Synthesis of 5-cinnamoyl-3,4-dihydropyrimidine-2(1H)-ones

Article abstract of DOI:10.1080/00397911.2013.869341

Two different approaches to the synthesis of 1-unsubstituted 5-cinnamoyl-3,4-dihydropyrimidine-2(1H)-ones have been developed. The first includes N(1)-protection of the starting 5-acetyl-3,4-dihydropyrimidine-2(1H)- one, further Claisen-Schmidt reaction,

Full text of DOI:10.1080/00397911.2013.869341

This article was downloaded by: [Moskow State Univ Bibliote]
On: 10 February 2014, At: 11:11
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of 5-cinnamoyl-3,4-
dihydropyrimidine-2(1 H)-ones
Maksim A. Kolosov a , Olesia G. Kulyk a , Elena G. Shvets a & Valeriy D. Orlov a
a Department of organic chemistry , V.N. Karazin Kharkiv National University , Svobody sq.,
4, Kharkiv , 61022 , Ukraine Phone: +38 (057) 707 56 13 Fax: +38 (057) 707 56 13
Accepted author version posted online: 10 Feb 2014.Published online: 10 Feb 2014.
To cite this article: Synthetic Communications (2014): Synthesis of 5-cinnamoyl-3,4-dihydropyrimidine-2(1 H)-ones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry
To link to this article: http://dx.doi.org/10.1080/00397911.2013.869341
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

ACCEPTED MANUSCRIPT
Maksim A. Kolosov
5-Cinnamoyl-3,4-dihydropyrimidine-2(1H)-ones
Synthesis of 5-cinnamoyl-3,4-dihydropyrimidine-2(1H)-ones
An International Journal for Rapid Communication of Synthetic Organic Chemistry
Maksim A. Kolosov1,, Olesia G. Kulyk1, Elena G. Shvets1, Valeriy D. Orlov1
1Department of organic chemistry, V.N. Karazin Kharkiv National University, Svobody
sq., 4, Kharkiv 61022, Ukraine, Phone: +38 (057) 707 56 13, Fax: +38 (057) 705-12-36
Address Correponding toMaksim A. Kolosov, Department of organic chemistry, V.N.
Karazin Kharkiv National University, Svobody sq., 4, Kharkiv 61022, Ukraine email:
kolosov@univer.kharkov.ua
Abstract
Two different approaches to the synthesis of 1-unsubstituted 5-cinnamoyl-3,4-
dihydropyrimidine-2(1H)-ones have been developed. The first includes N(1)-protection
of the starting 5-acetyl-3,4-dihydropyrimidine-2(1H)-one, further Claisen-Schmidt
reaction and cleavage of the protecting group. The second approach consists of one-pot
condensation of urea, aldehyde and cinnamoylacetone as dicarbonyl component. The
ability of 5-cinnamoylderivatives synthesis starting from 5-acetyl-1,3-dialkyl-3,4-
dihydropyrimidine-2(1H)-ones is also shown.
ACCEPTED MANUSCRIPT
1

ACCEPTED MANUSCRIPT
KEYWORDS: 3,4-dihydropyrimidin-2(1H)-ones; Biginelli reaction; one-pot
condensation; protecting group; methoxymethylation.
INTRODUCTION
The use of 1,4-dihydropyridine calcium channel modulators for the treatment of
cardiovascular diseases is well known.[1] Nifedipine, amlodipine and their analogs are
widely introduced in medicinal practice.[2]
The derivatives of 3,4-dihydropyrimidin-2(1H)-one (DHPM) are the isosteres and 3-aza-
analogs of nifedipine and the range of biological activities of DHPMs is also very high.[3]
DHPMs are often synthesized by Biginelli reaction, which includes the ternary
condensation of urea, aldehyde and dicarbonyl compound (or its equivalent).[4]
Noteworthy, that these compounds may be readily functionalized by N(3)-position,[5] and
the latter compounds are the analogs of non-symmetrical 1,4-dihydropyridines. Usually,
ACCEPTED MANUSCRIPT
2

ACCEPTED MANUSCRIPT
the introduction of needed group in position 5 is usually performed by use of different
dicarbonyl compounds or their synthetic equivalents in the starting Biginelli
condensation.[4c,5b,5d,6]
Recently we have shown, that the activity of 5-acetyl-DHPMs towards different reagents
strongly depends on the presence of alkyl substituent in the position 1.[6c,7] For example,
the reaction of 1-unsubstituted 5-acetyl- DHPMs with 4-bromobenzaldehyde occurs in
the very hard conditions, while 1-alkylsubstituted 5-acetyl-DHPMs smoothly give
targeted 5-cinnamoylderivatives in high yields.[6c]
Thus, the significance of the common strategy, which should allow to obtain target
1-unsubstituted 5-functionalized DHPMs as by modification of substituent in the position
5 as by use of functionalized 1,3-dicarbonyl compounds is obvious. In the present work
we try to use this strategy for the synthesis of 5-functionalized DHPMs by the example of
their cinnamoylderivatives.
RESULTS AND DISCUSSION
The first approach to 5-cinnamoyl-DHPMs synthesis should include the introduction of
protecting group (PG) in the DHPM molecule (with the aim to increase the activity of 5-
acetyl group and solubility), further functionalization of 5-acetyl group and cleavage of
PG (Scheme 1). In this case the substituent in the position 5 of preformed DHPM ring is
under functionalization.
ACCEPTED MANUSCRIPT
3

ACCEPTED MANUSCRIPT
Methoxymethyl (MOM) PG was chosen. Being stable in the basic conditions, further it
should allow to carry out Claisen-Schmidt condensation, but it could be easily removed
in acidic conditions. Benzyl protecting group was undesirable in our case because of the
instability of cinnamoyl fragment to hydrogenolysis.[8] Of course, in the case of another
5-functionalized derivatives, Bn-group may also be used.[9]
We have investigated the alkylation of compound 1 by MOM-Cl under action of NaH in
DMF, 1,4-dioxane and THF. The best result was achieved in NaH/1,4-dioxane system
with the use of 1.1 equiv. excess of MOM-Cl (see experimental). In every case, both 1-
MOM- and 1,3-di-MOM-derivatives were obtained (compounds 2 and 3,
correspondingly), but they were efficiently separated by flash-column chromatography
using Al2O3 and CH2Cl2-EtOAc as eluents. Interestingly, that the action of the excess of
MOM-Cl and NaH in DMF on the starting compound 1 lead to the obtaining of oil 4,
being the MOM-ether of compound 3 enol form (Scheme 2).
The structure of compound 4 was established by NOE-experiment. Under irradiation of
6-methyl group signals (2.09 ppm) the signals of two МеО-groups (3.22 ppm and 3.26
ppm, respectively) gave the enhancement, as well as signals of N(1)CH2-protons (4.96
ppm and 5.14 ppm) and the signal of the only proton of СН2=С-group near 3.93 ppm
(Scheme 3).
ACCEPTED MANUSCRIPT
4

ACCEPTED MANUSCRIPT
4-Bromobenzaldehyde was used as model aldehyde in further reactions because of the
relatively low solubility of the reaction products and, thus, the ability of purification, as
well as ability of the identification of bromoderivatives by means of MS techniques.
Actually, compound 2 readily reacted with 4-bromobenzaldehyde in MeOH/KOH
solution, giving the yellow precipitate of 5-cinnamoylderivative 5. The latter was
smoothly deprotected by action of 30% aqueous H2SO4 in 1,4-dioxane, furnishing target
yellow crystals of compound 6a (Scheme 4).
Comparing with 1H NMR-spectrum of the compound 2, 1H NMR-spectrum of the
compound 5 has the only signal of Me-group. Instead of it, the amount of the aromatic
protons increases from 5 (compound 2) to 11 (compound 5), the signals of CH=CH-
protons appear in the area of aromatic protons. On the one hand, deprotected compound
6a has no MOM-group signals in 1H NMR-spectrum and the signal of N(1)H (9.26 ppm)
appears. On the other hand, MS-spectrum of compound 6a contains an intensive signal of
the molecular ion with m/z 397, that evidences the success of the chosen procedure.
Noteworthy, that aggregative states of the compounds 1 (mp 242–4°C), 2 (mp 114–6°C),
3 (oil at r. t.), 4 (oil at r. t.), 5 (mp 159–161°C), 6a (mp 228–231°C) are significant and,
obviously, are determined by the ability of mentioned compounds to the formation of
intermolecular hydrogen bonds.
ACCEPTED MANUSCRIPT
5

ACCEPTED MANUSCRIPT
The second general approach of 5-cinnamoylDHPMs synthesis is based on previously
formed functionality (3-phenyl-2-propenoyl moiety in cinnamoylacetone), which should
be introduced in the target molecule by effective one-pot Biginelli reaction.
We synthesized cinnamoylacetone 7 by action of cinnamoyl chloride on acetoacetic ester
and further ketone disintegration of cinnamoylacetoacetic ester in water under 140°C
(3 atm) accordingly to known procedure.[10] As expected, compound 7 readily reacted
with urea and different benzaldehydes in acidic media, giving target products 6b-d
(Scheme 5).
Interestingly, that in the case of benzaldehyde (compound 6b, R = H) standard conditions
for Biginelli reaction were used (EtOH/HCl), while synthesis of compound 6c with donor
substituent in aromatic ring (R = NMe2) required conc. HCl as reaction media and glacial
acetic acid was needed for compound 6d with acceptor (R = NO2) synthesis. These
results are in good agreement with data, obtained by us earlier for the synthesis of 5-
acetyl-4-arylDHPMs starting from benzaldehydes with substituent of different
polarity.[11]
At the same time, in the present work we carried out the reaction of
4-bromobenzaldehyde and 4-ethylDHPM 8, because 4-alkyl-3,4-dihydropyrimidin-
2(1H)-ones possess a number of advantages (greater solubility, smaller molecular weight
etc.), comparing with their 4-aryl analogues.[12] In fact, compound 8 easily produced
5-cinnamoyl derivative 9 in the reaction with 4-bromobenzaldehyde in mild conditions
ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
(Scheme 6), thus, it was shown, that 5-acetyl-1,4-dialkylDHPMs actually could form
5-cinnamoylderivatives, like compounds type 2 could.
The structure of compound 8 was confirmed by both 1H NMR spectrum (existence of
vinyl protons signals and absence of 6-Me-group signal) and MS-spectrum (peak of
molecular ion with m/z 363).
Finally, the contrary synthesis of 5-(4-bromocinnamoyl)-1-ethyl-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one 10,[6c] described earlier, was performed by ethylation of
compound 6a (Scheme 7).
All the spectroscopic data of compound 10 were identical to previously reported.[6c]
CONCLUSION
In summary, by the example of 5-cinnamoylderivatives synthesis we have shown, that 5-
functionalized DHPMs may be synthesized by two principal approaches: 1) by protecting
of position 1, 5-functionalization and removal of the protecting group; 2) starting from
pre-formed functionality in dicarbonyl component and its interaction in one-pot Biginelli
reaction with urea and aldehyde.
Additionally, the ability of 5-acetyl-1,3-dialkyl-3,4-dihydropyrimidine-2-(1H)-ones to
form corresponding 5-cinnamoylderivatives was also shown.
ACCEPTED MANUSCRIPT
7

ACCEPTED MANUSCRIPT
EXPERIMENTAL
Aldehydes, urea, 1,3-pentanedione, alkylhalides, solvents and inorganic reagents were
commercially available. NaH was used as 60% suspension in mineral oil.
Cinnamoylacetone was synthesized according to ref.[10] DMF and 1,4-dioxane were
distilled and stored under molecular sieves (4 Å). Reactions with air- and/or moisture-
sensitive compounds were performed under argon. Melting points were determined using
a Kofler hot-stage apparatus. Column chromatography was performed using Al2O3 (60–
100 μm) and silica with CH2Cl2, EtOAc and EtOAc/CH2Cl2 mixtures as eluents. The
purity of the compounds, monitoring of the reaction course and fraction selection in
preparative column chromatography were performed by TLC on MERCK ALUGRAM
Xtra SIL G/UV 254 and KAVALIER Silufol UV-254 plates, using EtOAc–CH2Cl2
mixtures as eluents). 1H NMR spectra were recorded at 200 MHz using a Varian Mercury
VX-200 spectrometer with Si(CH3)4 as internal standard, chemical shifts are performed in
ppm, coupling constants are given in Hz. 13C NMR-spectra were recorded in DMSO-d6 at
100 MHz using Bruker Avance 400 spectrometer with Si(CH3)4 as internal standard.
Mass spectra (EI, 70 eV) were obtained using a Varian 1200L instrument using a direct
probe exposure (DEP) method. IR spectra were recorded on KBr pellets using a Specord
IR-75 spectrometer. Elemental analyses (C, H, N) were obtained using EuroEA-3000
instrument.
ACCEPTED MANUSCRIPT
8

ACCEPTED MANUSCRIPT
Selected Procedures
5-Acetyl-6-methyl-1-methoxymethyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (2)
The solution of 1 (8 g, 0.035 mol) in 1,4-dioxane (60 ml) was added to the flask with
NaH (60% suspension in mineral oil, 1.53 g, 0.038 mol) with the use of syringe. The
reaction mixture was stirred for 1 h at 60°C. After cooling to the room temperature,
МОМ-Сl (3.08 g, 0.038 mol) was added dropwise. Then the mixture was stirred for 1 h at
room temperature and 30 min at 60°C. After filtration through the thin (3-5 mm) layer of
Al2O3, the obtained solution was evaporated to dryness. The residual solid was purified
by flash column chromatography (Al2O3, 250 mL of EtOAc) and then crystallized from
the mixture of benzene/hexane (1:1) to give compound 2. White solid; yield: 3.17 g
(33%); mp 114–116°C. IR (KBr): 1682, 1659, 1598, 1457, 3216 cm–1. 1H NMR (200
MHz, DMSO-d6): δH = 8.17 (d, J = 3.4 Hz, 1Н, NH), 7.2–7.4 (m, 5Н, Ph), 5.23 (d, J =
3.4 Hz, 1Н, H-4), 5.12 (d, J = 11.0 Hz, 1Н, CH2), 5.02 (d, J = 11.0 Hz, 1Н, CH2), 3.13 (s,
3Н, OCH3), 2.43 (s, 3Н, CH3), 2.11 (s, 3Н, CH3). 13C NMR (100 MHz, DMSO-d6): δ =
16.23, 31.12, 53.66, 56.03, 73.47, 114.39, 127.21, 128.35, 129.36, 143.72, 147.75,
153.18, 197.23. MS (EI, 70 eV): m/z (%) = 274 (M+·, 15), 259 (55), 229 (70), 167 (75),
45 (100). Anal. Calcd. for C15H18N2O3 (274.32): C, 65.68; H, 6.61; N, 10.21. Found: C,
65.63; H, 6.56; N, 10.20.
5-Acetyl-6-methyl-1-methoxymethyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (2)
and 5-acetyl-1,3-dimethoxymethyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-
one (3)
A solution of 1 (5 g, 0.022 mol) in DMF (30 mL) was added to the flask with NaH (60%
suspension in mineral oil, 1.15 g, 0.029 mol) with the use of syringe. The obtained
ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
mixture was stirred for 1 h at 0-5ºС. Then МОМ-Сl (1.93 g, 0.024 mol) was added
dropwise to the reaction mixture. After additional stirring for 1.5 h at room temperature,
the solution was poured into 350 mL of water and the product was extracted 3 times with
50 mL of EtOAc, The combined organic layers were dried over Na2SO4, filtered and
concentrated under vacuum. The residual solid was purified by column chromatography
(EtOAc/CH2Cl2 (1:1, 100 mL), EtOAc (150 mL)) to give compound 2 (0.65 g, 11%) as a
white solid and 3.
5-Acetyl-1,3-bis(methoxymethyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-
one (3).
Yellow viscous oil; yield: 0.9 g (13%). IR (KBr): 1682, 1662, 1614, 1456 cm–1. 1H NMR
(200 MHz, DMSO-d6): δH = 7.2–7.4 (m, 5Н, Ph), 5.46 (s, 1Н, H-4), 5.19 (d, J = 11.0 Hz,
1Н, CH2), 5.06 (d, J = 11.0 Hz, 1Н, CH2), 5.05 (d, J = 11.0 Hz, 1Н, CH2), 4.47 (d, J =
11.0 Hz, 1Н, N(3)CH2), 3.18 (s, 3Н, OCH3), 3.12 (s, 3Н, OCH3), 2.42 (s, 3Н, CH3), 2.21
(s, 3Н, CH3). 13C NMR (100 MHz, DMSO-d6): δ = 16.43, 31.43, 55.88, 56.39, 57.28,
74.68, 78.09, 116.25, 127.43, 128.65, 129.39, 141.37, 146.91, 153.47, 196.80. MS (EI, 70
eV): m/z (%) = 318 (M+·, 22), 303 (20), 285 (82), 241 (100), 198 (11), 45 (75). Anal.
Calcd for C17H22N2O4: C, 64.13; H, 6.97; N, 8.80. Found: C, 64.10; H, 6.90; N, 8.80.
5-[3-(4-Bromophenyl)-2-propenoyl]-1-methoxymethyl-6-methyl-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one (5)
A mixture of 2 (1.1 g, 4.01 mmol), 4-bromobenzaldehyde (0.81 g, 4.41 mmol) and KOH
(saturated solution in MeOH, 1.1 mL) in MeOH (7 mL) was stirred at ambient
temperature for 3.5 h. The product precipitated over night. After filtration and washing 3
times with MeOH (3 mL) the product was crystallized from EtOH to give compound 5.
ACCEPTED MANUSCRIPT
10

ACCEPTED MANUSCRIPT
Bright orange solid; yield: 0.80 g (45%); mp 159–161°C. IR (KBr) 1688, 1657, 1613,
1485 cm–1. 1H NMR (200 MHz, DMSO-d6): δH = 8.15 (d, J = 3.1 Hz, 1H, NH), 7.53–
7.67 (m, 4H, Ar), 7.16–7.36 (7H, m, CH=CH, Ph), 5.4 (d, J = 3.1 Hz, 1H, H-4), 5.15 (d, J
= 10.8 Hz, 1H, CH2), 5.04 (d, J = 10.8 Hz, 1H, CH2) 3.17 (s, 3Н, OCH3), 2.35 (s, 3Н,
CH3). 13C NMR (100 MHz, DMSO-d6): δ = 16.95, 53.92, 56.04, 73.46, 115.26, 124.29,
127.06, 127.79, 128.23, 129.24, 131.08, 132.51, 134.60, 141.08, 144.15, 145.73, 153.26,
190.53. MS (EI, 70 eV): m/z (%) = 440 (М+·, 90), 409 (16), 379 (33), 129 (98), 102 (80).
Anal. Calcd for C22H21BrN2O3: C, 59.87; H, 4.80; Br, 18.11; N, 6.35. Found: C, 59.81; H,
4.70; Br, 18.11; N, 6.33.
5-[3-(4-Bromophenyl)-2-propenoyl]-6-methyl-4-phenyl-3,4-dihydropyrimidin-
2(1H)-one (6a)
To a stirred solution of 5 (1 g, 2.26 mmol) in dioxane (10 mL) the 30% aqueous solution
of H2SO4 (30 ml) was added dropwise. The monitoring of MOM-group cleavage was
performed by TLC using mixture of EtOAc/CH2Cl2 (1:1) as eluent. The formed
precipitate was filtered off and washed 3 times with the mixture of dioxane/water (1:1, 3
mL) and 3 times with water (3 mL) giving compound 6a. Yellow solid; yield: 0.80 g
(89%); mp 228–231°C. IR (KBr) 1709, 1659, 1614, 1485, 3245 cm–1. 1H NMR (200
MHz, DMSO-d6): δH = 9.26 (s, 1H, NH), 7.89 (s, 1H, NH), 7.51–7.66 (m, 4H, Ar), 7.15–
7.36 (m, 7H, CH=CH, Ph), 5.47 (d, J = 3.1 Hz, 1H, H-4), 2.27 (s, 3Н, CH3). 13C NMR
(100 MHz, DMSO-d6): δ = 19.62, 54.61, 110.69, 123.85, 127.07, 127.63, 128.00, 129.17,
130.84, 132.46, 134.92, 139.59, 145.26, 148.55, 152.74, 187.90. MS (EI, 70 eV): m/z (%)
= 398 (М+·, 100), 334 (8), 274 (76), 185 (28), 153 (13), 128 (20). Anal. Calcd for
ACCEPTED MANUSCRIPT
11

ACCEPTED MANUSCRIPT
C20H17BrN2O2: C, 60.47; H, 4.31; Br, 20.11; N, 7.05. Found: C, 60.40; H, 4.27; Br,
20.15; N, 7.01.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website. Please
make the words “publisher’s website” a live DOI link.
ACCEPTED MANUSCRIPT
12

ACCEPTED MANUSCRIPT
REFERENCES
1.
(a) Kastron, V. V.; Vitolin', R. O.; Dubur, G. Ya. Pharm. Chem. J. 1990, 24, 394;
(b) Wan, J.-P.; Liu, Y. RSC Adv. 2012, 2, 9763; (c) Triggle D. J. Biochem. Pharmacol.
2007, 74, 1; (d) Shan, R.; Velazquez, C.; Knaus, E. E. J. Med. Chem. 2004, 147, 254; (e)
Mulder, P.; Litwinienko, G.; Lin, S.; MacLean, P. D.; Barclay, L. R. C.; Ingold, K. U.
Chem. Res. Toxicol. 2006, 19, 79; (f) Schade, D.; Lanier, M.; Willems, E.; Okolotowicz,
K.; Bushway, P.; Wahlquist, C.; Gilley, C.; Mercola, M.; Cashman, J. R. J. Med. Chem.
2012, 55, 9946; (g) Shukla, S.; Robey, R. W.; Bates, S. E.; Ambudkar, S. V.
Biochemistry 2006, 45, 8940; (h) Bagal, S. K.; Brown, A. D.; Cox, P. J.; Omoto, K.;
Owen, R. M.; Pryde, D.C.; Sidders, B.; Skerratt, S. E.; Stevens, E. B.; Storer, R. I.;
Swain, N. A. J. Med. Chem. 2013, 56, 593.
2.
(a) Lundy, A.; Lutfi, N.; Beckey, C. Vasc. Health Risk Manag. 2009, 5, 429; (b)
Gilpin, R. K.; Gilpin, C. S. Anal. Chem. 2009, 81, 4679; (c) Hopes, Ph. A.; Parker, A. J.;
Patel, I. Org. Process Res. Dev. 2006, 10, 808; (d) Wang J.-G. Vasc. Health Risk Manag.
2009, 5, 593.
3.
(a) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083 ; (b) Kappe С.
O. Molecules 1998, 3, 1 ; (c) Kappe C. O. Acc. Chem. Res., 2000, 33, 879; (d) Saini, A.;
Kumar, S.; Sandhu, J. S. J. Ind. Chem. Soc., 2007, 959; (e) Dallinger, D.; Gorobets, N.
Yu.; Kappe, C. O. Mol. Diversity 2003, 7, 229.
4.
(a) Biginelli, P. Gazz. Chim. Ital., 1893, 23, 360; (b) Kappe С. O. Tetrahedron
1993, 49, 6937; (c) Sandhu S., Sandhu J. S. ARKIVOC 2012, 1, 66; (d) Pellissier, H.
Chem. Rev. 2013, 113, 442.
ACCEPTED MANUSCRIPT
13

ACCEPTED MANUSCRIPT
5.
(a) Khanina, E. L.; Mutsenietse, D. Kh.; Dubur, G. Ya. Chem. Het. Compd. 1984,
20, 431; (b) Barrow, J. C.; Nanternet, P. G.; Selnick, H. G.; Glass, K. D.; Rittle, K. E.;
Gilbert, K. F.; Steele, T. G.; Homnick, C. F.; Freidinger, R. M.; Ransom, R. W.; Kling,
P.; Reiss, D.; Broten, T. P.; Schorn, T. W.; Chang, R. S. L.; O’Malley, S. S.; Olah, T. V.;
Ellis, J. D.; Barrish, A.; Kassahun, K.; Leppert, P.; Nagarathnam D.; Forray C.
J. Med. Chem. 2000, 43, 2703; (c) Schnell, B.; Krenn, W.; Faber, K.; Kappe, C. O. J.
Chem. Soc., Perkin Trans. I. 2000, 4382; (d) Folkers, K.; Johnson, T. B. J. Am. Chem.
Soc. 1933, 55, 2886.
6.
(a) Kolosov, M. A.; Orlov, V. D.; Beloborodov, D. A.; Dotsenko, V. V. Mol.
Diversity 2009, 13, 5; (b) Dondoni, A.; Massi, A. Mol. Diversity 2003, 6, 261; (c)
Kolosov, M. A.; Orlov, V. D.; Vashchenko, V. V.; Shishkina, S. V.; Shishkin, O. V.
Collect. Czech. Chem. Commun. 2007, 72, 1219; (d) Dzvinchuk, I. B.; Makitruk, T. V.;
Lozinskii, M. O. Chem. Heterocycl. Compd. 2003, 39, 455; (e) Liepin'sh, E. E.; Khanina,
E. L.; Dubur, G. Ya. Chem. Het. Compd., 1981, 17, 381; (f) Pisani, L.; Prokopcova, H.;
Kremsner, J. M.; Kappe, C. O. J. Comb. Chem. 2007, 9, 415; (g) Sedova, V. F.;
Krivopalov, V. P.; Shkurko, O. P. Russ. Chem. Bull. IE 2007, 56, 1184; (h) Matache, M.;
Dobrota, C.; Bogdan, N. D.; Dumitru, I.; Ruta, L. R.; Paraschivescu, C. C.; Farcasanu, I.
C.; Baciu, I.; Funeriu, D. P. Tetrahedron, 2009, 65, 5949.
7.
Kolosov, M. A.; Orlov, V. D. Chem. Het. Compd. 2008, 44, 1418.
8. (a) Greene, T. W.; Wuts, P. G. M. In Greene’s protective groups in organic
(a) Kolosov, M. A.; Orlov, V. D. Chem. Het. Compd. 2007, 43, 1349; (b)
chemistry; Wiley: Hoboken, 2007, 903; (b) Saito, S.; Sato, Y.; Ohwada, T.; Shudo, K. J.
ACCEPTED MANUSCRIPT
14

ACCEPTED MANUSCRIPT
Am. Chem. Soc. 1994, 116, 2312; (c) Mori, A.; Mizusaki, T.; Miyakawa, Y.; Ohashi, E.;
Haga, T.; Maegawa, T.; Monguchi, Y.; Sajiki, H. Tetrahedron 2006, 62, 11925.
9.
Jauk, B.; Belaj, F.; Kappe, C.O. J. Chem. Soc., Perkin Trans. I. 1999, 307.
Borsche, W.; Peter, W. Justus Liebigs Ann. Chem. 1927, 453, 148.
Kolosov, M. A.; Orlov, V. D. Zh. Org. Farm. Khim. 2005, 3, 17.
Kolosov, M. A.; Kulyk, O. G.; Beloborodov, D.A.; Orlov, V.D. J. Chem. Res.
10.
11.
12.
2013, 2, 115.
ACCEPTED MANUSCRIPT
15

ACCEPTED MANUSCRIPT
Scheme 1. Retrosynthetic plan of the synthesis of target 5-cinnamoyl-3,4-
dihydropyrimidin-2(1H)-ones by first approach.
ACCEPTED MANUSCRIPT
16

ACCEPTED MANUSCRIPT
Scheme 2. Alkylation of 5-acetyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one 1.
Scheme was changed!
ACCEPTED MANUSCRIPT
17

ACCEPTED MANUSCRIPT
Scheme 3. NOE-experiment for compound 4.
ACCEPTED MANUSCRIPT
18

ACCEPTED MANUSCRIPT
Scheme 4. Synthesis of cinnamoyl derivative 6a by first approach.
ACCEPTED MANUSCRIPT
19

ACCEPTED MANUSCRIPT
Scheme 5. Synthesis of compounds 6b-d by second approach.
ACCEPTED MANUSCRIPT
20

ACCEPTED MANUSCRIPT
Scheme 6. Synthesis of 5-acetyl-5-cinnamoyl-4-ethyl-3,4-dihydropyrimidin-2(1H)-one 8.
ACCEPTED MANUSCRIPT
21

ACCEPTED MANUSCRIPT
Scheme 7. Contrary synthesis of known compound 9 by ethylation of compound 6a.
ACCEPTED MANUSCRIPT
22