Evaluation of alcohols as substrates for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones under environmentally friendly conditions

Article abstract of DOI:10.1016/j.catcom.2019.105887

The aim of this research was to develop a procedure for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones under environmentally friendly conditions using alcohols as the starting materials in aqueous media. The developed protocol resulted in 3,4-dihydropyrimidin-2(1H)-ones derivatives, which are relevant intermediates with therapeutic and pharmacological properties. Target products were synthetized in a tandem process, which meets the requirements of pharmaceutical chemistry. The influence of the reaction conditions was investigated, and as a result, various substituted 3,4-dihydropyrimidin-2(1H)-ones were obtained with a yield of up to 81percent, free from heavy metal impurities.

Full text of DOI:10.1016/j.catcom.2019.105887

Journal Pre-proof
Evaluation of alcohols as substrates for the synthesis of
3
,4-dihydropyrimidin-2(1H)-ones under environmentally friendly
conditions
Aleksandra Kęciek, Daniel Paprocki, Dominik Koszelewski,
Ryszard Ostaszewski
PII:
S1566-7367(19)30348-6
DOI:
https://doi.org/10.1016/j.catcom.2019.105887
CATCOM 105887
Reference:
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
12 September 2019
4 November 2019
5 November 2019
Please cite this article as: A. Kęciek, D. Paprocki, D. Koszelewski, et al., Evaluation
of alcohols as substrates for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones under
environmentally friendly conditions, Catalysis Communications (2019), https://doi.org/
1
0.1016/j.catcom.2019.105887
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Evaluation of alcohols as substrates for the synthesis of 3,4-dihydropyrimidin-2(1H)-
ones under environmentally friendly conditions
Aleksandra Kęciek, Daniel Paprocki, Dominik Koszelewski and Ryszard Ostaszewski*
Institute of Organic Chemistry PolishAcademy of Sciences, Kasprzaka 44/52,01-224Warsaw, Poland
ABSTRACT
The aim of this research was to develop a procedure for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones under environmentally friendly conditions
using alcohols as the startingmaterials in aqueous media. The developed protocol resultedin 3,4-dihydropyrimidin-2(1H)-ones derivatives, which are
relevant intermediates with therapeutic and pharmacological properties. Target products were synthetizedin a tandem process, which meets the
requirements of pharmaceutical chemistry. The influence of the reaction conditions was investigated, and as a result, various substituted 3,4-
dihydropyrimidin-2(1H)-ones were obtained with a yield of up to 81%, free from heavy metal impurities.
Keywords: Biginelli reaction; tandem reaction; environmentally friendly conditions
1
. Introduction
,4-Dihydropyrimidin-2(1H)-ones (DHPMs) are well known for their biological and pharmacological properties such as
3
antifungal[1], antiviral[2], cardiotropic[3], anti-inflammatory[4], hypotensive[3], antitumor[5], and antioxidant[6] activities. DHPMs
can be obtained by a multicomponent reaction, discovered in the 19th century by Pietro Biginelli. This HCl-catalyzed reaction was
carried out with an aldehyde,urea, and β-keto esterin ethanol.However,productswere obtained with moderate yields (20-50%)[7]. To
enhance thereactionyield,variousmethods have been elaborated,suchas ultrasound irradiation[8]; usage ofionic liquids[9]; synthesis
on the solid phase[10]; microwave irradiation[11]; and application of Lewis acid such as Zn(OTf)
2 5 2
[12], TaBr [13], Sr(OTf) [14], and
RuCl [15] or Brønsted acid as a catalyst. Recently, Procopio et al. reported that ErCl under microwave irradiation catalyzes the
3
3
Biginelli reaction,providing products with high yield[16]. Nevertheless, the reported methods suffer fromsome drawbacks such as
harsh reaction conditions, toxic and expensive catalysts, moderate yields, and tedious product isolation. Moreover, because of
pharmaceutical requirements, the level of heavy metals must be maintained below 5 ppm[17], what makes the above-mentioned
methods barely acceptable for this industry.
In chemical reactions,uponformation of the desired product, several by-products and impurities may be formed. In recent years,
there has been significantincrease in public awareness of the environmental issues in chemical syntheses. Therefore, a new type of
chemical process that is green and environmentally friendly has become highly appreciated, where high emphasis is placed on the
reduction oftoxic wastes and solvents. As a result, new programs and principles are formulated, which support green chemistry, for
example, “American ProgramPresidentialGreen Chemistry Challenge Awards Program”[18]. Enzymes are a sustainable catalyst that
can be easily separated fromproducts in contrast to the metal catalysts.
For example, it has been shown that lipasescatalyze the Biginellireaction providing desired products, DHPMs, with high yield (73-
9
5%) in deep eutectic solvent (DES)[19]. Unfortunately,these solventsare expensive andtoxic.The DHPM synthesiswas also reported
by Feng Xu et al., in which CuCl x H O was applied as a catalyst underaqueousconditions[20].Furthermore,it has been demonstrated
2
2
that the application of surfactants such as sodiumdodecyl sulfonate and sodiumdodecyl sulfate has a beneficial effect on DHPM
synthesis,leading to the substantialincrease in the reaction yield.The application ofthe surfactants overcomes the main disadvantage
of the low solubility of the organic compounds in aqueous medium[20,21].
Aldehydes among the othertwo urea and β-keto esterare the substrate forthe Biginelli reaction.Unfortunately,aldehydesare highly
reactive compounds that readily undergooxidation,disproportionation,and aldolreaction[22].Formation ofthe aldehydesin situ in the
reaction mixture enables to overcome the drawbackoftheirinstability.The synthesis ofaldehydesthrough the reduction of carboxylic
acids oroxidation of alcohols may be not selective because of the possible over-reduction or over-oxidation. There are a number of
reported protocols for the selective oxidation of alcohols to aldehydes using pure oxygen with CuCl
2 2
/TEMPO/NaNO [23] or MNST
(magnetic core-shellnanoparticle-supported TEMPO)/TBN system[24] or application of iodoxybenzoic acid (IBX)[25,26]. However,
these reactions have some inconveniencessuch as harshreactionconditions[27] and usage of carcinogenic organic solvents and toxic
catalysts.In contrast to classicalcatalysts,laccasesare enzymes that catalyze the oxidation ofan alcoholto the corresponding aldehyde
by atmospheric oxygen in the presence of a mediatorundermild reaction conditionsin aqueous solution[28]. It was emphasized in our
previous works on tandemreactions in which alcohol was oxidized by laccase, followed by the subsequent Ugi[29] or Passerini[30]
multicomponent reactions. Tandem processes connect several chemical transformations in one reaction vessel, what significantly
simplifies and improves the overall synthesis[31].
The main idea ofourstudies was to develop an environmentally friendly one-pot protocolfor the synthesis of the pharmaceutically
relevant DHPMs. For the classical Biginelli reaction (highlighted in Scheme 1 as blue frame), an aldehyde is used as the starting
material. Because of aldehyde instability, we have proposed a new approach toward target DHPMs, which is based on the
chemoenzymatic tandemreactionsthat involve simultaneousin situ generation ofan aldehyde fromalcohols , followed by the Biginelli
reaction.Two different synthetic approaches have been considered: (1) one pot–two step (reaction A followed by reaction B), and (2)
one pot–one step (reactions A and B simultaneously). A
schematic representation ofthese conceptsis presented in Scheme
1.

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2
Scheme 1. Schematic representationofdifferent approaches towardDHPMs. First: classical Biginelli reactionwith aldehydes – blue frame.Second: one pot–
one-stepsynthesis, whichsimultaneously combines alcohol oxidationandBiginelli reaction – redframe. Third: one pot–two-step synthesis, which connected
oxidation reaction with subsequent Biginelli reaction separated in time – green frame.
2
. Results andDiscussion
To combine the alcohol oxidation to the corresponding aldehyde with Biginelli condensation in the same vessel, both
transformations must share the same reactionmedium. As the literature reports that the highest activity of laccase in the oxidation of
alcoholto aldehydes was observedin phosphate buffer at pH = 5.2, this mediumwas used as the solvent for the subsequent Biginelli
reaction [26]. First, a series ofexperiments were focused on finding an efficient catalyst for the Biginelli reaction, which promotes the
reaction in selected media because there are no literature reports of Biginelli reaction in phosphate buffer at pH = 5.2. As model
substrates for the Biginelli reaction, benzaldehyde (2a), urea (3a), and ethyl acetoacetate (4a) were selected. According to literature
data, to reaction mixture SDS was added, as a surfactant, which overcomes the main disadvantage of the low solubility of organic
compounds in phosphate buffer [20]. First,we investigated theinfluence ofdifferent typesofcatalysts suchas enzymes,Brønsted acid,
and Lewis acid on the Biginelli reaction course. The results are shown in Table 1.
Table 1. Investigation of catalyst for Biginelli reaction.
Catalyst
Yield 5a [5]
Entry
1
2
3
4
5
6
7
8
9
Laccase from Trametes versicolor
Lipase from Rhizopus niveus
Lipase from Mucor javanicus
Lipase from Pseudomonas fluorescens
Lipase from porcine pancreas
Citric acid
<1%
2%
9%
2%
3%
9%
9%
ZnCl
2
FeCl
Ce(SO
CuCl
3
17%
25%
55%
3%
<1%
<1%
57%
4 2
)
2
1
1
1
1
1
0
1
2
3
4
Cu(OAc)
CuO
2
CuI
4 2
CuSO x 5H O
a
Reaction conditions: 2a (1mmol), 3a (1.5mmol),4a (1mmol),SDS(0.2 mmol)catalyst (0.1mmol orforenzymes 2 U/ml)andphosphatebuffer pH = 5.2 (1.5
mL), 60 °C, 24 h.
As laccase fromTrametesversicolor hascopperatoms in its active site, it may catalyze oxidation reaction and Biginelli reaction at
the same time[32]. However, it did not catalyze the Biginelli reaction (Table 1, entry 1). In addition, various lipases were tested as
catalysts (Table 1,entries 2-5)[19]; this time, the desired product5a was obtainedwith lowyields ofup to 9%. The reaction was carried
out in the presence ofcitric acid (Table 1, entry 6), resulting in product 5a with a yield of 9%. Reaction in the presence of ZnCl
or Ce(SO (Table 1, entries 7-9) resulted in product 5a with the maximum yield of 25%. When we used Cu(OAc) , CuO, or CuI
Table 1, entries 11-13), product 5a was obtained with quite low yield of less than 3%. Reaction carried out in the presence of CuCl
Table 1, entry 10), which was reported in literature data[20],was less effective than that carried out with CuSO x 5H O (Table 1, entry
4), which resulted in product 5a with a yield of 57%. Our investigation revealed that CuSO x5H O is the most efficient catalyst.
2 3
, FeCl ,
4
)
2
2
(
2
(
4
2
1
4
2
Therefore, it was consequently used for further studies.
4 2
Furthermore,to improve the reaction efficiency, the influence of an amount of CuSO x5H O on the yield of 5a was tested. In the
absence of the catalyst, the formation of the product 5a was not observed. The reaction with 2a, 3a, and 4a was performed in the
presenceofvarious amountsofCuSO x 5H O, and the yields of 5a are presented in Figure S1 (Supplementary material). While upon
increasing the amount ofthe catalystfrom1 to 20 mol%, the yield of the target product 5aincreasedup to 82%, and further increase in
4
2
the catalyst from20 to 100 mol% did not enhance the reaction yield,what shows that 20 mol% CuSO
of catalyst, and it was consequently used throughout further studies.
4 2
x5H O was the optimal amount
Next, we investigatedthe influence ofdifferent types ofsurfactant such as cationic,anionic,amphoteric,and selected sugaresterson
the modelBiginelli reaction catalyzed by CuSO x 5H O in PBS pH 5.2. Moreover,the applicationofbiodegradable sugaresters,which
4
2
were synthetized from renewable substrates using enzymes as catalysts under mild conditions, fulfilled the aspects of sustainable
synthesis. The obtainedresultsare presentedin Table 2. Usage ofhexadecylpyridiniumchloride monohydrate (CPC) and Triton X-100
resulted in product5awith low yields, i.e., 33% or 24% (Table 2, entries 5 and 9). Dimethylmyristylammonio)propanesulfonate (SB3-
1
4), dilauryldimethylammonium bromide (DDAB), hexadecylpyridinium chloride monohydrate (CTAB), Tween 80, 6-O-glucose 2-
phenylacetate,6-O-glucose 3-phenylpropionate,6-O-glucose 4-phenylbutyrate,and 6-O-glucose5-phenylpentate (Table 2, entries 2, 4,
,10-14) did not significantly increasethe yield of the desired product 5a. Reaction carried out in the presence of 6-O-glucose laurate
6

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(
Table 2, entry 15) resulted in product5awith the yield of 59%. However, application of anionic surfactants such as sodiumdodecyl
sulfate (SDS) and dioctylsulfosuccinatesodiumsalt (AOT)and cationic surfactants such as dimethyldioctadecylammoniumbromide
(
DODAB) significantly increasedthe yield ofproduct 5aup to 82%.The collected resultsindicated that SDS is optimal for the tandem
Biginelli reaction, and hence, it was used for further investigation (Table 2).
a
Table 2. Influence of the surfactant type on the yield of 5a.
Entry
R (acid)
---
SB3-14
DODAB
DDAB
CPC
CTAB
AOT
SDS
Yield
51
47
79
48
33
53
72
82
24
56
42
52
48
45
59
1
2
3
4
5
6
7
8
9
Triton X-100
Tween 80
6-O-glucose 2-phenylacetate
6-O-glucose 3-phenylpropionate
6-O-glucose 4-phenylbutyrate
6-O-glucose 5-phenylpentate
6-O-glucose laurate
1
1
1
1
1
1
0
1
2
3
4
5
a
Reaction conditions: 2a(1 mmol), 3a(1.5mmol), 4a (1mmol), surfactant (0.2mmol), CuSO
0 °C for 24 h.
4
x 5H
2
O (0.2mmol) andphosphate bufferwith pH 5.2 (1.5mL)at
6
Regarding the fact that the concentration ofthe surfactanthasan impact on the reaction course[20],we investigated the influence of
this factor(from0 to 50 mol%) on the model Biginelli reaction.The resultsare presented in Figure S2 (Supplementary material). When
the amount ofSDS was changingfrom0 to 20 mol%, the yield of the product increased to up to 82%. Further addition of SDS did not
increase the reactionyield. On the basis ofthe obtained results, 20 mol% of SDS was selected as the optimal concentration and used
consequently for further studies.
Furthermore,to improve the reaction yields,we revised the influence oftemperature on the reaction yield. The results are presented
in Figure S3 (Supplementary material).The yield of the model product5aincreased with the increase in the temperature from25 to 60
°C. However,furtherelevation ofthe temperature to above60ᵒC significantly reduced the yield of product 5a. When the temperature
was changed,the value ofthe criticalmicelle concentrationalso changed[33], what explained the obtained results. Performed studies
revealed that the optimal temperature for the Biginelli reaction performed in phosphate buffer was 60 °C and as one was used for
further studies.
Having optimized reaction conditionsforthe Biginelli reaction, furtherstudies were conducted under the chemoenzymatic tandem
reaction using 1mmol of alcoholas the substrate. The first attempt to combine both reactions on a tandemprocess was by adding all
reagents together,not leadingto obtainingthe correspondingproduct5a.Ourinvestigation showed that the oxidation reaction without
connecting with the Biginelli reaction led to obtain aldehyde with quantitative yield.Therefore, we assessed the influence of reagents
for the Biginelli reaction on the oxidation of alcohol, which are shown in Table 3.
a
Table 3. Impact of the Biginelli reagents on the enzymatic oxidation of benzyl alcohol.
Entry
Reagents for Biginelli reaction
-
Amount of reagents for Biginelli reaction [mmol]
Yield of 2a [%]
1
2
3
4
5
---
99
16
32
99
<1
CuSO
4
x 5H
2
O
0.02
0.02
0.15
0.1
SDS
Urea
Ethyl acetoacetate
Reaction conditions: laccase from Trametes versicolor (2U/ml),benzyl alcohol(0.1mmol), TEMPO (0.01 mmol),andphosphatebuffer with pH 5.2 (150 µL)
at 20 °C for 24 h. [a]. Determined by GC.
This research showed that CuSO4 x H2O, ethyl acetoacetate, and SDS significantly decreased the oxidation rate of benzyl
alcohol. For this reason, the product 5 of the cascade reaction was not obtained in the one-step procedure; hence, we decided to
separate both reactions by adding the rest of the reactants after the oxidation step. Oxidation of 1a to aldehyde was catalyzed
quantitatively by laccase from Trametes versicolor in the presence of TEMPO in phosphate buffer for 24 h at roomtemperature.
Then, SDS, urea, CuSO4 x 5H2O, and ethyl acetoacetate were added to the reaction mixture. Then, the reaction was continued for
another24hours at 60°C. The corresponding product 5awas obtainedwith 48% yield. Subsequently,we investigated the influence of
alcoholon the tandemprocess without changing the amount of other reagents. The obtained yields of 5a are presented in Figure S4
(Supplementary material).
The results in Figure S4 indicated that when the amount of alcohol increased from1 mmol to 1.5 mmol, the yield of product 5a in
tandemone-pot process increased from48% to 81%. Upon further increasing the amount of 1a, the yield of the reaction decreased.
Therefore, 1.5 mmol of alcohol was used to perform the subsequent reaction cascade.
Table 4. Scope and limitation of the chemoenzymatic Biginelli reaction.

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4
Entry
R
1
R
2
X
Product
Yield
%]
[
1
2
3
4
5
6
7
8
9
C
6
H
C H
3 6 4
5
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
3
O
O
O
O
O
O
O
O
O
O
O
O
S
5a
5b
5c
5d
5e
5f
5g
5h
5i
81
75
34
63
81
52
27
80
46
30
41
50
0
4-CH
4-FC
4-ClC
4-BrC
4-MeOC
4-NO
CH=CH-C
(CH
6
H
4
H
4
H
4
6
6
6
H
4
2
C
6
H
4
6
H
5
2
)
10CH
3
1
1
1
1
0
1
2
3
C
6
C
6
C
6
C
6
H
5
5
5
5
C(CH
CH
(CH)11CH
CH CH
3
)
5j
5k
5l
H
H
H
2
C
6
H
5
3
2
3
5m
Using different substrates,12compounds(5a-5l) were obtained,with yields ranging from27% to 81%. Compounds 5a, 5b, 5e, and
h were obtained with high yield ofup to 75%. Benzyl alcoholderivatives that contain the halogengroup have influence on the reaction
5
yield. The more electronegative the halogen was, the lower the reaction yield was obtained (Table 4, entries 3-5), which was
corresponding with the literature.[34]Low yield of compound5i may be causedby ineffectivelaccase-catalyzedoxidation.The laccase
mainly catalyzes the oxidation ofalcohols with an aromatic ring, and aliphatic alcohols are much worse substratesforit.[28] This newly
developedprocedure produces 5f, which exhibits pharmaceutical properties.[35] The low yield of compound 5g is also related to the
low oxidation efficiency of p-nitrobenzylalcohol, and an unreacted substrate was found in the reaction mixture. The change of ethyl
acetoacetate to anotherβ-keto esterresultedin a significant decreasein reaction yield (Table 4, entries 1,10-12). Products 5j, 5k,and 5l
were obtained with yields 30%, 41%, and 50%, respectively. Moderate yield of products 5j and 5k was attributed to spatial
considerations. In the case of using thiourea under the developed conditions, the formation of the corresponding product was not
observed (Table 4, entry 13).
3
. Conclusions
A new environmentally friendly protocolforthe synthesis of3,4-dihydropyrimidin-2(1H)-ones (DHPMs)derivativeswas proposed.
Two different synthetic approacheswere considered: (1) one pot–two step,and (2)one pot–onestep.Ourresearchrevealedthat the one
pot-one stepmethod does notprovide targetDHPMs because the laccase is inhibited by the substrates used for the Biginelli reaction.
For these reasons, a tandem one pot–two step protocol based on the enzymatic oxidation of alcohol to aldehyde and subsequent
Biginelli reaction in phosphate bufferwas elaborated. Under the developed procedures, a series of new 3,4-dihydropyrimidin-2(1H)-
ones derivatives were obtained with yields ranging from27% to 81%. The presented protocol disclaims usage of flammable and toxic
organic solvents,heavyand expensive metals, and explosive pure oxygen, what meet the requirements of pharmaceutical chemistry.
4
. Experimental section
1
13
H NMR and C NMR NMR spectra were recorded in acetone-D6 or DMSO-D6 with Bruker 400 MHz spectrometers.
Tetramethylsilane (TMS) was used as internal standard. Gas chromatography were recorded on Clarus 680. High-resolution mass
spectrometry(HRMS)spectra were recorded on an Mariner (PerSeptiveBiosystems) and Synapt G2:SHD apparatus. Melting points
were determined with the model SMP-20 device (Büchi, Flawil, Switzerland). TLC was performed on Kieselgel 60 F254 aluminum
sheets.Laccase fromTrametes versicolor,powder,light brown,≥0.5 U/mg was purchasedfromSigma-Aldrich, product number 38429,
lot number BCBQ2928V. The remaining starting materials of analytical grade were purchased fromSigma-Aldrich or TCI.
General procedure for the synthesis of compound5. A mixture of laccase from Trametes versicolor (20 mg), benzyl alcohol (1.5
mmol), and TEMPO (16 mg) in phosphate buffer pH=5.2 (1.5 mL) was stirred at room temperature for 24 h. Then urea (1.5 mmol),
ethylacetoacetate (1 mmol), SDS (0.2 mmol), and CuSO x 5H O (0.2 mmol) were added,and the reaction mixture was stirred at 60 °C
4 2
for additional 24 h. In case of solid products (5a, 5b, 5c, 5d, 5e, 5f, 5k, and5l), cold water (5 mL) was added to the reaction mixture
and stirred for 10 min. The precipitate was filtered and washed with cold water (5 mL). Finally, the product was purified by
recrystallization fromethanol.If the productwas obtained as an oil (5g, 5h, 5i, 5j), then it was extracted with ethyl acetate (4 x8 mL).
Combined organic phases were dried with MgSO
AcOEt/hexane).
4
, and the crude product was purified by column chromatography (silica gel,
5
. Acknowledgments
This work was performed by A.K.during studiesleadingto bachelorthesis at the WarsawUniversity of Technology. We gratefully
acknowledge the financial support fromthe National Science Centre, Poland, project OPUS No. 2016/B/ST5/03307.
6
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Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal relationships that
could have appeared to influence the work reported in this paper.
☒
The authors declare the following financial interests/personal relationships which may be considered as potential
competing interests:
Ryszard Ostaszewski for manuscript entitled „ Evaluation of alcohols as the substrates for the synthesis of
3
,4-dihydropyrimidine-2(1H)-ones under environmentally friendly conditions”; Ref. No.: CATCOM-D-19-
0
0685R2.
Graphical abstract
Highlights
A new environmentally friendly method for the synthesis of DHPM was evaluated.
Two different synthetic approaches were considered.
A tandem one pot - two step protocol was elaborated.
Alcohols were enzymatically oxidized to aldehydes and used for subsequent Biginelli reaction.

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