Synthesis of structurally diverse 3,4-dihydropyrimidin-2(1H)-ones via sequential Biginelli and Passerini reactions

Article abstract of DOI:10.3762/bjoc.13.7

The Biginelli reaction was combined with the Passerini reaction for the first time in a sequential multicomponent tandem reaction approach. After evaluation of all possible linker components and a suitable solvent system, highly functionalized dihydropyrimidone-α-acyloxycarboxamide compounds were obtained in good to excellent yields. In a first reaction step, different 3,4-dihydropyrimidin-2(1H)-one acids were synthesized, isolated and fully characterized. These products were subsequently used in a Passerini reaction utilizing a dichloromethane/dimethyl sulfoxide solvent mixture. By variation of the components in both multicomponent reactions, a large number of structurally diverse compounds could be synthesized. In addition, a one-pot Biginelli-Passerini tandem reaction was demonstrated. All products were carefully characterized via 1D and 2D NMR as well as IR and HRMS.

Full text of DOI:10.3762/bjoc.13.7

Synthesis of structurally diverse 3,4-dihydropyrimidin-2(1H)-
ones via sequential Biginelli and Passerini reactions
Andreas C. Boukis, Baptiste Monney and Michael A. R. Meier*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 54–62.
Karlsruhe Institute of Technology (KIT), Institute of Organic
Chemistry, Materialwissenschaftliches Zentrum MZE, Building 30.48,
Straße am Forum 7, 76131 Karlsruhe, Germany
doi:10.3762/bjoc.13.7
Received: 29 July 2016
Accepted: 21 December 2016
Published: 09 January 2017
Email:
Michael A. R. Meier* - m.a.r.meier@kit.edu
This article is part of the Thematic Series "Organic porous materials".
Guest Editor: S. Bräse
* Corresponding author
Keywords:
Biginelli reaction; molecular diversity; multicomponent reactions;
Passerini reaction; tandem reactions
© 2017 Boukis et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The Biginelli reaction was combined with the Passerini reaction for the first time in a sequential multicomponent tandem reaction
approach. After evaluation of all possible linker components and a suitable solvent system, highly functionalized dihydropyrimi-
done–α-acyloxycarboxamide compounds were obtained in good to excellent yields. In a first reaction step, different 3,4-dihydro-
pyrimidin-2(1H)-one acids were synthesized, isolated and fully characterized. These products were subsequently used in a Passerini
reaction utilizing a dichloromethane/dimethyl sulfoxide solvent mixture. By variation of the components in both multicomponent
reactions, a large number of structurally diverse compounds could be synthesized. In addition, a one-pot Biginelli–Passerini tandem
reaction was demonstrated. All products were carefully characterized via 1D and 2D NMR as well as IR and HRMS.
Introduction
Multicomponent reactions (MCRs) are fascinating straightfor- processes [4-6]. MCRs found numerous applications, i.e., in
ward reactions for the preparation of diversely substituted prod- combinatorial chemistry, target oriented synthesis or polymer
ucts starting from three or more precursor molecules, forming science [6-8]. The most important MCRs are the Strecker amino
products containing atoms/moieties of all precursor compo- acid synthesis (1850), the Hantzsch dihydropyridine synthesis
nents. MCRs are often one-pot reactions with high-atom (1882), the Biginelli dihydropyrimidone synthesis (1891), the
economy, convergence and efficiency. Generally, one-pot pro- Mannich reaction (1912), the Passerini three-component reac-
cedures have many advantages compared to multiple-step syn- tion (1921) and the Ugi four-component reaction (1959) [9]. In
theses [1-3]. One-pot MCRs can shorten reaction times, provide this work, we used Biginelli and Passerini reactions to synthe-
high yields, reduce work-up steps and waste as well as energy size highly functionalized compounds, hence both reactions will
consumption and hence lead to more effective and sustainable be described in detail.
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Beilstein J. Org. Chem. 2017, 13, 54–62.
The Biginelli reaction
Lewis- or a Brønsted acid. In the next step, urea/thiourea 2 can
The Biginelli reaction is a three-component reaction between an serve as a nucleophile and react with the activated carbonyl car-
aldehyde (in many cases aromatic aldehydes give much better bon to form a heminal species. However, under acidic condi-
results than aliphatic ones), a β-keto ester (α-acidic compound) tions heminals can eliminate water and form an N-acyliminium
and urea or thiourea (some mono N-substituted ureas can also cation 3. This reactive cation 3 can then react with the nucleo-
be employed). The Biginelli reaction was discovered in 1891 by philic α-carbon atom of β-ketoester 4 to an open chain ureide 5.
the chemist Pietro Biginelli [10]. Later, Biginelli identified the Subsequent ring closure results in a hexahydropyrimidine inter-
reaction product as a 3,4-dihydropyrimidin-2(1H)-one (DHMP) mediate 6. In the last step, the irreversible elimination of water
[11]. DHMPs are of great interest due to their pharmaceutic ac- forms the thermodynamically favored DHMP product 7. This
tivities (i.e., calcium channel modulation, α1a adrenoceptor- accepted mechanism was supported by spectroscopic data.
selective antagonists, cancer therapy, anti-HIV alkaloids) [12- However, alternative mechanisms are discussed in the literature
15]. The mechanism of the Biginelli cyclocondensation was [17,18]. In the so called enamine route, urea 2 and the
proposed and investigated by Kappe and is illustrated in β-ketoester 4 form an enamine in the first reaction step. Subse-
Scheme 1a [16]. According to the generally accepted mecha- quently, the enamine reacts with the aldehyde 1 [19]. A third
nism of the Biginelli reaction, aldehyde 1 is activated by a mechanism discussed, is the Knoevenagel type reaction be-
Scheme 1: a) Proposed mechanism of the Biginelli reaction according to [6]. b) Proposed mechanism of the Passerini reaction.
55

Beilstein J. Org. Chem. 2017, 13, 54–62.
tween the aldehyde 1 and β-ketoester 4 followed by a subse- trated in Supporting Information File 1, Scheme S1. All synthe-
quent reaction with urea 2 [20].
sized substances are displayed in Supporting Information File 1,
Figure S1.
The Passerini reaction
The Passerini reaction was discovered in 1921 by Mario Results and Discussion
Passerini and is a three-component reaction between a car- For the Biginelli–Passerini sequential reaction, the Biginelli
boxylic acid 8, a carbonyl compound 9 and an isocyanide 11 reaction was performed first, in order to avoid undesired trans-
[21]. The Passerini reaction works best in non-polar solvents esterification reactions (of the Passerini product) due to the
like dichloromethane. The mechanism of the Passerini reaction acidic conditions of the Biginelli reaction [33]. A general chal-
(Scheme 1b) is proposed to proceed via the formation of a lenge, which has to be faced in this context, is the choice of sol-
hydrogen bond (H-bond) adduct between carboxylic acid 8 and vent and the selection of bifunctional components (which can
carbonyl component 9, resulting in a six-membered cyclic interlink both the Biginelli and the Passerini reaction). In the
H-bond adduct 10. Subsequently, isocyanide 11 reacts with 10, earlier reported Biginelli–Ugi tandem reaction of Wipf et al.
thereby showing a simultaneous nucleophilic and electrophilic [36], methanol was used as solvent. As mentioned previously,
reactivity (α-addition). The herein formed seven-membered the solvent of choice for the Passerini reaction is dichloro-
intermediate has not been isolated, because it immediately methane, providing the highest yields. The DHMP Biginelli
undergoes a rearrangement, affording the Passerini α-acyloxy- products, however, are in most cases very poorly soluble in
carboxamide adduct 12 [18].
non-polar solvents. In our investigations, a solvent mixture of
dichloromethane with a small amount of dimethyl sulfoxide
(polar but aprotic) allowed the successful combination of both
Tandem reactions
Tandem reactions (also known as cascade [22] or domino reac- chemistries. All possible bifunctional components for the
tions [23]) are chemical transformations that involve at least Biginelli–Passerini reaction are represented in Figure 1. Com-
two independent reactions utilizing different functional groups pared to the above mentioned multicomponent tandem ap-
with distinct chemical reactivities [24-27]. So far, only a few proaches, our strategy provides higher yields and makes use of
examples of multicomponent tandem reactions are described in more bifunctional linker components.
the literature [28,29]. Portlock et al. reported on Petasis–Ugi
tandem reactions leading to a product with six different side Careful evaluation of the bifunctional components allowed a
chains [30,31]. Al-Tel et al. combined the Groebke–Blackburn pre-selection: A3, B3 and C3 in Figure 1 carry an isocyanide
reaction with either Passerini or Ugi reactions in a sequential functionality, which could hydrolyze under the acidic condi-
one-pot procedure [32]. Furthermore, up to eight components tions for the Biginelli reaction [38]. Components A2, B2 and
were reacted by the combination of three multicomponent reac- C2 carry an aldehyde functional group for the Passerini reac-
tions [33]. In 2010, the Ugi reaction and the Ugi–Smiles reac- tion, but this could react on both sides in the Biginelli reaction.
tion were combined by Westermann et al. [34]. In addition, the Therefore, A2, B2, C2 as well as A3, B3, C3 were excluded
Ugi reaction was used in combination with the Biginelli reac- from our investigations. The remaining components A1, B1 and
tion by Brodsky et al. [35]. In this work, five Biginelli acids C1 seemed most promising for our purposes. Hence, we
were synthesized in 33–83% yields and utilized in a Ugi reac- focused on commercially available components with A1, B1
tion for the synthesis of six DHMP amides with 21–63% yields. and C1 like structures, i.e., C1: 4-formylbenzoic acid; B1:
In a similar reaction strategy, Wipf et al. synthesized a library N-carbamoylglycine, A1: benzyl acetoacetate for the Biginelli
of twelve Biginelli compounds and reacted them with the reaction and subsequent hydrogenolytic deprotection to the cor-
respective Ugi components under reflux in methanol to yield 30 responding acid.
different DHMP amides in 5–51% yield [36]. Furthermore, the
Biginelli reaction has been used in a polymerization process The Biginelli reactions were performed in dimethyl sulfoxide at
combined with the Hantzsch reaction to from copolyconden- 110 °C in order to remove the water formed in course of the
sates [37]. It is noteworthy that in the literature the term tandem reaction. After a simple washing procedure, the desired DHMP
is not always used consistently with the initial definition by acids 13–18 were obtained in 63–93% yield (Table 1). Alterna-
Tieze et al. [23].
tive syntheses for DHMP acids (13–15 and 17) were described
in literature and can be found in Supporting Information File 1.
In this work, the Biginelli reaction was combined in a sequen- However, our Biginelli approach is simple, utilizes p-TSA as a
tial approach with the Passerini reaction for the first time. cheap catalyst, provides high yields and can be used for the
Furthermore, both reactions were combined in a one-pot tandem preparation of various DHMP acids with different bifunctional
procedure. A general overview of our investigations is illus- linkers. Aliphatic aldehydes did not react well under these
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Beilstein J. Org. Chem. 2017, 13, 54–62.
Figure 1: Bifunctional components for the Biginelli–Passerini tandem reaction.
Table 1: Biginelli reactions for the preparation of DHMP acids.a
Entry
R1
R2
R3
Yield [%]
Product
1
Ph
Ph
Ph
Ph
H
Bn
H
91
93
63
78
13
14
15
16
2b
3
H
CH2CO2H
CH2CO2H
Et
Bn
4
5
6
H
H
Et
90
91
17
18
Bn
aConditions: 0.10 equiv p-TSA, 110 °C 8–48 h in DMSO. bObtained via hydrogenolytic deprotection of product 13 (entry 1). Conditions: H2 (balloon),
10 wt % Pd/C, acetic acid/ethanol (1:3), 50 °C, 15 h.
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Beilstein J. Org. Chem. 2017, 13, 54–62.
conditions (even after longer reaction periods of up to six days) reaction of DHMP 18 was not completely homogeneous, which
and product isolation was not straightforward.
might be responsible for the lower yield of 20 (22%). For the
other reactions investigated in this work, our Passerini protocol
For the subsequent Passerini reactions, the DHMP acids were proved to be robust and very effective providing very good to
dissolved in a mixture of dichloromethane and dimethyl sulf- quantitative yields (up to 99% for 23). In Figure 2, a representa-
oxide (4:1 → 2:1). After the subsequent addition of the alde- tive 1H NMR comparison between the DHMP acid 17 and the
hyde and isocyanide components, three days reaction time at Passerini product 19 is illustrated. The CO2H proton at
room temperature and subsequent purification via column chro- 12.9 ppm disappeared after the Passerini reaction, while all
matography, the Biginelli–Passerini products 19–25 were ob- other DHMP signals, i.e., the NHC at 9.2 ppm, the CHNH at
tained in 22–99% yield (Table 2).
5.2 ppm or the CCH3 at 2.3 ppm, did not shift. Furthermore, the
new characteristic signals for the CCHO at 4.9 ppm, the
The lower yield for 25 (39%) might be due to the tertiary amine C(CH3)3 at 1.2 ppm and the terminal CH2CH3 methyl group at
structure of the morpholinoethyl side chain, requiring a more 0.84 ppm strongly indicate the formation of the respective
complex purification. The reaction mixture for the Passerini Biginelli–Passerini product.
Table 2: Passerini reaction on DHMP acids.a
Entry DHMP
acid
R1
R2
H
R3
Et
R4
R5
t-Bu
Yield
[%]
Product
19
1
2
3
17
18
17
C6H13
C6H13
67
22
98
H
Bn
Et
t-Bu
20
H
cyclohexyl
21
4
5
6
15
15
15
Ph
Ph
Ph
CH2COOH
CH2COOH
CH2COOH
Et
Et
Et
iPr
t-Bu
t-Bu
Bn
76
99
76
22
23
24
C10H19
C7H15
7
15
Ph
CH2COOH
Et
C7H15
39
25
8
15
–
Ph
CH2COOH
CH2COOH
Et
Et
C5H11
C5H11
79
41
26
27
9b
p-C6H4Fc
p-C6H4Fc
aConditions: Room temperature, 3 d in DCM. bOne pot procedure: Biginelli acid was not isolated.
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Beilstein J. Org. Chem. 2017, 13, 54–62.
Figure 2: Stacked 1H NMR spectra and signal assignment. Top: DHMP acid 17; bottom: Biginelli–Passerini tandem product 19.
As a proof of principle, the Biginelli and Passerini reaction 40 °C, 60 °C and 80 °C were conducted. Even at higher temper-
were combined in a one-pot synthesis. In this experiment, the atures the peak splitting remained, evidencing that the splitting
Biginelli reaction was performed with an excess of the alde- was not caused by rotational barriers or conformational effects.
hyde component (three equivalents) in a minimal amount of Furthermore, the splitting was not observed in the DHMP acids
dimethyl sulfoxide. After completion of the Biginelli reaction, 13–18 (after the Biginelli reaction, which was performed first).
the crude reaction mixture was cooled to room temperature and In principle, the Biginelli and Passerini reactions both form
diluted with dichloromethane. Subsequently, an isocyanide was a new chiral centre, which was not controlled in our investiga-
added to the mixture enabling the Passerini reaction with the tions, leading to a racemic mixture (R and S). After the
exceeding aldehyde. The resulting one-pot product 27 was ob- Passerini reactions, four different stereoisomers (RR, RS, SR,
tained in 41% yield after column chromatography (Table 2, SS) are thus obtained. The homo (RR, SS) and hetero pairs (RS,
entry 9). However, the structural diversity in this approach is SR) are diastereomers with slightly different physical properties.
limited if compared to the previously described two-step ap- In the context of our experimental NMR data, it is thus fair to
proach (isolation of Biginelli acid) because the same aldehyde assume that the peak splitting is caused by these diastereomers
component is participating in both MCRs.
(Figure 4).
Interestingly, the 1H and 13C NMR spectra of the chromato- Conclusion
graphically pure Biginelli–Passerini products displayed a signal The Biginelli reaction was successfully combined with the
splitting for distinct signals (Figure 3).
Passerini reaction to obtain highly functionalized DHMP
heterocyclic products. For this purpose, different DHMP acids
A more detailed analysis revealed that most of the split signals were prepared by variation of the components and the bifunc-
were located either next to chiral centres in the molecule or in tional linker. The DHMP acids were then reacted in a Passerini
the six-membered DHMP core. In order to identify the cause of reaction employing a dichloromethane/dimethyl sulfoxide sol-
this peak splitting, high temperature NMR experiments at vent mixture. The respective Biginelli–Passerini reaction prod-
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Beilstein J. Org. Chem. 2017, 13, 54–62.
Figure 3: Representative HSQC spectrum of the pure Biginelli–Passerini tandem product 21, expansions and signal assignment for two asymmetric
carbon atoms. A: Diastereomeric signal splitting in 1H NMR solely. B: Diastereomeric splitting in both 1H and 13C NMR, two different species can be
identified.
Figure 4: Stereoisomers formed in the Biginelli–Passerini tandem reaction. The homo (RR, SS) and hetero pairs (RS, SR) are diastereomers.
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Beilstein J. Org. Chem. 2017, 13, 54–62.
14.Selvam, T. P.; James, C. R.; Dniandev, P. V.; Valzita, S. K.
ucts were in most cases obtained in good to excellent yields.
Furthermore, a one-pot Biginelli–Passerini reaction without
intermediate work-up was demonstrated. All compounds of this
investigation were carefully characterized via NMR (1D and
2D), IR and HRMS. The herein presented strategy is currently
under investigation for the preparation of sequence-defined
macromolecules [39,40]. Furthermore, the obtained compounds
present a rigid, geometrically fixed and highly functionalized
DHMP moiety, which could potentially be utilized for covalent
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Supporting Information File 1
Experimental section and NMR spectra of all synthesized
compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-7-S1.pdf]
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Acknowledgements
27.Batey, R. A. J. Am. Chem. Soc. 2007, 129, 7476.
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A.B. is grateful for a scholarship from the Fonds der Che-
mischen Industrie. We would like to thank SFB1176 (project
A3) for financial support and our colleague Prof. Podlech from
the Institute of Organic Chemistry at KIT for kindly sharing lab
space with us.
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