Bronsted acid catalyzed bisindolization of α-amido acetals: Synthesis and anticancer activity of bis(indolyl)ethanamino derivatives

Article abstract of DOI:10.1002/ejoc.201402055

A Bronsted acid catalyzed bisindolization reaction with suitable α-amido acetals that tolerates a wide range of indoles is reported. The method allows rapid access to the biologically relevant bisindolyl ethanamine scaffold in good to excellent yields upon mild amide basic hydrolysis. In preliminary pharmacological studies, some of these compounds display cytotoxic activity in U937 cancer cells. The marine natural alkaloid 2,2-di(6′- bromo-3′-indolyl)-ethylamine was the most active compound and could be a lead candidate for further optimization. For the first time, the biological role of this brominated bisindole marine alkaloid is presented. Bronsted acid catalyzed reaction of indoles with (acylamino)acetaldehyde dimethyl acetal efficiently affords bis(indolyl)ethanamino derivatives. The dibrominated marine natural product bisindole alkaloid 1 showed potent anticancer activity against U937 cells. Copyright

Full text of DOI:10.1002/ejoc.201402055

FULL PAPER
DOI: 10.1002/ejoc.201402055
Brønsted Acid Catalyzed Bisindolization of α-Amido Acetals: Synthesis and
Anticancer Activity of Bis(indolyl)ethanamino Derivatives
Michele Mari,[a] Aurora Tassoni,[b] Simone Lucarini,[a] Mirco Fanelli,[b]
Giovanni Piersanti,*[a] and Gilberto Spadoni[a]
Keywords: Medicinal chemistry / Drug discovery / Antitumor agents / Cytotoxicity / Natural products / Alkaloids /
Nitrogen heterocycles
A Brønsted acid catalyzed bisindolization reaction with
suitable α-amido acetals that tolerates a wide range of ind-
oles is reported. The method allows rapid access to the biolo-
play cytotoxic activity in U937 cancer cells. The marine natu-
ral alkaloid 2,2-di(6Ј-bromo-3Ј-indolyl)-ethylamine was the
most active compound and could be a lead candidate for fur-
gically relevant bisindolyl ethanamine scaffold in good to ex- ther optimization. For the first time, the biological role of this
cellent yields upon mild amide basic hydrolysis. In prelimi-
nary pharmacological studies, some of these compounds dis-
brominated bisindole marine alkaloid is presented.
pharmacokinetic profile. DIM has a low oral bioavailability
due to its highly lipophilic nature and chemical instability
in the stomach. The presence of the alkylamino side chain
in the marine alkaloid 1 could play a pivotal role not only
for possible enhancement of therapeutic activities, but it
could improve its solubility in water and impart acid resis-
tance. It should also be pointed out that the side chain al-
lows the possibility of further synthetic transformations by
amino derivatization and/or conjugation. Moreover, given
the high cytotoxicity typical of bromine-containing deriva-
tives,[8] the presence of two bromoindole units in compound
1 warrants its investigation as an anticancer agent.
Introduction
Marine organisms such as corals, sponges, ascidians, and
tunicates are rich sources of biologically active molecules.[1]
The unprecedented structures of these compounds and their
potent activity against a broad number of pharmacological
targets make them excellent synthetic targets and very good
lead candidates. Among the various structural classes, the
marine indole alkaloids have received much attention due
to the significant activity that they have elicited in cancer
and cytotoxicity assays and also for their unexplored poten-
tial on neurological targets and behavioral diseases.[2] In the
early 1990s, compounds containing brominated indole
rings, such as 2,2-bis(6-bromo-3-indolyl) ethylamine (1),
were isolated from the Californian tunicate Didemnum can-
didum and the New Caledonian sponge Orina sp.[3] How-
ever, no biological studies have been reported with this
brominated bisindole alkaloid.[4] On the other hand, several
natural products with anticancer activity (vibrindole A,
streptindole, etc. Figure 1) share a common 3,3Ј-diindolyl-
methane (DIM) molecular unit.[5] DIM itself is known to
exhibit antiproliferative as well as apoptotic activities
against various cancer cells,[6] and it is presently in clinical
trials for the treatment of prostate and breast cancer.[7]
However, the widespread pharmacological use of DIM is
limited owing to its poor efficacy and unacceptable
Figure 1. The marine natural product 1 and some natural antican-
cer agents having the DIM molecular unit.
[a] Department of Biomolecular Sciences, University of Urbino
“Carlo Bo“,
6, Piazza Rinascimento, 61029 Urbino (PU), Italy
E-mail: giovanni.piersanti@uniurb.it
Various protocols for the synthesis of bisindolylethyl-
amine derivatives have been reported. The majority of the
synthetic methods involve Friedel–Crafts alkylation of ind-
oles with nitrogen-protected glycinaldehydes[9] or their syn-
thetic equivalents such as nitrones.[10] Although the protec-
tion of nitrogen prevents undesired inter- and intramolecu-
http://www.uniurb.it/MedChem/PiersantiResearch/
[b] Department of Biomolecular Sciences, University of Urbino
“Carlo Bo” Molecular Pathology Lab. “PaoLa”,
2, Via Arco d’Augusto, 61032 Fano (PU), Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402055.
3822
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3822–3830

Brønsted Acid Catalyzed Bisindolization of α-Amido Acetals
lar self-condensation reactions, it can also have a detrimen- Table 1. Substrate scope.
tal effect on the final deprotection step of sensitive bis-ind-
ole substrates. An alternative method to obtain bisindolyl
ethylamine derivatives could be the selective reduction of
bis(indol-3-yl)nitroethane prepared by the Michael addition
of indoles on nitrovinylindole.[11] However, the reduction of
the nitro group to the corresponding free amine was found
to be difficult, and in situ acylation derivatization was
needed. Yet, although all of these synthetic strategies are
useful, they have some limitations in terms of the require-
Entry
Indole
R
Product[c]
Yield [%][a]
ment for stoichiometric amounts of promoters or activators
(e.g., Lewis or Brønsted acids), and/or the deprotection step
is low yielding and limited by poor functional-group toler-
ance.[12] Consequently, the development of new, catalytic
and efficient methods to broaden the substrate scope and
enhance the selective construction of such molecules is
highly desirable. As part of our ongoing research program
to develop new methodologies for the synthesis of bisind-
olyl derivatives[13] and to determine the mechanism by
which these molecules exhibit their anticancer activity,[14]
herein we report a practical and versatile organocatalytic
synthetic procedure for the synthesis of bisindolylethyl-
amine derivatives. The in vitro cytotoxicity was also evalu-
ated for some of these derivatives.
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
H
N-Me
2-Me
2-COOH
2-COOMe
2-Ph
2-Me, 5-Cl
4-Br
4a
4b
4c
4d
4e
4f
4g
4h
4i
99
98
88
n.r.[b]
n.r.[b]
94
89
75
42
98
48
98
99
29
67
53
45
65
90
87
68
9
4-OMe
5-F
5-Cl
10
11
12
13
14
15
16
17
19
20
21
22
23
24
2j
2k
2l
4j
4k
4l
5-Br
2m
2n
2o
2p
2q
2r
2s
2t
5-OMe
5-OH
5-Bpin
5-COOMe
5-NO2
6-Cl
6-Br
6-Me
7-Br
7-Me
4m
4n
4o
4p
4q
4r
4s
4t
Results and Discussion
2u
2v
2w
4u
4v
4w
For the synthesis of the bisindolylethylamine derivatives,
we explored a novel double indolization protocol with the
readily available (acetylamino)acetaldehyde dimethyl acetal
3a[15] as a suitable two-carbon, nitrogen-containing electro-
phile in the presence of diphenyl phosphate (DPP) as the
98
7-aza
n.r.[b]
[a] Isolated yield. [b] n.r.: no reaction.
organocatalyst.[16] To optimize the reaction conditions, we tion of steric hindrance and electron deficiency. In particu-
initially examined the effects of a range of parameters, in- lar, the reaction proceeded smoothly and the products were
cluding catalyst loading, concentration, reaction tempera- obtained in very good yields by using methyl- (2b, 2c, 2t,
ture, time, and solvent. Regarding the amount of catalyst, and 2v) or methoxy- (2i and 2m) indoles. Furthermore,
it was observed that as little as 5 mol-% DPP was sufficient various halogens, such as fluoro- (2j), chloro- (2k and 2r)
to promote the formation of N-[2,2-di(1H-indol-3-yl)]acet- and bromo- (2h, 2l, 2s and 2u) groups were well tolerated in
amide (4a) in excellent yield, although long reaction times different indole positions, and afforded the corresponding
(usually 72 h) were needed for full conversion. However, we products 4j, 4k, 4r, 4h, 4l, 4s, and 4u in 48–98% yield
found that the reaction performed in acetonitrile (5 h, 1 m (Table 1, entries 10, 11, 19, 8, 12, 20, and 22). High catalytic
solution) in the presence of 10 mol-% DPP provided the activities were also found in the coupling of indoles bearing
best results in terms of reaction time and yield (Table 1, strong electron-withdrawing nitro and methoxycarbonyl
entry 1). Notably, the newly designed reaction did not pro- groups (Table 1, entries 16 and 17). When 1H-pyrrolo-
ceed in the absence of catalyst, and the presence of water [2,3-b]pyridine (2w) was used as an alternative nucleophile,
had a detrimental effect. After establishing suitable condi- the desired product 4w was not obtained (Table 1, entry 24).
tions for the reaction, we demonstrated the generality of It is noteworthy that the formation of polymerization prod-
this catalytic process for the synthesis of various N-acetyl ucts as byproducts was not observed in any of these trans-
bisindolyethylamines (Table 1).
formations. Furthermore, the outstanding compatibility of
A range of commercially available indoles with either the functional groups, OMe, Br, Cl, COOMe, B (pin-
electron-donating or -withdrawing functional groups on the acolate), I, and NO2, is remarkable. Among them, the car-
benzo ring as well as alkyl and aryl substituents at the C-2 bon-OMe, -boron, and -halogen bonds should be useful for
position were highly compatible with the procedure de- further elaboration as a carbon–carbon bond.
scribed above (Table 1). In contrast, no reactivity was ob-
We then applied this reaction strategy for the total syn-
served with indoles bearing an electron-withdrawing group thesis of the marine natural product 1. For this purpose,
in the C-2 position, such as 2-indole-carboxylic acid or its we first examined the reaction of 6-bromoindole with N-
ester (Table 1, entries 4 and 5), probably due to a combina- unprotected aminoacetaldehyde dimethyl acetal by using
Eur. J. Org. Chem. 2014, 3822–3830
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3823

G. Piersanti et al.
FULL PAPER
the reaction conditions described above, but the desired
Interestingly, the N-trifluoroacetyl protecting group
product was not obtained. On the other hand, the acet- proved to be stable under the reaction conditions and was
amido moiety in 3a is well-known for its resistance to easily removed by simple basic hydrolysis, which was per-
hydrolysis even at low pH values, as well as its relative sta- formed directly on the crude trifluoroacetamido derivatives,
bility in alkaline media. This characteristic was confirmed to give bis-indolylethanamine derivatives 6 in very high
in failed attempts to hydrolyze compound 4s, and a com- yield. This reaction sequence was successfully applied to the
plex mixture of dimeric and oligomeric products was ob- synthesis of the natural marine bisindole alkaloid 1. The
served. It is known that bis-indolylmethanes are substan- overall yield of this synthesis was found to be very high
tially more stable in both weakly acidic and neutral aqueous (82%) in comparison to reported methods.[9b,10b] An area
solutions than at very low pH. In seeking an alternative of major concern in considering the production and utiliza-
strategy to protect the amino functional group, we opted tion of bisindoles as pharmaceuticals is their instability at
for the trifluoroacetyl group, not only because it is reputed normal gastric pH (pH 1–2). However, the incorporation of
to be one of the most labile N-protective amides available[17] an alkylamino side chain in these compounds can counter-
but also because it was expected to increase the electro- act the instability under acidic conditions. Stability studies
philicity of the acetals, thus allowing for even milder bis- in acidic medium revealed that compound 1 was surpris-
indolization reaction conditions. Moreover, the trifluoro- ingly stable in aqueous HCl solution. For example, heating
acetyl group can be conveniently removed under very mild a solution of 1 in deuterated dimethyl sulfoxide ([D6]-
basic conditions, which is orthogonal to most standard sub- DMSO) with DCl at 50 °C for 2 h caused no change in
1
stituents, and is compatible with the sensitive bisindole scaf- the H NMR spectrum, suggesting that the undesired acid-
fold. These reports led us to test the reactivity and selectiv- catalyzed elimination of the indole molecule and conse-
ity of acetal 3b, containing a trifluoroacetyl group, in the quent formation of indoleninium cations (generally ob-
bisindolization of α-amino acetals. The bisindolization reac- served with other bisindolemethanes) did not occur.
tion with N-trifluoroacetylamino acetal 3b proceeded well
in all cases (Table 2, entries 1–4), albeit more slowly than
with 3a.
We tested some of our compounds for cytotoxicity, in-
cluding 1, 4s, 8, the reference parent compound DIM, and
two other representative 3,3Ј-bisindoles: 6,6Ј-dibromo,3,3Ј-
diindolylmethane (9)[18] and the natural product 2,2-
bis(3,3Ј-indolyl)propionic acid (10) (Figure 2).[13]
Potential anticancer activity was evaluated on immortal-
ized promonocytic leukemia cells (U937). Cellular viability
was evaluated by a trypan blue dye exclusion assay after
treatment for 48 h at final compound concentrations of 1
and 5 μm (Figure 3, Panel A).[19] Moreover, to evaluate
more accurately the biological response, dose–response ex-
periments were performed by treating U937 cells with the
most effective compounds for 48 h (Figure 3, Panel B).
Some of the tested compounds, including 1 and 8, were
found to reduce cell count in comparison to the DMSO
control. Interestingly, the natural compound 1, exhibited
the highest anticancer potency, with 50% growth inhibition
(GI50) values in the 1–1.3 μm range. The results of the pres-
ent study indicated the importance of incorporating the alk-
ylamino side chain into the bioactive parent DIM. There
was also evidence that locating a bromine atom at position
Table 2. Bisindolization reaction with 3b and subsequent mild
hydrolysis.
Entry
Indole
R
Product
Yield [%][a]
1
2
3
4
2a
2l
2p
2s
H
5-Br
5-COOMe
5-Br
6a
6l
6p
1
55
88
68
82
[a] Isolated yield.
Figure 2. Compounds tested for anticancer activity.
3824
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3822–3830

Brønsted Acid Catalyzed Bisindolization of α-Amido Acetals
6 of the indole favored antiproliferative activity, whereas N-
acetylation strongly decreased the antiproliferative activity.
The biological activity of these compounds was further in-
vestigated by analyzing their effects on cell cycle pro-
gression.[20] Cell treatments with 1 and 8, each at 1 and
5 μm, for 48 h induced cell cycle perturbation. We moni-
tored a progressive accumulation of cells in the G1 phase
concomitantly with a decrease of cells in the G2/M phase
(Figure S1, in the Supporting Information). Cytotoxicity
was also monitored and quantified by evaluating the in-
crease of hypodiploid cells. Both compounds 1 and 8 in-
duced strong accumulation of hypodiploid cells (Figure S2,
in the Supporting Information). As observed in the cell sur-
vival studies, the other compounds tested did not coher-
ently induce cell cycle alterations or hypodyploid cell ac-
cumulation.
Conclusions
A simple and convenient method has been developed for
the preparation of a variety of substituted bisindolyl-ethyl-
amine derivatives through direct coupling of indoles with
(acetylamino)acetaldehyde dimethyl acetal by employing a
commercially available organocatalyst. The present proto-
col possesses several advantages over common reported
methods, such as the use of an inexpensive catalyst, readily
available starting materials, broad substrate scope, and ex-
cellent chemoselectivity. The choice of N-trifluoroacetyl
protecting group, which is easily removed by mild and selec-
tive basic hydrolysis, allowed the free amines 6a, 6l, 6p and
natural product 1 to be obtained in very high yield. Several
of the new bis-indolyl ethylamine derivatives were found to
have an interesting biological activity in U937 tumor cells,
and C-6 brominated marine natural product 1 was found to
be the most active. The present study demonstrates, for the
first time, the biological role of this marine alkaloid. The
presence of bromine atoms and the ethylamine chain seem
to have a fundamental synergic effect for the anticancer ac-
tivity.
Experimental Section
Material and Methods: All reactions were run under an air atmo-
sphere unless otherwise noted. Column chromatography purifica-
tions were performed in flash conditions using Merck 230–
400 mesh silica gel. Analytical thin-layer chromatography (TLC)
was carried out on Merck silica gel plates (silica gel 60 F254), which
were visualized by exposure to ultraviolet light and an aqueous
solution of cerium ammonium molybdate (CAM) or p-anisal-
dehyde. 1H and 13C NMR spectra were recorded with a Bruker
Avance 200 spectrometer, using CDCl3, CD3OD, [D6]acetone, or
[D6]DMSO as solvent. Chemical shifts (δ scale) are reported in
parts per million (ppm) relative to the central peak of the solvent.
Coupling constants (J values) are given in Hertz [Hz]. ESI-MS
spectra were recorded with a Waters Micromass ZQ instrument.
IR spectra were obtained with a Nicolet Avatar 360 FTIR spec-
trometer; absorbance values are reported in cm–1. Melting points
were determined with a Buchi SMP-510 capillary melting point
apparatus and are uncorrected. Elemental analyses were performed
with a Carlo Erba analyzer and the results are within Ϯ0.3 of the
theoretical values (C, H, N). Indoles 2a–n and 2p–w are commer-
cially available; indole 2o and acetals 3a–b were prepared as de-
scribed previously.[15]
Diphenyl Phosphate Catalyzed Coupling of Indoles with (Acet-
ylamino)acetaldehyde Dimethyl Acetal; General Procedure for the
Synthesis of N-[2,2-Di(1H-indol-3-yl)ethyl]acetamide Derivatives
4a–w: Diphenyl phosphate (0.01 mmol) was added to a solution of
the appropriate indole 2a–w (0.2 mmol) and (acetylamino)acetalde-
hyde dimethyl acetal (3a; 0.1 mmol) in anhydrous acetonitrile
(0.1 mL), and the resulting mixture was stirred at 80 °C for 5 h in
a sealed tube, monitoring the progress of the reaction by TLC and
HPLC-MS. After cooling to room temperature, saturated aqueous
NaHCO3 (15 mL) and dichloromethane (15 mL) were added and
the two phases were separated. The aqueous solution was extracted
with dichloromethane (3ϫ 15 mL). After drying over dry Na2SO4,
the combined organic phases were concentrated in vacuo and the
Figure 3. Reduction of cell survival induced by treatment with the
indicated compounds. (A) Treatment was carried out at the indi-
cated concentrations and repeated every 24 h, and analyzed by a
trypan blue dye exclusion assay. The data are reported as mean
Ϯstandard deviation resulting from three independent experiments.
(B) Dose–response experiments for compounds 1 (upper panel) and
8 (lower panel).
Eur. J. Org. Chem. 2014, 3822–3830
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3825

G. Piersanti et al.
FULL PAPER
resulting crude product was purified by column flash chromatog-
raphy on silica gel.
m.p. 199–200 °C; TLC: Rf = 0.50 (ethyl acetate; UV, CAM). FTIR
1
(neat): ν
= 3315, 1689 cm–1. H NMR (200 MHz, [D6]DMSO,
˜
max
25 °C): δ = 1.75 (s, 3 H, NHCOCH3), 3.73 (dd, J1 = 5.5, J2
=
N-[2,2-Di(1H-indol-3-yl)ethyl]acetamide (4a): Yield: 31 mg (99%);
white solid. The chemical-physical data are in agreement to those
reported.[9c] 1H NMR (200 MHz, CDCl3, 20 °C): δ = 1.88 (s, 3 H,
NHCOCH3), 4.00 (dd, J1 = 5.5, J2 = 7.0 Hz, 2 H, CHCH2NH),
4.71 (dd, J1 = J2 = 7.0 Hz, 1 H, CHCH2NH), 5.66 (br. t, J =
5.5 Hz, 1 H, NHCOCH3), 6.90 (d, J = 2.0 Hz, 2 H, Ar-H), 7.04
(ddd, J1 = 1.0, J2 = J3 = 8.0 Hz, 2 H, Ar-H), 7.18 (ddd, J1 = 1.0,
J2 = J3 = 8.0 Hz, 2 H, Ar-H), 7.33 (dd, J1 = 1.0, J2 = 8.0 Hz, 2 H,
Ar-H), 7.59 (dd, J1 = 1.0, J2 = 8.0 Hz, 2 H, Ar-H), 7.89 (br. d, J
= 2.0 Hz, 2 H, NH) ppm.
7.5 Hz, 2 H, CHCH2NH), 5.84 (dd, J1 = J2 = 7.5 Hz, 1 H,
CHCH2NH), 6.93 (d, J = 2.5 Hz, 2 H, Ar-H), 6.94 (dd, J1 = 7.5,
J2 = 8.0 Hz, 2 H, Ar-H), 7.11 (dd, J1 = 1.0, J2 = 7.5 Hz, 2 H, Ar-
H), 7.36 (dd, J1 = 1.0, J2 = 8.0 Hz, 2 H, Ar-H), 7.97 (br. t, J =
5.5 Hz, 1 H, NHCOCH3), 11.14 (br. d, J = 2.5 Hz, 2 H, NH) ppm.
13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 23.1, 33.7, 44.9, 111.6,
113.5, 118.1, 122.3, 123.1, 124.7, 125.3, 138.7, 169.5 ppm. MS
(ESI): m/z (%) = 472 (50), 474 (100), 476 (50). C20H17Br2N3O
(475.18): calcd. C 50.57, H 3.61, N 8.84; found C 50.71, H 3.55, N
8.69.
N-[2,2-Bis(1-methyl-1H-indol-3-yl)ethyl]acetamide (4b): Yield:
34 mg (98%); white solid. The chemical-physical data are in agree-
ment to those reported.[9c] 1H NMR (200 MHz, CDCl3, 20 °C): δ
= 1.80 (s, 3 H, NHCOCH3), 3.64 (s, 6 H, NCH3), 3.94 (dd, J1 =
6.0, J2 = 7.0 Hz, 2 H, CHCH2NH), 4.64 (dd, J1 = J2 = 7.0 Hz, 1
H, CHCH2NH), 5.66 (br. t, J = 6.0 Hz, 1 H, NHCOCH3), 6.80 (s,
2 H, Ar-H), 6.99 (ddd, J1 = 1.5, J2 = 7.0, J3 = 8.0 Hz, 2 H, Ar-H),
7.15 (ddd, J1 = 1.0, J2 = J3 = 8.0 Hz, 2 H, Ar-H), 7.23 (d, J =
8.0 Hz, 2 H, Ar-H), 7.56 (d, J = 7.0 Hz, 2 H, Ar-H) ppm.
N-[2,2-Bis(4-methoxy-1H-indol-3-yl)ethyl]acetamide (4i): Eluent:
ethyl acetate/cyclohexane (8:2), yield 16 mg (42%); brownish solid;
m.p. 134–136 °C; TLC: Rf = 0.46 (ethyl acetate; UV, CAM). FTIR
(neat): ν
= 3402, 2930, 1655, 1508 cm–1. 1H NMR (200 MHz,
˜
max
CDCl3, 20 °C): δ = 1.81 (s, 3 H, NHCOCH3), 3.80 (s, 3 H, OCH3),
3.82–3.96 (m, 2 H, CHCH2NH), 5.51 (dd, J1 = J2 = 7.5 Hz, 1 H,
CHCH2NH), 6.47 (d, J = 7.5 Hz, 2 H, Ar-H), 6.51 (br. s, 1 H,
NHCOCH3), 6.69 (d, J = 2.0 Hz, 2 H, Ar-H), 6.92 (d, J = 8.0 Hz,
2 H, Ar-H), 7.06 (dd, J1 = 7.5, J2 = 8.0 Hz, 2 H, Ar-H), 8.26 (br. s,
2 H, NH) ppm. 13C NMR (50 MHz, CDCl3, 20 °C): δ = 23.3, 34.2,
46.5, 55.2, 99.7, 104.8, 117.2, 119.0, 120.8, 122.4, 138.0, 154.4,
170.3 ppm. MS (ESI): m/z (%) = 378 [M + H]+, 400 [M + Na]+,
376 [M – H]–, 436 [M + CH3COO]–. C22H23N3O3 (377.44): calcd.
C 70.01, H 6.14, N 11.13; found C 69.83, H 6.09, N 11.20.
N-[2,2-Bis(2-methyl-1H-indol-3-yl)ethyl]acetamide
(4c):
Yield:
30 mg (88%); white solid. The chemical-physical data are in agree-
ment to those reported.[9c] 1H NMR (200 MHz, CDCl3, 20 °C): δ
= 1.71 (s, 3 H, NHCOCH3), 2.30 (s, 6 H, Ar-CH3), 3.90 (dd, J1 =
5.0, J2 = 8.0 Hz, 2 H, CHCH2NH), 4.57 (dd, J1 = J2 = 8.0 Hz, 1
H, CHCH2NH), 6.76 (dd, J1 = J2 = 7.0 Hz, 2 H, Ar-H), 6.88 (dd,
J1 = J2 = 7.0 Hz, 2 H, Ar-H), 7.16 (d, J = 7.0 Hz, 2 H, Ar-H), 7.33
(d, J = 7.0 Hz, 2 H, Ar-H), 7.74 (br. t, J = 5.0 Hz, 1 H,
NHCOCH3), 10.63 (br. s, 2 H, NH) ppm.
N-[2,2-Bis(5-fluoro-1H-indol-3-yl)ethyl]acetamide (4j): Eluent: ethyl
acetate/cyclohexane (8:2), yield 35 mg (98%); brownish oil; m.p.
140–142 °C; TLC: Rf = 0.41 (ethyl acetate; UV, CAM). FTIR
(neat): ν
= 3421, 3297, 1647, 1485 cm–1. 1H NMR (200 MHz,
˜
max
N-[2,2-Bis(2-phenyl-1H-indol-3-yl)ethyl]acetamide (4f): Eluent:
ethyl acetate/cyclohexane (3:7), yield 44 mg (94%); white solid; m.p.
209–211 °C; TLC: Rf = 0.38 (ethyl acetate/cyclohexane, 1:1; UV,
[D6]DMSO, 25 °C): δ = 1.75 (s, 3 H, NHCOCH3), 3.75 (dd, J1 =
5.5, J2 = 7.5 Hz, 2 H, CHCH2NH), 4.51 (dd, J1 = J2 = 7.5 Hz, 1
H, CHCH2NH), 6.86 (ddd, J1 = 2.5, J2 = J3 = 9.0 Hz, 2 H, Ar-
CAM). FTIR (neat): ν
= 3355, 2934, 1650 cm–1. 1H NMR
˜
H), 7.18 (dd, J1 = 2.5, J2 = 10.5 Hz, 2 H, Ar-H), 7.31 (dd, J1
=
max
(200 MHz, [D6]DMSO, 25 °C): δ = 1.55 (s, 3 H, NHCOCH3), 4.02
(dd, J1 = 5.0, J2 = 8.0 Hz, 2 H, CHCH2NH), 5.03 (dd, J1 = J2 =
8.0 Hz, 1 H, CHCH2NH), 6.83 (dd, J1 = J2 = 8.0 Hz, 2 H, Ar-H),
7.02 (dd, J1 = J2 = 7.0 Hz, 2 H, Ar-H), 7.24 (m, 10 H, , 2 H, Ar-
H), 7.57 (d, J = 8.0 Hz, 2 H, Ar-H), 7.66 (br. t, J = 5.0 Hz, 1
H,NHCOCH3),11.09(br. s,2H,NH) ppm.13CNMR(50 MHz,[D6]-
DMSO, 25 °C): δ = 22.8, 34.9, 44.3, 111.6, 113.7, 119.0, 120.9,
121.2, 127.7, 128.1, 128.5, 129.2, 133.9, 135.9, 136.5, 169.7 ppm.
MS (ESI): m/z = 468 [M – H]–, 492 [M + Na]+. C32H27N3O
(469.58): calcd. C 81.85, H 5.80, N 8.95; found C 81.72, H 5.71, N
9.06.
5.0, J2 = 9.0 Hz, 2 H, Ar-H), 7.31 (d, J = 2.0 Hz, 2 H, Ar-H), 7.94
(br. t, J = 5.5 Hz, 1 H, NHCOCH3), 10.95 (br. d, J = 2.0 Hz, 2 H,
NH) ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 23.1, 34.3,
43.8, 103.9 (d, J = 23 Hz, 1 C), 109.3 (d, J = 26 Hz, 1 C), 112.7 (d,
J = 10 Hz, 1 C), 116.7 (d, J = 5.0 Hz, 1 C), 125.1, 127.3 (d, J =
10 Hz, 1 C), 133.6, 156.8 (d, J = 229 Hz, 1 C), 169.8 ppm. MS
(ESI): m/z = 354 [M + H]+, 376 [M + Na]+, 352 [M – H]–.
C20H17F2N3O (353.37): calcd. C 70.01, H 6.03, N 11.15; found C
69.83, H 6.09, N 11.20.
N-[2,2-Bis(5-chloro-1H-indol-3-yl)ethyl]acetamide (4k): Eluent:
ethyl acetate/cyclohexane (7:3), yield 19 mg (48%); brownish solid;
m.p. 131–132 °C; TLC: Rf = 0.53 (ethyl acetate; UV, CAM). FTIR
N-[2,2-Bis(5-chloro-2-methyl-1H-indol-3-yl)ethyl]acetamide
(4g):
(neat): ν
= 3422, 3296, 1649, 1460 cm–1. 1H NMR (200 MHz,
Eluent: ethyl acetate, yield 37 mg (89%); brownish solid; m.p. 230–
˜
max
232 °C; TLC: Rf = 0.36 (ethyl acetate; UV, CAM). FTIR (neat):
CD3OD, 20 °C): δ = 1.83 (s, 3 H, NHCOCH3), 3.95 (dd, J1 = 5.0,
J2 = 7.5 Hz, 2 H, CHCH2NH), 4.73 (dd, J1 = J2 = 7.5 Hz, 1 H,
CHCH2NH), 7.05 (dd, J1 = 2.0, J2 = 8.5 Hz, 2 H, Ar-H), 7.27
(br. t, J = 5.0 Hz, 1 H, NHCOCH3), 7.32 (d, J = 2.0 Hz, 2 H, Ar-
H), 7.39 (d, J = 8.5 Hz, 2 H, Ar-H), 7.60 (d, J = 2.0 Hz, 2 H, Ar-
H), 10.30 (br. s, 2 H, NH) ppm. 13C NMR (50 MHz, CD3OD,
20 °C): δ = 22.1, 34.2, 43.8, 112.7, 116.5, 118.5, 121.2, 123.8, 124.3,
128.3, 135.5, 169.3 ppm. MS (ESI): m/z (%) = 384 (100), 386 (65)
[M – H]–. C20H17Cl2N3O (386.28): calcd. C 62.19, H 4.44, N 10.88;
found C 61.99, H 4.51, N 10.85.
ν
= 3412, 1642, 1371 cm–1. 1H NMR (200 MHz, [D6]DMSO,
˜
max
25 °C): δ = 1.75 (s, 3 H, NHCOCH3), 2.31 (s, 6 H, Ar-CH3), 3.87
(dd, J1 = 5.0, J2 = 7.5 Hz, 2 H, CHCH2NH), 4.56 (dd, J1 = J2 =
7.5 Hz, 1 H, CHCH2NH), 6.93 (dd, J1 = 2.0, J2 = 8.5 Hz, 2 H, Ar-
H), 7.23 (d, J = 8.5 Hz, 2 H, Ar-H), 7.28 (d, J = 2.0 Hz, 2 H, Ar-
H), 7.88 (br. t, J = 5.0 Hz, 1 H, NHCOCH3), 11.00 (br. s, 2 H,
NH) ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 12.7, 23.0,
34.1, 43.3, 111.5, 112.3, 117.7, 119.9, 123.1, 129.3, 134.0, 134.4,
169.8 ppm. MS (ESI): m/z (%) = 412 (100), 414 (65) [M – H]–.
C22H21Cl2N3O (414.33): calcd. C 63.77, H 5.11, N 10.14; found C
63.51, H 5.13, N 10.02.
N-[2,2-Bis(5-bromo-1H-indol-3-yl)ethyl]acetamide (4l): Yield: 47 mg
(98%); brownish solid. The chemical-physical data are in agreement
to those reported.[9c] 1H NMR (200 MHz, CDCl3, 20 °C): δ = 1.84
(s, 3 H, NHCOCH3), 3.89 (dd, J1 = 5.5, J2 = 7.0 Hz, 2 H,
N-[2,2-Bis(4-bromo-1H-indol-3-yl)ethyl]acetamide (4h): Eluent:
ethyl acetate/cyclohexane (8:2), yield 36 mg (75%); yellowish solid;
3826
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3822–3830

Brønsted Acid Catalyzed Bisindolization of α-Amido Acetals
CHCH2NH), 4.51 (dd, J1 = J2 = 7.0 Hz, 1 H, CHCH2NH), 5.55
(br. t, J = 5.5 Hz, 1 H, NHCOCH3), 6.94 (d, J = 2.0 Hz, 2 H, Ar-
H), 7.16–7.20 (m, 4 H, Ar-H), 7.57 (s, 2 H, Ar-H), 8.28 (br. s, J =
2.0 Hz, 2 H, NH) ppm.
1.70 (s, 3 H, NHCOCH3), 3.90 (dd, J1 = 5.0, J2 = 7.5 Hz, 2 H,
CHCH2NH), 4.87 (dd, J1 = J2 = 7.5 Hz, 1 H, CHCH2NH), 7.28
(br. t, J = 5.0 Hz, 1 H, NHCOCH3), 7.44 (d, J = 9.0 Hz, 2 H, Ar-
H), 7.47 (s, 2 H, Ar-H), 7.87 (dd, J1 = 2.0, J2 = 9.0 Hz, 2 H, Ar-
H), 8.43 (d, J = 2.0 Hz, 2 H, Ar-H), 10.76 (br. s, 2 H, NH) ppm.
N-[2,2-Bis(5-methoxy-1H-indol-3-yl)ethyl]acetamide (4m): Yield:
37 mg (99%); white solid. The chemical-physical data are in agree-
ment to those reported.[9c] 1H NMR (200 MHz, [D6]DMSO,
N-[2,2-Bis(6-chloro-1H-indol-3-yl)ethyl]acetamide (4r): Eluent: ethyl
acetate/cyclohexane (6:4), yield 25 mg (65%); brownish solid; m.p.
20 °C): δ = 1.76 (s, 3 H, NHCOCH3), 3.68 (s, 6 H, Ar-OCH3), 3.75 174–176 °C; TLC: Rf = 0.60 (ethyl acetate; UV, CAM). FTIR
(dd, J1 = 5.0, J2 = 7.0 Hz, 2 H, CHCH2NH), 4.51 (dd, J1 = J2 =
(neat): νmax = 3403, 1644, 1554 cm–1. 1H NMR (200 MHz, CDCl3,
7.0 Hz, 1 H, CHCH2NH), 6.68 (dd, J1 = 2.5, J2 = 8.5 Hz, 2 H, Ar- 20 °C): δ = 1.91 (s, 3 H, NHCOCH3), 3.97 (dd, J1 = 5.5, J2
˜
=
H), 7.03 (d, J = 2.5 Hz, 2 H, Ar-H), 7.11 (d, J = 2.0 Hz, 2 H, Ar-
H), 7.21 (d, J = 8.5 Hz, 2 H, Ar-H), 7.91 (br. t, J = 5.0 Hz, 1 H,
NHCOCH3), 10.64 (br. d, J = 2.0 Hz, 2 H, NH) ppm.
7.0 Hz, 2 H, CHCH2NH), 4.64 (dd, J1 = J2 = 7.0 Hz, 1 H,
CHCH2NH), 5.63 (br. t, J = 5.5 Hz, 1 H, NHCOCH3), 6.97 (s, 2
H, Ar-H), 7.00 (dd, J1 = 2.0, J2 = 7.5 Hz, 2 H, Ar-H), 7.36 (d, J
= 2.0 Hz, 2 H, Ar-H), 7.42 (d, J = 7.5 Hz, 2 H, Ar-H), 8.35 (br. s,
2 H, NH) ppm. 13C NMR (50 MHz, CDCl3, 20 °C): δ = 23.4, 34.1,
43.8, 111.2, 116.8, 120.2, 120.2, 122.6, 125.3, 128.1, 136.9,
170.4 ppm. MS (ESI): m/z (%) = 384 (100), 386 (65) [M – H]–.
C20H17Cl2N3O (386.28): calcd. C 62.19, H 4.44, N 10.88; found C
62.01, H 4.39, N 10.82.
N-[2,2-Bis(5-hydroxy-1H-indol-3-yl)ethyl]acetamide (4n): Eluent:
ethyl acetate; Yield: 10 mg (29%); brownish solid; m.p. 153–155 °C;
TLC: R = 0.42 (ethyl acetate; UV, CAM). FTIR (neat): ν
=
˜
f
max
3392, 2924, 1736, 1365 cm–1. 1H NMR (200 MHz, [D6]acetone,
20 °C): δ = 1.82 (s, 3 H, NHCOCH3), 3.88 (dd, J1 = 5.0, J2
=
7.5 Hz, 2 H, CHCH2NH), 4.55 (dd, J1 = J2 = 7.5 Hz, 1 H,
CHCH2NH), 6.67 (dd, J1 = 2.5, J2 = 8.5 Hz, 2 H, Ar-H), 7.02 (d,
N-[2,2-Bis(6-bromo-1H-indol-3-yl)ethyl]acetamide
(4s):
Yield:
J = 2.5 Hz, 2 H, Ar-H), 7.05 (d, J = 2.0 Hz, 2 H, Ar-H), 7.12 (br. t, 43 mg (90%); white solid. The chemical-physical data are in agree-
J = 5.0 Hz, 1 H, NHCOCH3), 7.19 (d, J = 8.5 Hz, 2 H, Ar-H), ment to those reported.[3a] 1H NMR (200 MHz, CD3OD, 20 °C): δ
7.67 (s, 2 H, Ar-OH), 9.75 (br. s, 2 H, NH) ppm. 13C NMR
(50 MHz, [D6]acetone, 20 °C): δ = 22.1, 34.5, 43.7, 103.4, 111.3,
111.5, 116.1, 122.9, 128.1, 131.8, 150.4, 169.1 ppm. MS (ESI): m/z
= 1.85 (s, 3 H, NHCOCH3), 3.85–391 (m, 2 H, CHCH2NH), 4.71
(dd, J1 = J2 = 7.5 Hz, 1 H, CHCH2NH), 7.03 (dd, J1 = 2.0, J2 =
8.5 Hz, 2 H, Ar-H), 7.07 (d, J = 0.5 Hz, 2 H, Ar-H), 7.41 (d, J =
= 372 [M + Na]+, 348 [M – H]–, 408 [M + CH3COO]–. C20H19N3O3 8.5 Hz, 2 H, Ar-H), 7.49 (d, J = 2.0 Hz, 2 H, Ar-H), 8.06 (br. t, J
(349.39): calcd. C 68.75, H 5.48, N 12.03; found C 68.56, H 5.57,
N 11.99.
= 5.5 Hz, 1 H, NHCOCH3), 10.48 (br. s, 2 H, NH) ppm.
N-[2,2-Bis(6-methyl-1H-indol-3-yl)ethyl]acetamide (4t): Eluent:
ethyl acetate/cyclohexane (7:3), yield 30 mg (87%); brownish solid;
m.p. 114–116 °C; TLC: Rf = 0.65 (ethyl acetate; UV, CAM). FTIR
N-{2,2-Bis[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
indol-3-yl]ethyl}acetamide (4o): Eluent: ethyl acetate, yield 38 mg
(67%); white solid; m.p. 243–245 °C; TLC: Rf = 0.50 (ethyl acetate;
(neat): ν
= 3404, 2923, 1648, 1454 cm–1. 1H NMR (200 MHz,
˜
max
1
UV, CAM). FTIR (neat): ν
= 3425, 1630, 1356 cm–1. H NMR
CDCl3, 20 °C): δ = 1.85 (s, 3 H, NHCOCH3), 2.44 (s, 6 H, Ar-
˜
max
(200 MHz, [D6]DMSO, 25 °C): δ = 1.33 (s, 24 H, Bpin), 1.80 (s, 3 CH3), 3.98 (dd, J1 = 5.5, J2 = 7.0 Hz, 2 H, CHCH2NH), 4.65 (dd,
H, NHCOCH3), 3.73 (dd, J1 = 5.5, J2 = 7.5 Hz, 2 H, CHCH2NH),
4.80 (dd, J1 = J2 = 7.5 Hz, 1 H, CHCH2NH), 7.10 (d, J = 2.0 Hz,
2 H, Ar-H), 7.38 (d, J = 8.0 Hz, 2 H, Ar-H), 7.46 (d, J = 8.0 Hz,
2 H, Ar-H), 7.96 (s, 2 H, Ar-H), 8.02 (br. t, J = 5.5 Hz, 1 H,
J1 = J2 = 7.0 Hz, 1 H, CHCH2NH), 5.64 (br. t, J = 5.5 Hz, 1 H,
NHCOCH3), 6.84 (d, J = 2.0 Hz, 2 H, Ar-H), 6.89 (d, J = 8.0 Hz,
2 H, Ar-H), 7.12 (s, 2 H, Ar-H), 7.46 (d, J = 8.0 Hz, 2 H, Ar-H),
8.11 (br. s, 2 H, NH) ppm. 13C NMR (50 MHz, CDCl3, 20 °C): δ
NHCOCH3), 11.04 (br. d, J = 2.0 Hz, 2 H, NH) ppm. 13C NMR = 21.7, 23.4, 34.2, 43.9, 111.2, 116.6, 119.1, 121.1, 121.5, 124.7,
(50 MHz, [D6]DMSO, 20 °C): δ = 23.1, 25.2, 29.5, 32.0, 83.5, 111.4,
117.6, 123.2, 123.2, 126.6, 127.0, 127.5, 138.9, 169.6 ppm. MS
(ESI): m/z (%) = 567 (55), 568 (100), 569 (40) [M – H]–.
C32H41B2N3O5 (569.31): calcd. C 67.51, H 7.26, N 7.38; found C
67.71, H 7.21, N 7.32.
131.8, 137.1, 170.4 ppm. MS (ESI): m/z = 346 [M + H]+, 368 [M
+ Na]+, 344, [M – H]–, 404, [M + CH3COO]–. C22H23N3O (345.44):
calcd. C 76.49, H 6.71, N 12.16; found C 76.61, H 6.73, N 12.12.
N-[2,2-Bis(7-bromo-1H-indol-3-yl)ethyl]acetamide (4u): Eluent:
ethyl acetate/cyclohexane (1:1), yield 32 mg (68%); white solid; m.p.
207–211 °C; TLC: Rf = 0.70 (ethyl acetate; UV, CAM). FTIR
Dimethyl
3,3Ј-(2-Acetamidoethane-1,1-diyl)bis(1H-indole-5-carb-
oxylate) (4p): Eluent: ethyl acetate/dichloromethane (8:2), yield
23 mg (53%); white solid; m.p. 247–249 °C; TLC: Rf = 0.26 (ethyl
(neat): νmax = 3420, 1630, 1433 cm–1. 1H NMR (200 MHz, CDCl3,
˜
20 °C): δ = 1.91 (s, 3 H, NHCOCH3), 4.03 (dd, J1 = 5.5, J2
=
acetate; UV, CAM). FTIR (neat): ν
= 3359, 2923, 1688 cm–1.
7.0 Hz, 2 H, CHCH2NH), 4.70 (dd, J1 = J2 = 7.0 Hz, 1 H,
CHCH2NH), 5.58 (br. t, J = 5.5 Hz, 1 H, NHCOCH3), 6.95 (dd,
˜
max
1H NMR (200 MHz, [D6]DMSO, 25 °C): δ = 1.75 (s, 3 H,
NHCOCH3), 3.73 (dd, J1 = 5.5, J2 = 7.0 Hz, 2 H, CHCH2NH), J1 = J2 = 8.0 Hz, 2 H, Ar-H), 7.12 (d, J = 2.0 Hz, 2 H, Ar-H), 7.35
3.79 (s, 6 H, Ar-COOCH3), 4.74 (dd, J1 = J2 = 7.0 Hz, 1 H, (d, J = 8.0 Hz, 2 H, Ar-H), 7.52 (d, J = 8.0 Hz, 2 H, Ar-H), 8.27
CHCH2NH), 7.30 (d, J = 2.0 Hz, 2 H, Ar-H), 7.41 (d, J = 8.5 Hz, (br. s, 2 H, NH) ppm. 13C NMR (50 MHz, CDCl3, 20 °C): δ = 23.4,
2 H, Ar-H), 7.68 (dd, J1 = 1.5, J2 = 8.5 Hz, 2 H, Ar-H), 8.01 (br. t,
J = 5.5 Hz, 1 H, NHCOCH3), 8.19 (d, J = 1.5 Hz, 2 H, Ar-H), 170.3 ppm. MS (ESI): m/z (%) = 472 (50), 474 (100), 476 (50) [M –
11.31 (br. d, J = 2.0 Hz, 2 H, NH) ppm. 13C NMR (50 MHz, [D6]- H]–. C20H17Br2N3O (475.18): calcd. C 50.55, H 3.61, N 8.84; found
34.7, 43.7, 104.9, 117.9, 118.7, 120.8, 122.6, 124.6, 127.9, 135.3,
DMSO, 25 °C): δ = 22.9, 33.7, 41.1, 53.6, 111.9, 118.2, 120.2, 121.8, C 50.41, H 3.56, N 8.77.
122.4, 124.8, 126.8, 139.5, 167.7, 169.8 ppm. MS (ESI): m/z = 434
N-[2,2-Bis(7-methyl-1H-indol-3-yl)ethyl]acetamide (4v): Eluent:
ethyl acetate/dichloromethane (1:1), yield 34 mg (98%); brownish
[M + H]+, 451 [M + NH4]+, 456 [M + Na]+, 432 [M – H]–.
C24H23N3O5 (433.46): calcd. C 66.50, H 5.35, N 9.69; found C
66.71, H 5.31, N 9.62.
solid; m.p. 228–230 °C; TLC; Rf = 0.30 (ethyl acetate; UV, CAM).
FTIR (neat): ν
= 3404, 2923, 1648, 1454 cm–1. 1H NMR
˜
max
N-[2,2-Bis(5-nitro-1H-indol-3-yl)ethyl]acetamide (4q): Yield: 18 mg
(45%); yellow solid. The chemical-physical data are in agreement
to those reported.[9c] 1H NMR (200 MHz, [D6]acetone, 20 °C): δ =
(200 MHz, [D6]DMSO, 25 °C): δ = 1.75 (s, 3 H, NHCOCH3), 2.42
(s, 6 H, Ar-CH3), 3.77 (dd, J1 = 5.5, J2 = 7.5 Hz, 2 H, CHCH2NH),
4.60 (dd, J1 = J2 = 7.5 Hz, 1 H, CHCH2NH), 6.75–6.84 (m, 4 H,
Eur. J. Org. Chem. 2014, 3822–3830
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3827

G. Piersanti et al.
Ar-H), 7.13 (d, J = 2.0 Hz, 2 H, Ar-H), 7.30–7.36 (m, 2 H, Ar-H), 7.36 (d, J = 8.5 Hz, 2 H, Ar-H), 7.54 (d, J = 1.5 Hz, 2 H, Ar-H),
FULL PAPER
7.91 (br. t, J = 5.5 Hz, 1 H, NHCOCH3), 10.76 (br. d, J = 2.0 Hz,
2 H, NH) ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ = 17.2,
23.2, 34.5, 44.2, 117.1, 117.3, 118.7, 120.8, 121.7, 122.5, 126.9,
136.4, 169.7 ppm. MS (ESI): m/z = 346 [M + H]+, 368 [M +
Na]+, 344 [M – H]–. C22H23N3O (345.44): calcd. C 76.49, H 6.71,
N 12.16; found C 76.64, H 6.66, N 12.05.
8.18 (br. s, 2 H, NH) ppm. 13C NMR (50 MHz, CDCl3, 20 °C): δ
= 33.9, 43.6, 114.4, 115.7, 115.7 (q, J = 286.0 Hz, 1 C), 116.2,
120.5, 122.5, 123.1, 125.3, 137.4, 157.3 (q, J = 37.0 Hz, 1 C) ppm.
MS (ESI): m/z (%) = 526 (50), 528 (100), 530 (50) [M – H]–.
A mixture of crude trifluoroacetamide derivative 5 and potassium
carbonate (1 mmol) in MeOH (1.87 mL) and H2O (0.13 mL) was
stirred and heated at reflux for 1–2 h. The MeOH was removed
under reduced pressure and water was added (30 mL). The aqueous
solution was extracted with dichloromethane (3ϫ 30 mL) and the
resulting solution was dried with Na2SO4 and concentrated in
vacuo. The crude material was purified by flash chromatography
on neutral alumina.
General Procedure for the Synthesis of 2,2-Di(1H-indol-3-yl)ethan-
amine Derivatives 6a, 6l, 6p and 1: Diphenyl phosphate (0.02 mmol)
was added to a solution of the appropriate indole derivative 2
(0.4 mmol) and (trifluoroacetylamino)acetaldehyde dimethyl acetal
(3b; 0.2 mmol) in anhydrous acetonitrile (0.2 mL), and the resulting
mixture was stirred at 80 °C for 12–48 h in a sealed tube, monitor-
ing the progress of the reaction by TLC and HPLC-MS. After cool-
ing to room temperature, saturated aqueous NaHCO3 (30 mL) and
dichloromethane (30 mL) were added and the two phases were sep-
arated. The aqueous solution was extracted with dichloromethane
(3ϫ 20 mL). After drying over dry Na2SO4, the combined organic
phases were concentrated in vacuo and the resulting crude product
5 was characterized and utilized without further purification.
2,2-Di(1H-indol-3-yl)ethanamine (6a): Yield: 30 mg (55%); white
solid. The chemical-physical data are in agreement to those re-
ported.[21] 1H NMR (200 MHz, [D6]DMSO, 25 °C): δ = 3.88 (d, J
= 7.0 Hz, 2 H, CHCH2NH2), 4.69 (dd, J1 = J2 = 7.0 Hz, 1 H,
CHCH2NH), 6.85 (dd, J1 =J2 = 8.0 Hz, 2 H, Ar-H), 6.98 (dd, J1
= J2 = 8.0 Hz, 2 H, Ar-H), 7.14 (d, J = 2.0 Hz, 2 H, Ar-H), 7.28
(d, J = 8.0 Hz, 2 H, Ar-H), 7.47 (d, J = 8.0 Hz, 2 H, Ar-H), 10.71
(br. s, 2 H, NH) ppm.
N-[2,2-Di(1H-indol-3-yl)ethyl]-2,2,2-trifluoroacetamide (5a): TLC:
Rf = 0.35 (cyclohexane/ethyl acetate, 7:3; UV, CAM). 1H NMR
(200 MHz, CDCl3, 20 °C): δ = 4.13 (dd, J1 = 5.5, J2 = 7.0 Hz, 2
H, CHCH2NH), 4.80 (dd, J1 = J2 = 7.0 Hz, 1 H, CHCH2NH),
6.49 (br. t, J = 5.5 Hz, 1 H, NHCOCH3), 6.98 (d, J = 2.0 Hz, 2 H,
Ar-H), 7.09 (dd, J1 = J2 = 8.0 Hz, 2 H, Ar-H), 7.23 (dd, J1 = J2 =
8.0 Hz, 2 H, Ar-H), 7.38 (d, J = 8.0 Hz, 2 H, Ar-H), 7.60 (d, J =
8.0 Hz, 2 H, Ar-H), 8.08 (br. s, 2 H, NH) ppm. 13C NMR (50 MHz,
CDCl3, 20 °C): δ = 34.0, 43.8, 111.4, 115.7, 115.8 (q, J = 286.0 Hz,
1 C), 119.3, 119.7, 122.2, 122.4, 126.5, 136.7, 157.2 (q, J = 37.0 Hz,
1 C) ppm. MS (ESI): m/z = 372 [M + H]+, 389 [M + NH4]+, 394
[M + Na]+, 370 [M – H]–.
2,2-Bis(5-bromo-1H-indol-3-yl)ethanamine (6l): Eluent: dichloro-
methane/methanol/ammonia, 98:1:1, yield 76 mg (88%); white so-
lid; m.p. 136–138 °C; TLC: Rf = 0.19 (silica gel; dichloromethane/
methanol/TEA, 90:9:1; UV, CAM). FTIR (neat): ν
= 3411,
˜
max
3012, 2962 cm–1. 1H NMR (200 MHz, CD3OD, 20 °C): δ = 3.32
(d, J = 7.5 Hz, 2 H, CHCH2NH2), 4.43 (dd, J1 = J2 = 7.5 Hz, 1
H, CHCH2NH2), 7.15 (dd, J1 = 2.0, J2 = 8.5 Hz, 2 H, Ar-H), 7.16
(s, 2 H, Ar-H), 7.27 (d, J = 8.5 Hz, 2 H, Ar-H), 7.61 (d, J = 1.5 Hz,
2 H, Ar-H) ppm. 13C NMR (50 MHz, CD3OD, 20 °C): δ = 37.1,
45.5, 111.4, 112.6, 115.8, 121.1, 123.4, 123.7, 128.6, 135.7 ppm. MS
(ESI): m/z (%) = 430 (50), 432 (100), 434 (50) [M – H]–.
C18H15Br2N3 (433.14): calcd. C 49.91, H 3.49, N 9.70; found C
49.89, H 3.48, N 9.75.
N-[2,2-Bis(5-bromo-1H-indol-3-yl)ethyl]-2,2,2-trifluoroacetamide
(5l): TLC: Rf = 0.47 (cyclohexane/ethyl acetate, 1:1; UV, CAM).
1H NMR (200 MHz, CDCl3, 20 °C): δ = 4.06 (dd, J1 = 5.5, J2 =
7.0 Hz, 2 H, CHCH2NH), 4.66 (dd, J1 = J2 = 7.0 Hz, 1 H,
CHCH2NH), 6.54 (br. t, J = 5.5 Hz, 1 H, NHCOCH3), 7.03 (d, J =
2.5 Hz, 2 H, Ar-H), 7.21–7.32 (m, 4 H, Ar-H), 7.65 (d, J = 1.0 Hz, 2
H, Ar-H), 8.31 (br. s, 2 H, NH) ppm. 13C NMR (50 MHz, CDCl3,
20 °C): δ = 33.9, 43.5, 113.0, 113.0, 114.9, 115.8 (q, J = 286.0 Hz,
1 C), 121.7, 123.3, 125.4, 128.1, 135.3, 157.4 (q, J = 37.0 Hz, 1
C) ppm. MS (ESI): m/z (%) = 526 (50), 528 (100), 530 (50) [M –
H]–.
Dimethyl 3,3Ј-(2-Aminoethane-1,1-diyl)bis(1H-indole-5-carboxylate)
(6p): Eluent: dichloromethane/methanol/ammonia (98:1:1), yield
53 mg (68%); white solid; m.p. 154–156 °C; TLC: Rf = 0.23 (silica
gel; dichloromethane/methanol/TEA, 90:9:1; UV, CAM). FTIR
(neat): ν
= 3413, 1642, 1433 cm–1. 1H NMR (200 MHz,
˜
max
CD3OD, 20 °C): δ = 3.44 (d, J = 7.5 Hz, 2 H, CHCH2NH2), 3.84
(s, 6 H, COOCH3), 4.67 (dd, J1 = J2 = 7.5 Hz, 1 H, CHCH2NH2),
7.26 (s, 2 H, Ar-H), 7.38 (dd, J1 = 0.5, J2 = 8.5 Hz, 2 H, Ar-H),
7.78 (dd, J1 = 1.5, J2 = 8.5 Hz, 2 H, Ar-H), 8.32 (dd, J1 = 0.5, J2
= 1.5 Hz, 2 H, NH) ppm. 13C NMR (50 MHz, CD3OD, 20 °C): δ
= 36.9, 45.6, 50.8, 110.8, 117.5, 120.1, 121.7, 122.3, 123.8, 126.4,
139.8, 168.7 ppm. MS (ESI): m/z = 392 [M + H]+, 414 [M + Na]
+, 390 [M – H]–. C22H21N3O4 (391.43): calcd. C 67.51, H 5.41, N
10.74; found C 67.44, H 5.36, N 10.68.
Dimethyl 3,3Ј-[2-(2,2,2-Trifluoroacetamido)ethane-1,1-diyl]bis(1H-
indole-5-carboxylate) (5p): TLC: Rf = 0.25 (cyclohexane/ethyl acet-
1
ate, 6:4; UV, CAM). H NMR (200 MHz, [D6]DMSO, 25 °C): δ =
3.80 (s, 6 H, NHCOCH3), 3.90 (dd, J1 = 5.0, J2 = 7.5 Hz, 2 H,
CHCH2NH), 4.90 (dd, J1 = J2 = 7.5 Hz, 1 H, CHCH2NH), 7.36
(d, J = 2.0 Hz, 2 H, Ar-H), 7.42 (d, J = 8.5 Hz, 2 H, Ar-H), 7.69
(dd, J1 = 1.5, J2 = 8.5 Hz, 2 H, Ar-H), 8.21 (d, J = 1.5 Hz, 2 H,
Ar-H), 9.61 (br. t, J = 5.0 Hz, 1 H, NHCOCH3), 11.36 (br. d, J =
2.0 Hz, 2 H, NH) ppm. 13C NMR (50 MHz, [D6]DMSO, 25 °C): δ
= 33.0, 44.8, 52.1, 112.0, 116.3 (q, J = 286.0 Hz, 1 C), 117.3, 120.4,
121.6, 122.5, 124.9, 126.7, 139.5, 156.7 (q, J = 36.0 Hz, 1 C),
167.7 ppm. MS (ESI): m/z = 488 [M + H]+, 505 [M + NH4]+, 510
[M + Na]+, 486 [M – H]–.
2,2-Bis(6-bromo-1H-indol-3-yl)ethanamine (1): Yield: 71 mg (82%);
white solid. The chemical-physical data are in agreement to those
reported.[3a] 1H NMR (200 MHz, [D6]DMSO, 25 °C): δ = 3.20 (d,
J = 7.0 Hz, 2 H, CHCH2NH2), 3.34 (br. s, 2 H, CHCH2NH2), 4.33
(dd, J1 = J2 = 7.0 Hz, 1 H, CHCH2NH), 6.98 (dd, J1 = 1.5, J2 =
8.5 Hz, 2 H, Ar-H), 7.25 (d, J = 1.5 Hz, 2 H, Ar-H), 7.38 (d, J =
8.5 Hz, 2 H, Ar-H), 7.48 (d, J = 1.5 Hz, 2 H, Ar-H), 10.99 (br. s,
2 H, NH) ppm.
N-[2,2-Bis(6-bromo-1H-indol-3-yl)ethyl]-2,2,2-trifluoroacetamide
(5s): TLC: Rf = 0.28 (cyclohexane/ethyl acetate, 7:3; UV, CAM).
1H NMR (200 MHz, CDCl3, 20 °C): δ = 4.08 (dd, J1 = 5.5, J2 =
7.0 Hz, 2 H, CHCH2NH), 4.71 (dd, J1 = J2 = 7.0 Hz, 1 H,
CHCH2NH), 6.43 (br. t, J = 5.5 Hz, 1 H, NHCOCH3), 7.01 (d, J
= 2.5 Hz, 2 H, Ar-H), 7.16 (dd, J1 = 1.5, J2 = 8.5 Hz, 2 H, Ar-H),
2,2-Bis(6-bromo-1H-indol-3-yl)-N,N-dimethylethanamine (8): To a
stirred solution of 2,2-bis(6-bromo-1H-indol-3-yl)ethanamine (1;
44 mg, 0.10 mmol) in methanol (2 mL) was added glacial acetic
acid (26 μL, 0.46 mmol) followed by sodium cyanoborohydride
(14 mg, 0.23 mmol) under Argon at 0 °C. A solution of formalde-
3828
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3822–3830

Brønsted Acid Catalyzed Bisindolization of α-Amido Acetals
hyde (38%, 21 μL, 0.28 mmol) in methanol (1.4 mL) was then
added. The resulting mixture was stirred at room temperature for
1 h. Aqueous Na2CO3 (2 n, 15 mL) was added to adjust the pH to
8–9 and the methanol was removed under reduce pressure. The
residue was partitioned between CHCl3 and water and the organic
layer was washed with water (15 mL) and brine (15 mL), dried with
Na2SO4, and concentrated in vacuo. The crude product was puri-
fied by column flash chromatography (silica gel; dichloromethane/
methanol/ammonia, 99:1:0.1) to afford 8 (42 mg, 90%) as a white
Acknowledgments
The authors thank the University of Urbino “Carlo Bo” for finan-
cial support. Silvia Bartolucci and Francesca Bartoccini are
thanked for skilful technical assistance.
[1] a) D. J. Faulkner, Nat. Prod. Rep. 2002, 19, 1–49; b) J. W. Blunt,
B. R. Copp, W.-P. Hu, M. H. G. Munro, P. T. Northcote, M. R.
Prinsep, Nat. Prod. Rep. 2009, 26, 170–244.
solid. TLC: Rf
95:5:0.1; UV, CAM). FTIR (neat): ν
=
0.49 (dichloromethane/methanol/ammonia,
= 3023, 1433 cm–1. 1H
˜
max
[2] a) W. Gul, T. Hamann, Life Sci. 2005, 78, 442–453; b) A. J.
Kochanowska-Karamyan, M. T. Hamann, Chem. Rev. 2010,
110, 4489–4497; c) S. B. Bharate, S. D. Sawant, P. P. Singh,
R. A. Vishwakarma, Chem. Rev. 2013, 113, 6761–6815.
[3] a) E. Fahy, B. C. M. Potts, D. J. Faulkner, K. Smith, J. Nat.
Prod. 1991, 54, 564–569; b) G. Bifulco, I. Bruno, R. Riccio, J.
Lavayre, G. Bourdy, J. Nat. Prod. 1995, 58, 1254–1260.
[4] Some natural product analogues have shown antiserotonin ac-
tivity and a strong affinity for somatostatin and neuropeptide
Y receptors in receptor-binding assays; see ref. 2a and 3b.
[5] a) M. Shiri, M. Ali-Zolfigol, H. G. Kruger, Z. Tanbakouchain,
Chem. Rev. 2010, 110, 2250–2293; b) K. S. Ryan, C. L. Dren-
nan, Chem. Biol. 2009, 16, 351–364.
[6] a) L. Xue, J. J. Pestka, L. Maoxiang, G. L. Firestone, L. F. Bjel-
danes, J. Nutr. Biochem. 2008, 19, 336–344; b) J. E. Riby, L.
Xue, U. Chatterji, E. L. Bjeldanes, G. L. Firestone, L. F. Bjeld-
anes, Mol. Pharmacol. 2006, 69, 430–439; c) S. Safe, S. Papi-
neni, S. Chintharlapalli, Cancer Lett. 2008, 269, 326–338; d)
P. K. Kandala, S. E. Wright, S. K. Srivastava, J. Pharmacol.
Exp. Ther. 2012, 341, 24–32; e) V. Singh-Gupta, S. Banerjee,
C. K. Yunker, J. T. Rakowski, M. C. Joiner, A. A. Konski, F. H.
Sarkar, G. G. Hillman, Cancer Lett. 2012, 318, 86–92.
[7] N. Bhatnagar, X. Li, Y. Chen, X. Zhou, S. H. Garrett, B. Guo,
Cancer Prev. Res. 2009, 2, 581–589. DIM is currently under-
going several clinical trials for the prevention and treatment of
human diseases in particular in cancer. For example, DIM is
in phase II/III trial studies for determining its efficacy in
patients with breast cancer; clinicaltrials.gov, identifier:
NCT01391689.
[8] a) G. W. Gribble, J. Nat. Prod. 1992, 55, 1353–1395; b) C.
Wagner, M. El Omari, G. M. König, J. Nat. Prod. 2009, 72,
540–553; c) G. W. Gribble, Heterocycles 2012, 84, 157–207.
[9] a) R. R. Jella, R. Nagarajan, Tetrahedron 2013, 69, 10249–
10253; b) P. S. Naidu, P. J. Bhuyan, Tetrahedron Lett. 2012, 53,
426–428; c) M. Chakrabarty, N. Ghosh, R. Basak, Y. Harigaya,
Synth. Commun. 2004, 34, 421–434; d) M. Chakrabarty, N.
Ghosh, R. Basak, Y. Harigaya, Tetrahedron Lett. 2002, 43,
4075–4078.
[10] a) J. N. Denis, H. Mauger, Y. Vallee, Tetrahedron Lett. 1997,
38, 8515–8518; b) H. Chalaye-Mauger, J. N. Denis, M. T. Aver-
buch-Pouchot, Y. Vallee, Tetrahedron 2000, 56, 791–804.
[11] a) M. Chakrabarty, R. Basak, N. Ghosh, Y. Harigaya, Tetrahe-
dron 2004, 60, 1941–1949; b) M. Chakrabarty, R. Basak, N.
Gosh, Tetrahedron Lett. 2001, 42, 3913–3915.
NMR (200 MHz, CDCl3, 20 °C): δ = 2.42 [s, 6 H, CHCH2N-
(CH3)2], 3.09 [d, J = 7.5 Hz, 2 H, CHCH2N(CH3)2], 4.68 [dd, J1 =
J2 = 7.5 Hz, 1 H, CHCH2N(CH3)2], 6.83 (d, J = 2.0 Hz, 2 H, Ar-
H), 7.12 (dd, J1 = 1.5, J2 = 8.5 Hz, 2 H, Ar-H), 7.19 (d, J = 1.5 Hz,
2 H, Ar-H), 7.38 (d, J = 8.5 Hz, 2 H, Ar-H), 8.56 (br. s, 2 H,
NH) ppm. 13C NMR (50 MHz, CDCl3, 20 °C): δ = 32.3, 45.6, 64.6,
114.1, 115.3, 117.7, 120.3, 122.3, 122.9, 125.5, 137.5 ppm. MS
(ESI): m/z = 458 (50), 460 (100), 462 (50) [M – H]–. C20H19Br2N3
(461.20): calcd. C 52.09, H 4.15, N 9.11; found C 52.00, H 4.11, N
9.01.
Bis(6-bromo-1H-indol-3-yl)methane (9): H2SO4 (96%, 2.6 μL) was
added to a solution of 6-bromoindole (195 mg, 0.92 mmol) and
aqueous 37% formaldehyde (37 μL, 0.49 mmol) in CH3OH (1 mL).
The mixture was stirred at room temperature in the dark for 2 h,
and concentrated in the dark to give a crude solid that was purified
by flash chromatography (neutral aluminum oxide; cyclohexane/
ethyl acetate, 7:3).[18] Yield: 92 mg (49%); white solid. The chemi-
cal-physical data are in agreement with those reported.[22] 1H NMR
(200 MHz, [D6]acetone, 20 °C): δ = 4.20 (s, 2 H, CH2), 7.09 (dd, J1
= 2.0, J2 = 8.5 Hz, 2 H, Ar-H), 7.17 (d, J = 2.0 Hz, 2 H, Ar-H),
7.49 (d, J = 8.5 Hz, 2 H, Ar-H), 7.57 (d, J = 1.5 Hz, 2 H, Ar-H),
10.17 (br. s, 2 H, NH) ppm.
Biological Tests
Cell Cultures, Treatments and Cell Survival Studies: Immortalized
promonocytic leukaemia (U937), obtained from American Type
Culture Collection (ATCC, Rochville, MD, USA), were grown in
RPMI 1640 (Cambrex, Walkersville, MD, USA) supplemented
with 10% foetal bovine serum, 1% penicillin-streptomycin and 1%
glutamine, in a humidified atmosphere at 37 °C as described pre-
viously.[20]
Compounds 1, 4s, 7, 8, 9, 10 were dissolved at concentrations rang-
ing from 10 to 25 mm in DMSO as stock solutions, stored at –80 °C
and subsequently diluted before use. Treatments were carried out
at the reported concentrations and repeated every 24 h. Cellular
viability was evaluated by a Trypan blue dye exclusion assay 48 h
after treatment start, with a TC-10 automated cell counter (Bio-
Rad).
Cell Cycle and Hypodiploidy Analysis: Cell cycle and hypodiploid
cells were analyzed by using the propidium iodide staining pro-
cedure as previously reported.[21] Cells were fixed in ice-cold 70%
ethanol and stained by using a propidium iodide staining solution
(50 mgmL–1). Cytofluorimetric acquisitions were carried out with
a BD FACScalibur flow cytometer (BD Biosciences, San Jose, CA,
USA) and sample analysis was carried out with FlowJo 8.6.3 soft-
ware (Tree Star, Inc., Ashland, OR, USA). Cell cycle percentage
values were calculated by using a Dean–Jett–Fox model and the
significance of changes was evaluated by a Student t-test (PϽ0.05).
[12] S. Kandekar, R. Preet, M. Kashyap, R. Prasad, P. Mohapatra,
D. Das, S. R. Satapathy, S. Siddharth, V. Jain, M. Choudhuri,
C. N. Kundu, S. K. Guchhait, P. V. Bharatam, ChemMedChem
2013, 8, 1873–1884.
[13] S. Lucarini, M. Mari, G. Piersanti, G. Spadoni, Rsc Adv. 2013,
3, 19135–19143.
[14] a) G. Brandi, A. Fraternale, S. Lucarini, M. Paiardini, M.
De Santi, B. Cervasi, M. F. Paoletti, L. Galluzzi, A. Duranti,
M. Magnani, Anti-Cancer Agents Med. Chem. 2013, 13, 654–
662; b) M. De Santi, L. Galluzzi, S. Lucarini, M. F. Paoletti,
A. Fraternale, A. Duranti, C. De Marco, M. Fanelli, N. Zaffa-
roni, G. Brandi, M. Magnani, Breast Cancer Res. 2011, 13,
R33.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all new compounds.
Cell cycle alterations and hypodiploidy studies of compounds 1 and
7–10 are reported.
[15]
a) M. Righi, F. Topi, S. Bartolucci, A. Bedini, G. Piersanti, G.
Spadoni, J. Org. Chem. 2012, 77, 6351–6357; b) M. Righi, A.
Eur. J. Org. Chem. 2014, 3822–3830
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3829

G. Piersanti et al.
FULL PAPER
Bedini, G. Piersanti, F. Romagnoli, G. Spadoni, J. Org. Chem.
2011, 76, 704–707.
[18] The synthesis of 9 was performed as described previously, see:
S. Lucarini, M. De Santi, F. Antonietti, G. Brandi, G. Diaman-
tini, A. Fraternale, M. F. Paoletti, A. Tontini, M. Magnani, A.
Duranti, Molecules 2010, 15, 4085–4093.
[19] S. Amatori, I. Bagaloni, E. Macedi, M. Formica, L. Giorgi, V.
Fusi, M. Fanelli, Br. J. Cancer 2010, 103, 239–248.
[20] S. Amatori, F. Papalini, R. Lazzarini, B. Donati, I. Bagaloni,
M. R. Rippo, A. Procopio, P. G. Pelicci, A. Catalano, M.
Fanelli, Lung Cancer 2009, 66, 184–190.
[21] M. Baron, E. Métay, M. Lemaire, F. Popowycz, Green Chem.
2013, 15, 1006–1015.
[22] C. Sun, X. Zou, F. Li, Chem. Eur. J. 2013, 19, 14030–14033.
Received: February 11, 2014
[16]
No reaction occurs without Brønsted acid catalyst. Whereas a
number of acids such as para-toluenesulfonic acid and tri-
fluoroacetic acid were viable catalysts, DPP gave rise to the
best results. DPP has already been recognized as an efficient
promoter for Friedel–Crafts-type reaction of indoles, see: a)
M. K. Vecchione, A. X. Sun, D. Seidel, Chem. Sci. 2011, 2,
2178–2181; b) M. C. Haibach, I. Deb, C. K. De, D. Seidel, J.
Am. Chem. Soc. 2011, 133, 2100–2103; c) M. Righi, F. Bartoc-
cini, S. Lucarini, G. Piersanti, Tetrahedron 2011, 67, 7923–7928.
[17] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Syn-
thesis 3rd ed., John Wiley & Sons, New York, 1999.
Published Online: May 6, 2014
3830
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3822–3830