Reaction of β-alkoxyvinyl α-ketoesters with acyclic NCN binucleophiles – Scalable approach to novel functionalized pyrimidines

Article abstract of DOI:10.1016/j.tet.2019.05.005

Two protocols for synthesis of series of low-molecular-weight di- and tri-substituted pyrimidines bearing a functional group at the 4th position, which rely on a base-mediated condensation of amidines or guanidines with β-alkoxyvinyl α-keto esters, have been developed. This approach allowed for multigram preparation of novel pyrimidine-4-carboxylates in 21–90% yield. The synthetic utility of these compounds was demonstrated by some standard functional group transformations providing promising building blocks for organic synthesis and drug discovery.

Full text of DOI:10.1016/j.tet.2019.05.005

Accepted Manuscript
Reaction of β-alkoxyvinyl α-ketoesters with acyclic NCN binucleophiles – Scalable
approach to novel functionalized pyrimidines
Oleksandr O. Stepaniuk, Tymofii V. Rudenko, Bohdan V. Vashchenko, Vitalii O.
Matvienko, Ivan S. Kondratov, Andrey A. Tolmachev, Oleksandr O. Grygorenko
PII:
S0040-4020(19)30512-5
https://doi.org/10.1016/j.tet.2019.05.005
TET 30326
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 February 2019
Revised Date: 29 April 2019
Accepted Date: 2 May 2019
Please cite this article as: Stepaniuk OO, Rudenko TV, Vashchenko BV, Matvienko VO, Kondratov
IS, Tolmachev AA, Grygorenko OO, Reaction of β-alkoxyvinyl α-ketoesters with acyclic NCN
binucleophiles – Scalable approach to novel functionalized pyrimidines, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.05.005.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Reaction of β-alkoxyvinyl α-ketoesters with acyclic NCN binucleophiles – scalable
approach to novel functionalized pyrimidines
Oleksandr O. Stepaniuk,a,b Tymofii V. Rudenko,a,b Bohdan V. Vashchenko,a,b Vitalii O. Matvienko,a
Ivan S. Kondratov,a,c* Andrey A. Tolmachev,a,b Oleksandr O. Grygorenkoa,b*
a Enamine Ltd., Chervonotkatska Street 78, Kyiv 02094, Ukraine, www.enamine.net
b Taras Shevchenko National University of Kyiv, Volodymyrska Street, 60, Kyiv 01601, Ukraine
c V.P. Kukhar Institute of Bioorganic Chemistry & Petrochemistry, NAS of Ukraine, Murmanska Street 1, Kyiv 02660, Ukraine
gregor@univ.kiev.ua (O. O. G.); kondratov@mail.enamine.net (I. S. K.)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Two protocols for synthesis of series of low-molecular-weight di- and tri-substituted
pyrimidines bearing a functional group at the 4th position, which rely on a base-mediated
condensation of amidines or guanidines with β-alkoxyvinyl α-keto esters, have been developed.
This approach allowed for multigram preparation of novel pyrimidine-4-carboxylates in 21–90%
yield. The synthetic utility of these compounds was demonstrated by some standard functional
group transformations providing promising building blocks for organic synthesis and drug
discovery.
Available online
Keywords:
nitrogen heterocycles
pyrimidines
2019 Elsevier Ltd. All rights reserved
.
amidines
guanidines
building blocks
popular in drug discovery;3 they are represented by numerous
1. Introduction
examples of marketed drugs with
a
broad range of
pharmacological activities, i.e. anticancer,4–10 antiviral,11–14
anxiolytic,15 antioxidant,16–18 antifungal,19 anticonvulsant,20 and
antibacterial agents.5,21 Within just 2017–2018, several
pyrimidine-containing drugs were approved by FDA.19
Pyrimidine is one of the most important heterocycles, which is
an essential constituent of natural compounds such as nucleic
acids and vitamins (thiamine, riboflavin and folic acid).1,2 It is not
surprising therefore that pyrimidine derivatives are extremely
Figure 1 Examples of pyrimidine-containing drugs

2
Tetrahedron
counterparts. This is an example of recent finding by Churcher
ACCEPTED MANUSCRIPT
and co-authors,74 who outlined that in many publications, the
scope of the synthetic methods have been shown only for the
most “convenient” substrates. Further application of such results
by medicinal and industrial chemists often requires additional
optimization of the protocols.
In this work, we have aimed at thorough and comprehensive
studying of the lowest-molecular-weight β-alkoxyvinyl carbonyl
compounds 1–3 as bis-electrophiles in the reactions with classical
NCN binucleophiles, i.e. amidines (4–10) S-methylthiuronium
salt (11), and guanidines (12–15) (Figure 2). These bis-
electrophiles were scarcely studied in the pyrimidine synthesis to
date; in fact, most of the resulting pyrimidine-4-carboxylates
obtained in this work were not described in the literature so far.
In addition to that, application of the resulting products for
preparation of multipurpose building blocks relevant for drug
discovery was envisaged. As a result of this, carboxylic acids (8
examples), alcohols (7 examples), aldehydes (3 examples),
chlorides (4 examples) and amines (4 examples) were obtained
on multigram scale; 43 out of 51 pyrimidines prepared were
novel compounds. Nearly all compounds are functionalized low-
molecular-weight building blocks highly compatible with
stringent compound quality criteria which are still important to
drug discovery.75
Scheme 1 Synthesis of pyrimidine-4-carboxylates by
reactions of 1,3-dicarbonyl compounds and NCN
binucleophiles
A general approach to pyrimidine derivatives relies on the
principal two-component condensation of NCN binucleophiles
with CCC bis-electrophiles. 1,3-Dicarbonyl compounds are
commonly used for that; however, this variation of the method
have found limited application for the preparation of pyrimidine-
4-carboxylates. Most reported examples referred to reactions of
oxaloacetic acid esters with amidines, thiuronium salts or
guanidine (Scheme 1, A).22–27 In another work, benzoyl- or (2-
thienoyl)pyruvate were first transformed into mixtures of the
corresponding β-chlorovinylketones, which then reacted with 1-
(β-d-ribofuranosyl)formamidine to give the corresponding
pyrimidine derivatives in 32–36% overall yields (B).28
β-Alkoxyvinyl carbonyl compounds are renown synthetic
equivalents of 1,3-dicarbonyl compounds which were widely
used for the synthesis of numerous heterocyclic systems,
including pyrimidines, and often led to better yields and purity of
the target products.29,30 Utility of these bis-electrophiles was
demonstrated mainly by the preparation of substituted
pyrimidines bearing alkyl, haloalkyl or aryl moiety at the C-4
position.31–62 It should be noted that the related methods were
reported in the patent literature.63–67 Some published papers
described synthesis of pyrimidine-5-carboxylates.29,55,56,68 In the
case of pyrimidine-4-carboxylates, only a few isolated examples
were published, in particular, reactions of β-alkoxyvinyl α-
ketoesters with only two specific substrates: 2-methylisothiourea
or 2-benzylisothiourea (Scheme 2, C).69 In turn, the reaction of
amidines or guanidine (D)70–73 led to the corresponding
pyrimidines in generally poor yields (up to 36%). Therefore, no
optimized protocols were developed.
Figure 2 Substrates studied in this work
NH
R2
CO2Et
2. Results/Discussion
R2
O
R1S
NH2
N
N
The compounds 1–3 were prepared according to the known
literature method.76 Typical procedure for the reaction of 1–3
with binucleophiles 4–15 included heating of the starting
materials at 70 °C in the presence of K2CO3 in MeCN for 2 h
(method A). The reaction proceeded smoothly only in the case of
3, which appeared to be the most reactive bis-electrophile in the
series studied, providing the target pyrimidines 16{3,4–10} and
16{3,13–15} in 67–90% yield (Table 1, Entries 16–26). Reaction
of 3 with trifluoroacetamidine (7) did not require a base,
providing 2-(trifluoromethyl)pyrimidine 16{3,7}, which was
used in the next step without isolation and purification (Entry
19).
Na2CO3,
EtOH, reflux
52 94%
MeO
CO2Et
C (ref. 69)
SR
R1 = Me, Bn; R2 = Me, Ph, p-FC6H4, p-BrC6H4, p-MeC6H4, p-MeOC6H4, p-O2NC6H4
+
NH2
CO2Et
Cl
NH2
R3
O
N
N
EtO
CO2Et
R3
D (ref. 70 73)
R3 = Me, EtONa, EtOH, N/A yield (ref. 62, 63)
R3 = o-tolyl, NaOAc, p-xylene, 36% (ref. 64)
R3 = NH2, TEA, PrCN, 27%; (ref. 65)
Scheme 2 Synthesis of pyrimidine-4-carboxylates by
reactions of β-alkoxyvinyl carbonyl compounds and NCN
binucleophiles
It should be noted that the reaction of 3 and guanidines 13–15
was accompanied with trans-esterification of the CO2Et moiety
with MeOH formed, so that the corresponding pyrimidines
bearing the dialkylamino moiety 16{3,13–15} contained up to
33% of the corresponding methyl ester 17{3,13–15}. Since
formation of this side product was not a problem for further
Furthermore, aryl-substituted binucleophiles were used
predominantly - they are generally more convenient to handle
and often have distinct reactivity as compared to their aliphatic

transformations, the resulting mixtures of 16{3,13–15} and
17{3,13–15} were used in the next steps without additional
purification (Table 1, Entries 24–26).
ammonia which was also released reacted with 1 to give the
corresponding enaminone, thus complicating isolation of the
target product. Therefore, the method B was used for less
reactive NCN binucleophiles in the reaction with 1 (75–85%
yield, Entries 6–8), as well as for all experiments with the
compound 2 (71–86% yield, Entries 9–15), which appeared to be
the least reactive among the 1,3-bis-electrophiles studied,
possibly due to the steric hindrance around the ketone moiety.
ACCEPTED MANUSCRIPT
In the case of guanidine 12, the reaction with 3 using method
A appeared to be too slow; therefore, alternative reaction
conditions were developed, i.e. heating of the starting compounds
in the presence of Et3N in 1,4-dioxane at 100 °C for 48 h (method
B), which gave the target product 16{3,12} in 82% yield (Table
1, Entry 23).
Unfortunately, the method B was unfruitful in all experiments
with formamidine acetate (4) (Entries 1, 9 and 16); meanwhile,
It was found that the method B was superior to the method A
in the case of the less reactive 1,3-bis-electrophile 1 and amidines
5, 8 or 10 (A: 39–57% yield; B: 65–80% yield; Table 1, Entries
2, 4 and 5). Lower yields and purity of the target products in the
case of method A could be related to partial hydrolysis of the
starting amidine with H2O formed in the reaction; moreover,
the method
A was applied for the preparation of the
corresponding pyrimidines 16{1,4} and 16{3,4} more or less
successfully (21% and 72% yield, respectively).
Table 1. Synthesis of substituted ethyl pyrimidine-4-carboxylates 16{1–3,4–15}
#
β-Alkoxyvinyl α-ketoester
NCN binucleophile
Product
R3
Yield, %
Method
A/B
A/B
A
1
4
16{1,4}
H
21 (A), 0 (B)a
2
5
16{1,5}
Me
39 (A), 65 (B)a
3
6
16{1,6}
CH2Cl
cyclopropyl
p-ClC6H4
SMe
69
4
8
16{1,8}
53 (A), 73 (B)a
A/B
A/B
B
5
10
11
12
14
4
16{1,10}
16{1,11}
16{1,12}
16{1,14}
16{2,4}
57 (A), 80 (B)a
6
75
7
NH2
76
B
8
pyrrolidin-1-yl
H
85
B
9
0
A/B
B
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
5
16{2,5}
Me
71
8
16{2,8}
cyclopropyl
p-ClC6H4
SMe
76
B
10
11
12
14
4
16{2,10}
83
B
16{2,11}
16{2,12}
16{2,14}
16{3,4}
75
B
NH2
77
B
pyrrolidin-1-yl
H
85
B
72
A
5
16{3,5}
Me
78
A
6
16{3,6}
CH2Cl
CF3
67
A
7
16{3,7}
N/Ad
Ac
8
16{3,8}
cyclopropyl
Ph
74
A
9
16{3,9}
81
A
10
12
13
14
15
16{3,10}
16{3,12}
16{3,13}+17{3,13}
16{3,14}+17{3,14}
16{3,15}+17{3,15}
p-ClC6H4
NH2
83
A
82
B
NMe2
90 (16:17 = 2.5:1)b
90 (16:17 = 2:1)b
89 (16:17 = 2:1)b
A
pyrrolidin-1-yl
piperidin-1-yl
A
A
aBoth methods A and B were evaluated
b16:17 ratio by 1H NMR – the product was obtained as a mixture of 16 and 17 at the given ratio and was used in the next step without additional purification
cThe reaction was performed without K2CO3
dThe compound was used in the next step without isolation

4
Tetrahedron
The least reactive β-alkoxyvinyl α-ketoester 2 gave no target
chemical shifts are reported in ppm (δ scale) downfield from
ACCEPTED MANUSCRIPT
product 16{2,4} under either reaction conditions. In the case of
chloromethyl-substituted amidine 6 (Entries 3 and 18), the
method B could not be used due to alkylation of Et3N with 6;
nevertheless, the corresponding products 16{1,6} and 16{3,6}
could be obtained using the method A.
TMS as an internal standard and are referenced using residual
NMR solvent peaks at 7.26 and 77.16 ppm for H and 13C in
1
CDCl3, 2.50 and 39.52 ppm for H and 13C in DMSO-d6.
1
Coupling constants (J) are shown in Hz. Spectra are reported
as follows: chemical shift (δ, ppm), multiplicity, integration,
coupling constants (Hz). Elemental analyses were performed
at the Laboratory of Organic Analysis, Department of
Chemistry, National Taras Shevchenko University of Kyiv.
Mass spectra were recorded on an Agilent 1100 LCMSD SL
instrument (chemical ionization (CI)) and Agilent 5890 Series
II 5972 GCMS instrument (electron impact ionization (EI)).
Elemental analysis was performed using Elementar Vario
MICRO Cube CHNS/O/Cl analyzer. Instant JChem v.
17.2.27.0 was used for the calculation of physico-chemical
parameters, Chemaxon, Hungary, www.chemaxon.com
It is important to outline that 20 of 24 synthesized pyrimidine
ester derivatives 16{1–3,4–15} are novel compounds which were
not described in the literature to date.
To demonstrate utility of the target esters 16, their
transformations into building blocks 18–22 was performed via
standard carboxylate group modifications. (Figure 3, see the
Supporting Information for more details).
4.1. General procedure for the preparation of esters 16 (Method
A).
K2CO3 (27.6 g. 0.180 mol) was added to a stirred solution of
the corresponding β-alkoxyvinyl α-ketoester 1–3 (0.100 mol) in
MeCN (300 mL) and the resulting mixture was heated to 70 °C.
Then, the corresponding NCN binucleophile 4–15 (0.130 mol, or
0.180 mol in the case of 4) was added in portions. The reaction
mixture was refluxed for 2 h, then cooled to rt and evaporated in
vacuo. The residue was diluted with H2O (200 mL) and extracted
with t-BuOMe (2×100 mL) (in the case of 16{1,8}, 16{1,10} and
16{3,9–10}) or CH2Cl2 (2×100 mL) (in other cases). The organic
phase was separated, washed with H2O (50 mL), dried over
Na2SO4, filtered through silica gel and evaporated in vacuo.
Figure 3. Pyrimidine-derived building blocks 18–22
3. Conclusion
The reaction of β-alkoxyvinyl α-keto esters 1–3 with amidines
4–10, S-methylthiuronium salt 11, and guanidines 12–15 in the
presence of K2CO3 in MeCN (method A, 21–90% yield) or upon
treatment with Et3N in 1,4-dioxane (method B, 65–85% yield) is
an efficient approach to the preparation of 4-
carboxylalkylpyrimidines 16. The method A was fruitful for the
most reactive substrates (i.e. 1,3-bis-electrophile 3 and amidines),
whereas in most other cases, the method B was more expedient.
Utility of these key intermediates was confirmed by some typical
functional group transformations; 43 out of 51 products were
novel compounds. Most of these functionalized pyrimidine
derivatives are low-molecular-weight and hydrophilic; they were
prepared on multigram scale and are therefore promising building
blocks for organic synthesis, drug discovery and agrochemistry,
which are readily available to scientific community and can
significantly expand the currently accessible lead-like chemical
space (Figure S1).
The products 16{3,13–15} contained the corresponding
methyl esters 17{3,13–15} formed by trans-esterification upon
the reaction with ethyl 4-methoxy-2-oxopent-3-enoate (3).
Ethyl pyrimidine-4-carboxylate 16{1,4}.8 5
Yielg 3.19 g (21 %); yellow crystals; mp = 39–41 °C
1
(hexanes) (lit.85 35–36 °C). H NMR (500 MHz, CDCl3) δ 9.36
(d, J = 1.4 Hz, 1H), 8.94 (d, J = 5.0 Hz, 1H), 7.97 (dd, J = 5.0,
1.4 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H).
13C NMR (126 MHz, CDCl3) δ 163.5, 158.8, 158.7, 154.5, 120.5,
62.3, 13.7. LC/MS (CI): m/z = 153 [M+H]+. Anal. calcd. for
C7H8N2O2: C, 55.26; H, 5.30; N, 18.41. Found: C, 55.37; H, 5.25;
N, 18.78.
Ethyl 2-(chloromethyl)pyrimidine-4-carboxylate
16{1,6}.
The compound was purified by distillation in vacuo. Yield
1
13.8 g (69%); brownish liquid; bp = 102–104 °C / 1 mmHg. H
4. Experimental section
NMR (500 MHz, CDCl3) δ 8.97 (d, J = 4.9 Hz, 1H), 7.87 (d, J =
4.9 Hz, 1H), 4.80 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.39 (t, J =
7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 166.1, 163.2, 159.5,
155.3, 119.1, 62.4, 46.2, 13.7. GC/MS (EI): m/z = 156/158
The solvents were purified according to the standard
procedures.77 The compounds 1–3,76 4,78 5,79 6,80 7,81 8,82
9
and 10,33 11,83 13,83 14 and 1584 were prepared according to
the literature methods. All other reagents and starting
materials were obtained from commercial sources. Melting
points were measured on MPA100 OptiMelt automated
melting point system. Analytical TLC was performed using
Polychrom SI F254 plates. Column chromatography was
performed using silica gel (230–400 mesh) as the stationary
[M-OEt+H]+, 173/175 [M-H2C=CH(CH3)+H]+ 201/203 [M+H]+.
,
Anal. calcd. for C8H9ClN2O2: C, 47.90; H, 4.52; N, 13.96; Cl,
17.67. Found: C, 47.55; H, 4.75; N, 14.01; Cl, 17.71.
Ethyl 6-methylpyrimidine-4-carboxylate 16{3,4}.
Yield 12.0 g (72%); colorless crystals, mp = 32–34 °C
1
(hexanes) (bp = 86–88 °C / 1 mmHg). H NMR (500 MHz,
1
phase. H and 13C NMR spectra were recorded on a Bruker
CDCl3) δ 9.22 (s, 1H), 7.85 (s, 1H), 4.46 (q, J = 7.2 Hz, 2H), 2.62
(s, 3H), 1.42 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
169.6, 164.3, 158.8, 154.6, 120.5, 62.6, 24.3, 14.1. LC/MS (CI):
m/z = 139 [M-H2C=CH(CH3)+H]+, 167 [M+H]+. Anal. calcd. for
C8H10N2O2: C, 57.82; H, 6.07; N, 16.86. Found: C, 57.51; H,
6.43; N, 16.86.
1
170 Avance 500 spectrometer (at 500 MHz for H NMR, 126
MHz for 13C NMR and 470 MHz for 19F NMR) and Varian
1
Unity Plus 400 spectrometer (at 400 MHz for H NMR, 101
MHz for 13C NMR and 376 MHz for 19F NMR). NMR

Ethyl 2,6-dimethylpyrimidine-4-carboxylate
16{3,5}.
165.4, 162.1, 154.9, 107.4, 61.2 36.4, 23.9. LC/MS (CI): m/z =
ACCEPTED MANUSCRIPT
195 [M+H]+.
Yield 14.1 g (78%); colorless crystals, mp = 44–47 °C
(hexanes) (bp = 94–96 °C / 1 mmHg). H NMR (500 MHz,
Ethyl 6-methyl-2-(pyrrolidin-1-yl)pyrimidine-4-
carboxylate 16{3,14}.
1
CDCl3) δ 7.66 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 2.79 (s, 3H), 2.59
(s, 3H), 1.42 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
169.4, 168.7, 164.6, 155.0, 117.4, 62.5, 26.1, 24.3, 14.2. LC/MS
(CI): m/z = 181[M+H]+. Anal. calcd. for C9H12N2O2: C, 59.99; H,
6.71; N, 15.55. Found: C, 59.91; H, 6.78; N, 15.34.
The compound was obtained as a mixture with methyl 6-
methyl-2-(pyrrolidin-1-yl)pyrimidine-4-carboxylate
17{3,14}
1
(16:17 = 2:1). Yield 21.2 (90%); yellowish oil. H NMR (400
MHz, CDCl3) δ 6.92 (s, 1H), 4.35 (q, J = 6.9 Hz, 2H), 3.62 – 3.54
(m, 4H), 2.36 (s, 3H), 1.95 – 1.91 (m, 4H), 1.35 (t, J = 6.9 Hz,
3H). 13C NMR (126 MHz, CDCl3) δ 168.4, 165.5, 160.9, 155.2,
107.9, 52.8, 46.6, 25.4, 24.4, 14.2. LC/MS (CI): m/z = 236
[M+H]+.
Ethyl 2-(chloromethyl)-6-methylpyrimidine-4-
carboxylate 16{3,6}.
The compound was purified by distillation in vacuo. Yield
14.4 g (67%); yellow powder; mp = 36–38 °C; bp = 117–119 °C
/ 1 mmHg. H NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 4.78 (s,
Methyl 6-methyl-2-(pyrrolidin-1-yl)pyrimidine-4-
carboxylate 17{3,14} (spectral data).
1H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H), 3.89 (s, 3H), 3.62
– 3.54 (m, 4H), 2.36 (s, 3H), 1.99 – 1.93 (m, 4H). 13C NMR (126
MHz, CDCl3) δ 169.6, 166.1, 161.2, 155.6, 108.0, 61.8, 46.7,
25.5, 24.5. LC/MS (CI): m/z = 222 [M+H]+.
1
2H), 4.48 (q, J = 7.2 Hz, 2H), 2.65 (s, 3H), 1.42 (t, J = 7.2 Hz,
3H). 13C NMR (126 MHz, CDCl3) δ 170.7, 166.2, 164.0, 155.5,
119.2, 62.7, 46.8, 24.4, 14.2. GC/MS (EI): m/z = 155/157
[M-OEt]+, 186/188 [M-H2C=CH(CH3)]+ 214/216 [M]+. Anal.
,
calcd. for C9H11ClN2O2: C, 50.36; H, 5.17; N, 13.05; Cl, 16.52.
Found: C, 50.25; H, 5.31; N, 12.73; Cl, 16.72.
Ethyl 6-methyl-2-(piperidin-1-yl)pyrimidine-4-
carboxylate 16{3,15}.
The compound was obtained as a mixture with methyl 6-
methyl-2-(piperidin-1-yl)pyrimidine-4-carboxylate
(16:17 = 2:1). Yield 22.2 g (89%); yellowish oil. H NMR (500
MHz, CDCl3) δ 6.94 (s, 1H), 4.40 (q, J = 7.0 Hz, 2H), 3.85 (s,
4H), 2.39 (s, 3H), 1.68 – 1.60 (m, 6H), 1.41 (t, J = 7.0 Hz,
3H).13C NMR (126 MHz, CDCl3) δ 169.6, 165.5, 162.1, 155.6,
108.0, 61.8, 44.6, 25.8, 24.8, 24.5,14.2. LC/MS (CI): m/z = 250
[M+H]+.
Ethyl 2-cyclopropyl-6-methylpyrimidine-4-
carboxylate 16{3,8}.
17{3,15}
1
Yield 15.3 g (74%); yellowish liquid. H NMR (400 MHz,
1
CDCl3) δ 7.53 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 2.30
(tt, J = 8.2, 2.7 Hz, 1H), 1.39 (t, J = 7.1 Hz, 3H), 1.16 – 1.13 (m,
2H), 1.05 – 1.02 (m, 2H). 13C NMR (126 MHz, CDCl3) δ 172.6,
169.1, 164.8, 154.5, 116.9, 62.2, 24.3, 18.3, 14.2, 11.0. LC/MS
(CI): m/z = 207 [M+H]+. Anal. calcd. for C11H14N2O2: C, 64.06;
H, 6.84; N, 13.58. Found: C, 64.05; H, 6.92; N, 13.77.
Methyl 6-methyl-2-(piperidin-1-yl)pyrimidine-4-
carboxylate 17{3,15} (spectral data).
1H NMR (500 MHz, CDCl3) δ 6.96 (s, 1H), 3.94 (s, 3H), 3.87
– 3.86 (m, 4H), 2.39 (s, 3H), 1.68 – 1.60 (m, 6H). 13C NMR (126
MHz, CDCl3) δ 169.6, 165.5, 162.1, 155.6, 108.1, 61.8, 44.7,
25.8, 24.8, 24.5. LC/MS (CI): m/z = 236 [M+H]+.
Ethyl 6-methyl-2-phenylpyrimidine-4-carboxylate
16{3,9}.
Yield 19.6 g (81%); yellowish solid; mp = 95–97 °C
1
(hexanes). H NMR (500 MHz, CDCl3) δ 8.54 (s, 2H), 7.72 (s,
1H), 7.52 – 7.47 (m, 3H), 4.51 (q, J = 6.7 Hz, 2H), 2.69 (s, 3H),
1.48 (t, J = 6.7 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.6,
165.0, 164.8, 155.4, 137.1, 130.9, 128.5, 128.5, 118.0, 62.3, 24.6,
14.2. LC/MS (CI): m/z = 213 [M-Et]-, 243 [M+H]+. Anal. calcd.
for C14H14N2O2: C, 69.41; H, 5.82; N, 11.56. Found: C, 69.47; H,
5.97; N, 11.35.
4.2. General procedure for the preparation of esters 16 (Method
B).
Et3N (27.9 mL, 20.2 g, 0.200 mol) was added to a stirred
mixture of β-alkoxyvinyl ester 1–3 (0.100 mol) and the
corresponding amidine/guanidine 4–15 (0.120 mol) in 1,4-
dioxane (200 mL). The resulting mixture was stirred at 100 °C
for 48 h, then cooled to rt and evaporated in vacuo. The residue
was diluted with H2O (150 mL) and extracted with t-BuOMe
(2×100 mL). The combined organic extracts were washed with
water (50 mL), dried over Na2SO4, filtered through silica gel and
evaporated in vacuo.
Ethyl 2-(4-chlorophenyl)-6-methylpyrimidine-4-
carboxylate 16{3,10}.
Yield 23.0 g (83%); colorless powder; mp = 107–109
(hexanes). °C. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J = 8.5 Hz,
2H), 7.73 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 4.51 (q, J = 7.0 Hz,
2H), 2.68 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz,
CDCl3) δ 169.7, 164.7, 164.0, 155.4, 137.2, 135.6, 129.9, 128.7,
118.1, 62.4, 24.6, 14.2. LC/MS (CI): m/z = 277/279 [M+H]+.
Anal. calcd. for C14H13ClN2O2: C,s 60.77; H, 4.74; N, 10.12; Cl,
12.81. Found: C, 60.55; H, 4.66; N, 10.01; Cl, 13.11.
Ethyl 2-methylpyrimidine-4-carboxylate 16{1,5}.
1
Yield 10.8 g (65%; Method A – 39%); brownish liquid. H
NMR (400 MHz, CDCl3) δ 8.81 (d, J = 4.9 Hz, 1H), 7.74 (d, J =
4.9 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.80 (s, 3H), 1.38 (t, J =
7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 169.1, 164.3, 159.0,
155.2, 117.7, 62.6, 26.2, 14.2. LC/MS (CI): m/z = 139
Ethyl 2-(dimethylamino)-6-methylpyrimidine-4-
carboxylate 16{3,13}.
The compound was obtained as a mixture with methyl 2-
[M-H2C=CH(CH3)+H]+ 167 [M+H]+. Anal. calcd. for
(dimethylamino)-6-methylpyrimidine-4-carboxylate
17{3,13}
,
1
(16:17 = 2.5:1). Yield 18.8 g (90%); yellowish liquid. H NMR
(500 MHz, CDCl3) δ 6.84 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.11
(s, 6H), 2.29 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (126
MHz, CDCl3) δ 168.9, 164.9, 162.1, 154.6, 107.3, 52.2, 36.3,
23.9, 13.7. LC/MS (CI): m/z = 210 [M+H]+.
C8H10N2O2: C, 57.82; H, 6.07; N, 16.86. Found: C, 57.94; H,
5.68; N, 17.19.
Ethyl 2-cyclopropylpyrimidine-4-carboxylate
16{1,8}.
1
Yield 14.0 g (73%; Method A – 53%); yellowish liquid. H
Methyl 2-(dimethylamino)-6-methyl-pyrimidine-4-
NMR (400 MHz, CDCl3) δ 8.71 (d, J = 4.9 Hz, 1H), 7.63 (d, J =
4.9 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 2.38 – 2.30 (m, 1H), 1.38
(t, J = 7.2 Hz, 3H), 1.16 – 1.12 (m, 2H), 1.08 – 1.04 (m, 2H). 13C
NMR (126 MHz, CDCl3) δ 173.1, 164.4, 158.9, 154.8, 117.2,
carboxylate 17{3,13} (spectral data).
1H NMR (500 MHz, CDCl3) δ 6.86 (s, 1H), 3.82 (s, 3H), 3.11
(s, 6H), 2.29 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 169.0,

6
Tetrahedron
62.4, 18.4, 14.1, 11.4. LC/MS (CI): m/z = 193 [M+H]+. Anal.
Ethyl 2-(methylthio)-5-methylpyrimidine-4-
ACCEPTED MANUSCRIPT
carboxylate 16{2,11}.
calcd. for C10H12N2O2: C, 62.49; H, 6.29; N, 14.57. Found: C,
62.22; H, 6.54; N, 14.96.
1
Yield 14.9 g (75%); brownish liquid. H NMR (500 MHz,
CDCl3) δ 8.38 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 2.28
(s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
169.8, 164.4, 160.1, 154.5, 124.0, 61.6, 15.1, 13.7, 13.6. LC/MS
(CI): m/z = 213 [M+H]+. Anal. calcd. for C9H12N2O2S: C, 50.93;
H, 5.70; N, 13.20; S, 15.10. Found: C, 50.55; H, 6.07; N, 13.51;
S, 15.17.
Ethyl 2-(4-chlorophenyl)pyrimidine-4-carboxylate
16{1,10}.
Yield 21.0 g (80%; Method A – 57%); colorless crystals; mp
= 90–93 °C (hexanes). 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J =
4.9 Hz, 1H), 8.46 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 4.9 Hz, 1H),
7.46 (d, J = 8.7 Hz, 2H), 4.50 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1
Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 163.9, 158.9, 155.2,
137.1, 134.9, 129.8, 129.5, 128.5, 118.1, 62.1, 13.8. LC/MS (CI):
m/z = 263/265 [M+H]+. Anal. calcd. for C13H11ClN2O2: C, 59.44;
H, 4.22; N, 10.66; Cl, 13.49. Found: C, 59.56; H, 4.30; N, 10.86;
Cl, 13.23.
Ethyl 5-methyl-2-(pyrrolidin-1-yl)pyrimidine-4-
carboxylate 16{2,14}.
Yield 20.0 g (85%); yellowish crystals; mp = 40–41 (hexanes)
1
°C. H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 4.37 (q, J = 7.1
Hz, 2H), 3.53 (s, 4H), 2.19 (s, 3H), 1.93 (s, 4H), 1.36 (t, J = 7.1
Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 165.7, 160.5, 158.8,
155.3, 114.8, 61.2, 46.2, 25.1, 14.5, 13.7. LC/MS (CI): m/z = 236
[M+H]+. Anal. calcd. for C12H17N3O2: C, 61.26; H, 7.28; N,
17.86. Found: C, 61.56; H, 7.20; N, 17.89.
Ethyl 2-(methylthio)pyrimidine-4-carboxylate
{1,11}.8 6
1
Yield 14.9 g (75%); yellowish liquid. H NMR (500 MHz,
CDCl3) δ 8.59 (d, J = 4.9 Hz, 1H), 7.45 (d, J = 4.9 Hz, 1H), 4.30
(q, J = 7.1 Hz, 2H), 2.45 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ 173.3, 163.3, 158.6, 154.7, 115.0,
62.0, 13.7, 13.6. LC/MS (CI): m/z = 199 [M+H]+. Anal. calcd. for
C8H10N2O2S: C, 48.47; H, 5.08; N, 14.13; S, 16.17. Found: C,
48.85; H, 4.75; N, 14.35; S, 16.54.
Ethyl 2-aminopyrimidine-4-carboxylate 16{1,12}.7 3
After evaporation in vacuo of the reaction mixture, the residue
was diluted with H2O (100 mL) and t-BuOMe (30 mL). The
precipitate formed was filtered, washed with H2O (2×10 mL) and
dried in vacuo. Yield 12.7 g (76%); beige powder; mp = 239–242
1
°C (EtOH). H NMR (500 MHz, DMSO-d6) δ 8.46 (dd, J = 4.9,
Ethyl 2-(pyrrolidin-1-yl)pyrimidine-4-carboxylate
16{1,14}.
2.2 Hz, 1H), 7.05 (s, 2H), 7.04 (dd, J = 4.4, 1.5 Hz, 1H), 4.30 (q,
J = 6.9 Hz, 2H), 1.29 (t, J = 6.9 Hz, 3H). 13C NMR (126 MHz,
DMSO-d6) δ 164.9, 164.4, 161.0, 156.1, 109.4, 61.9, 14.5.
LC/MS (CI): m/z= 122 [M-OEt]+, 168 [M+H]+. Anal. calcd. for
C7H9N3O2: C, 50.29; H, 5.43; N, 25.14. Found: C, 50.05; H, 5.15;
N, 25.10.
Yield 18.8 g (85%); yellowish crystals; mp = 54–57 °C
1
(hexanes). H NMR (500 MHz, CDCl3) δ 8.45 (d, J = 4.7 Hz,
1H), 7.03 (d, J = 4.7 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 3.65 –
3.55 (m, 4H), 1.99 – 1.93 (m, 4H), 1.37 (t, J = 7.2 Hz, 3H). 13C
NMR (126 MHz, CDCl3) δ 164.7, 160.2, 159.1, 155.5, 107.6,
61.5, 46.3, 25.0, 13.7. LC/MS (CI): m/z = 222 [M+H]+. Anal.
calcd. for C11H15N3O2: C, 59.71; H, 6.83; N, 18.99. Found: C,
59.76; H, 6.97; N, 19.18.
Ethyl 2-amino-5-methylpyrimidine-4-carboxylate
16{2,12}.
After evaporation in vacuo of the reaction mixture, the residue
was diluted with H2O (100 mL) and t-BuOMe (30 mL). The
precipitate formed was filtered, washed with H2O (2×10 mL) and
dried in vacuo. Yield 13.8 g (75%); yellowish powder; mp =
Ethyl 2,5-dimethylpyrimidine-4-carboxylate
16{2,5}.
Yield 13.0 g (71%); yellow liquid. 1H NMR (500 MHz,
CDCl3) δ 8.45 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.58 (s, 3H), 2.28
(s, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ
165.4, 164.7, 160.1, 153.9, 126.3, 61.7, 25.0, 15.5, 13.6. LC/MS
(CI): m/z = 181[M+H]+. Anal. calcd. for C9H12N2O2: C, 59.99; H,
6.71; N, 15.55. Found: C, 60.17; H, 6.38; N, 15.45.
1
195–199 °C (EtOH). H NMR (400 MHz, DMSO-d6) δ 8.27 (s,
1H), 6.67 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 2.14 (s, 3H), 1.30 (t, J
= 7.1 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 165.8, 162.5,
161.9, 155.9, 116.38, 61.7, 14.7, 14.5. LC/MS (CI): m/z= 182
[M+H]+. Anal. calcd. for C8H11N3O2: C, 53.03; H, 6.12; N, 23.19.
Found: C, 52.96; H, 6.44; N, 23.48.
Ethyl 2-cyclopropyl-5-methylpyrimidine-4-
Ethyl 2-amino-6-methylpyrimidine-4-carboxylate
carboxylate 16{2,8}.
16{3,12}.8 7
1
Yield 15.7 g (76%); yellowish liquid. H NMR (500 MHz,
After evaporation in vacuo of the reaction mixture, the residue
was diluted with H2O (100 mL) and t-BuOMe (30 mL). The
precipitate formed was filtered, washed with H2O (2×10 mL) and
dried in vacuo. Yield 14.9 g (82%); brownish powder; mp = 145–
147 °C (EtOH) (lit.87 151 °C). 1H NMR (500 MHz, DMSO-d6) δ
6.96 (s, 1H), 6.90 (s, 2H), 4.29 (q, J = 7.0 Hz, 2H), 2.31 (s, 3H),
1.29 (t, J = 7.0 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ
170.3, 165.1, 164.3, 156.0, 109.0, 61.8, 24.1, 14.5. LC/MS (CI):
m/z= 182 [M+H]+. Anal. calcd. for C8H11N3O2: C, 53.03; H, 6.12;
N, 23.19. Found: C, 53.06; H, 6.43; N, 23.46.
CDCl3) δ 8.50 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 2.39 (s, 3H), 2.28
(tt, J = 8.3, 3.9 Hz, 1H), 1.41 (t, J = 7.1 Hz, 3H), 1.12 – 1.09 (m,
2H), 1.07 – 1.03 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 170.0,
165.4, 160.4, 154.3, 126.0, 62.0, 17.8, 15.8, 14.1, 10.8. LC/MS
(CI):
m/z
=
135
[M-CO2-H2C=CH(CH3)+H]+,
179
[M-H2C=CH(CH3)+H]+ 207 [M+H]+. Anal. calcd. for
,
C11H14N2O2: C, 64.06; H, 6.84; N, 13.58. Found: C, 63.95; H,
6.68; N, 13.96.
Ethyl 2-(4-chlorophenyl)-5-methylpyrimidine-4-
carboxylate 16{2,10}.
1
Acknowledgments
Yield 23.0 g (83%); brownish liquid. H NMR (400 MHz,
CDCl3) δ 8.71 (s, 1H), 8.37 (d, J = 8.4 Hz, 2H), 7.46 – 7.38 (m,
2H), 4.47 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.44 (t, J = 7.2 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 165.3, 161.7, 160.8, 155.1,
137.0, 135.4, 129.5, 128.8, 127.7, 62.2, 16.1, 14.2. LC/MS (CI):
m/z = 277/279 [M+H]+. Anal. calcd. for C14H13ClN2O2: C, 60.77;
H, 4.74; N, 10.12; Cl, 12.81. Found: C, 61.08; H, 4.50; N, 10.09;
Cl, 13.04.
The work was funded by Enamine Ltd.
References and notes
1.
Gilchrist TL. Heterocyclic Chemistry, 3rd ed.,
Addison Wesley: Essex, England, 1997.

2.
3.
Joule JA, Mills K. Heterocyclic Chemistry, 5th ed.,
Wiley-Blackwell, 2010.
ACCEPTED MANUSHCoRsaIgPraThara V, Hameed S, Shinde V, Bathula C,
Humnabadkar V, Kumar N, Reddy J, Panduga V,
Sharma S, Ambady A, Hegde N, Whiteaker J,
McLaughlin RE, Gardner H, Madhavapeddi P,
Ramachandran V, Kaur P, Narayan A, Guptha S,
Awasthy D, Narayan C, Mahadevaswamy J, Vishwas
KG, Ahuja V, Srivastava A, Prabhakar K, Bharath S,
Kale R, Ramaiah M, Choudhury NR,
Panneer Selvam T, Richa James C, Vijaysarathy
Dniandev P, Karyn Valzita S. Res Pharm. 2012; 2: 1–
9.
4.
Kaur R, Kaur P, Sharma S, Singh G, Mehndiratta S,
Bedi PMS, Nepali K. Anti-cancer pyrimidines in
diverse scaffolds: a review of patent literature., 2015,
vol. 10.
Sambandamurthy VK, Solapure S, Iyer PS,
Narayanan S, Chatterji M. J Med Chem. 2013; 56:
9701–9708.
5.
6.
Rostom SAF, Ashour HMA, Abd El Razik HA. Arch
Pharm. 2009; 342: 299–310.
23.
24.
Webb TR, Moran T, Huang CQ, McCarthy JR,
Grigoriadis DE, Chen C. Bioorg Med Chem Lett.
2004; 14: 3869–3873.
Reynolds RC, Tiwari a, Harwell JE, Gordon DG,
Garrett BD, Gilbert KS, Schmid SM, Waud WR,
Struck RF. J Med Chem. 2000; 43: 1484–8.
Gillespie RJ, Bamford SJ, Clay A, Gaur S, Haymes T,
Jackson PS, Jordan AM, Klenke B, Leonardi S, Liu J,
Mansell HL, Ng S, Saadi M, Simmonite H, Stratton
GC, Todd RS, Williamson DS, Yule IA. Bioorg Med
Chem. 2009; 17: 6590–6605.
7.
8.
9.
Iyer V V., Griesgraber GW, Radmer MR, McIntee EJ,
Wagner CR. J Med Chem. 2000; 43: 2266–2274.
El-Deeb IM, Lee SH. Bioorg Med Chem. 2010; 18:
3860–3874.
25.
26.
Provenzani R, Tarvainen I, Brandoli G, Lempinen A,
Artes S, Turku A, Jäntti MH, Talman V, Yli-
Kauhaluoma J, Tuominen RK, Boije af Gennäs G.
PLoS One. 2018; 13: 1–27.
Yoon J seong, Jarhad DB, Kim G, Nayak A, Zhao
LX, Yu J, Kim HR, Lee JY, Mulamoottil VA,
Chandra G, Byun WS, Lee SK, Kim YC, Jeong LS.
Eur J Med Chem. 2018; 155: 406–417.
Masami Otsuka, Kobayashi S, Ohno M, Umezawa Y,
Morishima H, Umezawa H. Chem Pharm Bull. 1985;
33: 515–519.
10.
11.
Kumar S, Narasimhan B. Chem Cent J. 2018; 12: 38.
Tarnchompoo B, Sirichaiwat C, Phupong W,
Intaraudom C, Sirawaraporn W, Kamchonwongpaisan
S, Vanichtanankul J, Thebtaranonth Y, Yuthavong Y.
J Med Chem. 2002; 45: 1244–1252.
27.
28.
Ti JS, Steinfeld AS, Naider F, Gulumoglu A, Lewis S
V., Becker JM. J Med Chem. 1980; 23: 913–918.
Iaroshenko VO, Dudkin S, Sosnovskikh VY,
Villinger A, Langer P. Eur J Org Chem. 2013: 3166–
3173.
12.
13.
14.
Kraljević TG, Klika M, Kralj M, Martin-Kleiner I,
Jurmanović S, Milić A, Padovan J, Raić-Malić S.
Bioorg Med Chem Lett. 2012; 22: 308–312.
29.
30.
Kudyakova YS, Bazhin DN, Goryaeva M V, Burgart
Y V, Saloutin VI. Russ Chem Rev. 2014; 83: 120–
142.
Choi Y, Li L, Grill S, Gullen E, Lee CS, Gumina G,
Tsujii E, Cheng YC, Chu CK. J Med Chem. 2000; 43:
2538–2546.
Krapcho AP, Maresch MJ, Helgason AL, Rosner KE,
Hacker MP, Oliva SS, Menta E, Oliva A. J Het Chem.
1993; 30: 1597–1606.
Hopkins AL, Ren J, Tanaka H, Baba M, Okamato M,
Stuart DI, Stammers DK. J Med Chem. 1999; 42:
4500–4505.
31.
32.
Franke W, Kraft R. Angew Chem. 1955; 67: 395–399.
15.
16.
17.
Chinnasamy G, Subramani K, Srinivasan V. Biomed
Res-India. 2017; 28: 525–531.
Zanatta N, Fagundes MB, Ellensohn R, Marques M,
Bonacorso HG, Marcos A. P. Martins. J Heterocycl
Chem. 1998; 35: 451–455.
Mansouri M, Movahedian A, Rostami M, Fassihi A.
Res Pharm Sci. 2012; 7: 257.
33.
34.
35.
Golubev PR, Pankova AS, Kuznetsov MA. Eur J Org
Chem. 2014; 2014: 3614–3621.
Bano T, Kumar N, Dudhe R. Org Med Chem Lett.
2012; 2: 34.
Bellur E, Langer P. Tetrahedron. 2006; 62: 5426–
5434.
18.
19.
20.
Kumar S, Narasimhan B. Chem Cent J. 2018; 12: 38.
De La Torre BG, Albericio F. Molecules. 2018; 23.
Palanki MSS, Erdman PE, Gayo-fung LM, Shevlin
GI, Sullivan RW, Suto MJ, Goldman ME, Ransone
LJ, Bennett BL, Manning AM. J Med Chem. 2000;
43: 3995–4004.
Alam O, Mullick P, Verma SP, Gilani SJ, Khan SA,
Siddiqui N, Ahsan W. Eur J Med Chem. 2010; 45:
2467–2472.
36.
37.
Fandrick DR, Reinhardt D, Desrosiers JN, Sanyal S,
Fandrick KR, Ma S, Grinberg N, Lee H, Song JJ,
Senanayake CH. Org Lett. 2014; 16: 2834–2837.
21.
22.
Mohana Roopan S, Sompalle R. Synth Commun.
2016; 46: 645–672.
Shirude PS, Shandil R, Sadler C, Naik M,
Gerus II, Vdovenko SI, Gorbunova MG, Kukhar’ VP.

8
Tetrahedron
ACCEPTED MANUSCRIPT
Chem Heterocycl Compd. 1991; 27: 398–406.
55.
Yurugi S, Hieda M, Fushimi T, Kawamatsu Y,
Sugihara H, Tomimoto M. Chem Pharm Bull. 1972;
20: 1528–1535.
38.
Bonacorso HG, Bortolotto GP, Navarini J, Porte
LMF, Wiethan CW, Zanatta N, Martins MAP, Flores
AFC. J Fluor Chem. 2010; 131: 1297–1301.
56.
57.
McCombie SW, Tagat JR, Vice SF, Lin SI, Steensma
R, Palani A, Neustadt BR, Baroudy BM, Strizki JM,
Endres M, Cox K, Dan N, Chou CC. Bioorg Med
Chem Lett. 2003; 13: 567–571.
39.
40.
Liu B, Liu M, Xin Z, Zhao H, Serby MD, Kosogof C,
Nelson LTJ, Szczepankiewicz BG, Kaszubska W,
Schaefer VG, Falls HD, Lin CW, Collins CA, Sham
HL, Liu G. Bioorg Med Chem Lett. 2006; 16: 1864–
1868.
Palani A, Shapiro S, Clader JW, Greenlee WJ, Vice S,
McCombie S, Cox K, Strizki J, Baroudy BM. Bioorg
Med Chem Lett. 2003; 13: 709–712.
Dorigo P, Fraccarollo D, Santostasi G, Maragno I,
Floreani M, Borea PA, Mosti L, Sansebastiano L,
Fossa P, Orsini F, Benetollo F, Bombieri G. J Med
Chem. 1996; 39: 3671–3683.
58.
59.
60.
Mcfadden HG, Huppatz JL. Aust J Chem. 1992; 45:
1045–1050.
Effenberger F, Barthelmess I. J Heterocycl Chem.
1995; 32: 599–602.
41.
42.
Cameron M, Foster BS, Lynch JE, Shi Y-J, Dolling
U-H. Org Process Res Dev. 2006; 10: 398–402.
Lahm GP, Selby TP, Freudenberger JH, Stevenson
TM, Myers BJ, Seburyamo G, Smith BK, Flexner L,
Clark CE, Cordova D. Bioorg Med Chem Lett. 2005;
15: 4898–4906.
Zanatta N, Lopes ECS, Fantinel L, Bonacorso HG,
Martins MAP. J Heterocycl Chem. 2002; 39: 943–
947.
43.
44.
Yamada S. J-Stage. 1951; 71: 1349–1355.
61.
62.
63.
Zumbrunn A, Lamberth C, Schaub F. Synth Commun.
1998; 28: 475–483.
Flores DC, Fiss GF, Wbatuba LS, Martins MAP,
Burrow RA, Flores AFC. Synthesis. 2006: 2349–
2356.
Lemcke T, Messinger P. Arch Pharm. 1995; 328:
269–270.
45.
Zanatta N, Amaral SS, dos Santos JM, de Mello DL,
Fernandes L da S, Bonacorso HG, Martins MAP,
Andricopulo AD, Borchhardt DM. Bioorg Med Chem.
2008; 16: 10236–10243.
Fauber B., Niel, M. B. Van, Cridland, A., Hurley, C.,
Killen, J., Ward, S. WO2016177686 A1, 2016, 203
pages.
64.
65.
Schaus JM. WO2009131815 (A1), 2009, 42 pages.
46.
47.
48.
Bonacorso HG, Ferla A, Cechinel C a., Zanatta N,
Martins M a. P. J Heterocycl Chem. 2008; 45: 483–
487.
Honda T, Kawashima K, Okamoto K, Yamamoto M
EP1864977 (A1), 2007, 51 pages.
66.
67.
68.
Priestley ES, Posy SL, Tremblay F, Martel A,
Marinier A. WO2013163241 A1, 2013, 308 pages.
Bonacorso HG, Calheiro TP, Rodrigues MB,
Stefanello ST, Soares FAA, Zanatta N, Martins MAP.
Monatsh Chem. 2016; 147: 0.
Marra JM, Goehring RR, Perez J, Stasaitis LR, Liu Y.
WO2004111011 A2, 2004, 42 pages.
Zanatta N, Cortelini M de FM, Caspes MJS,
Bonacorso HG, Martins MAP. J Heterocycl Chem.
1997; 34: 509–513.
Goryaeva M V., Burgart Y V., Ezhikova MA, Kodess
MI, Saloutin VI. Beilstein J Org Chem. 2015; 11:
385–391.
49.
50.
Madruga CDC, Clerici E, Marcos AP. J Heterocycl
Chem. 1995; 32: 735–738.
69.
70.
Zanatta N, Fortes AS, Bencke CE, Marangoni MA,
Camargo AF, Fantinel CA, Bonacorso HG, Martins
MAP. Synthesis. 2015; 47: 827–835.
Aquino E da C, Lobo MM, Leonel G, Martins MAP,
Bonacorso HG, Zanatta N, F. Eur J Org Chem. 2017:
306–312.
Nesi R, Chimichi S, Scotton M, Degl’Innocenti A,
Adembri G. J Chem Soc, Perkin Trans 1. 1980; 0:
1667–1670.
51.
Marcos R, Martins P, Sinhorin AP, Rosa A, Flores
AFC, Wastowski AD, P CM, Flores DC, Beck P,
Freitag RA, Brondani S, Cunico W, Bonacorso HG.
Synthesis. 2002: 2353–2358.
71.
72.
73.
Reiner R, Eugster CH. Helv Chim Acta. 1967; 50:
128–136.
52.
53.
Jones RG, Whitehead CW. J Org Chem. 1955; 20:
1342–1347.
Kuwano R, Hashiguchi Y, Ikeda R, Ishizuka K.
Angew Chem. 2015; 54: 2423–2426.
Iaroshenko VO, Dudkin S, Sosnovskikh VY,
Villinger A, Langer P. Eur J Org Chem. 2013;
201300107: 3166–3173.
Moszczyński-Pętkowski R, Majer J, Borkowska M,
Bojarski Ł, Janowska S, Matłoka M, Stefaniak F,
Smuga D, Bazydło K, Dubiel K, Wieczorek M. Eur J
Med Chem. 2018; 155: 96–116.
54.
A. W. Stolle W, M. Veurink J, T. M. Marcelis A, Plas
HC van der. Tetrahedron. 1992; 48: 1643–1656.
74.
Blakemore DC, Castro L, Churcher I, Rees DC,
Thomas AW, Wilson DM, Wood A. Nat Chem. 2018;

10.
ACCEPTED MANUSCRIPT
75.
76.
77.
78.
79.
80.
81.
Goldberg FW, Kettle JG, Kogej T, Perry MWD,
Tomkinson NP. Drug Discov Today. 2015; 20: 11–17.
Stepaniuk OO, Matviienko VO, Kondratov IS, Vitruk
I V., Tolmachev AO. Synthesis. 2013; 45: 925–930.
Armarego WLF, Chai C. Purification of laboratory
chemicals, Elsevier: Oxford, 5th edn., 2003.
Krechl J, Böhm S, Smrčková S, Kuthan J. Collect
Czechoslov Chem Commun. 1989; 54: 673–683.
Liu MTH., Chishti NH, Burkholder CD, Jones WE,
Wasson J.S. J Org Chem. 1980; 45: 4515–4515.
Wharton CJ, Wrigglesworth R. J Chem Soc, Perkin
Trans 1. 1981; 0: 433–436.
Moss RA, Guo W, Denney DZ, Houk KN, Rondan
NG. J Am Chem Soc. 1981; 103: 6164–6169.
82.
83.
Shapiro R. WO 2006/121648 A2, 2016, 26 pages.
Mousdis GA, Ganotopoulos NM, Barkaoui H, Abid
Y, Psycharis V, Savvidou A, Raptopoulou CP. Eur J
Inorg Chem. 2017; 2017: 3401–3408.
84.
85.
86.
87.
Parveen H, Hayat F, Salahuddin A, Azam A. Eur J
Med Chem. 2010; 45: 3497–3503.
Sturala J, Bohacova S, Chudoba J, Metelkova R,
Cibulka R. J Org Chem. 2015; 80: 2676–2699.
Leprêtre A, Turck A, Plé N, Knochel P, Quéguiner G.
Tetrahedron. 2000; 56: 265–273.
Tsuda K, Ogawa Y. J-Stage. 1950; 70: 73–76.