A simple, efficient, regioselective and one-pot preparation of N-hydroxy- and N-O-protected hydroxyindoles via cycloaddition of nitrosoarenes with alkynes. Synthetic scope, applications and novel by-products

Article abstract of DOI:10.1016/j.tet.2013.10.072

The thermal reaction between nitrosoarenes and alkynes under alkylating conditions produces N-alkoxyindoles as the major products in moderate to good yields and excellent regioselectivity. Various electrophiles are used affording different N-O-protected hydroxyindoles in a multi-component fashion. Privileged acetylenic substrates used in reactions with substituted nitrosoarenes are arylalkynes or propiolates. Potentially bioactive compounds and other classes of highly functionalizable indole products were prepared. Reactions between o-carbomethoxy-nitrosoarenes and arylacetylenes provided tricyclic compounds containing an acylaziridine indoline skeleton.

Full text of DOI:10.1016/j.tet.2013.10.072

Tetrahedron xxx (2013) 1e15
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A simple, efficient, regioselective and one-pot preparation of
N-hydroxy- and NeO-protected hydroxyindoles via cycloaddition of
nitrosoarenes with alkynes. Synthetic scope, applications and novel
by-products
Gabriella Ieronimo a, Alessandro Mondelli a, Francesco Tibiletti a, Angelo Maspero a,
Giovanni Palmisano a, Simona Galli a, Stefano Tollari a, Norberto Masciocchi a,
,
Kenneth M. Nicholas b, Silvia Tagliapietra c, Giancarlo Cravotto c, Andrea Penoni a
*
a
ꢀ
Dipartimento di Scienza e Alta Tecnologia, Universita degli Studi dell’Insubria, Via Valleggio 11, 22100 Como, Italy
b Department of Chemistry and Biochemistry, University of Oklahoma, Stephenson Life Sciences Research Center, 101 Stephenson Parkway, Norman,
OK 73019-5251, USA
c
ꢀ
Dipartimento di Scienza e Tecnologia del Farmaco, Universita degli Studi di Torino, Via P. Giuria 9, 10235 Torino, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2013
Received in revised form 13 October 2013
Accepted 24 October 2013
Available online xxx
The thermal reaction between nitrosoarenes and alkynes under alkylating conditions produces N-al-
koxyindoles as the major products in moderate to good yields and excellent regioselectivity. Various
electrophiles are used affording different NeO-protected hydroxyindoles in a multi-component fashion.
Privileged acetylenic substrates used in reactions with substituted nitrosoarenes are arylalkynes or
propiolates. Potentially bioactive compounds and other classes of highly functionalizable indole products
were prepared. Reactions between o-carbomethoxy-nitrosoarenes and arylacetylenes provided tricyclic
compounds containing an acylaziridine indoline skeleton.
Keywords:
Nitrosoarenes
Alkynes
Ó 2013 Elsevier Ltd. All rights reserved.
Indoles
Annulation
N-Heterocycles
1. Introduction
alkoxyindole derivatives and their related compounds were studied
for their potential activity in reducing the risk of cancer.4 The 1-
Indoles are among the most interesting and well-known het-
erocycles. Their structure is particularly valuable in medicinal
chemistry, chemical biology and pharmaceutical sciences since the
indole ring is so prevalent in molecules that show biological ac-
tivities and. Many methods have been reported for the preparation
of the indole skeleton.1 Rarer N-hydroxy- and N-alkoxyindoles
were studied by different research groups both in academic and
industrial laboratories for their potential significance as novel re-
active compounds, useful synthetic intermediates and bioactive
natural products.2 The provocative ‘1-hydroxyindole hypothesis’
was introduced by Somei3 to support the biological role of 1-
hydroxyindoles in the biosynthesis and functionalization of in-
dole alkaloids and inside some biological pathways. The search for
new drugs has shown in recent years that N-hydroxyindole and N-
hydroxyindole nucleus was recently discussed in pigments from
flower pot parasol Leucocoprinus birnbaumii5 a specie of a gilled
mushroom in the family of Agaricaceae.5 Among naturally occur-
ring compounds with N-methoxyindole skeletons, paniculidine B
an alkaloid isolated from Murraya paniculata and phytoalexin an-
alogues of Wasabi (Wasabia japonica a plant member of the family
of the Brassicaceae) were found.6 In the last decade it was observed
that some indole-based pharmaceutical agents were improved af-
ter replacing the NeH with an N-alkoxy moiety.7
Although some methods to produce N-alkoxy- and N-hydrox-
yindoles and other complex structures containing the N-hydrox-
yindole unit have been published,8 their utility has been limited by
low yields and competing reactions. The most established synthetic
route to these compounds is Somei’s method, which starts from
a preformed indole via reduction to the indoline, followed by the
tungstate-catalyzed reoxidation to the N-hydroxyindole.2b More
recently, Nicolaou and Wojciechowski reported a new synthetic
pathway to produce N-hydroxyindoles by Sn(II)-induced reductive
* Corresponding author. Tel.: þ39 031 2386440; fax: þ39 031 2386449; e-mail
addresses: andrea.penoni@uninsubria.it, apenoni@gmail.com (A. Penoni).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.072
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2
G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
cyclizations of o-nitrounsaturated ketoesters and this technique
was efficiently used in the preparation and construction of noca-
thiacin I model systems.9 Baran and Myers independently reported
the total synthesis of dimeric stephacidin B and of the corre-
sponding monomer avrainvillamide.10 As reported by Chang, Zhao
and coauthors not many methods are known to produce the N-
alkoxyindole skeleton directly.11 Besides other less efficient or less
general methods, an efficient Pb-promoted reductive cyclization of
o-nitrobenzyl ketones to N-hydroxyindoles has been recently
described.12
The stability of N-hydroxyindoles has been discussed in many
reports and was a focus of debate.2b,13 Some N-hydroxyindoles
are elusive and highly unstable compounds and easily convert
to dehydrodimerization products, known as 1,10-diaza-9,20-
dioxakabutane named after an ancient helmet of the Japanese
Army2b,14 (Scheme 1). The first isolation and characterization of this
class of compounds was performed by Tedder in the sixties15 and
later confirmed by X-ray diffraction.16
explorative study of the reaction of arynes with nitrosobenzene
was originally reported by Steinhoff and Henry.27a By this way
carbazoles were synthesized as major products. Very recently this
reaction was deeply investigated by Studer and co-workers.27b
Using nitrosoarenes as starting materials we developed an unca-
talyzed version of the alkyne cycloaddition that produces N-
hydroxyindoles as the major products more rapidly and in higher
yields (Fig. 1).28 The efficiency of the ArNO/alkyne cycloaddition
can be improved significantly by alkylative trapping of the labile N-
hydroxyindoles with K2CO3eMe2SO4 isolating N-methoxyindoles
as the major products (Fig. 1).29 This method was used to achieve in
good yields and few synthetic steps a phytoalexin derived analogue
of Wasabi. The mechanism of the reaction was studied using kinetic
experimental probes and computational methods revealing the
likelihood of a stepwise radical pathway with the formation of the
carbonenitrogen bond as the rate determining step.30 More re-
cently the nitrosoareneealkyne cycloaddition was introduced as
a new synthetic approach to the meridianin natural products,
marine indole alkaloids established as kinase inhibitors.31 Some of
us reported an indole synthesis starting from arylhydroxylamines
via the intermediate formation of nitrosoaromatics.32 Very recently
Srivastava and co-workers implemented the indolization by an-
nulations of nitrosoarenes with alkynes adding gold33a and cop-
per33b catalysts to obtain indoles in one-pot procedure in the
presence of reducing agents.
Scheme 1. Dehydrodimerization of N-hydroxyindoles to kabutanes.
The elusive and labile nature of N-hydroxyindoles led to the
introduction of some techniques to produce the more stable N-
methoxy- and N-alkoxyindoles.17 N-Alkoxy-derivatization of in-
dole-3-carbinol was recently reported to increase the efficacy of G
cell cycle arrest and it was detected to be active in the regulation of
cell cycle gene transcription and activity in time guest cancer
cells.18 Most of the synthetic protocols to access the N-alkoxyindole
unit come from intramolecular reactions.19 A noteworthy and re-
markable synthetic approach to the formation of N-alkoxyindole
framework is the heterocyclization reported by Zhao and co-
workers on 3-alkoxyimine-2-arylalkylnitriles mediated by ferric
chloride.11 It is known that 2-nitrostyrenes and 2-nitrostilbenes
react in under reducing conditions giving the selective formation
of indoles.20 A theoretical study by Davies and Houk provided ev-
idence that in the deoxygenation of nitroaromatics for the con-
struction of nitrogen containing heterocycles an alternative
pathway through
a 6p-electron 5-atom electrocyclization of
nitrostyrenes, nitrostilbenes and nitrobiphenyls can give nitronate
intermediates that rapidly evolve to N-hydroxy heterocycles.21
Our group continues to show a strong interest in organic and
organometallic chemistry of indole derivatives.22 Previous experi-
ence in this research topic led some of us to introduce an
intramolecular synthesis of 2-substituted N-hydroxyindoles start-
ing from 2-nitrostilbenes by using Pd(TMB)2 (TMB¼trime-
thylbenzoate) as catalyst under CO.23 Very recent contributions by
Peet and co-workers24 on the study of the mechanism of the
Cadogan-Sundberg indole synthesis and on the preparation of
phytoalexin from Wasabi revealed the formation of N-hydrox-
yindoles as major products by reduction of nitrostilbenes with
triethyl phosphite under microwave irradiation24a and trimethyl
phosphite.24b From our ongoing studies on the activation/nitro-
genation of unfunctionalized hydrocarbons we also disclosed a new
synthetic, regioselective and versatile intermolecular approach to
indoles using nitro compounds as precursors (Fig. 1). The reductive
annulation of nitroarenes with alkynes under CO with Cp-iron and
-ruthenium complexes as catalysts furnished 3-substituted indoles
regioselectively.25 Ragaini and co-workers optimized this reaction
using Pd-26a and mixed PdeRu catalysts.26b A preliminary and
Fig. 1. Synthesis of indole compounds by cycloaddition of nitro- and nitrosoaromatics
with alkynes.
2. Results and discussion
In this paper an extended and detailed survey of the preparation
of N-alkoxyindoles and other O-protected 1-hydroxyindoles using
different electrophiles (alkylating and acylating reactants) in a one-
pot procedure by annulation of nitrosoarenes with alkynes is pre-
sented. In the aim to show the general purpose of the reaction, the
synthetic application and the substrate scope, other terminal and
internal alkynes were used and tested in a wide survey with both
electron-rich and electron-deficient nitrosoaromatics. The scope of
the present study is the general application of the synthetic pro-
tocol for the preparation of NeO-protected hydroxyindoles using
a variety of arylalkynes or propiolates and a wide range of elec-
trophiles. As already seen, to avoid the side reaction of the forma-
tion of kabutanes, we organized a multi-component procedure
to protect N-hydroxyindoles as the corresponding N-methoxy
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G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
3
derivatives.29 Multicomponent reactions (MCRs) are frequently and
deeply studied and known as convergent reactions, in which three
or more starting materials react in a sequential manner to form
prevalently a single product, where basically all or most of the
atoms are incorporated into the newly formed product in a highly
selective way.34 Different protecting groups were used showing the
potential to afford various indole protected compounds maintain-
ing the regioselectivity both with arylacetylenes and propiolates.
N-Alkoxyindoles are produced in moderate to excellent yields from
the reaction between substituted-nitrosoarenes and substituted-
arylacetylenes under alkylative conditions, in the presence of
K2CO3/Me2SO4. Generally, nitrosoarenes with electron withdraw-
ing groups react faster than electron-rich nitrosoaromatics and
show better yields and selectivities for the indole products. Nitro-
soarenes are usually used as the limiting reagents and with most of
the reactions being carried out with an excess of the alkyne. Con-
jugated alkynes were found to be the privileged partners for
the cyclization and reactions carried out with unconjugated al-
kynes and symmetrical internal alkynes (diphenylacetylene, bis-
trimethylsilylacetylene and 4-octyne) gave poor yields or no re-
actions at all. Terminal alkynes show better yields of the indole
compounds than internal alkynes and all the reactions show ex-
clusively the formation of 3-substituted indoles without any traces
of the other regioisomer. Nitrosoarenes 1aef reacted in the pres-
ence of an excess (12 fold) of the arylacetylenes 2aei using K2CO3 as
base and Me2SO4 as the methylating agent (6:1 molar ratio relative
to the nitrosoarene). Products 3aeq were achieved in 4e12 h in
good to excellent yields (Scheme 2 and Table 1).
Table 1
Reactions between nitrosoarenes and arylacetylenes with Me2SO4 as the alkylating
agenta
Entry
Product
X
Y
Yieldb (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-CN
4-Br
2,5-CO2Me
H
H
H
H
4-NO2
4-CN
4-Br
91
82
77
67
37
55
48
76
57
47
62
41
39
29
46
35
25
4-Cl
2-NHCOMe
4-NHCOMe
4-Me
4-OMe
H
9
10
11
12
13
14
15
16
17
H
H
4-NO2
4-CN
4-Cl
4-Me
4-OMe
H
H
4-OMe
a
All reactions were carried out for 4e12 h using ArNO (1 mmol) and ArC^CH
(12 mmol) with 6 equiv of K2CO3 and 6 equiv of Me2SO4 in 50 mL of toluene at 80 ꢀ
under nitrogen.
C
b
Isolated yields after chromatography.
afforded in good yields by using the base and the alkylating/acyl-
ating agent in a 6-fold excess (Scheme 3 and Table 2).
Using propiolates as the acetylenic component in reactions with
different nitrosoarenes the same regioselectivity was observed
Scheme 2. Synthesis of 3-aryl-substituted N-Methoxyindoles.
The electronic properties of the Ygroup on the arylacetylenes do
not have a dramatic effect on the efficiency of the reaction, al-
though kinetic studies provide some evidence that electron do-
nating groups were found to accelerate the cyclization.30
This synthetic route to indoles shows the formation of new CeN
and CeC bonds through the activation of an aromatic CeH bond. To
possibly extend the substrate scope and for mechanistic purposes
pentafluoronitrosobenzene (C6F5NO) was studied in a standard
reaction with phenylacetylene heating at 80 ꢀC in toluene. After
16 h only starting materials were recovered.
Several electrophiles (PG-X) reacted efficiently with the in-
termediate N-hydroxyindoles trapping them and giving the final
products 4aeh. The most reactive nitrosoarenes with EWG in para
position were used with the aim to generalize the multi-
component synthetic approach to NeO-protected hydroxyindoles
4aeh. Different protecting groups were found to be compatible
with the basic reaction conditions. All the compounds were
Scheme 3. Synthesis of 3-phenyl-substituted NeO-protected indoles.
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4
G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
Table 2
gave the target molecule 7 in 91% yield (Scheme 5) (overall yield
from 1a¼34%).
Reactions between nitrosoarenes and phenylacetylene in the presence of different
electrophilesa
Entry
Product
X
PG-X
Yieldb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-NO2
4-CN
Boc2O
PhCH2Br
ClCO2Et
Cbz-Cl
CH2]CHeCH2Br
TsCl
65
77
61
53
86
32
44
38
4g
4h
CH2]CHeCH2Br
PhCOCl
4-CN
Scheme 5. Synthesis of a representative b-carboline (7).
a
All reactions were carried out for 5e8 h using ArNO (1 mmol) and PhC^CH
(12 mmol) with 6 equiv of K2CO3 and 6 equiv of PG-X in 50 mL of toluene at 80 ꢀ
under nitrogen.
C
The serendipitous formation of polycyclic derivatives via the
intermediate formation of an indoline nitrone was also detected
and studied further. The reaction passes through the cyclization of
the nitrone via a 1,3-dipolar cycloaddition affording an unstable
isoxazoline derivative that is converted to the acylaziridine prod-
uct. During our survey of the nitrosoarene/alkyne annulation re-
actions we isolated an unexpected tricyclic byproduct from the
reaction between phenylacetylene and o-carbomethoxy nitro-
sobenzene (1g) that shed some light on the mechanism of the cy-
cloaddition. This polycyclic compound was detected, isolated and
characterized by X-ray diffraction as the major product.28 The re-
action was first carried out under standard alkylating conditions
and afforded the N-hydroxyindole 8a in 64% yield with only traces
of the corresponding N-methoxyindole 8b (Scheme 6). The alkyl-
ation may be inhibited by the formation of a hydrogen bond be-
tween the NeOH group and the carbonyl of the ester group in
position 7. In contrast to previous experiments, repeating the re-
action without an alkylating agent for a longer reaction time.
Compound 9f was produced as the major isolated product, (57%),
whose NMR and mass spectra indicated the incorporation of two
phenylacetylene units and one nitrosoarene moiety.
b
Isolated yields after chromatography.
with formation of NeO-protected-hydroxy-3-carboxyindoles being
formed exclusively. In this way a phytoalexin analogue from Wasabi
was previously prepared in few steps in good overall yield,29 in-
troducing an interesting shortcut to this target molecule. The base-
promoted multi-component reactions between methyl propiolate,
different electrophiles and various nitrosoarenes also led us to
produce indole compounds 6aee in good yields (Scheme 4 and
Table 3).
The phenylacetylene units in 9 are incorporated in a tail-to-tail
fashion C-2, C-2, (Scheme 7) and the carbomethoxy group has
migrated from the aromatic carbon to C-1 of an alkyne unit. Al-
though the tricyclic structure of 9 was surprising, a literature search
into the skeleton revealed other examples and suggested a pathway
for its formation. Analogues of 9 have been obtained from the re-
actions of indoline nitrones with alkynes, which proceed via di-
polar cycloaddition followed by electrocyclic rearrangement of the
intermediate isoxazole. A recent substrate survey of o-carbome-
thoxy-nitrosobenzene and 2,5-dicarbomethoxy-nitrosobenzene
with different arylacetylenes (Scheme 8 and Table 4) led us to ob-
Scheme 4. Synthesis of 3-carbomethoxy-substituted NeO-protected indoles.
Table 3
The reactions between nitrosoarenes and methyl propiolate in the presence of dif-
ferent electrophilesa
tain an isoxazoline intermediate derivative that is rapidly converted
Entry
Product
X
PG-X
Yieldb (%)
37
€
to acylaziridine product as described by Dopp and other groups.
1
2
3
4
5
6a
6b
6c
6d
6e
4-NO2
4-NO2
4-NO2
4-CN
ClCO2Et
TsCl
CbzCl
Me2SO4
PhCOCl
73
57
60
43
56
The structure of 9f was definitely established by X-ray diffraction
(Fig. 2) and possesses a 6,5,3-tricyclic skeleton with an aziridine
ring fused to an indoline core. An alternative procedure to give
compounds with acylaziridine indoline skeleton was reported by
Molina and co-workers by reaction of o-allylarylazides that gen-
erate a nitrene intermediate via loss of dinitrogen.38 The formation
4-CN
a
All reactions were carried out for 5e8 h using ArNO (1 mmol) and PhC^CH
(12 mmol) with 6 equiv of K2CO3 and 6 equiv of PG-X in 50 mL of toluene at 80 ꢀ
under nitrogen.
C
of
9 from the reaction between ortho-carbomethoxy nitro-
b
Isolated yields by chromatography.
sobenzene and phenylacetylene, therefore, suggests the in-
termediacy of a nitrone (Scheme 8). The intermediacy of an
indoline nitrone is implicated from the reaction with o-carbome-
thoxy-nitrosobenzene and arylacetylenes affording tricyclic com-
pounds, likely derived from trapping of an indoline nitrone with
a second molecule of arylacetylene to generate an oxazoline that
subsequently rearranges to afford acylaziridine indolines.
This species, in turn, may be derived from migratory rear-
rangement of a non-aromatic precursor, such as diradical A or
nitrone E. Working with a dicarbomethoxy substituted nitro-
soarene it was possible to isolate both of the diastereoisomers with
the aziridineindoline skeleton ring. The two diastereoisomers were
b
-Carboline alkaloids, widespread in plants and animals, have
been extensively studied and are well known for their biological
activity as monoamine oxidase inhibitors (MAOI).35 Some
-car-
bolines, notably tryptoline and pinoline, are formed naturally in
the human body. The latter is implicated along with melatonin in
the role of the pineal gland in regulating the sleep-wake cycle.36
We envisioned the opportunity to prepare N-methoxy-b-carbo-
lines by ring closure through a BischlereNapieralski type re-
action. Thus, treatment of the indole derivative 3e with POCl3
b
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G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
5
Scheme 6. Reaction between o-carbomethoxy-nitrosobenzene and phenylacetylene.
Table 4
Reactions between o-carbomethoxy- and 2,5-dicarbomethoxy-nitrosobenzene with
different arylacetylenesa
Entry
Product
X
Ar
Yieldb (%)
1
2
3
4
5
6
7
9a
9b
9c
9d
H
H
H
H
C6H5
57
60
48
56
4-NO2eC6H4
4-CNeC6H4
4-CleC6H4
4-MeOeC6H4
C6H5
9e
H
64
9fþ9g
CO2Me
CO2Me
52 (59/41 cis/trans)
44
9h
4-NO2eC6H4
a
All reactions were carried out for 4e8 h using ArNO (1 mmol) and PhC^CH
(12 mmol) in 50 mL of toluene at 80 ꢀC under nitrogen.
b
Isolated yields after chromatography.
Scheme 7. Reactions between o-carbomethoxy- and 2,5-dicarbomethoxynitrosoarene
and arylacetylenes.
Scheme 8. Proposed mechanism for the formation of compounds 9.
characterized and distinguished by coupling constants of the pro-
tons on the aziridine ring in 1H NMR (3Jcis¼7.0 Hz and 3Jtrans¼5.2 Hz)
(Scheme 7). One of these two diastereoisomers, 9f, was character-
ized by X-ray diffraction and the structure is shown in Fig. 2.
As already stated, computational methods together with kinetic
experiments led us to propose a mechanism that shows the in-
termediacy formation of a radical species that rapidly converts to
an indoline nitrone (Scheme 8).30
This last reaction works only when using ortho-carbomethoxy-
nitrosoarene with many different arylalkynes. Examination of the
reaction by 1H NMR showed that the five-membered pyrrole ring
temporarily loses aromaticity, as evidenced by the shift of the
CO2Me group.
To expand the substrate scope we studied this indolization
procedure with new substrates like 1-bromo-2-phenylacetylene39
and p-tosylacetylene. Three nitrosoarenes with different electronic
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6
G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
The electronic properties of the substituent on the nitro-
soaromatic seem to play a dramatic role driving the reaction to the
formation of the indole compound or to the -ketoamide product.
a
2-Bromoindoles are interesting scaffolds that can be further func-
tionalized by SuzukieMiyaura type reaction with boronic acids.41
Very recently, de Koning used this strategy for the synthesis of
indolizine alkaloids42 and other research groups has produced in-
dole analogues that inhibit tubulin polymerization.43
Evaluating another conjugated alkyne with the potential for
subsequent further functionalization of the indole product we
chose p-tosylacetylene to study its reaction with p-nitro-nitro-
sobenzene. Running the reaction without alkylative conditions led
to the isolation of 5-nitro-3-tosylindole 14 in 31% yield (Scheme 10,
path (a)). Studying the mass balance of the reaction we detected
that most of 4-nitronitrosobenzene was converted to the corre-
sponding azoxyarene; no traces of other byproducts were detected
and unconverted p-tosylacetylene was recovered. The reaction
under alkylating conditions showed the formation of a different
adduct, the compound 15 in 25% yield with two tosyl groups
(Scheme 10, path (b)). The characterization of compound 15 by 1H-
and 13C NMR initially did not lead us to an unambiguous structural
assignment. However, X-ray diffraction analysis of 15 (Fig. 4)
identified its structure as N-Tosyl-3-tosyl-5-nitroindole resulting
from loss of an ethyne molecule. Future studies will be carried out
to clarify the mechanism of the reaction that produces 15.
Fig. 2. ORTEP drawing of 9f, with partial labelling scheme. Thermal ellipsoids drawn at
the 50% probability levelꢀ. Hydrogen atoms were given arbitrary radii. Selected bond
ꢁ
distances (A) and angles ( ): N1eC2 1.439(2), N1eC9 1.491(2), N1eC10 1.491(2), C8eC9
1.537(3), C10eC11 1.506(3), C11eO1 1.211(2), C2eN1eC9 103.8(2), C2eN1eC10
113.8(2), C9eN1eC10 59.8(1).
properties, 4-nitronitrosobenzene, nitrosobenzene and 4-metho
xynitrosobenzene, were selected for reaction with 1-bromo-2-
phenylacetylene. 2-Bromo-3-phenylindole derivatives, 11a (45%)
and 11b (51%) were obtained as the major products from 4-
nitronitrosobenzene and nitrosobenzene, respectively. The product
11a was fully characterized and the X-ray diffraction structure is
It is noteworthy that a mixture of the diastereoisomers Z-dito-
sylethene 16a and E-ditosylethene 16b was obtained as a remark-
able dimerization product of p-tosylacetylene with the loss of and
ethyne fragment. These kinds of byproducts were afforded only by
using the addition of a base. A previous paper on the preparation of
16a and 16b was reported by Carpino and co-workers.44
given in Fig. 3. Unusual side products 12b and 12c with a a-ketoa-
An interesting class of target molecules can be prepared using
ethynylpyridines as reactants. The reactions were not carried out
under alkylative or acylative conditions to avoid the obvious for-
mation of pyridinium salts. One of the three 3-pyridinylindole
products, compound 18c obtained by the reaction with 4-
ethynylpyridine is an analogue of a molecule that is under in-
vestigation for its activity as a Rho-kinase inhibitor45 and an inosine
monophosphate dehydrogenase inhibitor.46 In all three cases the
planned products were obtained in moderate to good yields with
the primary formation of the corresponding indoles or N-hydrox-
yindoles (18a, 39%; 18b, 46%; and 18c, 57%) (Scheme 11).
Non-proteinogenic indole aminoacids were also produced by
the annulation of nitrosoarenes with alkynes. Unnatural amino
acids are of interest for their widespread and enormous applica-
tions and several recent patents were published on their uses.47
These aminoacids are deeply and frequently investigated in order
to expand the chemical properties available in native enzymes
through engineering t-RNA techniques. Unnatural aminoacids may
be introduced to enhance and expand the chemical and biological
properties in enzymes. Some changes in the primary structures can
generate and modify different aspects as the acidity, the nucleo-
mide fragment were isolated from the reactions between 1-bromo-
2-phenylacetylene and nitrosobenzene and 4-methoxynitro
sobenzene (Scheme 9). With p-methoxy-nitrosobenzene the che-
moselective formation of the a-ketoamide product 12c in 62% yield
occurs without any trace of indole product 11c. The reactions
leading to products 12b and 12c will be studied further to gain
mechanistic insights into their mode of formation. In a previous
report by Jiao the same
a-ketoamide compounds and analogues
were prepared by copper-catalyzed oxidative amidationediketoni-
zation of terminal alkynes.40 Conversely, no traces of 12a were
detected in the reaction between 4-nitronitrosbenzene and 1-
bromo-2-phenylacetylene.
philicity, the H-bonding potential, etc.
a-Aminoacids with
substituted aromatic ring are particularly interesting because they
provide valuable tools in the developments of highly selective li-
gands since aromatic residues play a relevant role in molecular
recognition processes.48
Following a literature procedure49 a more complicated and
variously substituted terminal aromatic alkyne was obtained from
phenylalanine through a multi-step synthetic strategy (Scheme 12).
A selective iodination in para position by iodine/KIO3 of Phe was
carried out following protection of the COOH group as a methyl
ester and of the amino group as a Boc amide.49a Then a Sonogashira
reaction and cleavage of the trimethysilyl moiety by treatment with
TBAF in THF led us to isolate the substrate 23.49b The procedure
provided the starting material on a large scale (5e10 g).
Fig. 3. ORTEP drawing of the adduct 11a, with partial labelling scheme. Thermal el-
lipsoids drawn at the 50% probability level.ꢀHydrogen atoms were given arbitrary radii.
ꢁ
Significant bond distances (A) and angles ( ): N1eC2 1.358(5), C2eC7 1.407(5), C7eC8
1.438(6), C8eC9 1.367(5), C9eN1 1.364(6), C9eBr 1.856(5), N1eC9eBr 117.9(3),
C8eC9eBr 130.8(4).
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G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
7
Scheme 9. Reactions between p-substituted nitrosoarenes and 1-bromo-2-phenylacetylene.
Scheme 10. Reactions between p-nitro-nitrosobenzene and p-tosylacetylene.
indole compounds 24a, 24b and 24c in 55%, 47% and 50% yield,
respectively. Related compounds of this series of unnatural ami-
noacids were previously prepared by Ortar and co-authors by an
efficient synthesis using Stille cross-coupling reaction with stan-
nylated phenylalanines (4-trimethylstannylphenylalanines) as
starting materials.50 The products isolated by this procedure could
be driven into amphiphilic environments.
3. Conclusions
A simple, efficient, highly regioselective, atom economical and
one-pot method to prepare 3-substituted-N-hydroxyindole- and
indole-derivatives via cycloaddition of nitrosoarenes with alkynes
has been developed. Different protecting groups were used to fa-
cilitate the isolation of generally unstable and elusive NeO-pro-
tected hydroxyindoles by using a multi-component version. N-
hydroxyindoles and N-methoxyindoles were afforded in good yields
using conjugated alkynes (arylacetylenes and propiolates) in a sub-
strate survey showing a general validity of the synthetic protocol. An
unexpected synthesis of tricyclic aziridino-indolines from o-carbo-
methoxy-nitrosobenzene was discovered via the intermediacy of
a nitrone that reacts with another molecule of alkyne. A natural
expansion of the alkyne substrate scope was studied by reaction of
nitrosoaromatics with 2-, 3- and 4-ethynylpyridine. An interesting
synthetic application of the annulation of nitrosoaromatics with
alkynes was tested in the synthesis of unnatural indole-derived
aminoacids. Furthermore functionalizable indoles were achieved
by using ethynyl-p-tolyl sulfone and 1-bromo-2-phenylacetlene.
Some aspects on the reaction mechanism are currently under in-
vestigation and particularly the electronic properties of the sub-
stituents on the nitrosoarene ring will be investigated. Future
evaluations will be carried out through electrochemical experi-
ments like cyclic voltammetry analyses and other techniques.
Fig. 4. ORTEP drawing of the adduct 15, with partial labelling scheme. Thermal el-
lipsoids drawn at the 50% probability level.ꢀHydrogen atoms were given arbitrary radii.
ꢁ
Significant bond distances (A) and angles ( ): N1eC2 1.376(6), C2eC3 1.358(7), C3eC4
1.447(7), C4eC9 1.406(7), C9eN 1.399(6), N1eS1 1.703(4), C3eS2 1.736(5), C2eN1eS1
124.1(3), C2eC3eS2 125.0(4).
Scheme
11. Reactions
between
p-nitro-nitrosobenzene
and
substituted
ethynylpyridines.
4. Experimental
4.1. General
Cycloaddition reactions of 23 with different nitrosoarenes were
carried out and produced indole derivatives containing the phe-
nylalanine unit as the major products (Scheme 13). The reactions
were conducted without alkylating conditions and afforded the
All substituted anilines, nitrosobenzene (1e), methyl propiolate
(5), phenylacetylene (2g), 4-ethynyltoluene (2h), ethynyl p-tolyl
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8
G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
Scheme 12. Preparation of a terminal aromatic alkyne starting from phenylalanine.
164.9, 161.7, 134.8, 134.0, 133.3, 130.0, 113.5, 53.4, 52.9. MS (CI): m/z
224. IR (KBr, cmꢁ1): 2959, 1722, 1435, 1288, 758. Elemental Analy-
sis: calcd C, 53.82; H, 4.06; N, 6.28; found C, 53.66; H, 4.09; N, 6.18.
4.3. Preparation of alkynes
1-Ethynyl-4-nitrobenzene52 (2a), 4-ethynylbenzonitrile53 (2b),
1-ethynyl-4-bromobenzene54 (2c), 1-chloro-4-ethynylbenzene55
(2d), 2-ethynylacetanilide56 (2e), 4-ethynylacetanilide57 (2f), 4-
ethynyl-1-methoxybenzene58 (2i) were prepared by Sonogashira-
type reaction starting from the corresponding commercially avail-
able substituted haloarene (bromo- or iodoarene) following the
procedure reported in literature. Compounds 10,59 17a,60 17b,60
17c,61 2349 were prepared as previously reported.
Scheme 13. Synthesis of indole derivatives containing the phenylalanine framework.
sulfone (13), phenylalanine (19), K2CO3, Me2SO4, Boc2O, PhCH2Br,
Cbz-Cl, allyl bromide, benzoyl chloride, tosyl chloride, ClCO2Et were
commercially available and were purchased from SigmaeAldrich
Chemical Co. and used directly. Distilled solvents were used for all
the reactions. NMR spectra were obtained using the Bruker Avance
400 MHz spectrometer. Positive mode chemical ionization (CI)
mass spectra (using isobutane as a reagent gas) were obtained by
VG 7070 EQ mass spectrometer. GCeMS analyses were run on
Shimadzu GCeMS-QP5000. IR spectra were obtained using the
Nicolet Magna-IR Spectrometer 550. Before elemental analyses, all
samples were kept under vacuum (<1 mbar) at rt for 8e10 h. El-
emental analyses were performed on a Perkin Elmer Series II CHNS/
O Analyzer 2400. Uncorrected melting points were measured with
4.3.1. Representative synthesis of indole compounds 3aeq, 8a,b,
15. A mixture containing nitrosoarene (1.0 mmol), alkyne
(12.0 mmol), K2CO3 (828 mg, 6.0 mmol) and Me2SO4 (570
mL,
6.0 mmol) in 80 mL of dry toluene was stirred at 80 ꢀC for 4e12 h
under nitrogen. After cooling to rt, the mixture was filtered and the
filtrate was concentrated by rotary evaporation. Flash chromatog-
raphy of the residue over silica gel afforded the indole derivatives.
Spectroscopic data are reported below.
4.3.2. Representative synthesis of indole compounds 4aeh, 6aee. A
mixture containing nitrosoarene (1.0 mmol), alkyne (12.0 mmol),
K2CO3 (828 mg, 6.0 mmol) and protecting group precursor
(6.0 mmol) in 80 mL of dry toluene was stirred at 80 ꢀC for 5e8 h
under nitrogen. After cooling to rt, the mixture was filtered and the
filtrate was concentrated by rotary evaporation. Flash chromatog-
raphy of the residue over silica gel afforded the indole derivatives.
Spectroscopic data are reported below.
€
a Buchi 535. Solid products were achieved by recrystallization using
CH2Cl2/hexane.
4.2. Preparation of nitrosoarenes
4-Nitro-nitrosobenzene31 (1a), 4-cyano-nitrosobenzene31 (1b),
4-bromo-nitrosobenzene51 (1c), 4-methoxy-nitrosobenzene51
(1f) and 2-(carbomethoxy)-nitrosobenzene51 (1g) were prepared
as reported in the literature.
4.3.3. Representative synthesis of indoline compounds 9aeh and of
indole compounds 11a,b, 14, 18aec, 24aec. A mixture containing
nitrosoarene (1.0 mmol), alkyne (12.0 mmol) in 80 mL of dry tol-
uene was stirred at 80 ꢀC for 4e8 h under nitrogen. After cooling to
rt, the mixture was filtered and the filtrate was concentrated by
rotary evaporation. Flash chromatography of the residue over silica
gel afforded the indole derivatives. Spectroscopic data are reported
below.
4.2.1. Nitroso-terephthalic acid dimethyl ester (1d). The synthetic
approach to 1d reported here is a slight modification of a literature
procedure using the oxidation of anilines with H2O2 and sodium
tungstate.51 To a solution of 2-aminoterephthalic acid dimethyl
ester (2.09 g, 10.0 mmol) in ethanol (20 mL), sodium tungstate
dihydrate (1.0 g, 3.4 mmol), phosphoric acid (1 mL of a 85% solu-
tion) and H2O2 (10 mL of a 30% solution) were added. The mixture
was heated at 65 ꢀC until TLC (CH2Cl2/AcOEt¼80:20) showed
complete consumption of the aniline. The reaction mixture was
then cooled to rt and the solid precipitate was isolated by filtration,
giving nitroso-terephthalic acid dimethyl ester as a pale yellow
solid (1.77 g, 7.9 mmol, 79% yield), mp 130 ꢀC.
4.3.3.1. 1-Methoxy-5-nitro-3-(4-nitrophenyl)-1H-indole
(3a). Reaction time: 4 h. Flash chromatography (hexaneeethyl
acetate¼75:25). Yellow prism, mp 216e218 ꢀC, yield¼91%, (286 mg,
0.91 mmol). 1H NMR (CDCl3, 400 MHz):
d
¼8.87 (d, 1H, J¼1.5 Hz,
H4), 8.37 (d, 2H, J¼8.6 Hz, H30 and H50), 8.28 (dd, 1H, 3J¼9.0 Hz,
4J¼1.5 Hz, H6), 7.80 (d, 2H, J¼8.6 Hz, H20 and H60), 7.76 (s, 1H, H2),
7.61 (d, 1H, J¼9.0 Hz, H7), 4.26 (s, 3H, NeOMe). 13C NMR (CDCl3,
1H NMR (400 MHz, CDCl3):
d
¼8.41 (dd, 1H, 3J¼7.9 Hz, 4J¼1.6 Hz,
100 MHz):
d
¼143.2, 140.0, 135.0, 130.9, 128.8, 127.7, 124.6, 124.4,
H5), 7.98 (d, 1H, J¼7.9 Hz, H6), 7.44 (d, 1H, J¼1.6 Hz, H3), 4.08 (s, 3H,
120.8, 119.0, 117.3, 109.0, 67.0. IR (KBr, cmꢁ1):
n
¼2962, 1727, 1598,
CO2Me), 3.99 (s, 3H, CO2Me). 13C NMR (100 MHz, CDCl3):
d
¼167.1,
1512, 1337, 1261, 1095, 1020, 800 cmꢁ1. MS (CI): m/z: 314 [Mþ1].
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G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
9
Elemental analyses for C15H11N3O5: calcd (%) C 57.51, H 3.54, N
13.41, found (%): C 57.32, H 3.43, N 13.17.
7.62 (d, 2H, J¼8.6 Hz, H30 and H50), 4.18 (s, 3H, NeOMe), 2.09 (s, 3H,
NHC(O)Me). 13C NMR (100 MHz, DMSO-d6):
d¼169.2, 142.6, 139.1,
135.1, 128.3, 127.9, 125.4, 121.1, 120.4, 118.6, 117.7, 115.8, 109.9, 67.6,
4.3.3.2. 4-(1-Methoxy-5-nitro-1H-indol-3-yl)benzonitrile
24.9. IR (film, cmꢁ1):
n
¼3280, 2928, 2855, 1661, 1578, 1520, 1443,
(3b). Reaction time:
4
h. Flash chromatography (hexane/
1376, 1328, 1302, 1064, 759 cmꢁ1. MS (CI): m/z: 326 [Mþ1]. Ele-
mental analyses for C17H15N3O4: calcd (%) C 62.76, H 4.65, N 12.92,
found (%): C 63.04, H 4.78, N 13.01.
EtOAc¼70:30, Rf¼0.35). Light brown prism, mp 166e168 ꢀC,
yield¼82%, (241 mg, 0.82 mmol). 1H NMR (400 MHz, CDCl3):
d
¼8.88 (d,1H, J¼2.0 Hz, H4), 8.38 (d, 2H, J¼8.7 Hz, H30 and H50), 8.28
4
(dd, 1H, 3J¼8.9 Hz, J¼2.0 Hz, H6), 7.80 (d, 2H, J¼8.7 Hz, H20 and
4.3.3.7. 1-Methoxy-5-nitro-3-p-tolyl-1H-indole
(3g). Reaction
H60), 7.76 (s, 1H, H2), 7.61 (d, 1H, J¼8.9 Hz, H7), 3.98 (s, 3H, NeOMe).
time: 4 h. Flash chromatography (hexane/EtOAc¼90:10). Orange
13C NMR (CDCl3,100 MHz):
d¼138.7,133.0, 130.9,129.9,128.8,127.8,
prism, mp 98e100 ꢀC, yield¼48%, (136 mg, 0.48 mmol). 1H NMR
126.1, 124.4, 124.1, 123.9, 119.0, 117.3, 109.0, 67.0. IR (KBr, cmꢁ1):
(400 MHz, CDCl3):
d
¼8.84 (d, 1H, J¼2.1 Hz, H4), 8.21 (dd, 1H,
n
¼2925, 2854, 2227, 1728, 1599, 1520, 1466, 1336, 1111, 1072,
3J¼9.0 Hz, 4J¼2.1 Hz, H6), 7.56 (s, 1H, H2), 7.53 (d, 1H, J¼9.0 Hz, H7),
7.51 (d, 2H, J¼7.9 Hz, H20 and H60), 7.31 (d, 2H, J¼7.9 Hz, H30 and
H50), 4.20 (s, 3H, NeOMe), 2.44 (s, 3H, Me). 13C NMR (100 MHz,
CDCl3): 142.4, 137.0, 134.7, 130.1, 129.8, 127.6, 122.6, 121.4, 118.3,
850 cmꢁ1. MS (CI): m/z: 294 [Mþ1]. Elemental analyses for
C
16H11N3O3: calcd (%) C 65.53, H 3.78, N 14.33, found (%): C 65.32, H
3.84, N 14.12.
117.9, 116.8, 108.4, 66.6, 21.2. IR (KBr, cmꢁ1):
n¼2921, 1606, 1518,
4.3.3.3. 3-(4-Bromophenyl)-1-methoxy-5-nitro-1H-indole
1467, 1331, 1310, 1064, 811, 737 cmꢁ1. MS (CI): m/z: 283 [Mþ1].
Elemental analyses for C16H14N2O3: calcd (%) C 68.07, H 5.00, N 9.92,
found (%): C 67.84, H 4.81, N 9.98.
(3c). Reaction time:
5
h. Flash chromatography (CH2Cl2/
hexane¼40:60). Light brown prism, mp 193e195 ꢀC, yield¼77%,
(267 mg, 0.77 mmol). 1H NMR (400 MHz, CDCl3):
d
¼8.81 (s, 1H, H4),
8.24 (d, 1H, J¼9.1 Hz, H6), 7.64 (d, 2H, J¼8.0 Hz, H30 and H50), 7.59 (s,
4.3.3.8. 1-Methoxy-3-(4-methoxyphenyl)-5-nitro-1H-indole
1H, H2), 7.55 (d, 1H, J¼9.1 Hz, H7), 7.50 (d, 2H, J¼8.0 Hz, H20 and
(3h). Reaction time:
4 h. Flash chromatography (toluene/
H60), 4.22 (s, 3H, NeOMe). 13C NMR (100 MHz, CDCl3):
d¼143.1,
hexane¼80:20). Yellow needle, mp 142e144 ꢀC, yield¼76%,
135.3, 132.7, 132.5, 129.6, 123.4, 121.6, 121.5, 119.0, 117.9, 116.0, 109.0,
(226 mg, 0.76 mmol). 1H NMR (400 MHz, CDCl3):
d¼8.68 (d, 1H,
67.1. IR (KBr, cmꢁ1):
n
¼2941, 1517, 1466, 1327, 1301, 1061, 833,
J¼2.1 Hz, H4), 8.25 (s, 1H, H2), 8.15 (dd, 1H, 3J¼9.0 Hz, 4J¼2.1 Hz,
H6), 7.73 (d, 1H, J¼9.0 Hz, H7), 7.68 (d, 2H, J¼8.7 Hz, H20þH60), 7.10
(d, 2H, J¼8.7 Hz, H30þH50), 4.20 (s, 3H, NeOMe), 3.82 (s, 3H, OMe).
797 cmꢁ1. MS (CI): m/z: 348/346 [Mþ1]. Elemental analyses for
C
15H11BrN2O3: calcd (%) C 51.90, H 3.19, N 8.07, found (%): C 52.01, H
3.07, N 8.23.
13C NMR (CDCl3, 100 MHz):
d
¼159.0, 142.4, 134.7, 128.9, 125.5,
122.3, 121.4, 118.3, 117.8, 116.6, 114.6, 108.3, 66.6, 55.4. MS (CI): m/z:
4.3.3.4. 3-(4-Chlorophenyl)-1-methoxy-5-nitro-1H-indole
298 [Mþ1]. IR (KBr, cmꢁ1):
¼2923, 2851, 1612, 1549, 1517, 1465,
n
(3d). Reaction time: 4.5 h. Flash chromatography (CH2Cl2/
hexane¼50:50). Yellow plate, mp 169e170 ꢀC, yield¼67%, (203 mg,
1330, 1248, 1065, 1032, 804, 735 cmꢁ1. Elemental analyses for
C16H14N2O4: calcd (%) C 64.42, H 4.73, N 9.39, found (%): C 64.27, H
0.67 mmol). 1H NMR (CDCl3, 400 MHz):
d
¼8.80 (d, 1H, J¼1.6 Hz,
4.71, N 9.45.
H4), 8.23 (dd, 1H, 3J¼9.0 Hz, 4J¼1.6 Hz, H6), 7.58 (s, 1H, H2),
7.57e7.54 (m, 3H, H30 and H50þH7), 7.48 (d, 2H, J¼8.4 Hz, H20 and
4.3.3.9. 1-Methoxy-3-phenyl-1H-indole-5-carbonitrile
H60), 4.22 (s, 3H, NeOMe). 1H NMR (400 MHz, DMSO-d6):
d¼8.73 (d,
(3i). Reaction time:
7
h. Flash chromatography (hexane/
1H, J¼2.1 Hz, H4), 8.43 (s, 1H, H2), 8.18 (dd, 1H, 3J¼9.0 Hz, 4J¼2.1 Hz,
EtOAc¼90:10). Orange plate, mp 101e103 ꢀC, yield¼57%, (142 mg,
H6), 7.77e7.75 (m, 3H, H30 and H50þH7), 7.58 (d, 2H, J¼8.5 Hz, H20
0.57 mmol). 1H NMR (400 MHz, DMSO-d6):
d¼8.40 (d, 1H, J¼1.2 Hz,
and H60) 4.21 (s, 3H, NeOMe). 13C NMR (100 MHz, CDCl3):
d¼143.1,
H4), 8.31 (s, 1H, H2), 7.74e7.72 (m, 3H, H7 and H20þH60), 7.64 (dd,
1H, 3J¼8.5 Hz, 4J¼2.1 Hz, H6), 7.48 (t, 2H, J¼7.6 Hz, H30þH50), 7.33 (t,
1H, J¼7.4 Hz, H40), 4.18 (s, 3H, NeOMe). 13C NMR (100 MHz, DMSO-
135.2, 133.5, 132.0,129.9,129.4,123.5,121.6, 119.0, 117.9, 116.1, 109.0,
67.1. IR (KBr, cmꢁ1):
n
¼2921, 2851, 1518, 1465, 1327, 1302, 1062, 837,
796 cmꢁ1. MS (CI): m/z: 305/303 [Mþ1 (37Cl/35Cl)]. Elemental
analyses for C15H11ClN2O3: calcd (%) C 59.52, H 3.66, N 9.25, found
(%): C 59.42, H 3.75, N 8.99.
d6):
d
¼134.1, 129.9, 128.0, 127.4, 126.4, 126.2, 125.0, 121.6, 121.1,
114.3, 110.7, 103.8, 67.6. MS (CI): m/z: 249 [Mþ1]. IR (KBr, cmꢁ1):
n
¼2940, 2221, 1604, 1463, 1067, 805, 761 cmꢁ1. Elemental analyses
for C16H12N2O: calcd (%) C 77.40, H 4.87, N 11.28, found (%): C 77.13,
H 4.95, N 11.39.
4.3.3.5. N-(2-(1-Methoxy-5-nitro-1H-indol-3-yl)phenyl)ethana-
mide (3e). Reaction time: 5 h. Flash chromatography (hexane/
EtOAc¼40:60). Yellow prism, mp 78e80 ꢀC, yield¼37%, (121 mg,
4.3.3.10. 5-Bromo-1-methoxy-3-phenyl-1H-indole (3j). Reaction
time: 8 h. Flash chromatography (hexane/EtOAc¼80:20). Yellow
plate, mp 58e60 ꢀC, yield¼47%, (142 mg, 0.47 mmol). 1H NMR
0.37 mmol). 1H NMR (400 MHz, CDCl3):
d
¼8.39 (d, 1H, J¼2.0 Hz,
H4), 8.24 (d, 1H, J¼8.0 Hz, H30), 8.15 (dd, 1H, 3J¼9.0 Hz, 4J¼2.0 Hz,
H6), 7.56 (s, 1H, H2), 7.55 (d, 1H, J¼9.0 Hz, H7), 7.43e7.35 (m, 3H,
H40þH60þNHC(O)Me), 7.24 (t, 1H, J¼8.0 Hz, H50), 4.24 (s, 3H,
NeOMe), 1.99 (s, 3H, NHC(O)Me). 13C NMR (100 MHz, CDCl3):
(400 MHz, DMSO-d6):
d
¼8.13 (s, 1H, H2), 8.00 (d, 1H, J¼1.8 Hz, H4),
7.66 (d, 2H, J¼7.4 Hz, H20þH60), 7.53 (d,1H, J¼8.7 Hz, H7), 7.46 (t, 2H,
J¼7.4 Hz, H30þH50), 7.41 (dd, 1H, 3J¼8.7 Hz, 4J¼1.8 Hz, H6), 7.29 (t,
1H, J¼7.4 Hz, H40), 4.14 (s, 3H, NeOMe). 13C NMR (100 MHz, CDCl3):
d
¼168.9, 142.9, 136.1, 134.9, 131.4, 129.2, 125.2, 125.1, 123.5, 123.1,
122.4, 119.1, 117.8, 112.2, 109.1, 67.3, 24.8. IR (KBr, cmꢁ1):
¼3283,
2924, 2853, 1669, 1582, 1516, 1447, 1372, 1331, 1301, 1064, 751 cmꢁ1
n
d
¼134.6, 131.6, 129.0, 127.9, 126.9, 126.1, 124.1, 123.1, 121.8, 114.3,
.
114.0, 110.4, 66.6. MS (CI): m/z: 304/302 [Mþ1]. IR (KBr, cmꢁ1):
MS (CI): m/z: 326 [Mþ1]. Elemental analyses for C17H15N3O4: calcd
n
¼2935, 1674, 1598, 1488, 1452, 1287, 1249, 1069, 795, 699 cmꢁ1
.
(%) C 62.76, H 4.65, N 12.92, found (%): C 62.57, H 4.53, N 13.08.
Elemental analyses for C15H12BrNO: calcd (%) C 59.62, H 4.00, N,
4.64, found (%): C 59.39, H 4.11, N 4.17.
4.3.3.6. N-(4-(1-Methoxy-5-nitro-1H-indol-3-yl)phenyl)ethana-
mide (3f). Reaction time: 5 h. Flash chromatography (hexane/
EtOAc¼40:60). Yellow oil, yield¼55%, (179 mg, 0.55 mmol). 1H NMR
4.3.3.11. Dimethyl 1-methoxy-3-phenyl-1H-indole-4,7-
dicarboxylate (3k). Reaction time: 7 h. Flash chromatography
(hexane/EtOAc¼85:15). Orange prism, mp 77e79 ꢀC, yield¼62%,
(400 MHz, DMSO-d6):
d
¼10.5 (s, 1H, NHC(O)Me), 8.69 (d, 1H,
J¼2.0 Hz, H4), 8.25 (s, 1H, H2), 8.11 (dd, 1H, 3J¼9.0 Hz, 4J¼2.0 Hz,
(211 mg, 0.62 mmol). 1H NMR (400 MHz, CDCl3):
d
¼7.62 (d, 1H,
H6), 7.73 (d, 2H, J¼8.6 Hz, H20 and H60), 7.69 (d, 1H, J¼9.0 Hz, H7),
J¼7.6 Hz, H5), 7.52 (d, 1H, J¼7.6 Hz, H6), 7.45 (s, 1H, H2), 7.42 (d, 2H,
Please cite this article in press as: Ieronimo, G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.072

10
G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
J¼7.4 Hz, H20þH60), 7.34 (m, 3H, H30þH40þH50), 4.16 (s, 3H,
NeOMe), 4.03 (s, 3H, COOMe), 3.98 (s, 3H, COOMe). 13C NMR
(t, 1H, J¼7.8 Hz, H6), 7.21 (t, 1H, J¼7.8 Hz, H5), 7.03 (d, 2H, J¼8.6 Hz,
H20þH60), 4.13 (s, 3H, NeOMe), 3.89 (s, 3H, OMe). 13C NMR (CDCl3,
(100 MHz, CDCl3):
d
¼168.8, 167.6, 145.3, 141.3, 137.3, 135.9, 128.8,
100 MHz):
d
¼158.2, 132.7, 128.7, 127.4, 122.7, 122.3, 120.4, 120.0,
128.7, 127.0, 125.9, 124.1, 122.0, 119.1, 116.3, 66.8, 53.4, 51.8. MS (CI):
120.0, 114.3, 113.6, 108.5, 65.9, 55.4. MS (CI): m/z: 254 [Mþ1]. IR
m/z: 340 [Mþ1]. IR (KBr, cmꢁ1):
n
¼2948, 1752, 1725, 1434, 1274,
(film, cmꢁ1):
n
¼2933, 2836, 1609, 1548, 1502, 1454, 1244, 1178,
1164, 1139, 746 cmꢁ1. Elemental analyses for C19H17NO5: calcd (%) C
67.25, H 5.05, N 4.13, found (%): C 67.42, H 4.95, N 4.17.
1033, 966, 834, 740 cmꢁ1. Elemental analyses for C16H15NO2: calcd
(%) C 75.87, H 5.97, N 5.53, found (%) C 76.03, H 6.05, N 5.59.
4.3.3.12. 1-Methoxy-3-(4-nitrophenyl)-1H-indole (3l). Reaction
time: 9 h. Flash chromatography (hexane/EtOAc¼75:25). Orange
oil, yield¼41%, (110 mg, 0.41 mmol). 1H NMR (400 MHz, CDCl3):
4.3.3.17. 1,5-Dimethoxy-3-phenyl-1H-indole (3q). Reaction time:
12 h. Flash chromatography (hexane/EtOAc¼90:10). Colourless oil,
yield¼25%, (63 mg, 0.25 mmol). 1H NMR (400 MHz, CDCl3):
¼7.66
d
d
¼8.32 (d, 2H, J¼8.8 Hz, H30þH50), 7.95 (d,1H, J¼8.2 Hz, H4), 7.80 (d,
(d, 2H, J¼7.6 Hz, H20þH60), 7.49 (t, 2H, J¼7.6 Hz, H30þH50), 7.44 (s,
1H, H2), 7.41 (m, 2H, H7þH4), 7.33 (t, 1H, J¼7.6 Hz, H40), 7.01 (d, 1H,
J¼8.9 Hz, H6), 4.15 (s, 3H, NeOMe), 3.90 (s, 3H, OMe). 13C NMR
2H, J¼8.8 Hz, H20þH60), 7.62 (s, 1H, H2), 7.55 (d, 1H, J¼8.2 Hz, H7),
7.38 (m, 1H, H5), 7.29 (m, 1H, H6), 4.20 (s, 3H, NeOMe). 13C NMR
(100 MHz, CDCl3):
d
¼147.9, 133.5, 131.6, 128.4, 126.4, 124.4, 121.8,
(100 MHz, CDCl3):
d
¼155.5, 135.5, 129.3, 129.2, 127.8, 126.5, 123.1,
121.4, 120.0, 119.8, 110.1, 108.2, 66.3. MS (CI): m/z: 269 [Mþ1].
121.6, 113.9, 113.5, 109.9, 102.3, 66.4, 56.4. MS (CI): m/z: 254 [Mþ1].
GCeMS (EI): m/z: 268 [Mþ], 253, 237, 221, 207, 194, 180, 165, 151,
IR (film, cmꢁ1):
n
¼2936, 2832, 1602, 1475, 1441, 1260, 1223, 1174,
139, 132, 111, 102, 82, 76, 63. IR (film, cmꢁ1):
n
¼2935, 2840, 1610,
1109, 1032, 970, 759, 699 cmꢁ1. Elemental analyses for C16H15NO2:
calcd (%) C 75.87, H 5.97, N 5.53, found (%) C 76.01, H 5.72, N 5.64.
1544, 1500, 1451, 1243, 1180, 1033, 836, 750 cmꢁ1. Elemental anal-
yses for C15H12N2O3: calcd (%) C 67.16, H 4.51, N 10.44, found (%): C
67.29, H 4.64, N 10.32.
4.3.3.18. tert-Butyl 5-nitro-3-phenyl-1H-indol-1-yl carbonate
(4a). Reaction time:
5
h. Flash chromatography (hexane/
4. 3. 3.13. 4-(1-Methoxy-1H-indol-3-yl)benzonitrile
(3m). Reaction time: 8.5 h. Flash chromatography (hexane/
EtOAc¼80:20, Rf¼0.32). Yellow brown oil, yield¼39%, (97 mg,
CH2Cl2¼30:70). Orange prism, mp 121e123 ꢀC, yield¼65%, (231 mg,
0.65 mmol). 1H NMR (400 MHz, CDCl3):
d
¼8.85 (d, 1H, J¼2.1 Hz,
H4), 8.23 (dd, 1H, 3J¼9.0 Hz, 4J¼2.1 Hz, H6), 7.63 (d, 2H, J¼7.5 Hz,
H20þH60), 7.53 (s, 1H, H2), 7.50 (t, 2H, J¼7.5 Hz, H30þH50), 7.38 (m,
2H, H7þH40), 1.55 (s, 9H, CMe3). 13C NMR (100 MHz, CDCl3):
0.39 mmol). 1H NMR (400 MHz, CDCl3):
d
¼7.91 (d, 1H, J¼8.0 Hz,
H4), 7.76 (d, 2H, J¼8.5 Hz, H30þH50), 7.72 (d, 2H, J¼8.5 Hz, H20þH60),
7.57 (s, 1H, H2), 7.54 (d, 1H, J¼8.0 Hz, H7), 7.36 (t, 1H, J¼8.0 Hz, H5),
7.26 (d, 1H, J¼8.0 Hz, H6), 4.19 (s, 3H, NeOMe). 13C NMR (CDCl3,
d
¼151.7, 143.4, 136.6, 133.0, 129.5, 128.3, 127.8, 124.8, 122.2, 119.4,
118.1, 117.9, 109.0, 85.6, 27.8. MS (CI): m/z: 355 [Mþ1]. IR (KBr,
100 MHz):
d
¼133.0, 132.6, 128.5, 127.4, 126.3, 123.3, 121.5, 121.4,
cmꢁ1):
n
¼3099, 2973, 1735, 1619, 1522, 1469, 1337, 1070, 751,
119.7, 119.3, 112.0, 110.4, 108.9, 66.3. MS (CI): m/z: 249 [Mþ1]. IR
699 cmꢁ1. Elemental analyses for C19H18N2O5: calcd (%) C 64.40, H
5.12, N 7.91, found (%) C 64.27, H 5.01, N 7.68.
(film, cmꢁ1):
n
¼2918, 2849, 2228, 1740, 1604, 1462, 1260, 1067, 909,
800, 732 cmꢁ1. Elemental analyses for C16H12N2O: calcd (%) C 77.40,
H 4.87, N 11.28, found (%) C 77.61, H 4.85, N 11.09.
4.3.3.19. 1-Benzyloxyl 5-nitro-3-phenyl-1H-indole (4b). Reaction
time: 5 h. Flash chromatography (hexane/CH2Cl2¼30:70). Yellow
plate, mp 104e106 ꢀC, yield¼77%, (266 mg, 0.77 mmol). 1H NMR
4. 3. 3.14. 3-(4-Chlorophenyl)-1-methoxy-1H-indole
(3n). Reaction time: 10 h. Flash chromatography (CH2Cl2/
EtOAc¼80:20, Rf¼0.30). Pale brown oil, yield¼29%, (75 mg,
(400 MHz, DMSO):
d
¼8.69 (d, 1H, J¼2.1 Hz, H4), 8.26 (s, 1H, H2),
8.07 (dd, 1H, 3J¼9.0 Hz, 4J¼2.1 Hz, H6), 7.68 (d, 2H, J¼7.2 Hz,
H20þH60), 7.57 (d, 1H, J¼9.0 Hz, H7), 7.51 (m, 4H, CH2Ph), 7.40 (m,
3H, H30þH40þH50), 7.36 (t, 1H, J¼7.2 Hz, CH2Ph), 5.41 (s, 2H, CH2Ph).
0.29 mmol). 1H NMR (400 MHz, CDCl3):
d¼8.04 (d, 1H, J¼7.8 Hz,
H4), 7.54 (d, 1H, J¼7.8 Hz, H7), 7.46 (s, 1H, H2), 7.50 (d, 2H, J¼8.5 Hz,
H30þH50), 7.38 (d, 2H, J¼8.5 Hz, H20þH60), 7.09 (t, 1H, J¼7.8 Hz, H5),
7.21 (t, 1H, J¼7.8 Hz, H6), 3.81 (s, 3H, NeOMe). 13C NMR (100 MHz,
13C NMR (100 MHz, CDCl3):
d
¼142.4,135.4,133.8,133.1,129.9,129.8,
129.1, 128.9, 127.7, 127.13, 124.1, 121.2, 118.2, 117.6, 116.4, 108.7, 81.2.
CDCl3):
d
¼135.5,133.4,128.9,128.81125.8,122.9,121.6,120.8,120.5,
MS (CI): m/z: 345 [Mþ1]. IR (KBr, cmꢁ1):
¼2919, 1603, 1517, 1332,
n
119.8, 112.7, 108.6, 68.1. MS (CI): m/z: 260/258 [Mþ1 (37Cl/35Cl)]. IR
1288, 1064, 747, 698 cmꢁ1. Elemental analyses for C21H16N2O3:
calcd (%)C, 73.24; H, 4.68; N, 8.13, found (%) C 73.51, H 4.79, N 8.02.
(film, cmꢁ1):
n
¼2933, 2836, 1609, 1549, 1503, 1454, 1244, 1178,
1033, 834, 741 cmꢁ1. Elemental analyses for C15H12ClNO: calcd (%) C
69.91, H 4.69, N 5.43, found (%) C 69.87, H 4.76, N 5.39.
4.3.3.20. Ethyl
5-nitro-3-phenyl-1H-indol-1-yl
carbonate
(4c). Reaction time:
5
h. Flash chromatography (hexane/
4.3.3.15. 1-Methoxy-3-p-tolyl-1H-indole (3o). Reaction time:
8 h. Flash chromatography (hexane/EtOAc¼90:10). Orange oil,
CH2Cl2¼50:50). Orange prism, mp 71e73 ꢀC, yield¼61%, (199 mg,
0.61 mmol). 1H NMR (400 MHz CDCl3):
d
¼8.87 (d, 1H, J¼2.1 Hz, H4),
yield¼46%, (109 mg, 0.46 mmol). 1H NMR (400 MHz, CDCl3):
d
¼7.95
8.25 (dd, 1H, 3J¼9.0 Hz, 4J¼2.1 Hz, H6), 7.64 (d, 2H, J¼7.5 Hz,
H20þH60), 7.53 (m, 3H, H30þH50þH2), 7.42 (m, 2H, H40þH7), 4.51 (q,
2H, J¼7.1.0 Hz, CO2CH2CH3), 1.51 ppm (t, 3H, J¼7.1 Hz, CO2CH2CH3).
(dt, 1H, 3J¼8.0 Hz, J¼0.8 Hz, H4), 7.59 (d, 2H, J¼8.1 Hz, H30þH50),
7.53 (dt, 1H, 3J¼8.0 Hz, 4J¼0.8 Hz, H7), 7.46 (s, 1H, H2), 7.34 (td, 1H,
3J¼8.0 Hz, 4J¼0.8 Hz, H6), 7.31 (d, 2H, J¼8.1 Hz, H20þH60), 7.23 (td,
1H, 3J¼8.0 Hz, 4J¼0.8 Hz, H5), 4.17 (s, 3H, NeOMe), 2.45 (s, 3H, Me).
4
13C NMR (100 MHz, CDCl3):
d
¼153.9, 143.5, 136.7, 132.9, 129.6,
128.3,128.0,124.6,122.4,119.6,118.3,118.1,109.0, 68.1,14.6. MS (CI):
13C NMR (100 MHz, CDCl3):
d
¼136.2, 133.1, 132.4, 129.9, 127.9, 123.1,
m/z: 327 [Mþ1]. IR (KBr, cmꢁ1):
¼3087, 2922, 2852, 1803, 1736,
n
122.7, 120.9, 120.7, 120.6, 114.4, 108.9, 66.3, 21.6. MS (CI): m/z: 238
1606, 1522, 1470, 1339, 1232, 1071, 837, 737, 700 cmꢁ1. Elemental
analyses for C17H14N2O5: calcd (%) C 62.57, H 4.32, N 8.59, found (%)
C 62.68, H 4.44, N 8.64.
[Mþ1]. IR (film, cmꢁ1):
¼2934, 1662, 1549, 1452, 1323, 1256, 1064,
n
967, 824, 740, 686 cmꢁ1. Elemental analyses for C16H15NO: calcd (%)
C 80.98, H 6.37, N 5.90, found (%) C 81.11, H 6.42, N 5.78.
4.3.3.21. Benzyl
5-nitro-3-phenyl-1H-indol-1-yl
carbonate
4.3.3.16. 1-Methoxy-3-(4-methoxyphenyl)-1H-indole
(4d). Reaction time:
5
h. Flash chromatography (hexane/
(3p). Reaction time:
8
h. Flash chromatography (toluene/
CH2Cl2¼50:50). Orange prism, mp 99e101 ꢀC, yield¼53%, (206 mg,
hexane¼60:40). Orange-brown oil, yield¼35%, (89 mg, 0.35 mmol).
0.53 mmol). 1H NMR (400 MHz, CDCl3):
d¼8.86 (d, 1H, J¼2.0 Hz,
1H NMR (400 MHz, CDCl3):
d
¼7.90 (d, 1H, J¼7.8 Hz, H4), 7.59 (d, 2H,
H4), 8.23 (dd, 1H, 3J¼9.0 Hz, 4J¼2.0 Hz, H6), 7.63 (d, 2H, J¼7.2 Hz,
J¼8.6 Hz, H30þH50), 7.51 (d, 1H, J¼7.8 Hz, H7), 7.40 (s, 1H, H2), 7.32
H20þH60), 7.54e7.46 (m, 8H, H2þH30þH50þPh (Cbz group)), 7.41 (t,
Please cite this article in press as: Ieronimo, G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.072

G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
11
1H, J¼7.3 Hz, H40), 7.37 (d, 1H, J¼9.0 Hz, H7), 5.43 (s, 2H, CH2Ph (Cbz
131.1,130.2,129.9,128.1,127.7,126.9,126.7,126.4,126.2,122.3,120.8,
group)). 13C NMR (100 MHz, CDCl3):
d
¼153.9, 143.6, 136.7, 133.7,
115.4, 111.2, 104.6. IR (film, cmꢁ1):
n
¼3064, 2918, 2855, 2228, 1731,
132.8, 130.0, 129.6, 129.4, 129.3, 128.3, 128.0, 124.6, 122.5, 119.6,
1690, 1606, 1520, 1473, 1339, 1260, 1074, 840, 739, 700 cmꢁ1. MS
(CI): m/z: 339 [Mþ1]. Elemental analyses for C22H14N2O2: calcd (%)
C 78.09, H 4.17, N 8.28, found (%) C 77.89, 4.22, N 8.37.
118.4, 118.1, 109.1, 73.4. MS (CI): m/z: 389 [Mþ1]. IR (KBr, cmꢁ1):
n
¼2923, 2853, 1734, 1604, 1521, 1473, 1338, 1262, 1074, 838, 738,
699 cmꢁ1. Elemental analyses for C22H16N2O5: calcd (%) C 68.04, H
4.15, N 7.21, found (%) C 68.23, H 4.28, N 7.05.
4.3.3.26. Methyl 1-(ethoxycarbonyloxy)-5-nitro-1H-indole-3-
carboxylate (6a). Reaction time: 5 h. Flash chromatography (hex-
ane/EtOAc¼80:20). Yellow plate, mp 119e121 ꢀC, yield¼73%,
4.3.3.22. 1-(Allyloxy)-5-nitro-3-phenyl-1H-indole (4e). Reaction
time: 5 h. Flash chromatography (hexane/EtOAc¼70:30). Orange
needles, mp 85e87 ꢀC, yield¼86%, (254 mg, 0.86 mmol). 1H NMR
(226 mg, 0.73 mmol). 1H NMR (400 MHz, CDCl3):
d
¼9.09 (d, 1H,
J¼2.1 Hz, H4), 8.23 (dd, 1H, 3J¼9.1 Hz, 4J¼2.1 Hz, H6), 8.05 (s, 1H,
H2), 7.41 (d, 1H, J¼9.1 Hz, H7), 4.50 (q, 2H, J¼7.1 Hz, CO2CH2CH3),
3.96 (s, 3H, COOMe), 1.47 (t, 3H, J¼7.1 H, CO2CH2CH3). 13C NMR
(400 MHz, CDCl3):
d
¼8.84 (d, 1H, J¼1.9 Hz, H4), 8.18 (dd, 1H,
3J¼8.2 Hz, 4J¼1.9 Hz, H6), 7.61 (d, 2H, J¼8.2 Hz, H20þH60), 7.56 (s,1H,
H2), 7.52e7.48 (m, 3H, H7 and H30þH50), 7.37 (t, 1H, J¼7.4 Hz, H40),
6.15 (m, 1H, CH2CH]CH2), 5.41 (dd, 2H, J¼13.5, 5.2 Hz, CH2CH]
CH2), 4.80 (d, 2H, J¼6.6 Hz, CH2CH]CH2). 13C NMR (100 MHz,
(100 MHz, CDCl3):
d
¼163.9, 153.3, 144.6, 135.8, 132.6, 122.1, 120.0,
119.3, 109.2, 107.5, 68.6, 52.2, 14.5. MS (CI): m/z: 309 [Mþ1]. IR (KBr,
cmꢁ1):
n
¼2955, 1799, 1710, 1524, 1452, 1373, 1343, 1239, 1208, 1096,
CDCl3):
d
¼142.8, 135.9, 135.5, 131.2, 129.6, 128.1, 127.6, 124.5, 123.3,
1013, 953, 808, 743, 624 cmꢁ1. Elemental analyses for C13H12N2O7:
calcd (%) C 50.65, H 3.92, N 9.09, found (%) C 50.49, H 3.98, N 9.11.
121.6, 118.7, 118.1, 116.8, 109.3, 80.4. MS (CI): m/z: 295 [Mþ1]. IR
(KBr, cmꢁ1):
n
¼2930, 1886, 1577, 1518, 1468, 1333, 1288, 1065, 941,
900, 864, 747, 699 cmꢁ1. Elemental analyses for C17H14N2O3: calcd
(%) C 69.38, H 4.79, N 9.52, found (%) C 69.51, H 4.65, N 9.48.
4.3.3.27. Methyl 5-nitro-1-(tosyloxy)-1H-indole-3-carboxylate
(6b). Reaction time:
6
h. Flash chromatography (hexane/
EtOAc¼70:30). Yellow plate, mp 145e147 ꢀC, yield¼57%, (223 mg,
4 . 3 . 3 . 2 3 . 5 - N i t r o - 3 - p h e n y l - 1 H - i n d o l - 1 - y l - 4 -
methylbenzenesulfonate (4f). Reaction time: 5 h. Flash chromatog-
raphy (hexane/EtOAc¼80:20). Brown oil, yield¼32%, (131 mg,
0.57 mmol). 1H NMR (400 MHz, CDCl3):
d¼9.02 (d, 1H, J¼2.2 Hz,
H4), 8.03 (dd, 1H, 3J¼9.1 Hz, 4J¼2.2 Hz, H6), 7.83 (s, 1H, H2), 7.75 (d,
2H, J¼8.3 Hz, H20þH60), 7.38 (d, 2H, J¼8.3 Hz, H30þH50), 7.05 (d, 1H,
J¼9.1 Hz, H7), 3.96 (s, 3H, COOMe), 2.49 (s, 3H, SO2C6H4Me). 13C
0.32 mmol). 1H NMR (400 MHz, CDCl3):
d
¼8.57 (d, 1H, J¼2.4 Hz,
H4), 8.20 (dd, 1H, 3J¼9.1 Hz, 4J¼2.4 Hz, H6), 7.51 (m, 2H, H7þH2),
7.38 (d, 2H, J¼8.3 Hz, H200þH600 (Ts group)), 7.29e7.25 (m, 3H,
H20þH60 and H40), 7.15 (m, 2H, H30þH50), 6.94 (d, 2H, J¼8.3 Hz,
H300þH500 (Ts group)), 2.50 (s, 3H, SO2C6H4eMe). 13C NMR
NMR (100 MHz, CDCl3):
d
¼163.7, 148.8, 144.5, 136.3, 133.2, 131.1,
129.9, 129.2, 122.0, 119.9, 119.1, 109.9, 108.1, 52.3, 22.4. MS (CI): m/z:
391 [Mþ1]. IR (KBr, cmꢁ1):
¼2955, 2924, 2853, 1716, 1623, 1594,
n
1529, 1444, 1402, 1344, 1197, 1181, 1090, 1013, 815, 744, 693 cmꢁ1
.
(100 MHz, CDCl3):
d
¼146.8, 146.2, 145.0, 144.7, 133.8, 130.9, 130.8,
Elemental analyses for C17H14N2O7S: calcd (%) C 52.31, H 3.61, N
7.18, found (%) C 52.45, H 3.75, N 7.21.
130.1, 129.9, 128.9, 128.7, 128.5, 127.0, 124.1, 123.3, 114.0, 21.8. IR
(film, cmꢁ1):
n
¼3064, 2924, 2854, 1760, 1597, 1526,1341, 1258, 1150,
1082, 750, 699 cmꢁ1. MS (CI): m/z: 409 [Mþ1]. Elemental Analysis
for C21H16N2O5S: calcd (%) C 61.76; H, 3.95; N, 6.86, found (%) C
61.88, H 4.04, N 6.99.
4.3.3.28. Methyl 1-(benzyloxycarbonyloxy)-5-nitro-1H-indole-3-
carboxylate (6c). Reaction time: 5 h. Flash chromatography (hex-
ane/EtOAc¼80:20). Yellow oil, yield¼60%, (223 mg, 0.60 mmol). 1H
NMR (400 MHz, DMSO-d6):
d
¼8.86 (d, 1H, J¼2.2 Hz, H4), 8.81 (s, 1H,
4.3.3.24. 1-(Allyloxy)-3-phenyl-1H-indole-5-carbonitrile
H2), 8.20 (dd, 1H, 3J¼8.7 Hz, 4J¼2.2 Hz, H6), 7.80 (d, 1H, J¼8.7 Hz,
(4g). Reaction time:
7
h. Flash chromatography (hexane/
H7), 7.53e7.42 (m, 5H, CH2Ph), 5.46 (s, 2H, CH2Ph), 3.89 (s, 3H,
EtOAc¼90:10). Orange prism, mp 83e85 ꢀC, yield¼44%, (121 mg,
COOMe). 13C NMR (100 MHz, DMSO-d6):
d¼163.9, 153.2, 144.3,
0.44 mmol). 1H NMR (400 MHz, CDCl3):
d
¼8.38 (m, 1H, H4), 8.25 (s,
136.0, 135.0, 134.6,129.9,129.6,128.8, 127.3, 122.0,120.1, 118.1, 111.0,
1H, H2), 7.72 (m, 3H, H7 and H20þH60), 7.63 (dd, 1H, 3J¼8.5 Hz,
73.5, 52.4. MS (CI): m/z: 371 [Mþ1]. IR (film, cmꢁ1):
¼2953, 1803,
n
4J¼1.4 Hz, H6), 7.47 (t, 2H, J¼8.0 Hz, H30þH50), 7.37 (tt, 1H,
1714, 1524, 1452, 1376, 1340, 1234, 1205, 1096, 1020, 959, 806 cmꢁ1
.
3
3J¼7.4 Hz, 4J¼1.2 Hz, H40), 6.20 (m, 1H, CH2CH]CH2), 5.40 (dd, 2H,
J¼17.1, 1.2 Hz, CH2CH]CH2), 5.33 (dd, 2H, J¼10.2, 1.2 Hz, CH2CH]
CH2), 4.87 (d, 2H, J¼6.6 Hz, CH2CH]CH2). 1H NMR (400 MHz,
Elemental analyses for C18H14N2O7: calcd (%) C 58.38, H 3.81, N 7.56,
found (%) C 58.51, H 3.90, N 7.63.
DMSO-d6):
d
¼8.38 (d, 1H, J¼1.4 Hz), 8.26 (s, 1H), 7.74e7.71 (m, 3H),
4.3.3.29. Methyl 5-cyano-1-methoxy-1H-indole-3-carboxylate
7.63 (dd,1H, 3J¼8.5 Hz, 4J¼1.4 Hz), 7.48 (tt, 2H, 3J¼7.7 Hz, 4J¼1.6 Hz),
7.33 (tt, 1H, 3J¼7.7 Hz, 4J¼1.6 Hz), 6.19 (m, 1H), 5.39 (dq, 1H, J¼17.1,
1.3 Hz), 5.33 (dq, 1H, J¼10.3, 1.0 Hz), 4.88 (dt, 2H, 3J¼6.6 Hz,
(6d). Reaction time:
7
h. Flash chromatography (hexane/
EtOAc¼70:30). Yellow oil, yield¼43%, (99 mg, 0.43 mmol). 1H NMR
(400 MHz, DMSO-d6):
d
¼8.73 (s, 1H, H2), 8.42 (d, 1H, J¼1.0 Hz, H4),
4J¼1.0 Hz). 13C NMR (100 MHz, CDCl3):
d
¼134.8, 133.8, 131.3, 129.5,
7.79 (d, 1H, J¼8.5 Hz, H7), 7.71 (dd, 1H, 3J¼8.5 Hz, 4J¼1.0 Hz, H6),
128.1, 127.4, 126.3, 125.8, 123.8, 123.1, 122.1, 120.9, 115.1, 110.1, 104.1,
4.19 (s, 3H, NeOMe), 3.86 (s, 3H, COOMe). 13C NMR (100 MHz,
80.2. MS (CI): m/z: 275 [Mþ1]. IR (KBr, cmꢁ1):
n
¼2924, 2216, 1867,
CDCl3):
d
¼164.4, 133.8, 130.7, 128.0, 126.8, 122.6, 120.2, 110.1, 106.3,
1606, 1544, 1469, 1371, 1207, 1069, 945, 800, 694 cmꢁ1. Elemental
analyses for C18H14N2O: calcd (%) C 78.81, H 5.14, N 10.21, found (%)
C 78.73, H 5.09, N 9.98.
105.1, 67.6, 51.9. MS (CI): m/z: 231 [Mþ1]. IR (film, cmꢁ1):
¼2954,
n
2850, 2229, 1769, 1707, 1601, 1523, 1454, 1372, 1242, 1212, 1123,
1096, 1021, 988, 803, 766, 689 cmꢁ1. Elemental analyses for
C12H10N2O3: calcd (%) C 62.60, H 4.38, N 12.17, found (%) C 62.77, H
4.3.3.25. 1-(Benzoyloxy)-5-cyano-3-phenyl-1H-indole
4.43, N 12.31.
(4h). Reaction time:
8
h. Flash chromatography (hexane/
EtOAc¼90:10). Orange oil, yield¼38%, (129 mg, 0.38 mmol). 1H
4.3.3.30. Methyl 5-cyano-1-(phenylcarbonyloxy)-1H-indole-3-
carboxylate (6e). Reaction time: 8 h. Flash chromatography (hex-
ane/EtOAc¼80:20). Colourless prism, mp 173e175 ꢀC, yield¼56%,
NMR (400 MHz, DMSO-d6):
d
¼8.45 (d, 1H, 4J¼1.4 Hz, H4), 8.32 (m,
1H, H7), 8.24 (dd, 2H, 3J¼7.1 Hz, J¼1.4 Hz, H200þH600), 7.87 (tt, 1H,
4
4
3J¼7.4 Hz, J¼1.4 Hz, H400), 7.76e7.68 (m, 4H, H20þH60 and
(180 mg, 0.56 mmol). 1H NMR (400 MHz, CDCl3):
d
¼8.62 (d, 1H,
H300þH500), 7.70 (s, 1H, H2), 7.64 (dd, 1H, 3J¼8.5 Hz, 4J¼1.4 Hz, H6),
J¼1.2 Hz, H4), 8.24 (dd, 2H, 3J¼7.5 Hz, 4J¼1.4 Hz, H20þH60), 8.07 (s,
3
4
7.50 (tt, 2H, J¼7.4 Hz, H30þH50), 7.36 (tt, 1H, 3J¼7.4 Hz, 4J¼1.2 Hz,
1H, H2), 7.80 (tt, 1H, 3J¼7.5 Hz, J¼1.4 Hz, H40), 7.63 (tt, 2H,
H40). 13C NMR (100 MHz, DMSO-d6):
d
¼165.0, 136.2, 135.9, 133.6,
3J¼7.5 Hz, J¼1.4 Hz, H30þH50), 7.55 (dd, 1H, 3J¼8.6 Hz, 4J¼1.2 Hz,
4
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12
G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
H6), 7.38 (d, 1H, J¼8.6 Hz, H7), 3.97 (s, 3H, COOMe). 13C NMR
J¼6.7 Hz, H1 aziridine ring), 3.77 (d, 1H, J¼6.7 Hz, H7a aziridine
ring), 3.75 (s, 3H, COOMe). 13C NMR (100 MHz, CDCl3):
172.0, 167.4, 153.0, 150.4, 147.3, 145.0, 140.3, 133.5, 130.2, 128.8,
(100 MHz, CDCl3):
d
¼164.2, 164.1, 135.9, 135.2, 132.4, 130.9, 129.7,
d¼190.9,
127.9, 127.3, 125.2, 122.8, 120.0, 110.0, 106.7, 106.2, 52.0. MS (CI): m/
z: 321 [Mþ1]. IR (KBr, cmꢁ1):
n
¼2917, 2849, 2224, 1774, 1709, 1600,
128.5, 127.6, 126.2, 124.0, 123.6, 122.9, 54.7, 54.1, 49.5. MS (CI): m/z:
1528, 1452, 1369, 1236, 1216, 1123, 1086, 1022, 989, 805, 767,
699 cmꢁ1. Elemental analyses for C18H12N2O4: calcd (%) C 67.50, H
3.78, N 8.75, found (%) C 67.43, H 3.87, N 8.66.
460 [Mþ1]. IR (KBr, cmꢁ1):
¼2956, 2924, 2853, 1935, 1735, 1695,
n
1604, 1525, 1350, 1241, 1209, 1108, 854, 737 cmꢁ1. Elemental anal-
yses for C24H17N3O7: calcd (%) C 62.75, H 3.73, N 9.15, found C 62.65,
H 3.87, N 9.24.
4.3.3.31. 6-Methyl-7H-7-methoxy-10-nitro-indolo[2,3-c]quino-
line (7). To a stirred solution of N-(2-(1-methoxy-5-nitro-1H-indol-
3-yl)phenyl)ethanamide 3e (70 mg, 0.22 mmol) in acetonitrile
4.3.3.35. Methyl 1-(4-cyanobenzoyl)-7-(4-cyanophenyl)-7,7a-di-
hydro-1H-azirino[1,2-a]indole-7-carboxylate(9c). Reaction
time:
(15 mL), POCl3 (30
m
L, 0.32 mmol) was added and the mixture was
5 h. Flash chromatography (hexane/EtOAc¼70:30, Rf¼0.28). Light
heated at reflux for 8 h. At reaction complete, the mixture was
cooled to 0 ꢀC, then poured into water and aqueous ammonia (28%
solution) was added dropwise until pH¼8 was reached. The
aqueous layers were extracted with EtOAc. The organic layers were
dried over Na2SO4, filtered and rotary evaporated to give 58 mg
(0.20 mmol) of an orange solid (prism), yield¼91%, mp 214 ꢀC.
brown oil, yield¼48%, (202 mg, 0.48 mmol). 1H NMR (400 MHz,
CDCl3):
d
¼8.03 (d, 2H, J¼8.2 Hz, H300þH500), 7.76 (d, 2H, J¼7.8 Hz,
H30þH50), 7.64 (d, 2H, J¼8.2 Hz, H200þH600), 7.60 (d, 1H, J¼7.5 Hz,
H6), 7.43 (d, 2H, 7.8 Hz, H20þH60), 7.35 (d, 1H, J¼7.5 Hz, H3), 7.15 (t,
1H, J¼7.5 Hz, H5), 7.07 (t, 1H, J¼7.5 Hz, H4), 4.65 (d, 1H, J¼6.6 Hz, H1
aziridine ring), 3.73 (s, 3H, COOMe), 3.68 (d, 1H, J¼6.6 Hz, H7a
1H NMR (400 MHz, DMSO-d6):
d
¼9.55 (d, 1H, J¼2.0 Hz, H11),
aziridine ring). 13C NMR (CDCl3, 100 MHz):
d
¼191.3, 171.2, 148.9,
8.91 (d, 1H, J¼7.9 Hz, H4), 8.58 (dd, 1H, 3J¼8.3 Hz, 4J¼2.0 Hz, H9),
8.25 (d, 1H, J¼7.9 Hz, H1), 8.12 (d, 1H, 3J¼8.3 Hz, H8), 7.88 (m, 2H,
H2þH3), 4.33 (s, 3H, NeOMe), 3.20 (s, 3H, Me). 13C NMR (100 MHz,
147.5, 139.5,137.8, 132.5, 132.2, 129.7, 128.8, 127.1, 127.0, 126.7, 125.6,
118.2, 117.7, 117.0, 116.5, 65.8, 54.3, 54.2, 49.5. MS (CI): m/z: 420
[Mþ1]. IR (film, cmꢁ1):
¼3064, 2961, 2928, 2229, 1730, 1693, 1605,
n
DMSO-d6):
d
¼145.7, 143.2, 142.6, 138.6, 130.1, 129.8, 128.0, 127.4,
1502, 1263, 1177, 1019, 840, 736 cmꢁ1. Elemental analyses for
123.6, 122.9, 122.6, 120.3, 117.9, 117.0, 110.6, 67.2, 22.5. MS (CI): m/z:
C26H17N3O3: calcd (%) C 74.45, H 4.09, N 10.02, found (%) C 74.57, H
4.01, N 10.21.
308 [Mþ1]. IR (KBr, cmꢁ1):
n¼2923, 2361, 1583, 1511, 1461, 1335,
1073 cmꢁ1. Elemental analyses for C17H13N3O3: calcd (%) C 66.44, H
4.26, N 13.67, found (%) C 66.38, H 4.35, N 13.75.
4.3.3.36. Methyl
1-(4-chlorobenzoyl)-7-(4-chlorophenyl)-7,7a-
dihydro-1H-azirino[1,2-a]indole-7-carboxylate (9d). Reaction time:
7 h. Flash chromatography (hexane/EtOAc¼70:30, Rf¼0.34). Orange
oil, yield¼56%, (246 mg, 0.56 mmol). 1H NMR (400 MHz, CDCl3):
4.3.3.32. Methyl 1-hydroxy-3-phenyl-1H-indole-7-carboxylate
(8a). Reaction time:
9
h. Flash chromatography (CH2Cl2/
hexane¼70:30 Rf¼0.38). Yellow prism, mp 99e101 ꢀC, yield¼64%,
d
¼7.56 (d, 1H, J¼7.8 Hz, H6), 7.47e7.42 (m, 2H, H5þH3), 7.29 (m, 1H,
(171 mg, 0.64 mmol). 1H NMR (400 MHz, CDCl3):
d
¼12.27 (s, 1H,
H4), 7.25 (d, 2H, J¼8.6 Hz, H200þH600), 7.14 (d, 2H, J¼8.6 Hz,
H300þH500), 6.95 (d, 2H, J¼8.6 Hz, H20þH60), 6.85 (d, 2H, J¼8.6 Hz,
H30þH50), 4.58 (d, 1H, J¼7.0 Hz, H1 aziridine ring), 3.71 (s, 3H,
COOMe), 3.65 (d, 1H, J¼7.0 Hz, H7a aziridine ring). 13C NMR (CDCl3,
NeOH), 8.17 (d, 1H, J¼7.8 Hz, H6), 7.99 (d, 1H, J¼7.8 Hz, H4), 7.64 (d,
2H, J¼7.6 Hz, H20þH60), 7.52 (s, 1H, H2), 7.50 (t, 2H, J¼7.6 Hz,
H30þH50), 7.36 (t,1H, J¼7.8 Hz, H4), 7.16 (t,1H, J¼7.6 Hz, H40), 4.07 (s,
3H, COOMe). 13C NMR (100 MHz, CDCl3):
d¼170.7, 134.7, 130.6,
100 MHz):
d
¼190.9, 172.5, 153.4, 139.6, 136.0, 134.1, 133.7, 133.5,
129.3, 128.3, 127.4, 127.3, 126.8, 124.9, 122.7, 119.2, 114.1, 112.2, 53.7.
129.9, 129.3, 128.7, 128.6, 128.3, 128.2, 127.4, 122.4, 61.9, 54.4, 53.3,
MS (CI): m/z: 268 [Mþ1]. IR (KBr, cmꢁ1):
n¼3118, 3007, 2957, 2858,
49.6. MS (CI): m/z: 440/438 [Mþ1 (37Cl/35Cl)]. IR (film, cmꢁ1):
2788,1718,1662,1600,1525,1442,1381,1269,1203,1143,1069, 993,
879, 752 cmꢁ1. Elemental analyses for C16H13NO3: calcd (%) C 71.90,
H 4.90, N 5.24, found (%) C 72.03, H 4.87, N 5.41.
n
¼2953, 2925, 2853, 1732, 1687, 1589, 1491, 1237, 1093, 1015, 959,
733 cmꢁ1. Elemental analyses for C24H17Cl2NO3: calcd (%) C 65.77, H
3.91, N 3.20, found (%) C 65.61, H 3.76, N 3.17.
4.3.3.33. Methyl
1-benzoyl-7-phenyl-7,7a-dihydro-1H-azirino
4.3.3.37. Methyl
1-(4-methoxybenzoyl)-7-(4-methoxyphenyl)-
[1,2-a]indole-7-carboxylate (9a). Reaction time: 5 h. Flash chro-
matography (CH2Cl2- EtOAc¼95:5 Rf¼0.28). Orange prism, mp
134e136 ꢀC, yield¼57%, (211 mg, 0.57 mmol). 1H NMR (400 MHz,
7,7a-dihydro-1H-azirino[1,2-a]indole-7-carboxylate (9e). Reaction
time: 4 h. Flash chromatography (hexane/EtOAc¼50:50, Rf¼0.30).
Light brown oil, yield¼64%, (275 mg, 0.64 mmol). 1H NMR
CDCl3):
d
¼7.57 (d, 1H, J¼7.8 Hz, H6), 7.51 (d, 1H, J¼7.6 Hz, H3), 7.44
(400 MHz, CDCl3):
d
¼7.56 (d,1H, J¼7.6 Hz, H6), 7.47 (d, 1H, J¼7.6 Hz,
(t, 1H, J¼7.6 Hz, H5), 7.31e7.25 (m, 4H, H4þH200þH600þH400), 7.10 (t,
2H, J¼7.7 Hz, H300þH500), 7.06 (d, 2H, J¼7.7 Hz, H20þH60), 6.89 (t, 2H,
J¼7.6 Hz, H30þH50), 6.75 (t, 1H, J¼7.4 Hz, H40), 4.63 (d, 1H, J¼7.0 Hz,
H1 aziridine ring), 3.71 (s, 3H, COOMe), 3.67 (d, 1H, J¼7.0 Hz, H7a
H3), 7.42 (t, 1H, J¼7.6 Hz, H5), 7.30 (d, 2H, J¼8.4 Hz, H200þH600), 7.24
(t, 1H, J¼7.6 Hz, H4), 6.92 (d, 2H, J¼8.5 Hz, H20þH60), 6.59 (d, 2H,
J¼8.4 Hz, H300þH500), 6.38 (d, 2H, J¼8.5 Hz, H30þH50), 4.55 (d, 1H,
J¼6.8 Hz, H1 aziridine ring), 3.80 (s, 3H, COOMe), 3.71 (s, 3H, OMe),
3.63 (d, 1H, J¼6.8 Hz, H7a aziridine ring), 3.51 (s, 3H, OMe). 13C NMR
aziridine ring). 13C NMR (100 MHz, CDCl3):
d
¼192.9, 173.4, 154.1,
137.4,136.6,134.4,132.9,129.4,128.8,128.1,128.0,127.8,127.7,127.3,
125.3, 122.6, 68.0, 54.9, 53.6, 50.2. MS (CI): m/z: 370 [Mþ1]. X-ray
characterization of compound 9a was previously reported.30 IR
(CDCl3, 100 MHz):
137.1, 131.4, 131.1, 130.9, 129.5, 128.9, 126.7, 114.5, 114.4, 113.6, 113.5,
d
¼190.9, 172.4, 168.2, 164.0, 158.9, 141.7, 141.6,
65.8, 56.7, 55.5, 55.3, 54.9, 49.1. MS (CI): m/z: 430 [Mþ1]. IR (film,
(KBr, cmꢁ1):
n
¼3077, 2953, 2849, 1959, 1732, 1687, 1598, 1469, 1450,
cmꢁ1):
n
¼2959, 2852, 1731, 1676, 1600, 1512, 1299, 1257, 1176, 1029,
1220, 1021, 956, 734 cmꢁ1. Elemental analyses for C24H19NO3: calcd
(%) C 78.03, H 3.79, N 12.99, found C 78.15, H 3.87, N 12.81.
801, 733 cmꢁ1. Elemental analyses for C26H23NO5: calcd (%) C 72.71,
H 5.40, N 3.26, found (%) C 72.55, H 5.48, N 3.32.
4.3.3.34. Methyl 1-(4-nitrobenzoyl)-7-(4-nitrophenyl)-7,7a-dihy-
dro-1H-azirino[1,2-a]indole-7-carboxylate (9b). Reaction time: 6 h.
Flash chromatography (CH2Cl2/EtOAc¼95:5 Rf¼0.22). Orange leaf-
let, mp 108e110 ꢀC, yield¼60%, (276 mg, 0.47 mmol). 1H NMR
4.3.3.38. cis-Dimethyl (1R*,7R*,7aR*)-1-benzoyl-7-phenyl-7,7a-
dihydro-1H-azirino[1,2-a]indole-4,7-dicarboxylate
(9f). Reaction
time: 8 h. Flash chromatography (hexane/EtOAc¼70:30, Rf¼0.22).
Colourless prism, mp 147e149 ꢀC, yield¼32%, (90 mg, 0.32 mmol).
(400 MHz, CDCl3):
d
¼8.02 (d, 2H, J¼8.7 Hz, H300þH500), 7.81 (d, 2H,
1H NMR (400 MHz, CDCl3):
d
¼8.20 (d, 1H, J¼1.2 Hz, H3), 7.97 (dd,
J¼8.7 Hz, H30þH50), 7.56e7.49 (m, 4H, H200þH600þH6þH3), 7.44 (t,
1H, 3J¼8.0 Hz, 4J¼1.2 Hz, H5), 7.58 (d, 1H, J¼8.0 Hz, H6), 7.32 (m, 3H,
1H, J¼7.3 Hz, H5), 7.30e7.34 (m, 3H, H20þH60þH4), 4.68 (d, 1H,
H200þH400þH600), 7.11 (t, 2H, J¼7.6 Hz, H300þH500), 7.03 (d, 1H,
Please cite this article in press as: Ieronimo, G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.072

G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
13
J¼7.6 Hz, H20þH60), 6.90 (t, 2H, J¼7.6 Hz, H30þH50), 6.77 (t, 1H,
IR (KBr, cmꢁ1):
n
¼3378, 3059, 2924, 2853, 1710, 1601, 1523, 1473,
J¼7.6 Hz, H40), 4.67 (d, 1H, J¼7.1 Hz, H1 aziridine ring), 3.97 (s, 3H,
COOMe), 3.72 (s, 3H, COOMe), 3.71 (d, 1H, J¼7.1 Hz, H7a aziridine
1445, 1327, 1264, 743, 699 cmꢁ1. Elemental analyses for C14H10BrN:
calcd (%) C 61.79, H 3.70, N 5.15, found (%) C 61.92, H 3.55, N 5.06.
Compounds 12b and 12c were characterized and spectra and
analyses are in agreement with data previously reported in
literature.40
ring). 13C NMR (CDCl3, 100 MHz):
136.7,136.0,132.7,131.3,128.5,128.4,127.8,127.5,127.3,126.7,126.4,
d
¼192.3, 172.4, 166.7, 154.1, 139.1,
123.3, 62.2, 54.8, 53.4, 52.2, 49.8. MS (CI): m/z: 428 [Mþ1]. IR (film,
cmꢁ1):
n
¼2951, 2928, 2856, 2257, 1753, 1722, 1689, 1596, 1580,
1435, 1289, 1250, 1222, 907, 733 cmꢁ1. Elemental analyses for
26H21NO5: calcd (%) C 73.06, H 4.95, N 3.28, found (%) 72.87, H 4.77,
N 3.43.
4.3.3.43. 5-Nitro-3-tosyl-1H-indole (14). Reaction time: 5 h.
Flash chromatography (hexane/ethyl acetate¼6:4). Light brown
plate, mp 204e206 ꢀC (dec), yield 31%, (98 mg, 0.31 mmol). 1H
C
NMR (400 MHz, CDCl3):
d
¼9.45 (s, 1H, NH), 8.84 (d, 1H, 4J¼2.2 Hz,
4.3.3.39. trans-Dimethyl 1-benzoyl-7-phenyl-7,7a-dihydro-1H-
H4), 8.18 (dd, 1H, 3J¼9.0 Hz, 4J¼2.2 Hz, H6), 8.05 (d, 1H, 3J¼3.0 Hz,
H2), 7.94 (d, 2H, J¼8.3 Hz, H20þH60), 7.50 (d, 1H, J¼9.0 Hz, H7), 7.32
(d, 2H, J¼8.3 Hz, H30þH50), 2.40 (s, 3H, SO2C6H4Me). 13C NMR
azirino[1,2-a]indole-4,7-dicarboxylate (9g). Reaction time: 8 h. Flash
chromatography (hexane/EtOAc¼70:30, Rf¼0.30). Orange-brown
oil, yield¼21%, (137 mg, 0.21 mmol). 1H NMR (400 MHz, CDCl3):
(CDCl3, 100 MHz):
d
¼148.6, 144.2, 143.7, 139.3, 139.0, 132.4, 130.0,
d
¼7.94 (d, 2H, J¼7.6 Hz, H200þH600), 7.80 (dd, 1H, 3J¼8.1 Hz,
127.0, 122.7, 119.5, 116.7, 112.5, 21.5 ppm. MS (CI): m/z: 317. IR (KBr,
cmꢁ1):
¼3346, 2961, 2924, 2854, 1593, 1527, 1466, 1419, 1339,
1261, 1143, 1093, 1020, 800 cmꢁ1
Elemental Analysis for
15H12N2O4S: calcd (%) C, 56.95; H, 3.82; N, 8.86, found (%) C 56.61,
H 3.97, N 8.88.
4J¼1.2 Hz, H5), 7.74 (d, 1H, J¼1.2 Hz, H3), 7.68 (d, 1H, 3J¼8.1 Hz, H6),
7.58 (t,1H, J¼7.6 Hz, H400), 7.46 (t, 2H, J¼7.6 Hz, H300þH500), 7.37e7.28
(m, 5H, H20-H30-H40-H50-H60), 4.02 (d, 1H, J¼5.2 Hz, H1 aziridine
ring), 3.88 (s, 3H, COOMe), 3.82 (s, 3H, COOMe), 3.79 (d, 1H,
n
.
C
J¼5.2 Hz, H7a aziridine ring). 13C NMR (CDCl3, 100 MHz):
¼192.5,
d
171.5, 166.4, 149.5, 144.8, 142.3, 137.0, 133.8, 130.4, 129.1, 128.7,
128.4, 127.9, 127.7, 126.7, 126.1, 122.1, 62.2, 55.3, 52.6, 52.2, 47.8. MS
4.3.3.44. 5-Nitro-1,3-ditosyl-1H-indole (15). Reaction time: 5 h.
Flash chromatography (hexane/CH2Cl2¼30:70). Colourless prism,
mp 239e240 ꢀC, yield¼25%, (118 mg, 0.25 mmol). 1H NMR
(CI): m/z: 428 [Mþ1]. IR (film, cmꢁ1):
¼2952, 2926, 2854, 2257,
n
1761, 1723, 1685, 1597, 1580, 1436, 1289, 1248, 1223, 909, 732 cmꢁ1
.
(400 MHz, CDCl3):
d
¼8.75 (d, 1H, 4J¼1.9 Hz, H4), 8.43 (s, 1H, H2),
Elemental analyses for C26H21NO5: calcd (%) C 73.06, H 4.95, N 3.28,
found (%) C 72.98, H 4.87, N 3.31.
8.28 (dd, 1H, 3J¼9.2 Hz, 4J¼1.9 Hz, H6), 8.08 (d, 1H, J¼9.2 Hz, H7),
7.95 (d, 2H, J¼8.2 Hz, H20þH60), 7.87 (d, 2H, J¼8.2 Hz, H200þH600),
7.37 (d, 4H, J¼8.2 Hz, H30þH50 and H300þH500), 2.43 (s, 6H,
4.3.3.40. Dimethyl 1-(4-nitrobenzoyl)-7-(4-nitrophenyl)-7,7a-di-
SO2C6H4Me). 13C NMR (CDCl3, 100 MHz):
d
¼147.6, 145.5, 145.4,
hydro-1H-azirino[1,2-a]indole-4,7-dicarboxylate
(9h). Reaction
138.3, 137.9, 133.9, 133.4, 131.1, 130.7, 130.1, 127.8, 125.6, 124.7, 121.6,
time: 6 h. Flash chromatography (hexane/EtOAc¼50:50, Rf¼0.26).
117.3,114.6, 22.2, 22.0 ppm. MS (CI): m/z: 471 [Mþ1]. IR (KBr, cmꢁ1):
Light orange oil, yield¼44%, (228 mg, 0.44 mmol). 1H NMR
n
¼2923, 2852, 2362, 1596, 1525, 1346, 1261, 1150, 1086, 812 cmꢁ1
.
(400 MHz, CDCl3):
d
¼8.14 (d, 1H, J¼1.5 Hz, H3), 8.03 (d, 2H,
Elemental analyses for C22H18N2O6S2: calcd (%) C 56.16, H 3.86, N
5.95, found (%) C 56.25, H 3.92, N 5.81.
J¼8.7 Hz, H300þH500), 8.02 (dd, 1H, 3J¼8.0 Hz, 4J¼1.5 Hz, H5), 7.82 (d,
2H, J¼8.8 Hz, H30þH50), 7.60 (d, 1H, J¼8.0 Hz, H6), 7.53 (d, 2H,
J¼8.7 Hz, H200þH600), 7.31 (d, 2H, J¼8.8 Hz, H20þH60), 4.73 (d, 1H,
J¼6.7 Hz, H1 aziridine ring), 3.98 (s, 3H, COOMe), 3.82 (d, 1H,
J¼6.7 Hz, H7a aziridine ring), 3.76 (s, 3H, COOMe). 13C NMR (CDCl3,
Compound 16a and compound 16b show the same spectro-
scopic data reported in literature.43
4.3.3.45. 5-Nitro-3-(pyridin-2-yl)-1H-indole
(18a). Reaction
100 MHz):
d
¼190.4, 171.0, 166.2, 153.1, 150.1, 146.9, 143.9, 139.8,
time: 5 h. Flash chromatography (CH2Cl2- EtOAc¼70:30). Orange
138.0, 132.0, 128.4, 128.0, 127.1, 127.1, 123.7, 123.5, 123.3, 59.5, 54.7,
oil, yield¼39%, (93 mg, 0.39 mmol). 1H NMR (400 MHz, CDCl3):
53.9, 52.4, 49.1. MS (CI): m/z: 518 [Mþ1]. IR (film, cmꢁ1):
n
¼2924,
d
¼9.41 (d, 1H, 4J¼2.0 Hz, H4), 8.93 (s, 1H, NH), 8.75 (d, 1H, J¼4.6 Hz,
2854, 2360,1757,1723,1690,1524,1494,1437,1349, 1291,1248, 854,
756 cmꢁ1. Elemental analyses for C26H19N3O9: calcd (%) C 60.35, H
3.70, N 8.12, found (%) C 60.48, H 3.82, N 8.00.
H60), 8.20 (dd, 1H, 3J¼9.0 Hz, 4J¼2.0 Hz, H6), 7.92 (d, 1H, J¼2.2 Hz,
H2), 7.78 (t,1H, J¼7.7 Hz, H40), 7.72 (d, 1H, J¼7.7 Hz, H30), 7.49 (d, 1H,
J¼9.0 Hz, H7), 7.22 (t, 1H, J¼6.5 Hz, H50). 1H NMR (400 MHz, DMSO-
d6):
d
¼12.33 (br, s, 1H, NH), 9.40 (d, 1H, J¼2.3 Hz, H4), 8.70 (d, 1H,
4.3.3.41. 2-Bromo-5-nitro-3-phenyl-1H-indole (11a). Reaction
time: 5 h. Flash chromatography (CH2Cl2/hexane¼70:30). Yellow
platelet, mp 180e182 ꢀC, yield¼45%, (193 mg, 0.45 mmol). 1H NMR
J¼4.2 Hz, H30), 8.42 (d,1H, J¼2.7, H2), 8.08 (dd,1H, J3¼9.0, J4¼2.3 Hz,
H6), 8.00 (d, 1H, J¼7.9 Hz, H60), 7.93 (t, 1H, J¼7 Hz, H50), 7.65 (d, 1H,
J¼9.0 Hz, H7), 7.32 (t, 1H, J¼5.8 Hz, H40). 13C NMR (CDCl3, 100 MHz):
(400 MHz, CDCl3):
d
¼8.62 (d, 1H, J¼1.9 Hz, H4), 8.59 (s,1H, NH), 8.18
d
¼148.6, 147.3, 142.1, 140.5, 138.5, 134.8, 130.4, 124.9, 121.1, 119.2,
4
(dd, 1H, 3J¼9.0 Hz, J¼1.9 Hz, H6), 7.63 (d, 2H, J¼7.4 Hz, H20þH60),
117.8, 113.0, 111.5. MS (CI): m/z: 240 [Mþ1]. IR (film, cmꢁ1):
¼3378,
n
7.56 (t, 2H, J¼7.4 Hz, H30þH50), 7.46 (t,1H, J¼7.4 Hz, H40), 7.43 (d,1H,
2923, 2330, 1611, 1548, 1505, 1454, 1344, 1320, 1114, 1055, 807,
790 cmꢁ1. Elemental analyses for C13H9N3O3: calcd (%) C 61.18, H
3.55, N 16.46, found (%) C 61.39, H 3.64, N 16.61.
J¼9.0 Hz, H7). 13C NMR (CDCl3, 100 MHz):
¼143.1, 139.2, 132.1,
d
129.7, 129.3, 128.2, 127.2, 119.9, 118.8, 116.7, 111.0, 110.8. MS (CI): m/
z: 320/318 [Mþ1]. IR (KBr, cmꢁ1):
n
¼3382, 2920, 2851, 1711, 1517,
1466, 1330, 1072, 810, 699 cmꢁ1
.
Elemental analyses for
4.3.3.46. 5-Nitro-3-(pyridin-3-yl)-1H-indol-1-ol (18b). Reaction
time: 5 h. Flash chromatography (CH2Cl2/EtOAc¼50:50). Yellow oil,
yield¼46%, (117 mg, 0.46 mmol). 1H NMR (400 MHz, DMSO-d6):
C
14H9BrN2O2: calcd (%) C 53.02, H 2.86, N 8.83, found (%) C 53.11, H
2.92, N 8.67.
d
¼12.24 (s, 1H, NeOH), 8.98 (s, 1H, H20), 8.76 (d, 1H, J¼2.0 Hz, H4),
4.3.3.42. 2-Bromo-3-phenyl-1H-indole (11b). Reaction time: 7 h.
Flash chromatography (CH2Cl2/hexane¼70:30). Yellow needles, mp
102e104 ꢀC, yield¼51%, (140 mg, 0.51 mmol). 1H NMR (400 MHz,
8.56 (d, 1H, J¼4.6 Hz, H40), 8.34 (s, 1H, H2), 8.23 (d, 1H, J¼7.9 Hz,
H60), 8.14 (dd, 1H, 3J¼9.0 Hz, 4J¼2.0 Hz, H6), 7.68 (d, 1H, J¼9.0 Hz,
H7), 7.59 (dd, 1H, 3J¼7.9 Hz, J¼4.6 Hz, H50). 13C NMR (DMSO-d6,
4
CDCl3):
d
¼8.23 (s, 1H, NH), 7.70 (d, 1H, J¼7.7 Hz, H4), 7.66 (d, 2H,
100 MHz):
d¼147.8, 147.5, 142.5, 136.8, 135.8, 130.7, 128.7, 125.3,
J¼7.5 Hz, H20þH60), 7.51 (t, 2H, J¼7.5 Hz, H30þH50), 7.41e7.37 (m,
120.7, 118.4, 117.4, 111.1, 110.6. MS (CI): m/z: 256 [Mþ1]. IR (film,
2H, H40þH7), 7.25 (t, 1H, J¼7.7 Hz, H6), 7.17 (t, 1H, J¼7.7 Hz, H5). 13C
cmꢁ1):
n
¼3375, 2924, 2331, 1610, 1548, 1503, 1459, 1342, 1319, 1110,
NMR (CDCl3, 100 MHz):
d
¼136.6, 133.9, 129.9, 129.0, 127.7, 127.3,
1053, 804, 799 cmꢁ1. Elemental analyses for C13H9N3O3: calcd (%) C
61.18, H 3.55, N 16.46, found (%) C 60.99, H 3.47, N 16.15.
123.2, 121.2, 119.5, 117.5, 111.0, 108.0. MS (CI): m/z: 275/273 [Mþ1],
Please cite this article in press as: Ieronimo, G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.072

14
G. Ieronimo et al. / Tetrahedron xxx (2013) 1e15
4.3.3.47. 5-Nitro-3-(pyridin-4-yl)-1H–1H-indol-1-ol
4.4.1. X-ray crystallographic analysis. Well defined single-crystals of
species 9f, 11a and 15 were chosen for conventional X-ray crystal
structure analysis. Diffraction data were collected at rt on an Enraf
(18c). Reaction time: 5 h. Isolated by filtration. Orange-brown
plate, mp 255e260 (dec), yield¼57%, (145 mg, 0.57 mmol). 1H
NMR (400 MHz, DMSO-d6)
d
: 12.28 (br, 1H, NeOH), 8.86 (d, 1H,
Nonius CAD4 diffractometer with graphite-monochromatized Mo-
J¼2.1 Hz, H4), 8.62 (br, 2H, H30þH50), 8.49 (s, 1H, H2), 8.14 (dd, 1H,
Ka
radiation (
l
¼0.71069 A). Generator settings: 50 kV, 30 mA).
ꢁ
3J¼9.0 Hz, 4J¼2.1 Hz, H6), 7.77 (d, 2H, J¼4.9 Hz, H20þH60), 7.69 ppm
Lorentz-polarization correction and, for 11, an empirical absorption
correction, were applied. The structures was solved by direct
methods (SIR92)62 and expanded using Fourier techniques
(SHELX97).63 Non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were included as riding on their pertinent atoms.
The final cycles of full-matrix least-squares refinements were based
on F2. All calculations were performed using the WINGX Crystallo-
graphic Software Suite.64 CCDC deposition numbers 948744/948745/
948746 for compounds 9f,11a and 15, respectively. Copies of the data
can be obtained free of charge via http://www.ccdc.cam.ac.uk/conts/
retrieving.html(orfromthe Cambridge CrystallographicData Centre,
12, Union Road, Cambridge, CB2 1EZ, UK; fax: þ44 1223 336033; e-
mail: deposit@ccdc.cam.ac.uk).
(d, 1H, J¼9.0 Hz, H7). 13C NMR (100 MHz, DMSO-d6)
d: 150.6, 142.3,
141.5, 136.7, 129.5, 127.8, 120.2, 118.1, 1161, 111.3, 110.3. MS (CI): m/z:
256 [Mþ1]. IR (KBr, cmꢁ1):
¼3373, 2923, 2331, 1607, 1550, 1505,
n
1460, 1342, 1316, 1112, 1055, 806, 790 cmꢁ1. Elemental analyses for
C
13H9N3O3: calcd (%) C 61.18, H 3.55, N 16.46, found (%) C 61.01, H
3.62, N 16.27.
4.3.3.48. (S)-Methyl 2-(tert-butoxycarbonylamino)-3-(4-(5-nitro-
1H-indol-3-yl)phenyl)propanoate (24a). Reaction time: 5 h. Flash
chromatography (hexane/EtOAc¼60:40). Yellow prism, mp
101e103 ꢀC, yield¼55%, (242 mg, 0.55 mmol). 1H NMR (400 MHz,
CDCl3):
d
¼8.83 (d, 1H, 4J¼2.2 Hz, H4), 8.76 (s, 1H, NH indole ring),
7.94 (dd, 1H, 3J¼8.8 Hz, 4J¼2.2 Hz, H6), 7.89 (s, 1H, H2), 7.35 (d, 2H,
J¼7.5 Hz, H30 and H50), 7.21 (d, 2H, J¼7.5 Hz, H20 and H60), 6.92 (d,
1H, J¼8.8 Hz, H7), 5.10 (m, 1H, NH), 4.57 (m, 1H, ArCH2CH), 3.74 (s,
3H, CO2Me), 3.13 (m, 2H, ArCH2CH),1.42 ppm (s, 9H, CMe3). 13C NMR
Crystallographic data for 9f: C26H21NO5, fw¼427.44 g molꢁ1
,
colourless prism (crystal size, 0.10ꢃ0.20ꢃ0.20 mm3), monoclinic,
P21/a, a¼11.026(2) A, b¼16.372(2) A, c¼12.072(1) A,
b
¼104.709(1)ꢀ,
ꢁ
ꢁ
ꢁ
V¼2107.0(5) A , Z¼4, Dcalcd¼1.347 g cmꢁ3
,
m
(Mo-K
u-2q, measured
a
)¼0.94 cmꢁ1
,
3
ꢁ
(100 MHz, CDCl3):
d
¼172.4, 157.8, 155.8, 145.8, 137.8, 136.0, 132.8,
scan width¼(1.00þ0.35 tan
q
), scan mode¼
130.4, 130.3, 127.6, 126.4, 122.4, 117.5, 97.3, 87.3, 52.8, 38.5, 30.1,
reflections¼3814, observed reflections¼2597, no. of parame-
ters¼289, R1¼0.0444, wR2¼0.1131, goodness of fit indicator¼1.011.
28.7. MS (CI): m/z: 440 [Mþ1]. IR (KBr, cmꢁ1):
¼3368, 2978, 1711,
n
1616, 1596, 1521, 1468, 1334, 1289, 1166, 1064, 804, 738 cmꢁ1. Ele-
mental analyses for C23H25N3O6: calcd (%) C 62.86, H 5.73, N 9.56,
Crystallographic data for 11a: C14H9BrN2O2, fw¼317.14 g molꢁ1
,
yellow platelet (crystal size, 0.01ꢃ0.30ꢃ0.40 mm3) monoclinic, P21/
found (%) C 62.72, H 5.81, N 9.47. ½a D20
ꢂ
þ7.81.
c, a¼7.912(3) A, b¼22.639(4) A, c¼7.974(4) A,
¼115.83(3)ꢀ,
ꢁ
ꢁ
ꢁ
b
V¼1285.6(8) A , Z¼4, Dcalcd¼1.639 g cmꢁ3
,
m
(Mo-K
u-2q, measured
a
)¼31.2 cmꢁ1
,
3
ꢁ
4.3.3.49. (S)-Methyl
3-(4-(5-bromo-1H-indol-3-yl)phenyl)-2-
scan width¼(1.00þ0.35 tan
q
), scan mode¼
(tert-butoxycarbonylamino)propanoate (24b). Reaction time: 7 h.
Flash chromatography (hexane/EtOAc¼70:30). Pale red prism, mp
165e167 ꢀC, yield¼47%, (222 mg, 0.47 mmol). 1H NMR (400 MHz,
reflections¼2332, observed reflections¼1289, no. of parame-
ters¼172, R1¼0.0470, wR2¼0.1055, goodness of fit indicator¼1.053.
Crystallographic data for 15:
C
22H18NOS2$½CH2Cl2, fw¼
CDCl3):
d
¼8.39 (s, 1H, NH indole ring), 8.04 (s, 1H, H4), 7.55 (d, 2H,
512.97 g molꢁ1, colourless prism (crystal size, 0.08ꢃ0.12ꢃ0.40 mm3),
J¼8.0 Hz, H30 and H50), 7.36e7.31 (m, 2H, H6þH7), 7.33 (s, 1H, H2),
7.23 (d, 2H, J¼8.0 Hz, H20 and H60), 5.06 (m, 1H, NH), 4.66 (m, 1H,
C6H4eCH2CH), 3.78 (s, 3H, CO2Me), 3.16 (m, 2H, C6H4eCH2CH),
monoclinic, ꢀC2/c, a¼26.322(4) A, b¼8.101(2) A, c¼24.287(3) A,
ꢁ
ꢁ
ꢁ
3
ꢁ
b
¼116.20(1) , V¼4646(1) A , Z¼8, Dcalcd¼1.466 g cmꢁ3
,
m(Mo-Ka)¼
3.87 cmꢁ1, scanwidth¼(0.80þ0.35 tan
q
), scan mode¼
u-2q, measured
1.46 ppm (s, 9H, CMe3). 13C NMR (100 MHz, CDCl3):
135.7, 134.3, 133.9, 130.3, 127.9, 125.7, 123.2, 122.7, 118.1, 114.0, 113.2,
d¼172.8, 155.5,
reflections¼4210, observed reflections¼2372, no. of parameters¼303,
R1¼0.0704, wR2¼0.2210, goodness of fit indicator¼1.020.
80.4, 88.3, 52.6, 38.5, 30.1, 28.7. MS (CI): m/z: 474/472 [Mþ1]. IR
(KBr, cmꢁ1):
n
¼3313, 2975, 2927, 2853, 1741, 1693, 1504, 1454, 1366,
Acknowledgements
1165, 1058, 1021, 798, 737 cmꢁ1
. Elemental analyses for
C
23H25BrN2O4: calcd (%) C 58.36, H 5.32, N 5.92, found (%) C 58.11, H
We acknowledge Dr. Enrica Alberti and Dr. Marta Brucka for
5.24, N 5.99. ½a 2D0
þ5.18.
ꢂ
ꢀ
NMR experiments. MIUR (Ministero dell’Istruzione dell’Universita e
della Ricerca) is kindly acknowledged for financial support PRIN
2008 e Programmi di Ricerca Scientifica di Rilevante Interesse
Nazionale (Ottimizzazione della sintesi di molecole eterocicliche e
carbocicliche mediante l’uso di procedure non convenzionali).
K.M.N. is grateful for financial support provided by the U.S. National
Science Foundation.
4.3.3.50. (S)-Methyl 3-(4-(1H-indol-3-yl)phenyl)-2-(tert-butox-
ycarbonylamino)propanoate (24c). Reaction time: 8 h. Flash chro-
matography (hexane/EtOAc¼70:30). Pale yellow prism, mp
178e180 ꢀC, yield¼50%, (197 mg, 0.50 mmol). 1H NMR (400 MHz,
CDCl3):
d
¼8.31 (s, 1H, NH indole ring), 7.94 (d, 1H, J¼7.4 Hz, H4),
7.43 (d, 1H, J¼8.4 Hz, H7), 7.32 (d, 2H, J¼8.2 Hz, H30 and H50), 7.10 (d,
2H, J¼8.2 Hz, H20 and H60), 7.01 (t, 1H, J¼8.4 Hz, H5), 6.82 (t, 1H,
J¼7.4 Hz, H6), 6.70 (s, 1H, H2), 5.05 (m, 1H, NH), 4.56 (m, 1H,
C6H4eCH2CH), 3.73 (s, 3H, CO2Me), 3.02 (m, 2H, C6H4eCH2CH),
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.10.072.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
1.42 ppm (s, 9H, CMe3). 13C NMR (100 MHz, CDCl3):
152.7,138.8,136.5,131.6,131.2,130.1, 129.9,126.7, 125.9,125.9,118.3,
d
¼172.6, 155.7,
97.0, 88.2, 52.7, 38.3, 30.1, 28.7. MS (CI): m/z: 395 [Mþ1]. IR (KBr,
cmꢁ1):
n
¼3364, 2976, 2931,1712,1685, 1508,1440,1366, 1258,1166,
1059, 1020, 799, 742 cmꢁ1. Elemental analyses for C23H26N2O4:
calcd (%) C 70.03, H 6.64, N 7.10, found (%) C 70.13, H 6.72, N 7.21.
References and notes
½
a 2D0
ꢂ
þ6.27.
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Please cite this article in press as: Ieronimo, G.; et al., Tetrahedron (2013), http://dx.doi.org/10.1016/j.tet.2013.10.072