New potent fluorescent analogues of strigolactones: Synthesis and biological activity in parasitic weed germination and fungal branching

Article abstract of DOI:10.1002/ejoc.201100616

In this work we report the synthesis of new fluorescent analogues of strigolactones, their spectroscopic properties and the evaluation of their biological activity both on seeds of Orobanche aegyptiaca and on the AM fungus Gigaspora margarita. The synthes

Full text of DOI:10.1002/ejoc.201100616

FULL PAPER
DOI: 10.1002/ejoc.201100616
New Potent Fluorescent Analogues of Strigolactones: Synthesis and Biological
Activity in Parasitic Weed Germination and Fungal Branching
Cristina Prandi,*[a] Ernesto G. Occhiato,[b] Silvia Tabasso,[a] Paola Bonfante,[c]
Mara Novero,[c] Dina Scarpi,[b] Maria Elena Bova,[b] and Ivana Miletto[d]
Keywords: Natural products / Plant hormones / Strigolactones / Parasitic weeds / Fungal branching / Cross-coupling /
Fluorescence
In this work we report the synthesis of new fluorescent ana- to two different synthetic plans and allows the introduction
logues of strigolactones, their spectroscopic properties and
the evaluation of their biological activity both on seeds of
of various substituents on the A and C rings of the frame-
work, thus enabling access to bioactive molecules with dif-
Orobanche aegyptiaca and on the AM fungus Gigaspora ferent spectroscopic properties.
margarita. The synthesis has been accomplished according
studies have been conducted both for natural and synthetic
Introduction
SLs analogues.[7,19–26] Very recently Akiyama demonstrated
that the structural features needed to achieve biological ac-
tivity in AM fungi are very similar but not identical to those
observed in root parasitic weeds, especially with respect to
the enol ether bridge linking the C and D rings.[9] The pro-
duction of signalling molecules and the elicitation of re-
sponses in either partner represent the first steps in the cas-
cade of events that lead to the biological effect. With respect
to this, increasing evidence suggests that the induction of
seed germination in parasitic weeds or hyphal branching in
AM fungi proceeds through a receptor-mediated mecha-
nism. Thus far very little is known about the protein struc-
ture or location of this hypothetical receptor.[27–30] Detailed
knowledge of the receptor protein would provide insight
into the mechanisms responsible for the biological effects.
Moreover, such information would enable the design of per-
fectly fitting non-natural stimulants or inhibitors that may
be used to control parasitic weeds or to develop new green
and white biotechnologies exploiting AM fungi as biofertili-
zers in agriculture. In this sense labelled synthetic active SLs
can be considered useful tools for the detection of the recep-
tor in vivo or for protein identification experiments.
We recently reported the synthesis of a new class of SL
analogues (PL series, Figure 1) featuring an unprecedented
extended conjugated system and whose bioactiphore is an
α,β-unsaturated ketone instead of the more common α,β-
unsaturated lactone. All of these new molecules showed re-
markable activity in Orobanche aegyptiaca seed germination
tests.[31] Furthermore, some of these molecules showed
interesting luminescent properties that prompted us to de-
sign and develop new fluorescent analogues whose spectro-
scopic properties could be exploited in bioimaging studies.
In this work we report the synthesis of new fluorescent ana-
Several hundreds of organic compounds released from
plants, insects, animals and microbes are known to affect
the growth, development and distribution of the receiving
organism. Among them are signalling molecules, which play
key roles in the intricate communication network within the
soil. Very recently a new class of signalling molecules, the
strigolactones (SLs), has garnered particular interest both
by biologists and chemists.[1–5] SLs were originally isolated
from plant root exudates as germination stimulants for root
parasitic plants of the family Orobanchaceae, including
witchweeds (Striga spp.), boomrapes (Orobanche and Pheli-
panche spp.) and Alectra spp. and so were regarded as detri-
mental to the producing plants.[6–8] Subsequently, their role
as indispensable chemical signals for the establishment of
arbuscular mycorrhizas (AM), the widespread symbiosis
between most land plants and a small group of soil fungi,
was unveiled.[9–13] In addition to these functions in the
rizosphere, it has recently been shown that SLs represent a
new class of plant hormones that inhibit shoot
branching.[14–18] Extensive structure-activity relationship
[a] Dipartimento di Chimica Generale e Chimica Organica,
Università di Torino,
Corso Massimo D’Azeglio 48, 10125 Torino, Italy
Fax: +39-011-670-7643
E-mail: cristina.prandi@unito.it
[b] Dipartimento di Chimica “U. Schiff”, Università di Firenze,
via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
[c] Dipartimento di Biologia Vegetale dell’Università,
Viale Mattioli 25, 10125 Torino, Italy
[d] Dipartimento di Chimica Inorganica, Fisica e dei Materiali,
Università di Torino,
via Pietro Giuria 7, 10125 Torino, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100616 or from
the author.
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logues of SLs, their spectroscopic properties and the evalu- ated with a remarkable biological activity. We then decided
ation of their biological activity both on seeds of Orobanche to focus our efforts on the synthesis of highly conjugated
aegyptiaca and on the AM fungus Gigaspora margarita.
nitrogen derivatives with different patterns of substitution
on the A ring in order to accurately tune the spectroscopic
behavior while sparing the majority of biological activity
thus allowing us to attain SL-like molecules for use as fluo-
rescent probes. Towards this purpose, two main synthetic
pathways were designed. The first, leading to the EGO
series (Scheme 1, Schemes 2 and 3), was specifically de-
signed for large scale synthesis applications; this approach
required few steps, cheap reagents and feasible reaction
conditions.[32] The EGO-derived molecules were obtained
as racemates and the enantiomers separated by chiral High
Performance Liquid Chromatography (HPLC). The second
pathway, leading to the ST series (Scheme 4 and 5), was
intended to be more versatile as it allows the introduction
of substituents on the C ring. In this case, the molecules
were obtained as diastereomeric mixtures and, at this stage,
could be tested directly in biological assays.
Figure 1. Natural strigol, synthetic GR 24 and synthetic PL series.
Results and Discussion
Synthesis
In our previous work,[31] nitrogen-derived SL analogues
showed the most promising fluorescent properties associ-
Scheme 3. Synthesis of 6-thienyl EGO molecule 15.
According to Scheme 1, the ABC nucleus of the mole-
cules was easily obtained in two steps starting from com-
mercially available 3-(indol-3-yl)propanoic acid 1, after N-
Scheme 1. Synthesis of unsubstituted EGO 5.
Scheme 2. Synthesis of 7-functionalized EGO molecules 7, 9a–c.
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New Potent Fluorescent Analogues of Strigolactones
Scheme 4. Synthesis of the ST derivatives.
Scheme 5. Synthesis of SL derivative 28.
methylation (2, 86% yield) and subsequent cyclization with scopic behavior. The last step, linkage of the D ring, was
PPA (polyphosphoric acid) in refluxing toluene (3, 76% performed under the usual conditions and led to SL ana-
yield). Ultimately, the D ring was introduced using pre- logues 9a–c in 35, 56 and 50% overall yields, respectively.
viously reported conditions.[31] The final molecule was
The presence of an unsaturated substituent in the 6-posi-
thereby obtained in only three steps (5, 40%) as a racemate. tion of ring A would allow a more extended conjugate sys-
The enantiomers were then easily separated by chiral HPLC tem which might have consequences on the luminescent be-
(see Exp. Section) and their biological activities determined havior of these molecules. To this purpose we planned the
(vide infra).
synthetic path represented in Scheme 3. Commercially
In order to obtain EGO derivatives functionalized at the available 6-bromoindole 10 was N-protected as methyl de-
7-position of the A ring, a slight modification of the pro- rivative 11 and successively treated with acrylic acid at high
posed sequence was accomplished (Scheme 2). 4-Methyl- temperature to give 12 (52%). Usual cyclization of the C
1,2-dihydrocyclopenta[b]indol-3(4H)-one 3 obtained ac- ring with polyphosphoric acid gave 13 as a key intermedi-
cording to Scheme 1 was reacted with NBS to selectively ate. For the following step, a Suzuki–Miyaura cross cou-
produce 7-bromo analogue 6 in 67% yield and then func- pling, 2-thienylboronic acid was chosen as the cross cou-
tionalized with bromobutenolide 4 to yield corresponding pling partner due to the well documented luminescent prop-
SL analogue 7. Interestingly, intermediate 6 could also be erties of the thiophene moiety and its wide use in the syn-
used as a substrate for Suzuki–Miyaura cross-coupling re- thesis of fluorescent probes.[33] Compound 14 was obtained
actions in order to introduce p-nitrophenyl, p-(dimeth- in 74% yield and then coupled with bromobutenolide 4 as
ylamino)phenyl, or 2-thienyl substituents specifically at the usual to obtain the final SL-like molecule 15 (38%) as the
7-position of ring A. The corresponding boronic acids were racemate.
properly chosen with the aim of introducing substituents
The ST series of molecules was synthesized according to
with different electronic properties – electron-withdrawing a more versatile synthetic plan which, in principle, allows
for p-nitrophenyl and electron-donating for p-(dimeth- the introduction of substituents on the C ring. In this
ylamino)phenyl and thienyl – that might influence spectro- case all SL analogues were isolated as diastereomeric mix-
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tures. Commercially available 1-methylindolin-2-one 16 of the ST 23 a–d series were characterized by intense ab-
(Scheme 4) was selectively brominated with NBS to afford sorption bands in the 200–400 nm range, with relative max-
5-bromo-1-methylindolin-2-one 17. Compound 17 was then ima, ranging from 300 to 335 nm, chosen as the λex. The
used as a coupling partner in a Suzuki–Miyaura reaction in effects of substituents on the A ring were evaluated, show-
order to functionalize the A ring of the final molecule with ing that the PMP and the PMN groups similarly affect the
various substituents. Coupling partners p-methoxyphenyl- photoemission properties of the molecules, with emission
(PMP), p-(dimethylamino)phenyl- (p-DMAP), 2-thienyl-, 6- bands centered at ca. 480 nm and fluorescence quantum
methoxy-2-naphthyl-boronic acids (PMN) were used, and yields of 0.10 (ST 23a) and 0.12 (ST 23d). A strong re-
corresponding coupling products 18a–d were obtained in duction of the quantum yield (0.03), along with a signifi-
good yields. The corresponding triflates 19a–d were then cant red-shift of the emission band (560 nm), was found for
generated in the presence of KHMDS and N-phenyl- the p-DMAP-substituted ST molecule (ST 23b), whereas
triflimide, and coupled with the ethoxy dienyl boronic ester the thienyl-substituted molecule (ST 23c) was characterized
20 to afford compounds 21a–d which were then cyclized by an emission band centered at ca. 506 nm and a quantum
according to a Nazarov electrocyclic process catalyzed by yield of about 0.06.
o-benzenedisulfonimide,[34] and finally coupled with bromo-
butenolide 4 under the usual conditions.[31]
Table 1. Selected photophysical properties of ST and EGO deriva-
tives.
The synthesis of derivative 28 required a different se-
Entry Sample
λex/nm λem/nm
Φf[a]
τ1/ns
τ2/ns
quence of synthetic steps due to the acid lability of the 2,3-
dihydrothieno[3,4-b][1,4]dioxin moiety which was incapable
of surviving Nazarov reaction conditions. Consequently, 5-
bromo-1-methylindolin-2-one (17) was directly converted
into triflate 24 and then coupled with the alkoxydienyl
boronate 20 to give product 25 in 77% yield (Scheme 5).
Electrocyclization using o-benzenedisulfonimide gave 7-
bromo-1,4-dimethyl-1,2-dihydrocyclopenta[b]indol-3(4H)-
one (26) which was then coupled with 2-(2,3-dihydro-
thieno[3,4-b][1,4]dioxin-7-yl)-5,5-dimethyl-1,3,2-dioxa-
borinane to provide the corresponding adduct 27. The final
1
2
3
4
5
6
ST 23a
ST 23b
ST 23c
ST 23d
EGO 15
EGO 9c
335
300
325
335
365
320
480
560
506
480
437
484
0.10
0.03
0.06
0.12
0.02
0.14
7.26 (100%)
4.37 (56%)
4.69 (47%)
5.99 (57%)
0.80 (100%)
4.64 (100%)
–
11.9 (44%)
5.78 (53%)
7.96 (43%)
–
–
[a] Fluorescence quantum yields (Φf) were determined at 25 °C
using anthracene as the standard, upon selection of λex and λem
and the excitation and emission wavelengths.
With respect to the EGO 9c and 15 molecules the effect
step, coupling to bromobutenolide 4, performed under the of the position of the thienyl substituent on photophysical
usual conditions provided SL derivative 28 in 53% yield.
properties was investigated. The 7-substituted EGO mole-
cule (EGO 9c) was characterized by a broad absorption
band in the 220–400 nm range, with a maximum at 320 nm,
which is the wavelength chosen as the λex. The emission
band was found to be 164 nm red-shifted, being centered at
484 nm; this molecule was characterized by a good fluores-
cence quantum yield (ca. 0.14).
The corresponding 6-substituted EGO derivative (EGO
15) was characterized by an absorption band different in
both shape and position, with a maximum at 365 nm, which
was the wavelength chosen as the λex. The emission band
was found to be only 72 nm red-shifted, being centered at
437 nm and the fluorescence quantum yield was strongly
reduced (ca. 0.02) The position of the thienyl substituent
on the A ring of the molecule was found to dramatically
affect the photophysical properties of the resulting EGO
derivative. The 7-substituted derivative showed more inter-
esting properties including a larger Stokes shift (e.g., the
shift between absorption and emission band) and signifi-
cantly higher quantum yield than observed for the corre-
sponding 6-substituted derivative.
Spectroscopic Properties
In Figure 2 absorption and emission spectra of ST 23 a–
d, EGO 9c and 15 derivatives are reported. Solutions of the
molecules in dichloromethane, isoabsorbent at the selected
excitation wavelength, were prepared and emission spectra
were acquired. In Table 1 selected photophysical properties
of interest for future imaging application (e.g., fluorescence
quantum yields and lifetimes) are displayed. The molecules
Due to the large Stokes shift and the high quantum yield
the EGO 9c and ST 23d molecules appear to be the most
promising derivatives to be used in fluorescence imaging ap-
plications. Further studies may focus on the evaluation of
their photophysical properties in complex media (e.g., in
the presence of seeds studied for germination), since these
features, in particular fluorescence lifetimes, can be highly
affected by external environmental factors.
Figure 2. Absorption (dashed lines) and emission (solid lines) spec-
tra of selected ST and EGO derivatives.
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New Potent Fluorescent Analogues of Strigolactones
Biological Activity
The ST series of molecules, whose main differentiating
feature with respect to the EGO series is the substituent on
C1 of the ABC nucleus were tested in similar assays of seed
germination. The results are represented as a bar chart in
Figure 5. Compounds 23d (Ar = 6-methoxy-2-naphthyl)
and 23a (Ar = p-methoxyphenyl) showed stimulant activity
on germination at 10–6 m (23a and 23d) and at 10–4 m (23a).
These data were statistically different from water and sim-
ilar to GR 24. Remarkable activity was also displayed by
23b [Ar = p-(dimethylamino)phenyl)]; its activity was higher
than that of GR 24 in four out of the five concentrations
examined. Compound 23c (Ar = 2-thienyl) was found to be
Bioassays were carried out according to the standard
procedures (see Exp. Section). Water and acetone were used
as negative controls and a diastereomeric mixture of GR 24
(10–7 m) served as a positive control. The results obtained
with the EGO 5 and 15, both as racemic mixtures, are rep-
resented as a bar graph in Figure 3. The bioassays revealed
that racemic 5 had remarkable activity in stimulating the
germination of Orobanche seeds. As can be deduced from
the data, at all the concentrations tested EGO 5 possessed
a germination stimulant activity higher than those obtained
with GR 24, the positive control. EGO 15, possessing a
thienyl group in the 6 position of ring A proved to be less
active with germination percentages lower than those ob-
tained with EGO 5 and statistically similar to those ob-
tained with water, even though at 10–6 m data generated
with 15 was statistically similar to that obtained with GR
24. Based on these data EGO 15 can be considered active.
the less active compound; only at a concentration of 10–6
m
could it can be considered active even though the value was
lower than obtained with the other compounds, thus con-
firming the similar trend observed in the EGO series for
compound EGO 15. ST series member 22c deserves a
deeper discussion. Since recent data have spurred questions
about the effective role of the enol ether bridge,[35] as well
as the D ring itself[9] in determining the biological activity,
we decided to test 22c, a molecule lacking both functionali-
ties.
Figure 3. Bar graph representation of percentages of germinated
seeds of Orobanche aegyptiaca after exposure to various concentra-
tions of racemic EGO series members 5 and 15.
On the basis of literature data indicating that enantio-
mers with the same configuration at C2Ј of the D ring as
the natural strigol are more biologically active, we separated
the racemic mixtures of EGO 5 by semipreparative chiral
HPLC and tested each optically pure enantiomer in seed
germination bioassays. We exploited those concentrations
that had previously given the best results with racemates; in
the case of EGO 5 the concentration was set to 10–8 m. As
can be deduced from the bar chart reported in Figure 4, we
Figure 5. Bar graph representation of percentages of germinated
seeds of Orobanche aegyptiaca after exposure to diastereomeric
mixtures of ST 23a–d and to ST 22c.
As can be deduced from the bar chart reported in Fig-
could not observe a statistically significant difference in the ure 5, a remarkable activity, statistically comparable to GR
activity between the two enantiomers of 5.
24, has been observed at 10–10 m. This result seems to con-
firm that, lacking specific information about the receptor
active site, further structure-activity investigations are re-
quired to undoubtedly assess the role of each functional
group in the molecular structure.
As a further step, we tested some of the more promising
molecules in seed germination tests, as inducers of hyphal
branching in the fungus Gigaspora margarita. The results
are represented in Figure 6. ST series members 23a and 23d
which proved to be so active on Orobanche, lacked activity
on Gigaspora; data were found to be statistically different
from GR 24 data and similar to water data. EGO series
member 5 retained an activity statistically comparable with
GR 24, even though much weaker than its previously deter-
mined activity on Orobanche. Remarkably and in disagree-
Figure 4. Bar graph representation of percentages of germinated
seeds of Orobanche aegyptiaca after exposure to each optically pure
enantiomer of EGO 5.
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ment with what we had observed in seed assays, the two focused on providing a rapid and feasible route to bioactive
pure enantiomers of EGO 5 showed different levels of ac- compounds starting from commercially available and cheap
tivity in the hyphal branching assay.
reagents (EGO series). This sequence should provide bioac-
tive compounds in large amounts for agricultural applica-
tions. The second set of molecules (the ST series) can be
obtained using a more versatile synthetic approach which
Figure 6. Bar graph representation of percentages of hyphal
branching of Gigaspora margarita after exposure to diastereomeric
mixtures of ST 23a,b,d and to the two pure enantiomers of EGO
5.
In Figure 7 the results concerning molecules with a thi-
enyl group in the 6- or 7-positions of the A ring both for
the EGO and ST series are reported. As usual, the concen-
trations of the bioactive molecule that gave the best result
in the seed germination assays were chosen to test bioactiv-
ity on Gigaspora margarita. On the basis of the statistical
analysis we determined that only GR 24, ST 23c, and ST
23b acted as hyphal branching inducers showing an en-
hanced bioactivity with respect to water. Both EGO 15 and
ST 22c (lacking the D ring) were found to not be statistic-
ally different from water and thus can not be considered
active branching factors.
Figure 7. Bar graph representation of percentages of hyphal
branching of Gigaspora margarita after exposure to diastereomeric
mixtures of EGO 15, ST series members 22c, and 23b,c.
These data confirm the results of Akiyama and co-
workers[9] in that they demonstrate divergent structural
requirements for achieving biological activity in seed germi-
nation and fungal hyphal branching processes.
Conclusions
In this work we accomplished the synthesis of new SL-
like molecules with the specific aim of obtaining potent new
germination or hyphal branching stimulants which can be
exploited both in field applications and as probes to ident-
ify the SL receptor in vivo. The synthesis has been designed
Figure 8. Bioactivity of the ST and EGO series of molecules with
according to two main paths, the first of which is mainly respect to GR 24.
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New Potent Fluorescent Analogues of Strigolactones
signal. DAS6 decay analysis software was used for lifetime calcula-
tion.
can, in principle, allow the introduction of various func-
tional groups in different positions of the ABC nucleus. All
new molecules have been tested on Orobanche aegyptiaca
seeds and on Gigaspora margarita spores in order to evalu-
ate their bioactivity and to decipher possible structure-ac-
tivity relationships.
Biological Test: Plant material. Seeds of Orobanche aegyptiaca were
collected from field-grown tomato in the West Galilli of Israel. The
seeds were stored in glass vials in the dark at room temperature
until use in germination tests. Preparation of test solutions: the
compound to be tested was weighted out very accurately and dis-
solved in 1 mL of EtOH and then diluted with sterile distilled water
to reach the desired concentrations. All solutions were prepared
just before use.
The results are summarized in Figure 8, where a red col-
our indicates an activity superior to the universal standard
GR 24, yellow indicates comparable activity and blue indi-
cates an activity not statistically different from water which
served as negative control in these experiments. As can be
deduced from the Figure it is quite evident that there is no
direct correlation between bioactivity in seeds and fungi,
since molecules with a strong activity on seeds [(–)-β-EGO
5, ST 23a,d] are not active on fungi. Interestingly, the bioac-
tivity on fungi seems to be strongly dependent on the con-
figuration at C2Ј of the D ring, since (+)-α-EGO 5 was
found to be much more active than (–)-β-EGO 5. Even
more intriguing was the behaviour of ST 22c lacking the
enol ether and the D ring, as this compound retained ac-
tivity comparable to GR 24 in seeds but was completely
inactive in fungi. Furthermore, all molecules herein synthe-
sized and tested were found to be fluorescent with UV light
irradiation, inspiring us to investigate their spectroscopic
properties. This property will allow us to finely tune the role
of the substituents on the ABC core and to identify a puta-
tive SL-like probe to be used in the identification the SL
receptor in vivo. Due to their large Stokes shifts and to the
high quantum yields EGO 9c and ST 23d appear to be the
most promising candidates for use in future fluorescence
imaging applications.
Seeds were surface-sterilized and preconditioned according to the
experimental procedure indicated in ref.[31] Briefly seeds were ex-
posed for 5 min to 50% (v/v) aqueous solutions of commercial
bleach (2% hypochlorite) and rinsed with sterile distilled water. For
preconditioning seeds were sown by using a sterile toothpick on a
glass fiber filter paper disc (approximately 20 seeds per disc), the
glass fiber discs were placed on 2 filter paper discs, wetted with
sterile distilled water and incubated at 25 °C in the dark for 6 days.
The preconditioned seeds were then allowed to dry completely in
the laminar flow hoods, treated with the SL analogue solutions at
5 different concentrations: 10–4, 10–6, 10–8, 10–10 and 10–12 m and
the germination rates were evaluated under a stereomicroscope 7
days after treatment. For each concentration at least 100 seeds were
analyzed, synthetic SL GR 24 10–7 m was included as a positive
control, while an aqueous solution of 0.1% EtOH and sterile dis-
tilled water was included as a negative control. Seeds were consid-
ered to be germinated if the radicle protruded through the seed
coat.
Fungal Material: Spores of Gigaspora margarita Becker and Hall
were collected form already established trap culture of clover, steri-
lized with a solution of chloramine T (3% P/V) and streptomycine
sulfate (0.03% P/V), rinsed with distilled water and placed in a
Petri plate filled with 0.2% Phytagel gel (Sigma–Aldrich) contain-
ing 3 mm MgSO4. The plates were incubated vertically for 5 days
at 30 °C in the dark. Paper discs (6 mm diameter) impregnated with
the strigolactone analogues were positioned on either side of the
germinating hyphae tips. The number of newly formed hyphal apex
were recorded 24 h after treatment. GR 24 10–7 m was included as
a positive control whereas an aqueous solution of 0.1% acetone
and sterile distilled water was included as a negative control.
3-(1-Methyl-1H-indol-3-yl)propionic Acid (2):[36] To a solution of 3-
(1H-indol-3-yl)propionic acid 1 (1.21 g, 6.40 mmol) in acetone
(60 mL), cooled to 0 °C, were added powdered KOH (2.15 g,
38.26 mmol) and, dropwise, MeI (1.99 mL, 31.99 mmol). The re-
sulting pale yellow reaction mixture was left under vigorous stirring
at 25 °C for 4 h. After evaporation of the solvent, the residue was
dissolved in water (130 mL) and KOH (1.79 g, 31.87 mmol) was
added. The mixture was then heated to reflux while stirring for 2 h
and, after cooling, 6 n HCl was added until complete precipitation
of a white solid which was filtered and washed with heptane, thus
obtaining acid 2 (1.12 g) in 86% yield. Analytical and spectroscopic
data as reported.[1] 1H NMR (400 MHz, [D6]DMSO): δ = 12.04 (s,
1 H), 7.52 (d, J = 7.7 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.21–
7.00 (m, 3 H), 3.72 (s, 3 H), 2.92 (t, J = 7.2 Hz, 2 H), 2.57 (t, J =
7.2 Hz, 2 H) ppm.
Experimental Section
General Remarks: Chromatographic separations were carried out
on silica gel using flash-column techniques; Rf values refer to TLC
carried out on 0.25-mm silica gel plates (Merck F254), with the
same eluent indicated for the column chromatography. Unless indi-
cated otherwise 1H NMR spectra and NOESY 2D experiments
were recorded at 200 and 400 MHz and 13C NMR spectra were
recorded at 50 and 100 MHz. MS spectra were recorded at an ion-
izing voltage of 70 eV. For the determination of optical rotations a
Jasco P-2000 polarimeter was used. The enantiomers were sepa-
rated on a semi-preparative Chiralpak IC column (Φ 10ϫ250 mm,
Daicel, Osaka, Japan) employing an isocratic elution with CH2Cl2
and 1% EtOH at a flow rate of 4.7 mL/min. Absorption UV/Vis
spectra were collected with a Cary 300 instrument. Fluorescence
spectra were acquired with a Horiba Jobin Yvon Fluorolog3
TCSPC spectrofluorimeter equipped with a 450 W Xenon lamp
and a Hamamatsu R928 photomultiplier. The spectral response
was corrected for the spectral sensitivity of the photomultiplier.
Fluorescence lifetimes were measured using a time-correlated single
photon counting (TCSPC) technique (Horiba Jobin Yvon) with ex-
citation source NanoLed at 297 nm (Horiba) and impulse repeti-
tion rate of 1 MHz at 90° to a TBX-4 detector. The detector was
set to the emission wavelength indicated in Table 1 for each sample.
The instrument was set in the Reverse TAC mode, where the first
detected photon represented the start signal by the time-to-ampli-
tude converter (TAC), and the excitation pulse triggered the stop
4-Methyl-1,4-dihydro-2H-cyclopenta[b]indol-3-one (3): Warm poly-
phosphoric acid (115% in H3PO4, 3.65 mL, 66.77 mmol) was
added by a graduated pipette to 3-(1-methyl-1H-indol-3-yl)propi-
onic acid 2 (0.90 g, 4.47 mmol) followed by toluene (45 mL). The
mixture was refluxed for 4 h, during which time it turned brown.
After cooling to room temp. a mixture of ice and water (90 g) was
added, followed by extraction with CH2Cl2 (4ϫ80 mL). The com-
Eur. J. Org. Chem. 2011, 3781–3793
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C. Prandi et al.
FULL PAPER
bined organic layers were dried with Na2SO4, filtered and the sol-
vents evaporated. The residue was chromatographed (n-hexane/
EtOAc, 3:1, Rf = 0.38) to afford compound 3 (0.63 g) as a solid in
76% yield. Analytical and spectroscopic data as reported;[1] m.p.
135.1–136.1 °C. 1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J =
7.9 Hz, 1 H), 7.45–7.35 (m, 2 H), 7.21–7.16 (m, 1 H), 3.92 (s, 3 H),
[M + H]+, 151(27). C12H10BrNO (264.12): calcd. C 54.57, H 3.82,
N 5.30; found C 54.62, H 3.65, N 5.01.
7-Bromo-4-methyl-2-(4-methyl-5-oxo-2,5-dihydrofuran-2-yloxy-
methylene)-1,4-dihydro-2H-cyclopenta[b]indol-3-one (7): Prepared as
reported for compound 5. Starting from 7-bromo-4-methyl-1,4-di-
hydro-2H-cyclopenta[b]indol-3-one 6 (158 mg, 0.6 mmol), com-
pound 7 (48 mg) was obtained after chromatography (CH2Cl2/
MeOH, 30:1, 1% Et3N, Rf = 0.41) as a solid in 21% yield; m.p.
3.09–3.05 (m,
2 H), 3.01–2.97 (m, 2
H) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 194.8 (s), 145.0 (s), 144.8 (s), 138.9 (s),
126.8 (d), 123.1 (s), 121.7 (d), 120.2 (d), 110.9 (d), 41.2 (t), 30.0 (q),
19.6 (t) ppm. MS (EI): m/z (%) = 185 (100) [M]+, 157 (53), 142
(13).
1
167.1–180.0 °C (dec). H NMR (400 MHz, CDCl3): δ = 7.80 (d, J
= 1.9 Hz, 1 H), 7.47 (dd, J = 8.9, 1.9 Hz, 1 H), 7.45 (s, 1 H), 7.27–
7.23 (m, 1 H), 6.99–6.96 (m, 1 H), 6.22–6.19 (m, 1 H), 3.95 (s, 3 H),
3.56 (s, 2 H), 2.05 (s, 3 H) ppm. 13C NMR (100.4 MHz, CDCl3): δ
= 183.0 (s), 170.5 (s), 146.5 (d), 142.9 (s), 141.5 (s), 141.2 (d), 135.7
(s), 135.5 (s), 129.2 (d), 124.2 (s), 124.0 (d), 123.5 (s), 113.6 (s),
112.4 (d), 100.6 (d), 30.3 (q), 22.3 (t), 10.7 (q) ppm. MS (ESI): m/z
(%) = M+ not found. C18H14BrNO4 (388.21): calcd. C 55.69, H
3.63, N 3.61; found C 55.87, H 3.46, N 3.28.
(؎)4-Methyl-2-(4-methyl-5-oxo-2,5-dihydrofuran-2-yloxymeth-
ylene)-1,4-dihydro-2H-cyclopenta[b]indol-3-one (5): To a solution of
compound 3 (0.29 g, 1.07 mmol) in anhydrous THF (18 mL), co-
oled to 0 °C and under nitrogen atmosphere, were added ethyl for-
mate (0.86 mL, 10.7 mmol) and, dropwise, a 1 m solution of tBuOK
(2.14 mL, 2.14 mmol) in THF. The pink reaction mixture was left
stirring at room temp. with monitoring by TLC (n-hexane/EtOAc,
3:2). After complete consumption of the substrate (3 h), the solvent
was evaporated under strong nitrogen flow rendering a solid resi-
due to which were added anhydrous DME (16 mL) and, after cool-
ing to 0 °C, bromobutenolide 4 (0.21 g, 1.18 mmol). The resulting
dark green mixture was left while stirring at room temp. for 16 h
and then quenched by addition of a saturated NH4Cl aqueous solu-
tion (15 mL). The mixture was extracted with Et2O (5ϫ10 mL),
the combined organic layers washed with brine (2ϫ15 mL) and
dried with K2CO3. After filtration and evaporation of the solvent,
chromatography (n-hexane/EtOAc, 1:1, 1% Et3N, Rf = 0.39) gave
4-Methyl-7-(4-nitrophenyl)-1,4-dihydro-2H-cyclopenta[b]indol-3-one
(8a): Starting from 6 (221 mg, 0.84 mmol) and (p-nitrophenyl)bo-
ronic acid (419 mg, 2.51 mmol), compound 9 (176 mg) was ob-
tained after chromatography (CH2Cl2/MeOH, 60:1, Rf = 0.41, red
spot with p-anisaldehyde stain) as a solid in 69% yield; m.p. 198.4–
1
200.0 °C. H NMR (400 MHz, CDCl3): δ = 8.31 (d, J = 9.0 Hz, 2
H), 7.96 (d, J = 1.8 Hz, 1 H), 7.79 (d, J = 9.0 Hz, 2 H), 7.69 (dd,
J = 8.8, 1.8 Hz, 1 H), 7.48 (d, J = 8.8 Hz, 1 H), 3.97 (s, 3 H), 3.15–
3.10 (m, 2 H), 3.05–3.01 (m, 2 H) ppm. 13C NMR (100.4 MHz,
CDCl3): δ = 194.7 (s), 148.1 (s), 146.7 (s), 145.0 (s), 144.9 (s), 140.0
(s), 131.1 (s), 127.7 (d, 2 C), 126.1 (d), 124.2 (d, 2 C), 123.6 (s),
120.8 (d), 111.7 (d), 41.4 (t), 30.3 (q), 19.6 (t) ppm. MS (ESI): m/z
compound 5 (136 mg) as a solid in 40% yield; m.p. 176.2–176.8 °C
1
(dec). H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.2 Hz, 1 H), (%) = 329 (100) [M + Na]+. C18H14N2O3 (306.32): calcd. C 70.58,
7.43 (s, 1 H), 7.41–7.30 (m, 2 H), 7.17 (pseudo t, J = 8.0 Hz, 1 H),
6.99–6.95 (m, 1 H), 6.22–6.18 (m, 1 H), 3.94 (s, 3 H), 3.59 (s, 2 H),
2.03 (s, 3 H) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 184.8 (s),
170.5 (s), 145.9 (d), 144.5 (s), 141.3 (d), 140.7 (s), 136.9 (s), 135.6
(s), 126.6 (d), 124.0 (s), 122.7 (s), 121.6 (d), 120.4 (d), 110.9 (d),
100.6 (d), 30.2 (q), 22.4 (t), 10.7 (q) ppm. MS (ESI): m/z (%) =
310.07 (8) [M + H]+, 264 (81), 213 (100). C18H15NO4 (309.32):
calcd. C 69.89, H 4.89, N 4.53; found C 69.77, H 4.61, N 4.18.
H 4.61, N 9.15; found C 70.76, H 4.60, N 9.02.
4-Methyl-2-(4-methyl-5-oxo-2,5-dihydro-furan-2-yloxymethylene)-7-
(4-nitrophenyl)-1,4-dihydro-2H-cyclopenta[b]indol-3-one (9a): Pre-
pared as reported for compound 5. Starting from 8 (157 mg,
0.51 mmol), compound 9a (77 mg) was obtained after chromatog-
raphy (CH2Cl2/MeOH, 50:1, 1% Et3N, Rf = 0.32, red spot with p-
anisaldehyde stain) as a solid in 35% yield; m.p. 245.1–247.3 °C.
1H NMR (400 MHz, CDCl3): δ = 8.32 (d, J = 9.0 Hz, 2 H), 7.93
(d, J = 1.4 Hz, 1 H), 7.79 (d, J = 9.0 Hz, 1 H), 7.68 (dd, J = 8.8,
1.4 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.48 (s, 1 H), 7.00–6.98 (m,
1 H), 6.24–6.21 (m, 1 H), 4.02 (s, 3 H), 3.66 (s, 2 H), 2.05 (s, 3
H) ppm. 13C NMR (100.4 MHz, [D6]DMSO): δ = 182.2 (s), 170.9
(s), 147.9 (s), 147.2 (s), 146.1 (d), 144.1 (s), 143.4 (d), 141.2 (s),
136.8 (s), 133.7 (s), 130.1 (s), 127.6 (d, 2 C), 125.7 (d), 124.1 (d, 2
C), 122.8 (s), 122.3 (s), 120.7 (d), 112.5 (d), 101.2 (d), 30.3 (q), 22.1
(t), 10.2 (q) ppm. MS (ESI): m/z (%) = 431 (17) [M + H]+, 239
(100). C24H18N2O6 (430.41): calcd. C 66.97, H 4.22, N 6.51; found
C 67.12, H 3.93, N 6.40.
7-Bromo-4-methyl-1,4-dihydro-2H-cyclopenta[b]indol-3-one (6): To a
solution of 3 (0.10 g, 0.54 mmol) in anhydrous CH3CN (15 mL),
cooled to 0 °C, was added NBS (0.11 g, 0.65 mmol) while stirring
under a nitrogen atmosphere. The resulting green solution was
gradually heated and left 1 h at room temp. with monitoring by
TLC (n-hexane/EtOAc, 2.5:1. Compound 3 had Rf = 0.48, and gave
a red spot with p-anisaldehyde stain, and was fluorescent at 254 nm
under the UV lamp; reaction product 6 has Rf = 0.51, gave a red
spot with p-anisaldehyde stain, but was not fluorescent at 254 nm).
After 1 h, the reaction mixture was cooled to 0 °C again and fur-
ther NBS (0.05 g, 0.27 mmol) was added. The mixture was heated
to room temp. and allowed to stir for 1.5 h, after which time the
consumption of the starting material was complete (total reaction
time: 6 h). The reaction mixture was diluted with H2O (15 mL),
7-[4-(Dimethylamino)phenyl]-4-methyl-1,4-dihydro-2H-cyclopenta-
[b]indol-3-one (8b): A solution of 6 (0.07 g, 0.28 mmol) in anhy-
drous THF (6 mL) was added to a mixture of K3PO4 (0.24 g,
1.12 mmol), [4-(dimethylamino)phenyl]boronic acid (0.14 g,
extracted with Et2O (4ϫ15 mL) and the combined organic layers 0.84 mmol) and 2-dicyclohexylphosphanyl-2Ј,6Ј-dimethoxybi-
dried with Na2SO4. After filtration and evaporation of the solvent,
phenyl (S-Phos, 0.01 g, 0.028 mmol) under nitrogen atmosphere,
followed by Pd(OAc)2 (0.003 g, 0.014 mmol). The mixture was re-
fluxed while stirring and monitored by TLC (n-hexane/EtOAc,
2.5:1, Rf = 0.25, red spot with p-anisaldehyde stain). After 4 h, the
mixture was cooled to room temp. and diluted with H2O (25 mL),
extracted with Et2O (5ϫ25 mL) and the combined organic layers
dried with Na2SO4. After filtration and evaporation of the solvent,
chromatography (n-hexane/EtOAc, 3:1, 1% Et3N, Rf = 0.28) gave
chromatography (n-hexane/EtOAc, 2.5:1, Rf = 0.51) gave com-
1
pound 6 (95 mg) as a solid in 67% yield; m.p. 124.4–126.1 °C. H
NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 1.9 Hz, 1 H), 7.47 (dd,
J = 8.8, 1.9 Hz, 1 H), 7.24 (dd, J = 8.8, 0.4 Hz, 1 H), 3.89 (s, 3 H),
3.02–2.93 (m, 2 H), 2.91–2.82 (m, 4 H) ppm. 1 3 C NMR
(100.4 MHz, CDCl3): δ = 194.4 (s), 143.3 (s), 143.2 (s), 139.5 (s),
129.4 (d), 124.4 (s), 124.1 (d), 113.4 (s), 112.4 (d), 41.5 (t), 30.3 (q),
19.6 (t) ppm. MS (ESI): m/z (%) = 266 (97) and 264 (100)
1
8 (0.065 g) as a solid in 76% yield; m.p. 212.6–214.2 °C. H NMR
3788
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3781–3793

New Potent Fluorescent Analogues of Strigolactones
(400 MHz, CDCl3): δ = 7.82 (d, J = 1.6 Hz, 1 H), 7.65 (dd, J =
Na2SO4. After filtration and evaporation of the solvent, compound
8.6, 1.6 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 2 H), 7.37 (d, J = 8.6 Hz, 1 11 (1.071 g, 100%) was obtained in a sufficiently pure form for the
H), 6.84 (d, J = 8.8 Hz, 2 H), 3.92 (s, 3 H), 3.10–3.06 (m, 2 H),
3.02–2.97 (m, 2 H + 6 H) ppm. 13C NMR (100.4 MHz, CDCl3): δ
= 194.7 (s), 149.7 (s), 145.0 (s), 144.0 (s), 139.2 (s), 133.9 (s), 129.7
(s), 127.8 (d, 2 C), 126.4 (d), 123.5 (s), 118.6 (d), 112.9 (d, 2 C),
111.0 (d), 41.5 (t), 40.6 (q, 2 C), 30.1 (q), 19.6 (t) ppm. MS (ESI):
m/z (%) = 305 (7) [M + H]+, 290 (100). C20H20N2O (304.39): calcd.
C 78.92, H 6.62, N 9.20; found C 79.03, H 6.44, N 8.87.
next step. Analytical and spectroscopic data as reported.[2] 1
H
NMR (400 MHz, CDCl3): δ = 7.49 (br. s, 1 H), 7.48 (d, J = 8.4 Hz,
1 H), 7.21 (dd, J = 8.4, 1.8 Hz, 1 H), 7.02 (d, J = 3.1 Hz, 2 H),
6.46 (dd, J = 3.1, 0.8 Hz, 1 H), 3.76 (s, 3 H) ppm.
3-(6-Bromo-1-methyl-1H-indol-3-yl)propionic Acid (12):[38] To com-
pound 11 (1.07 g, 5.1 mmol) were added in sequence acetic acid
(2.5 mL), acrylic acid (0.929 mL, 14.3 mmol) and acetic anhydride
(0.9 mL) under nitrogen atmosphere. The mixture was left whilst
stirring at 140 °C for 4 h and then at room temp. for 16 h. Acetic
acid was then removed by distillation and the residue was diluted
with H2O (10 mL), the organic phase was extracted with Et2O
(5 ϫ 10 mL) and the combined organic layers were dried
7-[4-(Dimethylamino)phenyl]-4-methyl-2-(4-methyl-5-oxo-2,5-di-
hydro-furan-2-yloxymethylene)-1,4-dihydro-2H-cyclopenta[b]indol-3-
one (9b): Prepared as reported for compound 5. Starting from 8
(0.095 g, 0.31 mmol), compound 9b (75 mg) was obtained after
chromatography (CH2Cl2/MeOH, 40:1, 1% Et3N, Rf = 0.43, wine-
colored spot with p-anisaldehyde stain) as a solid in 56% yield; with Na2SO4. After filtration and evaporation of the solvent,
m.p. 202.7 °C (dec). 1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = chromatography (n-hexane/EtOAc, 4:1, Rf = 0.23, fuchsia-colored
1.4 Hz, 1 H), 7.60 (dd, J = 8.6, 1.4 Hz, 1 H), 7.51 (d, J = 8.8 Hz,
2 H), 7.42–7.40 (m, 1 H), 7.35 (d, J = 8.6 Hz, 1 H), 6.95–6.92 (m, 52% yield; m.p. 128.5–137.0 °C. H NMR (400 MHz, CDCl3): δ =
1 H), 6.81 (d, J = 8.8 Hz, 2 H), 6.18–6.15 (m, 1 H), 3.93 (s, 3 H), 7.44 (d, J = 1.9 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 7.20 (dd, J =
3.58 (s, 2 H), 2.98 (s, 6 H), 2.01 (s, 3 H) ppm. 13 C NMR 8.2, 1.9 Hz, 1 H), 6.84 (s, 1 H), 3.69 (s, 3 H), 3.06 (t, J = 7.6 Hz, 2
spot with p-anisaldehyde stain) gave acid 12 (0.75 g) as a solid in
1
(100.4 MHz, CDCl3): δ = 182.9 (s), 170.5 (s), 149.7 (s), 145.9 (d),
143.5 (s), 141.4 (d), 141.1 (s), 137.0 (s), 135.5 (s), 134.1 (s), 129.7
(s), 127.8 (d, 2 C), 126.2 (s), 124.0 (d), 123.2 (s), 118.5 (d), 112.9
(d, 2 C), 111.0 (d), 100.6 (d), 40.6 (q, 2 C), 30.3 (q), 22.4 (t), 10.7
(q) ppm. MS (ESI): m/z (%) = 429.14 (5) [M+ + H]+, 414 (17), 401
(31), 332 (100), 303 (18). C26H24N2O4 (428.48): calcd. C 72.88, H
5.65, N 6.54; found C 73.09, H 5.31, N 6.28.
H), 2.74 (t, J = 7.6 Hz, 2 H) ppm. 13C NMR (100.4 MHz, CDCl3):
δ = 179.2 (s), 137.8 (s), 126.9 (d), 126.4 (s), 122.0 (d), 120.0 (d),
115.4 (s), 113.4 (s), 112.3 (d), 34.7 (t), 32.7 (q), 20.0 (t) ppm. MS
(ESI): m/z (%) = 282 (3) [M + H]+, 264 (13), 222 (100), 203 (32).
C12H12BrNO2 (282.13): calcd. C 51.09, H 4.29, N 4.96; found C
51.33, H 4.17, N 4.58.
6-Bromo-4-methyl-1,4-dihydro-2H-cyclopenta[b]indol-3-one (13):
1,2-Dihydro-4-methyl-7-(thiophen-2-yl)cyclopenta[b]indol-3(4H)-one Prepared as reported for compound 3. Starting from 12 (0.75 g,
(8c): Prepared as reported for compound 8a. Starting from 6
(264 mg, 1 mmol) and 2-thienylboronic acid (384 mg, 3 mmol),
compound 8c (215 mg) was obtained after chromatography (petro-
2.67 mmol), compound 13 (337 mg) was obtained after chromatog-
raphy (n-hexane/EtOAc, 3:1, Rf = 0.36) as a solid in 48% yield;
m.p. 161.7–163.2 °C. H NMR (400 MHz, CDCl3): δ = 7.53 (d, J
1
leum ether/EtOAc, 7:3, Rf = 0.48, blue spot with p-anisaldehyde
stain) as a yellow oil in 80% yield. H NMR (200 MHz, CDCl3): 1 H), 3.86 (s, 3 H), 3.05–3.00 (m, 2 H), 2.98–2.94 (m, 2 H) ppm.
= 8.6 Hz, 1 H), 7.51 (d, J = 1.8 Hz, 1 H), 7.26 (dd, J = 8.6, 1.8 Hz,
1
δ = 7.71 (s, 1 H), 7.51 (d, J = 10.6 Hz, 1 H), 7.13 (m, 3 H), 6.94
(m, 1 H), 3.73 (s, 3 H), 2.83 (m, 4 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 194.5 (s), 144.8 (s), 144.7 (s), 144.1 (s), 139.4 (s), 127.9
13C NMR (100.4 MHz, CDCl3): δ = 194.6 (s), 145.4 (s), 144.5 (s),
139.3 (s), 123.7 (d), 122.8 (d), 121.8 (s), 120.5 (s), 114.0 (d), 41.4
(t), 30.1 (q), 19.4 (t) ppm. MS (ESI): m/z (%) = 264 (14)
(d), 125.4 (d), 123.9 (d), 123.1 (s), 122.3 (d), 121.5 (s), 118.5 (d), [M + H]+, 222 (100). C12H10BrNO (264.12): calcd. C 54.57, H 3.82,
111.1 (d), 41.2 (t), 29.9 (q), 19.4 (t) ppm. C16H15NOS (269.09):
calcd. C 71.34, H 5.61, N 5.20; found C 72.06, H 5.83, N 5.88.
N 5.30; found C 54.86, H 3.55, N 5.02.
4-Methyl-6-thiophen-2-yl-1,4-dihydro-2H-cyclopenta[b]indol-3-one
(؎) (2E)-2-[(2,5-Dihydro-4-methyl-5-oxofuran-2-yloxy)methylene]- (14): Prepared as reported for compound 8 but by using 10 mol-%
1,2-dihydro-4-methyl-7-(thiophen-2-yl)cyclopenta[b]indol-3(4H)-one
(9c): Prepared as reported for compound 5. Starting from 8c
(0.215 g, 0.8 mmol), compound 9c (74 mg) was obtained after
chromatography (petroleum ether/EtOAc, 7:3, 1% Et3N, Rf = 0.20,
grey spot with p-anisaldehyde stain) as a solid in 24% yield. 1H
NMR (200 MHz, CDCl3): δ = 7.78 (s, 1 H), 7.60 (d, J = 10.5 Hz,
1 H), 7.36 (s, 1 H), 7.29–7.17 (m, 3 H), 7.04–7.02 (m, 1 H), 6.89
(br. s, 1 H), 6.13 (br. s, 1 H), 3.87 (s, 3 H), 3.51 (br. s, 2 H), 1.99
(s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 182.8 (s), 170.4 (s),
146.0 (d), 144.8 (s), 143.7 (s), 141.3 (s), 141.1 (d), 136.8 (s), 135.4
of Pd(OAc)2. Starting from 13 (337 mg, 1.28 mmol) and from 2-
thienylboronic acid (490 mg, 3.83 mmol), compound 14 (254 mg)
was obtained after chromatography (n-hexane/EtOAc, 6:1, Rf =
0.25, blue, then green spot with p-anisaldehyde stain) as a solid in
1
74% yield; m.p. 161.8–163.9 °C. H NMR (400 MHz, CDCl3): δ =
7.66 (dd, J = 8.4, 0.6 Hz, 1 H), 7.52 (bs s, 1 H), 7.45 (dd, J = 8.4,
1.6 Hz, 1 H), 7.40 (dd, J = 3.7, 1.2 Hz, 1 H), 7.32 (dd, J = 5.0,
1.2 Hz, 1 H), 7.11 (dd, J = 5.0, 3.7 Hz, 1 H), 3.92 (s, 3 H), 3.06–
3.01 (m, 2 H), 2.99–2.96 (m, 2 H) ppm. 13C NMR (100.4 MHz,
CDCl3): δ = 194.4 (s), 145.3 (s), 144.9 (s), 144.7 (s), 139.4 (s), 133.0
(s), 127.9 (d), 127.1 (s), 125.3 (d), 124.0 (d), 123.6 (s), 122.9 (s), (s), 128.1 (d), 125.0 (d), 123.5 (d), 122.4 (s), 122.0 (d), 119.1 (d),
122.4 (d), 118.4 (d), 111.1 (d), 100.4 (d), 30.2 (q), 22.3 (t), 10.6
107.6 (d), 41.4 (t), 30.0 (q), 19.5 (t) ppm. MS (ESI): m/z (%) = 268
(q) ppm. MS/MS (ESI): m/z (%) = 392 (7) [M + H]+, 374 (4), 346
(6) [M + H]+, 253 (11), 226 (100). C16H13NOS (267.35): calcd. C
(10), 330 (7), 295 (100). C22H17NO4S (391.4): calcd. C 67.53, H 71.88, H 4.90, N 5.24; found C 71.92, H 4.76, N 4.99.
4.38, N 3.58; found C 67.55, H 4.30, N 3.25.
(؎) 4-Methyl-2-(4-methyl-5-oxo-2,5-dihydro-furan-2-yloxymeth-
6-Bromo-1-methyl-1H-indole (11):[37] To a solution of 6-bromo-
indole 12 (1.0 g, 5.1 mmol) in acetone (26 mL), cooled to 0 °C, were
added powdered KOH (1.71 g, 30.5 mmol) and, dropwise, MeI
ylene)-6-thiophen-2-yl-1,4-dihydro-2H-cyclopenta[b]indol-3-one (15):
Prepared as reported for compound 5. Starting from 14 (317 mg,
1.19 mmol), compound 15 (182 mg) was obtained after chromatog-
(1.59 mL, 25.5 mmol). The mixture stirred vigorously for 4 h at raphy (CH2Cl2/MeOH, 80:1, 1% Et3N, Rf = 0.27, blue spot with
room temp. and solvent then was evaporated and the residue di-
luted with H2O (20 mL). The aqueous phase was extracted with
Et2O (4ϫ20 mL) and the combined organic layers were dried with
p-anisaldehyde stain) as a solid in 38% yield; m.p. 189.7–192.8 °C.
1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.4 Hz, 1 H), 7.55
(br. s, 1 H), 7.47 (dd, J = 8.4, 1.4 Hz, 1 H), 7.44 (br. s, 1 H), 7.40
Eur. J. Org. Chem. 2011, 3781–3793
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C. Prandi et al.
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(d, J = 3.5 Hz, 1 H); 7.32 (d, J = 4.9 Hz, 1 H), 7.12 (dd, J = 4.9,
(d), 122.0 (d), 108.1 (d), 35.5 (q), 26.1 (d) ppm. C13H11NOS
3.5 Hz, 1 H), 6.98–6.96 (m, 1 H), 6.2 (br. s, 1 H), 3.99 (s, 3 H), 3.56 (229.06): calcd. C 68.09, H 4.84, N 6.11; found C 68.85, H 5.04, N
(s, 2 H), 2.04 (s, 3 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 182.5 6.67.
(s), 170.5 (s), 145.9 (d), 144.8 (s), 144.7 (s), 141.4 (d), 141.3 (s),
5-(2-Methoxynaphthalen-6-yl)-1-methylindolin-2-one (18d): Starting
136.7 (s), 135.5 (s), 132.8 (s), 128.1 (d), 125.0 (d), 123.9 (s), 123.4
from 17 (452 mg, 2 mmol), compound 18d (519 mg) was obtained
(d), 122.0 (s), 121.9 (d), 119.2 (d), 107.5 (d), 100.6 (d), 30.2 (q),
after chromatography (petroleum ether/EtOAc, 7:3, Rf = 0.10,
22.3 (t), 10.7 (q) ppm. MS (ESI): m/z (%) = 392 (11) [M + H]+,
brown spot with p-anisaldehyde stain) as an orange solid in 85%
295 (100). C22H17NO4S (391.44): calcd. C 67.50, H 4.38, N 3.58;
found C 67.74, H 4.31, N 3.47.
1
yield. H NMR (200 MHz, CDCl3): δ = 7.85 (s, 1 H), 7.73 (m, 2
H), 7.57 (m, 3 H), 7.11 (m, 2 H), 6.84 (d, J = 7.6 Hz, 1 H), 3.88
(s, 3 H), 3.54 (s, 2 H), 3.19 (s, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 174.9 (s), 157.5 (s), 144.2 (s), 135.8 (s), 135.6 (s), 133.4
(s), 129.4 (d), 129.0 (s), 127.1 (d), 126.6 (d), 125.6 (d), 125.0 (d),
124.9 (s), 123.1 (d), 119.1 (d), 108.1 (d), 105.4 (d), 55.1 (q), 35.7
(t), 26.1 (q) ppm. C20H17NO2 (303.13): calcd. C 79.19, H 5.65, N
4.62; found C 79.79, H 5.83, N 4.94.
5-Bromo-1-methylindolin-2-one (17): NBS (1.2 equiv., 12 mmol,
2.14 g) was recrystallized from water and added to a solution of
compound 16 (10 mmol, 1.47 g) in CH3CN at 0 °C. The reaction
mixture was then brought to room temp. and left stirring overnight.
Et2O was added to the solution and it was washed with water. The
aqueous phase was extracted three times with Et2O (20 mL). The
combined organic phases were dried with Na2SO4 anhydrous and
the solvent was evaporated under reduced pressure, to afford, with-
out any further purification, 2.15 g (9.5 mmol, 95%) of the product
General Procedure for the Synthesis of Compounds 19a–d and 24:
Triflates 19a–d have been prepared as previously reported.[39]
1
as a pink solid. H NMR (200 MHz, CDCl3): δ = 7.29 (m, 2 H),
General Procedure for the Synthesis of Compounds 21a–d and 25:
To a solution of the corresponding crude triflate in THF, under a
nitrogen atmosphere, (Ph3P)2PdCl2 (0.05 equiv.), (E)-2-(1-ethox-
ybuta-1,3-dienyl)-5,5-dimethyl-1,3,2-dioxaborinane (1.2 equiv.),
and a 2 m aqueous K2CO3 solution (1 mL) were added. The mix-
ture was stirred for 3 h at room temp. H2O (25 mL) was then
added, the mixture extracted with Et2O (3 x 20 mL) and dried with
anhydrous Na2CO3. Evaporation of the solvent afforded a yellow
oil which was purified by chromatography.
6.63 (d, J = 8.2 Hz, 1 H), 3.46 (s, 2 H), 3.13 (s, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 174.1 (s), 144.0 (s), 130.5 (d), 127.1
(d), 126.2 (s), 114.7 (s), 109.2 (d), 35.3 (t), 26.1 (q) ppm. C9H8BrNO
(224.98): calcd. C 47.80, H 3.59, N 6.21; found C 47.81, H 3.57, N
6.20.
General Procedure for the Synthesis of 18a–d: To a degassed solu-
tion of Pd2OAc2 (5 %), S-Phos (10 %), K3PO4 (3 equiv.), and
3 equiv. of the corresponding boronic acid, in THF (20 mL),
2 mmol (0.452 g) of 5-bromo-1-methylindolin-2-one (17) were
added. The reaction was then left stirring at reflux overnight. Water
(25 mL) was then added, the mixture was extracted with Et2O
(3ϫ20 mL), and dried with anhydrous K2CO3. Evaporation of the
solvent afforded the crude mixture of solid products which were
purified by chromatography.
2-[(E)-1-Ethoxybuta-1,3-dienyl]-5-(4-methoxyphenyl)-1-methyl-
1H-indole (21a): Compound 21a (405 mg) was obtained after
chromatography (petroleum ether/EtOAc, 8:2, 1% Et3N, Rf = 0.7,
brown spot with p-anisaldehyde stain) as a yellow oil in 75% yield.
1H NMR (200 MHz, CDCl3): δ = 7.71 (s, 1 H), 751 (d, J = 8.5 Hz,
2 H), 7.37 (d, J = 8.6 Hz, 1 H), 7.29 (d, J = 8.6 Hz, 1 H), 6.92 (d,
J = 8.5 Hz, 2 H), 6.54 (s, 1 H), 6.35 (dt, J = 16.0, 10.8 Hz, 1 H),
5.79 (d, J = 10.8 Hz, 1 H), 5.15 (dd, J = 16.0, 1.5 Hz, 1 H), 4.82
(dd, J = 10.8, 1.5 Hz, 1 H), 3.88 (q, J = 6.8 Hz, 2 H), 3.79 (s, 3 H),
3.65 (s, 3 H), 1.32 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 158.2 (s), 149.8 (s), 136.7 (s), 134.9 (s), 134.1 (s), 133.5
(d), 132.7 (s), 128.0 (d, 2 C), 127.4 (s), 121.8 (d), 118.7 (d), 113.9
(d, 2 C), 113.1 (t), 109.4 (d), 108.5 (d), 104.8 (d), 65.7 (t), 55.2 (q),
30.7 (q), 14.0 (q) ppm. C22H23NO2 (333.17): calcd. C 79.25, H 6.95,
N 4.20; found C 80.05, H 6.73, N 4.48.
5-(4-Methoxyphenyl)-1-methylindolin-2-one (18a): Starting from 17
(452 mg, 2 mmol), compound 18a (500 mg) was obtained after
chromatography (petroleum ether/EtOAc, 7:3, Rf = 0.12, brown
spot with p-anisaldehyde stain) as an orange solid in 98% yield. 1H
NMR (200 MHz, CDCl3): δ = 8.15 (d, J = 6.8 Hz, 2 H), 7.45 (m,
3 H), 6.95 (t, J = 6.2 Hz, 2 H), 3.90 (s, 3 H), 3.76 (s, 2 H), 3.25 (s,
3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 175 (s), 158.7 (s), 149.3
(s), 143.9 (s), 138.5 (s), 134 (s), 133.3 (s), 128.1 (d, 2 C), 126.2 (d),
122.9 (s), 119.3 (d), 114.1 (d, 2 C), 111 (d), 55.2 (q), 36.4 (t), 35.1
(q) ppm. C16H15NO2 (253.11): calcd. C 75.87, H 5.97, N 5.53;
found C 76.78, H 6.02, N 5.73.
4-{2-[(E)-1-Ethoxybuta-1,3-dienyl]-1-methyl-1H-indol-5-yl}-N,N-
dimethylbenzenamine (21b): Compound 21b (191 mg) was obtained
after chromatography (petroleum ether/EtOAc, 8:2, 1% Et3N, Rf =
0.6, brown spot with p-anisaldehyde stain), as a yellow oil in 55%
5-[4-(Dimethylamino)phenyl]-1-methylindolin-2-one (18b): Starting
from 17 (452 mg, 2 mmol), compound 18b (425 mg) was obtained
after chromatography (petroleum ether/EtOAc, 9:1, Rf = 0.20,
brown spot with p-anisaldehyde stain) as an orange solid in 98%
1
yield. H NMR (200 MHz, CDCl3): δ = 7.23 (m, 7 H), 6.53 (s, 1
H), 6.36 (dt, J = 17, 10.6 Hz, 1 H), 5.80 (d, J = 10.6 Hz, 1 H), 5.09
(dd, J = 17, 1.8 Hz, 1 H), 4.95 (dd, J = 10.1, 1.8 Hz, 1 H), 3.89 (q,
J = 7 Hz, 2 H), 3.65 (s, 3 H), 2.93 (s, 6 H), 1.32 (t, J = 7 Hz, 3
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 150.1 (s), 149.4 (s), 136.7
(s), 134.0 (s), 133.7 (s), 133.3 (d), 130.8 (s), 127.8 (d, 2 C), 127.6
(s), 121.8 (d), 118.2 (d), 113.2 (t), 112.9 (d, 2 C), 109.5 (d), 108.5 (d),
104.9 (d), 63.5 (t), 40.6 (q, 2 C), 30.8 (q), 14.6 (q) ppm. C23H26N2O
(346.20): calcd. C 79.73, H 7.56, N 8.09; found C 79.50, H 7.43, N
8.16.
1
yield. H NMR (200 MHz, CDCl3): δ = 6.96 (m, 7 H), 3.45 (s, 2
H), 3.12 (s, 3 H), 2.88 (s, 6 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 174.9 (s), 149.6 (s), 143.4 (s), 135.9 (s), 128.8 (s), 127.2 (d, 2
C), 125.5 (d), 124.8 (s), 122.4 (d), 112.7 (d, 2 C), 108.0 (d), 40.4 (q,
2 C), 35.8 (t), 26.1 (q) ppm. C17H18N2O (266.14): calcd. C 76.66,
H 6.81, N 10.52; found C 77.80, H 6.40, N 10.84.
1-Methyl-5-(thiophen-2-yl)indolin-2-one (18c): Starting from 17
(452 mg, 2 mmol), compound 18c (366 mg) was obtained after
chromatography (petroleum ether/EtOAc, 7:3, Rf = 0.50, blue spot
with p-anisaldehyde stain) as an orange solid in 80 % yield. 1H
2-[(E)-1-Ethoxybuta-1,3-dienyl]-1-methyl-5-(thiophen-2-yl)-1H-
indole (21c): Compound 21c (243 mg) was obtained after
NMR (200 MHz, CDCl3): δ = 7.40 (m, 2 H), 7.14 (m, 2 H), 6.98 chromatography (petroleum ether/EtOAc, 7:3, 1% Et3N, Rf = 0.50,
(m, 3 H), 6.71 (d, J = 8 Hz, 2 H), 3.88 (s, 3 H), 3.44 (s, 2 H), 3.13
blue spot with p-anisaldehyde stain), as a yellow oil in 53% yield.
(s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 174.7 (s), 144.4 (s),
1H NMR (200 MHz, CDCl3): δ = 7.82 (s, 1 H), 7.50 (d, J =
144.1 (s), 128.9 (s), 127.9 (d), 125.4 (d), 125.0 (s), 124.0 (d), 122.1 14.0 Hz, 1 H), 7.22 (m, 3 H), 7.02 (m, 1 H), 6.54 (s, 1 H) 6.35 (dt,
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New Potent Fluorescent Analogues of Strigolactones
1
J = 16.0, 10.5 Hz, 1 H), 5.83 (d, J = 10.5 Hz, 1 H), 5.10 (dd, J =
16.0, 1.5 Hz, 1 H), 4.83 (dd, J = 10.5, 1.5 Hz, 1 H), 3.90 (q, J =
7 Hz, 2 H), 3.66 (s, 3 H), 1.33 (t, J = 7 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 149.6 (s), 145.9 (s), 137.1 (s) 133.4 (d) 127.7
orange waxy solid in 55% yield H NMR (200 MHz, CDCl3): δ =
7.18 (m, 7 H) 3.86 (s, 3 H), 3.51–3.49 (m, 1 H), 3.17 (dd, J = 18.2,
6.2 Hz, 1 H), 2.95 (s, 6 H), 2.48 (dd, J = 18.2, 2 Hz, 1 H), 1.44 (d,
J = 7 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 194.1 (s),
(d), 127.3 (s), 126.3 (s), 123.3 (d), 121.8 (d), 121.1 (d), 118.2 (d), 149.6 (s), 149.3 (s), 143.7 (s), 138.3 (s), 133.8 (s) 129.5 (s), 127.7 (d,
113.3 (t), 109.6 (d), 108.5 (d), 104.9 (d), 63.5 (t), 30.8 (q), 14.5 2 C), 126.1 (d), 122.9 (s), 118.6 (d), 112.8 (d, 2 C), 111.0 (d), 503.5
(q) ppm. C19H19NOS (309.12): calcd. C 73.75, H 6.19, N 4.53; (t), 40.5 (q, 2 C), 29.9 (d), 27.9 (q), 20.9 (q) ppm. C21H22N2O
found C 74.05, H 6.27, N 4.60.
(318.17): calcd. C 79.21, H 6.96, N 8.80; found C 79.25, H 6.88, N
8.58.
2-[(E)-1-Ethoxybuta-1,3-dienyl]-5-(2-methoxynaphthalen-6-yl)-1-
methyl-1H-indole (21d): Compound 21d (384 mg) was obtained af-
ter chromatography (petroleum ether/EtOAc, 8:2, 1% Et3N, Rf =
0.65, brown spot with p-anisaldehyde stain), as a yellow oil in 60%
yield. 1H NMR (200 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.89 (s, 1 H),
7.75 (m, 3 H), 7.56 (d, J = 8.6 Hz, 1 H), 7.36 (d, J = 8.6 Hz, 1 H),
7.12 (m, 2 H), 6.60 (s, 1 H), 6.41 (dt, J = 17.0, 10.6 Hz, 1 H), 5.82
(d, J = 10.6 Hz, 1 H), 5.11 (dd, J = 17.0, 1.7 Hz, 1 H), 4.81 (dd, J
= 10.6, 1.7 Hz), 3.88 (m, 5 H), 3.68 (s, 3 H), 1.26 (t, J = 6.8 Hz, 3
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 157.2 (s), 137.5 (s), 137.0
(s), 134.2 (s), 133.5 (s), 133.1 (d), 133.0 (s), 129.4 (d), 129.2 (s),
128.9 (d), 127.6 (d), 126.9 (d), 126.5 (d), 125.2 (d), 122.1 (d), 119.3
(d), 118.8 (t), 113.2 (d), 109.6 (d), 108.5 (d), 105.4 (d), 104.9 (d),
63.5 (t), 55.4 (q), 30.8 (q), 14.5 (q) ppm. C26H25NO2 (383.19):
calcd. C 81.43, H 6.57, N 3.65; found C 81.85, H 6.48, N 3.58.
(؎)-1,2-Dihydro-1,4-dimethyl-7-(thiophen-2-yl)cyclopenta[b]indol-
3(4H)-one (22c): Compound 22c (139 mg) was obtained after
chromatography (CH2Cl2, 1% Et3N, Rf 0.30, blue spot with p-anis-
aldehyde stain), as an orange waxy solid in 30% yield 1H NMR
(200 MHz, CDCl3): δ = 7.85 (s, 1 H), 7.58 (d, J = 13.8 Hz, 1 H),
7.24–7.19 (m, 3 H), 7.06–7.01 (m, 1 H), 3.83 (s, 3 H), 3.48–3.46 (m,
1 H), 3.15 (dd, J = 18.4, 6.2 Hz, 1 H), 2.47 (dd, J = 18.4, 2.0 Hz),
1.44 (d, J = 7 Hz) ppm. 13C NMR (50 MHz, CDCl3): δ = 194.1 (s),
149.2 (s), 144.8 (s), 144.1 (s), 138.7 (s), 127.8 (d), 126.9 (d), 125.4
(d), 124.0 (d), 122.7 (s), 122.4 (s), 118.7 (d), 111.2 (d), 50.4 (t), 30.0
(q), 27.9 (d), 20.9 (q) ppm. C17H15NOS (281.09): calcd. C 72.57, H
5.37, N 4.98; found C 72.05, H 5.27, N 4.60.
(؎)-1,2-Dihydro-7-(2-methoxynaphthalen-6-yl)-1,4-dimethylcyclo-
penta[b]indol-3(4H)-one (22d): Compound 22d (76 mg) was ob-
tained after chromatography (petroleum ether/EtOAc, 9:1, 1%
Et3N, Rf = 0.20, brown spot with p-anisaldehyde stain), as an
5-Bromo-2-[(E)-1-ethoxybuta-1,3-dienyl]-1-methyl-1H-indole (25):
Compound 25 (700 mg) was obtained after chromatography (petro-
leum ether/EtOAc, 9:1, 1% Et3N, Rf = 0.43, brown spot with p-
anisaldehyde stain), as a yellow oil in 77 % yield. 1H NMR
(200 MHz, CDCl3): δ = 7.88 (s, 1 H), 7.46–7.25 (m, 3 H), 7.18 (d,
J = 8.6 Hz, 1 H), 6.66 (s, 1 H), 6.56 (dt, J = 17.0, 10.4 Hz, 1 H),
5.82 (d, J = 10.4 Hz, 1 H), 5.34 (dd, J = 17.0, 1.2 Hz, 1 H), 5.05
(dd, J = 10.4, 1.2 Hz), 4.00 (q, J = 7 Hz, 2 H), 3.70 (s, 3 H), 1.48
(t, J = 7 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 157.6 (s),
136.8 (s), 135.7 (s), 130.4 (s), 121.3 (d), 121.1 (d), 118.8 (t), 117.8
(s), 106.4 (d), 102.8 (d), 63.8 (t), 36.4 (q), 14.8 (q) ppm.
C15H16BrNO (305.04): calcd. C 58.84, H 5.27, N 4.57; found C
59.05, H 5.47, N 4.52.
1
orange waxy solid in 40% yield. H NMR (200 MHz, CDCl3): δ =
7.98 (s, 2 H), 7.75–7.69 (m, 4 H), 7.39 (d, J = 8.8 Hz, 1 H), 7.20–
7.11 (m, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 3.51–3.49 (m, 1 H), 3.19
(dd, J = 18.2, 6.2 Hz, 1 H), 2.51 (dd, J = 18.2, 1.8 Hz, 1 H), 1.47
(d, J = 7 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 194.2
(s), 157.5 (s), 149.4 (s), 144.1 (s), 138.6 (s), 136.6 (s), 133.6 (s), 133.3
(s), 129.4 (d), 129.1 (s), 127.1 (d), 126.5 (d), 126.2 (d), 125.3 (d),
122.9 (s), 119.9 (d), 119.0 (d), 111.2 (d), 105.4 (d), 55.2 (q), 50.5
(t), 30.0 (q), 27.9 (d), 21.0 (q) ppm. C24H21NO2 (355.16): calcd. C
81.10, H 5.96, N 3.94; found C 81.35, H 5.42, N 3.83.
General Procedure for the Synthesis of Compounds 22a–d and 26:
To a solution of 21 in 4 mL of DCE o-benzenedisulfonimide was
added (30 mol-%) and the reaction mixture was stirred in an open
air vessel at 80 °C until TLC analyses showed no further reaction
progress. The crude reaction mixture was treated with CH2Cl2/H2O
(1:1, 20 mL) and the aqueous phase extracted with CH2Cl2
(20 mL); combined organic extracts were dried with anhydrous
Na2CO3. Evaporation of the solvent afforded the crude products,
which were purified by flash chromatography.
(؎)-7-Bromo-1,2-dihydro-1,4-dimethylcyclopenta[b]indol-3(4H)-one
(26): Compound 26 (140 mg) was obtained after chromatography
(CH2Cl2, 1% Et3N, Rf 0.20, brown spot with p-anisaldehyde stain)
, as brown oil in 22% yield. 1H NMR (200 MHz, CDCl3): δ = 7.77
(s, 1 H), 7.39 (d, J = 8.8 Hz, 1 H), 7.16 (d, J = J = 8.8 Hz, 1 H),
3.80 (s, 3 H), 3.48–3.32 (m, 1 H), 3.13 (dd, J = 18.4, 6.2 Hz), 2.45
(dd, J = 18.4, 2.0 Hz), 1.38 (d, J = 7 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 194.1 (s), 147.8 (s), 143.1 (s), 138.8 (s), 129.1
(d), 124.1 (d), 113.2 (s), 112.4 (d), 50.4 (t), 30.0 (s), 27.8 (d), 20.8
(q) ppm.
(؎)-1,2-Dihydro-7-(4-methoxyphenyl)-1,4-dimethylcyclopenta[b]-
indol-3(4H)-one (22a): Compound 22a (61 mg) was obtained after
chromatography (petroleum ether/EtOAc, 8:2, 1% Et3N, Rf = 0.32,
brown spot with p-anisaldehyde stain), as an orange waxy solid in
50% yield. 1H NMR (200 MHz, CDCl3): δ = 7.78 (s, 1 H), 7.48
(m, 2 H), 7.30 (d, J = 8.8 Hz, 2 H), 6.91 (d, J = 8.8 Hz, 2 H), 3.82
(t, 3 H), 3.77 (t, 3 H), 3.51–3.49 (m, 1 H), 3.15 (dd, J = 18.0,
5.9 Hz, 1 H), 2.45 (dd, J = 18.0 Hz, 1 H, 1.8 Hz), 1.41 (d, J =
6.8 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 194.1 (s), 158.7
(s), 149.3 (s), 143.9 (s), 138.5 (s), 134.0 (s), 133.3 (s), 128.1 (d, 2 C),
126.2 (d), 122.9 (s), 119.3 (d), 114.1 (d, 2 C), 111.0 (d), 55.2 (q), 50.5
(q), 30.0 (t), 27.9 (d), 20.9 (q) ppm. C20H19NO2 (305.14): calcd. C
78.66, H 6.27, N 4.59; found C 78.75, H 6.32, N 4.63.
2-(2,3-Dihydrothieno[3,4-b][1,4]dioxin-7-yl)-5,5-dimethyl-1,3,2-di-
oxaborinane: A solution of 3,4-ethylenedioxythiophene (1.14 g,
8 mmol) in dry THF (20 mL), was cooled to –78 °C under N2 and
treated with 1.6 m solution of nBuLi (5.5 mL). The temperature
was slowly raised to 0 °C and the mixture was stirred at the same
temperature for 20 min. The reaction mixture was recooled to
–78 °C and treated with triisopropyl borate (3 g, 16 mmol) and
stirred for 2.5 h, then NH4Cl was added and the crude product was
extracted into (3ϫ20 mL) and dried with anhydrous Na2SO4. Af-
ter filtration and evaporation of the solvent, the crude product was
dissolved in anhydrous toluene (30 mL) and 2,2-dimethyl-1,3-pro-
panediol (0.83 g, 8 mmol) was added under N2. The mixture was
stirred at room temp. overnight, washed with water (30 mL), ex-
tracted with Et2O (3ϫ30 mL) and dried with anhydrous Na2SO4.
After filtration and evaporation of the solvent, the product was
obtained as a white solid 1.94 g (95 %). 1H NMR (200 MHz,
(؎)-7-[4-(Dimethylamino)phenyl]-1,2-dihydro-1,4-dimethylcyclo-
penta[b]indol-3(4H)-one (22b): Compound 22b (117 mg) was ob-
tained after chromatography (petroleum ether/EtOAc, 8:2, 1%
Et3N, Rf = 0.60, brown spot with p-anisaldehyde stain), as an
Eur. J. Org. Chem. 2011, 3781–3793
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3791

C. Prandi et al.
CDCl3): δ = 7.20 (s, 1 H), 4.20 (s, 4 H), 3.87 (s, 4 H), 1.12 (s, 6 (s), 141.3 (s), 140.2 (s), 135.4 (s), 129.3 (d), 127.9 (d), 127.1 (d),
FULL PAPER
H) ppm.
125.3 (d), 124.0 (s), 122.5 (d), 118.4 (d), 111.2 (d), 100.6 (d), 30.6
(d), 30.1 (q), 18.6 (q), 10.6 (q) ppm. MS/MS (ESI): m/z (%) = 406
(5) [M + H]+, 360 (4), 309 (100). C23H19NO4S (405.10): calcd. C
68.13, H 4.72, N 3.45; found C 68.25, H 4.47, N 3.61.
1,2-Dihydro-7-(2,3-dihydrothieno[3,4-b][1,4]dioxin-7-yl)-1,4-di-
methylcyclopenta[b]indol-3(4H)-one (27): Prepared as reported for
compounds 22. Starting from 26 (140 mg, 0.50 mmol), compound
27 (65 mg) was obtained after chromatography (CH2Cl2, 1% Et3N,
Rf = 0.18, blue spot with p-anisaldehyde stain) as a yellow waxy
(2E)-2-[(2,5-Dihydro-4-methyl-5-oxofuran-2-yloxy)methylene]-1,2-di-
hydro-7-(2-methoxynaphthalen-6-yl)-1,4-dimethylcyclopenta[b]-
indol-3(4H)-one (23d): Prepared as reported for compound 5. Start-
ing from 22d (76 mg, 0.21 mmol), compound 23d (30 mg) was ob-
tained after chromatography (petroleum ether/EtOAc, 6:4, 1%
Et3N, Rf = 0.36, orange spot with p-anisaldehyde stain) as a yellow
solid in 30% yield. 1H NMR (200 MHz, CDCl3): δ = 7.94–7.90 (m,
2 H), 7.79–7.63 (m, 4 H), 7.42–7.35 (m, 2 H), 7.12–7.11 (m, 2 H),
6.93 (s, 1 H), 6.14 (s, 1 H), 4.08–4.10 (m, 1 H), 3.93 (s, 3 H), 3.89
(s, 3 H), 1.99 (s, 3 H), 1.52 (two d superimposed, J = 7.99 Hz, 3
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 182.7 (s), 170.4 (s), 167.6
(s), 157.4 (s), 146.0 (d), 143.7 (s), 143.0 (s), 141.1 (d), 140.05 (s),
136.6 (s), 135.4 (s), 133.8 (s), 130.7 (d), 129.4 (d), 129.3 (s), 129.0
(s), 128.6 (d), 127.1 (d), 126.2 (d), 125.4 (d), 122.6 (s), 119.8 (d),
119.1 (d), 111.2 (d), 105.4 (d), 100.6 (d), 55.2 (q), 30.3 (d), 30.1 (q),
18.6 (q) ppm. MS (ESI): m/z (%) = 981 (100) [2M + Na]+, 480 (29)
[M + H]+. C30H25NO5 (479.17): calcd. C 75.14, H 5.25, N 2.92;
found C 74.88, H 5.30, N 3.02.
1
solid in 38% yield. H NMR (200 MHz, CDCl3): δ = 7.94 (s, 1 H),
7.70 (d, J = 8.8 Hz, 1 H), 7.27 (d, J = 8.8 Hz, 1 H), 6.22 (s, 1 H),
4.28–4.19 (m, 4 H), 3.83 (s, 3 H), 3.55–3.43 (m, 1 H), 3.15 (dd, J
= 18.4, 6.2 Hz), 2.46 (dd, J = 18.4, 2.8 Hz), 1.42 (d, J = 7 Hz) ppm.
13C NMR (50 MHz, CDCl3): δ = 194.1 (s), 149.3 (s), 143.6 (s),
142.1 (s), 138.5 (s), 137.2 (s), 125.6 (d), 125.4 (s), 122.6 (s), 119.0
(d), 117.7 (s), 110.9 (d), 96.6 (d), 64.6 (t), 64.3 (t), 50.4 (t), 29.9 (d),
27.9 (q), 25.4 (q) ppm. C19H17NO3S (339.09): calcd. C 67.24, H
5.05, N 4.13; found C 67.37, H 5.49, N 4.63.
(2E)-2-[(2,5-Dihydro-4-methyl-5-oxofuran-2-yloxy)methylene]-1,2-di-
hydro-7-(4-methoxyphenyl)-1,4-dimethylcyclopenta[b]indol-3(4H)-
one (23a): Prepared as reported for compound 5. Starting from
22a (61 mg, 0.20 mmol), compound 23a (34 mg) was obtained after
chromatography (petroleum ether/EtOAc, 7:3, 1% Et3N, Rf = 0.40,
orange spot with p-anisaldehyde stain) as a yellow solid in 40%
1
yield. H NMR (200 MHz, CDCl3): δ = 7.75 (s, 1 H), 7.55 (d, J =
(2E)-2-[(2,5-Dihydro-4-methyl-5-oxofuran-2-yloxy)methylene]-1,2-di-
hydro-7-(2,3-dihydrothieno[3,4-b][1,4]dioxin-7-yl)-1,4-dimethyl-
cyclopenta[b]indol-3(4H)-one (28): Prepared as reported for com-
pound 5. Starting from 27 (65 mg, 0.19 mmol), compound 28
(50 mg) was obtained after chromatography (petroleum ether/
EtOAc, 6:4, 1% Et3N, Rf = 0.16, grey spot with p-anisaldehyde
stain) as an orange solid in 56% yield. 1H NMR (200 MHz,
CDCl3): δ = 7.91 (s, 1 H), 7.69 (d, J = 10.4 Hz, 1 H), 7.32–7.25 (m,
2 H), 6.91 (s, 1 H), 6.22 (s, 1 H), 6.13 (s, 1 H), 4.28–4.19 (m, 4 H),
4.04–3.94 (m, 1 H), 3.88 (s, 3 H), 1.98 (s, 3 H), 1.20 (2d superim-
posed, J = 4.6 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
182.6 (s), 170.4 (s), 145.9 (s), 143.2 (s), 143.0 (s), 142.1 (s), 141.2
(s), 140.0 (s), 137.2 (s), 135.5 (s), 135.4 (s), 129.5 (d), 125.6 (d),
122.2 (d), 118.8 (s), 117.6 (d), 110.9 (d), 100.6 (d), 96.7 (d), 64.6
(t), 64.3 (t), 30.6 (d), 30.1 (q), 18.5 (q), 10.6 (q) ppm. MS/MS (ESI):
m/z (%) = 464 (6) [M + H]+, 436 (12), 366 (100), 323 (11).
C25H21NO6S (463.11): calcd. C 64.80, H 4.58, N 3.04; found C
64.85, H 4.62, N 3.37.
8.78 Hz, 3 H), 7.34 (m, 2 H), 6.93 (d, J = 8.78 Hz, 3 H), 6.15 (s, 1
H), 3.92–4.05 (m, 1 H), 3.90 (s, 3 H), 3.80 (s, 3 H), 1.98 (s, 3 H),
1.48 (two d superimposed, J = 6.75 Hz, 3 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 182.6 (s), 170.4 (s), 158.6 (s), 145.9 (s), 143.5
(d), 142.9 (d), 141.2 (s), 139.9 (s), 135.5 (s), 134.0 (s), 129.4 (s),
129.3 (s), 128.1, 102 (d, 2 C), 126.12 (d), 122.5 (s), 119.1 (d), 114.0
(d, 2 C), 111.0 (d), 100.6 (d), 55.2 (q), 30.6 (d), 30.2 (q), 18.4 (q),
10.6 (q) ppm. MS (ESI): m/z (%) = 430 (71) [M + H]+, 359 (77),
214 (100). C26H23NO5 (429.16): calcd. C 72.71, H 5.42, N 3.42;
found C 72.88, H 5.94, N 3.80.
(2E)-2-[(2,5-Dihydro-4-methyl-5-oxofuran-2-yloxy)methylene]-7-
[4-(dimethylamino)phenyl]-1,2-dihydro-1,4-dimethylcyclopenta[b]-
indol-3(4H)-one (23b): Prepared as reported for compound 5. Start-
ing from 22b (117 mg, 0.37 mmol), compound 23b (49 mg) was ob-
tained after chromatography (petroleum ether/EtOAc, 7:3, 1%
Et3N, Rf = 0.42, orange spot with p-anisaldehyde stain) as a yellow
solid in 30% yield. 1H NMR (200 MHz, CDCl3): δ = 7.59–6.76 (m,
3 H), 7.48 (d, J = 8.9 Hz, 2 H), 7.31 (s, 1 H), 6.92 (br. s, 1 H), 6.78
(d, J = 8.9 Hz, 2 H), 6.14 (br. s, 1 H), 4.04–3.90 (m, 1 H), 3.91 (s,
3 H), 2.95 (s, 6 H), 1.99 (s, 3 H), 1.49 (2d superimposed, J = 3.6 Hz,
3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 182.6 (s), 170.4 (s),
149.5 (s), 145.8 (d), 143.4 (s), 142.9 (s), 141.2 (d), 139.8 (s), 135.5
(s), 134.0 (s), 129.6 (s), 129.5 (s), 127.7 (d, 2 C), 126.1 (d), 122.5
(s), 118.5 (d), 112.7 (d, 2 C), 110.9 (d), 100.5 (d), 40.5 (q, 2 C), 30.6
(d), 30.2 (q), 18.4 (q), 10.6 (q) ppm. MS/MS (ESI): m/z (%) = 443
(11) [M + H]+, 415 (38), 346 (100), 317 (52), 302 (28). C27H26N2O4
(442.19): calcd. C 76.66, H 6.81, N 10.52; found C 76.58, H 6.84,
N 10.70.
Acknowledgments
We thank Prof. Gianmario Martra for the fluorescence spectra.
This research project has been supported by the Regione Piemonte
(BIOBIT, Converging Technologies – Cipe 2007). E. G. O. thanks
Ente Cassa di Risparmio di Firenze for granting a 400 MHz NMR
instrument.
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Received: May 3, 2011
Published Online: June 28, 2011
Eur. J. Org. Chem. 2011, 3781–3793
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3793