Efficient preparation of 2-indolyl-1-nitroalkane derivatives employing nitroalkenes as versatile Michael acceptors: New practical linear approach to alkyl 9H-β-carboline-4-carboxylate

Article abstract of DOI:10.1021/jo048776w

(Chemical Equation Presented) The combination of cerium(III) chloride heptahydrate and sodium iodide supported on silica gel is known to promote Michael-type additions. Continuing our work on solvent-free conditions, the CeCl₃·7H₂O-N

Full text of DOI:10.1021/jo048776w

Efficient Preparation of
-Indolyl-1-nitroalkane Derivatives
SCHEME 1
2
Employing Nitroalkenes as Versatile
Michael Acceptors: New Practical Linear
Approach to Alkyl
9
H-â-Carboline-4-carboxylate
†
†
‡
Giuseppe Bartoli, Marcella Bosco, Sandra Giuli,
‡
‡
Arianna Giuliani, Laura Lucarelli,
Enrico Marcantoni,*,‡ Letizia Sambri, and
†
Elisabetta Torregiani†
from fully explored. The use of CeCl
3
‚7H
2
2
O-SiO as
9
“friendly” Lewis acid promoter in Michael reactions with
Dipartimento di Scienze Chimiche, Universit a` di Camerino,
via S. Agostino 1, I-62032 Camerino (MC), Italy, and
Dipartimento di Chimica Organica “A. Mangini”, Universita`
di Bologna, viale Risorgimento 4, I-40136 Bologna, Italy
poorly reactive indoles has not been reported previously.
Among the strongest Michael acceptors, nitroalkenes are
also attractive because the nitro group can serve as a
5
masked functionality. This synthetic chameleon can be
transformed after the Michael addition has taken place.
enrico.marcantoni@unicam.it
Received July 17, 2004
6
Results and Discussion
It is well established that our CeCl
bination supported on SiO is optimal in suppressing
polymerization of electron-rich heteroaromatic rings
3
‚7H O-NaI com-
2
2
1
0
(
such as indoles) under acid-catalyzed conditions. Our
procedure could find many other useful applications in
Michael conditions. In our study of the addition of indoles
to nitroalkenes (Scheme 1), treatment of indole (1a) with
trans-â-nitrostyrene11 in the presence of 0.3 equiv of
CeCl
3
2 2
‚7H O and 0.3 equiv of NaI supported on SiO (0.5
g/mmol of nitroalkene) gives a heterogeneous mixture
that affords, after simple workup, the corresponding
The combination of cerium(III) chloride heptahydrate and
sodium iodide supported on silica gel is known to promote
Michael-type additions. Continuing our work on solvent-free
conditions, the CeCl3‚7H2O-NaI-SiO2 system catalyzes the
addition of a variety of indoles and nitroalkenes, giving
(3) Reports on solvent-free reactions have become increasingly
frequent and specialized over the past few years, see: (a) Banerjee, A.
K.; Laya Mim o` , M. S.; Vera Vegas, W. J. Russ. Chem. Rev. 2001, 70,
9
71-990. (b) Bhalay, G.; Dunstan, A.; Glen, A. Synthesis 2000, 1846-
859. (c) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025-1074. (d)
1
2
-indolyl-1-nitroalkane derivatives in good yields. Develop-
Metzger, J. O. Angew. Chem., Int. Ed. 1998, 37, 2975-2978.
(4) Jung, M. E. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 1-67.
ment of this method has resulted in a new protocol for the
synthesis of 4-substituted â-carbolines.
(5) (a) Zhou, J.; Ye, M.-C.; Huang, Z. Z.; Tang, Y. J. Org. Chem. 2004,
69, 1309-1320. (b) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lann,
H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780-10783. (c) Bandini,
M.; Fagioli, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Tetra-
hedron Lett. 2003, 44, 5843-5846. (d) Bandini, M.; Cozzi, P. G.;
Giacomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi, A. J. Org.
Chem. 2002, 67, 3700-3704.
We reported recently that indoles react with R,â-
unsaturated ketones in the presence of cerium(III) chlo-
ride heptahydrate and sodium iodide supported on silica
gel leading to good yields of indoles alkylated at the
(6) (a) Chakrabarty, M.; Basak, R.; Ghosh, N.; Harigaya, Y. Tetra-
hedron 2004, 60, 1941-1949. (b) Bandini, M.; Melchiorre, P.; Melloni,
A. Umani-Ronchi, A. Synthesis 2002, 1110-1114.
1
3
-position. The reaction may be regarded as a Friedel-
2
Crafts-type conjugated addition of indoles in solvent-free
(
7) Bartoli, G.; Marcantoni, E.; Sambri, L. Synlett 2003, 2101-2116.
3
4
conditions. However, several Michael acceptors failed
to react under our conditions, including vinyl sulfones,
R,â-unsaturated esters, and acrylonitrile.
For Lewis acidic activation of various functionalities, see: Yamamoto,
H. In Lewis Acidic in Organic Synthesis; Wiley-VCH: Weinhein, 2000.
(
8) (a) Masesane, I. B.; Steel, P. G. Synlett 2003, 735-737. (b)
Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877-
1894. (c) Rimkus, A.; Sewald, N. Org. Lett. 2002, 4, 3289-3291. (d)
Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York,
7
Although the Michael addition of nucleophilic indoles
to nitroalkenes has been well studied, the area is far
8
2
1
001. (e) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem.
998, 63, 3528-3529. (f) Calderari, G.; Seebach, D. Helv. Chim. Acta
*
To whom correspondence should be addressed. Phone: +39 0737
1995, 68, 1592-1604. (g) Bartoli, G.; Bosco, M.; Sambri, L.; Marcantoni,
E. Tetrahedron Lett. 1994, 35, 8651-8654. (h) Pecunioso, A.; Menicagli,
L. J. Org. Chem. 1989, 54, 2391-2396.
4
02255. Fax: +39 0737 402297.
†
Universit a` di Bologna.
Universit a` di Camerino.
‡
(9) Rosini, G.; Ballini, R. Synthesis 1988, 833-847.
(1) Bartoli, G.; Bartolacci, M.; Bosco, M.; Foglia, G.; Giuliani, A.;
(10) (a) Bartoli, G.; Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni,
E.; Sambri, L. Synthesis 2004, 859-864. (b) Okauchi, T.; Itonaga, M.;
Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. Org. Lett. 2000, 2, 1485-
1489.
Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem. 2003, 68,
594-4597.
2) This reaction can also be viewed as a Michael addition reaction,
4
(
but the majority of literature references regarded such a reaction as a
Friedel-Crafts reaction; see a recent review: Krause, N.; Hoffmann-
R o¨ der, A. Synthesis 2001, 171-196.
(11) (a) Kotrusz, P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J. Org.
Chem. 2004, 1577-1583. (b) Alexakis, A.; Andrey, O. Org. Lett. 2002,
4, 3611-3614. (c) Enders, D.; Seki, A. Synlett 2002, 26-28.
1
0.1021/jo048776w CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/28/2005
J. Org. Chem. 2005, 70, 1941-1944
1941

2
-indolyl-1-nitroalkane (3aa) in good yield. Encouraged
TABLE 1. Michael Addition of Indoles to Nitroalkenes
Catalyzed by CeCl3‚7H2O-NaI Combination Supported
on SiO2a
by this result, we have carried out the addition of a
variety of indoles and nitroalkenes, summarized in Table
1
. This synthetic approach allows the facile introduction
of 2-nitroethyl-functionalized substituents into the 3-po-
sition of indole nucleus, possibly serving as a source for
the corresponding amino compounds.12 These derivatized
indole stock compounds would be valuable intermediates
for the preparation of molecules of biological interest.13
It has been observed that the electronic properties of
the aromatic ring have an effect on the rate of this
Michael reaction. The rate is accelerated if an electron-
donating group is present on the indole nucleus (Table
1
, entry 2). Even indole substrates bearing an electron-
withdrawing group such as 5-cyanoindole (1d) afford the
corresponding adduct14 in satisfactory yield (Table 1,
entry 4). In the case of an indole derivative containing a
hydroxyl group (1c), our catalyzed Michael addition ran
cleanly and in good yields (3ca and 3cg). Direct reaction
of hydroxyindoles is generally problematic, often result-
ing in low Michael adduct yields due to interaction of the
indolyl hydroxyl group with the Lewis acid catalyst.15
Unfortunately, where the pyrrole moiety of indole carries
electron-withdrawing substituents such as a carbomethoxy
or a benzenesulfonyl group, synthesis of the correspond-
ing Michael adducts has not been successful. The pres-
ence of electron-withdrawing groups in pyrrole ring
reduces the overall nucleophilicity.
With nitroalkenes substituted in the R- or â-position,
the reaction proceeds with good yields. Moreover, with
R,â-disubstituted nitroalkenes we observed low diaste-
reoselectivity and approximately equal parts of syn and
anti products. Only in the case of nitrocyclohexene (2c)
as a Michael acceptor we have obtained moderate dia-
stereoselectivity (Table 1, entry 6) in 2-indolyl-1-nitro-
cyclohexane (3ac). Moreover, Michael addition of indole
to 1-furyl-2-nitropropene 2d and 1-(3-pyridyl)-2-nitro-
ethene 2e gave the corresponding adducts 3ad and 3ae
without any interference of the sensitive heterocyclic
nucleus (Table 1, entries 7 and 8). Furthermore, we have
investigated the use of our CeCl
tem to add indoles to the R-carbon atom of R,â-unsatur-
ated carbonyl compounds having a strongly electron-
3
‚7H
2
2
O-NaI-SiO sys-
16
withdrawing group at the â-carbon. The readily available
trans-â-nitroacrylate (2g)17 gave very good yields in all
cases (Table 1, entries 10 and 11). Upon oxidative
removal of the nitro group, this is a useful, high-yielding
method for synthesizing indoles having a malonate
18
moiety at the 3-position. Finally, our conditions can lead
to the nitro indole 3ah.19 Indole reacts with nitroalkene
(
12) (a) Denmark, S. E.; Thorarensen, A.; Middleton, D. S. J. Am.
Chem. Soc. 1996, 118, 8266-8277. (b) Corey, E. J.; Estreicher, H. J.
Am. Chem. Soc. 1978, 100, 6294-6295.
(
13) (a) McNulty, J.; Mo, R. Chem. Commun. 1998, 933-934. (b)
Weller, T.; Seebach, D. Tetrahedron Lett. 1982, 23, 935-938.
14) Neef, G.; Eder, U.; Huth, A.; Rahtz, D.; Schmiechen, R.;
Seidelmann, P. Heterocycles 1983, 20, 1295-1313.
15) Yamamoto, H. In Lewis Acid Reagents; Oxford University
Press: New York, 1999.
(
(
a
Reactions performed in the presence of 30 mol % CeCl3‚7H2O
(
16) (a) Chatfield, D. C.; Angsten, A.; D’Cunha, C.; Lewandowska,
b
and 30 mol % NaI supported on silica gel. All products were
E.; Wnuk, S. F. Eur. J. Org. Chem. 2004, 313-322. (b) Lewandowska,
E.; Kinastowsk, B.; Wnuk, S. F. Can J. Chem. 2002, 80, 192-199.
c
identified by their IR, NMR, and GC/MS spectra. Yields of
d
(
17) Chandler, M.; Conroy, R.; Cooper, A. W. J.; Lamont, R. B.;
products isolated by flash chromatography. As a mixture of two
e
Scicinski, J. J.; Smart, J. E.; Storer, R.; Weir, N. G.; Wilson, R. D.;
diastereomers in about 1:1 ratio. Calculated syn/anti ratio
Wyatt, P. G. J. Chem. Soc., Perkin Trans. 1 1995, 1189-1197.
(78:22) on the mixture of diastereomers isolated by column
chromatography.
(
18) (a) Gibe, R.; Kerr, M. A. J. Org. Chem. 2002, 67, 6247-6249.
(
b) Mahboobi, S.; Bernauer, K. Helv. Chim. Acta 1988, 71, 2034-2041.
1942 J. Org. Chem., Vol. 70, No. 5, 2005

SCHEME 2 a
derivative (2h), giving a mixture of diastereomers that
we have not been able to separate. This mixture is,
however, easily converted to the enantiomerically pure
alkaloid (-)-(S)-brevicolline.20 The chiral nitroalkene
synthon 2h has been obtained starting from natural
amino acid (S)-proline.21
The present methodology can be applied widely. The
preparation of 3-(2-aminoethyl)-1H-indole, tryptamine
and its derivatives, the neurotransmitter serotonin, and
the tissue hormone melatonin constitute especially im-
portant examples.22 In general, the tryptamines are an
important class of compounds frequently used as building
blocks in the construction of numerous indole alkaloids
with useful biological activity,2 but they are not very
stable. Therefore, syntheses have been designed to pass
through stable intermediates likely 3-(2-nitroethyl)in-
dolyl derivatives, and subsequently transformed to the
3
a
Reagents and conditions: (a) (i) H2 (1 atm), Raney nickel, room
temp for 16 h; (ii) 4 N HCl-dioxane, 78%. (b) (i) 37% aq HCHO,
amino compounds. Synthetic routes to tryptamines via
MeOH, room temp for 18 h; (ii) 6% aq K2CO3, EtOAc, room temp,
reduction of the nitro compounds2
4-26
have been demon-
1
h; 90%. (c) Pd/C, xylenes, refluxing for 4 h, 83%.
strated. Our novel synthetic approach using the Lewis
acid promoter cerium(III) salt provides an easy and
convenient method of making tryptamines by Michael
addition of indoles to nitroalkenes. One of the most
important aspects in this methodology is that the solvent-
free conditions suppress any polymerization phenomena
of the acid-sensitive substrates.
cerium(III) chloride heptahydrate and sodium iodide.
While â-carbolines can be synthesized via tryptamines
31
(
vide supra), 4-substituted â-carbolines lacking substitu-
tion at the 3-position are not well represented in the
literature. We have been especially interested in dem-
onstrating the value of our present procedure by synthe-
sis of methyl 9H-â-carbolines-4-carboxylate (6). Busacca’s
The â-carbolines represent a large group of biologically
active alkaloids widespread in nature.2
7-29
A number of
32
method of derivatization of an intermediate to generate
central nervous system pharmacological effects have been
attributed to such alkaloids.30 Synthesis of pyrido[3,4-b]-
indoles, the â-carbolines (Scheme 2), was examined to
further evaluate the general utility of silica gel-supported
a diverse group of 4-substituted â-carbolines requires
N-protection, whereas our linear approach involves in-
troduction of the 4-substituent in the first synthetic step.
Toward this goal, we began with Michael addition of
indole (1a) to methyl â-nitroacrylate (2g) under our
conditions (Table 1, entry 10). The reaction affords indole
(19) (2-Nitroethyl)indolyl derivative 3ah was obtained under Michael
conditions using indole-anion but in 47% yield and the use of bulky
protecting groups in the 1-position was needed; see: Mahboobi, S.;
Wiegrebe, W.; Popp, A. J. Nat. Prod. 1999, 62, 577-579.
3
ag in excellent yield, and the nitro group has been
efficiently reduced by hydrogenation in the presence of
Raney nickel to give the â-substituted tryptamine deriva-
tive 4.33 The hydrochloride of 4 was converted in modest
yield under protic conditions according to the standard
(
20) (a) Towers, G. H. N.; Abramovski, Z. J. Nat. Prod. 1983, 46,
5
72-577. (b) Lazurjevsld, G.; Terentjeva, I. Heterocycles 1976, 4, 1783-
1
810.
(
21) (a) Mahboobi, S.; Eibler, E.; Koller, M.; Kumar, S.; Popp, A. J.
Org. Chem. 1999, 64, 4697-4704. (a) Mahboobi, S.; Popp, A.; Burge-
meister, T.; Schollmeyer, D. Tetrahedron: Asymmetry 1998, 9, 2369-
34
procedure into the 4-substituted 1,2,3,4-tetrahydro-â-
2
376. (c) Pettit, G. R.; Singh, S. B.; Herald, D. L.; Lloyd-Williams, P.;
carboline 5 by condensation with formaldehyde followed
by Pictet-Spengler cyclization of the imine. By compari-
Kantoci, D.; Burkett, D. D.; Bark o` czy, J.; Hogan, F.; Wardlaw, T. R.
J. Org. Chem. 1994, 59, 6287-6295.
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(
5
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2727. (e) Cui, C.-B.; Kakeya, H.; Osada, H. Tetrahedron 1997, 53, 59-
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182.
(
23) (a) Tanino, H.; Fukuishi, K.; Ushiyama, M.; Okada, K. Tetra-
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Handbook of Heterocyclic Chemistry; Pergamon: Oxford, 2000; Chapter
4
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Molecular Transformations); Thomas, E. J., Ed.; Georg Thieme Ver-
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J.; Factor-Litvak, P.; Parides, M. Neurology 2002, 95, 1940-1944. (b)
May, Y.; Rommelspacher, H.; Pawlik, M. J. Neurochem. 1991, 56, 490-
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Hutchins, L.; DiPierro, M. J. Org. Chem. 1979, 44, 535-545. Tradi-
tionally, â-carbolines have been synthesized from tryptamines, even
if attempts have been made recently to synthesize the â-carbolines
from non tryptamine precursors; see: Kannadasan, S.; Srinivasan, P.
C. Synth. Commun. 2004, 34, 1325-1335.
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esters of 3-amino-2-(1H-3-indolyl)propanoic acid exist in the literature
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901-910). However, these routes either are laborious, are comprised
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J. Org. Chem, Vol. 70, No. 5, 2005 1943

son, preparation of the hydrochloride of 5 proceeded in
good yield when a 37% formalin solution was added to 4
in methanol at room temperature and stirred overnight.35
The salt of 5 was converted to the free base and
dehydrogenated in the presence of Pd/C to afford â-car-
boline 6 in 83% isolated yield.36
solvent-free conditions are expected to be of use in the
synthesis of a range of indole alkaloids.
Acknowledgment. The authors are grateful to Prof.
Roberto Ballini (University of Camerino) for many
useful suggestions. This work was carried out under the
framework of the National Project “Sintesi e Rattivit a` .
Attivit a` di Sistemi Insaturi Funzionalizzati” supported
by MIUR, Rome, and by the University of Camerino.
The authors would like to thank Dr. Robert C. Fried-
mann and Dr. Massimo Bartolacci for their help in the
revision of the English of this manuscript.
In conclusion, we have demonstrated that the readily
3 2 2
available and economical CeCl ‚7H O-NaI-SiO system
is a viable means for Lewis acid-promoted Michael
addition of indoles with functionalized nitroalkene Michael
acceptors. The results show that our present synthetic
methodology can be applied widely and especially to the
synthesis of â- carbolines that are difficult to make by
other means. These cerium(III)-promoted reactions in
Supporting Information Available: Detailed description
of experimental procedures for the compounds 3, product
1
13
characterization data and H and C NMR peak listing for
compounds not reported previously, and additional details on
the reaction methodology and the isolation and characteriza-
tion of products 4-6. This material is available free of charge
via the Internet at http://pubs.acs.org.
(
35) Saiga, Y.; Ijima, I.; Ishida, A.; Miyagishima, T.; Takamura, N.;
Oh-ishi, T.; Matsumoto, M.; Matsuoka, Y. Chem. Pharm. Bull. 1987,
5, 3705-3712.
36) Venden Eynde, I.-J.; D’Orazio, R.; Van Hoverbeke, Y. Tetra-
hedron 1994, 50, 2479-2484.
3
(
JO048776W
1944 J. Org. Chem., Vol. 70, No. 5, 2005