New potential of the classical Biginelli reaction

Abstract

The published data on the Biginelli reaction are generalised and systematised. The major attention is focused on the publications of the last seven years. Possible reaction mechanisms and its application for the synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives are considered. Examples of rare versions of this reaction are given.

Full text

Abstract. The published data on the Biginelli reaction areThe published data on the Biginelli reaction are
generalised and systematised. The major attention isgeneralised and systematised. The major attention is
focused on the publications of the last seven years. Possiblefocused on the publications of the last seven years. Possible
reaction mechanisms and its application for the synthesis ofreaction mechanisms and its application for the synthesis of
3,4-dihydropyrimidin-2(13,4-dihydropyrimidin-2(1HH )-one derivatives are consid-)-one derivatives are consid-
ered. Examples of rare versions of this reaction are given.ered. Examples of rare versions of this reaction are given.
The bibliography includes 115 referencesThe bibliography includes 115 references..
I. Introduction
Pyrimidinones and their derivatives play an important role
in human vital functions. The pyrimidine structural frag-
ment is the component of a series of natural compounds
(nucleic acids, vitamin B
1
), synthetic medicines (barbitu-
rates) chemotherapeutic drugs (fluorouracil). Biological
importance of pyrimidine derivatives caused a significant
interest in their synthesis.
The strategy for the pyrimidine ring closure includes
four main approaches (I±IV) based on condensation of
different fragments.
The most popular is approach I,i.e., the coupling of
compounds providing a three-carbon fragment and an
N7C7N fragment. This method is called `common syn-
thesis' due to its general applicability for the preparation of
a wide range of pyrimidine derivatives and experimental
simplicity. b-Dicarbonyl compounds, viz., dialdehydes, keto
aldehydes, aldehydo and keto esters), b-aldehydonitriles,
cyanoacetic acid derivatives (for example, ethyl ethoxyme-
thylcyanoacetate), dinitriles, etc., are most often used as
synthetic equivalents of the three-carbon synton
C
+
7C7C
+
.
In 1891, an Italian chemist Biginelli suggested
1
yet
another version of the pyrimidine ring construction based
on the use of b-dicarbonyl compounds as a source of a two-
carbon fragment in accordance with the retrosynthetic
scheme given below where one carbonyl group remains
intact. Later, this method for the synthesis of pyrimidine
structures has been named the Biginelli reaction.
Ab-dicarbonyl compound, an aldehyde and urea are used
as the reactants.
This reaction has been ignored for more than a century.
However, lately a great number of compounds with valu-
able properties has been discovered among 3,4-dihydropyr-
imidinones (DHPM). Some of them are used in medicine as
calcium channel-blocking agents (A), as antihypertensive
drugs (B,C)anda
1a
-antagonists (D). Other exhibit pro-
nounced antiviral (E) and antitumour (F) activities.
2
Natu-
ral dipeptide antibiotic TAN-1057 A,B (Ref. 3) having a
strong antistaphylococcus activity has been designed based
on dihydropyrimidine derivatives. In addition, it was found
that some alkaloids isolated from seaweeds, which contain a
dihydropyrimidinone-5-carboxylate ring, are powerful HIV
inhibitors.
4
The Biginelli reaction is attractive, because substituents
that can readily be transformed into different functional
groups required for further syntheses, can easily be intro-
II III IVI
N
27
C
+
C
C N
C
+
C
2+
7
N
C
+
7
N
N
7
C
N
7
C
C
N
7
C
N
7
C
C
C
+
C
+
C
C
+
NH
N
R
3
R
2
O
O
H
R
1
+
+(7)
R
1
O
R
2
R
3
+(7)
7
N
O
7
N
H
H
S V Vdovina, V A Mamedov A E Arbuzov Institute of Organic and
Physical Chemistry, Kazan Research Centre of the Russian Academy of
Sciences, ul. Akad. Arbuzova 8, 420088 Kazan, Russian Federation.
Fax (7-843) 273 22 53, tel. (7-843) 272 73 04,
e-mail: mamedov@iopc.knc.ru
Received 5 August 2008
Uspekhi Khimii 77 (12) 1091 ± 1128 (2008); translated by M G Ezernitskaya
DOI 10.1070/RC2008v077n12ABEH003894
New potential of the classical Biginelli reaction
S V Vdovina, V A Mamedov
Contents
I. Introduction 1017
II. Mechanism of the Biginelli reaction 1018
III. Synthesis of dihydropyrimidinones using immobilised components of the Biginelli reaction 1020
IV. Synthesis of dihydropyrimidinones by the one-pot Biginelli reaction 1021
V. Supplements 1026
Russian Chemical Reviews 77 (12) 1017 ± 1053 (2008) #2008 Russian Academy of Sciences and Turpion Ltd

duced into the reaction products. However, in its classic
version (catalyst HCl, solvent EtOH), the yields of this one-
pot reaction are low (20% ± 50%) and it takes a long time
(15 ± 20 h).
1, 5 ± 10
Due to low efficiency of the classical method of coupling
and great demand in 3,4-dihydropyrimidine derivatives as
components of pharmaceutical compositions, more than
one hundred publications appeared to date that describe
improved procedures, which are, in essence, modifications
of the classical one-pot Biginelli synthesis. The starting
reagents (a dicarbonyl compound, an alhehyde or urea),
catalysts and solvents vary in these methods. Polyphosphate
ester (PPE),
7, 11 ± 13
montmorillonite clays,
14, 15
Yb
III
-resins,
16
molecular iodine,
17, 18
different organic
19, 20
and inorganic
1, 5 ± 10, 21
acids, Lewis acids [BF
3.
OEt
2
,
21
FeCl
3
,
22 ± 24
ZnI
2
,
25
InCl
3
,
26
LaCl
3
,
27
LiClO
4
,
28
Mn(OAc)
3
(Ref. 29)], metal triflates,
30 ± 32
ionic liquids
like 1-n-butyl-3-trimethylimidazolium tetrafluoroborate
bmim[BF
4
],
33
alkylammonium perhalophosphates and per-
haloaluminates,
34
etc. are used as catalysts instead of hydro-
chloric acid. A great number of solvents has been suggested
for the reaction: alcohols, acetonitrile, tetrahydrofuran,
dimethylformamide, dichloromethane, water. It is known
that sonication,
35±37
microwave
12,38±44
and infrared
45
irradiation, as well as application of high pressure
46
accel-
erate the Biginelli reaction and increase the product yields.
Despite availability of numerous original publications
devoted to the Biginelli reaction, no comprehensive review
on this topic has yet been published. Syamala
47
considered
different three-component reactions, that is why the mate-
rial on the Biginelli reaction cannot be exhaustive. A review
by Kappe
48
was published 15 years ago, but it is over the
last decade that many new versions of the classic reaction
have appeared. Recent review
49
by Kappe is worth noting;
it is devoted to the methods of solid-phase synthesis and the
application of the combinational chemistry approaches, as
well as to the role of the Biginelli reaction in the synthesis of
natural compounds.
At present, diverse reagents are used in the Biginelli
reaction. They are systematised and listed in Supplement 1,
where their notation used in the text and the tables is also
given. A variety of combinations of the reactants used under
different conditions are described in the literature. In order
to present this material in the most complete and compact
way, it is arranged in the form of tables.
Among publications devoted to modified methods for
the preparation of the `Biginelli compounds', there are only
several works where the mechanism of the reaction is
discussed. It is remarkable that until now the details of the
mechanism have not been completely clarified, and there are
different points of view concerning this problem.
48
II. Mechanism of the Biginelli reaction
At first it was supposed
5
that the primary bimolecular
condensation product of benzaldehyde (A18) with urea
(U1), i.e. the first intermediate of this reaction, is N,N
0
-
benzylidenebisurea (1a). For this reason, this mechanism
was named urea-crotonic.
Later, the so-called carbocationic mechanism has been
suggested,
50
where acid-catalysed aldol condensation was
the first and rate-limiting step.
Ph
HN
HN
NH
2
NH
2
O
O
Ph
O
H
O
NH
2
H
2
N
(U1)
A18 1a
EtO
2
C
O
Me
Ph
OH
OMe
EtO
2
C
E2
A18,H
+
2
H
+
,7H
2
O
N
NS
O
O
Me
O N
CF
3
F
Pr
i
O
H
N
F
N
O
MeO
Me
O
O
N
N
N
O
NH
2
F
H
H
N
NO
O
OEt
Me
EtO
O
NO
2
H
N
NO
O
NH
2
Me
O
NO
2
Pr
i
O
H
DAB(SQ 32,926) C(SQ 32,547)
Me
O
MeO
N
NH
O
H
O
O
2
N
NH
NSMe
EtO
O
OH
H
NH
N N NH
2
O
O
N
Me
ONH
2
N
H
2
N
NH
H
H
EF(Monastrol)
TAN-1057 A,B
1018 S V Vdovina, V A Mamedov

It was supposed that upon acid catalysis, benzaldehy-
de (A18) and ethyl acetoacetate (E2) react to form the
corresponding aldol 2, which dehydrates in the presence of
an acid into resonance-stabilised carbocation 3. The reac-
tion of the latter with urea (U1)orN-methylurea (U2)
results in urea derivative 4, which is cyclised into the
Biginelli compound 5. This mechanism is supported by the
fact that, irrespective of the action of the acid catalyst, the
reaction of enone 6with N-methylurea affords dihydropyr-
imidinone 5b in moderate yield.
50
Protonation of enone 6
results in the carbocationic intermediate 3, which reacts
with urea (3?4?5).
About a decade ago, the mechanism of the Biginelli
condensation was reinvestigated
51
using the data from
1
H
and
13
C NMR spectroscopy in order to determine possible
intermediates of this reaction.
Three possible sequences of the reaction of the starting
components have been considered:
1) ethyl acetoacetate + benzaldehyde + urea,
2) ethyl acetoacetate + urea + benzaldehyde,
3) benzaldehyde + urea + ethyl acetoacetate.
Let us consider in more detail these pathways.
The first version (ethyl acetoacetate + benzaldehy-
de + urea) corresponds essentially to the above-considered
carbocationic mechanism based on acid-catalysed aldol
condensation. Although the aldol condensation is more
often initiated by bases, a possibility of an acid-catalysed
reaction of benzaldehyde with a 1,3-dicarbonyl compound
cannot be ruled out. The final products of this condensation
should be predominantly a,b-unsaturated carbonyl com-
pounds (like 6)ratherthanb-hydroxycarbonyl (aldol)
products 2. In the case of the reaction of benzaldehyde
with ethyl acetoacetate, no evidence for aldol reaction or
other reactions of these compounds that could occur at
room temperature was obtained by
1
Hor
13
C NMR spec-
troscopy. Benzaldehyde does not react with ethyl acetoace-
tate under the conditions where the Biginelli condensation
proceeds readily. This fact excludes the carbocationic mech-
anism as the major reaction pathway, because, according to
this mechanism, this reaction is the first stage.
The possibility of the formation of the carbocationic
intermediate (3) in the Biginelli condensation is even
smaller, if thiourea is substituted for urea. Both thiourea
(U10)andN-methylthiourea (U11) react with benzaldehyde
and ethyl acetoacetate under the standard conditions of the
Biginelli reaction to give the expected dihydropyrimidine-
2-thiones (the Biginelli compounds). A the same time, the
acid-catalysed reaction of intermediate 3with thioureas
U10,U11 affords isomeric 2-amino-1,3-thiazines 7a,bin
excellent yields. However, the fact that the three-component
Biginelli reaction with thioureas does not result in thiazine
products 7rules out the intermediate of carbocation 3.
If the reaction follows the second pathway (ethyl ace-
toacetate + urea + benzaldehyde), `urea-crotonic' inter-
mediates 8a,bmight be formed. This reaction occurs on
keeping a mixture of ethyl acetoacetate and urea in a
dessicator over concentrated sulfuric acid for several days,
which is at variance with the conditions for the classical
Biginelli reaction.
Another argument against the transient formation of
this compound is that N-methylurea (U2) reacts with ethyl
acetoacetate to form a single regioisomer 8b with the methyl
substituent at the terminal amino group. Cyclocondensa-
tion of putative intermediate 8b with benzaldehyde (follow-
ing the [5+1] scheme) should result in the N-substituted
dihydropyrimidinone 9, as the Biginelli product, which is
observed for neither the three-component Biginelli reaction
nor the reaction of urea derivative 8b with benzaldehyde. In
both cases, only isomeric dihydropyrimidinone 5b is
formed.
Thus, this reaction sequence is also non-realistic.
The third pathway (benzaldehyde + urea + ethyl ace-
toacetate), i.e., the urea-crotonic mechanism consisting of
nucleophilic addition of urea to benzaldehyde to form
N-(1-hydroxybenzyl)urea 10, seems the most preferable.
In the presence of acid, hemiaminal intermediate 10 under-
goes dehydration, and the equilibrium shifts towards the
reactive N-carbamoyliminium ion 11. In the absence of
1,3-dicarbonyl compound, the second equivalent of urea
reacts with cation 11 to form bisureas 1a,b, which can be
easily isolated from the reaction mixture due to low sol-
EtO
2
C
O
Me
Ph
NH
HN
O
R
OMe
EtO
2
C
Ph
6
EtO
2
C
O
Me
Ph
H
3
+
7H
+
H
+
O
NHR
H
2
N
(U1 or U2)
7H
+
7H
2
O
4a,b
R=H(a), Me (b).
NH
N
EtO
2
C
Ph
Me O
R
5a,b
H
+
Me
EtO
2
C
O
Ph
H
3
+
U10 or U11
N
S
EtO
2
C
Me
Ph
N
R
H
7a,b
R=H(a), Me (b).
Me
EtO
2
C
O
Ph
6
+
H
2
N NHR
O
R=H(U1),
Me (U2).
H
+
N
HN
EtO
2
C
Me O
R
H
8a,bE2
Me
EtO
2
C
O
R=H(a), Me (b).
8b
A18
N
EtO
2
C
Me
Ph
NHMe
O
H
9
New potential of the classical Biginelli reaction 1019

ubility. Thus, the presence of ethyl acetoacetate in the
reaction mixture presumes its reaction (probably, as the
enol tautomer) with cation 11 to form intermediates 4a,b,
which are further cyclised to the Biginelli compounds 5a,b.
However, in the
1
H NMR spectra of the samples taken after
definite intervals, no signals for intermediates 10,whichare
represented in the suggested scheme, were observed.
The first addition stage (A18 ?10) seems to be the
limiting stage of the process, while two subsequent stages
[acid-catalysed dehydration (10 ?11) and addition of the
second equivalent of urea to the cation (11 ?1)] are fast,
which prevents detection of intermediate 10 by spectral
methods.
Remarkable that the Biginelli reaction with non-sym-
metrical dicarbonyl compounds virtially always occurs
regioselectively and the products, dihydropyrimidinones,
are obtained in high yields. If keto esters or keto amides
are used as dicarbonyl compounds, the keto group, in which
the carbon atom is more electrophilic, always participates in
the cyclisation (its substituent occupies position 6), while
the ester or amide group occupies position 5 in the DHPM
ring. If a non-symmetrical diketone is involved in the
reaction, the direction is determined by the balance between
steric and electronic factors. The carbonyl group bearing a
less bulky and more electron-withdrawing substituent takes
part in cyclisation. Thus in the case of MeCOCH
2
COPh and
Ph groups (K5), the benzoyl group appears in position 5,
while the Me substituent occupies position 6; at the same
time, for diketone K2 with Me and CF
3
groups, the acetyl
group occupies position 5, while the CF
3
group goes to
position 6. In order to avoid confusion, substituents in
diketones in Supplement 1 are denoted so that in the
Biginelli reaction, R
1
is at position 6 of DHPM and
R
2
C(O) is at position 5.
In the case of monosubstituted ureas, the position of a
substituent at the nitrogen atom seems to be determined by
steric factors. The substituent in the product occupies
position 1.
III. Synthesis of dihydropyrimidinones using
immobilised components of the Biginelli reaction
The majority of currently existing methods for the prepara-
tion of 3,4-dihydropyrimidinones are modifications of the
one-pot Biginelli synthesis, however, first publications after
almost a hundred-year oblivion of this reaction were
devoted to the synthesis of dihydropyrimidinones with the
use of immobilised reagents.
The strategy of such syntheses is reduced to the prepa-
ration of DHPM derivatives on solid supports
49, 52 ± 59
or in
a liquid phase
52, 53, 60
with recourse to different polymers
and resins. Currently, these methods are supplemented with
microwave irradiation.
52, 53
In this case, either of the three
components can be immobilised. However, most often it is
urea
49, 54, 55
or a b-dicarbonyl compound,
49, 56, 57
while
immobilised aldehydes came to use only in the last three
years.
These syntheses can be carried out by two methods. In
both cases, the first stage is immobilisation of one of the
reactants on a carrier. The first method consists of acid-
catalysed coupling of the immobilised compound with two
other reactants to form a dihydropyrimidine derivative. In
the last stage, the DHPM molecule is removed from the
carrier. The second method
58
includes condensation of a
dicarbonyl compound with aldehyde in the presence of a
base (the Knoevenagel condensation) to give an enone,
which then reacts with an immobilised isothiourea in the
presence of a base. This reaction results in the immobilised
2-thio derivative of DHPM, which, after the corresponding
treatment, gives the target Biginelli compounds in high
overall yields.
58
This method is named the Atwal modifica-
tion, because it is similar to the method for the synthesis of
3-substituted DHPM starting from O-methylisourea or
S-(4-methoxybenzyl)isothiourea suggested by Atwal et
al.
61
Although this approach requires preliminary synthesis
of the enone, it is rather attractive, because it ensures high
yields of DHPM, which are difficult to obtain by the one-
pot Biginelly process.
All these methods can be divided into three groups
deppending on the carriers used and the phase where the
processes proceed:
1) liquid-phase processes with the use of polymers;
53, 60
Ph
H
O
A18
Ph
HN
HN
N
O
N
O
R
R
H
H
1a,b
E2
7H
+
7H
2
O
EtO
2
C
O
Me
Ph
NH
HN
O
R4a,b
Ph
HN
H
NH
O
R
11a,b
+
H
+
,U1 or U2
NH
N
EtO
2
C
Ph
Me O
R
5a,b
R=H(a), Me (b).
U1 or U2 Ph
HN
OH
NH
O
R
10a,b
H
+
,7H
2
O
R
2
R
1
O
O
+
O H
R
3
R
2
R
1
O
O
H
R
3
HN S
NH
2
P
R
2
R
1
O
N
NH
R
3
S P
P is polymer.
R
2
R
1
O
N
NH
R
3
X
base
H
+
,H
2
O (X = O), or
CF
3
CO
2
H, EtSH (X = S), or
aminolysis (X = NR)
1020 S V Vdovina, V A Mamedov

2) solid-phase syntheses on carriers;
49, 53 ± 59
3) processes with the use of soluble polymeric sup-
ports.
52
All these methods have their advantages and drawbacks.
In liquid-phase syntheses, substances bound to the polymer
can possess low reactivity; identification of intermediates
becomes problematic, difficulties arise in separation of
pyrimidinones obtained from admixture of the poly-
mer.
53, 60
Solid-phase strategies provide possibility to avoid
recrystallisation and chromatographic purification of the
products obtained, which is sometimes rather important.
Their drawback consists of uneconomical consumption of
the reactants.
53 ± 59
Soluble polymeric supports are devoid of
the above-mentioned disadvantages; these supports allow
fast change in the reaction conditions (transition from the
solid to the liquid phase and vice versa) and the economic
use of the reactants. That is why processes on soluble
polymeric supports find wide application.
52
Disadvantages
of this method are complex instrumentation and often their
multi-stage nature; however, it does not influence the yields
and purity of the reaction products. Microwave irradiation
at the stage of the Biginelli reaction decreases the duration
of these processes. It is noteworthy that application of
immobilised reagents allows the parallel syntheses of vast
libraries of DHPM derivatives.
57, 58
However, most
researches give preference to the one-pot method for the
preparation of dihydropyrimidinones from classical compo-
nents of the Biginelli reaction suggesting improved versions
of the implementation of this condensation, because multi-
stage processes with the use of polymeric supports are
laborious, and carriers are expensive.
IV. Synthesis of dihydropyrimidinones
by the one-pot Biginelli reaction
1. Classical combination of reactants in the Biginelli reaction
The most popular product of the Biginelli reaction is ethyl
6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylate synthesised by the condensation of the classical
reactants, viz., ethyl acetoacetate (E2), benzaldehyde (A18)
and urea (U1). More than 60 sets of reaction conditions for
the synthesis of this compound are given in Table 1.
E2 +A18 +U1
N
NH
Ph
OMe
EtO
2
C
H
Table 1. The versions of the classical Biginelli reaction: ethyl acetoacetate+benzaldehyde+urea.
Catalyst Solvent Other Reaction Yield Ref. Catalyst Solvent Other Reaction Yield Ref.
conditions time (%) conditions time (%)
PPE THF D24 h 94 7
PPE 7mn 90 s 85 11
Mont. KSF 7130 8C 48 h 82 14
Mont. KSF MeOH D8 ± 10 s 92 15
Yb
III
-Resin 7120 8C 48 h 80 16
I
2
PhMe D4 h 95 17
TsOH H
2
O stirring 5 min 91 19
SSA EtOH D6 h 91 20
BF
3.
OEt
2
, THF D18 h 94 21
CuCl, AcOH
H
2
SO
4
EtOH D18 h 71 21
FeCl
3.
6H
2
O, HCl EtOH D4 h 94 22
FeCl
3.
6H
2
O EtOH D4 h 94 23
NiCl
2.
6H
2
O, EtOH D5 h 97 23
HCl
InCl
3
THF D7 h 95 26
LiClO
4
or LiOTf MeCN D6 h 89 28
Mn(OAc)
3.
2H
2
O MeCN D2 h 96 29
Yb(OTf)
3
, AcOH EtOH 120 8C 10 min 92 30
Bi(OTf)
3
MeCN room tem- 1 h 90 31
perature,
stirring
CAN MeOH US 3.5 h 92 35
77100 ± 150 8C1h 81 36
TAFF 7IR 2 h 55 45
Yb(OTf)
3
7100 8C 20 min 98 62
LaCl
3.
7H
2
O, HCl EtOH D5 h 95 63
HCl EtOH US 2 ± 5 min 95 64
FSA EtOH D84 h 65 65
InBr
3
EtOH D7 h 98 66
(TMS)Cl, NaI MeCN room tem- 30 min 98 67
perature,
stirring
LiBr MeCn D3 h 92 68
NH
2
SO
3
H EtOH US, 40 min 97 69
20±308C
NH
2
SO
3
H EtOH 20 ± 30 8C, 40 min 62 69
stirring
Cu(OTf)
2
MeCN 25 8C, 6 h 95 70
stirring
NH
4
Cl 7100 8C3h 9071
TsOH 7mn 5 min 92 72
CuCl
2.
2H
2
O7100 8C 60 min 96 73
CuCl
2.
2H
2
O7mn 1 min 98 73
CuSO
4.
5H
2
O7100 8C 70 min 96 73
CuSO
4.
5H
2
O7mn 1 min 98 73
HBO
3
glacial 100 8C 0.5±2h 97 74
AcOH
ZnCl
2
780 8C 20 min 73 75
PABC EtOH D2 h 94 76
CdCl
2
MeCN D4 h 83 77
Cu(NTf
2
)
2
H
2
O stirring 24 h 88 78
Sr(OTf)
2
770 8C4h 9779
FeCl
3
, Si(OEt)
4
Pr
i
OH D3 h 88 80
RuCl
3
7100 8C 30 min 91 81
CHCl
2
CO
2
H790 8C 30 min 91 82
H
3
PW
12
O
40
MeCN 80 8C1h 9283
H
3
PMo
12
O
40
MeCN 80 8C1h 8783
H
4
SiW
12
O
40
MeCN 80 8C1h 9383
Dowex-50W 7130 8C3h 9084
New potential of the classical Biginelli reaction 1021

As is seen from Table 1, the highest yields (up to 98%)
and the shortest reaction times (1 ± 1.5 min) are achieved
where the Biginelli condensation is assisted by microwave
irradiation.
11, 73
In this case, however, the isolation techni-
que of the target product becomes more complicated;
besides, decomposition of urea occurs.
94
It was shown
64
that sonication (sonochemical synthesis)
accelerates more than 40-fold the formation of ethyl 4-R-
6-methyl-2-oxo- and 4-R-6-methyl-2-thioxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylates, i.e., the synthesis lasts for
2 ± 5 min. The amount of side products decreases due to
high selectivity of the process, in most cases, no additional
purification (crystallisation) is required, which leads to
simplification of the process and to an increase in the yields
of the target compounds to 90% ± 95% irrespective of the
aldehyde.
Environmentally safe versions of the Biginelli reaction
are of special note, namely, the use of montmorillonite clays
as a catalyst, as well as reactions under catalyst-free and
solvents-free conditions.
Environmentally friendly montmorillonite clays are
often used in organic synthesis due to their availability.
They are easy in handling, provide high yields of target
products, ensure high selectivity of the processes and can
easily be separated from the reaction mixtures. The Biginelli
reaction can be performed under solvent-free condition with
the use of montmorillonite KSF, though this process has its
drawbacks, for example, long duration (8 ± 10 h).
15
It was found
36, 90
that the Biginelli reaction is efficiently
accomplished using mixture of pure reactants at
100 ± 105 8C for 20 min ±1 h without solvents and catalysts;
high and moderate yields are achieved.
2. New combinations of reactants in the Biginelli reaction
At present, when choosing reactants for the Biginelli con-
densation, it is aldehydes that are varied most often, while
keto esters, which are the source of a two-carbon fragment
for the DHPM molecule, are replaced much more rarely.
Examples where keto esters with a benzoyl fragment (for
instance, E16,E17) are used are especially seldom; in most
cases, the presence of this fragment prevents the formation
of the pyrimidine ring (see, for example, Refs 95 ± 97). The
yields of final products in these cases are usually not
high.
21, 27, 41, 95
The most successful method for the synthesis of ethyl
2-oxo-4,6-diphenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate
is stirring of a mixture of reactants in acetonitrile at room
temperature with the addition of catalytic amounts of
trimethylsilyl chloride and sodium iodide.
76
As for b-dicarbonyl compounds as a source of a two-
carbon fragment for the Biginelli reaction, keto esters have
been the most comprehensively studied. However, a range
of reactants used is gradually widening due to inclusion of
diketones, keto amides, cyclic imides, etc. Among dike-
tones, as among keto esters, derivatives with benzoyl groups
(for example, K5 ±K9), which are difficult to inroduce into
the DHPM molecule by other methods, are especially
interesting.
Different combinations of the starting components and
reaction conditions for the one-pot process are summarised
in Supplement 2. Combinations of components are given in
series according to the carbonyl compound used: keto esters
(E1 ±E35), then diketones (K1 ±K13), keto amides and their
analogues (Am1 ±Am8) and, finally, equivalents of dicar-
bonyl compounds (Eq1,Eq2) (Supplement 1).
Mono- and bisreactant, either of three, can be used in
the Biginelli reaction. In the latter case, the products
contain two dihydropyrimidinone fragments.
Thus Tu et al. reported
92
the one-pot synthesis of rigidly
oriented bis(dihydropyrimidinones) BD1 ±BD4 from iso-
(A89) and terephthalic aldehydes (A90). Compound BD2 is
also described in other publications.
27, 97
Zhidovinova et al.
103
used podands with the terminal
aldehyde (A91)orurea(U15) fragments; derivatives of
BD5 ±BD8 and BD9,BD10, respectively, were obtained.
NH
HN
O
R
1
R
2
BD1 ±BD4
Isomers meta (BD1,BD3), ortho (BD2,BD4);
R
1
= Me, R
2
=CO
2
Et (BD1,BD2);
R
1
±R
2
= (CH
2
)
3
C(O) (BD3,BD4).
R
1
NHHN
O
R
2
Table 1 (continued).
Catalyst Solvent Other Reaction Yield Ref. Catalyst Solvent Other Reaction Yield Ref.
conditions time (%) conditions time (%)
PhB(OH)
2
MeCN D18 h 87 85
VCl
3
MeCN D2 h 96 86
bmim[BF
4
]7100 8C 30 min 95 87
bmim[PF
6
]7100 8C 30 min 94 87
bmimCl 7100 8C 30 min 56 87
CNSP H
2
O808C 4.5 h 92 88
Yb(OTf)
3
THF stirring 787 89
BDMPEAB 7100 8C 20 min 96 90
NH
4
Br 7100 8C 20 min 81 90
77100 8C 20 min 73 90
PPAA EtOAc D6 h 77 91
KHSO
4
ethylene 100 8C 0.5±2h 95 92
glycol
(TMS)Cl DMF 20 8C 14 h 80 93
Note. Hereinafter, the following notation is used: BDMPEAB is butyldimethyl(1-phenylethyl)ammonium bromide; bmim is 1-n-butyl-3-
methylimidazolium; CAN is cerium ammonium nitrate; CNSP is CeO
2
nanoparticles on a 4-vinylpyridine ± p-divinylbenzene copolymer; FSA is
silica aerogel containing ferrihydrate particles (5 Fe
2
O
3.
9H
2
O); Mont. KSF is montmorillonite caoline; PABS is complex obtained by the
interaction of polyaniline with BiOCl in acetone; PPAA is propanephosphonic anhydride; PPE is polyphosphoric ester; Pro-Me is methyl ester of
L-proline; SSA is silica gel with grafted sulfo groups; TAFF is a bentonite glue (74.5% SiO
2
, 9.3% Al
2
O
3
, 4.0% CaO, 1.3% Fe
2
O
3
, 0.4% MgO,
0.4% K
2
O, 0.4% TiO
2
, 9.7% H
2
O); TMS is trimethylsilyl; IR is IR irradiation; US is sonication; Dis boiling; mn is microwave irradiation.
1022 S V Vdovina, V A Mamedov

The Biginelli reaction of compound E35 with two keto
ester fragments in the benzene ring reacted
104, 105
with urea
and different aldehydes (A18,A19,A31,A64,A66,A71,
A72) to afford bis(dihydropyrimidinones) BD11 ±BD17 as
the reaction products.
The conditions of the reaction with bis-reagents and the
product yields are listed in Table 2.
These bis(dihydropyrimidinones), undoubtedly, are of
interest, because biological activity of bisheterocyclic com-
pounds, as a rule, is highly competitive with that of their
monocyclic analogues.
106, 107
Three-component condensation of b-dicarbonyl com-
pounds with aldehydes and urea does not always result in
3,4-dihydropyrimidinones. In some cases, hydroxy tetrahy-
dropyrimidinones (THPM) were isolated in moderate and
high yields as intermediate or final products (Table 3).
As a rule, this result is obtained, if a dicarbonyl
compound contains a strong electron-withdrawing group,
for example, CF
3
,C
3
F
7
,CHCl
2
,etc. (compounds
E20 ±E24,E26,K2,K3,K6 ±K8,K10,K11). Usually,
hydroxy tetrahydropyrimidinones can be converted into
DHPM by boiling (for example, in benzene or toluene)
with an acidic catalyst (p-TsOH).
The formation of 4-hydroxytetrahydropyrimidinones
containing strong electron-withdrawing groups, which is
not typical of the Biginelli reaction, can be considered as a
confirmation of the fact that the limiting stage of dehydra-
tion is protonation of the hydroxyl oxygen atom.
Z
HN
OOO
NH
Z
Me
CO
2
Et
Me
EtO
2
C
BD5 ±BD8
Z = NHC(O) (BD5), NHC(S) (BD6),
[X = CH (BD7),N(BD8)].
N
N
X
N
R = Me (BD9), Ph (BD10).
HN N
O
R
EtO
2
C
Me
O N NH
O
R
CO
2
Et
Me
BD9,BD10
HN NH
EtO
2
C
R
O
HN NH
O
R
CO
2
Et
R = Ph (BD11), PhCH
=
CH (BD12), 4-Me
2
NC
6
H
4
(BD13),
4-ClC
6
H
4
(BD14), 2,4-Cl
2
C
6
H
3
(BD15), 4-BrC
6
H
4
(BD16),
4-IC
6
H
4
(BD17).
BD11 ±BD17
R
2
R
1
O
O
+
H O
R
3
+HN X
HN
R
4
R
5
N
NR
2
O R
3
R
4
X
R
5
HO
R
1
THPM
Table 2. Preparation of bis(dihydropyrimidinones) by the Biginelli reaction.
Pro- Reactants Reaction Reaction Yield Ref. Pro- Reactants Reaction Reaction Yield Ref.
duct conditions time (%) duct conditions time (%)
BD1 E2+A89+U1 a0.5±2h 96 92
BD2 E2+A90+U1 a0.5±2h 99 92
E2+A90+U1 b10 min 78 27
E2+A90+U1*658C4h 8597
BD3 K12+A89+U1 a0.5±2h 92 92
BD4 K12+A90+U1 a0.5±2h 95 92
BD5 E2+A91+U1 c5 min 50 103
E2+A91+U1 d30 h 30 103
BD6 E2+A91+U10 c5 min 45 103
E2+A91+U10 d30 h 25 103
BD7 E2+A91+U16 c10 min 56 103
E2+A91+U16 d30 h 40 103
BD8 E2+A91+U17 c10 min 60 103
E2+A91+U17 d32 h 42 103
BD9 E2+A2+U15 c7 min 62 103
E2+A2+U15 d30 h 38 103
BD10 E2+A18+U15 c7 min 65 103
E2+A18+U15 d26 h 45 103
BD11 E35+A18+U1 e25 h 56 104, 105
BD12 E35+A19+U1 e25 h 59 104, 105
BD13 E35+A31+U1 e25 h 60 104, 105
BD14 E35+A64+U1 e25 h 66 104, 105
BD15 E35+A66+U1 e25 h 50 104, 105
BD16 E35+A71+U1 e25 h 53 104, 105
BD17 E35+A72+U1 e25 h 52 104, 105
Note. Notation Catalyst Solvent Other conditions
aKHSO
4
ethylene glycol 100 8C
bYb(OTf)
3
EtOH 100 8C
cHCl EtOH US
dHCl EtOH D
e(TMS)Cl DMPA+MeCN 80 8C
New potential of the classical Biginelli reaction 1023

3. Side reactions
An advantage of the Biginelli reaction is its high selectivity.
However, even this reaction is sometimes accompanied by
side processess.
When cyclic dicarbonyl compounds are used, the stand-
ard Biginelli reaction products are often formed in low
yields (11% ± 25%) (Table 4); in this case, spiroheterocyclic
compounds are isolated as major (sometimes the only)
products, which can be considered as a result of four-
component condensation of a cyclic dicarbonyl compound,
two aldehyde molecules and urea.
101, 111, 112
R
1
Z
O O
+R
3
CHO + (NH
2
)
2
C X
N
NH
R
3
X
R
1
Z
O
HO H
X = O, S; Z = R
2
or OR
2
.
Table 3. Formation of tetrahydropyrimidinones under the conditions of the Biginelli reaction.
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E20+A18+U1 HCl EtOH D6 h 75 108
E21+A18+U1 bmim[BF
4
]7100 ± 125 8C6h 7833
ZrCl
4
EtOH D6 h 80 99
E21+A18+U10 bmim[BF
4
] 100 ± 125 8C6h 8533
HCl EtOH D6 h 43 108
E21+A39+U1 ZrCl
4
EtOH D6 h 85 99
E21+A60+U10 bmim[BF
4
]7100 ± 125 8C6h 7733
E22+A18+U1 HCl EtOH D6 h 79 108
E22+A18+U10 HCl EtOH D6 h 50 108
E23+A18+U1 HCl EtOH D6 h 73 108
E23+A18+U10 HCl EtOH D6 h 47 108
E24+A18+U1 HCl EtOH D6 h 80 108
E24+A18+U10 HCl EtOH D6 h 45 108
E26+A18+U1 InBr
3
THF D24 h 70 109
E26+A18+U10 InBr
3
THF D24 h 65 109
E26+A23+U1 InBr
3
THF D24 h 67 109
E26+A23+U10 InBr
3
THF D24 h 62 109
E26+A45+U1 InBr
3
THF D24 h 86 109
E26+A64+U1 InBr
3
THF D24 h 84 109
E26+A64+U10 InBr
3
THF D24 h 88 109
E26+A84+U1 InBr
3
THF D24 h 71 109
K2+A18+U1 HCl EtOH D6 h 32 108
K3+A18+U1 HCl EtOH D6 h 33 108
K6+A18+U1 Yb(OTf)
3
7100 8C 20 min 98 62
HCl EtOH D6 h 42 108
K6+A18+U10 HCl EtOH D6 h 30 108
K7+A18+U1 bmim[BF
4
]780 ± 100 8C 1±2h 62 33
HCl EtOH D6 h 38 108
K7+A18+U10 bmim[BF
4
]780 ± 100 8C 1±2h 66 33
HCl EtOH D6 h 36 108
K7+A60+U1 bmim[BF
4
]780 ± 100 8C 1±2h 92 33
K7+A60+U10 bmim[BF
4
]780 ± 100 8C 1±2h 84 33
K7+A88+U1 bmim[BF
4
]780 ± 100 8C 1±2h 34 33
K8+A18+U1 AcOH MeOH D4 h 91 110
K8+A45+U1 AcOH MeOH D4 h 93 110
K8+A71+U1 AcOH MeOH D4 h 80 110
K8+A72+U1 AcOH MeOH D4 h 71 110
K10+A18+U1 Yb(OTf)
3
7100 8C 20 min 99 62
K11+A18+U1 bmim[BF
4
]720±308C 30 min 75 33
K11+A18+U10 bmim[BF
4
]720±308C 30 min 88 33
K11+A60+U1 bmim[BF
4
]720±308C 30 min 92 33
K11+A60+U10 bmim[BF
4
]720±308C 30 min 83 33
K11+A88+U1 bmim[BF
4
]720±308C 30 min 82 33
1024 S V Vdovina, V A Mamedov

If dicarbonyl compound is non-symmetrical (for exam-
ple, keto lactone E31), spiroheterocyclic compounds are
formed as a stereoisomeric pair (Aand B).
112
Another example of a side reaction is the Hantzsch
condensation. Dihydropyridines 13 were obtained in low
yields (6 %± 11%) together with dihydropyrimidinones as
the major products.
45
Probably, urea or thiourea undergoes
partial decomposition under the action of IR radiation to
form ammonia; the latter reacts with aldehyde and ethyl
acetoacetate resulting in the corresponding dihydropyri-
dines.
4. Miscellaneous methods for the synthesis of Biginelli
compounds
Dihydropyrimidinone derivatives can also be synthesised by
the three-component condensation of aromatic ketones,
aldehydes and urea.
113, 114
The reaction is catalysed by
Lewis acids [FeCl
3
,(TMS)Cl,
113
ZnI
2
].
114
Z
H
N
NH
R
X
O
Z+
Z
HN NH
X
R R
12DHPM
R = Ph, 4-MeC
6
H
4
, 4-FC
6
H
4
, 4-ClC
6
H
4
, 4-O
2
NC
6
H
4
;X=O,S;
Z=CH
2
O, OCMe
2
O, NHC(O)NH, NMeC(O)NMe.
+
R H
O
+
H
2
N NH
2
X
O
O
O
O
A
O
PhPh
O
NHHN
O O
B
O
PhPh
O
NHHN
O O
Me
EtO
2
C
O
+
R O
H
+
H
2
N NH
2
XTAFF
IR, 2 h
N
NH
EtO
2
C
R
XMe
H
+
N
EtO
2
C
R
MeMe
CO
2
Et
H
DHPM 13
R = Ph, 4-MeC
6
H
4
, 4-MeOC
6
H
4
, 2-ClC
6
H
4
;X=O,S.
O
Me
Z+H O
R
H
2
N O
NH
2
+H
+
N
NH
O
R
ZH
R = Ph, 4-MeC
6
H
4
, 2-ClC
6
H
4
, 4-ClC
6
H
4
, 4-O
2
NC
6
H
4
; Z = H, 4-Me,
4-Bu
t
, 4-HO, 4-CHO, 2-MeO, 3-MeO, 4-MeO, 3-MeO-4-HO,
3,4-(MeO)
2
, 2-Cl, 4-Cl, 3-Br, 2,4-Cl
2
, 2,6-Cl
2
, 3,5-Br
2
-4-HO.
Table 4. Formation of spiroheterocyclic compounds 12 under the conditions of the Biginelli reaction.
Reactants Reaction Yield (%) Ref. Reactants Reaction Yield (%) Ref.
conditions conditions
E31+A18+U1 dsee
a
111
E32+A18+U1 f56 112
E32+A23+U1 f54 112
E32+A60+U1 f53 112
E32+A64+U1 f52 112
K12+A18+U10 g77 102
K12+A23+U1 g78 102
K12+A23+U10 g79 102
K12+A34+U1 g69 102
K12+A60+U1 g80 102
K12+A64+U1 g70 102
Am5+A18+U1 f71 112
Am5+A23+U1 f70 112
Am5+A60+U1 f63 112
Am5+A64+U1 f68 112
Am6+A18+U1 f69 112
Am6+A23+U1 f71 112
Am6+A60+U1 f62 112
Am6+A64+U1 f63 112
a
In this case, two isomers are formed.
Note. Notation Catalyst Solvent Other conditions Reaction time /h
dHCl EtOH D3
f77 80 8C4
g(TMS)Cl DMF+MeCN stirring 2
New potential of the classical Biginelli reaction 1025

The formation of the Biginelli products was also
observed, when oxazinanes (OAN) and oxazolidines
(OALD) were used as a source of a one-carbon fragment
instead of aromatic aldehydes.
115
Application of these compounds allows the preparation
of dihydropyrimidinones with fragments which are impos-
sible to introduce using corresponding aldehydes due to
their instability or low reactivity (aliphatic alde-
hydes)
71, 82, 95
of the latter under the conditions of the
Biginelli reaction.
Remarkably under these conditions, cyclic ketones also
give the Biginelli products.
92, 100 ± 102
Thus tetrahydrothio-
pyran-3-one S,S-dioxide gave the corresponding dihydro-
pyrimidinone in a yield of *64%.
100
***
An analysis of the published data shows that at present
there is a great number of experimental methods for
performing the Biginelli reaction differing in the reactants,
reaction conditions, catalysts, etc. It is noteworthy that the
comparison of efficiency of different approaches is not a
simple task, moreover, many exotic methods did not find
wide application due to high cost and low availability of the
corresponding reagents. The material considered in this
review provides an idea on the progress in this very
important reaction of synthetic organic chemistry.
This work was performed with the financial support of
the Russian Foundation for Basic Research (Project No. 07-
03-00 613-a) and the State contract No. 02.512.11.2237 of
the Federal target programme `Research and Development
of Priority Directions of Scientific and Technical Complex
of Russia for 2007 ± 2012'.
V. Supplements
NH
OR
2
R
1
H
R
2
R
2
OAN
O
N
Me Me
Me
H
CH
2
CN
OALD
R
2
=H:R
1
= H, 4-MeOC
6
H
4
, 3,4-(MeO)
2
C
6
H
3
, 3,4,5-(MeO)
3
C
6
H
2
,
2-O
2
NC
6
H
4
, 3-O
2
NC
6
H
4
;R
2
= Me: R
1
= Me, Et, Ph, CH
2
CO
2
Et.
Me
EtO
2
C
O
+ OAN (or OALD) + H
2
N NH
2
XMeCN
CF
3
CO
2
H
N
NH
EtO
2
C
Me X
R
H
R = H, Me, Et, CH
2
CO
2
Et, CH
2
CN, Ph, 2-O
2
NC
6
H
4
, 3-O
2
NC
6
H
4
,
4-MeOC
6
H
4
, 3,4-(MeO)
2
C
6
H
3
;X=O,S.
S
O O
O
+ +
H O
Ph S
O O
NH
N O
Ph
H
H
2
N O
NH
2
H
+
EtOH
Z O
O O
Z=CH
2
(E31), OCMe
2
(E32), o-phenylene (E33), 4-Me-1,2-phenylene (E34),
EtO
O O
OEt
OO(E35).
Supplement 1. Compound used in the Biginelli reaction.
a. Dicarbonyl compounds
Keto esters (E)
Compound R
1
R
2
Compound R
1
R
2
Compound R
1
R
2
E1 Me Me
E2 Me Et
E3 Me Pr
i
E4 Me Bu
t
E5 Me CH
2
=
CH
E6 Me
E7 Me Ph
E8 Me PhCH
=
CHCH
2
E9 Me Ph
2
CHCH
2
E10 Me BnN(Ph)(CH
2
)
2
E11 Et Me
E12 Et Et
E13 Pr
n
Et
E14 cyclo-C
3
H
5
Me
E15 Bu
t
Me
E16 Ph Et
E17 Ph Bn
E18 Ph(CH
2
)
2
Et
E19 MeOCH
2
Me
E20 CHF
2
Et
E21 CF
3
Et
E22 CHF
2
CF
2
Me
E23 n-C
3
F
7
Me
E24 n-C
4
F
9
Et
E25 CHCl
2
Me
E26 CCl
3
Et
E27 ribosyl Et
E28 galactosyl Et
E29 mannosyl Et
E30 indol-3-yl Me
R
1
OR
2
O O
Pr
i
Me
1026 S V Vdovina, V A Mamedov

Diketones (K)
R
1
R
2
O O
b. Aldehydes (A)
Monoaldehydes RCHO
a
R=
R0HN
O
N
N
N
HN
(R0= Pr
i
C(O)).
OR0
OR0
R0O
O
Z
O O
Z=CH
2
(K12), CMe
2
(K13).
Keto amides and their analogues (Am)
Me NR
1
R
2
O O R
1
=H:R
2
=H(Am1),
Me (Am2), Ph (Am3);
R
1
=R
2
=Et(Am4).
N N
O O
R R
X
X=O:R=H (Am5), Me (Am6);
X=S:R=H (Am7), Ph (Am8).
Equivalents of dicarbonyl compounds (Eq):
MeO OMe
O OMe
Me
O
O
2
N
(Eq1), (Eq2).
Supplement 1 (continued).
Compound R
1
R
2
Compound R
1
R
2
Compound R
1
R
2
K1 Me Me K5 Me Ph K9 Ph ferrocenyl
K2 CF
3
Me K6 CF
3
Ph K10 CF
3
2-thienyl
K3 CHF
2
CF
2
Me K7 CHF
2
CF
2
Ph K11 CF
3
CF
3
K4 Me ferrocenyl K8 CHCl
2
Ph
Compound R Compound R Compound R
A1 HA31 4-Me
2
NC
6
H
4
A61 3,4-F
2
C
6
H
3
A2 Me A32 2-O
2
NC
6
H
4
A62 2-ClC
6
H
4
A3 Et A33 3-O
2
NC
6
H
4
A63 3-ClC
6
H
4
A4 Pr
n
A34 4-O
2
NC
6
H
4
A64 4-ClC
6
H
4
A5 Pr
i
A35 2-O
2
N-4-MeC
6
H
3
A65 2,3-Cl
2
C
6
H
3
A6 Bu
n
A36 2-O
2
N-5-ClC
6
H
3
A66 2,4-Cl
2
C
6
H
3
A7 Bu
i
A37 2-HOC
6
H
4
A67 3,4-Cl
2
C
6
H
3
A8 Bu
t
A38 3-HOC
6
H
4
A68 3,5-Cl
2
C
6
H
3
A9 n-C
5
H
11
A39 4-HOC
6
H
4
A69 2-BrC
6
H
4
A10 Pr
n
C(Me)H A40 2-HO-4-ClC
6
H
3
A70 3-BrC
6
H
4
A11 CHEt
2
A41 2-HO-4-BrC
6
H
3
A71 4-BrC
6
H
4
A12 cyclo-C
6
H
11
A42 2-HO-5-BrC
6
H
3
A72 4-IC
6
H
4
A13 n-C
6
H
13
A43 2-MeOC
6
H
4
A73 1-naphthyl
A14 n-C
7
H
15
A44 3-MeOC
6
H
4
A74 2-naphthyl
A15 n-C
9
H
19
A45 4-MeOC
6
H
4
A75 anthracen-9-yl
A16 Bn A46 2,4-(MeO)
2
C
6
H
3
A76 benzodioxol-5-yl
A17 Ph(CH
2
)
2
A47 2,5-(MeO)
2
C
6
H
3
A77 ferrocenyl
A18 Ph A48 3,4-(MeO)
2
C
6
H
3
A78 ribosyl
A19 PhCH
=
CH A49 3,5-(MeO)
2
C
6
H
3
A79 galactosyl
A20 PhC:CA50 3,4,5-(MeO)
3
C
6
H
2
A80 mannosyl
A21 2-MeC
6
H
4
A51 2-MeO-5-BrC
6
H
3
A81 pyrrol-2-yl
A22 3-MeC
6
H
4
A52 3-MeO-4-HOC
6
H
3
A82 2-pyridyl
A23 4-MeC
6
H
4
A53 3-MeO-4-HO-5-O
2
NC
6
H
2
A83 indol-2-yl
A24 2,5-Me
2
C
6
H
3
A54 2-EtOC
6
H
4
A84 2-furyl
A25 2-(CH
2
=
CH)C
6
H
4
A55 3,4-(EtO)
2
C
6
H
3
A85 3-furyl
A26 2-(CH
2
=
CHCH
2
)C
6
H
4
A56 3-(cyclo-C
5
H
9
)O-4-MeOC
6
H
3
A86 3-nitrofuran-2-yl
A27 4-NCC
6
H
4
A57 3-PhOC
6
H
4
A28 see
a
A58 2-FC
6
H
4
A87
A29 2-F
3
CC
6
H
4
A59 3-FC
6
H
4
A30 4-F
3
CC
6
H
4
A60 4-FC
6
H
4
A88 2-thienyl
O
O
New potential of the classical Biginelli reaction 1027

Dialdehydes Z(CHO)
2
c. Ureas and their equivalents (U)
Zism-phenylene (A89), p-phenylene (A90),
Ureas and thioureas X C
NHR
1
NHR
2
O O O
(A91).
Bisurea (U15)H
2
NC(O)NH(CH
2
)
2
O(CH
2
)
2
.
Urea equivalents
XN
N
N
H
2
N
H
X=CH(U16), N (U17).
Supplement 1 (continued).
Compound (X = O) R
1
R
2
Compound (X = S) R
1
R
2
U1
a
HH U10
a
HH
U2 HMe U11 HMe
U3 H All U12 HPh
U4 HPh U13 H 2-F
3
CC
6
H
4
U5 HBn U14 H 4-FC
6
H
4
U6 H ribosyl
U7 H galactosyl
U8 H mannosyl
U9 Me Me
a
Urea (U1) and thiourea (U10) were sometimes used as hydrogensulfates X
=
C(NH
2
)(NH
3)HSOÿ
4. In these cases, they are denoted in
Supplement 2 as U1* and U10*, respectively. Final products were isolated as free bases, that is why the use of U1 and U1* as reagents (and also
U10 and U10*) resulted in the same dihydropyrimidinone.
Z=R
2
,OR
2
, NRR0.
R
1
Z
O O
+ R
3
CHO + HR
4
NCNH
2
O
N
NH
R
3
R
4
R
1
Z(O)C
X
Supplement 2. The versions of performing the one-pot Biginelli reaction.
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E1+A4+U1 Pro-Me
.
HCl EtOH D18 h 63 95
E1+A5+U1 CH
2
ClCO
2
H790 8C5h5082
VCl
3
MeCN D2 h 80 86
E1+A18+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 51 6
CeCl
3.
7H
2
O EtOH D3 h 90 10
CeCl
3.
7H
2
OH
2
OD3 h 88 10
CeCl
3.
7H
2
O7D 3 h 70 10
Mont. KSF MeOH D8 ± 10 h 90 15
Yb
III
-Resin 7120 8C 48 h 71 16
I
2
MeCN D6.5 h 93 18
SSA EtOH D6 h 96 20
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 88 21
H
2
SO
4
EtOH D18 h 42 21
FeCl
3.
6H
2
O, HCl EtOH D4 h 86 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 86 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 92 23
InCl
3
THF D9 h 91 26
LiClO
4
or LiOTf MeCN D6 h 90 28
Bi(OTf)
3
MeCN stirring 1.5 h 85 31
(TMS)OTf MeCN room temperature, stirring 20 min 90 32
1028 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E1+A18+U1 bmim[AlCl
4
]7120 ± 125 8C1h7834
77100 ± 105 8C1h8036
Yb(OTf)
3
7100 8C 20 min 98 62
LaCl
3.
7H
2
O, HCl EtOH D5 h 97 63
InBr
3
EtOH D7 h 98 66
NH
4
Cl 7100 8C3h9271
Sr(OTf)
2
770 8C4h9379
FeCl
3
, Si(OEt)
4
Pr
i
OH D2.5 h 94 80
CH
2
ClCO
2
H790 8C3h9282
H
3
PW
12
O
40
MeCN 80 8C1h9383
H
3
PMo
12
O
40
MeCN 80 8C1h8583
H
4
SiW
12
O
40
MeCN 80 8C1h8683
VCl
3
MeCN D2 h 92 86
BDMPEAB 7100 8C 30 min 98 90
NH
4
Br 7100 8C 30 min 87 90
77100 8C 30 min 81 90
(TMS)Cl DMF 20 8C 14 h 62 93
Pro-Me
.
HCl EtOH D18 h 99 95
E1+A18+U1*7765 8C2h9397
E1+A18+U10 I
2
MeCN D6 h 91 18
[NHEt
3
][PF
6
]7120 ± 125 8C1h8334
CH
2
ClCO
2
H790 8C5h8382
VCl
3
MeCN D2 h 85 86
E1+A21+U1 Yb(OTf)
3
EtOH 100 8C 10 min 73 27
E1+A23+U1 InBr
3
EtOH D7 h 97 66
CH
2
ClCO
2
H790 8C3h9382
H
3
PW
12
O
40
MeCN 80 8C1h9683
H
3
PMo
12
O
40
MeCN 80 8C1h9483
H
4
SiW
12
O
40
MeCN 80 8C1h9683
CNSP H
2
O808C 4.5 h 89 88
BDMPEAB 7100 8C 60 min 98 90
NH
4
Br 7100 8C 60 min 85 90
77100 8C 60 min 80 90
E1+A23+U10 LaCl
3
EtOH 120 8C 20 min 58 27
E1+A24+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 96 21
H
2
SO
4
EtOH D18 h 62 21
E1+A27+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 81 96
E1+A30+U1 Yb
III
-Resin 7120 8C 48 h 65 16
E1+A31+U1 CeCl
3.
7H
2
O EtOH D4 h 88 10
CeCl
3.
7H
2
OH
2
OD4 h 82 10
CeCl
3.
7H
2
O7D 4 h 68 10
(TMS)OTf MeCN room temperature, stirring 15 min 88 32
Sr(OTf)
2
770 8C4h9079
H
3
PW
12
O
40
MeCN 80 8C1h8883
H
3
PMo
12
O
40
MeCN 80 8C1h8083
H
4
SiW
12
O
40
MeCN 80 8C1h8283
E1+A31+U10 CeCl
3.
7H
2
O EtOH D4 h 86 10
CeCl
3.
7H
2
OH
2
OD4 h 84 10
CeCl
3.
7H
2
O7D 4 h 69 10
(TMS)OTf MeCN room temperature, stirring 20 min 86 32
E1+A32+U1 H
3
BO
3
AcOH 100 8C 0.5±2h 95 74
FeCl
3
, Si(OEt)
4
Pr
i
OH D10 h 81 80
VCl
3
MeCN D2 h 87 86
KHSO
4
ethylene glycol 100 8C 0.5±2 h 90 92
E1+A32+U10 VCl
3
MeCN D2 h 80 86
E1+A33+U1 NH
4
Cl 7100 8C3h8071
Sr(OTf)
2
770 8C4h9379
E1+A34+U1 Yb
III
-Resin 7120 8C 48 h 61 16
I
2
MeCN D7 h 90 18
SSA EtOH D6 h 95 20
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 92 21
New potential of the classical Biginelli reaction 1029

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E1+A34+U1 H
2
SO
4
EtOH D18 h 41 21
FeCl
3.
6H
2
O, HCl EtOH D4 h 88 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 87 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 90 23
InCl
3
THF D6 h 91 26
Bi(OTf)
3
MeCN stirring 2 h 87 31
Yb(OTf)
3
7100 8C 20 min 91 62
LaCl
3.
7H
2
O, HCl EtOH D5 h 68 63
InBr
3
EtOH D7 h 72 66
NH
4
Cl 7100 8C3h7971
H
3
BO
3
AcOH 100 8C 0.5±2h 92 74
FeCl
3
, Si(OEt)
4
Pr
i
OH D4 h 86 80
H
3
PW
12
O
40
MeCN 80 8C1h7583
H
3
PMo
12
O
40
MeCN 80 8C1h6983
H
4
SiW
12
O
40
MeCN 80 8C1h7383
KHSO
4
ethylene glycol 100 8C 0.5±2h 93 92
Pro-Me
.
HCl EtOH D18 h 68 95
E1+A34+U1*7765 8C3h9297
E1+A34+U9 Dowex-50W 7130 8C3h6284
E1+A36+U1 H
3
BO
3
AcOH 100 8C 0.5±2h 90 74
KHSO
4
ethylene glycol 100 8C 0.5±2h 89 92
E1+A39+U1 VCl
3
MeCN D2 h 90 86
BDMPEAB 7100 8C 45 min 99 90
NH
4
Br 7100 8C 45 min 90 90
77100 8C 45 min 80 90
E1+A43+U1 FeCl
3
, Si(OEt)
4
Pr
i
OH D4 h 73 80
FeCl
3
, Si(OEt)
4
cyclo-C
6
H
11
OH D3 h 88 90
E1+A44+U1 Yb
III
-Resin 7120 8C 48 h 71 16
Sr(OTf)
2
770 8C4h8979
Pro-Me
.
HCl EtOH D18 h 82 95
E1+A45+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 43 6
Yb
III
-Resin 7120 8C 48 h 71 16
I
2
MeCN D6.5 h 88 18
SSA EtOH D6 h 95 20
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 87 21
H
2
SO
4
EtOH D18 h 28 21
FeCl
3.
6H
2
O, HCl EtOH D4 h 88 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 88 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 85 23
InCl
3
THF D7 h 92 26
Bi(OTf)
3
MeCN stirring 1.75 h 88 31
Yb(OTf)
3
7100 8C 20 min 99 62
LaCl
3.
7H
2
O, HCl EtOH D5 h 82 63
InBr
3
EtOH D7 h 94 66
NH
4
Cl 7100 8C3h9071
H
3
BO
3
AcOH 100 8C 0.5±2h 94 74
FeCl
3
, Si(OEt)
4
Pr
i
OH D4 h 92 80
CH
2
ClCO
2
H790 8C3h9782
H
3
PW
12
O
40
MeCN 80 8C1h9783
H
3
PMo
12
O
40
MeCN 80 8C1h9083
H
4
SiW
12
O
40
MeCN 80 8C1h9583
VCl
3
MeCN D2 h 88 86
CNSP H
2
O808C5h8788
KHSO
4
ethylene glycol 100 8C 0.5±2h 90 92
Pro-Me
.
HCl EtOH D18 h 86 95
E1+A45+U1*7765 8C3h8397
E1+A46+U1 CeCl
3.
7H
2
O EtOH D2.5 h 95 11
CeCl
3.
7H
2
OH
2
OD2.5 h 90 11
CeCl
3.
7H
2
O7D 2.5 h 75 11
(TMS)OTf MeCN room temperature, stirring 15 min 95 32
E1+A50+U1 Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 62 27
1030 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E1+A51+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 89 96
E1+A52+U1 Sr(OTf)
2
770 8C4h8579
Pro-Me
.
HCl EtOH D18 h 70 95
E1+A53+U1 Sr(OTf)
2
770 8C4h8879
E1+A57+U1 VCl
3
MeCN D2 h 86 86
E1+A60+U1 Yb
III
-Resin 7120 8C 48 h 70 16
Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 81 27
Yb(OTf)
3
7100 8C 20 min 81 62
H
3
BO
3
AcOH 100 8C 0.5±2h 89 74
VCl
3
MeCN D2 h 86 86
KHSO
4
ethylene glycol 100 8C 0.5±2h 87 92
E1+A61+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 36 6
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 88 21
H
2
SO
4
EtOH D18 h 62 21
E1+A62+U1 NH
4
Cl 7100 8C3h8571
E1+A63+U1 H
3
PW
12
O
40
MeCN 80 8C1h8883
H
3
PMo
12
O
40
MeCN 80 8C1h8383
H
4
SiW
12
O
40
MeCN 80 8C1h9083
E1+A64+U1 Yb
III
-Resin 7120 8C 48 h 71 16
I
2
MeCN D7 h 89 18
SSA EtOH D6 h 94 20
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 95 21
H
2
SO
4
EtOH D18 h 56 21
FeCl
3.
6H
2
O, HCl EtOH D4 h 96 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 96 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 94 23
InCl
3
THF D6 h 93 26
77100 ± 105 8C1h 8336
LaCl
3.
7H
2
O, HCl EtOH D5 h 96 63
InBr
3
EtOH D7 h 93 66
NH
4
Cl 7100 8C3h8571
H
3
BO
3
AcOH 100 8C 0.5±2h 98 74
Sr(OTf)
2
770 8C4h9379
CH
2
ClCO
2
H790 8C3h9782
H
3
PW
12
O
40
MeCN 80 8C1h9083
H
3
PMo
12
O
40
MeCN 80 8C1h8583
H
4
SiW
12
O
40
MeCN 80 8C1h9183
VCl
3
MeCN D2 h 65 86
BDMPEAB 7100 8C 40 min 97 90
NH
4
Br 7100 8C 40 min 86 90
77100 8C 40 min 79 90
KHSO
4
ethylene glycol 100 8C 0.5±2h 95 92
E1+A64+U1*7765 8C3h9497
E1+A64+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 92 96
E1+A66+U1 CeCl
3.
7H
2
O EtOH D4 h 90 10
CeCl
3.
7H
2
OH
2
OD4 h 84 10
CeCl
3.
7H
2
O7D 4 h 70 10
SSA EtOH D6 h 96 10
(TMS)OTf MeCN room temperature, stirring 18 min 90 32
Yb(OTf)
3
7100 8C 20 min 83 62
CH
2
ClCO
2
H790 8C3h9382
E1+A66+U1*7765 8C 2.5 h 95 97
E1+A68+U10 Yb(OTf)
3
MeCN mn, 120 8C 20 min 87 40
E1+A69+U1 Yb
III
-Resin 7120 8C 48 h 68 16
E1+A71+U1 Pro-Me
.
HCl EtOH D18 h 69 95
E1+A73+U1 FeCl
3
, Si(OEt)
4
Pr
i
OH D4 h 86 80
E1+A73+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 84 96
E1+A75+U1 FeCl
3
, Si(OEt)
4
Pr
i
OH D19 h 95 80
E1+A76+U1 VCl
3
MeCN D2 h 82 86
E1+A77+U1 InCl
3.
4H
2
O EtOH D6 h 68 98
E1+A82+U1 Bi(OTf)
3
MeCN stirring 3 h 89 31
New potential of the classical Biginelli reaction 1031

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E1+A86+U1 Yb(OTf)
3
EtOH 100 8C 10 min 34 27
E1+A88+U1 bmim[AlCl
4
]7120 ± 125 8C1h 8034
VCl
3
MeCN D2 h 85 86
E1+A88+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 82 96
E1+A88+U10 bmim[AlCl
4
]7120 ± 125 8C1h 8434
ZnBr
2
(CH
2
Cl)
2
D24 h 85 96
E2+A1+U1 InBr
3
EtOH D7 h 80 66
E2+A1+U10 InBr
3
EtOH D7 h 70 66
E2+A2+U1 PPE THF D24 h 53 7
InCl
3
THF D7 h 75 26
Yb(OTf)
3
EtOH 100 8C 20 min 67 27
HCl EtOH US 2 ± 5 min 92 64
InBr
3
EtOH D7 h 75 66
NH
4
Cl 7100 8C3h4271
E2+A3+U1 ZnI
2
MeCN 80 8C, 300 MPa 4 h 73 25
E2+A4+U1 CeCl
3.
7H
2
O EtOH D4 h 83 10
CeCl
3.
7H
2
OH
2
OD4 h 76 10
CeCl
3.
7H
2
O7D 4 h 73 10
I
2
PhMe D4.2 h 76 17
I
2
MeCN D7 h 79 18
SSA EtOH D6 h 86 20
FeCl
3.
6H
2
O, HCl EtOH D4 h 73 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 72 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 64 23
ZnI
2
MeCN 80 8C, 300 MPa 4 h 37 25
InCl
3
THF D7 h 85 26
(TMS)OTf MeCN room temperature, stirring 20 min 83 32
77100 ± 105 8C1h 7836
LaCl
3.
7H
2
O, HCl EtOH D5 h 60 63
NH
2
SO
3
H EtOH US, 20 ± 30 8C1h 7069
NH
4
Cl 7100 8C3h7871
CH
2
ClCO
2
H790 8C5h7582
H
3
PW
12
O
40
MeCN 80 8C1h5783
H
3
PMo
12
O
40
MeCN 80 8C1h5583
H
4
SiW
12
O
40
MeCN 80 8C1h5483
BDMPEAB 7100 8C 25 min 86 90
NH
4
Br 7100 8C 25 min 64 90
77100 8C 25 min 52 90
KHSO
4
ethylene glycol 100 8C 0.5±2h 85 92
E2+A4+U1*7765 8C2h9197
E2+A4+U10 I
2
MeCN D6.5 h 82 18
ZnI
2
MeCN 80 8C, 300 MPa 4 h 11 25
E2+A5+U1 ZnI
2
MeCN 80 8C, 300 MPa 4 h 77 25
(TMS)OTf MeCN room temperature, stirring 25 min 80 32
CH
2
ClCO
2
H790 8C5h4782
VCl
3
MeCN D2 h 87 86
CNSP H
2
O808C 5.5 h 76 88
KHSO
4
ethylene glycol 100 8C 0.5±2h 86 92
ZnBr
2
(CH
2
Cl)
2
D24 h 77 96
E2+A6+U1 Mont. KSF 7130 8C 48 h 86 14
Yb(OTf)
3
7100 8C 40 min 87 62
NH
4
Cl 7100 8C3h6571
CuCl
2.
2H
2
O7100 8C 110 min 80 73
CuCl
2.
2H
2
O7mn 1.5 min 80 73
CuSO
4.
5H
2
O7100 8C 110 min 85 73
CuSO
4.
5H
2
O7mn 1.5 min 85 73
ZnCl
2
780 8C 40 min 38 75
E2+A7+U1 ZnI
2
MeCN 80 8C, 300 MPa 4 h 55 25
E2+A8+U10 ZnI
2
MeCN 80 8C, 300 MPa 4 h 10 25
E2+A9+U1 I
2
MeCN D7 h 80 18
LiClO
4
or LiOTf MeCN D7 h 82 28
1032 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A9+U1 LiBr MeCN D4 h 72 68
PABC EtOH D4 h 86 76
Cu(NTf
2
)
2
H
2
O stirring 24 h 80 78
Yb(NTf
2
)
2
H
2
O stirring 71 h 55 78
RuCl
3
7100 8C 90 min 76 81
H
3
PW
12
O
40
MeCN 80 8C1h5083
H
3
PMo
12
O
40
MeCN 80 8C1h4783
H
4
SiW
12
O
40
MeCN 80 8C1h5283
bmim[BF
4
]7100 8C 30 min 93 87
BDMPEAB 7100 8C 65 min 92 90
NH
4
Br 7100 8C 65 min 79 90
77100 8C 65 min 66 90
E2+A10+U1 ZnI
2
MeCN 80 8C, 300 MPa 4 h 60 25
E2+A11+U1 ZnI
2
MeCN 80 8C, 300 MPa 4 h 77 25
E2+A12+U1 LiClO
4
or LiOTf MeCN D8 h 87 28
Bi(OTf)
3
MeCN stirring 3.5 h 83 31
CAN MeOH US 3.5 87 35
(TMS)Cl, NaI MeCN stirring 45 min 84 67
Cu(OTf)
2
MeCN 70 8C 12 h 60 70
CdCl
2
MeCN D6 h 82 77
H
3
PW
12
O
40
MeCN 80 8C1h6883
H
3
PMo
12
O
40
MeCN 80 8C1h6183
H
4
SiW
12
O
40
MeCN 80 8C1h6583
E2+A13+U1 I
2
PhMe D4.1 h 69 17
SSA EtOH D6 h 84 20
InCl
3
THF D8 h 81 26
Bi(OTf)
3
MeCN stirring 4 h 58 31
CAN MeOH US 3.5 h 85 25
77100 ± 105 8C1h 8026
NH
2
SO
3
H EtOH US, 0 ± 30 8C1h 8967
RuCl
3
7100 8C 95 min 74 82
BDMPEAB 7100 8C 55 min 93 90
NH
4
Br 7100 8C 55 min 86 90
77100 8C 55 min 75 90
PPAA EtOAc D6 h 53 91
(TMS)Cl DMF 20 8C 14 h 37 93
E2+A13+U1*7765 8C2h8997
E2+A13+U10 I
2
MeCN D7 h 83 18
CdCl
2
MeCN D6 h 82 77
E2+A14+U1 (TMS)Cl DMF 20 8C 14 h 32 93
E2+A15+U1 Cu(OTf)
2
MeCN 70 8C 12 h 60 70
BDMPEAB 7100 8C 65 min 91 90
NH
4
Br 7100 8C 65 min 78 90
77100 8C 65 min 68 90
E2+A16+U1 CAN MeOH US 6 h 91 33
Yb(OTf)
3
THF stirring 782 89
E2+A17+U1 LiClO
4
or LiOTf MeCN D7 h 81 28
E2+A18+U1 ZrCl
4
EtOH D4 h 90 98
E2+A18+U1*7765 8C2h9397
E2+A18+U2 PPE THF D24 h 95 7
PPE 7mn 90 s 89 11
Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 18 27
(TMS)Cl DMF 20 8C 14 h 73 93
ZnBr
2
(CH
2
Cl)
2
D24 h 85 96
E2+A18+U5 Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 43 27
PPE THF D24 h 91 28
E2+A18+U6 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 48 43
E2+A18+U7 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 41 43
E2+A18+U8 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 40 43
E2+A18+U9 Dowex-50W 7130 8C3h5943
E2+A18+U10 PPE 7mn 90 s 82 11
New potential of the classical Biginelli reaction 1033

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A18+U10 I
2
MeCN D6.5 h 92 18
TsOH H
2
O stirring 15 min 81 19
SSA EtOH D6 h 93 20
InCl
3
THF D9 h 91 26
LaCl
3
AcOH+EtOH 120 8C 10 min 56 27
7EtOH mn 3 min 44 42
Al
2
O
3
7mn 9 min 85 42
77mn2.5 min 90 42
TAFF 7IR 2 h 45 45
LaCl
3.
7H
2
O, HCl EtOH D5 h 96 63
HCl EtOH US 2 ± 5 min 90 64
InBr
3
EtOH D7 h 94 66
(TMS)Cl, NaI MeCN stirring 30 min 90 67
LiBr MeCN D3 h 85 68
NH
4
Cl 7100 8C3h8871
CuCl
2.
2H
2
O7100 8C 60 min 97 73
CuCl
2.
2H
2
O7mn 1.5 min 88 73
CuSO
4.
5H
2
O7100 8C 70 min 97 73
CuSO
4.
5H
2
O7mn 1.5 min 88 73
Sr(OTf)
2
770 8C4h9279
RuCl
3
7100 8C 50 min 86 81
CH
2
ClCO
2
H790 8C5h8482
H
3
PW
12
O
40
MeCN 80 8C1h9483
H
3
PMo
12
O
40
MeCN 80 8C1h8683
H
4
SiW
12
O
40
MeCN 80 8C1h9183
PhB(OH)
2
MeCN D18 h 60 85
VCl
3
MeCN D2 h 92 86
Yb(OTf)
3
THF stirring 781 89
BDMPEAB 7100 8C 53 min 93 90
NH
4
Br 7100 8C 53 min 77 90
77100 8C 53 min 75 90
PPAA EtOAc D6 h 80 91
ZrCl
4
EtOH D5 h 90 98
E2+A18+U10*7765 8C2h9197
E2+A18+U11 PPE 7mn 90 s 78 11
LaCl
3
EtOH 120 8C 10 min 41 27
E2+A18+U13 7EtOH mn,D11 min 86.4 38
E2+A18+U14 7EtOH mn,D6 min 82.4 38
E2+A19+U1 CeCl
3.
7H
2
O EtOH D4.5 h 88 10
CeCl
3.
7H
2
OH
2
OD4.5 h 83 10
CeCl
3.
7H
2
O7D 4.5 h 77 10
Mont. KSF 7130 8C 48 h 70 14
I
2
MeCN D7 h 82 18
SSA EtOH D6 h 90 20
Yb(OTf)
3
7100 8C 20 min 81 22
InCl
3
THF D9 h 90 26
LiClO
4
or LiOTf MeCN D7 h 83 28
Bi(OTf)
3
MeCN stirring 1.5 h 82 31
(TMS)OTf MeCN room temperature, stirring 15 min 88 32
CAN MeOH US 4 h 85 35
77100 ± 105 8C1h 7836
HCl EtOH US 2 ± 5 min 95 64
InBr
3
EtOH D7 h 68 66
(TMS)Cl, NaI MeCN stirring 45 min 85 67
LiBr MeCN D5 h 81 68
NH
2
SO
3
H EtOH US, 20 ± 30 8C 25 min 90 69
CuCl
2.
2H
2
O7100 8C 100 min 82 73
CuCl
2.
2H
2
O7mn 1 min 85 73
CuSO
4.
5H
2
O7100 8C 110 min 82 73
CuSO
4.
5H
2
O7mn 1 min 85 73
ZnCl
2
780 8C 60 min 36 75
1034 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A19+U1 PABC EtOH D4 h 98 76
CdCl
2
MeCN D4 h 82 77
RuCl
3
7100 8C 55 min 89 81
H
3
PW
12
O
40
MeCN 80 8C1h 9083
H
3
PMo
12
O
40
MeCN 80 8C1h 8983
H
4
SiW
12
O
40
MeCN 80 8C1h 8883
Yb(OTf)
3
THF stirring 781 89
ZrCl
4
EtOH D6 h 83 98
E2+A19+U1*7765 8C2h 9697
E2+A20+U1 PPE THF D24 h 92 7
E2+A21+U1 PPE 7mn90 s 86 11
InBr
3
EtOH D7 h 94 66
NH
4
Cl 7100 8C3h 8171
Cu(NTf
2
)
2
H
2
O stirring 24 h 77 78
E2+A22+U1 PhB(OH)
2
MeCN D18 h 75 85
E2+A23+U1 Mont. KSF MeOH D8 ± 10 h 88 15
I
2
PhMe D3 h 89 17
I
2
MeCN D7 h 86 18
LiClO
4
or LiOTf MeCN D7 h 89 28
TAFF 7IR 2 h 50 45
InBr
3
EtOH D7 h 98 66
(TMS)Cl, NaI MeCN stirring 45 min 89 67
NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 87 69
CuCl
2.
2H
2
O7100 8C 60 min 95 73
CuCl
2.
2H
2
O7mn1 min 97 73
PABC EtOH D4 h 96 76
CdCl
2
MeCN D3.3 h 90 77
Sr(OTf)
2
770 8C4h 8779
RuCl
3
7100 8C 50 min 90 81
CH
2
ClCO
2
H790 8C3h 8682
H
3
PW
12
O
40
MeCN 80 8C1h 9583
H
3
PMo
12
O
40
MeCN 80 8C1h 9283
H
4
SiW
12
O
40
MeCN 80 8C1h 9483
PhB(OH)
2
MeCN D18 h 70 85
CNSP H
2
O808C5h 8888
BDMPEAB 7100 8C 61 min 97 90
NH
4
Br 7100 8C 61 min 86 90
77100 8C 61 min 85 90
PPAA EtOAc D6 h 69 91
ZrCl
4
EtOH D4 h 88 98
E2+A23+U10 Bi(OTf)
3
MeCN stirring 2 h 90 31
TAFF 7IR 2 h 53 45
InBr
3
EtOH D7 h 94 66
Sr(OTf)
2
770 8C4h 9279
H
3
PW
12
O
40
MeCN 80 8C1h 9683
H
3
PMo
12
O
40
MeCN 80 8C1h 9383
H
4
SiW
12
O
40
MeCN 80 8C1h 9483
E2+A25+U1 HCl MeOH D15 h 78
E2+A26+U1 HCl MeOH D15 h 39 8
E2+A28+U1 I
2
PhMe D3±5h 717
E2+A29+U1 PPE THF D24 h 68 7
PPE 7mn90 s 76 11
E2+A30+U1 Yb
III
-Resin 7120 8C 48 h 70 16
Bi(OTf)
3
MeCN stirring 2 h 85 31
Yb(OTf)
3
7100 8C 40 min 87 62
PPAA EtOAc D6 h 73 91
E2+A31+U1 FeCl
3.
6H
2
O EtOH D4 h 80 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 81 23
Bi(OTf)
3
MeCN stirring 2 h 92 31
CAN MeOH US 4 h 88 35
Cu(OTf)
2
MeCN 50 8C9h 6570
New potential of the classical Biginelli reaction 1035

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A31+U1 H
3
BO
3
AcOH 100 8C 0.5±2h 86 74
PABC EtOH D6 h 93 76
CdCl
2
MeCN D4.3 h 88 77
Sr(OTf)
2
770 8C4h9379
H
3
PW
12
O
40
MeCN 80 8C1h9483
H
3
PMo
12
O
40
MeCN 80 8C1h9083
H
4
SiW
12
O
40
MeCN 80 8C1h9683
PPAA EtOAc D6 h 16 91
KHSO
4
ethylene glycol 100 8C 0.5±2h 86 92
ZrCl
4
EtOH D6 h 90 98
E2+A31+U9 Dowex-50W 7130 8C3h2784
E2+A31+U10 Sr(OTf)
2
770 8C4h8679
E2+A32+U1 PPE THF D24 h 84 7
CeCl
3.
7H
2
O EtOH D5 h 82 10
CeCl
3.
7H
2
OH
2
OD5 h 78 10
CeCl
3.
7H
2
O7D 5 h 65 10
I
2
PhMe D3.5 h 80 17
SSA EtOH D6 h 87 20
Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 54 27
Mn(OAc)
3.
2H
2
O MeCN D4 h 77 29
(TMS)OTf MeCN room temperature, stirring 20 min 82 32
(TMS)Cl, NaI MeCN stirring 1 h 90 67
VCl
3
MeCN D2 h 90 86
BDMPEAB 7100 8C 65 min 99 90
NH
4
Br 7100 8C 65 min 85 90
77100 8C 65 min 82 90
E2+A32+U1*7765 8C 2.5 h 92 97
E2+A32+U9 Dowex-50W 7130 8C3h6284
E2+A32+U10 (TMS)Cl, NaI MeCN stirring 1 h 85 67
VCl
3
MeCN D2 h 85 86
E2+A33+U1 PPE THF D24 h 87 7
PPE 7mn 90 s 93 11
I
2
PhMe D3.4 h 92 17
SSA EtOH D6 h 93 20
Mn(OAc)
3.
2H
2
O MeCN D4 h 75 29
NH
2
SO
3
H EtOH US, 20 ± 30 8C 30 min 91 69
Cu(OTf)
2
MeCN 60 8C9h7570
NH
4
Cl 7100 8C3h8071
CuCl
2.
2H
2
O7100 8C 60 min 86 73
CuCl
2.
2H
2
O7mn 1.5 min 88 73
ZnCl
2
780 8C 20 min 72 75
CdCl
2
MeCN D3.3 h 92 77
Sr(OTf)
2
770 8C4h9479
H
3
PW
12
O
40
MeCN 80 8C1h8983
H
3
PMo
12
O
40
MeCN 80 8C1h8083
H
4
SiW
12
O
40
MeCN 80 8C1h9083
Dowex-50W 7130 8C3h9384
PhB(OH)
2
MeCN D18 h 75 85
Yb(OTf)
3
THF stirring 790 89
E2+A33+U1*7765 8C3h9297
E2+A33+U2 HCl MeOH D4 h 60 9
InBr
3
EtOH D7 h 95 66
Dowex-50W 7130 8C3h6384
E2+A33+U4 HCl MeOH D6 h 52 9
E2+A33+U9 Dowex-50W 7130 8C3h5884
E2+A33+U10 PPE 7mn 90 s 71 11
SSA EtOH D6 h 92 20
7EtOH mn,D4 min 78 38
NH
4
Cl 7100 8C3h7871
Sr(OTf)
2
770 8C4h9279
Yb(OTf)
3
THF stirring 788 89
1036 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A33+U10*7765 8C3h 9397
E2+A33+U14 7EtOH mn,D7 min 70 38
E2+A34+U1 PPE THF D24 h 77 7
PPE 7mn90 s 86 11
Mont. KSF MeOH D8 ± 10 h 89 15
Yb
III
-Resin 7120 8C 48 h 72 16
I
2
PhMe D4.7 h 89 17
I
2
MeCN D7.5 h 89 18
TsOH H
2
O stirring 15 min 90 19
SSA EtOH D6 h 94 20
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 91 21
H
2
SO
4
EtOH D18 h 54 21
FeCl
3.
6H
2
O, HCl EtOH D4 h 83 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 83 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 86 23
InCl
3
THF D6 h 93 26
LiClO
4
or LiOTf MeCN D5 h 90 28
Bi(OTf)
3
MeCN stirring 2 h 85 31
CAN MeOH US 7 h 85 35
77100± 105 8C1h 8536
Yb(OTf)
3
7100 8C 20 min 94 62
LaCl
3.
7H
2
O, HCl EtOH D5 h 80 63
InBr
3
EtOH D7 h 86 66
(TMS)Cl, NaI MeCN stirring 1 h 86 67
LiBr MeCN D5 h 93 68
NH
2
SO
3
H EtOH, US, 20± 30 8C 40 min 94 69
Cu(OTf)
2
MeCN 70 8C 12 h 60 70
NH
4
Cl 7100 8C3h 8371
CuCl
2.
2H
2
O7100 8C 60 min 90 73
CuCl
2.
2H
2
O7mn1 min 92 73
CuSO
4.
5H
2
O7100 8C 70 min 90 73
CuSO
4.
5H
2
O7mn1 min 92 73
H
3
BO
3
AcOH 100 8C 0.5±2h 89 74
ZnCl
2
780 8C 12 min 85 75
PABC EtOH D6 h 93 76
CdCl
2
MeCN D5.3 h 89 77
Sr(OTf)
2
770 8C4h 9879
RuCl
3
7100 8C 72 min 84 81
H
3
PW
12
O
40
MeCN 80 8C1h 9083
H
3
PMo
12
O
40
MeCN 80 8C1h 8683
H
4
SiW
12
O
40
MeCN 80 8C1h 9183
bmim[BF
4
]7100 8C 30 min 92 87
bmim[PF
6
]7100 8C 30 min 90 87
CNSP H
2
O808C5h 8488
BDMPEAB 7100 8C 45 min 98 90
NH
4
Br 7100 8C 45 min 89 90
77100 8C 45 min 83 90
PPAA EtOAc D6 h 74 91
KHSO
4
ethylene glycol 100 8C 0.5±2h 92 92
ZrCl
4
EtOH D6 h 88 98
E2+A34+U1*7765 8C3h 9697
E2+A34+U2 Dowex-50W 7130 8C3h 6984
ZnBr
2
(CH
2
Cl)
2
D24 h 89 96
E2+A34+U9 Dowex-50W 7130 8C3h 6584
E2+A34+U10 I
2
MeCN D7 h 90 18
InBr
3
EtOH D7 h 70 66
H
3
PW
12
O
40
MeCN 80 8C1h 8683
H
3
PMo
12
O
40
MeCN 80 8C1h 8083
H
4
SiW
12
O
40
MeCN 80 8C1h 8783
E2+A35+U1 Cu(OTf)
2
MeCN 60 8C9h 7070
E2+A37+U1 FeCl
3.
6H
2
O, HCl EtOH D4 h 61 23
New potential of the classical Biginelli reaction 1037

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A37+U1 NiCl
2.
6H
2
O, HCl EtOH D5 h 58 23
InCl
3
THF D7 h 91 26
LaCl
3.
7H
2
O, HCl EtOH D5 h 76 63
LiBr MeCN D4.75 h 82 68
NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 91 69
Cu(OTf)
2
MeCN 50 8C6h8070
H
3
BO
3
AcOH 100 8C 0.5±2h 86 74
I
2
MeCN D8 h 71 75
H
3
PW
12
O
40
MeCN 80 8C1h5283
H
3
PMo
12
O
40
MeCN 80 8C1h5783
H
4
SiW
12
O
40
MeCN 80 8C1h6083
Yb(OTf)
3
THF stirring 786 89
KHSO
4
ethylene glycol 100 8C 0.5±2h 86 92
E2+A38+U1 SSA EtOH D6 h 93 20
InCl
3
THF D9 h 88 26
InBr
3
EtOH D7 h 90 66
LiBr MeCN D5 h 88 68
H
3
PW
12
O
40
MeCN 80 8C1h7383
H
3
PMo
12
O
40
MeCN 80 8C1h7083
H
4
SiW
12
O
40
MeCN 80 8C1h7183
Yb(OTf)
3
THF stirring 781 89
E2+A38+U1*7765 8C3h9197
E2+A38+U9 Dowex-50W 7130 8C3h3884
E2+A38+U10 PPE 7mn 10 ± 20 s 60 12
I
2
MeCN D8 h 76 18
Yb(OTf)
3
EtOH 100 8C 20 min 45 27
(TMS)OTf MeCN room temperature, stirring 15 min 95 32
RuCl
3
7100 8C 65 min 89 81
H
3
PW
12
O
40
MeCN 80 8C1h7183
H
3
PMo
12
O
40
MeCN 80 8C1h6883
H
4
SiW
12
O
40
MeCN 80 8C1h6283
Yb(OTf)
3
THF stirring 780 89
E2+A38+U10*7765 8C3h9097
E2+A39+U1 Mont. KSF 7130 8C 48 h 88 14
TsOH H
2
O stirring 15 min 92 19
FeCl
3.
6H
2
O, HCl EtOH D4 h 84 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 84 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 87 23
InCl
3
THF D8 h 91 26
Mn(OAc)
3.
2H
2
O MeCN D4 h 79 29
LaCl
3.
7H
2
O, HCl EtOH D5 h 89 63
InBr
3
EtOH D7 h 93 66
NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 92 69
Cu(OTf)
2
MeCN 40 8C5h9070
H
3
BO
3
AcOH 100 8C 0.5±2h 89 74
ZnCl
2
780 8C 50 min 73 75
PABC EtOH D5 h 92 76
Cu(NTf
2
)
2
H
2
O stirring 24 h 71 78
Sr(OTf)
2
770 8C4h8879
RuCl
3
7100 8C 85 min 84 81
PhB(OH)
2
MeCN D18 h 91 85
VCl
3
MeCN D2 h 92 86
BDMPEAB 7100 8C 55 min 98 90
NH
4
Br 7100 8C 55 min 86 90
77100 8C 55 min 77 90
PPAA EtOAc D6 h 44 91
KHSO
4
ethylene glycol 100 8C 0.5±2h 87 92
ZrCl
4
EtOH D5 h 98 98
E2+A39+U10 Bi(OTf)
3
MeCN stirring 2.5 h 87 31
PABC EtOH D6 h 82 76
Sr(OTf)
2
770 8C4h8779
CH
2
ClCO
2
H790 8C5h7982
1038 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A39+U10 ZrCl
4
EtOH D6 h 80 98
VCl
3
MeCN D2 h 86 86
E2+A40+U1 Mn(OAc)
3.
2H
2
O MeCN D3 h 85 29
Cu(OTf)
2
MeCN 50 8C6h8570
E2+A41+U1 Cu(OTf)
2
MeCN 70 8C9h6570
E2+A42+U1 Cu(OTf)
2
MeCN 70 8C9h8070
E2+A43+U1 SSA EtOH D6 h 92 14
PPAA EtOAc D6 h 86 91
E2+A43+U1*7765 8C2h9697
E2+A44+U1 Yb
III
-Resin 7120 8C 48 h 68 16
I
2
PhMe D4 h 95 17
InCl
3
THF D9 h 90 26
Bi(OTf)
3
MeCN stirring 3 h 85 31
77100 ± 105 8C1h 8236
Sr(OTf)
2
770 8C4h9479
RuCl
3
7100 8C 55 min 87 81
PPAA EtOAc D6 h 81 91
E2+A44+U10 InCl
3
THF D9 h 90 26
77100 ± 105 8C1h 8236
RuCl
3
7100 8C 50 min 89 81
E2+A45+U1 CeCl
3.
7H
2
O EtOH D2.5 h 95 10
CeCl
3.
7H
2
OH
2
OD3 h 90 10
CeCl
3.
7H
2
O7D 10 h 80 10
Mont. KSF 7130 8C 48 h 79 14
Mont. KSF MeOH D8 ± 10 h 82 15
Yb
III
-Resin 7120 8C 48 h 72 16
I
2
PhMe D3.8 h 91 17
I
2
MeCN D6.5 h 87 18
TsOH H
2
O stirring 15 min 94 19
SSA EtOH D6 h 95 20
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 85 21
H
2
SO
4
EtOH D18 h 37 21
FeCl
3.
6H
2
O, HCl EtOH D4 h 94 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 94 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 90 23
InCl
3
THF D9 h 90 26
Bi(OTf)
3
MeCN stirring 1.5 h 95 31
(TMS)OTf MeCN room temperature, stirring 15 min 95 32
77100 ± 105 8C1h 8336
TAFF 7IR 2 h 62 45
Yb(OTf)
3
7100 8C 20 min 96 62
LaCl
3.
7H
2
O, HCl EtOH D5 h 93 63
FSA EtOH D84 h 61 65
InBr
3
EtOH D7 h 97 66
(TMS)Cl, NaI MeCN stirring 40 min 90 67
LiBr MeCN D3.25 h 94 68
NH
2
SO
3
H EtOH US, 20 ± 30 8C 30 min 62 69
Cu(OTf)
2
MeCN 40 8C5h9070
NH
4
Cl 7100 8C3h8471
CuCl
2.
2H
2
O7100 8C 60 min 96 73
CuCl
2.
2H
2
O7mn 1.5 min 99 73
CuSO
4.
5H
2
O7100 8C 70 min 96 73
CuSO
4.
5H
2
O7mn 1.5 min 99 73
PABC EtOH D2 h 98 76
CdCl
2
MeCN D4.3 h 81 77
RuCl
3
7100 8C 45 min 93 81
CH
2
ClCO
2
H790 8C3h9582
H
3
PW
12
O
40
MeCN 80 8C1h9683
H
3
PMo
12
O
40
MeCN 80 8C1h9183
New potential of the classical Biginelli reaction 1039

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A45+U1 H
4
SiW
12
O
40
MeCN 80 8C1h 9283
PhB(OH)
2
MeCN D18 h 97 85
VCl
3
MeCN D2 h 90 86
bmim[BF
4
]7100 8C 30 min 95 87
bmim[PF
6
]7100 8C 30 min 98 87
CNSP H
2
O808C5h 8688
BDMPEAB 7100 8C 45 min 96 90
NH
4
Br 7100 8C 45 min 88 90
77100 8C 45 min 75 90
PPAA EtOAc D6 h 59 91
ZrCl
4
EtOH D5 h 97 98
E2+A45+U1*7765 8C 2.5 h 89 97
E2+A45+U9 Dowex-50W 7130 8C3h 5684
E2+A45+U10 I
2
MeCN D6 h 87 18
TAFF 7IR 2 h 58 45
LaCl
3.
7H
2
O, HCl EtOH D5 h 85 63
InBr
3
EtOH D7 h 98 66
LiBr MeCN D3.5 h 88 68
NH
4
Cl 7100 8C3h 8671
PABC EtOH D5 h 85 76
CH
2
ClCO
2
H790 8C5h 8682
H
3
PW
12
O
40
MeCN 80 8C1h 9783
H
3
PMo
12
O
40
MeCN 80 8C1h 9183
H
4
SiW
12
O
40
MeCN 80 8C1h 9383
PhB(OH)
2
MeCN D18 h 75 85
E2+A45+U14 7EtOH mn,D6 min 75.2 38
E2+A46+U1 Mn(OAc)
3.
2H
2
O MeCN D3 h 82 29
RuCl
3
7100 8C 40 min 92 81
E2+A47+U1 BDMPEAB 7100 8C 35 min 93 90
NH
4
Br 7100 8C 35 min 84 90
77100 8C 35 min 84 90
E2+A48+U1 PPE THF D24 h 75 7
SSA EtOH D6 h 94 20
Yb(OTf)
3
EtOH 100 8C 10 min 52 27
LiClO
4
or LiOTf MeCN D8 h 87 28
Mn(OAc)
3.
2H
2
O MeCN D3.5 h 94 29
CAN MeOH US 4.5 h 92 35
LiBr MeCN D3 h 93 68
Cu(OTf)
2
MeCN 50 8C6h 8570
I
2
MeCN D6 h 87 75
CdCl
2
MeCN D4.3 h 90 77
BDMPEAB 7100 8C 35 min 97 90
NH
4
Br 7100 8C 35 min 93 90
77100 8C 35 min 72 90
PPAA EtOAc D6 h 47 91
E2+A49+U1 I
2
PhMe D3.7 h 92 17
E2+A50+U1 I
2
PhMe D3.8 h 94 17
Bi(OTf)
3
MeCN stirring 1 h 89 31
CAN MeOH US 3.5 h 90 35
Cu(OTf)
2
MeCN 50 8C6h 8570
CdCl
2
MeCN D4 h 91 77
E2+A50+U1*7765 8C2h 9091
E2+A50+U9 Dowex-50W 7130 8C3h 4884
E2+A52+U1 I
2
MeCN D8 h 90 18
FeCl
3.
6H
2
O, HCl EtOH D4 h 86 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 86 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 88 23
Yb(OTf)
3
EtOH 100 8C 15 min 46 27
Mn(OAc)
3.
2H
2
O MeCN D4 h 76 29
77100± 105 8C1h 8536
1040 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A52+U1 LaCl
3.
7H
2
O, HCl EtOH D5 h 92 63
LiBr MeCN D3 h 91 68
NH
2
SO
3
H EtOH US, 20 ± 30 8C 30 min 96 69
Cu(OTf)
2
MeCN 50 8C6h 8570
Sr(OTf)
2
770 8C4h 9579
BDMPEAB 7100 8C 35 min 96 90
NH
4
Br 7100 8C 35 min 91 90
77100 8C 35 min 73 90
E2+A52+U10 I
2
MeCN D7.5 h 88 18
E2+A55+U1 LiClO
4
or LiOTf MeCN D8 h 90 28
E2+A56+U1 Cu(OTf)
2
MeCN 50 8C6h 8070
E2+A57+U1 LiClO
4
or LiOTf MeCN D6 h 90 28
PABC EtOH D4 h 96 76
CdCl
2
MeCN D4 h 89 77
VCl
3
MeCN D2 h 92 86
BDMPEAB 7100 8C 60 min 97 90
NH
4
Br 7100 8C 60 min 92 90
77100 8C 60 min 84 90
ZrCl
4
EtOH D4 h 96 98
E2+A59+U1 Yb(OTf)
3
AcOH+EtOH 120 8C 20 min 49 27
7EtOH mn,D6 min 80 38
Yb(OTf)
3
THF stirring 780 89
E2+A60+U1 Yb
III
-Resin 7120 8C 48 h 68 16
SSA EtOH D6 h 92 20
7EtOH mn,D6 min 86 38
Yb(OTf)
3
7100 8C 20 min 94 62
VCl
3
MeCN D2 h 88 86
ZrCl
4
EtOH D5 h 95 98
E2+A60+U1*7765 8C3h 9097
E2+A60+U12 7EtOH mn,D6 min 88 38
E2+A60+U13 7EtOH mn,D10 min 65 38
E2+A61+U1 PPE THF D24 h 84 7
PPE 7mn90 s 87 11
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 81 21
H
2
SO
4
EtOH D18 h 66 21
Yb(OTf)
3
EtOH 100 8C 10 min 61 27
E2+A62+U1 PPE THF D24 h 83 7
PPE 7mn90 s 95 11
Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 68 27
Mn(OAc)
3.
2H
2
O MeCN D2.5 h 76 29
TAFF 7IR 2 h 60 45
InBr
3
EtOH D7 h 75 66
Cu(OTf)
2
MeCN 50 8C9h 7070
NH
4
Cl 7100 8C3h 8571
H
3
BO
3
AcOH 100 8C 0.5±2h 93 74
ZnCl
2
780 8C 40 min 41 75
Cu(NTf
2
)
2
H
2
O stirring 24 h 34 78
Yb(NTf
2
)
2
H
2
O stirring 24 h 38 78
Ni(NTf
2
)
2
H
2
O stirring 24 h 25 78
Sr(OTf)
2
770 8C4h 8879
H
3
PW
12
O
40
MeCN 80 8C1h 9183
H
3
PMo
12
O
40
MeCN 80 8C1h 8983
H
4
SiW
12
O
40
MeCN 80 8C1h 8983
Yb(OTf)
3
THF stirring 773 89
PPAA EtOAc D6 h 86 91
KHSO
4
ethylene glycol 100 8C 0.5±2h 91 92
E2+A62+U10 TAFF 7IR 2 h 60 45
Yb(OTf)
3
THF stirring 778 89
New potential of the classical Biginelli reaction 1041

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A63+U1 FeCl
3.
6H
2
O, HCl EtOH D4 h 82 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 82 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 95 23
E2+A63+U1 LaCl
3.
7H
2
O, HCl EtOH D5 h 87 63
InBr
3
EtOH D7 h 70 66
NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 94 69
Cu(OTf)
2
MeCN 60 8C9h 8070
H
3
PW
12
O
40
MeCN 80 8C1h 9083
H
3
PMo
12
O
40
MeCN 80 8C1h 9083
H
4
SiW
12
O
40
MeCN 80 8C1h 8783
PhB(OH)
2
MeCN D18 h 76 85
PPAA EtOAc D6 h 86 91
E2+A64+U1 Mont. KSF 7130 8C 48 h 76 14
Mont. KSF MeOH D8 ± 10 h 89 15
Yb
III
-Resin 7120 8C 48 h 65 16
I
2
MeCN D8 h 91 18
TsOH H
2
O stirring 15 min 90 19
SSA EtOH D6 h 95 20
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 92 21
H
2
SO
4
EtOH D18 h 56 21
FeCl
3.
6H
2
O, HCl EtOH D4 h 93 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 93 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 82 23
InCl
3
THF D6.5 h 92 26
Mn(OAc)
3.
2H
2
O MeCN D3.5 h 78 29
Bi(OTf)
3
MeCN stirring 1 h 93 31
CAN MeOH US 4 h 89 35
77100± 105 8C1h 8536
Yb(OTf)
3
7100 8C 20 min 97 62
LaCl
3.
7H
2
O, HCl EtOH D5 h 92 63
FSA EtOH D84 h 34 65
InBr
3
EtOH D7 h 86 66
(TMS)Cl, NaI MeCN stirring 30 min 92 67
LiBr MeCN D4.5 h 86 68
NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 94 69
Cu(OTf)
2
MeCN 50 8C4h 8570
NH
4
Cl 7100 8C3h 8371
CuCl
2.
2H
2
O7100 8C 60 min 97 73
CuCl
2.
2H
2
O7mn1 min 96 73
CuSO
4.
5H
2
O7100 8C 60 min 97 73
CuSO
4.
5H
2
O7mn1 min 96 73
ZnCl
2
780 8C 10 min 71 75
PABC EtOH D5 h 88 76
CdCl
2
MeCN D5 h 89 77
Cu(NTf
2
)
2
H
2
O stirring 24 h 74 78
Sr(OTf)
2
770 8C4h 9579
RuCl
3
7100 8C 40 min 87 81
CH
2
ClCO
2
H790 8C3h 9882
H
3
PW
12
O
40
MeCN 80 8C1h 9183
H
3
PMo
12
O
40
MeCN 80 8C1h 8783
H
4
SiW
12
O
40
MeCN 80 8C1h 9283
VCl
3
MeCN D2 h 90 86
bmim[BF
4
]7100 8C 30 min 96 87
bmim[PF
6
]7100 8C 30 min 98 87
BDMPEAB 71008C 25 min 87 90
NH
4
Br 7100 8C 25 min 81 90
77100 8C 25 min 72 90
PPAA EtOAc D6 h 69 91
KHSO
4
ethylene glycol 100 8C 0.5±2h 93 92
ZrCl
4
EtOH D6 h 95 98
1042 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A64+U1*7765 8C 3.5 h 95 97
E2+A64+U10 I
2
MeCN D7 h 88 18
LiBr MeCN D4 h 81 68
CuCl
2.
2H
2
O7100 8C 75 min 95 73
CuCl
2.
2H
2
O7mn1.5 min 97 73
Sr(OTf)
2
770 8C4h 9379
RuCl
3
7100 8C 60 min 91 81
CH
2
ClCO
2
H790 8C5h 8782
H
3
PW
12
O
40
MeCN 80 8C1h 8583
H
3
PMo
12
O
40
MeCN 80 8C1h 8183
H
4
SiW
12
O
40
MeCN 80 8C1h 8083
E2+A65+U1 PPE THF D24 h 79 7
PPE 7mn90 s 711
H
3
BO
3
AcOH 100 8C 0.5±2h 93 74
E2+A66+U1 FeCl
3.
6H
2
O, HCl EtOH D4 h 92 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 91 23
Yb(OTf)
3
7100 8C 20 min 89 62
LaCl
3.
7H
2
O, HCl EtOH D5 h 93 63
NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 86 69
H
3
BO
3
AcOH 100 8C 0.5±2h 94 74
CdCl
2
MeCN D5 h 93 77
CH
2
ClCO
2
H790 8C3h 8982
KHSO
4
ethylene glycol 100 8C 0.5±2h 91 92
E2+A67+U1 LiClO
4
or LiOTf MeCN D10 h 85 28
CAN MeOH US 5 h 90 35
PhB(OH)
2
MeCN D18 h 78 85
PPAA EtOAc D6 h 77 91
E2+A68+U1 PhB(OH)
2
MeCN D18 h 80 85
E2+A69+U1 Yb
III
-Resin 7120 8C 48 h 63 16
Yb(OTf)
3
MeCN mn, 120 8C 15 min 73 39
Yb(OTf)
3
7100 8C 40 min 97 62
E2+A70+U1 I
2
PhMe D3.6 h 91 17
FeCl
3.
6H
2
O, HCl EtOH D4 h 83 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 83 23
NiCl
2.
6H
2
O, HCl EtOH D5 h 94 23
Yb(OTf)
3
MeCN mn, 120 8C 15 min 85 39
LaCl
3.
7H
2
O, HCl EtOH D5 h 97 63
E2+A71+U1 I
2
PhMe D4 h 90 17
Yb(OTf)
3
MeCN mn, 120 8C 15 min 77 39
Yb(OTf)
3
THF stirring 782 89
BDMPEAB 7100 8C 60 min 92 90
NH
4
Br 7100 8C 60 min 87 90
77100 8C 60 min 75 90
E2+A71+U9 Dowex-50W 7130 8C3h 4284
E2+A73+U1 LiClO
4
or LiOTf MeCN D8 h 87 28
77100± 105 8C1h 8336
(TMS)Cl, NaI MeCN stirring 30 min 84 67
Cu(OTf)
2
MeCN 50 8C6h 8570
PABC EtOH D5 h 88 76
RuCl
3
7100 8C 70 min 86 81
H
3
PW
12
O
40
MeCN 80 8C1h 7783
H
3
PMo
12
O
40
MeCN 80 8C1h 7983
H
4
SiW
12
O
40
MeCN 80 8C1h 7083
E2+A73+U3 Yb(OTf)
3
EtOH 100 8C 10 min 41 27
E2+A74+U1 CAN MeOH US 4.5 h 84 35
CdCl
2
MeCN D4.3 h 89 77
E2+A75+U1 LiClO
4
or LiOTf MeCN D12 h 81 28
E2+A76+U1 I
2
MeCN D7 h 84 18
FeCl
3.
6H
2
O, HCl EtOH D4 h 82 22
FeCl
3.
6H
2
O, HCl EtOH D4 h 82 23
New potential of the classical Biginelli reaction 1043

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A76+U1 NiCl
2.
6H
2
O, HCl EtOH D5 h 82 23
LiClO
4
or LiOTf MeCN D7 h 90 28
77100± 105 8C1h 8536
LaCl
3.
7H
2
O, HCl EtOH D5 h 91 63
LiBr MeCN D3.5 h 91 68
NH
2
SO
3
H EtOH US, 20 ± 30 8C 50 min 89 69
Cu(OTf)
2
MeCN 50 8C6h 8570
H
3
BO
3
AcOH 100 8C 0.5±2h 90 74
ZnCl
2
780 8C 40 min 62 75
CdCl
2
MeCN D5 h 86 77
VCl
3
MeCN D2 h 85 86
KHSO
4
ethylene glycol 100 8C 0.5±2h 90 92
E2+A76+U10 LiBr MeCN D3.5 h 87 68
E2+A77+U1 InBr
3
EtOH D7 h 86 99
InCl
3.
4H
2
O EtOH D7 h 69 99
E2+A77+U10 InCl
3.
4H
2
O EtOH D10 h 79 99
E2+A78+U1 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 63 43
E2+A79+U1 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 65 43
E2+A80+U1 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 57 43
E2+A81+U1 LiBr MeCN D3.5 h 94 68
CdCl
2
MeCN D5 h 87 77
E2+A82+U1 Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 30 27
CdCl
2
MeCN D4 h 80 77
E2+A83+U10 EtOH 7mn>24 min 41 42
Al
2
O
3
7mn10 min 82 42
77mn4 min 84 42
E2+A84+U1 I
2
MeCN D7.5 h 72 18
NiCl
2.
6H
2
O, HCl EtOH D5 h 56 23
Yb(OTf)
3
EtOH 100 8C 20 min 50 27
LiClO
4
or LiOTf MeCN D5 h 85 28
Bi(OTf)
3
MeCN stirring 4 h 90 31
CAN MeOH US 3 h 87 35
LaCl
3.
7H
2
O, HCl EtOH D5 h 67 63
InBr
3
EtOH D7 h 95 66
LiBr MeCN D4.5 h 85 68
NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 87 69
Cu(OTf)
2
MeCN 70 8C6h 7070
CuCl
2.
2H
2
O7100 8C 60 min 80 73
CuCl
2.
2H
2
O7mn1.5 min 82 73
CuSO
4.
5H
2
O7100 8C 70 min 80 73
CuSO
4.
5H
2
O7mn1.5 min 82 73
ZnCl
2
780 8C 10 min 77 75
PABC EtOH D4 h 85 76
CdCl
2
MeCN D3 h 90 77
Sr(OTf)
2
770 8C4h 9079
RuCl
3
7100 8C 45 min 90 81
H
3
PW
12
O
40
MeCN 80 8C1h 9583
H
3
PMo
12
O
40
MeCN 80 8C1h 9083
H
4
SiW
12
O
40
MeCN 80 8C1h 9183
CNSP H
2
O808C6h 8288
Yb(OTf)
3
THF stirring 787 89
PPAA EtOAc D6 h 30 91
KHSO
4
ethylene glycol 100 8C 0.5±2h 85 92
ZrCl
4
EtOH D6 h 84 98
E2+A84+U10 7EtOH mn 3 min 42 42
Al
2
O
3
7mn8.5 min 81 42
77mn1.5 min 86 42
E2+A86+U1 Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 35 27
E2+A88+U1 PPE THF D24 h 86 7
Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 89 27
1044 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E2+A88+U1 LiClO
4
or LiOTf MeCN D5 h 90 28
CAN MeOH US 3.5 h 90 35
HCl EtOH US 2 ± 5 min 93 64
InBr
3
EtOH D7 h 90 66
(TMS)Cl, NaI MeCN stirring 45 min 87 67
CdCl
2
MeCN D5 h 80 77
H
3
PW
12
O
40
MeCN 80 8C1h 9383
H
3
PMo
12
O
40
MeCN 80 8C1h 9183
H
4
SiW
12
O
40
MeCN 80 8C1h 9283
PhB(OH)
2
MeCN D18 h 82 85
VCl
3
MeCN D2 h 87 86
CNSP H
2
O808C6h 7888
PPAA EtOAc D6 h 69 91
E2+A88+U10 InBr
3
EtOH D7 h 86 66
CuCl
2.
2H
2
O7100 8C 60 min 92 73
CuCl
2.
2H
2
O7mn1.5 min 90 73
H
3
PW
12
O
40
MeCN 80 8C1h 8983
H
3
PMo
12
O
40
MeCN 80 8C1h 8583
H
4
SiW
12
O
40
MeCN 80 8C1h 8483
E3+A18+U1 PPE THF D24 h 84 7
Yb
III
-Resin 7120848 h 78 16
Yb(OTf)
3
EtOH 100 8C 10 min 50 27
FeCl
3
, Si(OEt)
4
Pr
i
OH D3 h 85 80
E3+A30+U1 Yb
III
-Resin 7120 8C 48 h 68 16
E3+A33+U1 PPE 7mn90 s 94 11
Yb(OTf)
3
EtOH 100 8C 15 min 73 27
E3+A33+U3 Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 34 27
E3+A34+U1 Yb
III
-Resin 7120 8C 48 h 73 16
E3+A44+U1 Yb
III
-Resin 7120 8C 48 h 73 16
E3+A45+U1 Yb
III
-Resin 7120 8C 48 h 75 16
E3+A60+U1 Yb
III
-Resin 7120 8C 48 h 71 16
E3+A64+U1 Yb
III
-Resin 7120 8C 48 h 64 16
E3+A69+U1 Yb
III
-Resin 7120 8C 48 h 70 16
E4+A18+U1 PPE 7mn90 s 81 11
Yb(OTf)
3
EtOH 100 8C 10 min 49 27
FeCl
3
, Si(OEt)
4
Pr
i
OH D4 h 92 80
E4+A48+U10 CeCl
3.
7H
2
O EtOH D3 h 95 10
CeCl
3.
7H
2
OH
2
OD3 h 86 10
CeCl
3.
7H
2
O7D3 h 71 10
(TMS)OTf MeCN stirring 15 min 95 32
E4+A50+U1 CeCl
3.
7H
2
O EtOH D2.5h 95 10
CeCl
3.
7H
2
OH
2
OD2.5 h 90 10
CeCl
3.
7H
2
O7D2.5 h 80 10
(TMS)OTf MeCN stirring 15 min 95 32
E4+A85+U1 CeCl
3.
7H
2
O EtOH D3 h 93 10
CeCl
3.
7H
2
OH
2
OD3 h 85 10
CeCl
3.
7H
2
O7D3 h 70 10
(TMS)OTf MeCN stirring 15 min 93 32
E5+A18+U10 Yb(OTf)
3
MeCN mn, 120 8C 20 min 46 41
E5+A23+U10 Yb(OTf)
3
MeCN mn, 120 8C 20 min 67 41
E5+A33+U2 Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 51 27
Yb(OTf)
3
MeCN mn, 120 8C 20 min 35 41
E5+A33+U9 PPE THF D24 h 85 13
NaH Me
2
SO
4
+PhMe 70 8C6h 8513
E5+A33+U10 Yb(OTf)
3
MeCN mn, 120 8C 20 min 61 41
E5+A62+U10 Yb(OTf)
3
MeCN mn, 120 8C 20 min 37 41
E5+A64+U10 Yb(OTf)
3
MeCN mn, 120 8C 20 min 74 41
E5+A71+U1 Yb(OTf)
3
MeCN mn, 120 8C 20 min 48 41
E6+A18+U1 NH
4
Cl MeOH US, 60 8C5h 6537
New potential of the classical Biginelli reaction 1045

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E6+A33+U1 NH
4
Cl MeOH US, 60 8C 3.5 h 65 37
E7+A18+U1 Yb(OTf)
3
MeCN mn, 120 8C 20 min 62 41
NH
4
Cl 7100 8C3h 8071
FeCl
3
, Si(OEt)
4
Pr
i
OH D6 h 79 80
FeCl
3
, Si(OEt)
4
Bu
i
OH D4 h 86 80
E7+A18+U2 Yb(OTf)
3
MeCN mn, 120 8C 20 min 28 41
E7+A18+U9 PPE THF D24 h 713
NaH Me
2
SO
4
+PhMe 70 8C6h 713
E7+A23+U1 Yb(OTf)
3
MeCN mn, 120 8C 20 min 43 41
E7+A45+U1 NH
4
Cl 7100 8C3h 7571
E7+A65+U2 PPE THF D24 h 93 7
Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 25 27
E7+A65+U9 PPE THF D24 h 93 13
NaH Me
2
SO
4
+PhMe 70 8C6h 8413
E8+A18+U1 NH
4
Cl MeOH US, 60 8C 3.5 h 75 37
E8+A33+U1 NH
4
Cl MeOH US, 60 8C 3.5 h 70 37
E9+A18+U1 NH
4
Cl MeOH US, 60 8C 3.5 h 75 37
E9+A33+U1 NH
4
Cl MeOH US, 60 8C 3.5 h 73 37
E10+A18+U1 NH
4
Cl MeOH US, 60 8C 2.5 h 80 37
E10+A33+U1 NH
4
Cl MeOH US, 60 8C3h 9037
E11+A18+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 81 21
H
2
SO
4
EtOH D18 h 42 21
InCl
3
THF D6 h 95 26
E11+A18+U10 HCl EtOH D63 h 30 24
H
3
BO
3
AcOH 100 8C6h 6224
FeCl
3.
6H
2
O, HCl EtOH D5 h 38 24
E11+A21+U10 HCl EtOH D140 h 16 24
H
3
BO
3
AcOH 100 8C 6.5 h 15 24
FeCl
3.
6H
2
O, HCl EtOH D6 h 78 24
E11+A22+U10 HCl EtOH D133 h 24 24
FeCl
3.
6H
2
O, HCl EtOH D6 h 46 24
E11+A23+U10 HCl EtOH D245 h 35 24
H
3
BO
3
AcOH 100 8C7h 1424
FeCl
3.
6H
2
O, HCl EtOH D5 h 14 24
E11+A32+U10 HCl EtOH D196 h 11 24
H
3
BO
3
AcOH 100 8C7h 2424
E11+A33+U10 HCl EtOH D70 h 16 24
H
3
BO
3
AcOH 100 8C 7.5 h 62 24
FeCl
3.
6H
2
O, HCl EtOH D5.5 h 8 24
E11+A34+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 90 21
H
2
SO
4
EtOH D18 h 64 21
InCl
3
THF D6 h 91 26
77100± 105 8C1h 8336
E11+A42+U10 HCl EtOH D35 h 26 24
H
3
BO
3
AcOH 100 8C 7.5 h 93 24
FeCl
3.
6H
2
O, HCl EtOH D5 h 58 24
E11+A43+U10 HCl EtOH D35 h 17 24
H
3
BO
3
AcOH 100 8C 7.5 h 12 24
FeCl
3.
6H
2
O, HCl EtOH D3 h 52 24
E11+A45+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 85 21
H
2
SO
4
EtOH D18 h 25 21
InCl
3
THF D8 h 91 26
E11+A54+U10 HCl EtOH D56 h 29 24
H
3
BO
3
AcOH 100 8C 8.5 h 21 24
E11+A58+U10 HCl EtOH D70 h 8 24
H
3
BO
3
AcOH 100 8C 8.5 h 17 24
E11+A59+U10 HCl EtOH D126 h 10 24
FeCl
3.
6H
2
O, HCl EtOH D5 h 77 24
1046 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E11+A61+U1 PPE 7mn90 s 65 11
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 82 21
H
2
SO
4
EtOH D18 h 55 21
Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 64 27
E11+A62+U10 HCl EtOH D105 h 12 24
H
3
BO
3
AcOH 100 8C 8.5 h 30 24
FeCl
3.
6H
2
O, HCl EtOH D5.5 h 26 24
E11+A63+U10 HCl EtOH D175 h 36 24
FeCl
3.
6H
2
O, HCl EtOH D5 h 42 24
E11+A64+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 89 21
H
2
SO
4
EtOH D18 h 66 21
InCl
3
THF D7 h 92 26
77100± 105 8C1h 8536
E11+A64+U10 HCl EtOH D112 h 26 24
H
3
BO
3
AcOH 100 8C9h 1224
E11+A65+U2 Yb(OTf)
3
EtOH 100 8C 10 min 26 27
E11+A70+U10 HCl EtOH D154 h 21 24
FeCl
3.
6H
2
O, HCl EtOH D5 h 69 24
E11+A71+U10 HCl EtOH D105 h 12 24
H
3
BO
3
AcOH 100 8C8h 2124
E12+A18+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 83 21
H
2
SO
4
EtOH D18 h 41 21
InCl
3
THF D7 h 89 26
77100± 105 8C1h 8136
E12+A34+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 90 21
H
2
SO
4
EtOH D18 h 44 21
InCl
3
THF D6 h 90 26
77100± 105 8C1h 8536
E12+A45+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 79 21
H
2
SO
4
EtOH D18 h 40 21
InCl
3
THF D8 h 85 26
E12+A48+U1 CeCl
3.
7H
2
O EtOH D3 h 91 10
CeCl
3.
7H
2
OH
2
OD3 h 89 10
CeCl
3.
7H
2
O7D3 h 73 10
(TMS)OTf MeCN stirring 15 min 91 32
E12+A61+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 82 21
H
2
SO
4
EtOH D18 h 61 21
E12+A64+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 84 21
H
2
SO
4
EtOH D18 h 46 21
InCl
3
THF D6 h 92 26
E13+A18+U1 Mont. KSF MeOH D8 ± 10 h 80 15
InCl
3
THF D9 h 84 26
LiClO
4
or LiOTf MeCN D10 h 75 28
E13+A34+U1 Yb(OTf)
3
EtOH 100 8C 10 min 41 27
E14+A18+U1 CNSP H
2
O808C 10 h 55 88
E14+A60+U1 CNSP H
2
O808C 10 h 51 88
E15+A18+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 85 6,
21
H
2
SO
4
EtOH D18 h 32 21
E16+A18+U1 Mont. KSF 7130 8C 48 h 75 14
SSA EtOH D6 h 87 20
BF
3.
OEt
2
, CuCl, AcOH THF D18 h 70 21
H
2
SO
4
EtOH D18 h 10 21
(TMS)Cl, NaI MeCN stirring 40 min 83 67
NH
4
Cl 7100 8C3h 7771
Pro-Me
.
HCl EtOH D18 h 10 95
E16+A18+U1*7765 8C4h 9197
E16+A18+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 91 96
E16+A23+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 81 96
New potential of the classical Biginelli reaction 1047

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
E16+A27+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 85 96
E16+A33+U1 Yb(OTf)
3
AcOH+EtOH 120 8C 20 min 40 27
E16+A34+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 97 96
E16+A34+U9 Dowex-50W 7130 8C3h 5584
E16+A51+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 93 96
E16+A64+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 94 96
E16+A73+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 90 96
E16+A88+U2 ZnBr
2
(CH
2
Cl)
2
D24 h 91 96
E17+A18+U1 Yb(OTf)
3
MeCN mn, 120 8C 20 min 17 41
E18+A18+U1 Yb
III
-Resin 7120 8C 48 h 80 16
E18+A44+U1 Yb
III
-Resin 7120 8C 48 h 70 16
E18+A45+U1 Yb
III
-Resin 7120 8C 48 h 75 16
E18+A60+U1 Yb
III
-Resin 7120 8C 48 h 73 16
E19+A33+U1 Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 35 27
E19+A61+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 42 6
E19+A84+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 31 6
E20+A18+U1 BF
3.
OEt
2
, CuCl, AcOH THF D18 h 39 6
E21+A23+U1 CAN MeOH US 5 h 88 35
E21+A45+U1 CAN MeOH US 4 h 88 35
E21+A76+U1 CAN MeOH US 4.5 h 90 35
E25+A18+U1 HCl dioxane 85 ± 90 8C1h 6059
E25+A23+U1 HCl dioxane 85 ± 90 8C1h 7259
E25+A33+U1 HCl dioxane 85 ± 90 8C1h 2759
E25+A60+U1 HCl dioxane 85 ± 90 8C1h 6859
E25+A61+U1 HCl dioxane 85 ± 90 8C1h 7059
E25+A62+U1 HCl dioxane 85 ± 90 8C1h 6559
E25+A65+U1 HCl dioxane 85 ± 90 8C1h 3259
E25+A73+U1 HCl dioxane 85 ± 90 8C1h 6459
E27+A18+U1 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 92 43
E27+A78+U1 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 42 43
E28+A18+U1 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 75 43
E28+A79+U1 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 35 43
E29+A18+U1 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 70 43
E29+A80+U1 BF
3.
OEt
2
, CuCl, AcOH THF D24 h 36 43
E30+A64+U1 [pyrH]OTs 77761 100
E33+A18+U1 VCl
3
MeCN D2 h 90 86
E33+A32+U1 VCl
3
MeCN D2 h 82 86
E33+A57+U1 VCl
3
MeCN D2 h 86 86
E33+A64+U1 VCl
3
MeCN D2 h 85 86
E34+A18+U1 VCl
3
MeCN D2 h 86 86
E34+A39+U1 VCl
3
MeCN D2 h 85 86
E34+A60+U1 VCl
3
MeCN D2 h 75 86
E34+A64+U1 VCl
3
MeCN D2 h 82 86
K1+A18+U1 Mont. KSF 7130 8C 48 h 74 14
Yb
III
-Resin 7120 8C 48 h 71 16
I
2
MeCN D6 h 85 18
SSA EtOH D6 h 87 20
InCl
3
THF D7 h 94 26
Yb(OTf)
3
EtOH 100 8C 10 min 53 27
LiClO
4
or LiOTf MeCN D7 h 88 28
[NHEt
3
][PF
6
]7120 ± 125 8C1h 8834
77100 ± 105 8C1h 8536
Yb(OTf)
3
7100 8C 20 min 94 62
(TMS)Cl, NaI MeCN stirring 50 min 85 67
NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 96 69
NH
4
Cl 7100 8C3h 7971
CuCl
2.
2H
2
O7100 8C 60 min 96 73
CuCl
2.
2H
2
O7mn2 min 98 73
1048 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
K1+A18+U1 CuSO
4.
5H
2
O7100 8C 70 min 96 73
CuSO
4.
5H
2
O7mn2 min 98 73
ZnCl
2
780 8C 10 min 80 75
CH
2
ClCO
2
H790 8C3h 8882
H
3
PW
12
O
40
MeCN 80 8C1h 9383
H
3
PMo
12
O
40
MeCN 80 8C1h 8983
H
4
SiW
12
O
40
MeCN 80 8C1h 9083
VCl
3
MeCN D2 h 85 86
bmim[BF
4
]7100 8C 30 min 99 87
CNSP H
2
O808C5h 7888
Pro-Me
.
HCl EtOH D18 h 66 95
K1+A18+U1*7765 8C2h 8797
K1+A18+U10 I
2
MeCN D6 h 86 18
SSA EtOH D6 h 93 20
InCl
3
THF D7 h 92 26
bmim[Al
2
Cl
7
]7120 ± 125 8C1h 8034
77100 ± 105 8C1h 8136
ZnCl
2
780 8C 60 min 89 75
VCl
3
MeCN D2 h 80 86
PPAA EtOAc D6 h 72 91
K1+A18+U10*7765 8C2h 9297
K1+A19+U1 ZnCl
2
780 8C 60 min 48 75
K1+A21+U1 (TMS)Cl, NaI MeCN stirring 45 min 90 67
K1+A22+U1 Yb(OTf)
3
EtOH 100 8C 10 min 68 27
K1+A23+U1 CuCl
2.
2H
2
O7100 8C 65 min 93 73
CuCl
2.
2H
2
O7mn1.5 min 95 73
K1+A32+U1 (TMS)Cl, NaI MeCN stirring 1 h 86 67
VCl
3
MeCN D2 h 80 86
K1+A33+U1 [NHEt
3
][PF
6
]7120 ± 125 8C1h 8634
K1+A34+U1 I
2
MeCN D8 h 85 18
SSA EtOH D6 h 92 20
Yb(OTf)
3
7100 8C 20 min 90 62
NH
2
SO
3
H EtOH US, 20 ± 30 8C 50 min 92 69
NH
4
Cl 7100 8C3h 8371
CuCl
2.
2H
2
O7100 8C 60 min 80 73
CuCl
2.
2H
2
O7mn1.5 min 80 73
CuSO
4.
5H
2
O7100 8C 70 min 80 73
CuSO
4.
5H
2
O7mn1.5 min 80 73
H
3
BO
3
AcOH 100 8C 0.5±2h 92 74
ZnCl
2
780 8C 30 min 78 75
H
3
PW
12
O
40
MeCN 80 8C1h 7183
H
3
PMo
12
O
40
MeCN 80 8C1h 7083
H
4
SiW
12
O
40
MeCN 80 8C1h 7283
bmim[BF
4
]7100 8C 30 min 92 87
KHSO
4
ethylene glycol 100 8C 0.5±2h 91 92
K1+A34+U1*7765 8C3h 9097
K1+A34+U10 [NHEt
3
][PF
6
]7120 ± 125 8C1h 7434
bmim[AlCl
4
]7120 ± 125 8C1h 7034
K1+A39+U1 ZnCl
2
780 8C 30 min 85 75
VCl
3
MeCN D2 h 82 86
K1+A44+U1 Yb
III
-Resin 7120 8C 48 h 65 16
InCl
3
THF D9 h 92 26
PPAA EtOAc D6 h 60 91
K1+A45+U1 Yb
III
-Resin 7120 8C 48 h 71 16
I
2
MeCN D7 h 83 18
SSA EtOH D6 h 86 20
InCl
3
THF D9 h 91 26
Yb(OTf)
3
7100 8C 20 min 91 62
(TMS)Cl, NaI MeCN stirring 40 min 90 67
New potential of the classical Biginelli reaction 1049

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
K1+A45+U1 NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 97 69
NH
4
Cl 7100 8C3h 8671
H
3
BO
3
AcOH 100 8C 0.5±2h 93 74
CH
2
ClCO
2
H790 8C3h 9482
H
3
PW
12
O
40
MeCN 80 8C1h 9183
H
3
PMo
12
O
40
MeCN 80 8C1h 8783
H
4
SiW
12
O
40
MeCN 80 8C1h 8683
VCl
3
MeCN D2 h 88 86
KHSO
4
ethylene glycol 100 8C 0.5±2h 91 92
Pro-Me
.
HCl EtOH D18 h 22 95
K1+A45+U1*7765 8C3h 8197
K1+A57+U1 VCl
3
MeCN D2 h 85 86
K1+A60+U1 Yb
III
-Resin 7120 8C 48 h 70 16
VCl
3
MeCN D2 h 80 86
K1+A60+U10 [NHEt
3
][PF
6
]7120 ± 125 8C1h 8934
bmim[AlCl
4
]7120 ± 125 8C1h 7234
K1+A63+U1 PPAA EtOAc D6 h 64 91
K1+A64+U1 NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 92 69
ZnCl
2
780 8C 13 min 78 75
CH
2
ClCO
2
H790 8C3h 9782
VCl
3
MeCN D2 h 86 86
K1+A64+U10 [NHEt
3
][PF
6
]7120 ± 125 8C1h 8634
bmim[Al
2
Cl
7
]7120 ± 125 8C1h 7434
VCl
3
MeCN D2 h 82 86
K1+A66+U1 NH
2
SO
3
H EtOH US, 20 ± 30 8C 40 min 85 69
K1+A82+U1 InCl
3
THF D6 h 93 26
77100 ± 105 8C1h 8136
K1+A84+U1 InCl
3
THF D8 h 90 26
77100 ± 105 8C1h 8036
ZnCl
2
780 8C 10 min 78 75
K1+A88+U1 bmim[Al
2
Cl
7
]7120 ± 125 8C1h 8034
K4+A18+U1 InBr
3
EtOH D14 h 86 99
K4+A18+U10 InBr
3
EtOH D12 h 96 99
K4+A23+U1 InBr
3
EtOH D36 h 73 99
InCl
3.
4H
2
O EtOH D14 h 82 99
K4+A34+U1 InCl
3.
4H
2
O EtOH D36 h 70 99
K4+A64+U1 InBr
3
EtOH D36 h 62 99
K5+A18+U1 Mont. KSF 7130 8C 48 h 74 14
I
2
MeCN D6 h 85 18
InCl
3
THF D9 h 88 26
77100 ± 105 8C1h 8336
K5+A18+U10 InCl
3
THF D8 h 90 26
77100 ± 105 8C1h 8036
K5+A34+U9 Dowex-50W 7130 8C3h 5084
K5+A45+U1 InCl
3
THF D9 h 90 26
77100 ± 105 8C1h 8236
K9+A18+U1 InBr
3
EtOH D36 h 42 99
K10+A18+U1 Bi(OTf)
3
MeCN stirring 3 h 87 31
NH
4
Cl 7100 8C3h 8971
K12+A4+U1 (TMS)Cl DMF+MeCN stirring 3 h 93 101
K12+A4+U10 (TMS)Cl DMF+MeCN stirring 3 h 77 101
K12+A5+U1 (TMS)Cl DMF+MeCN stirring 3 h 82 101
K12+A6+U10 (TMS)Cl DMF+MeCN stirring 3 h 80 101
K12+A7+U1 (TMS)Cl DMF+MeCN stirring 3 h 86 101
K12+A7+U10 (TMS)Cl DMF+MeCN stirring 3 h 85 101
K12+A13+U1 (TMS)Cl DMF+MeCN stirring 3 h 83 101
K12+A18+U1 (TMS)Cl DMF+MeCN stirring 3 h 86 101
1050 S V Vdovina, V A Mamedov

Supplement 2 (continued).
Reactants Catalyst Solvent Other conditions Reaction time Yield (%) Ref.
K12+A18+U10 (TMS)Cl DMF+MeCN stirring 2 h 21 101
K12+A23+U10 (TMS)Cl DMF+MeCN stirring 2 h 11 101
K12+A33+U1 KHSO
4
ethylene glycol 100 8C 0.5±2h 92 92
(TMS)Cl DMF+MeCN stirring 2 h 90 101
K12+A33+U10 (TMS)Cl DMF+MeCN stirring 3 h 80 101
K12+A34+U1 (TMS)Cl DMF+MeCN stirring 2 h 25 101
K12+A34+U10 (TMS)Cl DMF+MeCN stirring 3 h 74 101
K12+A43+U10 (TMS)Cl DMF+MeCN stirring 2 h 85 101
K12+A58+U1 (TMS)Cl DMF+MeCN stirring 2 h 90 101
K12+A58+U10 (TMS)Cl DMF+MeCN stirring 2 h 82 101
K12+A60+U1 (TMS)Cl DMF+MeCN stirring 2 h 23 101
K12+A60+U10 (TMS)Cl DMF+MeCN stirring 3 h 76 101
K12+A62+U1 KHSO
4
ethylene glycol 100 8C 0.5±2h 91 92
K12+A64+U1 KHSO
4
ethylene glycol 100 8C 0.5±2h 93 92
K12+A64+U10 (TMS)Cl DMF+MeCN stirring 2 h 13 101
K12+A66+U1 KHSO
4
ethylene glycol 100 8C 0.5±2h 95 92
K12+A67+U1 KHSO
4
ethylene glycol 100 8C 0.5±2h 95 92
K12+A69+U1 (TMS)Cl DMF+MeCN stirring 2 h 93 101
K12+A69+U10 (TMS)Cl DMF+MeCN stirring 2 h 92 101
K12+A88+U1 [NHEt
3
][PF
6
]7120 ± 125 8C1h 6534
K13+A18+U1 VCl
3
MeCN D2 h 80 86
K13+A18+U10 H
2
SO
4
H
2
OD3 h 98 102
[NHEt
3
][BF
4
]7120 ± 125 8C1h 7034
K13+A31+U1 H
2
SO
4
H
2
OD3 h 95 102
K13+A31+U10 H
2
SO
4
H
2
OD3 h 94 102
K13+A32+U1 VCl
3
MeCN D2 h 80 86
K13+A34+U10 [NHEt
3
][BF
4
]7120 ± 125 8C1h 6834
K13+A39+U1 VCl
3
MeCN D2 h 82 86
K13+A45+U1 VCl
3
MeCN D2 h 85 86
K13+A57+U1 VCl
3
MeCN D2 h 88 86
K13+A60+U1 VCl
3
MeCN D2 h 85 86
K13+A64+U1 H
2
SO
4
H
2
OD3 h 95 102
K13+A64+U10 H
2
SO
4
H
2
OD3 h 93 102
K13+A73+U1 H
2
SO
4
H
2
OD3 h 90 102
K13+A73+U10 H
2
SO
4
H
2
OD3 h 94 102
Am1+A18+U12 HCl EtOH 100 8C 15 min 21 27
Am1+A34+U1 HCl EtOH 100 8C 15 min 59 27
Am2+A32+U1 Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 66 27
Am3+A18+U1 Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 55 27
Am3+A52+U1 HCl EtOH 100 8C 15 min 28 27
Am3+A62+U1 LaCl
3
AcOH+EtOH 120 8C 10 min 89 27
Am4+A71+U1 Yb(OTf)
3
AcOH+EtOH 120 8C 10 min 61 27
Am7+A18+U10 AcOH EtOH D48 h 65 44
AlCl
3
, HCl MeOH mn 7.5 h 82 44
Am7+A76+U10 AcOH EtOH D25 h 68 44
AlCl
3
, HCl MeOH mn 3.5 h 86 44
Am7+A84+U10 AcOH EtOH D24 h 63 44
AlCl
3
, HCl MeOH mn 6 h 84 44
Am8+A18+U10 AcOH EtOH D48 h 64 44
AlCl
3
, HCl MeOH mn 8 h 80 44
Am8+A76+U10 AcOH EtOH D26 h 67 44
AlCl
3
, HCl MeOH mn 3.5 h 87 44
Am8+A84+U10 AcOH EtOH D24 h 62 44
AlCl
3
, HCl MeOH mn 6.5 h 83 44
Eq1+A18+U1 Yb(OTf)
3
EtOH 100 8C 20 min 31 27
Eq1+A50+U1 HCl EtOH 100 8C 20 min 31 27
Eq1+A61+U1 Yb(OTf)
3
EtOH 100 8C 20 min 35 27
Eq2+A18+U1 LaCl
3
AcOH+EtOH 120 8C 15 min 83 27
New potential of the classical Biginelli reaction 1051

References
1. P Biginelli Chem. Ber.24 2962 (1891)
2. G C Rovnyak, S D Kimball, B Beyer, G Cucinotta,
J D DiMarco, J Gougoutas, A Hedberg, M Malley, J P McCarthy,
R Zhang, S Moreland J. Med. Chem.38 119 (1995)
3. M Brands, R Endermann, R Gahlmann, J Kru
Èger, S Raddatz
Bioorg. Med.Chem. Lett.13 241 (2003)
4. B B Snider, Z Shi J. Org. Chem.58 3828 (1993)
5. K Folkers, T B Johnson J. Am. Chem. Soc.55 3784 (1933)
6. T G Steele, C A Coburn, M A Patane, M G Bock Tetrahedron
Lett.39 9315 (1998)
7. C O Kappe, S F Falsone Synlett 718 (1998)
8. B Jauk, F Belaj, C O Kappe J. Chem. Soc., Perkin Trans. 1 307
(1999)
9. H Namazi, Y R Mirzaei, H Azamat J. Heterocycl. Chem.38 1051
(2001)
10. D S Bose, L Fatima, H B Mereyala J. Org. Chem.68 587 (2003)
11. C O Kappe, D Kumar, R S Varma Synthesis 1799 (1999)
12. C O Kappe, O V Shishkin, G Uray, P Verdino Tetrahedron 56
1859 (2000)
13. B Schnell, W Krenn, K Faber, C O Kappe J. Chem. Soc.,
Perkin Trans. 1 4382 (2000)
14. F Bigi, S Carloni, B Frullanti, R Maggi, G Sartori Tetrahedron
Lett.40 3465 (1999)
15. H Lin, J Ding, X Chen, Z Zhang Molecules 51240 (2000)
16. A Dondoni, A Massi Tetrahedron Lett.42 7975 (2001)
17. R S Bhosale, S V Bhosale, Sh V Bhosale, T Wang,
P K Zubaidha Tetrahedron Lett.45 9111 (2004)
18. K V N S Srinivas, B Das Synthesis 2091 (2004)
19. A K Bose, M S Manhas, S Pednekar, S N Ganguly, H Dang,
W He, A Mandadi Tetrahedron Lett.46 1901 (2005)
20. P Salehi, M Dabir, M A Zolfigol, M A B Fard Tetrahedron Lett.
44 2889 (2003)
21. E H Hu, D R Sidler, U-H Dolling J. Org. Chem.63 3454 (1998)
22. J I Lu, H Ma Synlett 63 (2000)
23. J I Lu, Y Bai Synthesis 466 (2002)
24. I S Zorkun, S SaracË , S CË elebi, K Erol Bioorg. Med. Chem.14 8582
(2006)
25. G Jenner Tetrahedron Lett.45 6195 (2004)
26. B C Ranu, A Hajra, U Jana J. Org. Chem.65 6270 (2000)
27. A Stadler, C O Kappe J. Comb. Chem.3624 (2001)
28. J S Yadav, B V S Reddy, R Srinivas, C Venugopal,
T Ramalingam Synthesis 1341 (2001)
29. K A Kumar, M Kasthuraiah, C S Reddy, C D Reddy
Tetrahedron Lett.42 7873 (2001)
30. S Antoniotti Synlett 1566 (2003)
31. R Varala, M M Alam, S R Adapa Synlett 67 (2003)
32. D S Bose, R K Kumar, L Fatima Synlett 279 (2004)
33. E S Putilova, N A Troitskii, S G Zlotin, O G Khudina,
Ya V Burgart, V I Saloutin, O N Chupakhin Zh. Org. Khim. 42
1407 (2006)
a
34. E S Putilova, G V Kryshtal', G M Zhdankina, N A Troitskii,
S G Zlotin Zh. Org. Khim. 41 524 (2005)
a
35. J S Yadav, B V S Reddy, K B Reddy, K S Raj, A R Prasad
J. Chem. Soc., Perkin Trans. 1 1939 (2001)
36. B C Ranu, H Alakananda, S S Dey Org.Process Res. Dev.6817
(2002)
37. H A Stefani, C B Oliveira, R B Almeida, C M P Pepeira,
R C Braga, R Cella, V C Borges, L Savegnago, C W Nogueira
Eur. J. Med. Chem.41 513 (2006)
38. A Dandia, M Saha, H Taneja J. Fluorine Chem.90 17 (1998)
39. J Wannberg, D Dallinger, C O Kappe, M Larhed J. Comb. Chem.
7574 (2005)
40. A Lengar, C O Kappe Org. Lett.6771 (2004)
41. B Desai, D Dallinger, C O Kappe Tetrahedron 62 4651 (2006)
42. M Kidwai, S Saxena, R Mohan, R Venkataramanan J. Chem.
Soc., Perkin Trans. 1 1845 (2002)
43. A Dondoni, A Massi Mol. Diver.6261 (2003)
44. M Kidvai, R Mokhan, S Saksena Izv. Akad. Nauk, Ser. Khim.
2323 (2003)
b
45. R Osnaya, G A Arroyo, L Parada, F Delgado, J Trujillo,
M Salmo
'n, R Miranda Arkivoc (xi) 112 (2003)
46. I P Sedishchev, G A Gazieva, A N Shumskii, E S Putilova,
V M Zhulin Kondens. Sredy Mezhfaz. Granitsy 4225 (2002)
47. M Syamala Org. Prep. Proced. Int.37 103 (2005)
48. C O Kappe Tetrahedron 49 6937 (1993)
49. C O Kappe Acc. Chem. Res.33 879 (2000)
50. F Sweet, J D Fissekis J. Am. Chem. Soc.95 8741 (1973)
51. C O Kappe J. Org. Chem.62 7201 (1997)
52. M Xia, Y-G Wang Tetrahedron Lett.43 7703 (2002)
53. M Xia, Y-G Wang Synthesis 262 (2003)
54. P Wipf, A Cunningham Tetrahedron Lett.36 7819 (1995)
55. M J Lusch, J A Tallarico Org. Lett.63237 (2004)
56. M G Valverde, D Dallinger, C O Kappe Synlett 741 (2001)
57. L Zhang, T M Rana J. Comb. Chem.6457 (2004)
58. G A Gross, H Wurziger,A Schober J. Comb. Chem.8153 (2006)
59. R Pe
Âres, T Beryozkina, O I Zbruyev, W Haas, C O Kappe
J. Comb. Chem.4501 (2002)
60. J-C Legeay, J J V Eynde, J P Bazureau Tetrahedron 61 12386
(2005)
61. K S Atwal, G C Rovnyak, B C O'Reilly, J Schwartz J. Org.
Chem.54 5898 (1989)
62. Y Ma, C Qian, L Wang, M Yang J. Org. Chem.65 3864 (2000)
63. J Lu, Y Bai, Z Wang, B Yang, H Ma Tetrahedron Lett.41 9075
(2000)
64. M S Zhidovinova, O V Fedorova, G L Rusinov,
I G Ovchinnikova Izv.Akad. Nauk, Ser. Khim. 2389 (2003)
b
65. S Martõ
Ânez, M Meseguer, L Casas, E Rodrõ
Âguez, E Molins,
M Moreno-Man
Äas, A Roig, R M Sebastia
Ân, A Vallribera
Tetrahedron 59 1553 (2003)
66. N-Y Fu, Y-F Yuan, Z Cao, S-W Wang, J-T Wang, C Peppe
Tetrahedron 58 4801 (2002)
67. G Sabitha, G S K K Reddy, C S Reddy, J S Yadav Synlett 858
(2003)
68. G Maiti, P Kundu, C Guin Tetrahedron Lett.44 2757 (2003)
69. J Li, J-F Han, J-H Yang, T-S Li Ultrason. Sonochem.10 119
(2003)
70. A S Paraskar, G K Dewkar, A Sudalai Tetrahedron Lett.44
3305 (2003)
71. A Shaabani, A Bazgir, F Teimouri Tetrahedron Lett.44 857
(2003)
72. M S Manhas, S N Ganguly, S Mukherjee, A K Jain, A K Bose
Tetrahedron Lett.47 2423 (2006)
73. M Gohain, D Prajapati, J S Sandhu Synlett 235 (2004)
74. S Tu, F Fang, C Miao, H Jiang, Y Feng, D Shi, X Wang
Tetrahedron Lett.. 44 6153 (2003)
75. Q Sun, Y-Q Wang, Z-M Ge, T-M Cheng, R-T Li Synthesis 1047
(2004)
76. B Gangadasu, S Palaniappan, V J Rao Synlett 1285 (2004)
77. A V Narsaiah, A K Basak, K Nagaiah Synthesis 1253 (2004)
78. I Suzuki, Y Suzumura, K Takeda Tetrahedron Lett.47 7861
(2006)
79. W Su, J Li, Z Zheng, Y Shen Tetrahedron Lett.46 6037 (2005)
80. I Cepanec, M Litvic
', A Bartolinc
Ïic
', M LovricZh Tetrahedron 61
4275 (2005)
81. S K De, R A Gibbs Synthesis 1748 (2005)
82. Y Yu, D Liu, C Liu, G Luo Bioorg. Med. Chem. Lett.17 3508
(2007)
83. E Rafiee, H Jafari Bioorg. Med. Chem. Lett.16 2463 (2006)
84. K Singh, D Arora, S Singh Tetrahedron Lett.47 4205 (2006)
85. A Debache, B Boumoud, M Amimour, A Belfaitah, S Rhouati,
B Carboni Tetrahedron Lett.47 5697 (2006)
86. G Sabitha, G S K K Reddy, K B Reddy, J S Yadav
Tetrahedron Lett.44 6497 (2003)
87. J Peng, Y Deng Tetrahedron Lett.42 5917 (2001)
88. G Sabitha, K B Reddy, J S Yadav, D Shailaja, K S Sivudu
Tetrahedron Lett.46 8221 (2005)
89. Y Huang, F Yang, C Zhu J. Am. Chem. Soc.127 16386 (2005)
90. K R Reddy, C V Reddy, M Mahesh, P V K Raju,
V V N Reddy Tetrahedron Lett.44 8173 (2003)
91. F L Zumpe, M Flu
Èb, K Schmitz, A Lender Tetrahedron Lett.48
1421 (2007)
1052 S V Vdovina, V A Mamedov

92. S Tu, F Fang, S Zhu, T Li, X Zhang, Q Zhuang Synlett 537
(2004)
93. S I Zav'yalov, L B Kulikova Khim.-Farm. Zh. (7 ± 8) 116 (1992)
c
94. A Stadler, C O Kappe J. Chem. Soc., Perkin Trans. 2 1363 (2000)
95. J Mabry, B Ganem Tetrahedron Lett.47 55 (2006)
96. A A A Abdel-Fattah Synthesis 2358 (2003)
97. P Salehi, M Dabiri, M A Zolfigol, M Baghbanzadeh
Heterocycles 65 1177 (2005)
98. C V Reddy, M Mahesh, P V K Raju, T R Babu, V V N Reddy
Tetrahedron Lett.43 2657 (2002)
99. N-Y Fu, Y-F Yuan, M-L Pang, J-T Wang, C Peppe
J. Organomet. Chem.672 52 (2003)
100. M M Abelman, S C Smith, D R James Tetrahedron Lett.44
4559 (2003)
101. Y Zhu, Y Pan, S Huang Heterocycles 65 133 (2005)
102. Z Hassani, M R Islami, M Kalantari Bioorg. Med. Chem. Lett.
16 4479 (2006)
103. M S Zhidovinova, O V Fedorova, G L Rusinov,
I G Ovchinnikova Mol. Diver.6323 (2003)
104. S V Vdovina, L V Mustakimova, V A Mamedov Zh. Org.
Khim. 44 638 (2008)
a
105. V A Mamedov, S V Vdovina, E I Vorkunova, L V Mustakimova,
A F Saifina, A T Gubaidullin, I Kh Rizvanov, Ya A Levin,
I A Litvinov Izv.Akad. Nauk, Ser. Khim. 1233 (2008)
b
106. J Guillon, P Grellier, M Labaied, P Sonnet, J-M Le
Âger,
RDe
Âprez-Poulain, I Forfar-Bares, P Dallemagne, N LemaõÃtre,
FPe
Âhourcq, J Rochette, C Sergheraert, C Jarry J. Med. Chem.
47 1997 (2004)
107. S Raines, S Y Chai, F P Palopodi J.Heterocycl.Chem.13 711
(1976)
108. V I Saloutin, Ya V Burgart, O G Kuzueva, C O Kappe,
O N Chupakhin J. Fluorine Chem.103 17 (2000)
109. M A P Martins, M V M Teixeira, W Cunico, E Scapin,
R Mayer, C M P Pepeira, N Zanatta, H G Bonacorso,
C Peppe, Y-F Yuan Tetrahedron Lett.45 8991 (2004)
110. V A Mamedov, L V Mustakimova, A T Gubaidullin,
S V Vdovina, I A Litvinov, V S Reznik Khim. Geterotsikl.
Soedin. 1414 (2006)
d
111. G Byk, H E Gottlieb, J Herscovici, F Mirkin J. Comb. Chem.2
732 (2000)
112. A Shaabani, A Bazgir, H R Bijanzadeh Mol. Diver.8141 (2004)
113. Z-T Wang, L-W Xu, C-G Xia, H-Q Wang Tetrahedron Lett.45
7951 (2004)
114. B Liang, X Wang, J-X Wang, Z Du Tetrahedron 63 1981 (2007)
115. K Singh, J Singh, P K Deb, H Singh Tetrahedron 55 12873
(1999)
a
ÐRuss. J. Org. Chem. (Engl. Transl.)
b
ÐRuss. Chem. Bull., Int. Ed. (Engl. Transl.)
c
ÐPharm. Chem. J. (Engl. Transl.)
d
ÐChem. Heterocycl. Compd. (Engl. Transl.)
New potential of the classical Biginelli reaction 1053