Organocatalyzed Biginelli Reactions

C H A P T E R
12
Organocatalyzed Biginelli Reactions:
A Greener Chemical Approach for
the Synthesis of Biologically Active
3,4-Dihydropyrimidin-2(1H)-ones/-thiones
Ângelo de Fátima, Bruna Silva Terra, Leonardo da Silva Neto,
Taniris Cafiero Braga
Grupo de Estudos em Química Orgânica e Biológica (GEQOB), Departamento de Química, Instituto de Ciências Exatas,
Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
O U T L I N E
1. Introduction 317 2.4 Enzymes and Biocatalysts for the Biginelli

1.1 The Biginelli Reaction 317 Reaction328
1.2 Mechanism of the Biginelli Reaction: 2.5 Other Organocatalysts Used in Biginelli
An Overview 318 Reactions331
2. Classes of Organocatalysts Used in the 3. Biological Significance of 3,4-Dihydropyrimidin-
Biginelli Reaction 320 2(1H)-ones/-thiones332
2.1 Organic Acids: Catalysts for Biginelli Reactions 320
4. Concluding Remarks 334
2.2 Amino Acids: Useful and Stereoselective
Catalysts for the Biginelli Reaction 324 Abbreviations334
2.2.1 l-Proline Derivatives 324
Acknowledgments335
2.2.2 Other Amino Acids 327
2.3 Polymers and Macrocycles 328 References335
1. INTRODUCTION
1.1 The Biginelli Reaction

In 1891, the Italian chemist Pietro Biginelli reported a multicomponent reaction involving the acid-catalyzed
cyclocondensation of ethyl acetoacetate (1), benzaldehyde (2), and urea (3) [1]. The reaction was carried out simply
by heating a mixture of the three components as a solution in ethanol in the presence of a catalytic amount of hydro-
chloric acid at reflux temperature. The product of this three-component reaction was identified as a dihydropyrim-
idin-2(1H)-one (4, Figure 1). This synthesis is now known as the Biginelli reaction, the Biginelli condensation, or the
synthesis of Biginelli dihydropyrimidinone (DHPM); the reaction products are called Biginelli adducts.
Green Synthetic Approaches for Biologically Relevant Heterocycles 317

http://dx.doi.org/10.1016/B978-0-12-800070-0.00012-8 © 2015 Elsevier Inc. All rights reserved.
318 12. ORGANOCATALYZED BIGINELLI REACTIONS
FIGURE 1 The first example of a Biginelli reaction, described by Biginelli in 1893 [1].
The first examples of this cyclocondensation typically involved keto esters, aromatic aldehydes, and urea. How-
ever, the scope of this reaction has been substantially explored by varying the substrates employed [2–5].
Of the three substrates involved in the Biginelli reaction, the aldehyde component is the most commonly explored
regarding structural variation (Figure 2). In general, the reaction works best with aromatic aldehydes that are ortho-,
meta-, or para-substituted. Aromatic aldehydes with donor groups or groups that remove electron density at the
meta- or para-positions usually provide the desired products in good yields. Aldehydes with bulky substituents on
the ortho-position may afford substantially smaller yields. Heterocyclic aldehydes such as furan derivatives and pyri-
dine rings can also be used, while the use of aliphatic aldehydes provides moderate product yields [2–5]. Usually,
simple alkyl acetoacetates are employed as substrates in the Biginelli reaction. β-Keto-substituted acetoacetates and
thioesters can also be used successfully as substrates [2–5]. Acetamides can be used instead of keto esters to produce
pyridine-5-carboxamides. Substrates such as cyclic or acyclic β-diketones are also viable components in Biginelli
reactions (Figure 2). Of the Biginelli reaction components, the urea has greater restrictions in terms of structural
variation (Figure 2). Most examples use urea as a substrate. However, substituted ureas also provide good yields.
Thioureas and substituted thioureas are also widely used, although the yields are usually smaller and longer reaction
times are required compared to the corresponding ureas [2–5].
In 2011, we celebrated the 120th anniversary of the discovery of the Biginelli reaction, Biginelli condensation
reaction, or the synthesis of Biginelli adducts. Among Biginelli adducts, 3,4-DHPMs/thiones are remarkably impor-
tant due to their wide spectrum of therapeutic and pharmacological applications, including antiviral, antitumor,
antibacterial, and anti-inflammatory activities. Biginelli adducts have also emerged as calcium channel blockers,
antihypertensive agents, and α-adrenergic antagonists. Because of this, many synthetic methodologies have been
developed for the synthesis of Biginelli adducts. A variety of inorganic Brønsted-Lowry acids have been used as
catalysts in the Biginelli reaction, and more recently, Lewis acids have been utilized for this purpose. The use of ionic
liquids, microwave irradiation, solid phase reagents, baker’s yeast, polymer-supported catalysts, zeolites, dodecyl
sulfonic acid, and polyethylene glycol has also been reported. Only a few examples of organocatalysts have been
described for the Biginelli reaction. This chapter describes and discusses state-of-the-art synthetic approaches based
on environmental-friendly organocatalysts for obtaining a series of 3,4-DHPMs/thiones.
1.2 Mechanism of the Biginelli Reaction: An Overview

Three main mechanisms have been proposed for the Biginelli reaction. In 1933, Folkers and Johnson proposed three
potential key intermediates (5–7) involved in the Biginelli reaction (Figure 3) [6]. Intermediate 5 could be formed via
an iminium mechanism from the condensation of aldehyde and urea. Intermediate 6 may be formed via an enamine
mechanism from the condensation of urea and 1,3-dicarbonyl compound. The third option involves intermediate 7,
which can be formed via a Knoevenagel condensation of an aldehyde and a 1,3-dicarbonyl compound. Folkers and
Johnson believed that intermediate 5 was preferentially formed over 6 or 7.
In the 1990s, Kappe revisited the Biginelli reaction mechanism using 1H and 13C nuclear magnetic resonance (NMR)
as tools to obtain further information on the intermediates involved in the reaction [7]. Kappe’s studies were based
on performing reactions between urea/aldehyde, ethyl acetoacetate/urea and aldehyde/ethyl acetoacetate with
CD3OH as the solvent. He detected the formation of intermediate 5 (after 15–20 min) in the reaction between urea and
benzaldehyde, while in the presence of ethyl acetoacetate, the formation of DHPM (4) was observed after 1–2 h [7].
Intermediate 7 was not observed in the reaction between benzaldehyde and ethyl acetoacetate. However, Kappe and
collaborators observed benzaldehyde acetal formation when using Ph-CH(OCD3)2 as the solvent. Intermediate 6 was
observed by Kappe in the reaction between urea and acetoacetate. However, this intermediate rapidly hydrolyzed
back to the starting materials. The results obtained by Kappe and collaborators thus eventually suggest that the Bigi-
nelli reaction occurs preferentially via an iminium mechanism [7], as originally proposed by Folkers and Johnson [6].
1. Introduction 319
FIGURE 2 Examples of building blocks employed in the Biginelli reaction [2–5].
Latter on, de Souza and colleagues studied the mechanism of Biginelli reaction with mass spectrometry by direct infu-
sion electrospray (electron-spray ionization mass spectroscopy, ESI-MS) [8]. In their studies, they found that reacting benz-
aldehyde and urea leads to the formation of ions of m/z 209, 167, and 149 (Figure 4). When the reaction was carried out with
the three components (urea, acetoacetate, and benzaldehyde), existences of the same intermediates were also detected.
Additionally, the reaction between urea and acetoacetate (via an enamine mechanism) produced an intermediate of
m/z 191 (Figure 5) instead of the expected intermediate 6 (m/z 173 for 6.H+). According to de Souza and collaborators,
FIGURE 3 Proposed mechanisms for the Biginelli reaction.
FIGURE 4 Structures of selected ions observed in the Biginelli reaction.
FIGURE 5 Structures of the ions proposed by de Souza and collaborators [8].
the inability to detect intermediate 6 was due to the brief existence of this ion in the reaction medium [8]. None of
the expected ions for the Biginelli reaction from the Knoevenagel mechanism were detected by ESI-MS, even after
2 h of continuous monitoring. These ions were observed only after 24 h, demonstrating that this mechanism was not
involved in the Biginelli reaction; in general, these reactions get completed after 8–12 h.
In 2012, Ramos and collaborators also studied this mechanistic pathway by means of ESI-MS, NMR, and theoreti-
cal calculations in their approach [9]. In this work, the mechanism of the Biginelli reaction was explored by studying
the influence of Lewis acid catalysts in the presence of ionic liquids. Once again, the researchers noticed the exclusive
formation of iminium intermediate m/z 149 (Figure 4), indicating that under Lewis Acid catalysis and in ionic liquids,
the preferred mechanistic pathway was the iminium mechanism [9].
Thus, through the experimental evidence obtained both by Kappe, de Souza and collaborators, and by Ramos and
colleagues, we can verify the preference for the iminium mechanism as proposed initially by Folkers and Johnson [6].
2. CLASSES OF ORGANOCATALYSTS USED IN THE BIGINELLI REACTION
2.1 Organic Acids: Catalysts for Biginelli Reactions

Organocatalysts are quickly replacing the use of metal-based catalysts [10]. The use of such catalysts is growing
because they have low or no toxicity. Additionally, organocatalysts have low sensitivity to atmospheric oxygen or
water, are easy to manipulate, and are usually not expensive [11]. Organic acids are organocatalysts with all of such
desired characteristics. Some of these compounds were obtained directly from natural sources or prepared in the
laboratory. Regardless of their origin, organic acids are reported to be useful catalysts for preparing Biginelli adducts,
including for obtaining a pure enantiomer of such compounds.
2. Classes of Organocatalysts Used in the Biginelli Reaction 321
TABLE 1 Biginelli Reactions Catalyzed by Natural Organic Acids
Catalyst Yield (%) Reaction Time Solvent Molar Ratioa References
CAT-1 (5 mmol%) 61–88 4 h EtOHb 1:1:1.5 [13]
CAT-2 (5 mmol%) 70–96 4 h EtOHb 1:1:1.5 [13]
CAT-3 (25–40 mmol%) 79–92 2.5–4 h EtOHb 1:1:1.5 [12]
CAT-4 (5 mol%) 53–85 6–12 h --c 1:1:1.5 [14]

aMolar ratio of reagents: aldehyde:1,3-dicarbonyl compound:urea or thiourea.
bThesereactions were performed at reflux.
cUnder solvent-free conditions and at 80 °C.
Tartaric, citric, and lactic acids (CAT-1, CAT-2, and CAT-3, respectively) were efficiently used as catalysts in the
Biginelli reactions. These natural organic acids afforded Biginelli adducts in excellent yields from aromatic aldehydes
bearing either electron-donating or electron-withdrawing substituents. Urea and thiourea were found to be suitable
substrates in these reactions (Table 1) [12,13]. Ascorbic acid (CAT-4) is an efficient catalyst; however, it requires a
long reaction time, and when thiourea is used, the corresponding products are obtained in lower yields compared
to those from urea. Additionally, the use of nonaromatic aldehydes afforded the Biginelli adducts in lower yields
(Table 1) [14].
Other organic acids have been evaluated as organic catalysts for the Biginelli reaction (Table 2). Kargar and co-
workers [15] reported the use of imidazole-1yl-acetic acid (CAT-5). Imidazole-1yl-acetic acid (CAT-5) is a bifunctional
catalyst, possessing Lewis/Brønsted-acid or Lewis/Brønsted-base sites. This catalyst produced the Biginelli adducts
in good-to-excellent yields (>85%). The reactions were performed under either solvent-free conditions or with water
as the solvent. There was no difference in yield when using urea or thiourea as the starting material. CAT-5 was able
to be reused seven times without losing efficacy. However, only aromatic aldehydes were utilized in these studies
(Table 2) [15].
Karimi-Jaberi and co-workers [16] reported the use of trifluoroacetic acid (TFA; CAT-6) as an organic catalyst to
synthesize Biginelli adducts (Table 2). The use of CAT-6 afforded a series of Biginelli adducts with short reaction
times and excellent yields (Table 2). CAT-6 catalyzed the Biginelli reaction efficiently with a wide variety of alde-
hydes, 1,3-dicarbonyl compounds, and urea or thiourea. The reaction in the absence of CAT-6 produced lower yields
(20%), as starting materials were primarily recovered from the reaction medium [16].
Borik and collaborators [17] disclosed that sulfanilic acid (CAT-7) had a catalytic effect in the Biginelli reaction
under conventional heating, microwave irradiation or ultrasound irradiation (Table 2). Normally, the use of ultra-
sound irradiation affords the desired products in slightly higher yields than those obtained by microwave irradiation.
Both irradiation techniques allowed the use of aldehydes bearing either electron-donating or electron-withdrawing
substituents. Reactions carried out under conventional heating provided the corresponding products in lower yields
(less than 12%) and required long reaction times (usually 6–8 h, Table 2) [17].
TABLE 2 Biginelli Reactions Catalyzed by Organic Acids
CAT-5 (24 mmol%) 85–94 30–50 min H2Od 1:1:1.5 [15]
CAT-6 (20 mol%) 84–96 2–50 min --e 1:1:1 [16]
CAT-7(10 mol%) 74–98b 3.5–5 minb H2O 1:1:1 [17]

68–94c 90–120 minc
CAT-8 (10 mol%) 65–97 480 min MeCNf 1:1:1 [18]
CAT-9(10 mol%) 40–86 4 days DCM 1:1.2:5 [19]
CAT-10 (5 mol%) 80–98 3 days Xyleneg 1:1.2:3 [20]

bMicrowave irradiation.
cUltrasound irradiation. The following reactions were carried out.
dReflux temperature or solvent-free.
eUnder solvent-free conditions and at 70 °C.
fReflux temperature.
g50 °C.
Sagar and collaborators [18] described phenyl phosphonic acid (CAT-8) as a useful catalyst in Biginelli reactions
(Table 2). CAT-8-catalyzed reactions were explored; it was found that aromatic aldehydes with electron-donating or
electron-withdrawing substituents, aliphatic aldehydes, and heteroaromatic aldehydes were good substrates in such
reactions. The Biginelli adducts were obtained in excellent yields (86–97%) when urea was employed, and moderate-
to-good yields (65–72%) were observed with thiourea (Table 2) [18].
The first asymmetric version of the Biginelli reaction catalyzed by an acid compound used a chiral phosphoric
acid derived from BINOL and was reported by Chen and collaborators (2006) (Table 2). Among all evaluated cata-
lysts, CAT-9 was the best in providing the Biginelli adduct, showing an enantiomeric excess greater than 88% and a
good yields (51–86%) from aromatic aldehydes bearing electron-donating or electron-withdrawing substituents. Ali-
phatic aldehydes also afforded Biginelli adducts with greater enantioselectivity (88–92% ee); however, lower yields
were observed (40–44%) in such reactions (Table 2) [19].
Xu and co-workers [20] reported the use of SPINOL-phosphoric acid (CAT-10) to catalyze an enantioselective
version of the Biginelli reaction (Table 2). These authors evaluated six chiral catalysts that had different substituents
TABLE 3 Biginelli Reactions Catalyzed by Heterogeneous Acids
CAT-11 (0.005 g)b 71–93 60 min HOAce 1:1:1.25 [21]
CAT-12 (0.1 g)c 80–92 15–30 min --f 1:1:1.5 [22]
CAT-13 (1 mol%) 68–88 480 min EtOHg 1:1.1:1.5 [23]
CAT-14 (3 mol%) 69–96 2–4 min MeCNh 1:1:1 [24]
CAT-15 (0.05 g)d 65–90 210–390 min H2O 1:1.2:1 [25]
CAT-16 (0.05 g)d 80–95 330 min EtOHg 1:1:1.2 [26]
CAT-17 (10 mol%) 84–94 240 min MeCN 1:1:1.5 [27]
CAT-18 (10 mol%) 80–92 240–270 min MeCN 1:1:1.5 [28]

bAmount of catalyst for each 2 mmol of aldehyde.
cAmount of catalyst for each 4 mmol of aldehyde.
dAmount of catalyst for each 1 mol of aldehyde. The following reactions were carried out.
eTemperature at 110 °C.
fUnder solvent-free conditions at a temperature of 140 °C.
gReflux temperature.
hMicrowave irradiation.
on the aromatic ring. Among the catalysts studied, CAT-10 was the most efficient. CAT-10 produced the Biginelli
adduct in good yield (>80%) and excellent enantioselectivity (91–99% ee). According to these authors, the presence
of 1-naphthyl groups at the ortho-position on the aromatic ring of the catalyst afforded higher enantioselectivities
due to steric effects. However, aliphatic aldehydes were found to be poor substrates for CAT-10-catalyzed reactions
(40–44% yield; 88–92% ee) [20].
Heterogeneous catalysts based on organic acids are also used in Biginelli reactions. Several solid supports have
been tried, and most of them are recyclable. These include polymers, zeolites and silica, among others.
Tajbakhsh and co-workers [21] showed that silica-bonded S-sulfonic acid (CAT-11) afforded the Biginelli adducts
in good yields (Table 3). Aromatic aldehydes with both electron-donating and electron-withdrawing substituents
gave the corresponding products in good yields, whereas low yields were observed with nonaromatic aldehydes.
There was no difference in the yields when urea or thiourea was used in such reactions. Good yields were also
observed when cyclic 1,3-dicarbonyl compounds were used. Additionally, CAT-11 was reused without any appre-
ciable loss in the catalytic activity over more than four cycles [21].
Moghaddas and collaborators [22] developed a methodology using sulfonated carbon materials (CAT-12) as a
catalyst for the Biginelli reaction (Table 3). This catalyst was synthesized from the sulfonation reaction of naphtha-
lene with sulfuric acid. CAT-12 produced the Biginelli adduct in excellent yield from aromatic aldehydes with elec-
tron-donating and electron-withdrawing substituents or aliphatic aldehydes with both urea and thiourea as starting
materials. CAT-12 was reused at least four times and only a slight reduction in its catalytic activity was observed
(Table 3) [22].
Shi and co-workers [23] reported the use of sulfonic acid-functionalized polypropylene fibers (CAT-13) as
heterogeneous catalysts in the Biginelli reaction (Table 3) [23]. CAT-13 is an environmentally harmless solid
material. The reaction in the absence of catalyst produced only 6% of the desired product. Several Biginelli
adducts were synthesized using CAT-13 in ethanol under reflux. Aromatic aldehydes with electron-donating
substituents afforded the products in higher yields (85–89%) than aldehydes with electron-withdrawing sub-
stituents (68–76%). The yields were not significantly different when urea or thiourea was used in these reactions.
CAT-13 was recycled 10 times without any loss in catalytic efficiency (Table 3) [23]. Another heterogeneous
acid used as a catalyst in the Biginelli reaction is 1,3,5-triazine-2,4,6-triyltrisulfamic acid (CAT-14) [24]. CAT-14
afforded Biginelli adducts in excellent yields (Table 3). Aromatic aldehydes, aliphatic aldehydes and hetero-
aromatic aldehydes were shown to be useful starting materials for the synthesis of Biginelli adducts, showing
good yield, under CAT-14 catalysis. Thiourea afforded the corresponding Biginelli adducts in moderate-to-good
yields (69–72%). Although the authors mentioned that CAT-14 is a recyclable catalyst, they did not use the cata-
lyst more than once for the reaction [24].
Cellulose sulfuric acid (CAT-15) was also shown to be an effective catalyst in the Biginelli reaction and afforded
good yields (Table 3). In fact, CAT-15 catalyzed these reactions with 65–95% and 70–90% yields for the Biginelli
adducts derived from thiourea and urea, respectively. This catalyst was reused up to 4 times with no loss in catalytic
activity [25].
Jetti and collaborators [26] reported that ion exchange resins, such as amberlyst-70, amberlyst-15-dry, indion-130,
indion-190, nafion-H, envirocat-E, and montmorillonite, catalyze Biginelli reactions [26]. Among the catalysts tested,
amberlyst-15-DRY (CAT-16) showed the best results. The catalytic efficiency of CAT-16 was higher in ethanol, a
protic solvent, giving yields over 80% (Table 3). Recycling of CAT-16 was evaluated, and this catalyst maintains its
efficiency for at least five cycles [26].
Hankari and collaborators studied the catalytic efficiency of hybrid zwitterionic acids (CAT-17) in the Biginelli reac-
tion (Table 3) [27]. In this work, the authors showed that reusing catalyst CAT-17 is possible without losing its catalytic
ability for at least for five cycles. The non-catalyzed reaction produced Biginelli adducts in less than 10% yield [27].
Konkala and collaborators [28] reported the use of bioglycerol derivatives (CAT-18) as catalysts in the synthesis of
Biginelli adducts [28]. These catalysts consist of “leaves” of polycyclic aromatic rings with sulfonic groups (SO3H) as
substituents. In this study, the authors demonstrated that 10 mol% of CAT-18 produced the desired products in good
yields (>80%) (Table 3). Additionally, CAT-18 can be reused for an additional three cycles without significant loss of
catalytic efficiency [28].
2.2 Amino Acids: Useful and Stereoselective Catalysts for the Biginelli Reaction
2.2.1 l-Proline Derivatives
l-Proline and its derivatives are often used as stereoselective catalysts in the Biginelli reactions [29–31]. This amino
acid leads to the formation of enamines, key intermediates involved in the formation of Biginelli adducts (Table 4) [29].
Pandey and collaborators reported the use of l-proline (CAT-19) in combination with TFA in Biginelli reactions
(Table 4). The Biginelli adducts were obtained in good yields (>79%) and with a cis relative configuration, as deter-
mined by NOESY experiments (Figure 6). In these experiments it was shown that H-4 is cis to H-5 and trans to H-10
(Figure 6) [29].
Chohamarani and Zamani reported the use of l-proline supported on silica (CAT-20). This methodology provided
the Biginelli adducts in good yields (>80%) from aromatic aldehydes. However, the adducts prepared from benzal-
dehyde and thiourea gave poor yields (50%, Table 4) [30].
Sohn and colleagues [31] evaluated the use of l-proline esters (CAT-21, Table 4) in the Biginelli reaction. They also
investigated the mechanism of CAT-21 asymmetric catalysis in such reactions. Initially, they evaluated three possible
pathways that could influence the enantioselectivity observed for this reaction (Figure 7). One of these pathways
involves the condensation of the aldehyde with urea leading to the formation of a chiral acyl imine. In this sense, the
TABLE 4 Biginelli Reactions Catalyzed by Proline Derivatives
Catalyst Yield Reaction Time Solvent Molar Ratioa References
CAT-19 (15 mol%) 79–90 7 h MeCNf,g,j 1:1:1.5 [29]
CAT-20 (808 mol%)b 50–90 6 h EtOHk 1:1.1:1.5 [30]
CAT-21 (10 mol%) 80–87c 24 h THFg,l 0.2:1:1.2 [31]
CAT-22 (10 mol/%) 48–68d 72–96 h Dioxane/THFh 1:20:2 [32]
CAT-23 (80 mol%) 78–89 4–5 h EtOH 1:1:1,5 [33]
CAT-24 (10 mol%) 63–99 18 h EtOHk 2:1:1.5 [34]
CAT-25 (10 mol%) 5–91e 48–72 h dioxane/CHCl3i 1:3:3 [35]

bCalculated from Ref. [36]. These catalysts showed the following enantiomeric excesses (ee).
c16–36.
d94–98.
e7–99. These reactions used the following additives.
f6 mol% TFA.
gBinol phosphoric acid.
h10 mol% PFBA or TFA.
i10 mol% HCl. The following reactions were carried out.
jTemperature at 85 °C.
kReflux temperature.
lTemperature at 70 °C.
FIGURE 6 NOESY experiment conducted by Pandey and collaborators to determine the relative configuration of the obtained Biginelli
adduct [29].
FIGURE 7 Three possible key steps involved in the transfer of chirality in the Biginelli reaction catalyzed by l-proline and its derivatives.
A: Activation of acylimine by the chiral Bronsted acid; B: Stereoselectivy attack of chiral enamine to the acylimine; C: Involvement of both (A and
B) activation properties on the asymmetric induction to provide chiral Biginelli adducts.
FIGURE 8 Catalysts evaluated by Sohn and collaborators for the Biginelli reaction. The values presented in parenthesis correspond to the
molar ratio of the mixture.
catalyst acts as a chiral Brønsted acid (Figure 7(a)). Another mechanism in which the acyl imine is stereoselectively
attacked by a chiral β-ketoester to provide a chiral enamine is possible (Figure 7(b)). Both of the previous mentioned
pathways could also occur in a single step to provide chiral Biginelli adducts (Figure 7(c)) [31].
The ester salts derived from l-proline (type I compounds; Figure 8) afforded the Biginelli adducts in good yields
(>80%) and enantioselectivity. The enantioselectivity was correlated with increasing steric hindrance of the R1 group
present on these catalysts [31]. Additionally, type II compounds (Figure 8), which would not lead to the formation of
enamine intermediates, provided Biginelli adducts in lower yields and enantioselectivities. This result confirms the
hypothesis that the enantioselectivity observed in the former reaction involves an enamine intermediate. Notably,
the use of d-proline provided the same products but with a reverse enantioselectivity [31].
In 2011, Saha and Moorthy reported the use of proline amides (CAT-22) as enantioselective catalysts for the Bigi-
nelli reaction. The authors evaluated 16 catalysts and found that CAT-22 (Table 4) was the best, providing the Bigi-
nelli adducts in moderate yields (>68%) and excellent enantioselectivities (94–99% ee) [32].
Thorat and co-workers [33] demonstrated that N-(4-F-phenyl)-1-tosylpyrrolidine-2-carboxamide (CAT-23) is an
efficient catalyst for the Biginelli reaction (Table 4) [33]. An example of an organic salt that catalyzes the Biginelli reac-
tion was reported by Ganem and collaborators in 2006. This methodology uses l-proline methyl ester hydrochloride
(CAT-24, Table 4) as a catalyst and provides the Biginelli adducts in reasonable yields (>77%); however, the adducts
obtained from aliphatic aldehydes are obtained in more modest yields (<66%) [34].
TABLE 5 Biginelli Reactions Catalyzed by Novel Amino Acids
Catalyst Yield (%) Reaction Times Solvent Molar Ratioa References
CAT-26 (0.5 mol%) 85–98 120 min --b 1:1:1.2 [37]
CAT-27 (160 mol%) 72–96 10 min EtOHc 1:1:1 [38]
CAT-28 (0.03 mol%) 89 60 min MeCNc 1:1:1 [39]

bUnder solvent-free conditions and at 100 °C.
cReflux temperature.
Xu and collaborators [35] evaluated the use of chiral amines as asymmetric catalysts for the Biginelli reaction and
found that amines with large alkyl chains effectively catalyze asymmetric Biginelli reactions [35]. The most effective
amine used by Xu and collaborators is CAT-25. This catalyst provided the highest conversion and stereoselectivity
(Table 4). Notably, apolar solvents play an important role in the enantioselectivity of this reaction. However, these
reaction conditions also lead to low yields. To overcome this disadvantage, the authors used Brønsted acids as addi-
tives and found that a solution of 10 mol% HCl provided the Biginelli adducts in excellent yields and enantioselec-
tivity (52–91% yield; 93–99% ee). However, the positive effect of HCl on the Biginelli reactions of aldehydes with
strongly electron-withdrawing substituents was not observed (Table 4) [35].
2.2.2 Other Amino Acids

In addition to l-proline, other amino acids have been described as useful catalysts for preparing Biginelli adducts.
Karthikeyan and collaborators [37] used l-amino acids supported on aluminum chloride (L-AAL/AlCl3; CAT-26;
Table 5). CAT-26 was shown to be robust and tolerant to water and also functioned as a base or Lewis acid in the
reaction medium. This catalyst was reused in up to five reaction cycles without losing catalytic activity. The scope of
this methodology was evaluated using various aldehydes, and the Biginelli adducts were obtained in excellent yields
(>85%) (Table 5) [37]. Sharma and colleagues [38] used glycine nitrate (CAT-27) as a catalyst in the Biginelli reaction.
This methodology provided the desired products in excellent yields (>72%), and the catalyst remained effective even
after 10 reuse cycles (Table 5) [38]. According to the authors and based on some experimental results, the mechanism
of this reaction involves the formation of a bis-urea intermediate that is then converted into the Biginelli adducts [38].
Glutamic acid (CAT-28) also showed good catalytic efficacy in the Biginelli reaction when only 0.03 mol% of CAT-28
was utilized (Table 5) [39].
2.3 Polymers and Macrocycles

Chitosan with a high molecular weight (CAT-29) was reported to be an effective catalyst for the Biginelli reac-
tion (Table 6). Chitosan is biodegradable and soluble in a mixture of water and acetic acid (2% w/w), has no
significant toxicity and can be reused in up to five catalytic cycles without losing efficiency. In addition to these
desired characteristics, CAT-29 does not undergo any structural changes, as analyzed by NMR spectroscopy, even
after reuse. The authors suggest that the mechanism of catalysis by CAT-29 involves the Knoevenagel condensa-
tion [40].
Silva and collaborators described calixarenes (CAT-30) as efficient catalysts in the Biginelli reaction [41]. They
found that the presence of a sulfonyl group on these calixarenes improved their catalytic properties, and the calix-
arene CAT-30 showed better results for the preparation of Biginelli adducts than other catalysts (Table 6). They also
showed that macrocyclic monomers, in amounts equivalent to CAT-30, resulted in lower efficiency, justifying the
use of calixarenes as supramolecular catalysts in these reactions. Aromatic aldehydes were good substrates (yields
>52%), while nonaromatic aldehydes were poor substrates (yields >34%). CAT-30 was reused in up to five cycles
without any loss of efficiency.
In 2011, Li used a chiral calixarene (CAT-31) to perform an asymmetric version of the Biginelli reaction (Table 6).
CAT-31 produced the Biginelli adducts in moderate yields and enantioselectivities (54%; 44% ee). As possible addi-
tives, a piperidine-TFA salt and p-toluic acid were used to provide the Biginelli adducts in 42% yield and 68% ee.
The monomer did not efficiently promote enantioselectivity in these reactions. From all tested aldehydes, those with
substituents in the meta-position had a better ee (80–98%), while those with substituents in the para-position had a
lower ee (20–69%). The proposed mechanism by the authors involved the enamine intermediate, which interacts with
the calixarene cavity in some manner, as confirmed by NMR experiments [42].
Verma and collaborators evaluated a series of polyethylene glycol (CAT-32) compounds adsorbed with urea
dioxide (TUD-I) or urea (TU-I) as well as some polyethylene glycol analogs with urea dioxide (TUD-II) and urea
(TU-II) (Figure 9) [43]. The authors found that both TUD-I and TUD-II showed satisfactory conversion to the prod-
ucts (>89%) under solvent-free conditions. Additionally, TUD-I was no longer efficient after the eighth cycle, while
TUD-II did not lose its efficiency even after eight cycles of reuse. The authors suggested that TUD-I loses the thiourea
dioxide bonding nucleus, which does not occur with TUD-II (CAT-33) as this analog is covalently bound to thiourea
dioxide (Table 6) [43].
Liberto and collaborators used cyclodextrin (CAT-33), a cyclic oligosaccharide derived from the enzymatic
degradation of starch, as a catalyst for the Biginelli reaction (Table 6) [44]. The authors evaluated the effect of
the cavity size of these macrocycles and found that the size of the cavity was not important for the catalytic
effects of these compounds [44]. The Biginelli reactions were carried out under solvent-free conditions. β-
Cyclodextrin (CAT-33) was the most efficient catalyst. Aromatic aldehydes showed better yields (>60%) than
aliphatic or heteroaromatic aldehydes (<38%). The cyclodextrin was reused at least five times without any loss
of efficiency [44].
Asghari and collaborators demonstrated the catalytic properties of sulfonated β-cyclodextrin (CAT-34,
Table 6). The catalyst works better under solvent-free conditions, and the Biginelli adducts were obtained
in good yields (>71%) under these conditions [45]. Zhou and collaborators showed that β-cyclodextrin, in
combination with HCl (CAT-35), provided the Biginelli adduct in 48% yield after 12 h (Table 6) [46]. Aliphatic
aldehydes were good substrates, and excellent yields (>84%) were observed when aromatic aldehydes were
employed [46].
2.4 Enzymes and Biocatalysts for the Biginelli Reaction

In 2011, Patil and colleagues reported the use of pineapple juice (CAT-36) as a catalyst for the preparation of
22 Biginelli adducts (Table 7) [47]. The versatility of this catalyst in the Biginelli reaction allowed researchers to
obtain the desired Biginelli adducts in moderate-to-excellent yields (60–93%) in reactions lasting 2–4.5 h (Table 7).
Sharma and collaborators reported the use of different lipases for catalyzing the Biginelli reaction (Table 7) [48].
The enzymes (CAT-37) used in this work were obtained and purified from microorganism, animal or plant species.
These authors found that the use of 50 mg of bovine serum albumin (BSA) and 0.25 mmol of the aldehydes in etha-
nol provided the best yields for the Biginelli adducts. A series of 17 Biginelli adducts were synthesized with good
TABLE 6 Biginelli Reactions Catalyzed by Polymers and Macrocycles
Catalyst Yield (%) Time Reaction Solvents Molar Ratioa References
CAT-29 (0.08 g)b 94–97 1.3–1.5 h H2Od,e 1:1:1.2 [40]
CAT-30 (0.5 mol%) 34–92 8 h EtOHf 1:1.5:1.5 [41]
CAT-31 (5 mol%) 22–48 3–4.5 h THF 1.2:2:1 [42]
CAT-32 (10 mol%) 89–98 24 h --g,h 1:1:1 [43]
CAT-33 (0.5 mol%) 26–91 3 h --g,i 1:1.5:1.5 [44]
CAT-34 (0.04 g)c 71–93 2 h --g,i 1:1:1.5 [45]
CAT-35 (10 mol%) 48–96 8 h EtOHf 1:1.2:1.5 [46]

cAmount of catalyst for each 2 mmol of aldehyde.
dAcOH was used as an additive. The following reactions were carried out.
fReflux temperature.
gUnder solvent-free conditions.
hTemperature at 50ºC.
iTemperature at 100 °C.
yields (69–83%); however, these lipases (CAT-37) lost their efficiency after two cycles (Table 7) [48]. In 2012, Borse
and collaborators developed a methodology for the Biginelli reaction using a lipase (CAT-38) as catalyst (Table 7)
[49]. This enzyme was obtained and purified from Rhizopus oryzae. Notably, only 5 mol% of the lipase (CAT-38) in
the mixture of choline chloride and urea was needed to afford the Biginelli adducts with good-to-excellent yields
2 2
2 + +1 2 + + 1
2 2 2
6
2 2 6
2 + +1 2 + +1 2
2 2
78',
78,
2
2
2 20H
2 20H
+
+ 1 1+
1 1+ 2
2
2 6
2 6
2 2
78',, 78,,
FIGURE 9 Hybrid catalysts derived from polyethylene glycol, urea dioxide, and/or urea.
TABLE 7 Biginelli Reactions Catalyzed by Enzymes or Biocatalysts
R2 O
O O HN O R 2
NH
H H X N N X
H H
N N
R1 O O X R1
Reaction: Catalyst
or + R2 + H2N NH2 or
O R1
R1 CHO R2 NH
N X
H
R1 = H, Ph, (CH2)5CH3, 4-OMe-C6H4, 2,4,5-(OMe)C6H2,
3,4-(-OCH2O-)C6H3, 3-OMe-4-OHC6H3, 4-OH-C6H4,
3-OH-C6H4, 4-Cl-C6H4, 3-Br-C6H4, 4-NO2-C6H4, C10H7,
4N,N(CH3)2C6H4, 4-Me-C6H4, 2-Cl-C6H4, 2-OH-C6H4,
2-NO2-C6H4, CH=CHPh, furfuryl,
or
H3CO
N
R2 = OEt, Me, OtBu or OMe

X = O or S
Catalysts: -Pineapple juice (CAT-36)

-Bovine Serum Albumin (BSA) (CAT-37)
-Lipase from Rhizopus oryzae (CAT-38)
CAT-36 (0.05 g)b 60–93 2–4.5 h --d 1:1:1 [47]
CAT-37 (100 μL)c 69–83 8–12 h EtOHe 1:1:1 [48]
CAT-38 (5% w/w) 73–95 4–6 h DESf 1:1.1:1.2 [49]

cAmount of catalyst for each 0.25 mmol of aldehyde. These reactions were carried out as follows.
dSolvent-free and room temperature.
fDES = deep eutectic solvent (mixture of choline chloride and urea). Temperature at 55 °C.
(Table 7). CAT-38 was reused in at least five cycles without significant loss of efficacy. The Biginelli reactions without
CAT-38 produced less than 20% of the desired products (Table 7) [49].
2.5 Other Organocatalysts Used in Biginelli Reactions

In 2008, Suzuki and colleagues reported the use of derivatives of hydrazine as organocatalysts for the Biginelli
reaction [50]. Among the catalysts employed, CAT-39 (Table 8) gave better yields with shorter reaction times. CAT-39
gave the desired compounds with good yields (70–97%) when isopropyl alcohol or DMSO was used as the solvent.
TABLE 8 Biginelli Reactions Catalyzed by Others Organocatalysts
CAT-39 (10 mol%) 70–97 180–2880 min iPrOH or DMSO 1:1.5:1.5 [50]
CAT-40 (5 mol%) 47–94 15–35 min Waterd 1:1:1.5 [51]
CAT-40 (10 mol%) 82–92 2.5–16 min --e 1:1:1.5 [52]
Continued
TABLE 8 Biginelli Reactions Catalyzed by Others Organocatalysts—cont’d

CAT-41 (10 mmol)b 35–98 8–35 min --f 1:1:1.5 [53]
CAT-42 (10 mol%) 85–97 120–240 min MeCNg 1:1:1.5 [54]
CAT-43 (50 mol%) 60–98 10–40 min --h 1:1:1.5 [55]
CAT-44 (0.05 g)c 90–95 3–4 min --i 1:1:1 [56]
CAT-45 (10 mol%) 54–81 180–480 min --j 1:1:1.5 [57]

cAmount of catalyst for each 10 mmol of aldehyde. These reactions were carried out.
dRoom temperature and ultrasound irradiation.
eSolvent-free and microwave irradiation.
fSolvent-free and temperature at 80 °C.
gRoom temperature.
hSolvent-free, temperature at 90 °C, and microwave irradiation.
iSolvent-free, temperature at 90–100 °C, and microwave irradiation.
jSolvent-free, temperature at 80 °C.
Thiamine hydrochloride (CAT-40) was also evaluated as a catalyst for the Biginelli reaction by Mandhane and col-
laborators (Table 8) [51]. Thiamine hydrochloride (CAT-40) at 5 mol% under ultrasound irradiation with water as the
solvent gave the best yields (>47%) for the Biginelli adducts (Table 8) [51]. Furthermore, Badadhe and collaborators
reported that the use of CAT-40 (10 mol%) under solvent-free and microwave irradiation conditions afforded the
Biginelli adducts in good-to-excellent yields (>82%) [52]. In both works, the authors confirmed the need for a cata-
lyst in the Biginelli reaction because no formation of Biginelli adducts was observed in the absence of CAT-40. Raju
and colleagues reported the synthesis of a series of Biginelli adducts obtained using ammonium trifluoroacetate as
a catalyst (CAT-41, Table 8) [53]. The Biginelli adducts were obtained under solvent-free conditions; however, it was
necessary to use 10 equivalents of CAT-41 relative to the aldehyde in these reactions (Table 8) [53]. Pentafluorophe-
nylammonium triflate (CAT-42), a Brønsted acid, was used by Khaksar and collaborators as an efficient catalyst for
the synthesis of Biginelli adducts [54]. CAT-42, in acetonitrile and at room temperature, afforded Biginelli adducts
in high yields (>85%) (Table 8). This methodology was useful for aldehydes with electron-donating or electron-
withdrawing substituents as well as for aliphatic aldehydes. No product was observed in the absence of CAT-42.
Raju and collaborators also reported the use of pyridinium trifluoroacetate (CAT-43) as an alternative catalyst for
the Biginelli reaction [55]. Under microwave irradiation and in the absence of solvents, 11 Biginelli adducts were
synthesized in yields ranging from 60% to 98% (Table 8). Although some of the principles of green chemistry were
involved in the methodology described here, the reuse of CAT-43 was not evaluated. Tetrabutylammonium bromide
(CAT-44) was also demonstrated to act as a catalyst in a Biginelli reaction [56]. Accordingly, CAT-44 was able to
catalyze the Biginelli reactions under solvent-free conditions and microwave irradiation. The Biginelli adducts were
obtained under these conditions in yields higher than 90% (Table 8). Debache and collaborators (2012) demonstrated
the catalytic properties of potassium tert-butoxide (CAT-45) in the Biginelli reaction [57]. All reactions were carried
out in the absence of solvents and 10 mol% of CAT-45 was sufficient to provide the Biginelli adducts in moderate-to-
good yields (Table 8).
3. BIOLOGICAL SIGNIFICANCE OF 3,4-DIHYDROPYRIMIDIN-2(1H)-ONES/-THIONES
Currently, the interest in the Biginelli reaction relies on the release of a series of publications about the biological
activities of DHPMs. These include antiproliferative [58], antimicrobial [59], anti-inflammatory [60], antioxidant [61],
and calcium channel modulation [62] activities.
Monastrol (Figure 10), the most representative Biginelli adduct in anticancer drug development, showed to be
a cell permeable molecule whose mechanism of action on cancer cells involves the selective inhibition of kinesin
Eg5 [63]. Kinesin Eg5 is a motor enzyme that is responsible for the formation and maintenance of mitotic spindles.
The inhibition of this enzyme activity by monastrol leads to the loss of chromosome alignments and bipolar
spindle formation. The resulting “monastral phenotype” inspired scientists to name this specific Biginelli com-
pound as monastrol [63]. Fluorastrol (Figure 10), a monastrol-derived Eg5 inhibitor, showed to be more potent
3. BIOLOGICAL SIGNIFICANCE OF 3,4-DIHYDROPYRIMIDIN-2(1H)-ONES/-THIONES 333
FIGURE 10 Biginelli compounds tested against cancer cell lines.
FIGURE 11 Biginelli adducts that exhibit antimicrobial activity.
than monastrol as the former can interact with an allosteric site of this enzyme due to the presence of fluorine
atoms [64].
Biginelli compounds can also modulate the protein Hsp 70 [65]. DHPM-peptoid (Figure 10) is one of the most
active Biginelli adducts on Hsp 70 [66]. This protein, known to be overexpressed in some cancer cell lines, is respon-
sible for many cellular processes, such as rearrangement and transport of protein complex [66].
In 2011, Akhaja and co-workers reported several Biginelli adducts with pronounced activity against Escherichia
coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Staphylococcus aureus. The DHPM 8 (Figure 11) exhibited good
activity against all microbial strains tested [67]. Singh and co-workers [68] reported the antifungal activity of Biginelli
adducts against three species of fungi, among them are Aspergillus niger and Trichoderma hammatum. The dihydro-
pyrimidinone 9 (Figure 11) was one of the most potent synthesized molecules against A. niger, exhibiting an MIC
value of 0.35 mg/mL [68]. Recently, Kim and co-workers disclosed the anti-HIV activity of a series of dihydropyrim-
idinones. Thirty four dihydropyrimidinones were synthesized and the molecule 10 (Figure 11) was found to exhibit
significant inhibitory activity against HIV-1 in a cell-based assay [69].
Dihydropyridines (DHPs), such as nifedipine, were introduced to clinical medicine in 1975 to treat cardiovascular
diseases, such as hypertension, cardiac arrhythmias or angina [70]. Many nifedipine analogs were synthesized and
the dihydropyridiminone 11 (Figure 12) was demonstrated as the first DHP derivative to exhibit moderate hypoten-
sive and coronary relaxation properties [71].
Other structural modifications on the dihydropyrimidine ring were described, which led to Biginelli adducts
bearing an ester group at N3. The most potent compound was the thiourea derivative 12 (Figure 12) [62]. The cal-
cium channel blocking activity of 12 was comparable to that of DHPs. However, compound 12 did not exhibit anti-
hypertensive activity in in vivo model as this Biginelli adduct is quickly metabolized after oral administration [62].
Then, the derivatives 13 and 14 (Figure 12) were synthesized in an attempt to overcome the fast metabolism post
oral administration. Indeed, 13 and 14 presented antihypertensive activity due to its higher bioavailability when
compared to 12. Compounds 13 and 14 were also more potent and exhibited longer action than nifedipine [72,73].
Rovnyak and co-workers performed a detailed pharmacological study with a large set of dihydropyrimidine ana-
logs to better understand the structure–activity relationships for N3-functionalized compounds with respect to their
potential as calcium channel blockers [73]. The authors found that an ortho and/or meta aromatic substitution and
the presence of an ester alkyl group at C5 were critical for the in vitro activity of the Biginelli compounds tested. The
(R)-enantiomers of Biginelli compounds such as 13 and 14 where shown to be more potent than the corresponding
(S)-enantiomers [72,73].
FIGURE 12 Structure of nifedipine and related dihydropyrimidines, which are known as calcium channel blockers.
4. CONCLUDING REMARKS
The diverse biological profile exhibited by Biginelli adducts brought new perspectives for the development of new
drugs based on DHPM core. In turn, the advent of organocatalysis in the Biginelli reaction opened a new window
for a complementary mode of catalysis with the potentials in saving cost, time, and energy, an easier experimental
procedure, and reduction in chemical waste. It is expected that interest in this approach grows even more and new
organocatalysts will come into light in near future. However, a better understanding on how these organocatalysts
cause rate acceleration and induce stereoselectivities requires more studies. This knowledge will certainly contribute
to the rational design of more efficient and selective catalysts as a whole.
ABBREVIATIONS

BINOL 1,1′-Bi-2-naphthol
BSA Bovine serum albumin
CAPES Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
CAT Catalyst
CNPq Conselho Nacional de Desenvolvimento Científico e Tecnológico
DCM Dichloromethane
DES Deep eutectic solvent
DHPs Dihydropyridines
DHPMs Dihydropyrimidinones
DMSO Dimethyl sulfoxide
ESI-MS Mass spectrometry by direct infusion electrospray
FAPEMIG Fundação de Amparo à Pesquisa do Estado de Minas Gerais
HIV Human immunodeficiency virus
L-ALL/AlCl3 L-amino acids supported on aluminum chloride
MIC Minimum inhibitory concentration
MW Microwave irradiation
NMR Nuclear magnetic resonance
NOESY Nuclear Overhauser effect spectroscopy
PEG Polyethyleneglycol
PFBA Perfluorobutyric acid
PPF Polypropylene fibers
SBSSA Silica-bonded S-sulfonic acid
SCMs Sulfonated carbon materials
SPINOL 1,10-Spirobiindane-7,70-diol
THF Tetrahydrofuran
TFA Trifluoroacetic acid
TTSA 1,3,5-Triazine-2,4,6-triylsulfamic acid
TUD-I Polypropylene glycol adsorbed with urea dioxide
References 335
TUD-II Polypropylene glycol analogues with urea dioxide
TU-I Polypropylene glycol adsorbed with urea
TU-II Polypropylene glycol analogues with urea
Acknowledgments
Authors are thankful to the financial support provided by Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Conselho
Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).
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Organocatalyzed Biginelli Reactions

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Organocatalyzed Biginelli Reactions

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C H A P T E R

1. Introduction 317 2.4 Enzymes and Biocatalysts for the Biginelli

1.1 The Biginelli Reaction

Green Synthetic Approaches for Biologically Relevant Heterocycles 317

1.2 Mechanism of the Biginelli Reaction: An Overview

FIGURE 2 Examples of building blocks employed in the Biginelli reaction [2–5].

FIGURE 3 Proposed mechanisms for the Biginelli reaction.

FIGURE 4 Structures of selected ions observed in the Biginelli reaction.

FIGURE 5 Structures of the ions proposed by de Souza and collaborators [8].

2. CLASSES OF ORGANOCATALYSTS USED IN THE BIGINELLI REACTION

2.1 Organic Acids: Catalysts for Biginelli Reactions

Catalyst Yield (%) Reaction Time Solvent Molar Ratioa References

CAT-1 (5 mmol%) 61–88 4 h EtOHb 1:1:1.5 [13]

CAT-2 (5 mmol%) 70–96 4 h EtOHb 1:1:1.5 [13]

CAT-3 (25–40 mmol%) 79–92 2.5–4 h EtOHb 1:1:1.5 [12]

CAT-4 (5 mol%) 53–85 6–12 h --c 1:1:1.5 [14]

TABLE 2 Biginelli Reactions Catalyzed by Organic Acids

Catalyst Yield (%) Reaction Time Solvent Molar Ratioa References

CAT-5 (24 mmol%) 85–94 30–50 min H2Od 1:1:1.5 [15]

CAT-6 (20 mol%) 84–96 2–50 min --e 1:1:1 [16]

CAT-7(10 mol%) 74–98b 3.5–5 minb H2O 1:1:1 [17]

CAT-8 (10 mol%) 65–97 480 min MeCNf 1:1:1 [18]

CAT-9(10 mol%) 40–86 4 days DCM 1:1.2:5 [19]

CAT-10 (5 mol%) 80–98 3 days Xyleneg 1:1.2:3 [20]

Catalyst Yield (%) Reaction Time Solvent Molar Ratioa References

CAT-11 (0.005 g)b 71–93 60 min HOAce 1:1:1.25 [21]

CAT-12 (0.1 g)c 80–92 15–30 min --f 1:1:1.5 [22]

CAT-13 (1 mol%) 68–88 480 min EtOHg 1:1.1:1.5 [23]

CAT-14 (3 mol%) 69–96 2–4 min MeCNh 1:1:1 [24]

CAT-15 (0.05 g)d 65–90 210–390 min H2O 1:1.2:1 [25]

CAT-16 (0.05 g)d 80–95 330 min EtOHg 1:1:1.2 [26]

CAT-17 (10 mol%) 84–94 240 min MeCN 1:1:1.5 [27]

CAT-18 (10 mol%) 80–92 240–270 min MeCN 1:1:1.5 [28]

Catalyst Yield Reaction Time Solvent Molar Ratioa References

CAT-19 (15 mol%) 79–90 7 h MeCNf,g,j 1:1:1.5 [29]

CAT-20 (808 mol%)b 50–90 6 h EtOHk 1:1.1:1.5 [30]

CAT-21 (10 mol%) 80–87c 24 h THFg,l 0.2:1:1.2 [31]

CAT-22 (10 mol/%) 48–68d 72–96 h Dioxane/THFh 1:20:2 [32]

CAT-23 (80 mol%) 78–89 4–5 h EtOH 1:1:1,5 [33]

CAT-24 (10 mol%) 63–99 18 h EtOHk 2:1:1.5 [34]

CAT-25 (10 mol%) 5–91e 48–72 h dioxane/CHCl3i 1:3:3 [35]

Catalyst Yield (%) Reaction Times Solvent Molar Ratioa References

CAT-26 (0.5 mol%) 85–98 120 min --b 1:1:1.2 [37]

CAT-27 (160 mol%) 72–96 10 min EtOHc 1:1:1 [38]

CAT-28 (0.03 mol%) 89 60 min MeCNc 1:1:1 [39]

2.2.2 Other Amino Acids

2.3 Polymers and Macrocycles

2.4 Enzymes and Biocatalysts for the Biginelli Reaction

Catalyst Yield (%) Time Reaction Solvents Molar Ratioa References

CAT-29 (0.08 g)b 94–97 1.3–1.5 h H2Od,e 1:1:1.2 [40]

CAT-30 (0.5 mol%) 34–92 8 h EtOHf 1:1.5:1.5 [41]

CAT-31 (5 mol%) 22–48 3–4.5 h THF 1.2:2:1 [42]

CAT-32 (10 mol%) 89–98 24 h --g,h 1:1:1 [43]

CAT-33 (0.5 mol%) 26–91 3 h --g,i 1:1.5:1.5 [44]

CAT-34 (0.04 g)c 71–93 2 h --g,i 1:1:1.5 [45]

CAT-35 (10 mol%) 48–96 8 h EtOHf 1:1.2:1.5 [46]

TABLE 7 Biginelli Reactions Catalyzed by Enzymes or Biocatalysts

R2 = OEt, Me, OtBu or OMe

Catalysts: -Pineapple juice (CAT-36)

Catalyst Yield (%) Reaction Time Solvent Molar Ratioa References

CAT-36 (0.05 g)b 60–93 2–4.5 h --d 1:1:1 [47]

CAT-37 (100 μL)c 69–83 8–12 h EtOHe 1:1:1 [48]

CAT-38 (5% w/w) 73–95 4–6 h DESf 1:1.1:1.2 [49]

2.5 Other Organocatalysts Used in Biginelli Reactions

1. Introduction 317 2.4 Enzymes and Biocatalysts for the Biginelli