TiCl4/Et3N-promoted three-component condensation between aromatic heterocycles, aldehydes, and active methylene compounds

Article abstract of DOI:10.1021/jo800529q

(Chemical Equation Presented) A one-pot methodology for the synthesis of polyfunctionalized indole derivatives by a TiCl₄/Et ₃N-promoted trimolecular condensation of aldehydes, indole heterocycles, and various activated carbonyl compounds is reported. Rationalization of these reactions and extension to other heterocyclic systems is also described.

Full text of DOI:10.1021/jo800529q

chemistry. The usefulness of MCRs is even greater if they
provide access to “privileged medicinal scaffolds” like, for
example, pyridines and 1,4-dihydropyridines, decahydroquino-
lin-4-ones, or dihydropyrimidines.3–5
TiCl4/Et3N-Promoted Three-Component
Condensation between Aromatic Heterocycles,
Aldehydes, and Active Methylene Compounds
In previous works, we have shown that the Yonemitsu
trimolecular condensation,6 involving indole, Meldrum’s acid,
and an aldehyde combined with simple functional group
transformations, was efficient for the synthesis of various
ꢀ-substituted tryptophans, heterocycle-fused tryptamines, ꢀ-car-
bolines, and carbazoles of biological interest.7
Andrea Renzetti,†,‡ Emmanuel Dardennes,†
Antonella Fontana,‡ Paolo De Maria,‡ Janos Sapi,*,† and
Ste´phane Ge´rard*,†
Institut de Chimie Mole´culaire de Reims, UMR CNRS 6229,
UniVersite´ de Reims-Champagne-Ardenne, Faculte´ de
Pharmacie, 51 rue Cognacq-Jay, F-51096 Reims, Cedex,
France, and Dipartimento di Scienze del Farmaco,
UniVersita` “G. d’Annunzio”, Via dei Vestini 31,
I-66013 Chieti, Italy
Toward a direct approach of such tryptophans and heterocyclic
systems, we have envisaged the replacement of the Meldrum’s acid
moiety by malonesters and other 1,3-bifunctional carbonyl deriva-
tives like acetoacetates, nitroacetates, and phosphonoacetates. As
the above-mentioned active methylene compounds failed to react
under the usual Yonemitsu reaction conditions6 probably due
to their higher pKa values, we focused our attention to a Lewis
acid activated version. Lewis acids have been well documented
to facilitate numerous C-C bond formation reactions. In
particular, in the 1970’s, Lehnert8 and later on Reetz9 described
various Ti(IV) derivative-promoted syntheses of Knoevenagel
adducts. Although Ti(IV)-catalyzed Knoevenagel reactions have
scarcely been documented10 since that time, we chose this
approach to extend our trimolecular condensation to various
activated carbonyl compounds.
janos.sapi@uniV-reims.fr; stephane.gerard@uniV-reims.fr
ReceiVed March 7, 2008
We speculated that titanium species would not only help the
formation of the corresponding enolate but could also promote
Friedel-Crafts-type reaction between indole and an in situ
formed Knoevenagel intermediate. Friedel-Crafts alkylation of
indoles with R,ꢀ-unsaturated carbonyl derivatives,11 especially
the Lewis acid catalyzed asymmetric version,12 have recently
attracted great attention, but its multicomponent version remains
unprecedented.
A one-pot methodology for the synthesis of polyfunction-
alized indole derivatives by a TiCl4/Et3N-promoted trimo-
lecular condensation of aldehydes, indole heterocycles, and
various activated carbonyl compounds is reported. Ratio-
nalization of these reactions and extension to other hetero-
cyclic systems is also described.
(3) Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.; Kornienko, A. Org.
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Since the publication of the Strecker reaction in 1850, which
could be considered as the beginning of the multicomponent
reaction (MCR) story,1 this strategy has been shown to be a
valuable tool in the preparation of structurally diverse chemical
libraries of druglike heterocyclic compounds.2 MCRs often
involve domino processes with at least three different simple
partners reacting in a well-defined manner to create complexity
and diversity by the facile formation of several new bonds. This
methodology is particularly well adapted for combinatorial
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P.; Sapi, J.; Laronze, J.-Y. Tetrahedron Lett. 2004, 45, 1703–1708. (c) Dardennes,
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122.
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Tetrahedron 2000, 56, 7667–7671. (b) Noguchi, M.; Yamada, H.; Takamura,
S.; Uchida, T.; Hironaka, M.; Kakehi, A.; Yamamoto, H. Eur. J. Org. Chem.
2000, 1489–1496. (c) Hayashi, M.; Nakamura, N.; Yamashita, K. Tetrahedron
2004, 60, 6777–6783. (d) Yamashita, K.; Tanaka, T.; Hayashi, M. Tetrahedron
2005, 61, 7981–7985. (e) Zhang, X.-R.; Chao, W.; Chuai, Y.-T.; Ma, Y.; Hao,
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† Universite´ de Reims-Champagne-Ardenne.
‡ Universita` “G. d’Annunzio”.
(1) Strecker, A. Liebigs Ann. Chem. 1850, 75, 27–45.
(2) For some recent reviews, see: (a) Orru, R.; De Greef, M. Synthesis 2003,
1471–1499. (b) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80. (c)
Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957–
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6824 J. Org. Chem. 2008, 73, 6824–6827
10.1021/jo800529q CCC: $40.75 2008 American Chemical Society
Published on Web 08/09/2008

TABLE 1. Trimolecular Condensation and Optimization Studies
TABLE 2. Trimolecular Condensation Promoted by TiCl4/Et3N
Using Dimethyl Malonate and Various Aldehydes
entry
conditions
yield of 1 %a
1
2
3
4
5
6
7
8
9
Ti(O-i-Pr)4/Et3N/CH2Cl2
TiCl4/Et3N (2 equiv)/CH2Cl2
TiCl4/Et3N/toluene
no reaction
46
14
traces
81
50
traces
traces
traces
TiCl4/Et3N/THF
TiCl4/Et3N/CH2Cl2
TiCl4/pyridine/CH2Cl2
ZrCl4/Et3N/CH2Cl2
AlCl3/Et3N/CH2Cl2
SnCl4/Et3N/CH2Cl2
a Isolated yield after purification by silica gel chromatography.
Initially, we investigated the reaction between indole, isobu-
tyraldehyde, and dimethyl malonate in dichloromethane in the
presence of 1 equiv of titanium tetraisopropoxide and 1 equiv
of Et3N (Table 1).10dUnfortunately, we were unable to isolate
the corresponding condensation derivative (entry 1). As the
TiCl4-Et3N reagent system is widely used to generate titanium
enolates for applications in aldol and related reactions,13 we
tested this more reactive system in our MCR. We were pleased
to find that the trimolecular adduct 1 was isolated in 46% yield
using 2 equiv of base in dichloromethane (entry 2). A
preliminary optimization was then carried out varying solvent,
base, and Lewis acid (entries 3-9). Condensation in the
presence of 1 equiv of TiCl4 and Et3N in toluene proceeded
slowly at room temperature, and the yield was only 14% even
when the reaction time was increased to 72 h. In the case of
pyridine, the adduct was isolated in 50% yield. The use of other
strong Lewis acids such as zirconium, aluminum, or tin chlorides
did not give the desired product. According to Table 1, the best
yield of the trimolecular condensation product was obtained with
TiCl4/Et3N (1/1 ratio) in CH2Cl2 at 0 °C.
a Isolated yield after purification by silica gel chromatography.
b Unseparable epimeric (C-3) mixture (60/40).
As shown in Table 2, formation of the corresponding trimo-
lecular adduct proceeded in about 6 h in moderate to good yields
(entries 1, 2, and 5). Introduction of an electron-withdrawing
group in the para position did not modify the yield significantly
(entry 4 vs entry 3), while reaction with a more sensitive
aldehyde, derived from D-glucose, afforded 7 as an unseparable
mixture (60/40) of two diastereomers (entry 6). From the COSY
1H NMR spectrum of the mixture 7 we could identify two
distinct couplings, JH2-H3 ) 7.8 Hz (δ ) 4.16 ppm) and JH2-H3
) 4.7 Hz (δ ) 4.09 ppm), attributed to H-2 protons of the major
(7a) and the minor (7b) diastereomers, respectively. Since
chemical shifts and couplings of the sugar moiety remained
almost unchanged, the isolated adduct 7 proved to be a C-3
epimeric mixture.14 The (S) absolute configuration of this center
in 7a was determined by analyzing the coupling constants of
H-3 (JH6-H7 ) 10.3 Hz, JH7-H7a ) 3.2 Hz) of 9a. This latter
was obtained via the major alcohol 8a by debenzylation followed
To further explore the scope and limitations of this methodol-
ogy, we tested other aldehydes under optimized conditions
(Table 2). Both aliphatic and aromatic aldehydes were used.
(11) (a) Iqbal, Z.; Jackson, A. H.; Rao, K. R. N. Tetrahedron Lett. 1988, 29,
2577–2580. (b) Harrington, P. E.; Kerr, M. A. Synlett 1996, 1047–1048. (c)
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S.; Umani-Ronchi, A. J. Org. Chem. 2002, 67, 3700–3704. (f) Srivastava, N.;
Banik, B. K. J. Org. Chem. 2003, 68, 2109–2114. (g) Bandini, M.; Fagioli, M.;
Melloni, A.; Umani-Ronchi, A. Synthesis 2003, 397–402. (h) Bartoli, G.;
Bartolacci, M.; Bosco, M.; Foglia, G.; Giulani, A.; Marcantoni, E.; Sambri, L.;
Torregiani, E. J. Org. Chem. 2003, 68, 4594–4597. (i) Zou, X.; Wang, X.; Cheng,
C.; Kong, L.; Mao, H. Tetrahedron Lett. 2006, 47, 3767–3771.
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R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 160–163. (b) Zhuang,
W.; Hansen, T.; Jørgensen, K. A. J. Chem. Soc., Chem. Commun. 2001, 347–
348. (c) Zhou, J.; Tang, Y. J. Am. Chem. Soc. 2002, 124, 9030–9031. (d)
Jørgensen, K. A. Synthesis 2003, 1117–1125. (e) Bandini, M.; Fagioli, M.;
Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Tetrahedron Lett. 2003, 44, 5843–
5846. (f) Zhou, J.; Ye, M.-C.; Huang, Z.-Z.; Tang, Y. J. Org. Chem. 2004, 69,
1309–1320. (g) Palomo, C.; Oiarbide, M.; Kardak, B. D.; Garcia, J. M.; Linden,
A. J. Am. Chem. Soc. 2005, 127, 4154–4155. (h) Yamazaki, S.; Iwata, Y. J.
Org. Chem. 2006, 71, 739–743. (i) Lu, S.-F.; Du, D.-M.; Xu, J. Org. Lett. 2006,
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t
by BuOK-mediated lactonization (Scheme 1).
After having tested various aldehydes, 1,3-bifunctional car-
bonyl derivatives were varied (Table 3). Sterically hindered
malonic esters afforded the trimolecular adduct in good yields
(entries 1 and 2). Our approach could also be extended to
ꢀ-ketoester and other active methylene compounds, thus fur-
nishing new applications of the original multicomponent reaction
(13) (a) Periasamy, M. ArkiVoc 2002, 7, 152–166. (b) Karunakar, G. V.;
Periasamy, M. J. Org. Chem. 2006, 71, 7463–7466, and references cited therein.
(14) Similarly, on the basis of the COSY 1H NMR spectrum, 20 proved to
be a C-3 epimeric mixture, and by analogy, 14 could be considered as well.
J. Org. Chem. Vol. 73, No. 17, 2008 6825

SCHEME 1. Determination of the Stereochemistry of 7
SCHEME 2. Determination of the Relative Configuration of
13
TABLE 4. Extension to Other Heterocyclic Systems
TABLE 3. Condensation of Indole with Aldehydes and Active
Methylene Compounds
a Isolated yield after purification by silica gel chromatography.
b Relative configurations: (2S*, 3R*)-12; (2R*, 3R*)-13. c Unseparable
epimeric (C-3) mixture (50/50).
(entries 3-5). In this way, the use of methyl acetoacetate as
active methylene compound gave the corresponding trimolecular
condensation product 12 as one diastereomer (entry 3). Simi-
larly, with ethyl nitroacetate we obtained the desired ethyl
2-nitro-3-(3-indolyl)-3-(2-propyl)propanoate 13 as a single
diastereomer in 48% yield, offering the possibility to obtain new
non-natural ꢀ-substituted tryptophans after reduction of the nitro
group (entry 4).15
The relative stereochemistry (2R*,3R*) of 13 was determined
by chemical correlation with (2R*,3R*)-3-isopropyltryptophan
tert-butyl ester of known relative configuration,16,17according
to Scheme 2.
We were delighted to find that the less active trieth-
ylphosphonoacetate smoothly reacted with a D-glucose-derived
aldehyde and indole affording the corresponding condensation
product 14 as an epimeric mixture (entry 5). Its phosphonate
a Isolated yield after purification by silica gel chromatography.
b Unseparable epimeric (C-3) mixture (50/50).
function offers the possibility of further transformations by
Horner-Emmons-type reactions.
The scope and limitations of this reaction were further
investigated by using a variety of structurally different indole
and heterocyclic derivatives (Table 4). Both activated (entries
1-4) and unactivated (entry 5) indoles could be used in our
titano-promoted trimolecular condensation. Moreover, use of
C-3-substituted indole offered the possibility to obtain conden-
sation in the less reactive 2 position (entry 3). Trimolecular
adducts between dimethyl malonate, isobutyraldehyde, and furan
derivatives could also be obtained in good yields (entries 6 and
7).
(15) During the preparation of the manuscript, a synthesis of ꢀ-aryltryp-
tophans based on catalytic Friedel-Crafts alkylation of indoles with aryl
nitroacrylates followed by nitro group reduction has appeared: Sui, Y.; Lui, L.;
Zhao, J.-L.; Wang, D.; Chen, Y.-J. Tetrahedron 2007, 63, 5173–5183.
(16) Nemes, C.; Jeannin, L.; Sapi, J.; Laronze, M.; Seghir, H.; Auge´, F.;
Laronze, J.-Y. Tetrahedron 2000, 56, 5479–5492.
(17) For comparison, (2R*,3S*) 3-Isopropyltryptophan tert-butyl ester has
also been transformed into the corresponding ethyl ester 15b (for details, see
the Supporting Information).
6826 J. Org. Chem. Vol. 73, No. 17, 2008

give crude products. Purification by column chromatography on
silica gel or by recrystallization furnished the corresponding
trimolecular adduct.
The mechanism of these reactions probably involves com-
plexation of dimethyl malonate with TiCl4, increasing the acidity
of the R hydrogen that can then be easily removed by Et3N to
promote formation of a dark red enolate ion. Attack of this
reactive species on the aldehyde generates the Knoevenagel
adduct. Finally, the Friedel-Crafts-type alkylation of the
heterocyclic system by the alkylidene malonate leads to the
trimolecular condensation product. Condensation of indole with
isobutyraldehyde and methyl acetoacetate or ethyl nitroacetate
gave, after equilibration in the reaction mixture, the diastereo-
merically pure derivatives (12 or 13) bearing isopropyl and ester
functions in the anti position.18In the case of sugar-derived
aldehyde, titanium species may partially dissociate off the
activated enolate and chelate the R-alkoxyaldehyde, rendering
the Friedel-Crafts reaction less diastereoselective (C-3 epimers:
7, 14, 20).
Methyl 2-Methoxycarbonyl-3-(3-indolyl)-3-(2-propyl)propanoate
1. Prepared from 1 mL of dimethyl malonate (8.75 mmol), 960 µL
of TiCl4, 1.23 mL of Et3N, 800 µL of isobutyraldehyde and 1.025
g of indole to yield 1 (2.146 g; 81% yield) as a white solid: mp )
1
128-129 °C; H NMR(CDCl3) δ 0.86 (d, 3H, J ) 6.8 Hz), 0.88
(d, 3H, J ) 6.8 Hz), 2.08 (m, 1H), 3.35 (s, 3H), 3.74 (s, 3H), 3.82
(dd, 1H, J ) 11.0 Hz, J ) 4.8 Hz), 3.99 (d, 1H, J ) 11.0 Hz),
7.03 (d, 1H), 7.14 (m, 2H), 7.33 (d, 1H, J ) 7.4 Hz), 7.68 (d, 1H,
J ) 7.6 Hz), 8,08 (sl, 1H); 13C NMR (CDCl3) δ 17.9, 21.8, 30.5,
42.1, 52.1, 52.6, 56.2, 110.8, 112.8, 119.2, 119.5, 121.7, 122.7,
128.3, 135.5, 168.7, 169.3; IR (KBr) ν 3401, 3048, 2952, 1727,
1432, 1335, 1269, 1150, 1018, 741 cm-1; MS (EI) m/z 303, 260,
171, 156, 130, 101; HRMS calcd for C17H21NO4 303.1471, found
303.1463.
(2R*,3R*)-Ethyl 2-nitro-3-(3-indolyl)-3-(2-propyl)propanoate 13:
yield from ethyl nitroacetate (1 mL, 8.75 mmol), TiCl4 (960 µL),
Et3N (1.23 mL), isobutyraldehyde (800 µL), and indole (1.025 g):
1.267 g (48%) as a yellow solid; mp ) 124-125 °C; 1H
NMR(CDCl3) δ 0.90 (d, 3H, J ) 6.7 Hz), 0.92 (d, 3H, J ) 6.7
Hz), 1.21 (t, 3H, J ) 6.9 Hz), 2.14 (m, 1H), 3.99 (dd, 1H, J )
10.1 Hz, J ) 5.5 Hz), 4.23 (m, 2H), 5.52 (d, 1H, J ) 10.1 Hz),
7.25 (m, 4H), 7.62 (d, 1H, J ) 7.5 Hz), 8.18 (sl, 1H); 13C NMR
(CDCl3) δ 13.7, 18.5, 21.7, 29.9, 43.7, 62.9, 91.3, 110.1, 111.1,
118.9, 119.6, 122.1, 122.9, 128.1, 135.6, 164.3; IR (KBr) ν 3424,
2962, 1754, 1562, 1190, 1018 cm-1; MS (CI) m/z 305, 259, 172,
141, 82. Anal. Calcd for C16H20N2O4 (304.34): C, 63.14; H, 6.62;
N, 9.20. Found: C, 63.46; H, 6.76; N, 9.13.
In conclusion, we have demonstrated the efficiency of the
TiCl4-Et3N reagent system to achieve a trimolecular condensa-
tion involving aldehydes, indole, or furan heterocycles and
various activated carbonyl compounds in a simple one-pot
procedure. Mechanistic and stereochemical aspects of this
approach and its extension to the asymmetric Friedel-Crafts
reaction of heterocyclic systems using chiral Ti(IV) ligands are
currently under investigation.
Experimental Section
General Procedure for the Three-Component Reaction. In a
typical procedure, malonester derivative is added to a solution of
TiCl4 (1 equiv) in dry dichloromethane (20 mL/10 mmol), at 0 °C,
under nitrogen using 3 Å molecular sieves, resulting in the formation
of a yellow suspension. After 15 min, Et3N (1.0 equiv) was added
providing a deep red homogeneous solution. A few minutes later,
aldehyde (1.0 equiv) was added dropwise, and the mixture was
stirred for 1-1.5 h at 0 °C until its disappearance. Finally,
heterocycle (1.0 equiv) was added, and the mixture was allowed
to warm up to room temperature until the reaction was completed.
After quenching by an aqueous solution of 1 M HCl, the organic
layer was dried over MgSO4 and concentrated under vacuum to
Acknowledgment. We thank the French Ministry of Educa-
tion, Research and Technology for a Ph.D. fellowship to E.D.
Financial support from the French Ministry of Foreign Affairs
and from the “French-Italian University” to A.R. is gratefully
acknowledged. We thank P. Sigaut (MS) and C. Petermann
(NMR) for spectroscopic measurements.
Supporting Information Available: General experimental
procedures, characterization data, and copies of 1H NMR spectra
of all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) Pure 12 and 13 were partially epimerized under kinetic conditions (0
t
°C, 15 min by treatment with BuOK in THF or Et3N (for details, see the
Supporting Information).
JO800529Q
J. Org. Chem. Vol. 73, No. 17, 2008 6827