Ytterbium triflate catalyzed synthesis of β-functionalized indole derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.11.128

Ytterbium triflate was shown to be effective in promoting the synthesis of substituted indole derivatives starting from indole, aldehydes, and dimethyl malonate by a Yonemitsu-type three component reaction. The whole process was carried out in solvent-fre

Full text of DOI:10.1016/j.tetlet.2010.11.128

Tetrahedron Letters 52 (2011) 568–571
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ytterbium triflate catalyzed synthesis of b-functionalized indole derivatives
Francesco Epifano a, Salvatore Genovese a, Ornelio Rosati b, Silvia Tagliapietra c, Caroline Pelucchini b,
Massimo Curini b,
⇑
a Dipartimento di Scienze del Farmaco, Università ‘G. D’Annunzio’ di Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy
b Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy
c Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, Torino, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Ytterbium triflate was shown to be effective in promoting the synthesis of substituted indole derivatives
starting from indole, aldehydes, and dimethyl malonate by a Yonemitsu-type three component reaction.
The whole process was carried out in solvent-free conditions and furnished the desired adducts in
42–67% yield.
Received 28 September 2010
Revised 22 November 2010
Accepted 24 November 2010
Available online 29 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Heterogeneous catalysis
Indole derivatives
Multicomponent reactions
Yonemitsu-type reaction
Ytterbium triflate
1. Introduction
adducts only using Meldrum’s acid, while it failed or was poorly
efficient with other active methylene substrates. Only recently,
Multicomponent reactions (MCRs) represent nowadays a novel
and challenging frontier in synthetic organic chemistry. In this kind
ofprocessesthreeor morecomponentsreactin thesamevessel lead-
ing to the final product without the need of isolating any intermedi-
ates. Since the very beginning of their validation and application,
MCRs proved to be a very useful tool for the synthesis of structurally
complex molecules, in particular natural products, and in the field of
drug discovery. Several examples of ‘classic’ organic processes were
recently described in terms of a MCR version.1,2 In 1978 Yonemitsu
and co-workers discovered a multicomponent-based process by
which differently substituted indoles, aldehydes, and Meldrum’s
acid reacted to give tryptophan derivatives in good yields. Since its
first application in organic synthesis,3 the Yonemitsu reaction has
been largely applied to the synthesis of biologically active products,
mainly alkaloids, among which are b-substituted tryptophans,
tryptamines, b-carbolines, and carbazoles.4 This type of condensa-
tion has been routinely carried out with organic bases employed as
promoters, like DL-proline.5 In some instances the reaction is effec-
tive also in absence of catalysts and/or promoters, although there is
only one case described in the literature [e.g., the synthesis of
gem-(b-dicarbonyl)arylmethanes from indole and hydroxycouma-
rins].6 The major limitation of the original Yonemitsu protocol is
represented by the fact that the process leads to the desired
the search for new and alternative methods using both differently
substituted 1,3-dicarbonyl derivatives, other than Meldrum’s acid
and Lewis acids as catalysts, instead of Brønsted bases, to promote
this kind of three component condensation became subject of a
growing interest. However, until now only the method recently
reported by Sapi and co-workers was found to efficiently promote
the synthesis of substituted indoles, furans, pyrroles, and imida-
zoles. This process used Ti(IV)/Et3N complexes as catalysts to
perform the Yonemitsu-type trimolecular condensation of aro-
matic heterocycles, aldehydes, and active methylene substrates.7,8
Notably other Lewis acids, like Al3+, Zr4+, and Sn4+ did not promote
such a transformation. Although representing an effective method
for the synthesis of b-substituted p-rich aromatic compounds, the
Yonemitsu-type process described by Sapi and co-workers is
affected by some drawbacks: the need of high quantity of the
catalyst complex (up to 1:1 molar ratio with substrates) to
efficiently convert the substrates into the desired adducts and no
recycling of the catalyst. For these reasons this methodology
results in expensive and low application for large scale synthesis.
So the search for and development of a facile and good-yielding
Yonemitsu-type process is still of great importance. During the last
15 years, rare earth metal triflates have been found to be unique
Lewis acids since they are water tolerant reusable catalysts and
can effectively promote several carbon–carbon and carbon–hetero-
atom bond-formation reactions in high yield, including MCRs.9,10
In the course of our investigations we have recently seen that rare
⇑
Corresponding author. Tel.: +39 0755855106; fax: +39 0755855116.
E-mail address: curmax@unipg.it (M. Curini).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.128

F. Epifano et al. / Tetrahedron Letters 52 (2011) 568–571
569
Table 1
earth metal triflates are able to efficiently promote a variety of
Yb(OTf)3 catalyzed synthesis of b-functionalized indole derivatives
valuable and high yielding C–C bond-forming reactions.11
Entry
R
Product
Yielda (%)
In continuation of our ongoing studies aimed at developing mild
and practical protocols for the synthesis of useful building blocks
and/or biologically active compounds by using lanthanides as cat-
alysts, and employing water as solvent or solvent-free conditions,
herein we wish to report that a multicomponent Yonemitsu-type
reaction can be effectively catalyzed by Yb(OTf)3 hydrate in satis-
factory yields using indole, differently substituted aldehydes and
dimethyl malonate as a source of active methylene compound to
give b-functionalized indole derivatives (Scheme 1).
O
OCH3
OCH3
1
Ph
67
O
N
H
O2N
Meldrum’s acid has a pKa value by far lower than that of
dimethyl malonate (13.7 versus 4.97). So in theory the latter is less
prone to yield the enolate anion necessary to begin the process.
Anyway the choice of employing the cheaper dimethyl malonate
instead of the more expensive Medlrum’s acid is addressed by the
fact that is well known that b-diketonates readily react with lantha-
nides to give stable lanthanide/b-diketonate adducts in which the
dicarbonyl moiety is strongly coordinated via enolate anion to the
metal center.12 The efficient Michael addition of b-dicarbonyl
compounds to several acceptors is an example of the easy forma-
tion of enolate anion of active methylene compounds under the
catalysis of lanthanide triflates.11
As a preliminary test reaction we studied the conversion of an
equimolar mixture of indole, benzaldehyde, and dimethyl malon-
ate in the presence of Yb(OTf)3 as the catalyst. The reaction was
optimized by carrying it out under solvent-free conditions with
10 mol % catalyst and heating by ultrasonication for 12 h; after
the addition of 1 N NaOH to precipitate Yb+3 as the hydroxide,
the desired adduct was obtained in 67% yield after extraction with
Et2O and purification by SiO2 gel column chromatography. Sapon-
ification of the ester functions in the adducts was recorded to a
limited extent during the described recovery procedure. Sonication
revealed to be a key point for the success of the whole process, as
the same protocol carried out by heating at temperatures up to
120 °C led to extensive formation of by-products deriving from in-
dole polymerization, oxidation of aldehydes, and aldol condensa-
tion. All these were found also in the above reported procedure
but in low yields. To investigate the advantages and limitations
of our methodology, other aldehydes, having electron withdrawing
and donating substituents in the aromatic ring (entries 2–6), as
well as aliphatic aldehydes like isopropylcarboxyaldehyde (entry
7) or n-hexanal (entry 8) were subsequently used and the results
of their condensation with indole and dimethyl malonate are re-
ported in the Table 1.
O
2
3
4
4-NO2-Ph
4-OH-Ph
4-F-Ph
54
OCH3
OCH3
O
N
H
H
H
HO
O
O
47
OCH3
OCH3
O
O
N
F
42
OCH3
OCH3
N
Cl
O
5
4-Cl-Ph
47
OCH3
OCH3
O
N
H
NO2
O
Both aromatic aldehydes having electron donating or with-
drawing substituents as well as aliphatic aldehydes reacted
nearly to the same extent furnishing the desired adducts in
yields ranging from 42% to 54%. The catalyst was always recov-
ered by precipitation as Yb(OH)3, filtrated, and transformed into
6
7
3-NO2-Ph
48
44
OCH3
OCH3
O
O
N
N
H
H
O
OCH3
OCH3
(CH3)2CH
O
O
O
+
+
R
H
H3CO
OCH3
N
H
Yb(OTf)3
10% mol
O
O
8
CH3(CH2)4
43
R
OCH3
OCH3
OCH3
O
N
OCH3
O
N
H
H
a
Yields of pure isolated products, characterized by IR, GC–MS, 1H NMR, and 13C
NMR.
Scheme 1.

570
F. Epifano et al. / Tetrahedron Letters 52 (2011) 568–571
the triflate salt as already described.13 Recycled in this way, the
catalyst could be reused several times without any significant
loss of activity. For example the reaction leading to product of
entry 1 was repeated three additional times with the recovered
Lewis acid with yields in indole derivatives of 63%, 65%, and
62%, respectively.
The same reaction was also performed by using other metal
triflates from the lanthanide series, but the results were worse
than with Yb(OTf)3. The reason of this discrepancy of catalytic effi-
ciency in the lanthanide series could be explained by the fact that
Yb+3 is the ‘‘hardest’’ cation and thus the most oxophilic, due to its
smaller ionic radius.14 So, coordination of the oxygen atoms of
dimethyl malonate and aldehyde to Yb+3 would result in a greater
enhancement of the reactivity of substrates participating to the
multicomponent Yonemitsu-type condensation we are dealing
with. It’s also interesting to note that the use of Meldrum’s acid
instead of dimethyl malonate under the same experimental condi-
tions resulted in no reactions. This difference in reactivity may be
explained by the fact that malonates can adopt a cis configuration
of the corresponding enolate leading to a more efficient chelation
on the metal center.12
2.2. General procedure
To a mixture of indole (1.0 mmol), dimethyl malonate (1.0
mmol), and aldehyde (1.0 mmol), Yb(OTf)3 hydrate (0.1 mmol)
was added and the resulting suspension was sonicated in an ultra-
sound bath for 12 h. After the completion of the reaction, moni-
tored by TLC (elution mixture CH2Cl2/petroleum ether 9:1),
NaOH 1 N (20 mL) was poured into the mixture, that was then fil-
tered and the filtrate washed and extracted with Et2O (3 Â 10 mL).
The collected organic phases were evaporated to dryness and the
resulting crude mixture was purified by SiO2 gel column chroma-
tography (eluent CH2Cl2), yielding the desired adduct. The catalyst
was recovered and recycled as already described.10
Dimethyl 2-[1H-indol-3-yl(phenyl)methyl]malonate (entry 1):
Yield = 67% as a white solid, mp = 150–151 °C (n-hexane). Analyti-
cal data were identical to those already reported for the same com-
pound.6 Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15; O,
18.97. Found: C, 71.16; H, 5.67; N, 4.12; O, 18.98.
Dimethyl 2-[1H-indol-3-yl(4-nitrophenyl)methyl]malonate (entry
2): Yield = 54% as a pale red solid, mp = 146–148 °C (n-hexane).
Analytical data were identical to those already reported for the
same compound.6 Anal. Calcd for C20H18N2O6: C, 62.82; H, 4.74;
N, 7.33; O, 25.11. Found: C, 62.85; H, 4.73; N, 7.32; O, 25.12.
Dimethyl 2-[(4-hydroxyphenyl)(1H-indol-3-yl)methyl]malonate
(entry 3): Yield = 47% as a pale yellow solid, mp = 172–174 °C (n-
hexane). 1H NMR d 3.61 (s, 3H), 3.63 (s, 3H), 4.28 (d, 1H,
J = 11.6 Hz), 5.08 (d, 1H, J = 11.6 Hz), 6.64–7.52 (m, 9H), 7.94 (s
br, 1H), 8.17 (s br, 1H); 13C NMR d 38.4, 52.4, 57.7, 110.5, 111.8,
117.7, 117.8, 119.1, 120.9, 121.6, 125.7, 128.6, 128.7, 129.1,
138.0, 138.9, 153.5, 168.8, 169.2; IR (neat, cmÀ1) 3600 (br), 1710.
Anal. Calcd for C20H19NO5: C, 67.98; H, 5.42; N, 3.96; O, 22.64.
Found: C, 67.99; H, 5.44; N, 3.94; O, 22.62.
Dimethyl 2-[(4-fluorophenyl)(1H-indol-3-yl)methyl]malonate (en-
try 4): Yield = 42% as a pale yellow solid, mp = 158–159 °C (n-hex-
ane). 1H NMR d 3.62 (s, 3H), 3.66 (s, 3H), 4.22 (d, 1H, J = 11.8 Hz),
5.12 (d, 1H, J = 11.8 Hz), 7.08–7.67 (m, 9H), 8.20 (s br, 1H); 13C
NMR d 38.3, 52.3, 57.9, 110.3, 111.1, 117.6, 118.3, 120.2, 121.5,
125.5, 128.6, 128.7, 129.4, 138.2, 142.0, 142.1, 155.5, 162.0,
168.6, 169.5. IR (neat, cmÀ1) 1711. Anal. Calcd for C20H18FNO4: C,
67.60; H, 5.11; N, 3.94; O, 18.01. Found: C, 67.62; H, 5.12; N,
3.95; O, 18.02.
From a mechanistic point of view, it could be hypothesized that
Yb+3 first coordinates dimethyl malonate yielding a highly reactive
enolate species, that in turn could give an aldol condensation with
the aldehyde yielding an
a,b-unsaturated intermediate, still coor-
dinated to the lanthanide in the b-dicarbonyl portion. In fact the
reaction of only dimethyl malonate and aldehydes in the presence
of Yb(OTf)3 promptly led to this kind of adduct. The formation of
the a,b-unsaturated intermediate would result in a great enhance-
ment of the electrophilicity of adduct to which indole could easily
add leading to the desired product.
As a conclusion, in this manuscript we have demonstrated
that indole and differently substituted aldehydes undergo an
efficient condensation reaction with dimethyl malonate under
the catalysis of Yb(OTf)3 hydrate. The simple workup procedure,
mild reaction conditions, and satisfactory yields make our
methodology a valid and alternative contribution to the existing
processes in the field of the multicomponent Yonemitsu-type
condensations. To the best of our knowledge, the process de-
scribed herein represents the first example of the Yonemitsu
reaction catalyzed by a Lewis acid without the addition of other
promoters like amines. Moreover, this protocol introduces a
practical and viable technology of solvent-free reactions. Further
investigations to broaden the scope of this methodology are in
progress in our laboratories.
Dimethyl
2-[(4-chlorophenyl)(1H-indol-3-yl)methyl]malonate
(entry 5): Yield = 47% as a white solid, mp = 162–164 °C (n-hexane).
1H NMR d 3.65 (s, 3H), 3.68 (s, 3H), 4.28 (d, 1H, J = 11.7 Hz), 5.18 (d,
1H, J = 11.7 Hz), 7.02–7.62 (m, 9H), 8.15 (s br, 1H); 13C NMR d 38.2,
52.1, 57.6, 110.3, 111.4, 119.1, 120.2, 121.7, 122.7, 122.8, 125.6,
129.0, 129.6, 130.2, 130.3, 137.8, 144.9, 168.9, 169.4. IR (neat, cm
À1) 1713. Anal. Calcd for C20H18ClNO4: C, 64.61; H, 4.88; N, 3.77;
O, 17.21. Found: C, 64.63; H, 4.87; N, 3.75; O, 17.22.
2. Experimental
2.1. General remarks
Dimethyl
2-[1H-indol-3-yl(3-nitrophenyl)methyl]malonate
(entry 6): Yield = 47% as a pale brown solid, mp = 147–149 °C (n-
hexane). 1H NMR d 3.65 (s, 3H), 3.69 (s, 3H), 4.26 (d, 1H,
J = 11.9 Hz), 5.12 (d, 1H, J = 11.9 Hz), 7.16–8.23 (m, 9H), 8.28 (s
br, 1H); 13C NMR d 38.8, 52.4, 57.8, 110.1, 111.5, 119.9, 120.2,
120.8, 121.5, 123.7, 125.7, 127.0, 128.6, 132.7, 138.1, 144.9,
150.6, 169.1, 169.2. IR (neat, cmÀ1) 1715, 1556, 1361. Anal. Calcd
for C20H18N2O6: C, 62.82; H, 4.74; N, 7.33; O, 25.11. Found: C,
62.83; H, 4.75; N, 7.34; O, 25.12.
All reagents were obtained from commercial sources (Aldrich
Chemical Co.) and used without further purification. All solvents
were of analytical grade. All extracts were dried over anyhdrous
Na2SO4. 1H and 13C NMR spectra were recorded on a Bruker AC
200 (1H NMR, 200 MHz; 13C NMR, 50.32 MHz) CDCl3 was used as
the solvent and tetramethylsilane as an internal standard. Chem-
ical shifts are reported in d (ppm). Reactions were routinely
monitored by TLC using Merck silica gel F254 plates and visuali-
zation of TLC spots with a freshly prepared 7% ethanolic solution
of phosphomolybdic acid. Silica gel 40 (0.063–0.200 mm) from
Merck was used for column chromatography. Melting points
were measured on a Büchi melting point apparatus and are
uncorrected. Elemental analyses were carried out on a Carlo Erba
1106 elemental analyzer. The purity of the intermediates and the
final products was confirmed by combustion analysis.
Dimethyl
2-[1-(1H-indol-3-yl)-2-methylpropyl]malonate
(entry 7): Yield = 44% as a white solid, mp = 127–128 °C (n-hexane).
Analytical data were identical to those already reported for the
same compound.6 Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N,
4.62; O, 21.10. Found: C, 67.33; H, 6.94; N, 4.61; O, 21.12.
Dimethyl
2-[1-(1H-indol-3-yl)hexyl]malonate
(entry
8):
Yield = 43% as a pale yellow solid, mp = 138–140 °C (n-hexane).
1H NMR d 0.89 (t, 3H, J = 7.7 Hz), 1.12–1.43 (m, 8H), 3.42 (s, 3H),

F. Epifano et al. / Tetrahedron Letters 52 (2011) 568–571
571
4. (a) Dardennes, E.; Kovács-Kulyassa, A.; Renzetti, A.; Sapi, J.; Laronze, J. Y.
Tetrahedron Lett. 2003, 44, 221–223; (b) Cochard, F.; Laronze, M.; Sigaut, P.;
Sapi, J.; Laronze, J. Y. Tetrahedron Lett. 2004, 45, 1703–1708; (c) Dardennes, E.;
Kovács-Kulyassa, A.; Boisbrun, M.; Petermann, C.; Laronze, J. Y.; Sapi, J.
Tetrahedron: Asymmetry 2005, 16, 1329–1339; (d) Jeannin, L.; Boisbrun, M.;
Nemes, C.; Cochard, F.; Laronze, M.; Dardennes, E.; Kovács-Kulyassa, A.; Sapi, J.;
Laronze, J. Y. C. R. Chim. 2003, 6, 517–528.
3.43 (s, 3H), 3.86 (dt, 1H, J = 10.2 Hz, J = 3.2 Hz), 4.94 (d, 1H,
J = 10.2 Hz), 7.02–7.88 (m, 5H), 8.15 (s br, 1H); 13C NMR d 14.1,
22.7, 33.1, 33.4, 35.6, 38.7, 52.4, 57.8, 110.9, 111.0, 118.7, 119.3,
121.9, 124.0, 129.2, 137.0, 169.0, 170.1. IR (neat, cmÀ1) 1712. Anal.
Calcd for C19H25NO4: C, 68.86; H, 7.60; N, 4.23; O, 19.31. Found: C,
68.88; H, 7.58; N, 4.21; O, 19.30
5. Nemes, C.; Jeannin, L.; Sapi, J.; Laronze, M.; Seghir, H.; Augé, F.; Laronze, J. Y.
Tetrahedron 2000, 56, 5479–5492.
Acknowledgment
6. Appendino, G.Cicione, L.; Minassi, A. Tetrahedron Lett. 2009, 50, 5559–
5561.
7. Renzetti, A.; Dardennes, E.; Fontana, A.; De Maria, P.; Sapi, J.; Gerard, S. J. Org.
Chem. 2008, 73, 6824–6827.
8. Gerard, S.; Renzetti, A.; Lefèvre, B.; Fontana, A.; De Maria, P.; Sapi, J. Tetrahedron
2010, 66, 3065–3069.
9. Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. L. Chem. Rev. 2002, 102, 2227–
2264.
10. Kobayashi, S. Chem. Lett. 1991, 2187–2190.
Financial support from MIUR PRIN 2008 ‘A Green Approach to
Process Intensification in Organic Synthesis’ is gratefully
acknowledged.
References and notes
11. Genovese, S.; Epifano, F.; Pelucchini, C.; Curini, M. Eur. J. Org. Chem. 2009,
1132–1135. and references cited herein.
12. Bonadies, F.; Lattanzi, A.; Orelli, L. R.; Pesci, S.; Scettri, A. Tetrahedron Lett. 1993,
34, 7649–7650.
13. Fieser, M. In Reagents for Organic Synthesis; Wiley-Interscience: New York,
1989; Vol. 14, p. 188.
14. Pitzer, K. S. Acc. Chem. Res. 1974, 12, 271–276.
1. Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005.
pp. 1–21.
2. For some recent reviews on multicomponent reactions, see: (a) Ramon, D. J.;
Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634; (b) Dömling, A. Chem. Rev.
2006, 106, 17–89.
3. Oikawa, Y.; Hirasawa, H.; Yonemitsu, O. Tetrahedron Lett. 1978, 20, 1759–1764.