The Michael addition of indoles to α,β-unsaturated ketones catalyzed by CeCl3·7H2O-NaI combination supported on silica gel

Article abstract of DOI:10.1021/jo034303y

Alkylation of indoles by means of the Michael addition has been the subject of a number of investigation. It is well established that regioselectivity in the additions of indoles to electron-deficient alkenes is strongly controlled by the reaction medium. In a continuation of the work on developing greener and cleaner technologies, the cerium(III) chloride heptahydrate and sodium iodide combination supported on silica gel catalyzes the alkylation of various indoles with α,β-unsaturated ketones giving 3-(3-oxoalkyl)indole derivatives in good yields. The substitution on the indole nucleus occurred exclusively at the 3-position, and N-alkylation products have not been observed.

Full text of DOI:10.1021/jo034303y

6
existing methods with InCl3 and FeCl3.7 Indium salts
Th e Mich a el Ad d ition of In d oles to
r,â-Un sa tu r a ted Keton es Ca ta lyzed by
CeCl3‚7H2O-Na I Com bin a tion Su p p or ted
on Silica Gel1
produce lower Lewis acidity than cerium trichloride while
ferric chloride is very hygroscopic. However, this CeCl3‚
7H2O-NaI system provides a powerful tool for organic
transformations but stoichiometric amounts of cerium
salt are generally necessary.8 Therefore, development of
cerium-mediated reactions with a catalytic amount of a
cerium source is a challenging subject in organic chem-
istry.9
Giuseppe Bartoli,‡ Massimo Bartolacci,† Marcella Bosco,‡
Gioia Foglia,† Arianna Giuliani,† Enrico Marcantoni,*,†
Letizia Sambri,‡ and Elisabetta Torregiani†
Dipartimento di Scienze Chimiche, Universita` 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
In the course of our research on application of CeCl3
in organic reactions, we have found that the CeCl3‚
7H2O-NaI combination was an effective promoter in the
Michael additions of nucleophiles to R,â-unsaturated
ketones without using any organic solvents.10 The meth-
odology, which is desirable from an environmental point
of view, prompted us to apply it to the Friedel-Crafts-
type conjugate addition of aromatic compounds in solvent-
free conditions.11 Among the aromatic compounds, we
selected indoles as substrates because (i) a number of
indole derivatives occur in many pharmacologically and
biologically active compounds,12 (ii) there is high reactiv-
ity in the 3-position of indole moiety toward the electro-
philic substitution reaction,13 and (iii) over several years
some of us have been involved in developing newer
methodologies allowing the synthesis of indoles.14
enrico.marcantoni@unicam.it
Received March 7, 2003
Abstr a ct: Alkylation of indoles by means of the Michael
addition has been the subject of a number of investigation.
It is well established that regioselectivity in the additions
of indoles to electron-deficient alkenes is strongly controlled
by the reaction medium. In a continuation of the work on
developing greener and cleaner technologies, the cerium(III)
chloride heptahydrate and sodium iodide combination sup-
ported on silica gel catalyzes the alkylation of various indoles
with R,â-unsaturated ketones giving 3-(3-oxoalkyl)indole
derivatives in good yields. The substitution on the indole
nucleus occurred exclusively at the 3-position, and N-
alkylation products have not been observed.
It is well established that regioselectivity in the addi-
tions of indoles to electron-deficient alkenes is strongly
controlled by the reaction medium. Indoles are N-alkyl-
(6) Babu, L. R.; Perumal, P. T. Aldrichim. Acta 2000, 33, 16.
(7) Christoffers, J . Eur. J . Org. Chem. 1998, 1259, 9.
Michael reactions promoted by Lewis acids have at-
tracted much attention as one of the most important
carbon-carbon bond-forming reactions in organic syn-
thesis.2 In particular, they are totally atom-efficient
procedures3 and thus are inherently green transforma-
tions.4 There are several different metal-based Lewis acid
catalysts available for these Michael reactions and the
use of lanthanide triflates5 represents an attractive
alternative to their classical competitors such as AlCl3,
TiCl4, and SnCl4. Unfortunately, lanthanide triflates are
rather expensive and their use in large-scale synthetic
methodology is very limited. For this reason cheaper
Lewis acid catalysts that secure catalytic activity, low
toxicity, moisture, and air tolerance are desirable. In this
direction, the use of a cerium(III) chloride heptahydrate
and sodium iodide combination, which is relatively
nontoxic and inexpensive, is the center of our study. The
CeCl3‚7H2O-NaI system offers some advantages over
(8) (a) Badioli, M.; Ballini, R.; Bartolacci, M.; Bosica, G.; Torregiani,
E.; Marcantoni, E. J . Org. Chem. 2002, 67, 8938. (b) Bartoli, G.; Bosco,
M.; Dalpozzo, R.; Giuliani, A.; Marcantoni, E.; Mecozzi, T.; Sambri,
L.; Torregiani, E. J . Org. Chem. 2002, 67, 9111. (c) Reddy, L. R.; Reddy,
A. M.; Bhaunmathi, N.; Rao, K. R. Synthesis 2001, 831. (d) Bartoli,
G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.; Torregiani, E.; Sambri,
L. J . Org. Chem. 2001, 66, 4430. (e) Bartoli, G.; Bellucci, M. C.; Petrini,
M.; Marcantoni, E.; Sambri, L.; Torregiani, E. Org. Lett. 2000, 2, 1791.
(f) Bartoli, G.; Bellucci, M. C.; Bosco, M.; Marcantoni, E.; Massaccesi,
M.; Petrini, M.; Sambri, L. J . Org. Chem. 2000, 65, 4553.
(9) Marotta, E.; Foresi, E.; Marcelli, T.; Peri, F.; Righi, P.; Scardovi,
N.; Rosini, G. Org. Lett. 2002, 4, 4451.
(10) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.; Sambri,
L.; Torregiani, E. J . Org. Chem. 2001, 66, 9052. (b) Bartoli, G.; Bosco,
M.; Bellucci, M. C.; Marcantoni, E.; Sambri, L.; Torregiani, E. Eur. J .
Org. Chem. 1999, 617.
(11) (a) Tundo, P.; Anastas, P.; Black, D. C.; Breen, J .; Collins, T.;
Memoli, S.; Miyamoto, J .; Polyakoff, M.; Tumas, W. Pure Appl. Chem.
2000, 72, 1207. (b) Kotsuki, H.; Hayashida, K.; Shimanouchi, T.;
Nishizawa, H. J . Org. Chem. 1996, 61, 984.
(12) (a) Zhang, H.-C.; Ye, H.; Moretto, A. F.; Brumfield, K. K.;
Maryanoff, B. E. Org. Lett. 2000, 2, 89. (b) Faul, M. M.; Winneroski,
L. L.; Krumrich, C. A. J . Org. Chem. 1998, 63, 6053. (c) Wang, S.-F.;
Chuang, C.-P. Heterocycles 1997, 45, 347. (d) Bennasar, M.-L.; Vidal,
B.; Bosch, J . J . Org. Chem. 1997, 62, 3597. (e) Amat, M.; Hadida, S.;
Pshenichnyi, G.; Bosch, J . J . Org. Chem. 1997, 62, 3158. (f) Tani, M.;
Matsumoto, S.; Aida, V.; Arikawa, S.; Nakane, A.; Yokoyama, Y.;
Murakami, Y. Chem. Pharm. Bull. 1994, 42, 443.
(13) (a) Wynne, J . H.; Stalick, V. M. J . Org. Chem. 2002, 67, 5850.
(b) Yadav, J . S.; Reddy, B. V. S.; Abraham, S.; Sabitha, G. Synlett 2002,
1550. (c) Ottoni, O.; Neder, A. V. F.; Dias, A. K. B.; Cruz, R. P. A.;
Aquino, L. B. Org. Lett. 2001, 3, 1005. (d) Okauchi, T.; Itonaga, M.;
Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H. Org. Lett. 2000, 2, 1485.
(e) Kotsuki, H.; Nishiuchi, M.; Kobayashi, S.; Nishizawa, H. J . Org.
Chem. 1990, 55, 2969.
* To whom correspondence should be addressed. Phone: +39 0737
402255. Fax: +39 0737 637345.
† University of Camerino.
‡ University of Bologna.
(1) Dedicated to Prof. Domenico Spinelli the occasion of his 70th
birthday.
(2) For some recent examples, see: Christoffers, J . Synlett 2001,
723.
(3) (a) Trost, B. M. Acc. Chem. Res. 2002, 35, 695. (b) Trost, B. M.
Science 1991, 254, 1471.
(4) Anastas, P.; Warner, J . C. In Green Chemistry: Theory and
Practice; Oxford: Oxford, UK, 1998.
(5) (a) Mori, Y.; Kakumoto, K.; Manabe, K.; Kobayashi, S. Tetrahe-
dron Lett. 2000, 41, 3107. (b) Manabe, K.; Mori, Y.; Wekabayashi, T.;
Nagayama, S.; Kobayashi, S. J . Am. Chem. Soc. 2000, 122, 7202.
(14) (a) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron
Lett. 1989, 30, 2129. (b) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Palmieri,
G.; Marcantoni, E. J . Chem. Soc., Perkin Trans. 1 1991, 2757. (c)
Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R.; Petrini, M. J . Chem.
Soc., Perkin Trans. 2 1991, 657.
10.1021/jo034303y CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/06/2003
4594
J . Org. Chem. 2003, 68, 4594-4597

TABLE 1. Mich a el Ad d ition of In d oles to
SCHEME 1
r,â-Un sa tu r a ted Keton es Ca ta lyzed by CeCl3‚7H2O-Na I
a
Com bin a tion Su p p or ted on SiO2
ated by conjugate addition under alkaline conditions. On
the other hand, the formation of C-3 substituted indoles
is usually achieved in the acid-catalyzed additions. Thus,
in the last few years numerous methodologies have been
reported in the which the C-3 Michael additions of indoles
to R,â-unsaturated carbonyl compounds in the presence
of Lewis acids are involved.15 Even if several Lewis acids
are deactivated by the nitrogen of the indole moieties, it
is interesting to note catalytic asymmetric Lewis acid
mediated addition reactions with indoles reported by
J ørgensen16 and Umani-Ronchi.17 For all these reasons,
we wanted to apply the CeCl3‚7H2O-NaI combination
to catalyze 3-alkylation of indoles by Michael-type reac-
tion with R,â-unsaturated ketones on a silica gel surface18
under solvent-free conditions (Scheme 1).
The reaction of indole (1a ) with methyl vinyl ketone
(2a ) in the presence of a stoichiometric amount of the
CeCl3‚7H2O-NaI system adsorbed on silica gel19 proceeds
well giving the 3-oxoalkylation adduct 3a a in good yield
(85%) without dimerization and polymerization side
reactions.20 The fact that the reaction can be accom-
plished without solvent allowed us to adopt the best
experimental conditions to reduce the large amounts of
organic solvents.21 In general, an equimolar ratio of
cerium trichloride and NaI was found to give the best
results, and in optimizing the reaction conditions, we
tested several equimolar ratios of CeCl3‚7H2O/NaI. Our
results in Figure 1 indicate that 0.3 equiv of cerium salt
and 0.3 equiv of sodium iodide supported on SiO2 (0.5
g/mmol indole) were the most appropriate for this type
of reaction. The scope and efficiency of our method are
summarized in Table 1, and in all cases the yields of 3-(3-
oxoalkyl)indoles are satisfactory.
(15) (a) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.;
Selva, S.; Umani-Ronchi, A. J . Org. Chem. 2002, 67, 3700. (b) Yadav,
J . S.; Abraham, S.; Subba Reddy, B. V.; Sabitha, G. Tetrahedron Lett.
2001, 42, 8063. (c) Yadav, J . S.; Abraham, S.; Subba Reddy, B. V.;
Sabitha, G. Synthesis 2001, 2165. (d) Manabe, K.; Aoyama, N.;
Kobayashi, S. Adv. Synth. Catal. 2001, 174. (e) Harrington, P. E.; Kerr,
M. A. Synlett 1996, 1047. (f) Yadav, J . S.; Subba Reddy, B. V.; Murthy,
V. S. R.; Mahesh Kumar, G.; Madan, C. Synthesis 2001, 783.
(16) (a) J ensen, K. B.; Thorhange, J .; Hazel, R. G.; J ørgensen, K. A.
Angew. Chem., Int. Ed. 2001, 40, 160. (b) Zhuang, W.; Hausen, T.;
J ørgensen, K. A. Chem. Commun. 2001, 347.
(17) Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi, A. J .
Org. Chem. 2002, 67, 5386 and references therein.
(18) For some applications of catalysts adsorbed on silica gel, see:
(a) Benerjee, A. K.; Laya Mimo´, M. S.; Vera Vegas, W. J . Russ. Chem.
Rev. 2001, 70, 971. (b) Bianchini, C.; Burnaby, D. G.; Evans, J .;
Frediani, P.; Meli, A.; Oberhause, W.; Psaro, R.; Vizza, F. J . Am. Chem.
Soc. 1999, 121, 5961. (c) Anson, M. S.; Mirza, A. R.; Touks, L.; Williams,
J . M. J . Tetrahedron Lett. 1999, 40, 7147. (d) Davis, M. E. Chemtec
1992, 498. (e) Arhancet, J . P.; Davis, M. E.; Merola, J . S.; Hauson, B.
E. Nature 1989, 339, 454.
(19) The CeCl3‚7H2O-NaI system dispersed on chromatography
silica gel prepared by simple mixing both reagents in acetonitrile
followed by complete removal of the solvent.
(20) Sundberg, R. J . In The Chemistry of Indoles; Academic Press:
New York, 1996.
a
Reactions performed in the presence of 30 mol % of CeCl3‚7H2O
b
and 30 mol % of NaI supported on silica gel. All products were
identified by their IR, NMR, and GC/MS spectra. c Yields of
d
products isolated by column chromatography. No selectivity was
obtained, and double-conjugate addition also occurred. e The chro-
matographic purification was not necessary. f Yield by GC/MS
analysis.
(21) The reaction mixture was treated with an organic solvent
(dichloromethane) able to dissolve the organic material while the CeCl3‚
7H2O-NaI-SiO2 system could be easily removed by filtration.
J . Org. Chem, Vol. 68, No. 11, 2003 4595

It has been observed that the substitution on the indole
nucleus occurred exclusively at the 3-position. In ac-
cordance with this finding, 3-methylindole gave (Table
1, entry 12) only 9% of 1,4-adduct (3ga ) after the mixture
was mechanically stirred at an external temperature of
50 °C for 4 days, together with other uncharacterized
products.22 This important result provides a remarkable
contrast to similar reactions under palladium catalysis,
where N-alkylation is predominat.23 Furthermore, the
indole nitrogen did not require prior protection and the
avoidance of strong bases for deprotection permitted
compatibility with a wide range of functional groups.
Under our conditions we have observed that substituted
indole moieties are reactive substrates. The electronic
properties of the aromatic ring have an effect on the rate
of the Michael reaction. The rate was accelerated if an
electron-donating group is present on the indole nucleus
(Table 1, entries 8, 10, and 11). Even indolyl rings bearing
electron-withdrawing groups such as 5-bromoindole (1b)
and 1-methyl-5-nitroindole (1d ) afforded the correspond-
ing ketones 3ba and 3d a , respectively, in satisfactory
yields (Table 1, entries 7 and 9), but the presence of these
latter groups on the aromatic ring decelerated the desired
transformation.
F IGURE 1. Improvement of the reaction conditions.
The reaction also has been accomplished on the CeCl3‚
7H2O-NaI combination, i.e., without silica gel support,
but the Michael adduct was obtained in lower yield. In
fact, the treatment of indole 1a with enone 2a in the
presence of the CeCl3‚7H2O-NaI system gave, under the
same condition, the desired adduct 3a a in only 38% after
4 days. Then, although the mechanism of this reaction
is not clear, silica gel has an important role, and its
presence was found to be essential for the high efficacy
of the reaction. Undoubtely the presence of NaI is
essential too for the reaction, because when the same
additions were performed without NaI, no alkylation took
place. In considering the mechanistic role of NaI, it is
intriguing and complex since the exact nature of the
intermediates obtained by the reaction of reagents with
the CeCl3‚7H2O-NaI system on SiO2 is not yet known.
The characterization of all these components is being
carried out in our laboratories, but unfortunately, the
results are too complicated and many kinds seem to be
present.
F IGURE 2. R,â-Unsaturated ketones used as Michael accep-
tors.
With regard to Michael acceptors (Figure 2), cyclic
enones and R,â-disubstituted enones afforded the corre-
sponding 3-oxoalkylindole adducts in good yields. In all
cases the reaction proceeds at room temperature with
high selectivity, and no 1,2-adduct was obtained under
these reaction conditions. Further, the reaction proceeds
smoothly with good yields even in the case of sterically
hindered and less reactive enones,24 such as cyclohex-
enone (2d ) and cyclopentenone (2e), although longer
reaction times are required (Table 1, entries 4 and 5). It
should be noted that the reaction is poorly efficient for
enone 2f (Table 1, entry 6), only 10% of expected 3-(3-
oxoalkyl)indole 3a f being isolated. In this case, besides
the 3a f product, we observed the formation of a double
conjugate adduct. In a similar manner, this Michael
addition reaction of indoles does not work for R,â-
unsaturated esters and nitriles and, in the case of R,â-
unsaturated aldehydes such as acrolein, the reaction
suffers from regiochemical restriction caused by compet-
ing 1,2- versus 1,4-addition.
The fact that the reaction of our C-3 alkylation of
indoles can be carried out without solvent allowed us to
adopt a very simple workup procedure for the recovery
of the promoter system. The reaction mixture was treated
with a minimal amount of organic solvent (Et2O) able to
dissolve the organic material and not the catalyst, which
could be easily removed by filtration and regenerated in
an oven at 60 °C for 2 h. We have found that the CeCl3‚
7H2O-NaI combination supported on SiO2 can be fil-
tered, washed, dried under vacuum, and reused for five
cycles without noting any appreciable decrease in activ-
ity.
In summary, we have developed a simple procedure
for the direct formation of 3-(3-oxoalkyl)indoles in good
yields from indoles and R,â-unsaturated ketones with the
use of silica gel. Its promoting role, although not well
understood, could be explained through the adsorption
of the reactants that come into closer contact with each
(22) It is known (Iqbal, Z.; Kackson, A. H.; Nagaraja Rao, K. R.
Tetrahedron Lett. 1988, 29, 2577) that Michael addition of 3-meth-
ylindole involves attack at the indole 3-position to form 3,3-disubsti-
tuted derivative, which undergoes migration to the 2-position of
3-oxoalkyl moiety.
(23) Trost, B. M.; Molander, G. A. J . Am. Chem. Soc. 1981, 103,
5969.
(24) House, H. O. In Modern Synthetic Reactions, 2nd ed.; Benjamin
Inc.: Philippines, 1972; pp 595-623.
4596 J . Org. Chem., Vol. 68, No. 11, 2003

stirred overnight at room temperature. The acetonitrile was
removed by rotary evaporation and to the resulting mixture was
added indole (1a ) (0.070 g, 0.60 mmol) and 2-ethylhept-1-en-3-
one (2b) (0.042 g, 0.60 mmol). The mixture reaction was then
stirred at room temperature until the disappearance of the
starting indole (2.5 h, checked by TLC and GC analyses). After
addition of dichloromethane the mixture was passed through a
short pad of Celite and the filtrate was concentrate under
reduced pressure. The crude was purified by flash chromatog-
raphy on a silica gel column (eluent, hexanes-ethyl acetate, 60:
40) to give 0.136 g (88% yield) of the corresponding Michael
adduct 3a b.
other on the silica surface. The efficiency of our CeCl3‚
7H2O-NaI combination supported on silica gel, in con-
trast to the existing methods with many acidic catalysts,
is very general, simple, high yielding, and oxygen and
moisture tolerant. Then the mildness of the reaction
conditions and low cost of reagents should make the
present methodology synthetically useful. Further appli-
cations of this Michael reaction protocol to alkaloid total
synthesis will be reported in due course.
Exp er im en ta l Section
NMR spectra were recorded in CDCl3 solutions at 300 (1H)
and 75.5 MHz (13C). Mass spectra were determined by means
of the EI technique (70 eV). IR absorption spectra were recorded
with thin films on NaCl plates, and only noteworthy absorptions
(cm-1) are listed. The indoles used as starting materials were
obtained from commercial sources or were synthesized according
to reported methods in the literature.25 All solvents were dried
and distilled according to standard procedures.
Ack n ow led gm en t. This work was supported by the
Ministero dell’Istruzione, dell’Universita` e della Ricerca
(MIUR, Programma di Ricerca “Stereoselezione in Sin-
tesi Organica, Metodologie ad Applicazioni”), Italy, and
the University of Camerino. M.B. gratefully acknowl-
edges Pharmacia/Pfizer for a post-graduate fellowship.
Rep r esen ta tive P r oced u r e for th e Syn th esis of 3-(3-
Oxoa lk yl)in d oles (Ta ble 1, en tr y 2). Silica gel (0.276 g) was
added to a mixture of CeCl3‚7H2O (0.067 g, 0.18 mmol) and NaI
(0.027 g, 0.18 mmol) in acetonitrile (4 mL), and the mixture was
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, 1H and 13C NMR spectra, MS spectra, and other
characterization data for new compounds, not reported previ-
ously, designated by their entries in Table 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
(25) Coullet, F.; Morel, S.; Boyer, G.; Galy, J . P. Synth. Commun.
1998, 28, 147.
J O034303Y
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