Synthesis and Reactivity of Oxazinoindolones via Regioselective 6-exo-dig Iodolactonization

Article abstract of DOI:10.1002/ejoc.201801167

An efficient protocol for the facile construction of 3,4-dihydro-10-iodo-3-iodomethylene-[1,4]-oxazino[4,3-a]indol-1-ones has been developed by using a regio- and stereoselective iodolactonization reaction. Subsequent palladium cross-coupling reactions of 3,4-dihydro-10-iodo-3-iodomethylene-[1,4]-oxazino[4,3-a]indol-1-ones readily afforded functionalized oxazinoindolones.

Full text of DOI:10.1002/ejoc.201801167

A Journal of
Accepted Article
Title: Synthesis and Reactivity of Oxazinoindolones via Regioselective
6-exo-dig Iodolactonization Reaction
Authors: Sokaina Hammoud, Elsa Anselmi, Khalil Cherry, Jean-Claude
Kizirian, and Jérôme Thibonnet
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801167
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European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
Synthesis and Reactivity of Oxazinoindolones via Regioselective
-exo-dig Iodolactonization Reaction
6
[a]
[a, b]
[c]
[a]
Sokaina Hammoud, Elsa Anselmi,
Thibonnet*[a]
Khalil Cherry, Jean-Claude Kizirian, and Jérôme
Dedication ((optional))
Abstract: An efficient protocol for facile construction of 3,4-dihydro-
0-iodo-3-iodomethylene-[1,4]-oxazino[4,3-a]indol-1-ones has been
Synthetic methods for access to this kind of structure include
indoles,[
7]
1
lactonization
from
the
ester
Friedel-Crafts
or
acid
transesterification,[
3,8]
alkylation,[9]
developed by using a regio- and stereoselective iodolactonization
reaction. Subsequent palladium cross-coupling reactions of 3,4-
dihydro-10-iodo-3-iodomethylene-[1,4]-oxazino[4,3-a]indol-1-ones
readily afforded functionalized oxazinoindolones.
cyclodehydration from the free-NH indole,[10] aza-Michael
addition,[11] copper catalyzed cyclization, hydroamination[13] of
the acid system and more recently by gold catalyzed cyclization
of the carboxylic acid.[14] In contrast to these, the construction of
oxazinoindolones by iodolactonization is rare. To the best of our
knowledge, there is only one report by B. Joseph et al. which
described a system with NIS and 2,6-lutidine at -20 °C allowing
the formation of iodo-oxazinoindolone.[15] Herein, we report a new
protocol for the synthesis of a variety of substituted 1,2-fused
indoles under mild reaction conditions using an iodolactonization
methodology.
[12]
Introduction
Substituted N-fused indole moieties are important heterocyclic
molecules that are present in a large number of naturel products,
pharmaceuticals, alkaloids, and agrochemicals and exhibit potent
and wide-ranging biological activity.[1] In particular, indole-fused
oxazinones gained considerable attention in recent years
because of their great importance in biological sciences and they
are also of interest in the field of optoelectronic materials.[2] There
are various tricyclic oxazinoindolones among which are the
structures A, B or C (Figure 1). Substituted 3,4-dihydro-1H-
[
1,4]oxazino[4,3-a]indol-1-ones C have attracted much attention
due to the broad scope of their biological activities. They are
mainly 1,2-fused system types with six-membered rings fused to
indoles with substituents on C3, C8 and C10. For example, a
recent patent reported the effectiveness of the corresponding
oxazinoindolone 1 as an anticancer agent.[3] Oxazinoindolones 2
and 3 showed anti-inflammatory[4] and herbicidal activities,[5]
respectively (Figure 1). Moreover, oxazinoindolones can be used
as intermediates in the chemistry of bioactive compounds.[6] Also,
1,2-fused oxazinoindolones have rarely been described in the
literature and much less than the 2,3-fused system. So, we
envisioned that the incorporation of the indole moiety into the
oxazinone scaffold may lead to potentially bioactive molecules.
The exploration of new methodologies that allow rapid access to
these N-fused polycyclic indole scaffolds remains an important
challenge facing organic chemists.
[
a]
Dr. S. Hammoud, Dr. E. Anselmi, Dr. J.-C. Kizirian, Prof. J.
Thibonnet, Laboratoire SIMBA, EA7502, Université de Tours,
Faculté des Sciences et Techniques, Parc de Grandmont, 32 Av.
Monge, 37200 Tours, France
Figure 1. Fused tricyclic oxazinoindolone derivatives and examples of N-fused
polycyclic indole scaffolds.
E-mail: jerome.thibonnet@univ-tours.fr
[
[
b]
c]
Dr. E. Anselmi, Institut Lavoisier de Versailles, UMR 8180,
Université de Versailles-St-Quentin, UFR de Sciences Bâtiment
Lavoisier, 45 Av. des Etats-Unis, 78035 Versailles Cedex, France
Prof. K. Cherry, Laboratoire Matériaux, Catalyse, Environnement
et Méthodes Analytiques (MCEMA), Université Libanaise, Faculté
des Sciences, Campus Universitaire de Hadath, Liban
Driven by our interest in the preparation of 1,2-fused polycyclic
indoles, and in conjunction with our successful previous research
on the tandem coupling/cyclization reaction of iodo-carboxylic
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
indoles,[16] we explored the reactivity of carboxylic N-propargylic
indoles in the iodolactonization reaction, followed by palladium
cross-coupling functionalization of the residual iodine. This
approach allows the preparation of original substituted
oxazinoindolones in positions 3 and 10 (Scheme 1).
Scheme 2. Precursors preparation.
We next turned our attention to the N-propargylation of the
resulting iodo-indole compounds. The N-alkylation reaction was
carried out with NaH. Initially, the reaction was performed with
Scheme 1. Synthesis of indoles fused at 2,3 and 1,2.
[20]
1.1 equiv. of NaH followed by 1.2 equiv. of propargylic bromide in
THF at room temperature. Only 30% conversion was observed.
The choice of solvent was then optimized and we found that using
DMF, we effectively improved the conversion to reach 94% for the
product 6a in only 3 hours. It should be noted that the use of an
excess of NaH and propargyl bromide leads to both N-
propargylation and also to transesterification of the ethyl ester to
Results and Discussion
The appropriate cyclization precursors were obtained by
successive electrophilic iodination, N-alkylation of the ester indole,
followed by saponification of the ester. Two different approaches
were explored, from the starting iodine propargyl indole acids, or
from a non-iodinated precursor (Scheme 2).
[21]
the propargyl ester, in accordance with Vandavasi’ work. The
scope was investigated with the iodine indoles 5 to afford the N-
propargylated indoles 6a-6f and 6k with good yields. In the same
experimental conditions, products 6g-6h were obtained from the
corresponding tosylate substrates. The preparation of the non-
iodinated substrates 6i-6k was also carried out for the study of the
following iodolactonization reaction.
We started by the iodination reaction of the ester indole 4
(
commercially available or synthesized by the Hemetsberger-
Knittel method)[
17]
with the NaI/NCS system.[18] This method
allowed the preparation of various alkyl 3-iodo-1H-indole-2-
carboxylates 5, obtained cleanly and in excellent yields after
simple recrystallization.
We also attempted the iodination of compound 6i but only
introduction of iodine on the propargyl function to give 6’ was
observed (38% yield) (Scheme 3).
Scheme 3. Iodination of 6i.
Concerning the saponification step, we applied the previously
reported conditions to the compound 6a,[22] which involved 12%
aq. KOH in EtOH at 70 °C for 1 h, to produce a mixture of
compound 7a and its allene isomer 8 (62/38). Screening was
pursued with various amounts of KOH and different reaction times
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European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
Scheme 5. Scope of the saponification step.
(
Scheme 4). We observed the formation of the allene 8 as the
major product (90/10) when the temperature was increased to
0 °C with 23% aq. KOH. The reaction conducted at 45 °C with
7
For the iodolactonization reaction, we initially tested the non-
iodinated substrate 1-(prop-2-yn-1-yl)-1H-indole-2-carboxylic
acid 7k. Different iodine sources, bases, solvents and
temperatures were investigated and the results are summarized
in Table 1. Interestingly, the reaction provides exclusively the six-
membered ring product but always with a mixture of mono- 9k and
aq. KOH 12% led to the N-propargyl acid indole 7a with only 5%
of the allene 8.
2
di-iodinated 10a products (Table 1, entries 1-6). The use of I and
NaHCO [
23]
gave a better result than NIS and lutidine[24] but we
3
still obtained a mixture of mono and di-iodinated products (entries
-3). Temperature had no significant effect on the observed
1
results (entry 3). In the presence of iodine, silver nitrate and
sodium carbonate in THF at room temperature overnight, we
obtained the same result, with di-iodinated 10a as the major
product mixed with 9% of mono-iodinated 9k (entry 6). Indeed,
this system, described by Xu Zhang et al.[25] in 2011, is an
effective protocol for the synthesis of fused benzimidazoles using
iodine and silver nitrate through exo- or endo-dig cyclization
pathways. Silver nitrate is an important additive that significantly
improves the reaction yield because it prevents the formation of
the bis-iodine by-product.[26] We then tried to optimize these
conditions by varying the quantity of reagents, but unfortunately
we always had a small amount (9%) of mono-iodinated product
and it was impossible to remove it from the mixture.
Scheme 4. Optimization of the saponification reaction conditions.
The reaction of the different esters 6 with 3 equiv. of 12% aq. KOH
in ethanol at 45 °C afforded the corresponding acids 7 with good
to excellent yields (Scheme 5). The moderate yield of 7f could be
explained by its low solubility, leading to difficulties during the
purification process. However for 7e only the transesterification
product was observed. After optimization of the conditions
(
7
changing the solvent to MeOH, 2 days at 100 °C), 53% yield of
e was obtained. The saponification was also performed on non-
iodinated substrates 7i-7k with excellent results.
Table 1. Optimization of the iodolactonization step
Ratio
Reagent
equiv.)
T
(°C)
Time
(h)
Entry
Solvent
9k/10a
(
a]
[
%][
NIS (2),
1
2
3
4
5
CH
2
Cl
2
-20
0
3.5
2.5
4
17/83
12/88
8/92
2
,6-lutidine (1,5)
CHCl
3
/
I
2
(2), NaHCO
3
(2)
(2)
2
H O
CHCl
3
/
I
2
(2), NaHCO
3
70
20
20
20
2
H O
I
2
(1), Na
AgNO
(3), Na
AgNO
(8), Na
AgNO
2
CO
3
(3),
THF
THF
THF
12
12
12
71/14
58/42
9/91
(1)[b]
3
I
2
2
CO
3
(3),
(3),
3
(1)
I
2
2
CO
3
6
3
(1)
1
[
a] H NMR analysis. [b] 15% of starting material.
Finally, we prefered to carry out the reaction on the acid 7a to
obtain only the di-iodinated product 10a in the presence of
Na CO (3 equiv.), I (1.5 equiv.) and AgNO (1 equiv.) in THF at
2 3 2 3
r.t. (Scheme 6). Under these conditions, a good yield (86%) of
isolated pure (E)-oxazinoindol-1-one 10a was obtained and the
structure of this compound was unambiguously determined by a
single-crystal X-ray diffraction study (Scheme 6, for details see
Yields refer to isolated product. [a] MeOH, 100 °C, 2 days.
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European Journal of Organic Chemistry
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Supporting Information SI-1).[27] The scope of the reaction was
then investigated directly with the iodinated precursors 7b-7h
own observations. First, the alkyne function in the carboxylate A
is activated by coordination to the electrophilic iodine source I to
+
(
Scheme 6). The products 10a-10e were cleanly obtained by a
furnish the corresponding cyclic iodonium B. Subsequently,
regioselective intramolecular nucleophilic attack of the oxygen
then proceeds via a 6-exo-trig ring-closing pathway to form the
oxazinoindolones 10.The addition of silver nitrate will probably
allow for an ionic reaction.[31] The formation of AgI in the reaction
medium will prevent the iodide ions from attacking the
intermediate B thus avoiding the formation of bis-iodineated by-
products.
simple recrystallization in moderate to good yields (41-92%).
Furthermore, the scope of this iodolactonization reaction was
examined by using electron-rich or electron-deficient substrates
which successfully underwent this transformation with high
stereoselectivity. Significantly, the protocol is also tolerant to R3
substituents (Me or Ph) to furnish the products 10g and 10h in
7
9% and 87% yield respectively. The lower yields for 10b, 10f and
10e could be due to poor solubility of the corresponding starting
material and of the final desired product, but also formation of the
by-product from iodine decarboxylation, already described in the
literature.[23] After successfully examining the substrate scope, we
performed a gram-scale synthesis of 10a (3.24 g) starting from 7a.
Scheme 7. Proposed mechanism for iodolactonization.
We also performed the iodolactonization in these conditions on
the allene 8. It resulted in the formation of an unseparable mixture
of compounds including 10a and other undetermined products.
Having established a set of conditions for the formation of di-
iodide compounds, we turned our attention to the functionalization
of such derivatives, by exploiting the reactivity of both carbon-
iodine bonds by employing them in various cross-coupling
reactions (Scheme 8). Iododerivatives 10a-k were first
functionalized through a Stille cross coupling reaction.[32] This
reaction has many advantages, because the organotin reagents
are easily prepared, have a high stability against oxidation and
heating, and tolerate a wide variety of sensitive functional
groups.[33] This popular method has often been used in the
synthesis of synthetic natural products.[34]
Scheme 6. Scope of the iodolactonization and X-Ray structure of compound
10a with displacement ellipsoids drawn at the 50% probability level.
Considering stereoselectivity aspects, (Z)-isomers were never
observed in the crude reaction mixtures. Addition of iodine to 10a
(
3 equiv. for 7 days) did not allow us to observe the formation of
the (Z)-isomer. The thermodynamic stabilities of these two
diastereoisomers were also evaluated by AM1 calculations
(
B3LYP theory) with the B3LYP-def2-TZVP basis set. The results
reveal a higher stability of the E vs. Z stereoisomer, with a
difference of stability close to 1.1 kJ mol-1 (0.26 kcal mol ).
-1
[28, 29]
A proposed plausible mechanism for the iodolactonization is
depicted in Scheme 7 on the basis of the literature [26, 30] and our
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European Journal of Organic Chemistry
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Scheme 8. C-C coupling reactions: Stille, Sonogashira or Suzuki.
The reaction was carried out in classical conditions, and the
results are summarized in Scheme 9. Stille coupling was first
performed in the presence of tri-n-butyl(vinyl)stannane (1.1
2 2
equiv.), and a catalytic amount of PdCl (MeCN) in DMF at room
Scheme 9. Structures and yields of the Stille coupling. Reagents and
conditions: vinyltin (1.1 equiv.), PdCl MeCN (5 mol%), DMF, r.t., 18 h.
2 2
temperature. Under these stoichiometric conditions, mono-
coupling was successfully achieved and regioselectively on the
exocyclic vinyl iodine, providing the desired tricyclic derivatives
1
1a, 11c and 11d in 61-83% yield. Significantly, the protocol is
For Sonogashira[36] coupling we first investigated the reactivity of
the exocyclic carbon-iodine bond (Scheme 10). The first tests
were attempted on compounds 10a-10c and 1-hexyne using
palladium acetate, copper iodide as catalyst, triethyamine and
DMF as solvent at room temperature. The corresponding 11h-11j
were obtained with a moderate to good yields (48-85%). However,
the use of the alkynes phenylacetylene or methoxypropyne with
3
also tolerant to R substituents (Me or Ph) to afforded the products
11f and 11g in 74% and 40% yield respectively. The Stille mono-
coupling with (E)-trimethyl(2-(tri-n-butylstannyl)vinyl)silane gave
products 11b and 11e in lower yields (38% and 48% respectively).
Coupling carried out in the presence of an excess of tri-n-
butyl(vinyl)stannane (3 equiv) under the same operating
conditions made it possible to react the second carbon-iodine
bond, but gave the corresponding products with low yields,
respectively 30% and 26% (12a, 12b). A simple method for the
removal of organotin residues was by column chromatography
10a allowed us to obtain the products 11i and 11j only with low
yields (27% and 11% respectively), resulting probably from the
duplication of terminal alkynes. A double Sonogashira coupling
reaction with hexyne and di-iodide 10a furnished 12c but only in
2 3 2
using 10% w/w anhydrous K CO -SiO
as the stationary phase.[35]
34% yield.
To explain this difference in reactivity of the two C-I bonds, we
performed various calculations and analyzed the X-ray structure
of 10a.[ The X-ray analysis shows that the C-I bond [2.059 (6)
A˚] of the endocyclic-iodine (C7I1) moiety is slightly shorter than
the C-I bond [2.076 (6) A˚] of the exocyclic-iodine (C12-I2)
28]
(
Scheme 6). By calculation, we can see that C-I distances are
smaller in the case of the iodine atom localised in the endocyclic
position as the C15-I17 distances: 2.095 Å vs that obtained by
looking at C5-I6 (2.106 Å). Furthermore, the I17C15C16C2
dihedral angle is close to 1.6°, while the dihedral angle is close to
183.7° for O3C4C5I6. This shows in fact that the iodine atom in
position 17 is in the 3D Euclidean space than atoms in composing
the aromatic cycles, which is not the case of iodine in the position
exocyclic (see Supporting Information SI-2). These differences in
bond distances and dihedral angles could explain the better
reactivity of this exocyclic-iodine when the Pd catalyst is used.
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European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
allows access to products 11m, 11n and 11o with average to low
yields (Scheme 10).
We recently developed an efficient method for the Sonogashira
decarboxylative cross coupling reaction[39] between aryl halides
and alkynyl carboxylic acids, and we explored this reaction with
compound 10d and pent-2-ynoic acid (Scheme 11). The
corresponding decarboxylative coupling product 13 on the vinyl
iodine atom only was isolated in 70% yield.
Scheme 11. Sonogashira decarboxylative cross-coupling reaction with 10d.
Finally, we tried to extend this methodology to indoles with longer
alkynyl chains in order to obtain extended 7-membered or 8-
membered cycles (Scheme 12). Compound 14b was synthesized
according to the previously described procedure with a good yield.
However, the same strategy employed for the preparation of 14a
failed whatever the starting materiel employed (4-bromobut-1-yne,
but-3-yn-1-yl-methylbenzenesulfonate or 4-(trimethylsilyl)but-3-
yn-1-yl methylbenzenesulfonate in basic conditions). Fortunately,
Mitsunobu conditions[40] allowed the formation of the
homopropargyl indole 14a though the yield is low (35%), enabling
the next step, saponification, with a good yield (91%).
Scheme 10. Structures and yields of the Sonogashira and Suzuki couplings. [a]
Reagents and conditions for Sonogashira: Alkyne (1.5 equiv.), CuI (10 mol%),
Finally, iodocyclization of these two compounds was performed in
the conditions described previously, and led to the formation of
exclusively the exo-dig products in both cases. The low yield
could be explained by the formation of the corresponding
iodinated-decarboxylated by-products (observed in the propargyl
series). The structures of 16a and 17b, were confirmed by X-ray
crystallography (see Supporting Information SI-1). Effect of
substituant on the alkynyl chain led to the formation of a mixture
of undetermined products while it is not the case with propargyl
chain.[41]
Despite their ubiquitous existence within various biologically
active natural products and pharmaceuticals, the formation of 1,2-
fused indoles with medium sized rings is generally difficult to
achieve.[42] The methods for obtaining these products remains a
major challenge in organic synthesis and they are mainly based
on the use of metal complexes.[43] This new methodology
therefore makes it possible to access new 1,2-fused substituted
indoles with medium-sized (seven- to eight-membered) carbocyle.
PPh
3
(10 mol%), Pd(OAc)
2
(5 mol%), Et
3
N, DMF, 15 h. [b] Reagents and
3
conditions for Suzuki coupling: R BF
Cs CO (1.5 equiv.), toluene/H O (5/1), 70 °C, 24 h.
2 3 2
3
K (1.2 equiv.), PdCl
2
dppf (5 mol%),
Starting from compound 10a we finally tested the reactivity of the
exocyclic iodine toward a Suzuki-Miyaura[37] coupling reaction
with 4-methylphenylboronic acid. However
inseparable mixture of products was obtained. Finally, we
considered the Suzuki–Miyaura cross coupling conditions with
potassium vinyltrifluoroborate, which is commercially available
and air-stable. This compound has been widely employed as a
versatile vinylating agent in Suzuki–Miyaura cross-coupling
reactions in recent years, and has proven to be a powerful C2
building block to access a variety of styrenic derivatives.[38]
a complex and
Thus, the use of potassium vinyltrifluoroborate (1.2 equiv.) with
compound 10a in the presence of cesium carbonate (1.5 equiv.),
PdCl
2 2
dppf (5 mol%) in a 5:1 mixture of toluene/H O at 70 °C for
24 h furnished 11a in 60 % yield. In addition, potassium
vinyltrifluoroborate (3 equiv.) was also an efficient coupling
partner with 10b for a double transformation to give the desired
product 12b in 91% yield. Finally, the introduction of a heterocyclic
unit as a coupling partner (benzofuran, thiophene, isoxazole)
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European Journal of Organic Chemistry
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FULL PAPER
Scheme 13. Pyrrole extension.
Conclusions
In summary, we have developed an iodocyclization of N-propargyl
indoles, followed by palladium-catalyzed coupling, providing
potential
biologically
and
pharmaceutically
important
oxazinoindolones in moderate to excellent yields. We also carried
out analogous transformations to extend this methodology with
longer alkynyl chain in order to obtain extended 7-membered or
8-membered cycles. This method provides straightforward
access to 1,2-fused tricyclic indoles. After preliminary good
results toward resistant bacteria, others tests are in process.
Experimental Section
Scheme 12. Extended alkynyl chain indoles and X-Ray structures of
compounds 16a and 17b with displacement ellipsoids.
General Methods: All reactions were carried out under argon atmosphere
in dried glassware. THF was distilled under argon from sodium using
benzophenone as indicator. Dimethylformamide was dried and freshly
distilled from calcium hydride. Chemicals were purchased from
commercial sources (Sigma–Aldrich, Alfa Aesar, Fluorochem or ABCR)
and used without further purification except 5b, 5e, 5f obtained by
Hemetsberger-Knittel [1] method and 2c by Fischer [2] method.
Finally, we tested iodocyclization in the pyrrole series. By the
same methodology previously described for commercial pyrrole
1
8 (N-propargylation with propargyl bromide; saponification with
KOH), we obtained the pyrrole acid 20 in good yield (Scheme
3).[14, 43] Under the previously used iodocyclization conditions
Na CO (3 equiv.), I (1.5 equiv.) and AgNO (1 equiv.) in THF at
®
Reactions were monitored by TLC with Merck Silica gel 60 F254. The
developed TLC plates were visualized by using UV light (254 nm) or
1
[
KMnO
4
. Column chromatography was performed on silica gel (40-63 µm)
2
3
2
3
using various mixtures of EtOAc and petroleum ether (35-60 °C fraction)
r.t.], a moderate yield (30%) of isolated pure (E)-pyrrolo-oxazin-1-
one 21 was obtained (Scheme 13). The (E)-pyrrolo-oxazin-1-one
1
®
as eluent. H NMR spectra were recorded on a Bruker Avance 300 (300
MHz) NMR spectrometer, using as internal deuterium lock the solvents
CDCl
are quoted in ppm (δ
d = doublet, t = triplet, q = quartet, quin = quintet, sxt = sextet, m = multiplet
3
(δ 7.26), (CD
3
)
2 3 2
CO (δ 2.05) or (CD ) SO (δ 2.54). Chemical shifts
scaffold exhibits wide-ranging biological activity against
multitude targets, making it an important intermediate.
a
H
, δ ). Peak multiplicities are defined as: s = singlet,
C
13
and br = broad. Coupling constants (J) are reported in Hz. C NMR was
recorded at 75 MHz on the same instrument, using the solvent peak at as
3 3 2 3 2
(δ 77.16), (CD ) CO (δ 29.85) or (CD ) F
SO (δ 39.52). 19
reference CDCl
NMR was recorded at 282 MHz on the same instrument, using the CFCl
3
as internal reference (δ 0.0). Mass spectra were obtained on a Hewlett
Packard (engine 5988A) by direct inlet at 70eV. HRMS was obtained with
a LCMS-IT-TOF mass spectrometer under conditions of ESI. Infrared
spectra were recorded on
spectrophotometer with the sample being prepared as a thin film on a
diamond ATR module. Absorption maxima (max are quoted in
a
Perkin-Elmer Spectrum One
)
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European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
-
1
1H), 5.58 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). 13
NMR (75 MHz, CDCl ) δ = 162.0, 139.0, 127.0, 126.2, 125.6, 122.8, 121.2,
3
wavenumbers (cm ). Melting points were uncorrected. Analytical data for
already describes molecules can be find in SI.
C
1
C
11.5, 110.6, 89.2, 72.1, 60.9, 35.7, 14.4. HRMS (ESI): calcd. for
General procedure for iodination of indoles
+
14
H13INO
2
[M+H] 353.9991; found. 353.9976.
In a two-necked round bottom flask, 4.16 g of NCS (1.2 eq, 31 mmol) were
first dissolved in 40 mL of DMF and then, 4.67 g of NaI (1.2 eq, 31 mmol)
was added in small portions and the mixture was stirred for 30 min at room
temperature. 1 eq of indole (26 mmol) was dissolved in 10 mL of DMF and
added drop by drop to the mixture using a bromine bulb at 0 °C.
According to the solubility, 2 different protocols:
General procedure for N-alkylation: In a two-necked round bottom flask,
.82 g of NaH 60 % (1.3 equiv., 20.6 mmol) were dissolved in 15 mL of
0
DMF, and 1 equiv. of compound 5 (15.8 mmol) in 10 mL of DMF were
added drop by drop using a syringe at 0 °C under argon. The mixture was
stirred for 30 min at room temperature. 1.3 equiv. of propargyl bromide
Method A: The mixture was stirred for 4 h at room temperature. The
80 % (20.6 mmol) or tosylate were diluted with DMF and added to the
medium was hydrolyzed by 10 mL of Na
of water and then stirred for 30 min. The precipitate formed was dissolved
with Et O. The organic phase was washed with NH Cl (3 × 10 mL), NaCl
2 × 10 mL), dried by MgSO and evaporated under vacuum before
recrystallization with CH
Method B: The mixture was stirred for 4 h at room temperature. The
medium was hydrolyzed by 20 mL of Na (20 % aq. sol.) and 20 mL
2 2 3
S O (20 % aq sol.) and 10 mL
mixture drop by drop using a syringe at 0 °C under argon. After 4 h of
stirring at room temperature, the mixture was hydrolyzed by 10 mL of
NH
washed with NaCl (6 × 10 mL), dried by MgSO
vacuum. The product is obtained pure or the residue was purified by
column chromatography (eluent EtOAc/hexane).
2
4
4
Cl, extracted by diethyl ether (7 × 20 mL), and the organic phase was
(
4
4
and evaporated under
2
Cl2.
2 2 3
S O
of water and then stirred for 30 min. The precipitate was filtered on a
Büchner funnel and washed by hexane and the precipitate was left to dry
for 2 h.
The following products are already described and in accordance with the
litterature: Ethyl 1-(prop-2-ynyl)-1H-indole-2-carboxylate 6i[14]; 1-(but-2-
ynyl)-1H-indole-2-carboxylic acid 6k. [14]
The following products are already described and in accordance with the
Ethyl 3-iodo-1-(prop-2-yn-1-yl)-1H-indole-2-carboxylate 6a: Yellow
litterature : Ethyl 3-iodo-1H-indole-2-carboxylate (method A) 5a[16]; Methyl
solid (5.3 g, 95 %); m.p. 84-86 °C; R
NMR (300 MHz, CDCl ): δ = 7.59 (d, J = 9 Hz, 1 H), 7.46-7.44 (m, 2 H),
.30-7.25 (m, 1 H), 5.40 (d, J = 3 Hz, 2 H), 4.49 (q, J = 8 Hz, 2 H), 2.27 (t,
J = 2.5 Hz, 1 H), 1.51 (t, 3H, J = 6 Hz) ppm. 13C NMR (75 MHz, CDCl
): δ
161.2, 138.3, 130.7, 127.6, 126.7, 124.3, 122.0, 110.7, 78.6, 72.5, 69.0,
1.6, 35.2, 14.3 ppm. IR (ATR): max = 3277, 2985, 2121, 1690, 1609, 1568
= 0.67 (EtOAc/hexane, 20:80). 1
H
f
7
5
-iodo-5H-[1,3]dioxolo[4,5-f]indole-6-carboxylate (method B) 5b[18b]; Ethyl
-fluoro-3-iodo-1H-indole-2-carboxylate 5d[18b] (method B).
3
7
3
Ethyl 3-iodo-5-methoxy-1H-indole-2-carboxylate 5c: Method (B).
Brown solid (8.7 g, 97 %); m.p. 162-164 °C; R = 0.79 (EtOAc/PE, 20:80).
1H NMR (300 MHz, CDCl
): δ = 9.18 (s, 1 H), 7.28 (d, J = 9 Hz, 1 H), 7.03
dd, J = 9 Hz, J = 2.4 Hz, 1 H), 6.92 (d, J = 2.4 Hz, 1 H), 4.45 (q, J = 8 Hz,
H), 3.90 (s, 3 H), 1.46 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl
):
δ = 160.9, 155.7, 133.0, 131.4, 127.5, 118.7, 113.2, 103.3, 65.4, 61.6, 55.8,
=
6
f
3
-
1
14 13 2
C H O
NI [M+H]+ 353.9991; found
cm . HRMS (ESI): calcd. for
53.9904.
(
3
2
3
Methyl
7-iodo-5-(prop-2-yn-1-yl)-5H-[1,3]dioxolo[4,5-f]indole-6-
1
4.5 ppm. IR (ATR): max = 3292, 2976, 1678, 1505, 1248, 1202, 1158,
carboxylate 6b: White solid (6.09 g, 97%); m.p. 180-182 ° C; R
f
= 0.49
-
1
+.
1019, 771, 671 cm . MS (EI) m/z = 299 (M , 100), 75 (18), 76 (15), 101
1
(EtOAc/hexane, 20:80). H NMR (300 MHz, CDCl
3
): δ = 6.94 (s, 1 H), 6.87
(
3
3
13), 102 (13), 119 (33), 130 (10), 144 (26), 146 (14), 284 (23), 300 (15),
45 (56). HRMS (ESI): calcd. for C12
45.9936.
(
s, 1 H), 6.02 (s, 2 H), 5.34 (d, J = 3 Hz, 2 H), 3.96 (s, 3 H), 2.28 (t, J = 2.5
): δ = 161.4, 149.3, 145.5, 134.6,
26.2, 125.5, 101.9, 101.7, 90.7, 78.4, 72.7, 69.1, 51.7, 35.5 ppm. IR
ATR): max = 3260, 3001, 2952, 2895, 2123, 1690, 1509, 1495, 1480 cm-
H13INO
3
[M+H]+ 345.9940; found
Hz, 1 H) ppm.13C NMR (75 MHz, CDCl
3
1
(
1
Methyl
3-iodo-7-methoxy-1H-benzo[g]indole-2-carboxylate
5e:
= 0.41
+
.
4
HRMS (ESI): calcd. for C14H11INO [M+H] 383.9727; found 383.9719.
Method (B). White solid (9.36 g, 91 %); m.p. 263-265 °C; R
f
1
(EtOAc/PE, 20:80). H NMR (300 MHz, DMSO-d
6
): δ = 8.72 (d, J = 9 Hz,
Ethyl 3-iodo-5-methoxy-1-(prop-2-yn-1-yl)-1H-indole-2-carboxylate
1
H), 7.54 (d, J = 9 Hz, 1 H), 7.43 (s, 1 H), 7.42 (d, J = 12 Hz, 1 H), 7.25
6
c: Brown solid (5.75 g, 95 %); m.p. 108-110 °C; R
f
= 0.62 (EtOAc/PE,
(
(
dd, J = 9 z, J = 2.5 Hz, 1 H), 3.93 (s, 3 H), 3.89 (s, 3 H) ppm. 13C NMR
75 MHz, DMSO-d ): δ = 160.7, 157.5, 133.7, 133.4, 125.9, 124.9, 123.9,
22.2, 121.6, 117.2, 116.5, 108.6, 68.6, 55.3, 51.7 ppm. IR (ATR): max
1
20:80). H NMR (300 MHz, acetone-d
6
): δ = 7.57 (d, J = 9 Hz, 1 H), 7.12
6
(dd, J = 9 Hz, 3 Hz, 1 H), 6.95 (d, J = 3 Hz, 1 H), 5.47 (d, J = 3 Hz, 2 H),
1
3
9
1
7
3
=
+.
4
7
1
.45 (q, J = 7 Hz, 2 H), 3.89 (s, 3H), 2.80 (t, J = 2.5 Hz, 1 H), 1.47 (t, J =
-
1
299, 1685, 1435, 1168, 824, 663 cm . MS (EI) m/z = 382 (16), 381 (M ,
7), 350 (16), 349 (84), 224 (10), 196 (10), 195 (16), 194 (100), 174 (10),
69 (33), 152 (22), 127 (11), 126 (25), 125 (25), 99 (11), 97 (11), 76 (12),
.5 Hz, 3 H) ppm. 13C NMR (75 MHz, acetone-d
6
): δ = 161.4, 156.9, 134.3,
31.8, 128.9, 118.7, 113.2, 104.3, 79.8, 73.8, 67.7, 61.9, 55.9, 35.7, 14.5
ppm. IR (ATR): max = 3277, 2923, 1689, 1500, 1257, 1021, 772, 681 cm-
HRMS (ESI): calcd. for C15H15INO [M+H] 384.0091; found 384.0092.
3
5 (15), 63 (11), 51 (52). HRMS (ESI): calcd. for C15
81.9940; found 381.9930.
H13INO
3
[M+H]+
1
.
Ethyl 5-fluoro-3-iodo-1-(prop-2-yn-1-yl)-1H-indole-2-carboxylate 6d:
White solid (5.51 g, 94 %); m.p. 249-251 °C; R = 0.66 (EtOAc/PE, 20:80).
1H NMR (300 MHz, CDCl
): δ = 7.42 (dd, J = 3 Hz, 9 Hz, 1 H), 7.29-7.16
m, 3 H), 5.39 (d, J = 3 Hz, 2 H), 4.49 (q, J = 7 Hz, 2 H), 2.28 (t, J = 2.2 Hz,
Methyl 4-bromo-3-iodo-1H-pyrrolo[3,2-c]pyridine-2-carboxylate 5f:
f
Method (B). White solid (9.73 g, 95 %); m.p. 229-231 °C; R
f
= 0.34
1
3
(
EtOAc/PE, 50:50). H NMR (300 MHz, acetone-d
6
): δ = 13.08 (s, 1H), 8.07
(
(
d, J = 5.7 Hz, 1 H), 7.53 (d, J = 5.7 Hz, 1 H), 3.92 (s, 3 H). 13C NMR (75
1
1
H), 1.51 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, DMSO-d
60.2, 158.4 (d, JC-F = 238 Hz), 134.7, 130.4 (d, JC-F = 9 Hz), 129.4, 115.3
6
): δ =
MHz, DMSO-d
6
) : δ = 160.2, 142.1, 141.2, 135.7, 129.7, 123.6, 108.7, 63.9,
-
1
52.2. IR (ATR): max = 2955, 1713, 1654, 1250, 1184, 940 cm . HRMS
(
d, JC-F = 26 Hz), 113.6 (d, JC-F = 9 Hz), 107.6 (d, JC-F = 25 Hz), 79.2, 75.1,
+
(ESI): calcd. for C
9 7
H
BrIN
O
2 2
[M+H] 380.87301; found 380.87241; calcd.
19
6
=
1
3
8.7, 61.5, 35.3, 14.05 ppm. F NMR (252 MHz, CDCl
3
): δ = -121.37 (td, J
+
9 5 2
for C H BrIN O
2
[M-H] 378.85846, found 378.85915.
9 Hz, J = 4 Hz). IR (ATR): max = 3284, 2983, 1686, 1497, 1380, 1263,
-
1
H12FINO
2
[M+H]+ 371.9891; found
161 cm . HRMS (ESI): calcd. for C14
71.9892.
Ethyl 1-(3-iodoprop-2-yn-1-yl)-1H-indole-2-carboxylate 6‘:
Method (A). solid ( 2.2 g, 38 %). Purification by column chromatography
(
eluent EtOAc/PE, 5:95). 1H NMR (300 MHz, CDCl
3
) δ = 7.69 (d, J = 8.0
Methyl
3-iodo-7-methoxy-1-(prop-2-yn-1-yl)-1H-benzo[g]indole-2-
= 0.52
Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.44 - 7.33 (m, 2H), 7.20 (t, J = 7.4 Hz,
carboxylate 6e: White solid (5.06 g, 74 %); m.p: 197-199 °C; R
f
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
1
(
EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ = 8.60 (d, J = 12 Hz, 1
7-Iodo-5-(prop-2-yn-1-yl)-5H-[1,3]dioxolo[4,5-f]indole-6-carboxylic
H), 7.60-7.51 (m, 2 H), 7.34-7.28 (m, 2 H), 5.69 (d, J = 3 Hz, 2 H), 4.02 (s,
H), 3.97 (s, 3H), 2.47 (t, J = 2.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl
):
δ = 161.7, 157.6, 135.9, 134.6, 126.9, 126.8, 124.1, 123.6, 123.1, 117.4,
acid 7b: White solid (2.49 g, 90 %); m.p. 226-228 °C; R
f
= 0.08 (EtOAc/
1
3
3
6
hexane, 20:80). H NMR (300 MHz, acetone-d ): δ = 7.16 (s, 1 H), 6.89 (s,
1 H), 6.19 (s, 1 H), 5.51 (d, J = 3 Hz, 2 H), 2.81 (t, J = 3 Hz, 1 H) ppm. 13C
1
16.9, 109.4, 79.2, 73.9, 71.5, 55.5, 51.8, 39.1. IR (ATR): max = 3278,
6
NMR (75 MHz, DMSO-d ): δ = 161.7, 148.4, 144.8, 134.0, 127.0, 124.5,
-
1
1697, 1467, 1258, 1174, 690 cm . HRMS (ESI): calcd. for C18
H15INO
3
101.5, 100.5, 91.6, 79.6, 74.7, 69.3, 35.0 ppm. IR (ATR): max = 3279, 3261,
+
-1
[M+H] 420.0091; found 420.0092.
2894, 2579, 2506, 2123, 1667, 1509, 1495, 1480 cm . HRMS (ESI): calcd.
+
7
for C13H INO
4
[M-H] 367.9425; found 367.9424.
Methyl 4-bromo-3-iodo-1-(prop-2-yn-1-yl)-1H-pyrrolo[3,2-c]pyridine-
2
-carboxylate 6f: Beige solid (5.54 g, 81 %); m.p. 162-164 °C; R
f
= 0.28
3-Iodo-5-methoxy-1-(prop-2-yn-1-yl)-1H-indole-2-carboxylic acid 7c:
Beige solid (2.39 g, 90 %); m.p. 214-216 °C; R = 0.21 (EtOAc/PE, 20:80).
1H NMR (300 MHz, CDCl
): δ = 7.39 (d, J = 9 Hz, 1 H), 7.14 (dd, J = 2.5
Hz, J = 9 Hz, 1 H), 7.14 (dd, J 3, 9 Hz, 1 H), 6.96 (d, J = 3 Hz, 1 H), 5.42
(d, J = 3 Hz, 2H), 3.91 (s, 3 H), 2.28 (t, J = 3 Hz, 1 H) ppm. 13C NMR (75
1
(EtOAc/PE, 50:50). H NMR (300 MHz, CDCl
3
): δ = 8.21 (d, J = 5.9 Hz, 1
f
H), 7.42 (d, J = 5.9 Hz, 1 H), 5.28 (d, J = 2.5 Hz, 2 H), 4.04 (s, 3 H), 2.35
t, J = 2.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 161.3, 143.1, 137.9,
23.7, 106.2, 105.7, 76.9, 73.9, 73.8, 65.3, 52.6, 35.9 ppm. IR (ATR): max
3
(
1
=
C
3
-
1
3275, 2129, 1707, 1440, 1179, 1120 cm . HRMS (ESI): calcd. for
6
MHz, DMSO-d ): δ = 161.9, 155.3, 133.1, 130.3, 128.9, 117.3, 112.8,
+
H BrIN O
12 9 2 2
[M+H] 419.8920; found 419.8911.
103.1, 79.6, 74.7, 68.1, 55.4, 34.8 ppm. IR (ATR): max = 3258, 2922, 2512,
1
663, 1500, 1263, 1170, 1024, 845. HRMS (ESI): calcd. for C13
H11INO
3
+
Ethyl 1-(but-2-yn-1-yl)-3-iodo-1H-indole-2-carboxylate 6g:. White solid
[M+H] 355.9778; found 355.9777.
1
(
3.30 g, 57 %); m.p. 96-98 °C; R
MHz, CDCl
.29-7.23 (m, 1 H), 5.33 (q, J = 3 Hz, 2 H), 4.49 (q, J = 7 Hz, 2 H), 1.74 (t,
J = 2.3 Hz, 3 H), 1.51 (t, J = 6 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl
): δ
161.2, 138.3, 130.6, 127.7, 126.4, 124.1, 121.9, 110.9, 80.3, 74.0, 68.2,
f
= 0.7 (EtOAc/PE, 20:80). H NMR (300
3
): δ = 7.58 (dt, J = 8 Hz, J = 1 Hz, 1 H), 7.48-7.40 (m, 2 H),
5-Fluoro-3-iodo-1-(prop-2-yn-1-yl)-1H-indole-2-carboxylic acid 7d:
White solid (2.21 g, 86 %); m.p. 229-231 °C; R = 0.06 (EtOAc/PE, 20:80).
1H NMR (300 MHz, DMSO-d
): δ = 7.76-7.71 (m, 1 H), 7.32 (t, J = 9 Hz, 1
H), 7.19 (d, J = 8.5 Hz, 1 H), 5.46 (bs, 2 H), 3.30 (bs, 1 H) ppm. 13C NMR
(75 MHz, DMSO-d ) : δ = 161.7, 158.3 (d, JC-F = 237 Hz), 134.6, 130.5,
7
f
3
6
=
6
7
1.5, 35.6, 14.3, 3.6 ppm. IR (ATR): max = 2976, 1691, 1452, 1260, 1192,
6
+
39. HRMS (ESI): calcd. for C15
H15INO
2
[M+H] 368.0142; found 368.0141.
130.3, 115.0 (d, JC-F = 25 Hz), 113.4 (d, JC-F = 12 Hz), 107.3 (d, JC-F = 25
Hz), 79.4, 74.9, 67.9 (d, JC-F = 5 Hz), 35.0 ppm. IR (ATR): max = 3282,
Ethyl 3-iodo-1-(3-phenylprop-2-yn-1-yl)-1H-indole-2-carboxylate 6h:
2836, 1666, 1500, 1257, 1164, 799. HRMS (ESI): calcd. for C12
[M-H] 341.9432; found 341.9438.
H
6
FINO
2
1
+
Yellow oil (5.02 g, 74 %); R
CDCl
Hz, 1 H), 7.37-7.23 (m, 6 H), 5.62 (s, 2 H), 4.51 (q, J = 8 Hz, 2 H), 1.52 (t,
J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 161.2, 138.4, 131.8,
30.6, 128.5, 128.3, 127.7, 126.6, 124.2, 122.4, 122.0, 110.9, 84.2, 84.0,
f
= 0.7 (EtOAc/PE, 20:80). H NMR (300 MHz,
3
): δ = 7.61 (d, J = 6 Hz, 1 H), 7.54 (d, J = 6 Hz,1 H), 7.46 (t, J = 7.5
3-Iodo-7-methoxy-1-(prop-2-yn-1yl)-1H-benzo[g]indole-2-carboxylic
3
acid 7e: Beige solid (1.61 g, 53 %); m.p. 217-219 °C; R
f
= 0.01 (EtOAc/PE:
1
1
6
6
6
20/80). H NMR (300 MHz, DMSO-d ): δ = 8.59 (d, J = 9.3 Hz, 1 H), 7.64
8.6, 61.6, 36.0, 14.3 ppm. IR (ATR): max = 2981, 1698, 1240, 1191, 741,
(d, J = 8.8 Hz, 2 H), 7.54-7.49 (m, 2 H), 7.33 (dd, J = 9.2 Hz, J = 2.5 Hz,
Hz, 1 H), 5.78 (bs, 2 H), 3.91 (s, 3 H), 3.44 (bs, 1 H) ppm. 13C NMR (75
+
90. HRMS (ESI): calcd. for C20
H17INO
2
[M+H] 430.0298; found 430.0299.
6
MHz, DMSO-d ): δ = 162.1, 157.0, 135.2, 133.3, 127.9, 125.9, 124.1,
Ethyl 1-(3-phenylprop-2-yn-1-yl)-1H-indole-2-carboxylate 6j: Yellow oil
123.3, 122.4, 117.1, 116.4, 109.4, 79.8, 76.2, 71.4, 55.3, 38.2 ppm. HRMS
1
+
(
4.65 g, 97 %); R
f
= 0.86 (EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
):
(ESI): calcd. for C17H11INO
3
[M-H] 403.9783; found 403.9797.
δ = 7.70 (d, J = 9 Hz, 1 H), 7.61 (d, J = 9 Hz, 1 H), 7.41-7.18 (m, 8 H), 5.68
s, 2 H), 4.41 (q, J = 7 Hz, 2 H), 1.43 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75
MHz, CDCl ): δ = 162.2, 139.2, 131.9, 128.4, 128.3, 127.2, 126.3, 125.4,
22.8, 122.7, 121.1, 111.4, 111.0, 84.3, 83.8, 60.9, 34.8, 14.5 ppm. IR
(
4-Bromo-3-iodo-1-(prop-2-yn-1-yl)-1H-pyrrolo[3,2-c]pyridine-2-
3
carboxylic acid 7f: White solid (1.76 g, 58 %); m.p. 233-235 °C; R
f
= 0
1
1
(EtOAc/PE, 50:50). H NMR (300 MHz, DMSO-d
6
): δ = 8.17 (d, J = 6.0 Hz,
(
C
ATR): max = 2981, 1702, 1455, 1192, 748. HRMS (ESI): calcd. for
1 H), 7.86 (d, J = 6.0 Hz, 1 H), 5.38 (d, J = 2 Hz, 2 H), 3.41 (t, J = 2 Hz, 1
H) ppm. 13C NMR (75 MHz, DMSO-d
): δ = 162.3, 142.9, 142.4, 136.2,
23.0, 107.8, 107.6, 78.9, 76.3, 64.7, 35.9 ppm. IR (ATR): max = 3239,
+
20
H
18NO
2
[M+H] 304.1332; found 304.1330.
6
1
-
1
General procedure for saponification
In a round bottom flask, indole ester 6 (1 equiv., 7.5 mmol) was dissolved
in 20 mL of ethanol before the addition of 10.5 g of 12% aq. KOH (3 equiv.,
2900-2412, 1206, 1126, 1070, 804 cm . HRMS (ESI): calcd. for
+
C H BrIN O
11 7 2 2
[M+H] 405.8763; found 405.8755.
2
2.5 mmol) slowly. The mixture was stirred and heated at 45 °C. After 3 h,
1-(But-2-yn-1-yl)-3-iodo-1H-indole-2-carboxylic acid 7g: White solid
(2.51 g, 99 %);. m.p. 218-220 °C; R
= 0.17 (EtOAc/PE, 20:80). 1H NMR
(300 MHz, acetone-d ): δ = 7.63 (d, J = 8.4 Hz, 1 H), 7.55 (dm, J = 8.1 Hz,
1 H), 7.46 (t, J = 7.2 Hz, 1 H), 7.28 (t, J = 8 Hz, 1 H), 5.47 (q, J = 2.4 Hz, 2
H), 1.69 (t, J = 2.4 Hz, 3 H) ppm.13C NMR (75 MHz, acetone-d
): δ = 162.4,
the mixture was cooled on an ice bath and acidified with 25 mL of HCl (1
M) to obtain pH = 1. The precipitate obtained was filtered on a Büchner
funnel and washed with hexane.
f
6
6
Only the 1-(but-2-ynyl)-1H-indole-2-carboxylic acid 7i was already
described and is in accordance with the literature.[14, 44]
139.2, 131.3, 129.4, 127.0, 124.2, 122.6, 112.2, 80.3, 75.2, 68.1, 35.8, 3.1
-1
ppm. IR (ATR): max = 2507, 1665, 1266, 738 cm . HRMS (ESI): calcd. for
+
13 9
C H INO
2
[M-H] 337.9683; found 337.9689.
3
-Iodo-1-(prop-2-yn-1-yl)-1H-indole-2-carboxylic acid 7a: Beige solid
1
(
2.38 g, 98 %); m.p. 196-198 °C; R
f
= 0.08 (EtOAc/hexane, 20:80). H NMR
3-Iodo-1-(3-phenylprop-2-yn-1-yl)-1H-indole-2-carboxylic acid 7h:
Yellow solid (2.91 g, 97 %); m.p. 211-213 °C; R = 0.18 (EtOAc/PE, 20:80).
1H NMR (300 MHz, acetone-d
): δ = 7.74 (d, J = 8.3 Hz, 1 H), 7.56 (d, J =
8.1 Hz, 1 H), 7.50 (t, J = 7.2 Hz, 1 H), 7.37-7.28 (m, 6 H), 5.79 (s, 2 H)
ppm. 13C NMR (75 MHz, acetone-d
): δ = 162.4, 139.3, 132.3, 131.4, 129.4,
(
300 MHz, acetone-d
6
): δ = 7.67 (d, J = 8.5 Hz, 1 H), 7.56 (d, J = 8 Hz, 1
f
H), 7.49 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1 H), 5.57 (d, J = 3 Hz, 2
H), 2.82 (t, J = 3 Hz, 1 H) ppm.13C NMR (75 MHz, DMSO-d
): δ = 162.0,
37.9, 129.9, 128.8, 126.1, 123.1, 121.8, 111.5, 79.6, 74.7, 68.9, 34.7 ppm.
6
6
1
6
-
1
IR (ATR): max = 3277, 3052, 2985, 2121, 1690, 1610, 1568 cm . HRMS
129.3, 127.2, 124.4, 123.2, 122.8, 112.2, 85.5, 84.2, 68.5, 36.3 ppm. IR
+
(ESI): calcd. for C12
H
9
O
2
NI [M+H] 325.9678; found 325.9598.
(ATR): max = 2589, 1663, 1434, 742, 688. HRMS (ESI): calcd. for
+
18
C H11INO
2
[M-H] 399.9839; found 399.9844.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
1
-(3-Phenylprop-2-yn-1-yl)-1H-indole-2-carboxylic acid 7j: Pale pink
solid (1.81 g, 88 %); m.p. 186-188 °C; R
= 0.28 (EtOAc/PE, 20:80). 1
NMR (300 MHz, CDCl ): δ = 7.74 (d, J = 8.5 Hz, 1 H), 7.62 (d, J = 8.5 Hz,
H), 7.53 (d, J = 1 Hz, 1 H), 7.45 (t, J = 8 Hz, 1 H), 7.38-7.35 (m, 2 H),
.28-7.20 (m, 4 H), 5.69 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 165.3,
NMR (75 MHz, DMSO-d
119.2, 113.1, 102.1, 67.8, 64.9, 55.4, 43.5 ppm. IR (ATR): max = 3066,
6
): δ = 155.7, 153.6, 146.8, 131.8, 130.8, 120.4,
f
H
-
1
3
1728, 1511, 1319, 1080, 814 cm . HRMS (ESI): calcd. for C19
9
H I
2
NO
3
+
1
7
1
8
[M+H] 481.8744; found 481.8746.
3
39.8, 132.0, 128.5, 128.3, 126.3, 126.2, 125.6, 123.2, 121.4, 113.6, 111.1,
4.1, 34.9 ppm. IR (ATR): max = 687, 740, 1264, 1444, 1654, 2929. HRMS
(E)-8-Fluoro-10-iodo-3-(iodomethylene)-3,4-dihydro-1H-
[1,4]oxazino[4,3-a]indol-1-one 10d: Yellow solid (1.12 g, 80 %); m.p.
185-187 °C; R = 0.5 (EtOAc/PE, 20:80). H NMR (300 MHz, CDCl ): δ =
+
1
(ESI): calcd. for C18
H12NO
2
[M-H] 274.0873; found 274.0878.
f
3
7
.41 (m, 1 H), 7.27-7.33 (m, 2 H), 6.39 (t, J = 1.2 Hz, 1 H), 5.11 (d, J = 1.5
3-Iodo-1-(propa-1,2-dienyl)-1H-indole-2-carboxylic acid 8:
Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl
3
): δ = 159.4 (d, JC-F = 240 Hz),
In a round bottom flask, indole ester 6a (1 equiv., 8.5 mmol) was dissolved
in 3 mL of ethanol before the addition of 143 mg of KOH 23% (3 eq, 2.5
mmol) slowly. The mixture was stirred and heated at 70 °C. After 3 h, the
mixture was cooled in an ice bath and acidified with 5 mL of HCl (1 M) to
obtain pH = 1. The precipitate obtained was filtered on Büchner and
washed with hexane. White solid (240 mg, 87%); m.p. 158 °C. 1H NMR
153.7, 146.3, 133.4, 131.8 (d, JC-F = 9 Hz), 121.6, 117.7 (d, JC-F = 27 Hz),
111.9 (d, JC-F = 8 Hz), 108.7 (d, JC-F = 23 Hz), 68.4 (d, JC-F = 7 Hz), 64.4,
19
3
43.8 ppm. F NMR (188 MHz, CDCl ) δ = -119.25 (td, J = 8.6 Hz, J = 4.2
-
1
Hz) ppm. IR (ATR): max = 3067, 1735, 1510, 1152, 1066, 853 cm . HRMS
+
(ESI): calcd. for C12
6
H FI
2
NO
2
[M+H] 469.8544; found 469.8544.
(
300 MHz, CDCl
3
): δ = 7.83-7.73 (m, 2 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.42
(Z)-7-Iodo-10-(iodomethylene)-3-methoxy-10,11-dihydro-8H-
benzo[g][1,4]oxazino[4,3-a]indol-8-one 10e:
(
t, J = 7.7 Hz, 1 H), 7.29 (t, J = 7.4 Hz, 1 H), 5.73 (d, J = 6.5 Hz, 2 H) ppm.
solid (0.33 g, 21 %); m.p 219-221 °C. (EtOAc/EP, 20:80). 1H NMR (300
1
3C NMR (75 MHz, CDCl
23.3, 122.3, 112.4, 96.8, 86.8, 70.1 ppm. HRMS (ESI): calcd. for
H O NI [M+H] 325.9678; found 325.9593.
12 9 2
3
): δ = 203.7, 161.9, 137.1, 130.3, 129.4126.3,
MHz, DMSO-d
7.58 (d, J = 2.5 Hz, 1 H), 7.50 (d, J = 9.1 Hz, 1 H), 7.39 (dd, J = 9.1 Hz,
.5 Hz, 1 H), 6.66 (s, 1 H), 5.76 (m, 2 H), 3.93 (s, 3 H) ppm. 13C NMR (75
MHz, DMSO-d ): δ = 157.6, 153.7, 146.3, 135.5, 132.2, 126.6, 123.7,
6
): δ = 8.38 (d, J = 9.1 Hz, 1 H), 7.67 (d, J = 9.1 Hz, 1 H),
1
C
+
2
General procedure for iodo-cyclization: In a round bottom flask
containing the compound 7 (1 equiv., 3 mmol) and 10 mL of THF were
added 0.95 g of sodium carbonate (3 equiv., 9 mmol), 1.14 g of iodine (1.5
equiv., 4.5 mmol) and 0.51 g of silver nitrate (1 equiv., 3 mmol). The
mixture was stirred overnight at room temperature. The medium was
6
123.3, 121.7, 118.30, 117.5, 116.3, 109.8, 66.0, 55.4, 54.9, 47.3 ppm.
+
HRMS (ESI): calcd. for C17
11
H I
2
NO
3
[M+H] 531.8907; found 531.8920.
2
,3-Diiodo-7-methoxy-1-(prop-2-yn-1-yl)-1H-benzo[g]indole 10e‘:
White solid (0.9 g, 61 %); m.p. 209-211 °C; R = 0.65 (EtOAc/EP, 20:80).
1H NMR (300 MHz, CDCl
): δ = 8.41 (d, J = 9.1 Hz, 1 H), 7.48 (s, 2 H),
.32-7.27 (m, 2 H), 5.45 (d, J = 2.5 Hz, 1 H), 3.96 (s, 3 H), 2.47 (t, J = 2.5
Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 156.6, 133.4, 132.7, 128.0,
22.7, 122.5, 121.9, 117.6, 116.9, 108.7, 92.5, 77.8, 75.9, 74.8, 55.5, 43.4
f
hydrolyzed by saturated solution of Na
dichloromethane (4 × 15 mL). The organic phase was washed with NaCl
3 × 10 mL), dried with MgSO and evaporated under vacuum. Compound
2 2 3
S O (10 mL) then extracted by
3
7
(
4
3
were isolated by column chromatography on silica gel using 5/95: ethyl
acetate/petroleum ether as eluent.
1
-
1
ppm. IR (ATR): max = 3237, 2115, 1383, 1231, 1036, 852 cm . HRMS
+
(
ESI): calcd. for C16
11
H I
2
NO [M] 486.8930; found 486.8948 .
(
E)-10-Iodo-3-(iodomethylene)-3,4-dihydro-1H-[1,4]oxazino[4,3-
a]indol-1-one 10a: Yellow-brown solid (1.16 g, 86 %); m.p. 184-186 °C;
1
(E)-9-Bromo-10-iodo-3-(iodomethylene)-3,4-dihydro-1H-
R
f
= 0.32 (EtOAc/hexane, 20:80). H NMR (300 MHz, CDCl
3
): δ = 7.63 (d,
pyrido[3',4':4,5]pyrrolo[2,1-c][1,4]oxazin-1-one 10f: Yellow solid (0.82
J = 8.2 Hz, 1 H), 7.53 (t, J = 8.1 Hz, 1 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.34 (t,
J = 8.1 Hz, 1 H), 6.37 (t, J = 1 Hz, 1 H), 5.13 (d, J = 1 Hz, 2 H) ppm. 13C
g, 52 %); m.p. 255-257 °C; R
MHz, CDCl ): δ = 8.28 (d, J = 5.8 Hz, 1 H), 7.41 (d, J = 5.8 Hz, 1 H), 6.45
t, J = 1.1 Hz, 1 H), 5.12 (d, J = 1.1 Hz, 2H) ppm. 13C NMR (75 MHz,
= 0.12 (EtOAc/EP, 20:80). 1H NMR (300
f
3
NMR (75 MHz, CDCl
3
): δ = 153.8, 146.6, 136.7, 131.2, 128.1, 124.2, 122.9,
(
1
1
20.2, 110.5, 69.5, 64.0, 43.6 ppm. IR (ATR): max = 3078, 2922, 1739,
-1
[M+H]+ 451.8638;
6
DMSO-d ): δ = 153.3, 145.7, 143.0, 140.6, 136.3, 123.5, 123.2, 107.7, 67.6,
635, 1513 cm . HRMS (ESI): calcd. for C12H O NI
7 2 2
-
1
6
5.6, 43.9 ppm. IR (ATR): max = 1737, 1220, 1097, 985, 736 cm . HRMS
found 451.8635.
E)-10-Iodo-7-(iodomethylene)-6,7-dihydro-9H-[1,3]dioxolo[4,5-
+
(ESI): calcd. for for C11
6 2 2 2
H BrI N O [M+H] 531.7730, found 531.7726.
(
(
E)-10-Iodo-3-(1-iodoethylidene)-3,4-dihydro-1H-[1,4]oxazino[4,3-
f][1,4]oxazino[4,3-a]indol-9-one 10b: White solid (0.60 g, 41 %); m.p.
1
a]indol-1-one 10g: Yellow solid (1.10 g, 79 %); m.p. 194-196 °C; R
f
= 0.66
2
13 °C; R
f
= 0.40 (EtOAc/hexane, 20:80). H NMR (300 MHz, DMSO-d
6
):
1
(
EtOAc/EP, 20:80). H NMR (300 MHz, CDCl
3
): δ = 7.61 (d, J = 8.5 Hz, 1
δ = 7.78 (d, J = 0.5 Hz, 1 H), 7.32 (d, J = 0.5 Hz, 1 H), 6.93 (t, J = 1 Hz, 1
H), 6.57 (s, 2 H), 5.26 (d, J = 3 Hz, 2 H) ppm.13C NMR (75 MHz, DMSO-
H), 7.50 (t, J = 7.5 Hz, 1 H), 7.39 (d, J = 8 Hz, 1 H), 7.31 (t, J = 7.5 Hz, 1
H), 5.17 (q, J = 1.2 Hz, 2 H), 2.65 (t, J = 1.2 Hz, 3 H) ppm. 13C NMR (75
6
d ): δ = 153.3, 149.4, 146.8, 145.5, 132.8, 125.3, 118.8, 101.7, 99.6, 91.4,
MHz, CDCl
3
): δ = 154.3, 140.5, 136.6, 131.2, 127.9, 124.1, 122.8, 120.6,
6
9.0, 64.8, 43.6 ppm. IR (ATR): max = 3083, 2911, 1735, 1640, 1519, 1499
-
1
[M+H]+ 495.8537; found
13 8 4 2
C H O NI
110.5, 83.8, 68.9, 46.1, 25.5 ppm. IR (ATR): max = 2507, 1665, 1266, 738
cm . HRMS (ESI): calcd. for
95.8534.
-
1
10 2 2
H I NO
[M+H]+ 465.8795; found
cm . HRMS (ESI): calcd. for C13
65.8799.
4
4
6
,7-Diiodo-5-(prop-2-yn-1-yl)-5H-[1,3]dioxolo[4,5-f]indole 10b’: beige solid
1
(E)-10-iodo-3-(iodo(phenyl)methylene)-3,4-dihydro-1H-
(0.34 g, 25 %); m.p. 198 °C. H NMR (300 MHz, CDCl
3
): δ = 6.89 (s, 1 H),
[
1,4]oxazino[4,3-a]indol-1-one 10h: Yellow solid (1.37 g, 87 %); m.p.
6
.83 (s, 1 H), 5.98 (s, 2 H), 4.95 (d, J = 2.5 Hz, 2 H) 2.34 (t, J = 2.5 Hz, 1H)
1
ppm. 3C NMR (75 MHz, DMSO-d
1
195-197 °C; R
f
= 0.62 (EtOAc/EP, 20:80). H NMR (300 MHz, CDCl
3
): δ =
6
): δ = 145.4, 143.7, 132.3, 125.5, 110.9,
7
.64 ( d, J = 8.2 Hz, 1 H), 7.58-7.52 (m, 1 H), 7.49-7.44 (m, 3 H), 7.40-7.27
(m, 3 H), 5.38 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 153.8, 140.6,
37.9, 136.7, 131.2, 129.9, 129.0, 128.4, 128.0, 124.2, 122.9, 120.3, 110.5,
9
C
9.1, 94.0, 92.1, 78.7, 75.4, 73.3, 38.6 ppm. HRMS (ESI): calcd. for
+
3
12 7 2 2
H O NI [M] 450.8566; found 450.8554.
1
8
-
1
6.2, 69.2, 47.0 ppm. IR (ATR): max = 1737, 1220, 1097, 985, 736 cm .
(
[
E)-10-Iodo-3-(iodomethylene)-8-methoxy-3,4-dihydro-1H-
1,4]oxazino[4,3-a]indol-1-one 10c: Pale brown solid (1.32 g, 92 %); m.p.
+
HRMS (ESI): calcd. for C18
H
12
I
2
NO
2
[M+H] 527.8951, found 527.8956.
1
2
7
1
14-216 °C; R
f
= 0.62 (EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ =
General procedure for Stille Cross-coupling:
.32 (d, J = 9 Hz, 1 H), 7.17 (dd, J = 9 Hz, 2.4 Hz, 1 H), 6.93 (d, J = 3 Hz,
H), 6.35 (t, J = 1 Hz, 1 H), 5.09 (d, J = 1 Hz, 2 H), 3.92 (s, 3 H) ppm. 13C
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
Monocoupling: In a schlenk tube, dried by a flame and under argon,
compound 10 (1 equiv., 0.62 mmol) was introduced with 9 mg of
(d, J = 12 Hz, 1 H), 6.05 (s, 2 H), 5.41 (d, J = 18 Hz, 1 H), 5.31 (d, 1H, J =
12 Hz), 4.97 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 154.9, 150.2,
146.1, 142.4, 132.8, 128.2, 126.4, 120.8, 115.5, 101.9, 101.4, 89.8, 68.5,
3
PdCl
2
(CH
3
CN)
2
(5% mol) in 10 mL of DMF and the mixture was stirred for
of
-
1
15
min at room temperature before the addition of 0.24
g
39.8 ppm. IR (ATR): max = 2892, 1720, 1315, 1162, 1070, 900, 839 cm .
+
organostannane (1.2 equiv., 0.74 mmol). The mixture was stirred at room
temperature overnight, and 20 mL of ethylacetate and 10 mL of KF (1M)
were added and the mixture was stirred for 1 h at room temperature. The
precipitate obtained was filtered through a celite pad, washed by diethyl
ether and water then the filtrate was extracted by diethyl ether (3 × 20mL).
HRMS (ESI, positive mode): calcd. for C15
H11INO
4
[M+H] 395.9727; found
395.9726.
(E)-10-Iodo-8-methoxy-3-((E)-3-(trimethylsilyl)allylidene)-3,4-dihydro-
1H-[1,4]oxazino[4,3-a]indol-1-one 11e: Yellow oil (134 mg, 48%); R
0.72 (EtOAc/PE, 20:80). 1H NMR (300 MHz, CDCl
): δ = 7.17 (d, J = 8.9
f
=
The organic phase was washed by NaCl (2 × 10 mL), dried by MgSO
4
and
3
concentrated under vacuum. Compound were isolated by column
chromatography on silica gel using 2/98: ethyl acetate/petroleum ether as
eluent.
Hz, 1 H), 6.97 (dd, J = 8.9 Hz, J = 2.3 Hz, 1 H), 6.72 (d, J = 2.3 Hz), 6.42
(dd, J = 10.8 Hz, J = 18.1 Hz, 1 H), 6.03 (d, J = 11 Hz, 1 H), 5.95 (d, J =
18.1 Hz, 1 H), 4.92 (s, 2H), 3.73 (s, 3 H), 0.00 (s, 9 H) ppm. 13C NMR (75
Bis coupling: In a schlenk tube, dried by a flame and under argon,
compound 10 (1 equiv., 0.66 mmol) was introduced with 9.7 mg of
3
MHz, CDCl ): δ = 156.2, 155.2, 142.0, 139.3, 134.3, 131.8, 131.6, 121.5,
119.9, 117.6, 111.5, 103.1, 67.3, 55.8, 39.7, -1.2 ppm. HRMS (ESI,
+
PdCl
2 3
(CH CN)
2
(5% mol) in 10 mL of DMF and the mixture was stirred for
of
positive mode): calcd. for C18H21INO
3
Si [M+H] 454.0335; found 454.0344.
15
min at room temperature before the addition of 0.63 g
organostannane (3 equiv., 1.98 mmol). The mixture was stirred at room
temperature overnight. 20 mL of ethylacetate and 10 mL of KF (1M) were
added and the stirring was continued for an additional 1 h at room
temperature, then the precipitate obtained was filtered through a celite pad,
washed by diethyl ether and water. The filtrate was extracted by diethyl
ether (3 × 20 mL) and the organic phase was washed with NaCl (2 × 10
(E)-3-(But-3-en-2-ylidene)-10-iodo-3,4-dihydro-1H-[1,4]oxazino[4,3-
a]indol-1-one 11f: Yellow solid (0.17 g, 74%); m.p. 235-237 °C; R
f
= 0.56
1
(EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ = 7.62 (d, J = 9 Hz, 1 H),
7.52-7.25 (m, 3 H), 6.63 (dd, J = 10.9 Hz, J = 17 Hz, 1 H), 5.46 (d, J = 17
Hz, 1 H), 5.34 (d, J = 11 Hz, 1 H), 5.13 (s, 2 H), 2.02 (s, 3 H) ppm. 13C
NMR (CDCl , 75 MHz): δ = 155.6, 139.1, 136.5, 131.4, 131.2, 127.6, 124.2,
3
mL), dried by MgSO
isolated by column chromatography[34] on silica gel using 2/98: ethyl
acetate/petroleum ether as eluent.
4
and concentrated under vacuum. Compound were
122.6, 120.3, 117.4, 110.5, 110.3, 68.1, 39.7, 11.1. IR (ATR): max = 2922,
-1
1736, 1094, 730 cm . HRMS (ESI, positive mode): calcd. for C15
H
13INO
2
+
[M+H] 365.9985; found 365.9980.
(
E)-3-Allylidene-10-iodo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-1-
(Z)-10-Iodo-3-(1-phenylallylidene)-3,4-dihydro-1H-[1,4]oxazino[4,3-
one 11a: Yellow solid (0.13 g, 61 %); m.p. 154-156 °C; R
f
= 0.37
a]indol-1-one 11g: Yellow solid (0.11 g, 40%); m.p. 175-177 °C; R
f
= 0.62
1
1
(EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ = 7.63 (d, J = 8.2 Hz, 1
(EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ = 7.64 (d, J = 6 Hz, 1 H),
H), 7.51 (t, J = 8.5 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1 H), 7.32 (t, J = 8 Hz, 1
H), 6.45 (ddd, J = 10.2 Hz, J = 11.5 Hz, J = 16.5 Hz, 1 H), 6.22 (d, J = 11.5
Hz, 1 H), 5.42 (d, J = 16.5 Hz, 1 H), 5.32 (d, J = 10.2 Hz, 1 H), 5.09 (s, 2
7.55-7.35 (m, 5 H), 7.24 (d, J = 9 Hz, 2 H), 6.74 (dd, J = 9 Hz, J = 16.5 Hz,
1 H), 5.42 (d, J = 9 Hz, 1 H), 5.25 (s, 2 H), 5.10 (d, J = 18 Hz, 1 H) ppm.
13C NMR (75 MHz, CDCl
3
): δ = 154.9, 138.5, 136.5, 133.7, 131.8, 131.2,
H) ppm.13C NMR (75 MHz, CDCl
27.8, 124.2, 122.7, 121.6, 121, 115.6, 110.4, 68.7, 39.5 ppm. IR (ATR):
): δ = 155.3, 142.4, 136.5, 131.2, 128.2,
130.0, 128.4, 128.0, 127.7, 126.4, 124.2, 122.7, 121.9, 121.3, 110.4, 68.3,
3
1
40.2 ppm. IR (ATR): max = 1733, 1227, 737, 696. HRMS (ESI, positive
-1
+

max = 1720, 1513, 984, 896, 735 cm . HRMS (ESI, positive mode): calcd.
mode): calcd. for C20H15INO
2
[M+H] 428.0142; found 428.0141.
+
11 2
for C14H O NI [M+H] 351.9829; found 351.9825.
(
E)-3-Allylidene-10-vinyl-3,4-dihydro-1H-[1,4]oxazino[4,3-a]indol-1-
(
[
1
E)-10-Iodo-3-((E)-3-(trimethylsilyl)allylidene)-3,4-dihydro-1H-
one 12a: Yellow solid (49 mg, 30 %); m.p. 127-129 °C; R
f
= 0.37
1
1,4]oxazino[4,3-a]indol-1-one 11b: Yellow solid (99 mg, 38 %); m.p.
(EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ = 8.08 (d, J = 8.2 Hz, 1
1
63-165 °C; R
f
= 0.63 (EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ =
H), 7.62 (dd, J = 11.7 Hz, J = 18.2 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.40
(d, J = 9 Hz, 1 H), 7.30 (t, J = 6 Hz, 1 H), 6.48 (ddd, J = 10.3 Hz, J = 11.4
Hz, J = 16.5 Hz, 1 H), 6.19 (d, J = 11.3 Hz, 1 H), 6.07 (dd, J = 18.1 Hz, J
= 1.5 Hz, 1 H), 5.58 (dd, J = 11.6 Hz, J = 1.5 Hz, 1 H), 5.41 (d, J = 18 Hz,
1 H), 5.31 (d, J = 10.5 Hz, 1 H), 5.02 (s, 2 H), ppm. 13C NMR (75 MHz,
7
.62 (d, J = 9 Hz, 1 H), 7.51 (t, J = 9 Hz, 1 H), 7.42 (d, J = 9 Hz, 1 H), 7.31
(
t, J = 7.5 Hz, 1 H), 6.56 (dd, J = 10.5 Hz, J = 18 Hz, 1 H), 6.21 (d, J = 10.5
Hz, 1 H), 6.11 (d, J = 18 Hz, 1 H), 5.10 (d, J = 0.75 Hz, 2 H), 0.14 (s, 9 H)
ppm. 13C NMR (75 MHz, CDCl
): δ = 155.4, 142.0, 139.6, 136.6, 134.3,
31.3, 127.7, 124.3, 122.8, 121.8, 118.0, 110.4, 68.7, 39.7, -1.2 ppm. IR
3
1
3
CDCl ): δ = 156.2, 143.0, 136.4, 128.8, 128.4, 126.9, 125.4, 124.0, 123.2,
-
1
(ATR): max = 2953, 2895, 1749, 1661, 1615, 1518 cm . HRMS (ESI,
122.4, 120.6, 118.3, 118.2, 115.1, 110.1, 38.8 ppm. IR (ATR): max = 3060,
+
-1
positive mode): calcd. for C17
H
19
O
2
NISi [M+H] 424.0224; found 424.0219.
1714, 1523, 889, 734 cm . HRMS (ESI, positive mode): calcd. for
+
C
16
H
14NO
2
[M+H] 252.1019; found 252.1017.
(
E)-3-Allylidene-8-fluoro-10-iodo-3,4-dihydro-1H-[1,4]oxazino[4,3-
a]indol-1-one 11c: Pale yellow solid (0.16 g, 71 %); m.p. 163-165 °C; R
f
(E)-7-Allylidene-10-vinyl-6,7-dihydro-9H-[1,3]dioxolo[4,5-
1
=
0.45 (EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ = 7.38-7.23 (m, 3
f][1,4]oxazino[4,3-a]indol-9-one 12b: Yellow solid (51 mg, 26%); m.p.
1
H), 6.44 (ddd, J = 10.5 Hz, J = 11.2 Hz, J = 16.7 Hz, 1 H), 6.21 (d, J = 11.2
Hz, 1 H), 5.42 (d, J = 16.7 Hz, 1 H), 5.33 (d, J = 10.7 Hz, 1 H), 5.07 (s, 2
206 °C; R
f
= 0.21 (EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ = 7.54
(dd, J = 18 Hz, 12 Hz, 1 H), 7.36 (s, 1 H), 6.77 (s, 1 H), 6.50-6.37 (m, 1 H),
6.17 (d, J = 12 Hz, 1 H), 6.04 (s, 2 H), 5.89 (d, J = 18 Hz, 1 H), 5.52 (d, J
= 12 Hz, 1 H), 5.42-5.27 (m, 2 H), 4.90 (s, 2 H) ppm. 13C NMR (75 MHz,
H) ppm. 13C NMR (CDCl
1
1
, 75 MHz): δ = 159.3 (J = 239 Hz), 155.0, 142.1,
33.2, 131.8 (J = 10.4 Hz), 128.2, 128.0, 121.3, 117.3 (J = 27 Hz), 116.0,
11.7 (J = 10 Hz), 108.8 (J = 25 Hz), 67.6 (J = 5 Hz), 39.8 ppm. 19F NMR
): δ = -119.67 (td, J = 9 Hz, J = 5 Hz) ppm. IR (ATR): max
3
3
CDCl ): δ = 155.6, 149.3, 145.6, 142.9, 132.8, 128.9, 128.4, 124.3, 120.4,
(188 MHz, CDCl
3
119.8, 117.5, 114.9, 101.7, 100.4, 89.9, 39.0 ppm. HRMS (ESI, positive
-1
+
=
2970, 1724, 1515, 1224, 1159 cm . HRMS (ESI, positive mode): calcd.
mode): calcd. for C17
H
14NO
4
[M+H] 296.0923; found 296.0926.
+
for C14
H10FINO
2
[M+H] 369.9734; found 369.9736.
General procedure for Sonogashira Cross-coupling:
Monocoupling: In a schlenk tube dried by a flame and under argon,
compound 10 (1 equiv., 0.66 mmol) and alkyne (1.5 equiv., 0.99 mmol)
were introduced with 10 mL of DMF. The solution was cooled to 0 °C
(
E)-7-Allylidene-10-iodo-6,7-dihydro-9H-[1,3]dioxolo[4,5-
f][1,4]oxazino[4,3-a]indol-9-one 11d: Yellow solid (0.20 g, 83 %); m.p.
1
1
67-169 °C; R
f
= 0.13 (EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ =
before the addition of 0.2 mL of Et
3
N (2.2 equiv., 1.46 mmol) and the
6.94 (s, 1 H), 6.75 (s, 1 H), 6.42 (ddd, J = 21 Hz, 18 Hz, 12 Hz, 1 H), 6.19
solution was stirred for 15 min at 0 °C. Then 12.7 mg of CuI (0.066 mmol,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
1
0% mol), 17.3 mg of PPh
Pd(OAc) (0.033 mmol, 5% mol) were added and the mixture was stirred
at room temperature overnight.
3
(0.066 mmol, 10% mol) and 7.4 mg of
(E)-10-Iodo-3-(4-methoxybut-2-yn-1-ylidene)-3,4-dihydro-1H-
2
[1,4]oxazino[4,3-a]indol-1-one 11k: Yellow-orange solid (70 mg, 27 %);
1
m.p. 149-151 °C; R
f
= 0.31 (EtOAc/EP, 20:80). H NMR (300 MHz, CDCl
3
):
3
5
0 mL of diethyl ether were added and the reaction medium was stirred for
min at room temperature, then 10 mL of NH Cl were added and the
δ = 7.63 (d, J = 9 Hz, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.41 (d, J = 9 Hz, 1 H),
7.33 (t, J = 9 Hz, 1 H), 5.72 (t, J = 3 Hz, 1 H), 5.19 (s, 2 H), 4.32 (d, J = 3
4
mixture was stirred for 5 min. The precipitate formed was filtered on celite
and washed by diehyl ether and water, and the filtrate was extracted by
diethyl ether (3 × 20 mL). The organic phase was washed by saturated
Hz, 2 H), 3.45 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl
3
): δ = 153.8, 152.4,
136.6, 131.1, 127.9, 124.0, 122.8, 120.6, 110.5, 94.9, 93.3, 78.8, 69.5,
60.5, 58.0, 40.7 ppm. IR (ATR): max = 3050, 2953, 1744, 1670, 1614, 1518
-
1
solution of NH
4
Cl (2 × 5 mL) and saturated solution of NaCl (2 × 10 mL),
cm . HRMS (ESI, positive mode): calcd. for C16
12 3
H O NI [M+H] 393.9934;
dried by MgSO
4
and evaporated under vacuum. Compound were isolated
found 393.9930.
by column chromatography on silica gel using 5/95: ethyl
acetate/petroleum ether as eluent.
(E)-10-Iodo-3-(3-phenylprop-2-yn-1-ylidene)-3,4-dihydro-1H-
Biscoupling: In a schlenk tube dried by a flame and under argon, 0.4 g of
compound 10 (1 equiv., 0.88 mmol) were introduced with 0.3 mL of 1-
hexyne (3 equiv., 2.64 mmol) in 10 mL of DMF. The mixture was cooled to
[1,4]oxazino[4,3-a]indol-1-one 11l: Yellow solid (31 mg, 11 %); m.p. 127-
1
129 °C; R
f
= 0.77 (EtOAc/EP, 20:80). H NMR (300 MHz, CDCl
3
): δ = 7.76-
):
δ = 154.1, 151.6, 136.8, 131.6, 131.3, 129.1, 128.7, 128.1, 124.3, 123.0,
122.6, 120.9, 110.6, 97.4, 95.9, 81.8, 69.6, 40.9 ppm. IR (ATR): max
7.27 (m, 9 H), 5.90 (s, 1H), 5.25 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl
3
0
°C and 0.54 mL of Et
stirring was continued for 15 min at 0 °C before the addition of 17 mg of
CuI (10% mol), 23 mg of PPh (10 % mol) and 9.9 mg of Pd(OAc) (10 %
mol). The mixture was stirred at room temperature overnight. 30 mL of
Et O were added and the mixture was stirred for 5 min followed by the
addition of 10 mL of NH Cl and the stirring was continued for 5 min.
3
N (4.4 equiv., 3.9 mmol) were added and the
=
-
1
3
2
2922, 1736, 1512, 1090, 735 cm . HRMS (ESI, positive mode): calcd. for
+
20
C H13INO
2
[M+H] 425.9985; found 425.9985.
2
4
(E)-3-(Hept-2-yn-1-ylidene)-10-(hex-1-yn-1-yl)-3,4-dihydro-1H-
The precipitate was filtered on celite, washed with ether and water and the
filtrate was extracted by diethyl ether (3 × 20 mL). The organic phase was
[1,4]oxazino[4,3-a]indol-1-one 12c: Yellow oil (0.11 g, 34 %); R
f
= 0.72
1
(EtOAc/PE, 10:90). H NMR (300 MHz, CDCl
3
): δ = 7.83 (d, J = 6 Hz, 1 H),
washed by NH
4
Cl (2 × 5 mL) and NaCl (5 × 10 mL), dried by MgSO
4
and
7.50-7.44 (m, 1 H), 7.37 (d, J = 6 Hz, 1 H), 7.20-7.25 (m, 1 H), 5.64-5.62
(m, 1 H), 5.08 (s, 2 H), 2.60 (t, J = 6 Hz, 2 H), 2.42 (dt, J = 2.2 Hz, J = 7
Hz, 2 H), 1.74-1.42 (m, 8 H), 0.97 (t, J = 7 Hz, 3 H), 0.95 (t, J = 7 Hz, 3 H)
evaporated under vacuum. Compound were isolated by column
chromatography on silica gel using 5/95: ethyl acetate/petroleum ether as
eluent.
ppm. 13C NMR (75 MHz, CDCl
22.4, 122.2, 121.5, 110.2, 108.5, 100.2, 98.7, 96.0, 73.2, 71.9, 40.2, 30.9,
30.7, 22.1 (2C), 19.9, 19.5, 13.8, 13.7 ppm. IR (ATR): max = 2958, 2933,
3
): δ = 154.0, 151.3, 135.8, 129.2, 127.4,
1
(
E)-3-(Hept-2-yn-1-ylidene)-10-iodo-3,4-dihydro-1H-[1,4]oxazino[4,3-
-
1
a]indol-1-one 11h: Yellow solid (0.19 g, 74 %); m.p. 122-124 °C; R
f
= 0.54
1700, 1559, 739, 668 cm . HRMS (ESI, positive mode): calcd. for
1
+
(EtOAc/PE, 10:90). H NMR (300 MHz, CDCl
3
): δ = 7.63 (d, J = 9 Hz, 1 H),
C
24
H
26NO
2
[M+H] 360.1958; found 360.1959.
7
5
0
1
4
.52 (t, J = 7.5 Hz, 1 H), 7.39 (d, J = 9 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H),
.67 (s, 1 H), 5.16 (s, 2 H), 2.43 (t, J = 7.5 Hz, 2 H), 1.64-1.43 (m, 4 H),
General procedure for Suzuki-Miyaura Cross-coupling:
.97 (t, J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 154.5, 150.8,
36.8, 131.3, 127.9, 124.2, 122.8, 121.1, 110.5, 99.0, 96.5, 73.1, 69.2,
Monocoupling: In a schlenk tube dried by a flame, and under argon, 0.2
g of compound 10a (1 equiv., 0.44 mmol) were introduced with 10 mL of
toluene and 2 mL of water. Then 0.12 g of potassium vinyltrifluoroborane
3
-
1
0.7, 30.8, 22.2, 19.5, 13.7 ppm. IR (ATR): max = 1742, 1070, 735 cm .
+.
MS (EI) m/z = 406 (20), 405 (M , 100), 269 (26), 250 (31), 222 (13), 221
11), 208 (17), 207 (13), 180 (13), 178 (13), 128 (68), 114 (27), 102 (11),
01 (56), 77 (17), 75 (22), 51 (19), 39 (10). HRMS (ESI, positive mode):
calcd. for C18 [M+H] 406.0298; found 406.0296.
(1.2 equiv, 0.53 mmol), 0.43 g of Cs
2 3
CO (3 equiv., 1.33 mmol) and 36 mg
(
1
of PdCl dppf (0.1 equiv., 0.044 mmol) were added respectively. After 24
2
hours at 70 ºC, 10 mL of HCl (1M) were added and the precipitate was
filtered on Büchner then the filtrate was extracted by ethylacetate (3 ×
H17INO
2
20mL) and the organic phase was washed by NaCl (3 × 10mL), dried by
(
E)-7-(Hept-2-yn-1-ylidene)-10-iodo-6,7-dihydro-9H-[1,3]dioxolo[4,5-
MgSO and concentrated under vacuum. Compound were isolated by
4
f][1,4]oxazino[4,3-a]indol-9-one 11i: Yellow solid (0.25 g, 85 %); m.p.
column chromatography on silica gel using 2/98: ethyl acetate/petroleum
ether as eluent.
Biscoupling: In a schlenk tube dried by a flame, and under argon, 0.2 g
of compound 10a (1 equiv., 0.44 mmol) were introduced with 10 mL of
toluene and 2 mL of water. Then 0.13 g of potassium vinyltrifluoroborane
1
1
6
2
64-166 °C; R
f
= 0.84 (EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ =
.94 (s, 1 H), 6.76 (s, 1 H), 6.06 (s, 1 H), 5.64 (m, 1 H), 5.04 (d, J = 1.2 Hz,
H), 1.61-1.46 (m, 4 H), 2.40 (dt, J = 6, 3 Hz, 2 H), 0.97 (t, J = 6 Hz, 3 H)
ppm. 13C NMR (75 MHz, CDCl
3
): δ = 154.1, 150.8, 150.3, 146.1, 133.1,
26.4, 119.7, 102.0, 101.3, 98.9, 96.2, 89.9, 73.2, 68.9, 40.9, 30.8, 22.2,
9.6, 13.7 ppm. IR (ATR): max = 2951, 1729, 1491, 1037, 945, 841, 736
1
1
(2.2 equiv., 0.97 mmol), 0.43 g of Cs
mg of PdCl dppf (0.1 equiv., 0.044 mmol) were added respectively. After
24 hours at 70 ºC, 0.05 g of vinyltrifluoroborane and 0.02 g of PdCl dppf
2 3
CO (3 equiv., 1.33 mmol) and 36
2
-
1
+
cm . HRMS (ESI, positive mode): calcd. for C19
H17INO
4
[M+H] 450.0196;
2
found 450.0196.
were added and the reaction was let for 3 days. 10 mL of HCl (1M) were
added and the precipitate was filtered on Büchner then the filtrate was
extracted by ethylacetate (3 × 20 mL) and the organic phase was washed
by NaCl (3 × 10 mL), dried by MgSO and concentrated under vacuum.
4
Compound were isolated by column chromatography on silica gel using
2/98: ethyl acetate/petroleum ether as eluent.
(
[
(
E)-3-(Hept-2-yn-1-ylidene)-10-iodo-8-methoxy-3,4-dihydro-1H-
1,4]oxazino[4,3-a]indol-1-one 11j: Brown oil (0.14 g, 48 %); R
EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
f
= 0.61
1
3
): δ = 7.27 (d, J = 9 Hz, 1 H),
7
.15 (d, J = 9 Hz, 1 H), 6.90 (s, 1 H), 5.64 (s, 1 H), 5.10 (s, 2 H), 3.90 (s, 3
H), 2.42 (t, J = 6 Hz, 2 H), 1.61-1.46 (m, 4 H), 0.97 (t, J = 7.5 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl
): δ = 156.4, 154.3, 150.8, 132.2, 132.1, 121.0,
20.3, 111.6, 103.2, 99.0, 96.2, 73.1, 67.9, 55.9, 40.8, 30.8, 22.2, 19.5,
3
(E)-3-(Benzofuran-2-ylmethylene)-10-iodo-3,4-dihydro-1H-
1
1
[1,4]oxazino[4,3-a]indol-1-one 11m: Yellow solid (0.11 g, 57 %); m.p.
-
1
1
3.7 ppm. IR (ATR): max = 2928, 1734, 1512, 1449, 1167 cm . MS (EI)
177-179 °C; R
f
= 0.57 (EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ =
+.
m/z = 436 (21), 435 (M , 100), 299 (28), 284 (10), 280 (22), 238 (15), 158
21), 144 (12), 116 (13), 115 (19), 101 (12), 77 (17). HRMS (ESI, positive
mode):calcd. for C19 [M+H] 436.0404; found 436.0404.
7.62-7.45 (m, 5 H), 7.37-7.23 (m, 3 H), 6.73 (s, 1 H), 6.49 (s, 1 H), 5.60 (s,
2 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 155.1, 154.8, 150.0, 143.5, 136.7,
131.2, 128.2, 127.8, 125.3, 124.1, 123.6, 122.8, 121.3, 121.2, 111.1, 110.5,
08.5, 104.4, 68.7, 41.0 ppm. IR (ATR): max = 2917, 2850, 1731, 1232,
(
3
H
19INO
3
1
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European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
-
1
1
[
174, 1080, 734 cm . HRMS (ESI, positive mode): calcd. for C20
H
13INO
3
of DMF were added drop by drop using a bromine bulb at 0 °C under argon.
The mixture was stirred for 2 h at RT. 1.1 equiv. of 5-chloropent-1-yne
+
M+H] 441.9934; found 441.9931.
(
3.48 mmol) were added to the mixture drop by drop at 0 °C under argon
and the mixture was heated at 70 °C overnight. The mixture was
hydrolyzed by 10 mL of NH Cl, extracted by EtOAc (3 × 20 mL), and the
organic phase was washed with NaCl (6 × 10 mL), dried by MgSO and
(
[
1
E)-10-Iodo-3-(thiophen-2-ylmethylene)-3,4-dihydro-1H-
1,4]oxazino[4,3-a]indol-1-one 11n: Yellow solid (37 mg, 21 %); m.p.
4
1
88-190 °C; R
f
= 0.48 (EtOAc/PE, 20:80). H NMR (300 MHz, CDCl
3
): δ =
4
7.63 (d, J = 6 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.41-7.38 (m, 2 H), 7.32
evaporated under vacuum. Compound 14b was obtained as yellow oil (91
(
1
t, J = 9 Hz, 1 H), 7.11 (dd, J = 3.4 Hz, J = 5 Hz, 1 H), 7.04 (d, J = 3.4 Hz,
H), 6.80 (t, J = 0.9 Hz, 1 H), 5.32 (d, J = 3 Hz, 2 H) ppm. 13C NMR (75
MHz, CDCl ): δ = 155.0, 142.0, 136.6, 134.7, 131.2, 128.6, 128.0, 127.8,
26.6, 124.2, 122.8, 110.4, 109.2, 68.7, 40.3 ppm. IR (ATR): max = 1731,
mg, 76%).
1
R
f
= 0.71 (20:80 EtOAc/PE). H NMR (300 MHz, CDCl
3
): δ = 7.60 (d, J =
3
8.0 Hz, 1 H), 7.47 (d, J = 8.4 Hz,1 H), 7.41 (t, J = 8.4 Hz, 1 H), 7.25 (t, J =
8.0 Hz, 1 H), 4.67 (t, J = 7.2 Hz, 2 H), 4.49 (q, J = 7.2 Hz, 2 H), 2.26 (dt, J
= 7.2 Hz, J = 2.5 Hz, 2 H), 2.11 (t, J = 2.5 Hz, 1 H), 2.05 (quint, J = 7.2 Hz,
2 H), 1.53 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ= 161.2,
1
1
-
1
086, 735 cm . HRMS (ESI, positive mode): calcd. for C16
H11INO
2
S
+
[M+H] 407.9549; found 407.9551.
138.5, 130.3, 127.9, 126.2, 124.1, 121.6, 110.6, 83.3, 69.4, 67.5, 61.3,
(
[
2
E)-3-((3,5-Dimethylisoxazol-4-yl)methylene)-10-iodo-3,4-dihydro-1H-
44.8, 29.3, 16.0, 14.4 ppm. IR (ATR): max = 2917, 2849, 1737, 1706, 1464,
-
1
1,4]oxazino[4,3-a]indol-1-one 11o: Yellow solid (18 mg, 12 %), m.p.
2
1242 cm . HRMS (ESI, positive mode): calcd for C16H17INO (M+H)
1
42-244 °C; R
f
= 0.22 (EtOAc/PE, 20:80). H NMR (300 MHz, DMSO-d
6
):
382.02985, found 382.02983.
δ = 7.86 (d, J = 8 Hz, 1 H), 7.52-7.44 (m, 2 H), 7.29 (t, J = 7 Hz, 1 H), 6.27
s, 1H), 5.09 (s, 2 H), 2.35 (s, 3 H), 2.14 (s, 3H) ppm. 13C NMR (75 MHz,
CDCl ): δ = 165.9, 159.1, 154.8, 145.3, 136.4, 130.2, 127.0, 122.8, 122.4,
21.6, 112.3, 108.0, 101.9, 68.9, 40.2, 11.6, 10.0 ppm. IR (ATR): max
(
1-(But-3-ynyl)-3-iodo-1H-indole-2-carboxylic acid 15a:
3
General procedure of saponification with 60 mg of 14a: Brown solid (50
mg, 91%); R ): δ =
= 0.19 (20:80 EtOAc/PE). 1H NMR (300 MHz, CDCl
1
1
=
f
3
-
1
747, 1308, 1234, 1155, 1090, 745 cm . HRMS (ESI, positive mode):
(M+H) 421.0043, found 421.0046.
7.62 (d, J = 8.1 Hz, 1 H), 7.54-7.40 (m, 2H), 7.34-7.18 (m, 1 H), 4.81 (t, J
= 7.1 Hz, 2 H), 2.75 (td, J = 7.0, J = 2.4 Hz, 2 H), 2.01 (t, J = 2.5 Hz, 1 H)
2 3
calcd. for C17H14IN O
ppm. 13C NMR (75 MHz, CDCl
3
) : δ = 166.2, 139.2, 130.7, 127.2, 126.7,
(
[
E)-8-fluoro-10-iodo-3-(pent-2-yn-1-ylidene)-3,4-dihydro-1H-
1,4]oxazino[4,3-a]indol-1-one 13: To a solution of compound 10d (1
124.6, 122.2, 111.0, 80.7, 71.2, 71.1, 44.8, 20.6. IR (ATR): max = 2917,
1677, 1437, 1119, 720 cm . HRMS (ESI, positive mode): calcd for
C H11INO (M+H) 339.98290, found 339.98275.
13 2
-
1
equiv., 0.5 mmol) and pent-2-ynoic acid (3 equiv., 1.5 mmol) in DMF (3
mL), was added copper (I) iodide (0.025 mmol, 0.05 equiv.), palladium (II)
acetate (0.1 equiv., 0.05 mmol), triphenylphosphine (0.1 equiv., 0.05
mmol) and triethylamine (2 equiv., 1 mmol) under argon atmosphere. The
mixture was heated at 50 °C for 2 hours by microwave irradiation. After
cooling to room temperature, the reaction mixture was diluted with water
3-Iodo-1-(pent-4-ynyl)-1H-indole-2-carboxylic acid 15b: General
procedure of saponification with 0.77 g of 14b: White solid (0.7 g, 98%);
m.p. = 191-193 °C; R
CDCl ): δ = 7.61 (d, J = 8.1 Hz, 1,H), 7.49 (d, J = 8.2 Hz, 1,H), 7.41-7.46
(m, 1,H), 7.23-7.28 (m, 1,H), 4.74 (t,J = 7.2 Hz, 2,H), 2.25 (dt, J = 6.5 Hz,
2.6 Hz, 2,H), 2.02-2.11 (m, 3,H) ppm.13C NMR (75 MHz, CDCl
): δ = 165.7,
= 0.19 (20:80 EtOAc/PE). 1H NMR (300 MHz,
f
3
(10 mL) and extracted with diethyl ether (3 x 10 mL). The combined organic
phases were washed with brine (2 x 20 mL), dried over anhydrous
magnesium sulfate, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (90:10 PE/EtOAc) and
afforded 0.14 g of compound 13 as yellow solid with 70% yield. m.p. 148 °C.
3
139.3, 130.6, 127.1, 126.7, 124.6, 122.0, 110.9, 83.3, 70.4, 69.6, 45.1,
29.5, 16.2 ppm. IR (ATR): max = 3282, 2919-2504, 2163, 1666, 1263, 740
-
1
cm . HRMS (ESI, positive mode): calcd for C14
2
H13INO (M+H) 353.99855,
1H NMR (300 MHz, CDCl
.67 (bs, 1 H), 5.13 (s, 2 H), 2.43 (qd, J = 2.3 Hz, J = 7.5 Hz, 2 H), 1.24 (t,
J = 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 159.4 (J = 241.2 Hz),
54.1, 150.4, 133.4, 131.8, 122.5, 117.4 (J = 24.63 Hz), 112.0 (J = 9.45
Hz), 108.8 (J = 27.52 Hz), 100.5, 96.8, 72.3, 68.0, 40.9, 14.0, 13.6 ppm.
19F NMR (188 MHz, CDCl
) δ = -119.03 ppm. HRMS (ESI, positive mode):
calcd. for C16 12IFNO (M+H) 395.9897, found 395.9910.
): δ = 7.41-7.34 (m, 1 H), 7.33-7.27 (m, 2 H),
found 353.99821.
3
5
3
(E)-11-Iodo-3-(iodomethylene)-4,5-dihydro-1H,3H-[1,4]oxazepino[4,3-
a]indol-1-one 16a: General procedure of iodocyclization with 140 mg of
1
15a: Beige solid (79 mg, 41%); R
f
= 0.4 (20:80 EtOAc/PE). m.p. = 192-
): δ = 7.59 (d, J = 8.3 Hz, 1H), 7.47 (t, J
1
3
194 °C. H NMR (300 MHz, CDCl
3
H
2
= 8.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.27 (t, J = 8.2 Hz, 1H), 6.43 (t, J =
1
.5 Hz, 1H), 4.50 (t, J = 6.6 Hz, 2H), 3.17 (td, J = 6.6 Hz, 1.5 Hz, 2H) ppm.
1
3C NMR (75 MHz, CDCl
Ethyl 1-(but-3-ynyl)-3-iodo-1H-indole-2-carboxylate 14a: 0.72 g of
compound 4a (1.2 equiv., 2.28 mmol) were introduced in a round bottom
3
): δ = 158.4, 151.4, 137.1, 130.5, 127.4, 127.3,
124.1, 122.2, 110.0, 77.4, 70.8, 40.8, 34.6 ppm. IR (ATR): max = 1717,
-
1
flask with 0.13 mg of 3-butyn-1-ol (1 equiv., 1.9 mmol) and 596 mg of PPh
3
1350, 1061, 738 cm . HRMS (ESI, positive mode): calcd for C13
10 2 2
H I NO
(
1.2 equiv., 2.28 mmol) in 20 mL of THF, 450 µL of DIAD (1.2 equiv., 2.28
(M+H) 465.87954, found 465.87909.
mmol) were added at 0 °C and the mixture was stirred at RT overnight.
The solvent was evaporated under vacuum. Purification by flash
(E)-12-Iodo-3-(iodomethylene)-3,4,5,6-tetrahydro-1H-
[1,4]oxazocino[4,3-a]indol-1-one 17b:
General procedure of iodocyclization with 0.88 g of 15b: Beige solid (33
chromatography (95:5 PE/EtOAc) afforded the compound 14a as yellow
1
oil (244 mg, 35%). R
f
= 0.8 (EtOAc/PE, 5:95). H NMR (300 MHz, CDCl
3
)
1
δ = 7.68 (d, J = 8.1 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.35 (t, J = J = 7.3
Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 4.75 (t, J = 7.3 Hz, 2 H), 4.38 (q, J = 7.1
Hz, 2 H), 2.70 (dt, J = 7.3 Hz, J = 2.7 Hz, 2 H), 1.97 (t, J = 2.7 Hz, 1H),
mg, 28%); m.p. = 162-164 °C; R
MHz, CDCl
7.24 (m, 2 H), 5.73 (bs, 1 H), 4.41-4.34 (m, 2 H), 2.75 (t, J = 6.5 Hz, 2 H),
2.14-2.05 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl
): δ = 159.4, 155.0, 137.3,
f
= 0.38 (20:80 EtOAc/PE). H NMR (300
3
): δ = 7.51 (d, J = 8.1 Hz, 1 H), 7.41 (t, J = 8.5 Hz, 1 H), 7.30-
1
1
2
.43 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl
27.5, 126.1, 125.2, 122.8, 120.9, 111.1, 110.6, 81.1, 70.6, 43.5, 29.8,
3
) δ = 162.1, 139.2,
3
130.4, 129.5, 126.7, 123.6, 122.0, 110.0, 67.8, 67, 45.2, 31.9, 25.9 ppm.
IR (ATR): max = 3048, 1725, 1632, 1077, 1036, 731 cm . HRMS (ESI,
-
1
-1
0.5, 14.5 ppm. IR (ATR): max = 1703, 1436, 1185, 1119, 722, 541 cm .
15INO (M+H) 368.01420, found
HRMS (ESI, positive mode): calcd for C15
H
2
12 2 2
positive mode): calcd for C14H I NO (M+H) 479.89519, found 479.89536.
368.02992.
Ethyl 1-(prop-2-ynyl)-1H-pyrrole-2-carboxylate 19: General procedure
Ethyl 3-iodo-1-(pent-4-ynyl)-1H-indole-2-carboxylate 14b: In a two-
necked round bottom flask, 1.1 equiv. of NaH 60 % (3.48 mmol) were
dissolved in 6 mL of DMF, and 1 equiv. of indole 4a (3.16 mmol) in 5 mL
of propargylation with 2.1 g of 18: Colorless oil (1.92 g, 72%); R
f
= 0.73
1
(20:80 EtOAc/PE). H NMR (300 MHz, CDCl
3
): δ = 7.11 (dd, J = 2.5 Hz, J
= 1.8 Hz, 1 H), 6.98 (dd, J = 3.9 Hz, J = 1.8 Hz, 1 H), 6.17 (dd, J = 3.9 Hz,
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European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
J =2.5 Hz, 1 H), 5.17 (d, J = 2.5 Hz, 2 H), 4.28 (q, J = 7.1 Hz, 2 H), 2.43 (t,
[6]
[7]
M. Fedouloff, F. Hossner, M. Voyle, J. Ranson, J. Powles, G. Riley, G.
Sanger, Bioorg. Med. Chem. 2001, 9, 2119–2128.
J = 2.5 Hz, 1 H), 1.35 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl
):
δ = 161.0, 127.8, 121.9, 118.3, 108.5, 78.3, 73.7, 59.9, 38.1, 14.3 ppm. IR
3
a) J. A. Elvidge, F. S. Spring, J. Chem. Soc. 1949, 2935–2942; b) J.
Rokach, Y. Girard, J. G. Atkinson, Can. J. Chem. 1973, 51, 3765–3770;
c) H. F. Schuster, G. M. Coppola, J. Heterocycl. Chem. 1994, 31, 1381–
-
1
(
ATR, cm ): max = 3087, 1734, 1535, 1191, 867. HRMS (ESI, positive
mode): calcd for C10 (M+H) 178.08626, found 178.08634
H
12NO
2
.
1384.
1
-(Prop-2-ynyl)-1H-pyrrole-2-carboxylic acid 20: General procedure of
[8]
[9]
a) H. Yanai, T. Taguchi, Chem. Comm. 2012, 48, 8967–8969; b) C. O.
Salas, R. A. Tapia, Y. Prieto, Acta Cryst., Sect. E: 2011, 67, o318.
L. Wei, L. Liu, J. Zhang, Org. Biomol. Chem. 2014, 12, 6869–6877.
saponification with 0.52 g of 19: Pale yellow solid (0.39 g, 91%); R
f
= 0.21
1
(20:80 EtOAc/PE); m.p. = 148-150 °C. H NMR (300 MHz, CDCl
3
): δ = 7.21
(
t, J = 2.3 Hz, 1 H), 7.13 (dd, J = 4.0 Hz, J = 1.7 Hz, 1 H), 6.22 (dd, J = 4.0
[10] S. P. Hiremath, G. R. Badiger, A. S. Jivanagi, M. G. Purohit, Indian J.
Chem., Sect. B 1992, 31B, 583–589.
Hz, J = 2.3 Hz, 1 H), 5.17 (d, J = 2.5 Hz, 2 H), 2.45 (t, J = 2.5 Hz, 1 H) ppm.
13C NMR (75MHz, CDCl
): δ = 165.8, 129.3, 121.1, 120.9, 109.2, 78.1,
4.2, 38.5 ppm. IR (ATR): max = 3255, 2992-2548, 1654, 1260, 734 ppm.
HRMS (ESI, positive mode): calcd for C NO (M+H) 150.05496, found
50.05500.
3
[11] M. Bandini, A. Bottoni, A. Eichholzer, G. P. Miscione, M. Stenta, Chem.
Eur. J. 2010, 16, 12462–12473; b) H. He, L.-X. Dai, S.-L. You, Org.
Biomol. Chem. 2010, 8, 3207–3210.
7
H
8 8
2
1
[12] V. A. Vaillard, R. A. Rossi, S. E. Martin, Org. Biomol. Chem. 2011, 9,
4927–4935.
(
E)-3,4-Dihydro-3-(iodomethylene)pyrrolo[2,1-c][1,4]oxazin-1-one 21:
[13] J. K. Vandavasi, W.-P. Hu, G. C. Senadi, S. S. K. Boominathan, H.-Y.
Chen, J.-J. Wang, Eur. J. Org. Chem. 2014, 28, 6219–6226.
[14] S. Taskaya, N. Menges, M. Balci, Beilstein J. Org. Chem. 2015, 11, 897–
905.
General procedure of iodocyclization with 0.35 g of 20: Brown solid (0.19
g, 30%); R
CDCl
1
f
= 0.52 (20:80 EtOAc/PE); m.p.= 88-90 °C. H NMR (300 MHz,
3
): δ = 7.14 (dd, J = 4.1 Hz, J = 1.5 Hz, 1 H), 6.96-6.95 (m, 1H), 6.39
(
2
1
dd, J = 4.1 Hz, 2.5 Hz, 1 H), 6.25 (t, J = 1.2 Hz, 1 H), 4.98 (d, J = 1.2 Hz,
[15] a) A. Putey, G. Fournet, B. Joseph, Synlett 2006, 2755–2758; b) A. Putey,
G. Fournet, O. Lozach, L. Perrin, L. Meijer, B. Joseph, Eur. J. Med. Chem.
2014, 83, 617–629.
H) ppm. 13C NMR (75 MHz, CDCl
12.0, 62.9, 45.6 ppm. IR (ATR, cm ): max = 1718, 1327, 1166, 735.
INO (M+H) 275.95160, found
3
): δ = 153.7, 147.3, 125.7, 118.2, 116.6,
-
1
HRMS (ESI, positive mode): calcd for C
2
H
8 7
2
[16] S. Inack-Ngi, V. Guilloteau, M. Abarbri, J. Thibonnet, J. Org. Chem. 2011,
76, 8347–8354.
75.95138.
[
17] a) H. Hemetsberger, D. Knittel, Monatsch. Chem. 1972, 103, 194–204;
b) D. Knittel, Synthesis, 1985, 186–188; c) P. Roy, M. Boisvert, Y.
Leblanc, Org. Synth. 2007, 84, 262–271.
[
18] a) C. Poriel, M. Lachia, C. Wilson, J. R. Davies, C. J. Moody, J. Org.
Chem. 2007, 72, 2978–2987. b) C. Neagoie, E. Vedrenne, F. Buron, J.-
Y. Mérour, S. Rosca, S. Bourg, O. Lozach, L. Meijer, B. Baldeyrou, A.
Lansiaux, S. Routier, Eur. J. Med. Chem. 2012, 49, 379–396.
Acknowledgements ((optional))
We thank Vincent Guilloteau for the development of the synthesis
of allenic acid 8 and Dr. Johan Jacquemin for the calculation. We
also acknowledge Dr. Frédéric Montigny (Tours University) for
mass spectra and HRMS, Michel Giorgi (Spectropole of Marseille)
for all the performed RX analysis and Dr. Karen Wright (Versailles
University) for the careful reading and improvement of the English.
[19] The thermolysis of the acrylate (Hemetsberger-Knittel method) leads
exclusively to the product 4e.
[
[
[
20] Y. Durust, A. Sagirli, B. M. Kariuki, D. W. Knight, Tetrahedron 2014, 70,
012–6019.
6
Keywords: Iodolactonization • Oxazino[4,3-a]indolones • Cross-
coupling reaction • N-Fused indoles • Iodine
21] J. K. Vandavasi, W.-P. Hu, G. C. Senadi, S. S. K. Boominathan, H.-Y.
Chen, J.-J. Wang Eur. J. Org. Chem. 2014, 28, 6219–6226.
22] M. Sechi, M. Derrudas, R. Dallocchio, A. Dessi, A. Bacchi, L. Sannia, F.
Casta, M. Palomba, O. Ragab, C. Chen, R. Shoemaka, S. Sei, R. Dayam,
N. Neamati, J. Med. Chem. 2004, 47, 5298–5310.
[
1]
a) G. R. Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875–2911; b)
S. Katayama, N. Ae, R. Nagata, J. Org. Chem. 2001, 66, 3474–3483; c)
V. M. Lombardo, C. D. Thomas, K. A. Scheidt, Angew. Chem. Int. Ed.
[23] A. Putey, F. Popowycz, B. Joseph Synlett 2007, 419–422.
[24] A. Zakarian, A. Batch, R. A. Holton, J. Am. Chem. Soc. 2003, 125, 7822–
7823.
2013, 52, 12910-12914; Angew. Chem. 2013, 125, 13148–13152; d) T.
C. Leboho, J. P. Michael, W. A. L. van Otterlo, S. F. van Vuuren, C. B.
de Koning, Bioorg. Med. Chem. Lett. 2009, 19, 4948–4951; e) M. Bandini,
A. Eichholzer, M. Tragni, A. Umani-Ronchi, Angew. Chem. Int. Ed. 2008,
[25] X. Zhang, Y. Zhou, H. Wang, D. Guo, D. Ye, Y. Xu, H. Jiang, H. Liu, Adv.
Synth. Catal. 2011, 353, 1429–1437.
4
7, 3238–3241; Angew. Chem. 2008, 120, 3282–3285. f) Z. Chen, X.
[26] M. Alvarez-Corral, M. Munoz-Dorado, I. Rodriguez-Garcia, Chem. Rev.
2008, 3174–3198.
Zeng, B. Yan, Y. Zhao, Y. Fu, RSC Adv. 2015, 5, 100251–100255; g) J.
Liu, M. Shen, Y. Zhang, G. Li, A. Khodabocus, S. Rodriguez, B. Qu, V.
Farina, C. H. Senanayabe, B. Z. Lu, Org. Lett. 2006, 8, 3573–3575; h) M.
Lounasmaa, A. Tolvanen, Nat. Prod. Rep. 2000, 17, 175–191.
[27] CCDC 1496048, CCDC 1851526 and CCDC 1851393 contains the
supplementary crystallographic data for 10a, 16a and 17b. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Center via www.ccdc.cam.uk/data/_request/cif.
[
2]
3]
E. Deniz, M. Tomasulo, S. Sortino, F. Raymo, J. Phys. Chem. C, 2009,
113, 8491–8497.
[28] see supporting information (SI-2).
[
S. Ayral-Kaloustian, N. Zhang, A. M. Venkatesan, T. S. Mansour, T. H.
Nguyen, J. T. Anderson, U.S. Pat. Appl. Publ. 2009, US 20090192147
A1.
[29] P. Quinodoz, A. Quelhas, A.; K. Wright, B. Drouillat, J. Marrot, F. Couty,
Eur. J. Org. Chem. 2017, 2621–2626.
[30] a) T. Yao, R. C. Larock, J. Org. Chem. 2003, 68, 5936–5942; b) V.
Dubrovskiy, N. A. Markina, R. C. Larock, Comb. Chem. High Throughput
Screening, 2012, 15, 451–472; c) A. Gupta, B. L. Flynn, J. Org. Chem.
2016, 81, 4012–4019; d) H. Huang, X. Zhu, G. He, Q. Liu, J. Fan, H. Zhu,
Org. Lett. 2015, 17, 2510–2513; e) R. Mancuso, C. C. Pomelli, F.
[
4]
5]
a) W. T. Zimmerman, PCT Int. Appl. 1991, WO 9110668 A1; b) W. T.
Zimmerman, U.S. 1994, US 5356862 A.
[
S. Inaba, K. Ishizumi, M. Akatsu, R. Kume, K. Mori, H. Yamamoto, Jpn.
Tokkyo Koho 1974, JP 49004238 B.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201801167
FULL PAPER
Malafronte, A. Marino, C. Chiappe, B. Gabriele, Org. Biomol. Chem.
g) B. Prasad, B. Y. Sreenivas, D. Rambabu, G. R. Krishna, C. M. Reddy,
K. L. Kumar, M. Pal, Chem. Commun. 2013, 49, 3970–3972.
2017, 15, 4831–4841.
[
[
[
31] V. L. Heasley, D. F. Shellhamer, L. E. Heasley, D. B. Yaeger, G. E.
Heasley, J. Org. Chem. 1980, 45, 4649–4652.
[44] S. Basceken, S. Kaya, M. Balci, J. Org. Chem. 2015, 80, 12552–12561.
32] a) J. K Stille, Angew. Chem. Int. Ed. Engl. 1986, 25, 508–524; b) D.
Milstein, J. K. Stille, J. Am. Chem. Soc. 1979, 101, 4992–4998.
33] a) M. Pereyre, J.-P. Quintard, A. Rahm, Tin in Organic Synthesis;
Butterworths: London, 1987; b) A. G. Davies, Organotin Chemistry;
Wiley-VCH: Weinheim, 1997; c) Tin in Organic Synthesis. In Tin
Chemistry. Fundamentals, Frontiers, and Applications; A. G. Davies, M.
Gielen, K. H. Pannell, E. R. T. Tiekink, Eds.; John Wiley & Sons, Ltd.:
New York, 2008; pp. 497−665; d) T. Hiyama, Organosilicon and relating
Organotin Chemistry. In Organometallics in Synthesis, 3rd ed.;
Schlosser, M., Ed.; J. Wiley & Sons: Hoboken, NJ, 2013; pp. 373–544.
34] M.M Heravi, L. Mohammadkhani, J. Organometallic. Chem. 869, 2018,
[
[
106–200.
35] D. C. Harrowven, D. P. Curran, S. L. Kostiuk, I. L. Wallis-Guy, S. Whiting,
K. J. Stenning, B. Tang, E. Packard, L. Nanson, Chem. Commun. 2010,
46, 6335–6337.
[
[
[
36] a) K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett. 1975,
4
467–4470; b) Y. Tohda, K. Sonogashira, N. Hagihara, Synthesis, 1977,
77–778; c) K. Sonogashira, In Metal-Catalyzed Cross-Coupling
7
Reactions, P. J. Stang, F. Diederich, Eds.; Wiley-VCH: Weinheim, 1998,
pp. 203–229.
37] a) A. Suzuki, J. Organomet. Chem. 1999, 576, 147–168; b) A; Suzuki, In
Metal-Catalyzed Cross-Coupling Reactions P. J. Stang, F. Diederich,
Eds.; Wiley-VCH: Weinheim, 1998, pp. 49–97; c) N. Miyaura, Chem Rev.
1995, 95, 2457-2483; d) R. Jana, T. P. Pathak, M. S. Sigman, Chem.
Rev. 2011, 111, 1417–1492.
38] a) S. Darses, J.-P. Genet, Chem. Rev. 2008, 108, 288–325; b) G. A. L.
Molander, N. Ellis, Acc. Chem. Res. 2007, 40, 275–286; c) C.-N. Zhou,
H.-H. Xie, Z.-A. Zheng, Y.-C. Xiao, G. Li, Y.-H. Shen, W.-M. Peng, L.
Wang, Chem. Eur. J. 2018, 24, 5469–5473.
[
39] C. Maaliki, Y. Chevalier, E. Thiery, J. Thibonnet, Tetrahedron Lett. 2016,
57, 3358–3362.
[
40] a) Mitsunobu, Synthesis, 1, 1-28; b) K. C. Kumara Swamy, N. N. Bhuvan
Kumar, E. Balaraman, K. V. P. Pavan Kumar, Chem. Rev. 2009, 109,
2
551–2651; c) S. S. Bhagwat, C. Gude, Tetrahedron Lett. 1994, 35,
847–1850.
1
[
41]
[42] M. A. Winnik, Chem. Rev. 1981, 81, 491–524; b) J. Ackrell, F. Franco, R.
Greenhouse, A. Guzman, J. M. Muchowski, J. Heterocycl. Chem. 1980,
17, 1081–1085; c) F. Gatta, F. Ponti, Boll. Chim. Farm. 1981, 120, 102–
107; d) G. Mehta, V. Singh, Chem. Rev. 1999, 99, 881–930; e) T. Iwai,
H. Okochi, H. Ito, M. Sawamura, Angew. Chem. Int. Ed. 2013, 52, 4239–
242; Angew. Chem. 2013, 125, 4333–4336.
4
[
43] a) P. Gonzalez-Perez, L. Perez-Serrano, L. Casarrubios, G. Dominguez,
J. Perez-Castells, Tetrahedron Lett. 2002, 43, 4765–4767; b) M. L.
Bennasar, E. Zulaica, S. Tummers, Tetrahedron Lett. 2004, 45, 6283–
6285; c) A. L. J. Beckwith, J. M. D. Storey, J. Chem. Soc. Chem.
Commun. 1995, 977–978; d) N. Chernyak, D. Tilly, Z. Li, V. Gevorgyan,
Chem. Commun. 2010, 46, 150–152; e) S. Naoe, T. Saito, M. Uchiyama,
S. Oishi, N. Fujii, H. Ohno, Org. Lett. 2015, 17, 1774–1777; f) Y. Liu, Y.
Huang, H. Song, Y. Liu, Q. Wang, Chem. Eur. J. 2015, 21, 5337–5340;
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European Journal of Organic Chemistry
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Entry for the Table of Contents (Please choose one layout)
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A convenient approach to the
synthesis of oxazinoindolones is
described based on a regioselective
and stereoselective iodocyclization
reaction. Transition metal catalyzed
coupling reactions constitute an
efficient procedure for the preparation
of a series functionalized
Iodocyclization, oxazinoindolones*
Sokaina Hammoud, Elsa Anselmi, Khalil
Cherry, Jean-Claude Kizirian, Jérôme
Thibonnet*
Page No. – Page No.
Synthesis and Reactivity of
oxazinoindolones.
Oxazinoindolones via Regioselective
6-exo-dig Iodolactonization
*one or two words that highlight the emphasis of the paper or the field of the study
Layout 2:
FULL PAPER
*
*
Page No. – Page No.
Text for Table of Contents
*one or two words that highlight the emphasis of the paper or the field of the study
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