Yonemitsu-type condensations catalysed by proline and Eu(OTf)3

Article abstract of DOI:10.1039/c4ra08853k

We report a Yonemitsu-type trimolecular condensation of aromatic heterocycles, aldehydes, and active methylene compounds to afford polyfunctionalised heterocycles. The reaction is catalysed by l-proline and Eu(OTf)₃, takes place in methanol at room temperature, and in some cases is highly diastereoselective (d.e. >90%). The reaction offers two advantages with respect to the previously reported Ti(iv)-promoted condensation: (1) it adheres to some principles of green chemistry, and (2) it provides access to compounds that cannot be obtained by classical methodology. This journal is

Full text of DOI:10.1039/c4ra08853k

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Yonemitsu-type condensations catalysed by
proline and Eu(OTf)3†
Cite this: RSC Adv., 2014, 4, 47992
Andrea Renzetti, a Emanuela Boffa,b Marco Colazzo,b Stephane Gerard,c Janos Sapi,c
*
´
´
Tak-Hang Chan,d Hiroshi Nakazawa,a Claudio Villanie and Antonella Fontanab
We report a Yonemitsu-type trimolecular condensation of aromatic heterocycles, aldehydes, and active
methylene compounds to afford polyfunctionalised heterocycles. The reaction is catalysed by L-proline
and Eu(OTf)3, takes place in methanol at room temperature, and in some cases is highly
diastereoselective (d.e. >90%). The reaction offers two advantages with respect to the previously
reported Ti(IV)-promoted condensation: (1) it adheres to some principles of green chemistry, and (2) it
provides access to compounds that cannot be obtained by classical methodology.
Received 18th August 2014
Accepted 17th September 2014
DOI: 10.1039/c4ra08853k
www.rsc.org/advances
into TiOCl2, HCl, and Et3NH+Clꢀ during the reaction, gener-
ating large (stoichiometric) amounts of waste. Due to such
1 Introduction
limitations, the Ti(IV)-promoted condensation is far from being
green, despite being a one-pot process. In this work, we devel-
oped a green version of such reaction.
Green chemistry is the use of safe chemicals and of processes
that reduce or eliminate the generation of waste.1,2 In agree-
ment with the twelve principles of green chemistry,2,3 the ideal
reaction has 100% yield, is one-pot and catalytic, takes place at
room temperature and 1 atm pressure in the air, uses safe and
renewable reagents, and generates no waste. Although it is hard
to develop a reaction that satises all these criteria,4,5 it is
possible to make a reaction cleaner. Some years ago, we repor-
ted a Yonemitsu-type trimolecular condensation of aromatic
heterocycles, aldehydes, and active methylene compounds
promoted by Ti(IV) derivatives and Et3N.6,7 The reaction affords
polyfunctionalised aromatic heterocycles in a simple one-pot
procedure, and can be used to synthesize libraries of heterocy-
clic compounds in drug discovery.8 However, the Ti(IV)-
promoted reaction has two serious drawbacks. Firstly, it uses
dangerous reagents: TiCl4 or TiCl2(Oi-Pr)2 (corrosive), Et3N
(toxic and ammable), and dichloromethane (carcinogenic).
Secondly, it is not catalytic, because it requires equimolar
amounts of Ti(IV) salt and Et3N. These compounds are converted
2 Results and discussion
2.1 Catalytic system
The rst issue we addressed in our study was the development
of a catalytic system. To achieve this aim, we used our knowl-
edge on the mechanism of the Ti(IV)-promoted reaction, which
involves three steps:9 (1) deprotonation of active methylene
compound, (2) Knoevenagel condensation of enolate ion and
aldehyde, and (3) Michael addition of heterocycle to the Knoe-
venagel adduct. The generation of the enolate ion from active
methylene compound, being the rst step of mechanism, is
crucial for the outcome of the overall reaction. Thus, any system
that favours the formation of the enolate ion in principle may
catalyse the trimolecular condensation.
2.1.1 Micellar catalysis. Aqueous micelles are regarded as
green reaction media,10 essentially being made of water and
soap. They act both as a solvent, by dissolving apolar
compounds otherwise insoluble in water, and as a catalyst, by
stabilising transition states through specic interactions and
favouring the reactants encounter in a restricted environ-
ment.11–15 Because cationic micelles increase the acidity of
carbon acids by electrostatic as well as hydrophobic interactions
with the enolate ion,16,17 they are expected to favour the overall
condensation. The reaction of indole, isobutyraldehyde, and
methyl acetoacetate was chosen as a model reaction because it
only works in 45% yield under classical conditions,6 and is
therefore worth optimising. Catalytic amount (0.2 equiv.) of
cetyltrimethylammonium bromide in water only afforded 3,30-
(2-methylpropane-1,1-diyl)bis(1H-indole), whereas the same
aDepartment of Chemistry, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku,
558-8585 Osaka, Japan. E-mail: renzetti@sci.osaka-cu.ac.jp; Fax: +81-6-6605-2522;
Tel: +81-6-6605-2513
b
`
Dipartimento di Farmacia, Universita “G. d'Annunzio” di Chieti-Pescara, Via dei
Vestini 33, I-66100 Chieti, Italy
c
´
´
Institut de Chimie Moleculaire de Reims, UMR CNRS 6229, Universite de Reims
´
Champagne-Ardenne, Faculte de Pharmacie, 51 Rue Cognacq-Jay, F-51096 Reims
Cedex, France
dDepartment of Chemistry, McGill University, 801 Sherbrooke Street West, H3A 0B8
Montreal, QC, Canada
e
`
Dipartimento di Chimica e Tecnologie del Farmaco, Universita “La Sapienza”, P.le A.
Moro, I-00185 Rome, Italy
† Electronic supplementary information (ESI) available: Experimental procedure
and characterization data for all compounds, and Tables S1–S4. See DOI:
10.1039/c4ra08853k
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surfactant in the presence of bases (sat. aqueous NaHCO3, sat. above results indicate that the reaction outcome does not
aqueous Na2CO3, or Et3N) afforded the trimolecular condensa- depend on the basic strength of catalyst.
tion product 1 in very low yield (0–7%). Stoichiometric amount
Lewis acids are known to increase the acidity of carbonyl
of CTAB or other surfactants such as sodium dodecyl sulfate, compounds by complexation,23 favouring the generation of
lanthanum tris-dodecylsulfate, and triton X-100 were also enolate ion. Therefore, we studied their use as potential cata-
uneffective in promoting the reaction. This failure may be lysts in our reaction. The rst choice fell on bismuth triate
explained by the weak affinity of the active methylene because this salt catalyses Mannich-type reactions,24,25 which
compound for micelles and its consequent reduced enolisation are analogous to Yonemitsu-type condensations. Bi(OTf)3
or by the difficulty in solubilising three reagents in the same underwent solvolysis26 when used alone, providing a highly
micellar compartment.18,19
acidic (pH ¼ 1) solution and a complex mixture of compounds
2.1.2 Metal catalysis. Aer these unsuccessful experiments (Table 1, entry 5). However, the same salt afforded product 1 in
in aqueous micelles, we turned to an alternative strategy based 38–50% when used in combination with a Brønsted base (Table
on metal catalysis. To avoid the before-mentioned problems of 1, entries 6–8). Most importantly, the combination of bismuth
solubility, methanol as an alternative solvent was chosen. triate and base proved to be more effective than the two
Methanol, despite being toxic to humans, is considered a green compounds used separately. Such synergic effect is likely due to
solvent due to its safety and low environmental impact,20–22 and the fact that base stabilizes bismuth by complexation, thus
was used in the place of ethanol to avoid transesterication preventing solvolysis and allowing the metal ion to exert its
reactions. The reaction of indole, isobutyraldehyde, and methyl catalytic activity.27 From the above results, it appears that both a
acetoacetate proceeded spontaneously in methanol but yield Brønsted base and a Lewis acid are necessary to effectively
was low (16%, Table 1, entry 1); compounds recovered from the catalyse the reaction. L-Proline proved to be the most efficient
reaction mixture were mainly starting materials. The observed base in combination with Bi(OTf)3, affording product 1 in 50%
low reactivity is probably due to the weak acidity of methyl yield (Table 1, entry 8). In fact, L-proline has already been used
acetoacetate (pKa ¼ 11), which only generates a small amount of by Yonemitsu as an efficient catalyst in the three-component
enolate ion, thus limiting the conversion of reagents. In order to condensation of indole, aldehydes, and Meldrum's acid.28
facilitate the deprotonation of methyl acetoacetate, we tested Slightly higher (60%) yield was obtained when Bi(OTf)3 was
the reaction in the presence of three Brønsted bases in catalytic replaced with La(NO3)3$6H2O (Table 1, entry 9). Solvent
amount (Table 1, entries 2–4): L-proline (pKa2 ¼ 10.6), Et3N screening conrmed methanol as the best reaction medium in
(pKa ¼ 10.6), and proton sponge® (pKa ¼ 12.1). None of them the presence of molecular sieves (Table S1†).29
provided an improvement with respect to the uncatalysed
Then, we optimised metal salt (Table 2). We tested several
reaction (Table 1, compare entries 2–4 with entry 1). Proton cations maintaining triate as counter anion owing to its weakly
sponge®, which was expected to be the best catalyst due to its coordinating properties. The highest catalytic activity was dis-
strong basicity, was totally uneffective (Table 1, entry 4). The played by In3+ (Table 2, entry 4) and lanthanide ions, particu-
larly those in the middle of the f-block (Eu3+, Gd3+, and Tb3+;
Table 2, entries 13, 14, and 15, respectively). These ndings are
in line with the ability of such ions to catalyse other multi-
component reactions.30–33 In the case of Tb3+ and Ho3+, the
Table
1 Trimolecular condensation in the presence of various
1H NMR spectrum of the condensation product showed broad
signals, indicating complexation with metal (Table 2, entries
15 and 16, respectively).34,35 Aer ltration over silica gel, the
1H NMR spectrum of 1 displayed sharp signals, conrming the
removal of metal. Although terbium triate gave the best yield
(Table 2, entry 15), we kept europium as the elected cation in the
following experiments because this ion did not seem to com-
catalysts
1
plexate the product according to H NMR spectrum.
Entry
Base
Salt
Yielda (%)
Anion was varied keeping the europium cation constant
(Table S2†). The weakly coordinating triate was found to be the
best one. Thus, we selected europium triate as the metal
catalyst in the following experiments. Metal to ligand ratio was
optimized as well (Table S3†). The best yield was obtained by
using an equimolar ratio of Eu(OTf)3 and L-proline (0.1 equiv.
each).
During our work,36 Curini and colleagues reported a trimo-
lecular condensation of dimethyl malonate, indole, and alde-
hydes catalysed by Yb(OTf)3 monohydrate in neat under
ultrasounds.37 Because their reaction is carried out without
solvent and base, we checked whether their conditions afford
better results than our protocol. The reaction of indole,
1
2
3
4b
5
6
7
8
9
None
None
None
None
None
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
Bi(OTf)3
La(NO3)3$6H2O
16
16
L-Proline
Et3N
Traces
DMANc
None
0d
0e
Et3N
38
38
50
60
DMANc
L-Proline
L-Proline
a
b
c
Yield of puried product. Solvent was CH3CN. DMAN ¼ 1,8-bis-
d
(N,N-dimethylamino)naphthalene
(proton
sponge®).
3,30-(2-
Methylpropane-1,1-diyl)bis(1H-indole) and methyl acetoacetate were
recovered. e A complex mixture of compounds was obtained.
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Table 2 Trimolecular condensation in the presence of various metal Table 3 Trimolecular condensation using various amino acids
salts
Entry
Amino acid
Yielda (%)
Entry
Salt
Yielda (%)
1
2
3
4
5
6
7
8
9
None
L-Proline
trans-L-4-Hydroxyproline
L-4-Thiazolidinecarboxylic acid
L-Aspartic acid
50
78
64
29
69
14
20
59
60
1
2
3
4
5
6
7
8
None
16
50
41
78
37
66
64
40
56
38
65
69
78
74
88
58
32
Traces
40
Bi(OTf)3
Ga(OTf)3
In(OTf)3
Mg(OTf)2
Sc(OTf)3
Y(OTf)3
Cu(OTf)2
Zn(OTf)2
Pr(OTf)3
Nd(OTf)3
Sm(OTf)3
Eu(OTf)3
Gd(OTf)3
Tb(OTf)3
Ho(OTf)3
Yb(OTf)3
Yb(OTf)3$H2O
Eu(OTf)3
L-Lysine
L-Serine
L-Histidine
CSAb (0.1 equiv.) + PMPc (0.1 equiv.)
9
a
b
10
11
12
13
14
15
16
17
18b
19c
Yield of puried product. CSA ¼ (1S)-(+)-10-camphorsulfonic acid.
PMP ¼ (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine.
c
four-fold lower activity than L-histidine, despite both amino
acids possessing a basic side chain (14 and 59% yield; Table 3,
entries 6 and 8, respectively). The same result was observed for
trans-L-4-hydroxyproline and L-serine, both bearing a hydroxyl
group (64 and 20% yield; Table 3, entries 3 and 7, respectively).
Proline was the best among the tested amino acids, affording 1
in 78% yield (Table 3, entry 2). When an equimolar mixture of
(1S)-(+)-10-camphorsulfonic acid (CSA) and (S)-(+)-1-(2-pyrroli-
dinylmethyl)pyrrolidine (PMP) was used in the place of an
amino acid, 1 was still obtained in 60% yield (Table 3, entry 9).
This result indicates that amphiprotic compounds other than
amino acids also catalyse the reaction.
a
Yield of product aer crystallisation. b Conditions: Yb(OTf)3$H2O (0.1
c
equiv.), neat, sonication, rt, 12 h. Conditions: L-proline (0.1 equiv.),
Eu(OTf)3 (0.1 equiv.), neat, sonication, rt, 12 h.
isobutyraldehyde, and methyl acetoacetate, performed exactly
under the same experimental conditions (1.0 mmol scale, 0.1
equiv. of Yb(OTf)3$H2O, neat, ultrasounds, rt, 12 h, same work
up) provided 1 only in traces (Table 2, entry 18). We also
investigated the effect of sonication in the presence of Eu(OTf)3
(Table 2, entry 19) and L-proline (neat or in MeOH), but in all
cases yield was lower than that obtained under our optimised
conditions.
Four representative samples of 1 (entries 2, 5, 8, and 9 of
Table 3) were analysed by HPLC on a chiral stationary phase.38
Unfortunately, in all cases the analysis evidenced a racemic
mixture, indicating the absence of enantioselectivity.
2.2 Amino acid
2.3 Scope and limitations
Although L-proline proved to be effective in combination with a To check the scope and limitations of our new protocol, we
Lewis acid, we extended our investigation to other amino acids. varied the three reactants in turn. Ethyl nitroacetate, ethyl
The trimolecular condensation of indole, isobutyraldehyde, and methylsulfonylacetate, and ethyl benzoylacetate as the active
methyl acetoacetate was performed in the presence of europium methylene compounds were used in ethanol in order to avoid
triate and various L-amino acids as catalysts (Table 3). Some transesterication. Nine condensation products were syn-
amino acids enhanced the catalytic activity of Eu(OTf)3 (Table 3, thesised (Table 4). All of them were exclusively obtained in the
entry 1 vs. entries 2, 3, 5, and 8), others inhibited it (Table 3, keto form; neither enol nor other tautomeric forms were
1
entry 1 vs. entries 4, 6, and 7). Overall, yield varied from 14 to detected by H NMR spectroscopy. This result is in agreement
78%, indicating that amino acid plays a crucial role in the with the well-established evidence that for simple ketones the
catalytic activity. However, no correlation between yield and keto tautomer is favoured in polar solvents such as ethanol.39,40
amino acid type was observed. trans-L-4-Hydroxyproline, The absence of any tautomers of the keto form in the syn-
L-aspartic acid, and L-histidine, bearing three different types of thesised products, in addition to the high solvent polarity, can
side chain (polar, acidic, and basic, respectively) displayed be attributed to a double effect of the substituent on the
comparable performance (64, 69, and 59% yield; Table 3, entries a-carbon:41 (1) stabilisation of the keto form by hyper-
3, 5, and 8 respectively). On the contrary, L-lysine displayed a conjugation (electronic effect), and (2) destabilisation of enol as
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well as other tautomers by repulsion among substituents lying
on the same plane (steric effect).
Table 4 Trimolecular condensation of aromatic heterocycles, alde-
Unfortunately reaction yield was modest in most cases,
ranging from 15 to 78%. Ethyl methylsulfonylacetate, acetyla-
cetone, and ethyl benzoylacetate displayed low reactivity despite
being stronger acids than methyl acetoacetate, and were
recovered largely unreacted (Table 4, entries 2, 4, and 5).
Probably their enolate ion was too stabilised by metal ion to
undergo the Knoevenagel condensation. Ethyl nitroacetate
afforded a mixture of unidentied compounds in the presence
of Eu(OTf)3, but reacted in 38% yield when proline was used as
the only catalyst (Table 4, entry 3). Under these conditions, ethyl
nitroacetate proved to be more reactive than methyl acetoace-
tate (compare entry 3 in Table 4 with entry 1 in Table 1), prob-
ably due to its stronger acidity (pKa ¼ 5.7 and 10.7, respectively).
Despite average modest yield, the reaction afforded some
compounds (2, 4, 5, and 8) that cannot be obtained by our
previously described method based on Ti(IV).6,7,42 The above
results illustrate the synthetic utility of this modied Yonemitsu
reaction. An alternative method to the synthesis of 3-alkylated
indoles is the Michael-type reaction of indole and an a,b-
unsaturated carbonyl compound.43–48 This reaction can be per-
formed in high enantiomeric excess using Cu(OTf)2 or Sc(OTf)3
in the presence of a chiral Pybox-type ligand.38,49–51 However, it
requires the preliminary isolation and purication of the a,b-
unsaturated compound. Our reaction, although not enantiose-
lective, can be performed in one pot, avoiding the isolation of
intermediate.
hydes, and methylene active compounds
Entry
1
Product
Methoda
Yieldb (%)
A
78
2
3
4
Ae
40
38
15
B
A
5
6
Ae
20
26
2.4 Mechanism
Two mechanisms can be proposed for the proline/Eu(III)-cata-
lysed trimolecular reaction. The rst one (Scheme 1) involves
the Knoevenagel condensation of methyl acetoacetate and
aldehyde, followed by the Michael addition of indole. In such a
pathway, aldehyde and L-proline react to form a highly electro-
philic iminium ion (12). Methyl acetoacetate may be either
deprotonated by L-proline affording the enolate ion 10 or acti-
vated as a b-enaminoester (11) by condensation with L-proline.
It is worth noting that deprotonation reaction is an equilibrium
because methyl acetoacetate and proline's conjugate acid have
almost the same acidity (pKa ¼ 10.7 and 10.6, respectively). The
iminium ion 12 is attacked by 10 or 11, and the resulting species
13 eliminates proline to generate the Knoevenagel adduct 14.
Eu(III) ion complexates 14, thus favouring the Michael addition
of indole to afford the condensation product 1. According to the
mechanism proposed in Scheme 1, catalysis results from the
combined effect of L-proline and europium: L-proline catalyses
the Knoevenagel condensation by activating both nucleophile
(b-ketoester) and electrophile (aldehyde); europium catalyses
Michael addition by increasing the electrophilicity of the
Knoevenagel adduct by complexation. The second mechanism
(Scheme 2) involves the Michael addition of the enol of methyl
acetoacetate to an azafulvenium ion (18) obtained by the
condensation of aldehyde and indole. In this path, Eu(III) ion
complexates isobutyraldehyde, thus making aldehyde more
electrophilic. Activated aldehyde 16 is attacked by indole
A
7
8
A
35
A
A
47
35
9
a
˚
Method A: L-proline (0.1 equiv.), Eu(OTf)3 (0.1 equiv.), MeOH, MS 4 A,
rt, 6 days. Method B: L-proline (0.1 equiv.), neat, US, rt, 12 h. b Yield of
c
puried product. Relative stereochemistry has previously been
d
determined.6
Obtained as
a
single diastereomer; relative
e
f
stereochemistry was not determined. Solvent was ethanol. 50/50
mixture of diastereomers. g 55/45 mixture of diastereomers.
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Scheme 1 Mechanism via Knoevenagel adduct.
generating carbinol 17, which is unstable and rapidly loses consistent with the generally accepted mechanism for the
water to afford the azafulvenium ion 18. Nucleophilic addition Knoevenagel condensation catalysed by secondary bases.52,53
of the enol 20 of methyl acetoacetate to 18 provides the Furthermore, L-proline-catalysed aldol reactions, which are
condensation product 1. In the mechanism proposed in related to the Knoevenagel condensation, have been shown to
Scheme 2, the catalytic activity is attributed only to the metal involve the activation of aldehyde as an enamine.54–61 Lewis
ion. Both mechanisms are in agreement with some experi- acids such as Zn(ClO)4$6H2O also catalyse the formation of b-
mental evidences. Knoevenagel adduct 14 was recovered from enaminoesters from b-ketoesters and primary or secondary
the crude reaction mixture, and was isolated in 37% yield when amines.62,63 Therefore, the activation of methyl acetoacetate in
methyl acetoacetate and isobutyraldehyde were stirred in the the form of b-enaminoester 11 in addition to the enolate ion 10
presence of L-proline during 24 h. Reaction of puried 14 with can be proposed. Although 11 was not detected in the reaction
indole in the presence of Eu(OTf)3 afforded the condensation mixture, its formation as a transient species cannot be ruled
product 1 in 10% yield, conrming that 14 is an intermediate in out. The generation of Knoevenagel adduct-Eu(III) complex (15)
the trimolecular condensation. The structure of other inter- is consistent with the well-known ability of lanthanide ions to
mediates can be proposed based on mechanistic studies of chelate b-dicarbonyl compounds.64 Azafulvenium salt 18 could
analogous reactions. The formation of iminium ion 12 is not be isolated due to its high instability.65,66 However, its
Scheme 2 Mechanism via azafulvenium ion.
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formation is proved by the isolation of bis-indole derivative 19, crystallisation-induced asymmetric transformation of diaste-
which can only come from 18 by addition of a second molecule reomers has been reported in several reactions,79,80 including
of indole. The formation of 3,30-bis-indolylmethanes from multicomponent reactions.81,82 Obviously, this type of trans-
indole and carbonyl compounds is catalysed by Lewis acids67–71 formation depends solely on the relative thermodynamic
as well as strong Brønsted acids.65,66 Because L-proline is a weak stability of the corresponding crystal lattices and may only take
Brønsted acid, its catalytic effect in the mechanism of Scheme 2 place if at least one diastereomer is solid. If both diastereomers
is expected to be negligible with respect to that of europium ion. crystallise from the reaction medium (as in the case of 6a and
The role of solvent can be rationalised in the light of proposed 6b) no diastereoselectivity is observed.
mechanisms as well. Alcohols can stabilize several reactive
intermediates through specic interactions: intermediates 10
2.6 Greenness
and 12 (by H-bond donation), 15, 16, and 17 (by complexation of
The reaction developed in this work adheres to several principles
of green chemistry: (1) it is one-pot; (2) it is catalytic; (3) it uses
Eu3+ ion), and 18 (by H-bond acceptance from the indolic NH
group). Alcohols, being polar protic solvents, can also catalyse
safe catalysts (a natural amino acid and a water-stable salt); (4) it
proton transfer reactions involved in the formation of inter-
runs at room temperature; and (5) it takes place in a green solvent
mediates 10–13, 17, 18 and 20, thus favouring the overall reac-
(methanol). Reaction time, although long (6 days), is comparable
tion. In the light of the evidence reported above, both
to that of some green reactions such as the polyphosphate-
induced formation of peptides in water (10–15 days).83 Because
the reaction we developed is supposed to be green, we wondered
how green it is. One of the most common metrics to measure
mechanisms seem to take place simultaneously, although data
do not allow to establish which one is prevalent.
reaction “greenness” or cleanliness is the environmental factor
(E-factor),84,85 dened as the ratio of waste mass over product
mass. E-factor provides a realistic evaluation of the actual
amount of waste produced as it takes into account the reaction
yield as well as all reactants and solvents involved in the reaction,
including those necessary for work-up. E-factor calculated for the
reaction of indole, isobutyraldehyde, and methyl acetoacetate
catalysed by Eu(OTf)3 and proline in methanol is 0.70 (Table S4†).
In other words, the reaction produces 0.70 kg of waste per kg of
product. Considering that typical E-factors range from 0.01 (for
the cleanest reactions) to more than 100 (for the dirtiest ones),86
the Eu(III)/proline-catalysed reaction is quite clean. As a matter of
comparison, E-factor for the Ti(IV)-promoted reaction is 3.40. This
means that the catalytic reaction produces about ve times less
waste than the stoichiometric reaction.
2.5 Diastereoselectivity
Unlike chemical yield, diastereoselectivity was high, as most
compounds with two stereocenters (1, 2, 3, 5, and 8) were iso-
lated as a single diastereomer. Stereochemistry of 1 and 3 has
previously been determined.6 In principle, the observed dia-
stereoselectivity can be explained in two ways. The rst possi-
bility is that diastereoselectivity is induced by L-proline through
the formation of a Knoevenagel adduct-Eu(III)-proline complex.
In such a complex, L-proline would fold back and cover one face
of the adduct, thus forcing indole to attack the opposite face.
Protonation of the resulting intermediate on the same side with
respect to proline would lead to the condensation product
diastereoselectively. The formation of Eu(III)-proline complex is
reasonable in the light of the high oxophilicity of lanthanide
ions as well as the chelating ability of a-amino acids; Eu(III)-
proline complexes are actually known, both in solid phase72 and
in solution.73,74 Nevertheless, experimental evidences allowed us
to rule out this hypothesis. As a matter of fact, products 1 and 3
were obtained as a single diastereomer in the presence of both
optically pure and racemic proline or even without proline in
methanol (Table 3, entry 1). These results show that L-proline is
not involved in the stereochemical outcome of the reaction.75
Another more likely explanation for the observed diaster-
eoselectivity is that it is induced by crystallisation.76,77 The
condensation product bears an enolisable hydrogen on the a-
carbon, so the two diastereomers may interconvert via enoli-
sation. If one diastereomer crystallises, it is subtracted from the
reaction mixture, and the interconversion equilibrium is
continuously displaced towards the crystalline form until the
whole compound is present as one pure diastereomer (crystal-
lisation-induced asymmetric transformation). Based on this
model, diastereoselectivity is depending on the intrinsic solu-
bility properties of diastereomers. The hypothesis of diastero-
meric interconversion is supported by the fact that some active
methylene compounds such as a-nitroketones78 have an enan-
3 Conclusions
In conclusion, we have developed a Yonemitsu-type trimo-
lecular condensation of aromatic heterocycles, aldehydes, and
active methylene compounds catalysed by L-proline and euro-
pium triate. The importance of this study is twofold. From a
synthetic viewpoint, the reaction can nd application in the
synthesis of polyfunctionalised heterocycles. From a methodo-
logical viewpoint, the reaction respects a number of green
chemistry's principles, and works with substrates that are
unreactive under classical conditions, in some cases with high
diastereoselectivity.
This study showed how to convert a non-green reaction into
a green reaction in a rational way based on its reaction mech-
anism, and hopefully will pave the way to the development of
green protocols for other reactions.
Acknowledgements
tiomerisation barrier low enough to allow a rapid inversion of This work was carried out with support from the University ‘G.
their stereogenic centre at room temperature. In addition, d’Annunzio’ of Chieti-Pescara, the University of Rome, and
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