ꢀ(Methylsulfonyl)benzoyl]ꢀ1Hꢀindoline (3a). By following general procedure A, a yellow
solid resulted that contains 65ꢀ89% (w/w) of 3a in a mixture beside 2a. The crude product
was used for the next step (see general procedure C for synthesis of 5aꢀd and 5i). Rf = 0.28
(petroleum ether/ ethyl acetate 50:50); 1H NMR (acetoneꢀd6, 400 MHz): δ 3.10 (t, 3J = 8.6 Hz,
2H), 3.20 (s, 3H), 3.83 (td, 3J = 8.6 Hz, 3J = 3.4 Hz, 2H), 6.47 (t, 3J = 7.1 Hz, 3J = 8.1 Hz, 1H,
3
3
4
H), 7.04 (s, 1H), 7.11 (d, J = 8.2 Hz, 1H), 7.22 (d, J = 6.9 Hz, J = 1.1 Hz, 1H), 7.82 (d,
3J = 8.3 Hz, 2H), 8.05ꢀ8.12# (m, 3J = 8.3 Hz, 2H), further signals of
4ꢀ
(methylsulfonyl)benzonitrile (2a) in the spectra: 3.23 (s, 3H), 8.05ꢀ8.12# (m, 3J = 8.4 Hz, 2H),
3
8.17 (d, J = 8.4 Hz, 1H),# signal overlay from 2a and 3a; 13C {1H} NMR (acetoneꢀd6, 101
MHz): δ 28.4, 44.2, 47.4*, 114.7*, 115.8*, 128.1, 129.8, 129.9, 130.8, 132.9, 143.7, 145.5,
156.4*, 195.6, further signals of 4ꢀ(methylsulfonyl)benzonitrile (2a) in the spectra: 43.9,
117.8, 118.1, 129.1, 134.2, 146.1, *deuterium isotope shifts were observed in the range of 30
and 110 ppb.
7ꢀ(4ꢀFluorobenzoyl)ꢀ1Hꢀindoline (3b). Starting from 4ꢀfluorobenzonitrile (2b) (729 mg,
6.0 mmol) and indoline (449 ꢃL, 477 mg, 4.0 mmol), 3b was obtained by following general
procedure A as a yellow solid (842 mg, 87%). mp 135ꢀ137°C (Lit. 62: 131ꢀ133°C); Rf = 0.63
(petroleum ether/ ethyl acetate 50:50); 1H NMR (CDCl3, 400 MHz): δ 3.11 (t, 3J = 8.6 Hz, 2H),
3
3
3
3.80 (t, J = 8.6 Hz, 2H), 6.49 (t, J = 7.8 Hz, J = 7.3 Hz, 1H), 7.03 (br. s., 1H), 7.14 (t,
3
3
3JH,H = 3JH,F = 8.7 Hz, 2H), 7.18 (d, J = 6.8 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.68 (dd,
4
3J = 8.7 Hz, JH,F = 5.5 Hz, 1H); 13C {1H} NMR (CDCl3, 101 MHz): δ 28.3, 46.9, 114.9, 115.3,
2
3
4
115.3 (d, JC,F = 22 Hz), 128.8, 130.5, 131.4 (d, JC,F = 9 Hz), 131.7, 136.0 (d, JC,F = 3 Hz),
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155.6, 164.5 (d, JC,F = 251 Hz), 196.0; 19F NMR (CDCl3, 376 MHz): δ ꢀ114.0; MS (ASAP+):
4
5
m/z (%) = 242 (100) [M+H]+, 241 (72) [M]+.
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7ꢀ(4ꢀChlorobenzoyl)ꢀ1Hꢀindoline (3c). Starting from 4ꢀchlorobenzonitrile (2c) (826 mg,
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6.0 mmol) and indoline (449 ꢃL, 477 mg, 4.0 mmol), 3c was obtained by following general
procedure A as a yellow solid (1008 mg, 98%). mp 110ꢀ113°C (Lit. 62: 109ꢀ111°C); Rf = 0.64
(petroleum ether/ ethyl acetate 50:50); 1H NMR (CDCl3, 400 MHz): δ 3.11 (t, 3J = 8.5 Hz, 2H),
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(m, J = 8.3 Hz, 3J = 7.1 Hz, 4J = 0.8 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz,
2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 28.2, 46.9, 114.7, 115.3, 128.5, 128.9, 130.4, 130.4,
131.8, 137.1, 138.2, 155.7, 196.0; MS (ASAP+): m/z (%) = 260 (32) [M+H, 37Cl]+, 259 (32),
258 (100) [M+H, 35Cl]+, 257 (52) [M, 35Cl]+.
7ꢀBenzoylꢀ1Hꢀindoline (3d). Starting from benzonitrile (2d) (619 ꢃL, 619 mg, 6.0 mmol) and
indoline (449 ꢃL, 477 mg, 4.0 mmol), 3d was obtained by following general procedure A as a
yellow solid (746 mg, 84%). mp 122ꢀ124°C (Lit. 63: 124ꢀ125°C); Rf = 0.63 (petroleum ether/
1
ethyl acetate 50:50); H NMR (CDCl3, 400 MHz): δ 3.11 (t, 3J = 8.5 Hz, 2H), 3.81 (t,
3J = 8.6 Hz, 2H), 6.49 (dd, 3J = 8.1 Hz, 3J = 7.0 Hz, 1H), 7.10 (br. s., 1H), 7.18 (d, 3J = 6.9 Hz,
1H), 7.27 (d, 3J = 8.0 Hz, 1H), 7.43–7.54 (m, 3H), 7.65 (dd, 3J = 8.0 Hz, 4J = 1.3 Hz, 2H); 13
C
{1H} NMR (CDCl3, 101 MHz): δ 28.2, 46.9, 115.0, 115.2, 128.2, 128.7, 128.9, 130.8, 130.9,
131.6, 139.9, 155.6, 197.5; MS (ASAP+): m/z (%) = 224 (100) [M+H]+, 223 (83) [M]+.
7ꢀ(4ꢀMethylbenzoyl)ꢀ1Hꢀindoline (3e). Starting from 4ꢀtolunitrile (2e) (706 mg, 6.0 mmol)
and indoline (449 ꢃL, 477 mg, 4.0 mmol), 3e was obtained by following general procedure A
as a yellow solid (744 mg, 78%). mp 102ꢀ104°C; Rf = 0.67 (petroleum ether/ ethyl acetate
1
3
50:50); H NMR (CDCl3, 400 MHz): δ 2.43 (s, 3H), 3.10 (t, J = 8.6 Hz, 2H), 3.79 (t,
3J = 8.6 Hz, 2H), 6.49 (dd, 3J = 8.0 Hz, 3J = 7.1 Hz, 1H), 7.02 (br. s., 1H), 7.18 (d, 3J = 6.9 Hz,
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1H), 7.26 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H); 13C {1H}
NMR (CDCl3, 101 MHz): δ = 21.7, 28.3, 46.9, 115.2, 115.3, 128.5, 128.9, 129.2, 130.8,
131.5, 137.1, 141.4, 155.5, 197.3; MS (ASAP+): m/z (%) = 238 (100) [M+H]+, 237 (62) [M]+;
HRMS (ESI+) m/z calcd for C16H15NONa [M + Na+] 260.10458, found 260.10480.
Procedure B for the synthesis of 4ꢀ(Methylsulfonyl)benzoyl chloride (4e). The synthesis
followed the procedure described by Guo et al.64 modified by the removal of SOCl2 according
to Gubert et al.65 Under nitrogen atmosphere, 4ꢀ(methylsulfonyl)benzoic acid (269 mg,
1.34 mmol) was added to 1.13 mL SOCl2 and DMF (3 drops). The mixture was heated under
reflux (60ꢀ70°C) over night. A clear solution resulted. SOCl2 and DMF were removed under
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reduced pressure. Then three times, benzene (1.5 mL) was added at room temperature, the
mixture was stirred and the solvent was removed. The resulting colorless solid (mp 130ꢀ
135°C, Lit: 66) was used without further purification for the synthesis of 5eꢀh.
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General procedure C for the synthesis of Nꢀbenzoylꢀ7ꢀ(benzoyl)indolines (5aꢀi). Under
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nitrogen atmosphere, the corresponding acid chloride (0.87 mmol) in anhydrous THF
(1.0 mL) was added to a solution of the 7ꢀbenzoylindoline (0.87 mmol) and NEt3 (138 ꢃL, 101
mg, 1.00 mmol) in anhydrous THF (1.8 mL). The reaction mixture was stirred for 2 h at room
temperature. After that, the mixture was preꢀadsorbed on silica gel and purification was
carried out by column chromatography as given below.
Nꢀ(4ꢀFluorobenzoyl)ꢀ7ꢀ[4ꢀ(methylsulfonyl)benzoyl]indoline (5a). The crude starting
material 7ꢀ[4ꢀ(methylsulfonyl)benzoyl]ꢀ1Hꢀindoline (3a) (232 mg) was synthesized by
following general procedure A starting from indoline (126 ꢃL, 133 mg, 1.12 mmol) and 2a
(245 mg, 1.35 mmol)). 212 mg of this raw product of 3a were allowed to react with 4ꢀ
fluorobenzoyl chloride (4a) (84.3 ꢃL, 113.1 mg, 0.71 mmol) following general procedure C.
Purification was carried out by column chromatography (DCVC, petroleum ether/ ethyl
acetate 100:0ꢀ0:100, then chloroform/ methanol 90:10). By that, 5a was obtained as a pale
yellow solid (202 mg, 47% starting from indoline). mp 245ꢀ248°C; Rf = 0.14 (petroleum ether/
ethyl acetate 50:50); Rf = 0.59 (chloroform/ methanol 95:5); 1H NMR (CDCl3, 400
MHz): δ 3.04 (s, 3H), 3.17 (t, 3J = 7.9 Hz, 2H), 4.14 (t, 3J = 7.9 Hz, 2H), 7.05 (t,
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3
3JH,H = 3JH,F = 8.6 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.42–7.48 (m,
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3
3
3J = 8.8 Hz, JH,F = 5.2 Hz, 3H), 7.99 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H); 13C {1H}
2
NMR (CDCl3, 101 MHz): δ 29.7, 44.5, 52.9, 115.8 (d, JC,F = 22 Hz), 125.0, 127.4, 127.4,
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4
127.9, 128.1, 130.3 (d, JC,F = 9 Hz), 130.9, 131.4 (d, JC,F = 3 Hz), 134.6, 140.2, 141.8,
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143.5, 164.5 (d, JC,F = 253 Hz), 168.8, 192.9; 19F NMR (CDCl3, 376 MHz): δ ꢀ107.9; MS
(ESI+): m/z (%) = 424 (100%) [M+H]+; HRMS (ESI+) m/z calcd for C23H18FNO4SNa [M + Na+]
446.08328, found 446.08301.
Nꢀ(4ꢀChlorobenzoyl)ꢀ[4ꢀ(methylsulfonyl)benzoyl]indoline (5b). The crude starting
material 7ꢀ[4ꢀ(methylsulfonyl)benzoyl]ꢀ1Hꢀindoline (3a) (2884 mg) was synthesized by
following general procedure A starting from indoline (1038 ꢃL, 1.10 g, 9.24 mmol) and 2a
(2.00 g, 11.04 mmol). 500 mg of this raw product of 3a were allowed to react with 4ꢀ
chlorobenzoyl chloride (4b) (211 ꢃL, 290 mg, 1.66 mmol) following general procedure C.
Purification was carried out by column chromatography (DCVC, petroleum ether/ ethyl
acetate 50:50ꢀ0:100, then chloroform/ methanol 100:1). By that, 5b was obtained as a pale
yellow solid (345 mg, 49% starting from indoline). mp 272ꢀ274°C; Rf = 0.21 (petroleum ether/
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ethyl acetate 50:50); Rf = 0.60 (chloroform/ methanol 95:5); 1H NMR (CDCl3, 400
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MHz): δ 3.04 (s, 3H), 3.17 (t, J = 7.9 Hz, 2H), 4.12 (t, J = 7.9 Hz, 2H), 7.21 (t, J = 7.6 Hz,
3J = 7.4 Hz, 1H), 7.27 (d, 3J = 7.7 Hz, 1H), 7.34 (d, 3J = 8.6 Hz, 2H), 7.38 (d, 3J = 8.4 Hz, 2H),
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7.45 (d, J = 7.3 Hz, 1H), 7.99 (d, J = 8.3 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H); 13C {1H} NMR
(CDCl3, 101 MHz): δ 29.6, 44.5, 52.8, 125.1, 127.4, 127.5, 127.9, 128.1, 128.9, 129.3, 130.9,
133.7, 134.7, 137.7, 140.0, 141.8, 143.5, 168.7, 192.8; MS (ESI+): m/z (%) = 462 (84)
[M+Na, 35Cl]+, 440 (40) [M+H, 35Cl]+, 139 (100) [ClC6H4CO, 35Cl]+; HRMS (ESI+) m/z calcd for
C23H18ClNO4SNa [M + Na+, 35Cl] 462.05373, found 462.05348.
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N
ꢀBenzoylꢀ7ꢀ[4ꢀ(methylsulfonyl)benzoyl]indoline (5c). The crude starting material 7ꢀ[4ꢀ
(methylsulfonyl)benzoyl]ꢀ1Hꢀindoline (3a) (1028 mg) was synthesized by following general
procedure A starting from indoline (504 ꢃL, 534 mg, 4.48 mmol) and 2a (974 mg,
5.37 mmol). 250 mg of this raw product of 3a were allowed to react with benzoyl chloride (4c)
(96 ꢃL, 117 mg, 0.83 mmol) following general procedure C. Purification was carried out by
column chromatography (DCVC, petroleum ether/ ethyl acetate 90:10ꢀ50:50, then
chloroform/ methanol 90:10). By that, 5c was obtained as a pale yellow solid (180 mg, 41%
starting from indoline). mp 235ꢀ237°C; Rf = 0.11 (petroleum ether/ ethyl acetate 50:50);
1
Rf = 0.54 (chloroform/ methanol 95:5); H NMR (acetoneꢀd6, 400 MHz): δ 3.10 (s, 3H), 3.19
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(t, J = 7.9 Hz, 3H), 4.14 (t, J = 7.9 Hz, 2H), 7.27–7.33 (m, 3H), 7.37 (t, J = 7.6 Hz, 2H),
7.40–7.48 (m, 2H), 7.56 (dd, 3J = 7.4 Hz, 4J = 1.2 Hz, 1H), 7.96 (d, J = 8.8 Hz, 2H), 8.00 (d,
3
3J = 8.6 Hz, 2H); 13C {1H} NMR (acetoneꢀd6, 101 MHz): δ 30.0*, 44.2, 53.3, 125.8, 127.9,
128.1, 128.4, 128.5, 128.7, 129.1, 130.8, 131.8, 135.9, 136.6, 141.2, 142.9, 144.7, 169.9,
192.4, *signal overlay with the residual solvent peak; MS (ESI+): m/z (%) = 406 (100) [M+H]+;
Anal. Calcd for C23H19NO4S: C, 68.13; H, 4.72; N, 3.45; S, 7.91. Found: C, 68.45; H, 4.76; N,
3.48; S, 7.74. Crystals suitable for Xꢀray analysis were obtained by the following procedure.
A solution of 5c in DCM was slowly evaporated to dryness and, by that, crystals were formed
which were unsuitable for Xꢀray analysis. One wellꢀformed crystal was separated and
washed with a small amount of DCM. The rest was dissolved in DCM. To this solution the
isolated crystal was added and by slow evaporation of the solvent suitable crystals for Xꢀray
analysis were obtained.
N
ꢀ(4ꢀMethylbenzoyl)ꢀ7ꢀ[4ꢀ(methylsulfonyl)benzoyl]indoline (5d). The crude starting
material 7ꢀ[4ꢀ(methylsulfonyl)benzoyl]ꢀ1Hꢀindoline (3a) (234 mg) was synthesized by
following general procedure A starting from indoline (126 ꢃL, 133 mg, 1.12 mmol) and 2a
(245 mg, 1,35 mmol). 250 mg of this raw product of 3a were allowed to react with
4ꢀmethylbenzoyl chloride (4d) (98.7 ꢃL, 115 mg, 0.75 mmol) following general procedure C.
Purification was carried out by column chromatography (DCVC, petroleum ether/ ethyl
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acetate 100:0
ꢀ50:50, then chloroform/ methanol 90:10). By that, 5d was obtained as a pale
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yellow solid (255 mg, 57% starting from indoline). mp 255ꢀ257°C; Rf = 0.25 (petroleum ether/
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ethyl acetate 50:50); H NMR (CDCl3, 400 MHz): δ 2.34 (s, 3H), 3.01 (s, 3H), 3.14 (t,
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3J = 7.9 Hz, 2H), 4.13 (t, 3J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.20 (t, 3J = 7.6 Hz, 1H),
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7.32–7.27 (m, J = 8.1 Hz, J = 7.6 Hz, J = 1.1 Hz, 3H), 7.43 (dd, J = 7.4 Hz, J = 1.1 Hz,
1H), 7.97 (d, 3J = 8.5 Hz, 2H), 8.05 (d, 3J = 8.5 Hz, 2H); 13C {1H} NMR (CDCl3, 101
MHz): δ 21.6, 29.6, 44.5, 52.9, 124.9, 127.3, 127.5, 127.8, 127.9*, 129.2, 130.8, 132.3,
134.6, 140.3, 141.9, 142.0, 143.3, 169.9, 192.7, *two carbon atoms with identical chemical
shift; MS (ESI+): m/z (%) = 442 (50) [M+Na]+, 420 (16) [M+H]+, 118 (100); Anal. Calcd for
C24H21NO4S: C, 68.72; H, 5.05; N, 3.34; S, 7.64. Found: C, 68.62; H, 5.04; N, 3.35; S, 7.44.
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7ꢀ(4ꢀFluorobenzoyl)ꢀNꢀ[4ꢀ(methylsulfonyl)benzoyl]indoline (5e). The starting material
4ꢀ(methylsulfonyl)benzoyl chloride (4e) was synthesized by following general procedure B
starting from 4ꢀ(methylsulfonyl)benzoic acid (312 mg, 1.56 mmol). 3b (400 mg, 1.66 mmol)
and 4e were allowed to react in anhydrous THF (in total 7 mL) following general procedure
C. Purification was carried out by column chromatography (DCVC, petroleum ether/ ethyl
acetate 50:50ꢀ33:66, then chloroform/ methanol 100:0ꢀ100:1). By that, 5e was obtained as
a pale yellow solid (366 mg, 56%). mp 267ꢀ268°C; Rf = 0.21 (petroleum ether/ ethyl acetate
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33:66); Rf = 0.52 (chloroform/ methanol 95:5); H NMR (CDCl3, 400 MHz): δ 3.04 (s, 3H),
3.18 (t, J = 7.9 Hz, 2H), 4.10 (t, J = 7.9 Hz, 2H), 7.11 (t, JH,H = 3JH,F = 8.6 Hz, 2H), 7.22 (t,
3J = 7.6 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.43 (dd, J = 7.4 Hz, J = 0.8 Hz, 1H), 7.66 (d,
3J = 8.3 Hz, 2H), 7.92 (dd, 3J = 8.7 Hz, 4JH,F = 5.9 Hz, 2H), 7.95 (d, 3J = 8.3 Hz, 2H); 13C {1H}
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NMR (CDCl3, 101 MHz): δ 29.7, 44.5, 52.6, 115.5 (d, JC,F = 22 Hz), 125.3, 127.4, 127.8*,
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128.9*, 132.7 (d, JC,F = 9 Hz), 133.5 (d, JC,F = 3 Hz), 134.6, 139.7, 140.8, 142.8, 165.6 (d,
1JC,F = 254 Hz), 167.5,192.9, *two carbon atoms with identical chemical shift; 19F NMR
(CDCl3, 376 MHz): δ ꢀ106.5; MS (ASAP+): m/z (%) = 423 (100) [M]+; HRMS (ESI+) m/z calcd
for C23H18FNO4SNa [M + Na+] 446.08328, found 446.08376.
7ꢀ(4ꢀChlorobenzoyl)ꢀNꢀ[4ꢀ(methylsulfonyl)benzoyl]indoline (5f). The starting material
4ꢀ(methylsulfonyl)benzoyl chloride (4e) was synthesized by following general procedure B
starting from 4ꢀ(methylsulfonyl)benzoic acid (311 mg, 1.55 mmol). 3c (400 mg, 1.55 mmol)
and 4e were allowed to react in anhydrous THF (in total 8 mL) following general procedure
C. Purification was carried out by column chromatography (DCVC, petroleum ether/ ethyl
acetate 50:50ꢀ33:66, then chloroform/ methanol 100:0ꢀ100:1). By that, 5f was obtained as
a pale yellow solid (413 mg, 61%). mp 267ꢀ269°C; Rf = 0.23 (petroleum ether/ ethyl acetate
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33:66); Rf = 0.56 (chloroform/ methanol 95:5); H NMR (CDCl3, 400 MHz): δ 3.04 (s, 3H),
3.18 (t, J = 7.8 Hz, 2H), 4.09 (t, 3J = 7.9 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.30 (d,
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3J = 7.5 Hz, 1H), 7.40 (d, 3J = 8.5 Hz, 2H), 7.43 (d, 3J = 7.4 Hz, 1H), 7.64 (d, 3J = 8.3 Hz, 2H),
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7.83 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 29.7,
44.5, 52.5, 125.3, 127.5, 127.7, 127.8, 128.6, 128.7, 128.9, 131.5, 134.6, 135.5, 139.1,
139.6, 140.8, 142.8, 167.5, 193.1; MS (ASAP+): m/z (%) = 442 (27) [M+H, 37Cl]+, 441 (55) [M,
37Cl]+, 440 (67) [M+H, 35Cl]+, 439 (100) [M, 35Cl]+; HRMS (ESI+) m/z calcd for
C23H18ClNO4SNa [M + Na+, 35Cl] 462.05373, found 462.05421.
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7ꢀBenzoylꢀ
N
ꢀ[4ꢀ(methylsulfonyl)benzoyl]indoline
(5g).
The
starting
material
4ꢀ(methylsulfonyl)benzoyl chloride (4e) was synthesized by following general procedure B
starting from 4ꢀ(methylsulfonyl)benzoic acid (269 mg, 1.34 mmol). 3d (300 mg, 1.34 mmol)
and 4e were allowed to react in anhydrous THF (in total 7 mL) following general procedure
C. Purification was carried out by column chromatography (DCVC, petroleum ether/ ethyl
acetate 50:50ꢀ0:100, then chloroform/ methanol 97.5:2.5). By that, 5g was obtained as a
pale yellow solid (343 mg, 63%). mp 254ꢀ255°C; Rf = 0.22 (petroleum ether/ ethyl acetate
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33:66); Rf = 0.48 (chloroform/ methanol 95:5); H NMR (CDCl3, 400 MHz): δ 3.02 (s, 3H),
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3.17 (t, J = 7.8 Hz, 2H), 4.06 (t, 2J = 7.8 Hz, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.36 (d,
3J = 7.6 Hz, 1H), 7.39–7.45 (m, 3H), 7.52 (t, J = 7.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.86
(d, 3J = 7.5 Hz, 2H), 7.92 (d, 3J = 8.2 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 29.6, 44.5,
52.5, 125.3, 127.4, 127.7, 128.1, 128.3, 128.9, 129.1, 130.1, 132.7, 134.5, 137.1, 139.8,
140.9, 142.6, 167.5, 194.3; MS (ASAP+): m/z (%) = 406 (38) [M+H]+, 405 (100) [M]+; HRMS
(ESI+) m/z calcd for C23H19NO4SNa [M + Na+] 428.09270, found 428.09306.
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7ꢀ(4ꢀMethylbenzoyl)ꢀNꢀ[4ꢀ(methylsulfonyl)benzoyl]indoline (5h). The starting material
4ꢀ(methylsulfonyl)benzoyl chloride (4e) was synthesized by following general procedure B
starting from 4ꢀ(methylsulfonyl)benzoic acid (253 mg, 1.26 mmol). 3e (300 mg, 1.26 mmol)
and 4e were allowed to react in anhydrous THF (in total 7 mL) following general procedure
C. Purification was carried out by column chromatography (DCVC, petroleum ether/ ethyl
acetate 50:50ꢀ33:66, then chloroform/ methanol 100:0ꢀ100:1). By that, 5h was obtained as
a pale yellow solid (349 mg, 66%). mp 296°C; Rf = 0.21 (petroleum ether/ ethyl acetate
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33:66); Rf = 0.49 (chloroform/ methanol 95:5); H NMR (CDCl3, 400 MHz): δ 2.40 (s, 3H),
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3.02 (s, 3H), 3.17 (t, J = 7.8 Hz, 2H), 4.09 (t, J = 7.8 Hz, 2H), 7.18–7.25 (m, 3H), 7.32 (d,
3J = 7.4 Hz, 1H), 7.41 (d, 3J = 7.4 Hz, 1H), 7.64 (d, 2J = 8.2 Hz, 2H), 7.77 (d, 3J = 7.3 Hz, 2H),
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7.92 (d, J = 8.0 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 21.8, 29.7, 44.5, 52.5, 125.1,
127.2, 127.7*, 128.1, 129.0, 129.0, 130.3*, 131.2, 134.6, 141.0, 142.6, 143.6, 167.4, 194.2,
*two carbon atoms with identical chemical shift; MS (ASAP+): m/z (%) = 419 (100) [M+H]+,
236 (47) [MꢀCH3SO2C6H4CO]+; HRMS (ESI+) m/z calcd for C24H21NO4SNa [M + Na+]
442.10835, found 442.10902.
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7ꢀ[4ꢀ(Methylsulfonyl)benzoyl]ꢀNꢀ(4ꢀmethoxybenzoyl)indoline (5i). The crude starting
material 7ꢀ[4ꢀ(methylsulfonyl)benzoyl]ꢀ1Hꢀindoline (3a) (1028 mg) was synthesized by
following general procedure A starting from indoline (504 ꢃL, 534 mg, 4.48 mmol) and 2a
(974 mg, 5.37 mmol). 500 mg of this raw product of 3a were allowed to react with
4ꢀmethoxybenzoyl chloride (4f) (282 mg, 1.66 mmol) following general procedure C.
Purification was carried out by column chromatography (DCVC, petroleum ether/ ethyl
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acetate 80:20ꢀ50:50, then chloroform/ methanol 90:10). By that, 5i was obtained as a pale
yellow solid (506 mg, 54% starting from indoline). mp 237ꢀ240°C; Rf = 0.09 (petroleum ether/
ethyl acetate 50:50); Rf = 0.50 (chloroform/ methanol 95:5); 1H NMR (CDCl3, 400
MHz): δ 3.02 (s, 3H), 3.15 (t, 3J = 7.9 Hz, 2H), 3.81 (s, 3H), 4.16 (t, 3J = 8.0 Hz, 2H), 6.84 (d,
3J = 8.9 Hz, 2H), 7.19 (t, 3J = 7.6 Hz, 3J = 7.5 Hz, 1H), 7.29 (dd, 3J = 7.7 Hz, 4J = 1.1 Hz, 1H),
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7.39 (d, J = 8.9 Hz, 2H), 7.43 (dd, J = 7.4 Hz, J = 1.1 Hz, 1H), 7.96 (d, J = 8.6 Hz, 2H),
3
8.04 (d, J = 8.6 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 29.7, 44.5, 53.1, 55.6, 113.8,
124.8, 127.3*, 127.5, 127.8*, 130.0, 130.8, 134.6, 140.6, 142.0, 143.3, 162.2, 169.7, 192.8,
*two carbon atoms with identical chemical shift; MS (ESI+): m/z (%) = 474 (50) [M+K]+, 458
(24) [M+Na]+, 135 (48) [CH3OC6H4CO]+, 118 (100); Anal. Calcd for C24H21NO5S: C, 66.19; H,
4.86; N, 3.22; S, 7.36. Found: C, 65.65; H, 4.88; N, 3.37; S, 7.72.
General procedure D for the synthesis of 4,5ꢀdiphenylꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀ
hi]indoles (6aꢀi). Under nitrogen atmosphere, TiCl4 (146.2 ꢃL, 253 mg, 1.33 mmol) was
added to a suspension of the Nꢀbenzoylꢀ7ꢀ(benzoyl)indoline (0.62 mmol) 5aꢀi, respectively,
and Zn (163 mg, 2.5 mmol) in anhydrous THF (5.5 mL). The mixture was heated for 1.5ꢀ2 h
at 70°C under slight reflux. After cooling to room temperature, the mixture was preꢀadsorbed
on silica gel and purification was carried out by column chromatography as given below.
4ꢀ(4ꢀFluorophenyl)ꢀ5ꢀ[4ꢀ(methylsulfonyl)phenyl]ꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole (6a).
Purification was carried out by column chromatography (petroleum ether/ ethyl acetate
66:33ꢀ50:50). Starting from 5a (202 mg, 0.48 mmol), 6a was obtained following general
procedure D as colorless crystals (112 mg, 60%). mp 201ꢀ203°C; Rf = 0.49 (petroleum ether/
ethyl acetate 50:50); UV/vis: λmax (ε) = 293 (20000), 347 (14200); Fluorescence: λexc =
353, λem = 452 nm; 1H NMR (CDCl3, 400 MHz): δ 3.09 (s, 3H), 3.83 (t, 3J = 7.0 Hz, 2H), 4.55
3
(t, 3J = 7.0 Hz, 2H) , 7.03 (d, 3J = 6.8 Hz, 1H), 7.08ꢀ7.16 (m, JH,H = 3JH,F = 8.6 Hz,
4
3
3J = 7.3 Hz, 3H), 7.39 (dd, 3J = 8.5 Hz, JH,F = 5.3 Hz, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.58 (d,
3
3J = 8.3 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 33.7, 44.7,
2
49.7, 115.6, 116.4 (d, JC,F = 21 Hz), 116.5, 116.9, 119.6, 123.5, 125.1, 127.7, 128.1 (d,
4
4JC,F = 3 Hz), 129.2, 131.1 (d, JC,F = 8 Hz), 135.6, 136.8. 142.7, 147.9, 162.8 (d,
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1JC,F = 249 Hz); 19F NMR (CDCl3, 376 MHz): δ ꢀ112.9; MS (ASAP+): m/z (%) = 392 (91)
[M+H]+, 391 (100) [M]+, 149 (48); Anal. Calcd for C23H18FNO2S: C, 70.57; H, 4.63; N, 3.58; S,
8.19. Found: C, 70.97; H, 4.79; N, 3.53; S, 7.88. Crystals suitable for Xꢀray analysis were
obtained by slow evaporation of a solution of 5a in DCM layered with petroleum ether.
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4ꢀ(4ꢀChlorophenyl)ꢀ5ꢀ[4ꢀ(methylsulfonyl)phenyl]ꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole (6b).
Purification was carried out by column chromatography (petroleum ether/ ethyl acetate
70:30ꢀ60:40). Starting from 5b (280 mg, 0.63 mmol), 6b was obtained following general
procedure D as colorless crystals (186 mg, 72%). mp 224ꢀ227°C; Rf = 0.53 (petroleum ether/
ethyl acetate 50:50); UV/vis: λmax (ε) = 297 (20400), 348 (12600); Fluorescence: λexc =
299, λem = 476 nm; 1H NMR (CDCl3, 400 MHz): δ 3.09 (s, 3H), 3.84 (t, 3J = 6.9 Hz, 2H), 4.56
3
3
3
3
(t, J = 7.0 Hz, 2H), 7.03 (d, J = 6.7 Hz, 1H), 7.13 (t, J = 7.7 Hz, J = 7.0 Hz, 1H), 7.34 (d,
3J = 8.6 Hz, 2H), 7.38 (d, 3J = 8.6 Hz, 1H), 7.47 (d, 3J = 7.9 Hz, 1H), 7.58 (d, 3J = 8.4 Hz, 2H),
3
7.85 (d, J = 8.4 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz) 33.7, 44.7, 49.9, 116.0, 116.7,
116.9, 119.6, 123.6, 125.2, 127.8, 129.4, 129.5, 130.5*, 134.5, 135.3, 137.0, 142.5, 148.0,
*two carbon atoms with identical chemical shift; MS (ASAP+): m/z (%) = 410 (32) [M+H,
37Cl]+, 409 (52) [M, 37Cl]+, 408 (93) [M+H, 35Cl]+, 407 (100) [M, 35Cl]+; Anal. Calcd for
C23H18ClNO2S: C, 67.72; H, 4.45; N, 3.43; S, 7.86. Found: C, 68.13; H, 4.72; N, 3.34; S,
7.39.
.
5ꢀ(4ꢀ(Methylsulfonyl)phenyl)ꢀ4ꢀphenylꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole
fication was carried out by column chromatography (petroleum ether/ ethyl acetate
66:33 33:66). Starting from 5c (100 mg, 0.25 mmol), 6c was obtained following general
(6c).
Puriꢀ
ꢀ
procedure D as colorless crystals (79 mg, 85%). mp 199ꢀ202°C; Rf = 0.46 (petroleum ether/
ethyl acetate 50:50); UV/vis: λmax (ε) = 294 (19100), 349 (13500); Fluorescence: λexc =
353, λem = 452 nm; 1H NMR (CDCl3, 400 MHz): δ 3.08 (s, 3H), 3.83 (t, 3J = 7.0 Hz, 2H), 4.58
(t, 3J = 7.0 Hz, 2H), 7.02 (d, 3J = 6.7 Hz, 1H), 7.13 (t, 3J = 7.8 Hz, 3J = 6.9 Hz, 1H), 7.37ꢀ7.43
(m, 5H), 7.49 (d, 3J = 7.8 Hz, 1H), 7.60 (d, 3J = 8.6 Hz, 2H), 7.83 (d, 3J = 8.6 Hz, 2H); 13C {1H}
NMR (CDCl3, 101 MHz): δ 33.6, 44.7, 49.8, 115.5, 116.4, 116.9, 119.6, 123.4, 125.2, 127.7,
128.4, 129.1, 129.3, 129.3, 132.0, 136.6, 136.7, 142.9, 147.9; MS (ASAP+): m/z (%) = 374
(100) [M+H]+, 373 (56) [M]+; Anal. Calcd for C23H19NO2S: C, 73.97; H, 5.13; N, 3.75; S, 8.59.
Found: C, 74.34; H, 5.29; N, 3.72; S, 8.22.
4ꢀ(4ꢀMethylphenyl)ꢀ5ꢀ[4ꢀ(methylsulfonyl)phenyl]ꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole (6d).
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100:0ꢀ33:66). Starting from 5d (200 mg, 0.48 mmol), 6d was obtained following general
procedure D as a pale yellow solid (150 mg, 81%). mp 194ꢀ197°C; Rf = 0.52 (petroleum
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ether/ ethyl acetate 50:50); UV/vis: λmax (ε) = 295 (21100), 350 (14300); Fluorescence: λexc
1
= 354, λem = 454 nm; H NMR (CDCl3, 400 MHz): δ 2.41 (s, 3H), 3.08 (s, 3H), 3.82 (t,
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3J = 7.0 Hz, 2H), 4.56 (t, J = 7.0 Hz, 2H), 7.01 (d, J = 6.8 Hz, 1H), 7.12 (t, J = 7.9 Hz,
3J = 6.8 Hz, 1H), 7.21 (d, 3J = 8.1 Hz, 2H), 7.30 (d, 3J = 8.1 Hz, 2H), 7.48 (d, 3J = 7.9 Hz, 1H),
7.60 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 21.5,
33.7, 44.8, 49.7, 115.2, 116.3, 116.8, 119.7, 123.4, 125.1, 127.6, 129.1, 129.2, 129.2, 129.9,
136.5, 137.0, 138.5, 143.1, 147.8; MS (ASAP+): m/z (%) = 388 (68) [M+H]+, 387 (100) [M]+;
Anal. Calcd for C24H21NO2S: C, 74.39; H, 5.46; N, 3.61; S, 8.27. Found: C, 74.74; H, 5.56; N,
3.63; S, 8.04.
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5ꢀ(4ꢀFluorophenyl)ꢀ4ꢀ[4ꢀ(methylsulfonyl)phenyl]ꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole (6e).
Purification was carried out by column chromatography (petroleum ether/ ethyl acetate
70:30ꢀ60:40). Starting from 5e (250 mg, 0.59 mmol), 6e was obtained following general
procedure D as a beige solid (165 mg, 71%). mp 218ꢀ219°C; Rf = 0.48 (petroleum ether/
ethyl acetate 33:66); UV/vis: λmax (ε) = 264 (18100), 330 (13600); Fluorescence: λexc =
337, λem = 501 nm; 1H NMR (CDCl3, 400 MHz): δ 3.10 (s, 3H), 3.84 (t, 3J = 7.0 Hz, 2H), 4.59
3
3
4
(t, J = 7.0 Hz, 2H), 6.99–7.14 (m, 4H), 7.36 (dd, J = 8.6 Hz, JH,F = 5.5 Hz, 1H), 7.41 (d,
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3
3J = 7.9 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H); 13C {1H} NMR (CDCl3,
2
101 MHz): δ 33.7, 44.6, 50.6, 115.9 (d, JC,F = 21 Hz), 116.9, 117.3, 119.1, 120.2, 123.2,
3
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125.1, 127.9, 129.5, 130.9 (d, JC,F = 8 Hz), 131.7 (d, JC,F = 3 Hz), 133.0, 138.4, 139.0,
148.8, 161.7 (d, JC,F = 246 Hz); 19F NMR (CDCl3, 376 MHz): δ ꢀ116.4; MS (ASAP+): m/z
(%) = 392 (55) [M+H]+, 391 (100) [M]+; HRMS (ESI+) m/z calcd for C23H18FNO2SNa [M + Na+]
414.09345, found 414.09386. Crystals suitable for Xꢀray analysis were obtained by slow
evaporation of a solution of 6e in chloroform layered with petroleum ether.
1
5ꢀ(4ꢀChlorophenyl)ꢀ4ꢀ[4ꢀ(methylsulfonyl)phenyl]ꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole (6f).
Purification was carried out by column chromatography (petroleum ether/ ethyl acetate
70:30ꢀ60:40). Starting from 5f (250 mg, 0.57 mmol), 6f was obtained following general
procedure D as a colorless solid (177 mg, 76%). mp 205ꢀ207°C; Rf = 0.47 (petroleum ether/
ethyl acetate 33:66); UV/vis: λmax (ε) = 266 (17300), 332 (13600); Fluorescence: λexc =
340, λem = 501 nm; 1H NMR (CDCl3, 400 MHz): δ 3.11 (s, 3H), 3.84 (t, 3J = 7.0 Hz, 2H), 4.59
3
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3
3
(t, J = 7.0 Hz, 2H), 7.03 (d, J = 6.7 Hz, 1H), 7.10 (dd, J = 7.5 Hz, J = 7.1 Hz, 1H), 7.29–
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7.36 (m, 4H), 7.42 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.4 Hz, 2H);
13C {1H} NMR (CDCl3, 101 MHz): δ 33.7, 44.6, 50.5, 117.0, 117.3, 118.8, 120.0, 123.4, 125.1,
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127.9, 129.1, 129.6, 130.6, 132.2, 133.1, 134.3, 138.2, 139.2, 148.7; MS (ASAP+): m/z
(%) = 410 (63), 408 (100) [M+H, 35Cl]+, 407 (90) [M, 35Cl]+, 391 (78); HRMS (ESI+) m/z calcd
for C23H19ClNO2S [M + H+, 35Cl] 408.08195, found 408.08167.
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4ꢀ(4ꢀ(Methylsulfonyl)phenyl)ꢀ5ꢀphenylꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole (6g). Puriꢀ
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fication was carried out by column chromatography (petroleum ether/ ethyl acetate
70:30ꢀ50:50). Product containing fractions were combined and solvent was removed under
reduced pressure. The resulting solid was dissolved in DCM (10 mL) and petroleum ether
(15 mL) was added to the solution. A precipitate resulted which was isolated by filtration.
Starting from 5g (250 mg, 0.62 mmol), 6g was obtained following general procedure D as a
pale grey solid (129 mg, 56%). mp 229ꢀ231°C; Rf = 0.47 (petroleum ether/ ethyl acetate
1
33:66); UV/vis: λmax (ε) = 331 (13200); Fluorescence: λexc = 337, λem = 499 nm; H NMR
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(CDCl3, 400 MHz): δ 3.10 (s, 3H), 3.83 (t, J = 7.0 Hz, 2H), 4.59 (t, J = 7.0 Hz, 2H), 7.02 (d,
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3J = 7.0 Hz, 1H), 7.09 (dd, J = 7.9 Hz, J = 6.8 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.36 (t,
3J = 7.8 Hz, 3J = 7.3 Hz, 2H), 7.42 (dd, 3J = 8.1 Hz, 4J = 1.1 Hz, 2H), 7.46 (d, 3J = 7.8 Hz, 1H),
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7.60 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 33.7,
44.6, 50.5, 116.8, 117.6, 120.3*,123.1, 125.0, 126.4, 127.8, 128.9, 129.4, 129.5, 133.0,
135.7, 138.6, 138.8, 148.9, *two carbon atoms with identical chemical shift; MS (ASAP+): m/z
(%) = 374 (100) [M+H]+; HRMS (ESI+) m/z calcd for C23H19NO2SNa [M + Na+] 396.10287,
found 396.10298.
5ꢀ(4ꢀMethylphenyl)ꢀ4ꢀ[4ꢀ(methylsulfonyl)phenyl]ꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole (6h).
Purification was carried out by column chromatography (petroleum ether/ ethyl acetate
70:30ꢀ60:40). Starting from 5h (250 mg, 0.60 mmol), 6h was obtained following general
procedure D as a yellow solid (141 mg, 61%). mp 192ꢀ194°C; Rf = 0.49 (petroleum ether/
ethyl acetate 33:66); UV/vis: λmax (ε) = 332 (13800); Fluorescence: λexc = 340, λem = 505
nm; 1H NMR (CDCl3, 400 MHz): δ 2.39 (s, 3H), 3.10 (s, 3H), 3.83 (t, 3J = 7.0 Hz, 2H), 4.58 (t,
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3J = 7.0 Hz, 2H), 7.01 (d, J = 6.6 Hz, 1H), 7.08 (dd, J = 8.0 Hz, J = 6.7 Hz, 1H), 7.17 (d,
3J = 7.9 Hz, 2H), 7.31 (d, 3J = 8.1 Hz, 2H), 7.44 (d, 3J = 7.8 Hz, 1H), 7.60 (d, 3J = 8.6 Hz, 2H),
3
7.88 (d, J = 8.5 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 21.4, 33.7, 44.6, 50.6, 116.7,
117.6, 120.3, 120.4, 123.0, 125.0, 127.8, 129.3, 129.5, 129.7, 132.7, 132.9, 136.1, 138.7*,
148.9, *two carbon atoms with identical chemical shift; MS (ASAP+): m/z (%) = 388 (81)
[M+H]+, 387 (100) [M]+; Anal. Calcd for C24H21NO2S: C, 74.39; H, 5.46; N, 3.61; S, 8.27.
Found: C, 74.13; H, 5.59; N, 3.55; S, 7.79.
4ꢀ(4ꢀMethoxyphenyl)ꢀ5ꢀ[4ꢀ(methylsulfonyl)phenyl]ꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole
(6i). Purification was carried out by column chromatography (1. column: petroleum ether/
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ethyl acetate 80:20
ꢀ
0:100, 2nd column: chloroform). Starting from 5i (450 mg, 1.03 mmol), 6i
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was obtained following general procedure D as a pale yellow solid (317 mg, 76%). mp 213ꢀ
216°C; Rf = 0.43 (petroleum ether/ ethyl acetate 50:50); Rf = 0.65 (chloroform/ methanol
95:5); UV/vis: λmax (ε) = 297 (21500), 351 (13700); Fluorescence: λexc = 359, λem = 455
nm; 1H NMR (CDCl3, 400 MHz): δ 3.08 (s, 3H), 3.82 (t, 3J = 7.0 Hz, 2H), 3.86 (s, 3H), 4.55 (t,
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3J = 7.0 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 6.8 Hz, 1H), 7.11 (dd, J = 7.8 Hz,
3J = 6.9 Hz, 1H), 7.34 (d, 3J = 8.8 Hz, 2H), 7.48 (d, 3J = 7.9 Hz, 1H), 7.60 (d, 3J = 8.6 Hz, 2H),
7.83 (d, J = 8.6 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 33.7, 44.8, 49.6, 55.5, 114.7,
3
114.9, 116.2, 116.7, 119.7, 123.3, 124.3, 125.0, 127.7, 129.2, 130.6, 136.4, 136.8, 143.2,
147.8, 159.8; MS (ESI+): m/z (%) = 404 (100) [M+H]+; Anal. Calcd for C24H21NO3S: C, 71.44;
H, 5.25; N, 3.47; S, 7.95. Found: C, C, 71.48; H, 5.45; N, 3.40; S, 7.49.
4ꢀ(4ꢀHydroxyphenyl)ꢀ5ꢀ[4ꢀ(methylsulfonyl)phenyl]ꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀhi]indole
(6j). Under nitrogen atmosphere, 1 M BBr3 in DCM (2.1 mL, 2.1 mmol) was added to a
solution of 6i (222 mg, 0.55 mmol) in anhydrous DCM (10 mL) at ꢀ5°C. The solution was
stirred for 3 h and allowed to warm up slowly to room temperature. Additionally, 1 M BBr3 in
DCM (2.0 mL, 2.0 mmol) was added and the mixture was stirred at room temperature for
18 h. Then, the mixture was preꢀadsorbed on silicaꢀgel and purified by column
chromatography (chloroform/ methanol 98:2ꢀ97.5:2.5). This gave 6j as pale brown solid
(195 mg, 91%). mp 209ꢀ215°C; Rf = 0.24 (petroleum ether/ ethyl acetate 50:50); Rf = 0.24
(chloroform/ methanol 95:5); UV/vis: λmax (ε) = 297 (20300), 352 (13100); Fluorescence:
1
λexc = 356, λem = 454 nm; H NMR (acetoneꢀd6, 400 MHz): δ 3.11 (s, 3H), 3.79 (t,
3J = 7.0 Hz, 2H), 4.60 (t, 3J = 7.0 Hz, 2H), 6.92 (d, 3J = 8.7 Hz, 2H), 6.95 (d, 3J = 6.9 Hz, 1H),
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7.05 (dd, J = 7.8 Hz, J = 6.9 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 7.9 Hz, 1H),
7.64 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 8.70 (s, 1H); 13C {1H} NMR (acetoneꢀd6,
101 MHz): δ 33.9, 44.5, 50.1, 114.8, 116.6, 116.8*, 117.1, 120.4, 123.8, 124.0, 126.2, 128.3,
129.5, 131.5, 137.7, 138.1, 143.7, 148.4, 158.6*, *deuterium isotope shifts were observed in
the range of 89 and 91 ppb; MS (ASAP+): m/z (%) = 389 (100) [M]+; HRMS (ESI+) m/z calcd
for C23H19NO3SNa [M + Na+] 412.09779, found 412.09834..
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4ꢀ[4ꢀ(2ꢀFluoroethoxy)phenyl]ꢀ5ꢀ[4ꢀ(methylsulfonyl)phenyl]ꢀ1,2ꢀdihydropyrrolo[3,2,1ꢀ
hi]indole (6k). Under nitrogen atmosphere, 4ꢀnitrobenzenesulfonyl chloride (940 mg,
4.24 mmol) in anhydrous THF (6 mL) was added to a solution of 2ꢀfluoroethanol (197 ꢃL,
218 mg, 3.4 mmol) in anhydrous THF (4 mL) at 0°C. The mixture was stirred at this
temperature and potassium trimethylsilanolate (2.17 g, 16.95 mmol) was added in portions
over a period of 30 min. After stirring for additional 2 h at 0°C, the mixture was poured over
iceꢀcold water (100 mL) and extracted with DCM (3 x 50 mL). The organic phase was
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washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was reduced to
dryness under reduced pressure and purified by column chromatography (petroleum ether/
ethyl acetate 80:20
ꢀ60:40). A solid (608 mg) was obtained that contained 2ꢀfluoroethylꢀ4ꢀ
6
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8
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1
nitrobenzenesulfonate 7 in an amountꢀofꢀsubstance fraction of ca. 80% (calculated from Hꢀ
NMR) beside an unknown side product. 1H NMR (CDCl3, 400 MHz): δ 4.41 (dt,
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3JH,F = 27.3 Hz, 3J = 3,9 Hz, 2H), 4.80 (dt, JH,F = 47.0 Hz, 3J = 3.9 Hz, 2H), 8.13 (d,
3J = 8.9 Hz, 2H), 8.41 (d, J = 8.9 Hz, 2H), further signals of the unknown side product with
3
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an intensity of 20% in the spectra: 4.32 (dt, JH,F = 27.4 Hz, J = 4.0 Hz, 2H), 4.61 (dt,
2JH,F = 47.3 Hz, 3J = 4.0 Hz, 2H), 7.00 (d, 3J = 8.9 Hz, 2H), 8.22 (d, 3J = 8.9 Hz, 2H).
Under nitrogen atmosphere, crude 2ꢀfluoroethylꢀ4ꢀnitrobenzenesulfonate 7 (122 mg) was
added to a solution of 6j (75 mg, 0.19 mmol) and potassium tertꢀbutoxide (25.3 mg,
0.25 mmol) in anhydrous THF (3.15 mL). Then, the mixture was heated for 20 h at 70°C.
After cooling the mixture to room temperature and preꢀadsorption on silicaꢀgel, purification
was carried out by column chromatography (1. column: petroleum ether/ ethyl acetate
70:30
ꢀ
50:50, then chloroform/ methanol 95:5; 2nd column: (using a Merck Lichrolut Si SPE
cartridge) chloroform/ methanol 100:0
ꢀ
98:2). This gave 6k as a pale yellow solid (46 mg,
55%). mp 203ꢀ206°C (polymorphism at 176°C); Rf = 0.35 (petroleum ether/ ethyl acetate
50:50); Rf = 0.64 (chloroform/ methanol 95:5); UV/vis: λmax (ε) = 297 (20700), 352 (13300);
Fluorescence: λexc = 354, λem = 455 nm; 1H NMR (CDCl3, 400 MHz): δ 3.08 (s, 3H), 3.82 (t,
3J = 7.0 Hz, 2H), 4.27 (dt, 3JH,F = 27.7 Hz, 3J = 4.1 Hz, 2H), 4.55 (t, 3J = 7.0 Hz, 2H), 4.79 (dt,
2JH,F = 47.4 Hz, 3J = 4.1 Hz, 2H), 6.96 (d, 3J = 8.8 Hz, 2H), 7.01 (d, 3J = 6.8 Hz, 1H), 7.12 (dd,
3J = 7.8 Hz, J = 6.9 Hz, 1H), 7.34 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 7.9 Hz, 1H), 7.60 (d,
3J = 8.5 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H); 13C {1H} NMR (CDCl3, 101 MHz): δ 33.7, 44.8,
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3
2
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49.7, 67.3 (d, JC,F = 20 Hz), 82.0 (d, JC,F = 172 Hz), 115.0, 115.3, 116.3, 116.8, 119.7,
123.4, 124.9, 125.0, 127.7, 129.2, 130.7, 136.5, 136.6, 143.1, 147.8, 158.6; 19F NMR (CDCl3,
376 MHz): δ ꢀ224.3; MS (ASAP+): m/z (%) = 437 (32), 436 (100) [M+H]+, 435 (510) [M]+;
HRMS (ESI+) m/z calcd for C25H22FNO3SNa [M + Na+] 458.11966, found 458.12011.
General procedure E for the synthesis of 1,2ꢀdiphenylpyrrolo[3,2,1ꢀhi]indoles (8aꢀh).
Under nitrogen atmosphere,
a
solution of the corresponding 4,5ꢀdiphenylꢀ1,2ꢀ
(0.165 mmol) and 2,3ꢀdichloroꢀ5,6ꢀdicyanoꢀpꢀ
dihydropyrrolo[3,2,1ꢀhi]indole
6aꢀh
benzoquinone (DDQ, 130.8 mg, 0.576 mmol) in anhydrous benzene (9.3 mL) was heated
under reflux for 6 h. After cooling to room temperature, ethyl acetate (19 mL) was added and
the solution was transferred to a separatory funnel. The organic phase was washed with
saturated Na2SO4 (19 mL), saturated NaHCO3 (19 mL) and brine (9 mL). After that, the
organic phase was over Na2SO4, filtered, and the mixture was preꢀadsorbed on silicaꢀgel.
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The Journal of Organic Chemistry
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The purification was performed by column chromatography as given below. The raw and final
product should be stored cool and in the dark.
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2ꢀ(4ꢀFluorophenyl)ꢀ1ꢀ[4ꢀ(methylsulfonyl)phenyl]pyrrolo[3,2,1ꢀhi]indole (8a). Purification
9
was carried out by column chromatography (petroleum ether/ ethyl acetate 80:20ꢀ70:30).
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Starting from 6a (61.1 mg, 0.156 mmol) and DDQ (247.1 mg, 1.097 mmol), 8a was obtained
following general procedure E as a yellowꢀgreen solid (49.0 mg, 81%). mp 205ꢀ208°C;
Rf = 0.53 (petroleum ether/ ethyl acetate 50:50); UV/vis: λmax (ε) = 300 (20400), 362sh
(4800); Fluorescence: λexc = 306, λem = 487 nm; 1H NMR (CDCl3, 400 MHz): δ 3.12 (s, 3H),
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3
3
6.91 (d, J = 3.2 Hz, 1H), 7.17 (t, JH,H = 3JH,F = 8.6 Hz, 2H), 7.50 (d, J = 3.1 Hz, 1H), 7.52–
7.56 (m, 3J = 8.6 Hz, 4JH,F = 5.4 Hz, 3J = 7.4 Hz, 3H), 7.70 (d, 3J = 8.6 Hz, 2H), 7.75–7.79 (m,
3J = 7.4 Hz, 3J = 7.3 Hz, 2H), 7.93 (d, 3J = 8.5 Hz, 2H); 13C {1H} NMR (CDCl3, 101
MHz): δ 44.7, 111.8, 116.7 (d, 2JC,F = 22 Hz), 119.7, 120.7, 121.2, 122.0, 122.5, 124.3, 125.0,
4
3
127.0 (d, JC,F = 4 Hz), 128.0, 130.0, 131.6 (d, JC,F = 8 Hz), 135.3, 137.1, 138.2, 141.2,
1
163.2 (d, JC,F = 251 Hz); 19F NMR (CDCl3, 376 MHz): δ ꢀ111.6; MS (ASAP+): m/z (%) = 389
(100) [M]+; HRMS (ESI+) m/z calcd for C23H16FNO2SNa [M + Na+] 412.07780, found
412.07759.
2ꢀ(4ꢀChlorophenyl)ꢀ1ꢀ[4ꢀ(methylsulfonyl)phenyl]pyrrolo[3,2,1ꢀhi]indole (8b). Purification
was carried out by column chromatography (petroleum ether/ ethyl acetate 70:30). Starting
from 6b (67.1 mg, 0.164 mmol), 8b was obtained following general procedure E as a yellow
solid (27.6 mg, 41%). mp 224ꢀ227°C; Rf = 0.54 (petroleum ether/ ethyl acetate 50:50);
1
UV/vis: λmax (ε) = 301 (19400), 358 (4900); Fluorescence: λexc = 325, λem = 489 nm; H
3
3
NMR (CDCl3, 400 MHz): δ 3.12 (s, 3H), 6.92 (d, J = 3.2 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H),
3
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7.49 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 3.2 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.70 (d,
3
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3J = 8.6 Hz, 2H), 7.75–7.79 (m, J = 7.4 Hz, J = 7.3 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H); 13C
{1H} NMR (CDCl3, 101 MHz): δ 44.7, 111.8, 119.7, 121.0, 121.4, 122.0, 122.6, 124.4, 125.0,
128.0, 129.4, 129.8, 130.1, 130.9, 135.1, 135.4, 137.2, 138.4, 141.0; MS (ASAP+): m/z
(%) = 407 (47), 406 (53), 405 (100) [M, 35Cl]+; HRMS (ESI+) m/z calcd for C23H20ClN2O2S [M
+
+ NH4 , 35Cl] 423.09340, found 423.09280.
1ꢀ[4ꢀ(Methylsulfonyl)phenyl]ꢀ2ꢀphenylpyrrolo[3,2,1ꢀhi]indole (8c). Purification was
carried out by column chromatography (petroleum ether/ ethyl acetate 70:30ꢀ60:40).
Starting from 6c (61.5 mg, 0.165 mmol), 8c was obtained following general procedure E as a
pale yellow solid (51.4 mg, 84%). mp 161ꢀ164°C; Rf = 0.48 (petroleum ether/ ethyl acetate
50:50); UV/vis: λmax (ε) = 302 (20100), 366sh (4800); Fluorescence: λexc = 307, λem = 489
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