Efficient Preparation of SCHEME 1

2-Indolyl-1-nitroalkane Derivatives
Employing Nitroalkenes as Versatile
Michael Acceptors: New Practical Linear
Approach to Alkyl
9H-β-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 CeCl3‚7H2O-SiO2 as
Dipartimento di Scienze Chimiche, Università di Camerino, “friendly” Lewis acid promoter9 in Michael reactions with
via S. Agostino 1, I-62032 Camerino (MC), Italy, and poorly reactive indoles has not been reported previously.
Dipartimento di Chimica Organica “A. Mangini”, Università Among the strongest Michael acceptors,5 nitroalkenes are
di Bologna, viale Risorgimento 4, I-40136 Bologna, Italy also attractive because the nitro group can serve as a
masked functionality. This synthetic chameleon can be
[Link]@[Link] transformed after the Michael addition has taken place.6
Received July 17, 2004
Results and Discussion
It is well established that our CeCl3‚7H2O-NaI com-
bination supported on SiO2 is optimal in suppressing
polymerization of electron-rich heteroaromatic rings
(such as indoles) under acid-catalyzed conditions.10 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-β-nitrostyrene11 in the presence of 0.3 equiv of
CeCl3‚7H2O and 0.3 equiv of NaI supported on SiO2 (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 (3) Reports on solvent-free reactions have become increasingly
Michael-type additions. Continuing our work on solvent-free frequent and specialized over the past few years, see: (a) Banerjee, A.
conditions, the CeCl3‚7H2O-NaI-SiO2 system catalyzes the K.; Laya Mimò, M. S.; Vera Vegas, W. J. Russ. Chem. Rev. 2001, 70,
971-990. (b) Bhalay, G.; Dunstan, A.; Glen, A. Synthesis 2000, 1846-
addition of a variety of indoles and nitroalkenes, giving 1859. (c) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025-1074. (d)
2-indolyl-1-nitroalkane derivatives in good yields. Develop- Metzger, J. O. Angew. Chem., Int. Ed. 1998, 37, 2975-2978.
ment of this method has resulted in a new protocol for the (4) Jung, M. E. In Comprehensive Organic Synthesis; Trost, B. M.,
synthesis of 4-substituted β-carbolines. Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 1-67.
(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,
We reported recently that indoles react with R,β- M.; Fagioli, M.; Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Tetra-
unsaturated ketones in the presence of cerium(III) chlo- hedron Lett. 2003, 44, 5843-5846. (d) Bandini, M.; Cozzi, P. G.;
Giacomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi, A. J. Org.
ride heptahydrate and sodium iodide supported on silica Chem. 2002, 67, 3700-3704.
gel leading to good yields of indoles alkylated at the (6) (a) Chakrabarty, M.; Basak, R.; Ghosh, N.; Harigaya, Y. Tetra-
3-position.1 The reaction may be regarded as a Friedel- hedron 2004, 60, 1941-1949. (b) Bandini, M.; Melchiorre, P.; Melloni,
A. Umani-Ronchi, A. Synthesis 2002, 1110-1114.
Crafts-type conjugated addition of indoles2 in solvent-free (7) Bartoli, G.; Marcantoni, E.; Sambri, L. Synlett 2003, 2101-2116.
conditions.3 However, several Michael acceptors4 failed For Lewis acidic activation of various functionalities, see: Yamamoto,
to react under our conditions, including vinyl sulfones, H. In Lewis Acidic in Organic Synthesis; Wiley-VCH: Weinhein, 2000.
(8) (a) Masesane, I. B.; Steel, P. G. Synlett 2003, 735-737. (b)
R,β-unsaturated esters, and acrylonitrile. Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877-
Although the Michael addition of nucleophilic indoles7 1894. (c) Rimkus, A.; Sewald, N. Org. Lett. 2002, 4, 3289-3291. (d)
to nitroalkenes has been well studied,8 the area is far Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York,
2001. (e) Fornicola, R. S.; Oblinger, E.; Montgomery, J. J. Org. Chem.
1998, 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,
402255. Fax: +39 0737 402297. E. Tetrahedron Lett. 1994, 35, 8651-8654. (h) Pecunioso, A.; Menicagli,
† Università di Bologna. L. J. Org. Chem. 1989, 54, 2391-2396.
‡ Università 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,
Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem. 2003, 68, E.; Sambri, L. Synthesis 2004, 859-864. (b) Okauchi, T.; Itonaga, M.;
4594-4597. Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. Org. Lett. 2000, 2, 1485-
(2) This reaction can also be viewed as a Michael addition reaction, 1489.
but the majority of literature references regarded such a reaction as a (11) (a) Kotrusz, P.; Toma, S.; Schmalz, H.-G.; Adler, A. Eur. J. Org.
Friedel-Crafts reaction; see a recent review: Krause, N.; Hoffmann- Chem. 2004, 1577-1583. (b) Alexakis, A.; Andrey, O. Org. Lett. 2002,
Röder, A. Synthesis 2001, 171-196. 4, 3611-3614. (c) Enders, D.; Seki, A. Synlett 2002, 26-28.

10.1021/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
by this result, we have carried out the addition of a Catalyzed by CeCl3‚7H2O-NaI Combination Supported
on SiO2a
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 β-position,
the reaction proceeds with good yields. Moreover, with
R,β-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 CeCl3‚7H2O-NaI-SiO2 sys-
tem to add indoles to the R-carbon atom of R,β-unsatur-
ated carbonyl compounds having a strongly electron-
withdrawing group at the β-carbon.16 The readily available
trans-β-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
moiety at the 3-position.18 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 % CeCl ‚7H O
(16) (a) Chatfield, D. C.; Angsten, A.; D’Cunha, C.; Lewandowska, 3 2
E.; Wnuk, S. F. Eur. J. Org. Chem. 2004, 313-322. (b) Lewandowska, and 30 mol % NaI supported on silica gel. b All products were
c
identified by their IR, NMR, and GC/MS spectra. Yields of
E.; Kinastowsk, B.; Wnuk, S. F. Can J. Chem. 2002, 80, 192-199.
(17) Chandler, M.; Conroy, R.; Cooper, A. W. J.; Lamont, R. B.; products isolated by flash chromatography. d As a mixture of two
Scicinski, J. J.; Smart, J. E.; Storer, R.; Weir, N. G.; Wilson, R. D.; diastereomers in about 1:1 ratio. e 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
(18) (a) Gibe, R.; Kerr, M. A. J. Org. Chem. 2002, 67, 6247-6249. chromatography.
(b) Mahboobi, S.; Bernauer, K. Helv. Chim. Acta 1988, 71, 2034-2041.

1942 J. Org. Chem., Vol. 70, No. 5, 2005

derivative (2h), giving a mixture of diastereomers that SCHEME 2 a
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,23 but they are not very
stable. Therefore, syntheses have been designed to pass
through stable intermediates likely 3-(2-nitroethyl)in-
a Reagents and conditions: (a) (i) H (1 atm), Raney nickel, room
dolyl derivatives, and subsequently transformed to the 2

amino compounds. Synthetic routes to tryptamines via temp for 16 h; (ii) 4 N HCl-dioxane, 78%. (b) (i) 37% aq HCHO,
MeOH, room temp for 18 h; (ii) 6% aq K2CO3, EtOAc, room temp,
reduction of the nitro compounds24-26 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 cerium(III) chloride heptahydrate and sodium iodide.
convenient method of making tryptamines by Michael While β-carbolines can be synthesized via tryptamines31
addition of indoles to nitroalkenes. One of the most (vide supra), 4-substituted β-carbolines lacking substitu-
important aspects in this methodology is that the solvent- tion at the 3-position are not well represented in the
free conditions suppress any polymerization phenomena literature. We have been especially interested in dem-
of the acid-sensitive substrates. onstrating the value of our present procedure by synthe-
The β-carbolines represent a large group of biologically sis of methyl 9H-β-carbolines-4-carboxylate (6). Busacca’s
active alkaloids widespread in nature.27-29 A number of method32 of derivatization of an intermediate to generate
central nervous system pharmacological effects have been a diverse group of 4-substituted β-carbolines requires
attributed to such alkaloids.30 Synthesis of pyrido[3,4-b]- N-protection, whereas our linear approach involves in-
indoles, the β-carbolines (Scheme 2), was examined to troduction of the 4-substituent in the first synthetic step.
further evaluate the general utility of silica gel-supported Toward this goal, we began with Michael addition of
indole (1a) to methyl β-nitroacrylate (2g) under our
(19) (2-Nitroethyl)indolyl derivative 3ah was obtained under Michael conditions (Table 1, entry 10). The reaction affords indole
conditions using indole-anion but in 47% yield and the use of bulky
protecting groups in the 1-position was needed; see: Mahboobi, S.; 3ag in excellent yield, and the nitro group has been
Wiegrebe, W.; Popp, A. J. Nat. Prod. 1999, 62, 577-579. efficiently reduced by hydrogenation in the presence of
(20) (a) Towers, G. H. N.; Abramovski, Z. J. Nat. Prod. 1983, 46,
572-577. (b) Lazurjevsld, G.; Terentjeva, I. Heterocycles 1976, 4, 1783-
Raney nickel to give the β-substituted tryptamine deriva-
1810. tive 4.33 The hydrochloride of 4 was converted in modest
(21) (a) Mahboobi, S.; Eibler, E.; Koller, M.; Kumar, S.; Popp, A. J. yield under protic conditions according to the standard
Org. Chem. 1999, 64, 4697-4704. (a) Mahboobi, S.; Popp, A.; Burge-
meister, T.; Schollmeyer, D. Tetrahedron: Asymmetry 1998, 9, 2369- procedure34 into the 4-substituted 1,2,3,4-tetrahydro-β-
2376. (c) Pettit, G. R.; Singh, S. B.; Herald, D. L.; Lloyd-Williams, P.; carboline 5 by condensation with formaldehyde followed
Kantoci, D.; Burkett, D. D.; Barkòczy, J.; Hogan, F.; Wardlaw, T. R. by Pictet-Spengler cyclization of the imine. By compari-
J. Org. Chem. 1994, 59, 6287-6295.
(22) (a) Hibino, S.; Choshi, T. Nat. Prod. Rep. 2002, 19, 148-180.
(b) Semenov, B. B.; Smushkevich, Y. I. Russ. Chem. Bull., Int. Ed. 2002, (29) (a) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843-
51, 185-186. (c) Repke, D. B.; Grotjahn, D. B.; Shulgin, A. T. J. Med. 3846. (b) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 7048-7056.
Chem. 1985, 28, 892-896. (c) Busacca, C. A.; Dong, Y. Synth. Commun. 2000, 30, 501-509. (d)
(23) (a) Tanino, H.; Fukuishi, K.; Ushiyama, M.; Okada, K. Tetra- Madrigal, A.; Grande, M.; Avendano, C. J. Org. Chem. 1998, 63, 2724-
hedron 2004, 60, 3273-3282. (b) Katritzky, A. R.; Pozharskii, A. F. In 2727. (e) Cui, C.-B.; Kakeya, H.; Osada, H. Tetrahedron 1997, 53, 59-
Handbook of Heterocyclic Chemistry; Pergamon: Oxford, 2000; Chapter 72. (f) Wu, G.; Yamamaka, E.; Cook, J. Heterocycles 1978, 9, 175-
4. (c) Joule, J. A. In Science of Synthesis (Houben-Weyl Methods of 182.
Molecular Transformations); Thomas, E. J., Ed.; Georg Thieme Ver- (30) (a) Louis, E. D.; Zheng, W.; Jurewicz, E. C.; Watner, D.; Chen,
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Soc., Perkin Trans. 1 2000, 1045-1075. (e) Cordell, G. A. The Alkaloids; May, Y.; Rommelspacher, H.; Pawlik, M. J. Neurochem. 1991, 56, 490-
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Aquino, L. B. Org. Lett. 2001, 3, 1005-1007. (b) Okauchi, T.; Itonaga, D.; Sandrin, J.; Ungemach, F.; Mokry, P.; Wu, G. S.; Yamanaka, E.;
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1485-1487. tionally, β-carbolines have been synthesized from tryptamines, even
(25) Wynne, J. H.; Stalick, W. M. J. Org. Chem. 2002, 67, 5850- if attempts have been made recently to synthesize the β-carbolines
5953. from non tryptamine precursors; see: Kannadasan, S.; Srinivasan, P.
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J. Org. Chem, Vol. 70, No. 5, 2005 1943

son, preparation of the hydrochloride of 5 proceeded in solvent-free conditions are expected to be of use in the
good yield when a 37% formalin solution was added to 4 synthesis of a range of indole alkaloids.
in methanol at room temperature and stirred overnight.35
The salt of 5 was converted to the free base and Acknowledgment. The authors are grateful to Prof.
dehydrogenated in the presence of Pd/C to afford β-car- Roberto Ballini (University of Camerino) for many
useful suggestions. This work was carried out under the
boline 6 in 83% isolated yield.36
framework of the National Project “Sintesi e Rattività.
In conclusion, we have demonstrated that the readily Attività di Sistemi Insaturi Funzionalizzati” supported
available and economical CeCl3‚7H2O-NaI-SiO2 system by MIUR, Rome, and by the University of Camerino.
is a viable means for Lewis acid-promoted Michael The authors would like to thank Dr. Robert C. Fried-
addition of indoles with functionalized nitroalkene Michael mann and Dr. Massimo Bartolacci for their help in the
acceptors. The results show that our present synthetic revision of the English of this manuscript.
methodology can be applied widely and especially to the
Supporting Information Available: Detailed description
synthesis of β- carbolines that are difficult to make by
of experimental procedures for the compounds 3, product
other means. These cerium(III)-promoted reactions in characterization data and 1H and 13C NMR peak listing for
compounds not reported previously, and additional details on
(35) Saiga, Y.; Ijima, I.; Ishida, A.; Miyagishima, T.; Takamura, N.; the reaction methodology and the isolation and characteriza-
Oh-ishi, T.; Matsumoto, M.; Matsuoka, Y. Chem. Pharm. Bull. 1987, tion of products 4-6. This material is available free of charge
35, 3705-3712. via the Internet at [Link]
(36) Venden Eynde, I.-J.; D’Orazio, R.; Van Hoverbeke, Y. Tetra-
hedron 1994, 50, 2479-2484. JO048776W

1944 J. Org. Chem., Vol. 70, No. 5, 2005