Solvent-free indoles addition to carbonyl compounds promoted by CeCl 3·7H2O-NaI-SiO2: An efficient method for the synthesis of streptindole

Article abstract of DOI:10.1055/s-2004-815967

Efficient electrophilic substitution reactions of indoles with various carbonyl compounds proceed easily in solvent-free conditions using CeCl ₃·7H₂O-NaI-SiO₂. system promoter, to afford the corresponding bis(1H-indol-3-yl

Full text of DOI:10.1055/s-2004-815967

PAPER
895
Solvent-Free Indoles Addition to Carbonyl Compounds Promoted by
CeCl3·7H2O–NaI–SiO2: An Efficient Method for the Synthesis of Streptindole
S
olvent-Free Indol
i
es
A
dd
u
ition to Carb
s
onyl Com
e
pounds ppe Bartoli,a Marcella Bosco,a Gioia Foglia,b Arianna Giuliani,b Enrico Marcantoni,*b Letizia Sambria
a
Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, v.le Risorgimento 4, 40136 Bologna Italy
b
Dipartimento di Scienze Chimiche, Università di Camerino, v. S. Agostino 1, 62032 Camerino (MC), Italy
Fax +39(0737)402297; E-mail: enrico.marcantoni@unicam.it.it
Received 7 January 2004; revised 19 January 2004
avoid the use of any solvent.10 The solvent-free
approach11 is particularly appealing when one reagent is a
liquid and available in large quantities, such as carbonyl
compounds. Our studies in this area include Michael reac-
Abstract: Efficient electrophilic substitution reactions of indoles
with various carbonyl compounds proceed easily in solvent-free
conditions using CeCl3·7H2O–NaI–SiO2 system promoter, to afford
the corresponding bis(1H-indol-3-yl)alkanes in high yields. The
synthetic value of the present procedure is demonstrated by the syn- tions of 1,3-dicarbonyl compounds12 and amines13 to a,b-
thesis of streptindole (9), human intestinal bacteria metabolite.
enones. Lately, during the course of some synthetic stud-
ies directed towards the preparation of alkaloids embody-
ing an indolyl moiety, we had the opportunity to examine
the addition of indoles to electron-deficient alkenes pro-
Key words: addition reactions, carbonyl complexes, indoles, lan-
thanides, Lewis acids, natural products
moted by
a
cerium(III) chloride heptahydrate
(CeCl3·7H2O) and sodium iodide (NaI) combination sup-
ported on silica gel (SiO2). Thus, due to the current chal-
lenge for developing solvent-free and environmentally
benign synthetically systems14 and to extend our interest
in the applications of CeCl3·7H2O for various organic
transformations,15 we have described a simple, general
and efficient protocol for the synthesis of b-indol-3-ylke-
tones by Michael addition of indoles to a,b-enones.16
However, in the case of a,b-unsaturated aldehydes the
procedure suffers from regiochemical restriction caused
by a competing 1,2- versus 1,4-addition. Attention was
then focused on the use of the CeCl3·7H2O–NaI system in
the addition of indoles to saturated carbonyl compounds
on a silica gel surface under solvent-free17 conditions
(Scheme 1).
In the last years several researchers have reported many
examples of new natural products in which the bis(1H-in-
dol-3-yl)alkane structure is present.1 This unit has been
recently found to exhibit important biological activity,2
and, therefore, the synthesis of these moieties has become
an interesting target to synthetic organic chemists. In par-
ticular, there has been an interesting emphasis on pharma-
cological activity, and a direct synthesis of 3,3¢-
bis(indolyl)alkanes is desired.1 The plethora of ingenious
methods developed to obtain these bis(1H-indol-3-yl)al-
kane derivatives is a clear testimony to their paramount
importance, and several procedures have been reported in
the literature using Lewis acid4 or protic acid5 promoters
for the addition of indole to carbonyl compounds. Unfor-
tunately, most of these procedures require rather harsh
acidic conditions, often incompatible6 with other sensitive
functions present in the substrates. In the last decade,
milder protocols have emerged based upon the use of cat-
alytic amounts of Lewis acids,4e,f,7 but the long reaction
time and complicated manipulation, along with the use of
environmentally harmful organic solvents, limited their
extension from the environmentally friendly viewpoint.
More recently, these electrophilic substitution reactions of
indoles with various aldehydes and ketones have been car-
ried out using I2 in organic solvents7 or in ionic liquids
without additional catalyst.8 Thus, there is a general inter-
est in a simple and efficient synthetic access to com-
pounds containing a bis(1H-indol-3-yl)alkane moiety.
R'
R"
CeCl3⋅7H2O
+
NaI, SiO2
O
N
H
2a-n
1 equiv
1
2 equiv
R'
R"
N
H
N
H
3a-n
Scheme 1
The addition reaction of indole (1) with isobutyraldehyde
(2a) in the presence of 0.3 equivalents of cerium salt and
0.3 equivalents of NaI supported on SiO2 (0.5 g/mmol car-
bonyl compound) proceeds well giving bis(1H-indol-3-
yl)alkane 3a in good yield for indole/aldehyde ratios larg-
er than 2.0. The results are summarized in Table 1, which
shows the addition reaction of aliphatic and aromatic al-
dehydes and ketones with indole in solvent-free condi-
tions. Our initial observation has been that the indole
Although performing organic synthesis in an aqueous me-
dium is a current challenge that will attract considerable
attention in the coming years,9 from the point of view of
green chemistry it would be even more convenient to
SYNTHESIS 2004, No. 6, pp 0895–0900
x
x
.
x
x
.2
0
0
4
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-815967; Art ID: Z00304SS
© Georg Thieme Verlag Stuttgart · New York

896
G. Bartoli et al.
PAPER
nitrogen did not require protection. Furthermore, the data sites.21 Furthermore, the CeCl3·7H2O–NaI–SiO2 system
from entries 3–7 reflect the electronic effects of a substi- has been used for the addition of indole to benzaldehyde
tuent group at 4-position of aryl aldehydes towards the re- (2c) in the presence of 2,6-di-tert-butyl-4-methylpyri-
action. The consequences suggest that aromatic aldehydes dine,22 and, as expected, our Lewis acid promoter has af-
with an electron-withdrawing substituent (i.e. NO2, CF3) forded bis(1H-indol-3-yl)alkane 3c in high yield and with
react much faster than benzaldehyde or aldehydes with an absolute purity.
electron-donating substituent (i.e. OCH3), and again,18 an
It should be noted that neither CeCl3 nor NaI alone could
opposite chemoselective outcome with respect to other
effect the addition even after one week. Undoubtedly, the
Lewis acids3 has been observed. Otherwise, the present
presence of NaI is essential for the reaction too. There-
reaction of indole with ketones required longer reaction
fore, a substoichiometric amount of the CeCl3·7H2O–NaI
times compared to aldehydes (entry 9). Also, the efficien-
system adsorbed on silica gel is an efficient Lewis acid
cy of the procedure is influenced by the ring size of cy-
promoter for the addition of indoles to carbonyl com-
cloalkanones (entries 10 and 12), and the reaction fails
pounds, and the procedure allowed us to adopt a very sim-
with seven-membered ring ketones.
ple workup process for the recovery of the bis(1H-indol-
The use of a SiO2 support facilitates the workup of the re- 3-yl)alkane products. Indeed, the reaction mixture has
action mixture19 and gave a better yield of products even been treated with an organic solvent (Et2O) able to dis-
though the reaction has also been observed in its absence. solve the organic material, while the CeCl3–NaI silica gel
Presumably, silica gel acts as a carrier to increase the sur- support could be removed by filtration. Unfortunately, at-
face area in this heterogeneous reaction and it is very tempts to directly reuse the solid supported catalyst in a
probable as well that the cerium salt interacts with hy- new addition reaction have been unsuccessful as catalytic
droxyl or even oxide groups at the surface of the support activity is lost. The solid support, nevertheless, is regener-
forming new active sites with possible silica gel local ated by new treatment with the CeCl3·7H2O–NaI combi-
structures. However, the fact that our methodology is nation, and the CeCl3·7H2O–NaI–SiO2 system prepared
clean and the adducts have been obtained in high yields with used SiO2 shows the same catalytic activity affording
without formation of any side products such as dimers or the adduct in almost identical yield.
trimers, normally observed under the influence of strong
acids,20 exclude the existence in the solid of a distribution
of sites containing simultaneously Brønsted and Lewis
Table 1 Addition of Indole 1 to Carbonyl Compounds Promoted by CeCl3·7H2O–NaI (30%) Supported on SiO2 at Room Temperaturea
Entry
1
Carbonyl Compound
Time (h)
2
Productb
Yield (%)c
97
O
H
2a
N
N
H
H
3a
3b
2
3
7
88
95
O
H
2b
N
H
N
H
16
O
H
Ph
N
H
N
H
2c
3c
(4-CF3)-C6H4
O
H
4
2.5
85
F3C
N
H
N
H
2d
3d
Synthesis 2004, No. 6, 895–900 © Thieme Stuttgart · New York

PAPER
Solvent-Free Indoles Addition to Carbonyl Compounds
897
Table 1 Addition of Indole 1 to Carbonyl Compounds Promoted by CeCl3·7H2O–NaI (30%) Supported on SiO2 at Room Temperaturea
(continued)
Entry
5
Carbonyl Compound
Time (h)
5
Productb
Yield (%)c
78
(4-NO2)-C6H4
O
H
O2N
N
N
H
H
2e
3e
6
7
8
21
12
32
80
70
76
O
H
(4-MeO)-C6H4
MeO
N
H
N
H
2f
3f
(4-Cl)-C6H4
O
H
Cl
N
H
N
H
2g
3g
3h
3i
O
2h
N
H
N
H
9
140
34
21d
O
Ph
N
H
N
H
2i
10
81
O
2l
N
H
N
H
3l
But
11
12
34
72
76
O
But
N
H
N
H
2m
3m
3n
24d
O
2n
N
H
N
H
a Reactions performed in the presence of 30 mol% of CeCl3·7H2O and 30 mol% of NaI supported on silica gel.
b All products were identified by their IR, NMR and GC/MS spectra.
c Yields of products isolated by column chromatography.
d Starting materials recovered.
Synthesis 2004, No. 6, 895–900 © Thieme Stuttgart · New York

898
G. Bartoli et al.
PAPER
It has been observed that the substitution on the indole nu- thetically useful. This search for new methods for the con-
cleus occurs exclusively at the 3-position. The fact that struction of organic molecules allows us to develop a new
different ratios of reactants principally give bis(indolyl) protocol for the synthesis of a natural product with biolog-
adducts 3 led us to the suggestion that the reaction prob- ical activity. This result also suggests that the design of
ably follows the pathway indicated in Scheme 2. The car- new synthetic applications should be possible, which will
bonyl compound is first activated by the Lewis acid allow the already significant utility of cerium(III) salts to
promoter system, and carries out an electrophilic addition be developed further. Additional investigations of our
reaction at C-3 of the indole giving intermediate 4. After Lewis acid promoter system in new schemes of synthesis
loss of water, an azafulvene derivative 5 is generated for the preparation of other biologically important sub-
which reacts further with a second molecule of indole to stances are in progress in our laboratories.
form bis(1H-indol-3-yl)alkanes 3.
O
CeCl3⋅7H2O
OH
H
1
+
OEt
R'
R"
NaI, SiO2
85%
R'
R"
O
1
+
6
O
Ce3+
N
COOEt
4
LiAlH4, Et2O
72%
(-H2O)
R'
R'
R"
N
H
N
H
R"
1
7
OH
N
N
N
Ce3+
Mg(ClO4)2
H
H
3
5
Ac2O
98%
N
H
N
Scheme 2
H
8
OCOCH3
Since the synthesis of bis(1H-indol-3-yl)alkanes consti-
tutes an important reaction in organic synthesis and to
evaluate better the usefulness of the present methodology,
we focused our attention on the synthesis of a biologically
active bis(indole), such as streptindole (9), for its broad
range of pharmacological activity.23 It has been isolated
from intestinal bacteria Streptococcus faecium IB37 and
causes DNA lesions in Bacillus subtilis cells. Previous
syntheses of this genotoxic metabolite have been carried
out by several groups, however, these routes are either la-
borious, comprised of steps of low yield, or require harsh
reagents that may lead to degradation of the indole nucle-
us.24,25 Consequently, we have been interested in prepar-
ing this compound, and we report thereafter an improved
route to Streptindole by utilizing relatively eco-friendly
reaction conditions. The strategy proceeds through known
intermediates but via a new route and provides the highest
overall yield of indole to date. For this purpose
(Scheme 3), we started the reaction from indole (1) and
ethyl glyoxylate (6) to give ethyl di-1H-indol-3-ylacetate
(7) which is reduced to the corresponding alcohol 8 by ac-
tion of lithium aluminium hydride. Finally, alcohol 8 is O-
acetylated in the presence of a Lewis acid catalyst to af-
ford streptindole (9). This acylation reaction is facilitated
by the action of dried Mg(ClO4)2 as a useful alternative to
metal triflate promoters.26
N
H
N
H
9
Scheme 3
All starting materials were commercial products. CeCl3·7H2O and
NaI were purchased from Aldrich, and were used without further
purification. All the obtained bis(1H-indol-3-yl)alkanes were char-
acterized by IR, GC/MS, H and 13C NMR spectroscopy. Com-
1
pounds 3a,25b 3c,8 3e,27 3f,27 3g,28 3h,5b 3i,5b 3l,5e and 3n5e are all
known and their structures were consistent with their published
physical data. 1H and 13C NMR spectra were recorded with a Varian
VXR 300 spectrometer and referenced to the solvent as internal
standard. Mass spectra were recorded on a Hewlett-Packard 5988
gas chromatography with a mass-selective detector MSD HP 5790
MS, utilizing electron ionization (EI) at an ionizing energy of 70
eV. Microanalyses were performed with a Perkin-Elmer Analyzer
2400 CHN. Infrared spectra were recorded on Perkin-Elmer FTIR
Paragon 500 spectrometer using thin films on NaCl plates. Only the
characteristic peaks are quoted. Analytical GC was performed with
a capillary fused silica column (0.32 mm × 25 m), stationary phase
OV1 (film thickness 0.40–0.45 mm). Solutions were evaporated un-
der reduced pressure with a rotary evaporator and the residue was
chromatographed on a Baker silica gel (230–400 mesh) column us-
ing a EtOAc–hexanes mixture as eluent. Analytical thin layer chro-
matography was performed using pre-coated glass-backed plates
(Merck Kieselgel 60 F254) and visualized by UV light, Von’s re-
agent, KMnO4 or iodine staine.
In conclusion, we have shown that bis(1H-indol-3-yl)al-
kanes can be synthesized by a simple and highly efficient
addition of indoles to carbonyl compounds using a
CeCl3·7H2O–NaI combination supported on silica gel.
The mildness of the reaction conditions and low cost of
the reagents should make the present methodology syn-
Synthesis of bis(1H-Indol-3-yl)alkanes; Typical Procedure
(Table 1, entry 1)
Silica gel (0.5 g) was added to a mixture of CeCl3·7H2O (0.113 g,
0.3 mmol) and NaI (13.4 mg, 0.3 mmol) in CH3CN (7 mL) and the
mixture was stirred overnight at r.t. The solvent was removed and
Synthesis 2004, No. 6, 895–900 © Thieme Stuttgart · New York

PAPER
Solvent-Free Indoles Addition to Carbonyl Compounds
899
to the resulting mixture was added indole (1, 0.234 g, 2 mmol) and
isobutyraldehyde (2a, 0.072 g, 1 mmol). The reaction mixture was
then stirred at r.t. until the disappearance of the starting indole (2 h,
checked by TLC and GC analyses). After addition of Et2O the mix-
ture was passed through a short pad of Celite and the filtrate was
concentrated under reduced pressure. The crude product was puri-
fied by flash column chromatography (EtOAc–hexanes, 25:75) to
give 0.283 g (97% yield) of adduct 3a.
1H NMR (300 MHz, CDCl3): d = 1.29 (t, 3 H, J = 7.1 Hz), 4.27 (q,
2 H, J = 7.1 Hz), 5.23 (s, 1 H), 6.89 (d, 2 H, J = 2.2 Hz), 7.09–7.28
(m, 6 H), 7.67 (d, 2 H, J = 7.3 Hz), 7.96 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.9, 40.9, 61.4, 111.6, 113.7,
119.5, 119.7, 122.2, 123.7, 126.9, 136.6, 173.9.
MS (EI, 70 eV): m/z (%) = 318 [M+], 258, 245 (100), 202, 116, 106,
87.
Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C,
75.49; H, 5.68; N, 8.82.
3,3¢-Pentane-1,1-diylbis-1H-indole (3b)
Colorless oil.
IR (neat): 3403, 1609, 1457 cm–1.
2,2-Di-1H-indol-3-ylethanol (8)
A solution of 7 (0.80 g, 2.51 mmol) in anhyd Et2O (23 mL) was add-
ed drop-wise to a stirred and cooled (0 °C) suspension of LiAlH4
(0.22 g, 5.93 mmol) in anhyd Et2O (18 mL) under a nitrogen atmos-
phere. The resulting mixture was vigorously stirred at r.t. for 1 h,
then quenched by addition of a 10% aq solution of potassium and
sodium tartrate (25 mL). The product was extracted with CHCl3 and
the combined organic layers were washed with H2O and brine dried
(MgSO4). The solvent was evaporated giving crude alcohol 8 that
was used in the next stage of preparation without purification.
1H NMR (300 MHz, CDCl3): d = 0.92 (t, 3 H, J = 7.2 Hz), 1.27–
1.44 (m, H), 2.15–2.45 (m, 2 H), 4.44 (t, 1 H, J = 8.0 Hz), 6.83–7.04
(m, 2 H), 7.17–7.50 (m, 8 H), 8.00 (br s, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.3, 25.7, 30.1, 31.1, 36.0, 110.9,
116.3, 120.3, 121.0, 124.1, 125.6, 136.0, 138.3.
MS (EI, 70 eV): m/z (%) = 302 [M+], 273, 245 (100), 186, 130, 116,
106, 57.
Anal. Calcd for C21H22N2: C, 83.40; H, 7.33; N, 9.26. Found: C,
83.42; H, 7.28; N, 9.23.
Yield: 0.50 g (72%); mp 49–51 °C.
IR (neat): 3404, 3386, 1629 cm–1.
3,3¢-{[4-(Trifluoromethyl)phenyl]methylene}bis-1H-indole (3d)
1H NMR (300 MHz, CDCl3): d = 1.71 (br s, 1 H), 4.30 (d, 2 H, J
= 5.8 Hz), 4.80 (t, 1 H, J = 5.8 Hz), 6.98–7.23 (m, 6 H), 7.36 (dd, 2
H, J = 8.1, 0.7 Hz), 7.62 (d, 2 H, J = 7.7 Hz), 8.04 (br s, 2 H).
Colorless oil.
IR (neat): 3402, 1456, 1324 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.96 (s, 1 H), 6.65 (d, 2 H, J = 2.56
Hz), 7.04–7.08 (m, 2 H), 7.21–7.38 (m, 4 H), 7.83–7.91 (m, 5 H),
7.99–8.07 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 39.3, 110.7, 113.3, 117.8, 120.6,
121.0, 121.4, 122.8, 123.2, 125.7, 125.9, 127.5, 128.3, 131.2, 134.2,
140.7, 155.7.
13C NMR (75 MHz, CDCl3): d = 29.6, 65.3, 110.9, 118.3, 119.8,
120.9, 126.3, 130.4, 138.2.
MS (EI, 70 eV): m/z (%) = 276 [M+], 258 (100), 245, 130, 116, 31.
Anal. Calcd for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C,
78.20; H, 5.82; N, 10.13.
MS (EI, 70 eV): m/z (%) = 390 [M+, 100], 274, 245, 145, 116.
Streptindole (9)
To a round-bottomed flask and under nitrogen atmosphere were
added Ac2O (0.174 mL, 1.71 mmol), Mg(ClO4)2 (3.8 mg, 0.0171
mmol), anhyd Et2O (5 mL) and in three small portions 2,2-di-1H-
indol-3-ylethanol (8) (0.45 g, 1.63 mmol). The mixture was stirred
at 20 °C until the reaction was complete (1 h, checked by TLC and
GC analyses). After Et2O and aqueous NaHCO3 had been added, the
mixture was stirred for 30 min to decompose the slight excess of
Ac2O. The aqueous layer was separated and extracted with Et2O.
The combined organic layers were dried (MgSO4) and the solvent
was evaporated to give pure streptindole (9).
Anal. Calcd for C24H17F3N2: C, 73.84; H, 4.39; N, 7.18. Found: C,
73.81; H, 4.38; N, 7.23.
3,3¢-(4-tert-Butylcyclohexane-1,1-diyl)bis-1H-indole (3m)
Colorless oil.
IR (neat): 3404, 1489 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.85 (s, 6 H), 0.93 (s, 3 H), 1.27–
1.53 (m, 4 H), 1.71–1.76 (m, 1 H), 2.21–2.40 (m, 3 H), 2.91–2.98
(m, 1 H), 6.83–6.98 (m, 3 H), 7.04–7.19 (m, 2 H), 7.24–7.35 (m, 3
H), 7.49 (d, 1 H, J = 8.1 Hz), 7.67 (d, 1 H, J = 8.1 Hz), 7.77 (br s, 1
H), 8.02 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 23.6, 28.4, 32.2, 38.5, 46.0, 51.0,
109.1, 117.2, 119.7, 120.3, 123.1, 124.8, 126.0, 140.3.
Yield: 0.224 g (98%); uncertain low mp.
IR (neat): 3403, 1722, 1618 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.00 (s, 3 H), 4.75 (d, 2 H, J = 7.0
Hz), 4.97 (t, 1 H, J = 7.0 Hz), 6.99–7.27 (m, 6 H), 7.37 (d, 2 H,
J = 7.7 Hz), 7.64 (d, 2 H, J = 7.3 Hz), 8.00 (br s, 2 H).
MS (EI, 70 eV): m/z (%) = 370 [M+], 313, 271 (100), 130, 116, 57.
13C NMR (75 MHz, CDCl3): d = 21.3, 33.7, 67.5, 11.3, 116.5,
119.6, 122.2, 122.4, 127.2, 136.6, 171.5.
Anal. Calcd for C26H30N2: C, 84.28; H, 8.16; N, 7.56. Found: C,
84.32; H, 8.18; N, 7.53.
MS (EI, 70 eV): m/z (%) = 318 [M+], 275, 245 (100), 116, 103, 60.
43.
Ethyl Di-1H-indol-3-ylacetate (7)
To a combination of CeCl3·7H2O (0.143 g, 0.38 mmol) and NaI (17
mg, 0.38 mmol) supported on silica gel (1.92 g) prepared as de-
scribed above was added indole (0.9 g, 7.68 mmol) and a 50% solu-
tion of ethyl glyoxylate (6) in toluene (0.75 mL, 3.84 mmol). The
resulting mixture was stirred at r.t. until the disappearance of indole
(48 h, checked by TLC analysis). Then Et2O was added and the re-
sulting mixture was concentrated. The crude product was purified
by flash column chromatography (EtOAc–hexanes, 40:60) to give
acetate 7 (1.04 g, 85% yield) as oil.
Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C,
75.44; H, 5.66; N, 8.78.
Acknowledgment
We thank the Italian MIUR (National Project ‘Stereoselezione in
Sintesi Organica. Metodologie and Applicazioni’) and the Univer-
sity of Camerino (funds FAR) for financial support. G. F. gratefully
acknowledges the Teuco Guzzini Montelupone Plant for post-grad-
uate fellowship.
IR (neat): 3402, 1732, 1620 cm–1.
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G. Bartoli et al.
PAPER
(12) Bartoli, G.; Bosco, M.; Bellucci, M. C.; Marcantoni, E.;
References
Sambri, L.; Torregiani, E. Eur. J. Org. Chem. 1999, 617.
(13) Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.; Sambri,
L.; Torregiani, E. J. Org. Chem. 2001, 66, 9052.
(14) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
(15) Bartoli, G.; Marcantoni, E.; Sambri, L. Synlett 2003, 2101;
and references cited therein.
(16) Bartoli, G.; Bartolacci, M.; Bosco, M.; Foglia, G.; Giuliani,
A.; Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem.
2003, 68, 4594.
(17) In our methodology of Lewis acid promoted solvent-free
reaction the term ‘solvent-free’ refers solely to the reaction
itself. On the other hand, preparation of initial adsorbate and
purification of products invariably involve the use of
solvent.
(18) Bartoli, G.; Bosco, M.; Giuliani, A.; Marcantoni, E.;
Palmieri, A.; Petrini, M.; Sambri, L. J. Org. Chem. 2004, ,
DOI: 10.1021/jo035542o.
(1) Kam, T. S. In Alkaloids, Chemical and Biological
Perspectives, Vol. 4; Pelletier, S. W., Ed.; Pergamon:
Amsterdam, 1999, 285.
(2) (a) Morris, S. A.; Anderson, R. J. Tetrahedron 1990, 46,
715. (b) Umezawa, K.; Ohse, T.; Yamamoto, T.; Koyano,
T.; Takahashi, Y. Anticancer Res. 1994, 14, 2413.
(c) Bifulco, G.; Bruno, I.; Riccio, R.; Lavayre, J.; Bourdy, G.
J. Nat. Prod. 1995, 58, 1254. (d) Amino, N.; Ohse, T.;
Koyano, T.; Umezawa, K. Anticancer Res. 1996, 16, 55.
(e) Umezawa, K.; Taniguchi, T.; Toi, M.; Ohse, T.; Isutsumi,
T.; Yamamoto, T.; Koyano, T.; Ishizuka, M. Drugs Exp.
Clin. Res. 1996, 22, 35. (f) Irie, T.; Kubushirs, K.; Suzuki,
K.; Tsukazaki, K.; Umezawa, K.; Nozawa, S. Anticancer
Res. 1999, 8, 49.
(3) (a) Bell, R.; Carmeli, S.; Sar, N. J. Nat. Prod. 1994, 57,
1587. (b) Denis, J.-N.; Mauger, H.; Vallée, Y. Tetrahedron
Lett. 1997, 38, 8515. (c) Garattini, E.; Marzi, M.; Mineko,
T.; Moretti, G. P.; Penco, A.; Tinti, O. Blood 2002, 100,
3719.
(4) (a) Chatterjee, A.; Manna, S.; Benerji, J.; Pascard, C.;
Prange, T.; Shoolery, J. J. Chem. Soc., Perkin Trans. 1 1989,
553. (b) Earle, M. J.; Fairhurst, R. A.; Heaney, H.
Tetrahedron Lett. 1991, 32, 6171. (c) Chen, D.; Yu, L.;
Wang, P. G. Tetrahedron Lett. 1996, 37, 4467. (d) Babu,
G.; Sridhar, N.; Perumal, P. T. Synth. Commun. 2000, 30,
1609. (e) Yadav, J. S.; Subba Reddy, B. V.; Murthy, Ch. V.
S. R.; Kumar, G. M.; Madam, Ch. Synthesis 2001, 783.
(f) Nagarajan, R.; Perumal, P. T. Tetrahedron 2002, 58,
1229. (g) Ji, S.-J.; Zhon, M.-F.; Gu, D.-G.; Wang, S. Y.;
Loh, T.-P. Synlett 2003, 2077.
(5) (a) Roomi, M.; MacDonald, S. Can. J. Chem. 1970, 48, 139.
(b) Chakrabarty, M.; Ghosh, N.; Basak, R.; Harigaya, Y.
Tetrahedron Lett. 2002, 43, 4075. (c)Ramesh, C.;Banerjee,
J.; Pal, R.; Das, B. Adv. Synth. Commun. 2003, 345, 557.
(d) Mahadevan, A.; Sard, H.; Gonzalez, M.; McKew, J. C.
Tetrahedron Lett. 2003, 44, 4589. (e) Reddy, A. V.;
Ravinder, K.; Reddy, V. L. N.; Goud, T. V.; Ravikanth, V.;
Venkateswarlu, Y. Synth. Commun. 2003, 33, 3687.
(6) Kobayashi, S.; Araki, M.; Yasuda, M. Tetrahedron Lett.
1995, 36, 5773.
(19) Nishiguchi, T.; Kamio, C. J. Chem. Soc., Perkin Trans. 1
1999, 707.
(20) The acid-catalyzed addition of indoles requires careful
control of acidity to prevent side reactions such as
dimerization or polymerization, see: Okauchi, T.; Itonaga,
M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. Org. Lett.
2000, 2, 1485.
(21) Corma, A.; Garcia, H. Chem. Rev. 2003, 103, 4307; and
references cited therein.
(22) A strongly hindered base, namely 2,6-di-tert-butyl-4-
methylpyridine has been added to neutralize traces of HX,
which might contaminate the reaction mixture, without
deactivating the CeCl3·7H2O–NaI–SiO2 system, since
dimerization of the indoles is promoted by residual HX. For
the use of 2,6-di-tert-butyl-4-methylpyridine, see:
(a) Hollis, T. K.; Bosnich, B. J. Am. Chem. Soc. 1995, 117,
4570. (b) Barrett, A. G. M.; Braddock, D. C.; Henschke, J.
P.; Walker, E. R. J. Chem. Soc., Perkin Trans. 1 1999, 873.
(c) Mathieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219.
(23) Osawa, T.; Namiki, M.; Suzuki, K.; Mitsuoka, T. Mutat. Res.
1983, 122, 299.
(24) Osawa, T.; Namiki, M. Tetrahedron Lett. 1983, 24, 4719.
(25) (a) Hogan, I. T.; Sainsbury, M. Synthesis 1984, 872.
(b) Chalaye-Manger, H.; Denis, J.-N.; Averbuch-Pouchot,
T.; Vallée, Y. Tetrahedron 2000, 56, 791.
(26) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.;
Massaccesi, M.; Sambri, L. Synlett 2003, 39.
(7) Bandgar, B. P.; Shaikh, K. A. Tetrahedron Lett. 2003, 44,
1959.
(8) Yadav, J. S.; Subby Reddy, B. V.; Sunitha, S. Adv. Synth.
Catal. 2003, 345, 349.
(27) Meng, J.-B.; Du, D.-M.; Xiong, G.-X.; Wang, W.-G.; Wang,
Y.-M. J. Heterocycl. Chem. 1994, 31, 121.
(28) Xie, W.; Bloomfield, K. M.; Jin, N. Y.; Wang, P. G. Synlett
1999, 498.
(9) Okuhara, T. Chem. Rev. 2002, 102, 3641.
(10) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, 1998.
(11) (a) Metzger, J. O. Angew. Chem. Int. Ed. 1998, 37, 2975.
(b) Louppy, A. Top. Curr. Chem. 1999, 206, 153.
Synthesis 2004, No. 6, 895–900 © Thieme Stuttgart · New York