2-Carbamimidoylbenzoic Acid as a New Effective and Available Precursor for the Synthesis of Substituted 2-(Pyrimidin-2-yl)benzoic Acids

Article abstract of DOI:10.1055/s-0040-1705941

A new approach to the synthesis of 2-(pyrimidin-2-yl)benzoic acids based on the ring contraction of the 2-carbamimidoylbenzoic acid [(2-amidinobenzoic) acid] with 1,3-dicarbonyl compounds and their synthetic equivalents has been developed. The intramolecular condensation of the obtained acids with 1,3-dielectrophiles proceeds with the formation of the 4,6-dihydropyrimido[2,1- a ]isoindole-4,6-dione system, the pyrrolidone ring of which is easily opened under the action of weak nucleophiles. The reaction of 2-amidinobenzoic acid with chromones, which have an aryloxy group at 3-position does not stop at the step of pyrimidine ring formation and undergoes further spontaneous cyclization into 2-(benzo[4,5]furo[3,2- d ]pyrimidin-2-yl)benzoic acids.

Full text of DOI:10.1055/s-0040-1705941

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, 371–382
paper
371
de
V. A. Tkachuk et al.
Paper
Synthesis
2-Carbamimidoylbenzoic Acid as a New Effective and Available
Precursor for the Synthesis of Substituted 2-(Pyrimidin-2-yl)-
benzoic Acids
Volodymyr A. Tkachuka
Vyacheslav O. Shishkanua
MeO
O
CO2H
HN
O
CO2H
CO2H
NH2
Ar1
Tetiana M. Tkachukb
Svitlana V. Shishkinac
Olga V. Hordiyenko*a
0
0
0
0
-
0
0
0
2
-
8
6
8
0
-
7
7
9
0
N
1,3-dielectrophile
O
Ar1
Ar1 = 4-ClC6H4
N
NH
N
R1
0
0
0
0
-
0
0
0
2
-
4
7
4
9
-
7
1
9
5
R
1 = Me, Et, Ph, OH, NH2
(71–92%)
HO
69%
a Taras Shevchenko National University of Kyiv, Faculty of
Chemistry, 64/13 Volodymyrs’ka Str., Kyiv 01601, Ukraine
ov_hordiyenko@chem.knu.ua
MeO
O
O
R2 (H, CF3)
OAr2
H2O (R1 =/ NH2)
O
OMe
R2
CO2H
– H2O
b SMC Ecopharm Ltd, 136-B Naberezhno-Korchuvatska Str.,
Kyiv 03045, Ukraine
N
O
N
O
c SSI ‘Institute for Single Crystals’ of National Academy of
Sciences of Ukraine, 60 Nauky Ave., Kharkiv 61072,
Ukraine
N
– Ar2OH
(Ar2 = 4-ClC6H4, 2-O2NC6H4)
N
R1 = Me, Et, Ph, NH2
R1
(72–95%)
73–82%
OMe
OTeMalgraisClVSoo.hrvHre_eovhsrcopdhroiedynneidyknieonk
n
goNkAoa@tuitoc
h
nh
o
aerlmU.knnivue.ursaity of Kyiv, Faculty of Chemistry, 64/13 Volodymyrs’ka Str., Kyiv 01601, Ukraine
dines, the synthesis of which is often based on the conden-
sation of various arylamidines with 1,3-dicarbonyl
compounds, for example, acylacetic esters,2–12 malonic es-
ters,13–16 and malononitrile17,18 continues to this day, as evi-
denced by numerous literature data of recent years.
Derivatives of 3- and 4-(pyrimidin-2-yl)benzoic acids
are considered, in particular, to be useful for treating or pre-
venting diseases associated with nonsense mutations of
mRNA (cancer, cystic fibrosis, lysosomal storage disorders,
muscular dystrophies, hemophilia, etc.),19 as antagonists of
HIF prolyl hydroxylases,20 and are useful for treatment dis-
eases benefiting from the inhibition of this enzyme, anemia
being selective inhibitors of PI3 kinase enzymes.21 They are
accordingly of benefit in medicine, for example, in the
treatment of inflammatory, autoimmune, cardiovascular,
neurodegenerative, metabolic, oncological, nociceptive, or
ophthalmic conditions, use as inhibitors of allergic reac-
tions22 and plant growth regulators.23a That is why a screen-
ing of new biologically active molecules among pyrimidine
derivatives, in particular 2-phenylpyrimidines, is still on-
going.
Quite a number of isomeric pyrimidin-2-ylbenzoic acids
have been synthesized from the corresponding derivatives
of 3- or 4-carbamimidoylbenzoic acids by condensation of
amidino group with different 1,3-dicarbonyl compounds
and their equivalents.19–22 This synthetic approach is pre-
sented in the patent literature, however, until the 2-carba-
mimidoylbenzoic acid (1) was recently synthesized in our
lab,24 it was not investigated to obtain 2-(pyrimidin-2-
yl)benzoic acids. Therefore, we were interested to find out
what role this synthon can play among small molecule
building blocks in the diversity-orientated synthesis of li-
braries of 2-(pyrimidin-2-yl)benzoic acids.
Received: 25.06.2020
Accepted after revision: 16.09.2020
Published online: 16.11.2020
DOI: 10.1055/s-0040-1705941; Art ID: ss-2020-t0349-op
Abstract A new approach to the synthesis of 2-(pyrimidin-2-yl)ben-
zoic acids based on the ring contraction of the 2-carbamimidoylbenzoic
acid [(2-amidinobenzoic) acid] with 1,3-dicarbonyl compounds and
their synthetic equivalents has been developed. The intramolecular
condensation of the obtained acids with 1,3-dielectrophiles proceeds
with the formation of the 4,6-dihydropyrimido[2,1-a]isoindole-4,6-di-
one system, the pyrrolidone ring of which is easily opened under the ac-
tion of weak nucleophiles. The reaction of 2-amidinobenzoic acid with
chromones, which have an aryloxy group at 3-position does not stop at
the step of pyrimidine ring formation and undergoes further sponta-
neous cyclization into 2-(benzo[4,5]furo[3,2-d]pyrimidin-2-yl)benzoic
acids.
Key words 2-carbamimidoylbenzoic acid, ring closure, 2-(pyrimidin-
2-yl)benzoic acids, 4,6-dihydropyrimido[2,1-a]isoindole-4,6-dione,
chromone ring opening, green chemistry
A pyrimidine core is a structural element of a large
number of both natural and synthetic biologically active
substances, starting with nitrogenous bases, the building
blocks of living organisms, and ending with the latest drugs
to help combat a wide range of diseases and life-threaten-
ing disorders. Among them are 2-aryl-substituted pyrimi-
dines such as Bosentan, which is an endothelin receptor an-
tagonist used in the therapy of pulmonary arterial hyper-
tension, Sildenafil (Viagra) that was predominantly
employed for the treatment of erectile dysfunction and
treatment of pulmonary hypertension, and Emapunil that
is an anxiolytic drug, which acts as a selective benzodiaze-
pine receptor agonist.1 That is why screening of new biolog-
ically active pyrimidine derivatives, in particular 2-pyrimi-
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 371–382
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

372
V. A. Tkachuk et al.
Paper
Synthesis
A limited number of 2-(pyrimidin-2-yl)benzoic acids
were obtained in poor yields from phthalic, ortho-toluic
acid derivatives, or other developers. Unsubstituted 2-, 3-,
and 4-(2-pyrimidinyl)benzoic acids have been obtained by
Suzuki reaction from the corresponding carboxyphenylbo-
ronic acids and 2-bromopyrimidine, respectively.25 The
only 2-(4-methyl-6-oxo-1,6-dihydro-2-pyrimidinyl)benzo-
ic acid (2a) was obtained in poor yield by sodium ethoxide-
mediated cyclization of diethyl phthalate with -aminocro-
tonamide,26 and its 4-phenyl analogue 2b was prepared by
the oxidation of 4-phenyl-2H-pyrimido[2,1-a]isoquinolin-
2-one23b or of a methyl group of 4-chloro-6-phenyl-2-(o-
tolyl)pyrimidine.23a Amide derivative of 5-methyl-2-(py-
rimidin-2-yl)benzoic acid Filorexant was developed by
Merck as a dual orexin receptor antagonist for the treat-
ment of insomnia (Figure 1). Pyrimidine substituent was
introduced to 2-iodine-substituted amide by Stille coupling
in a final step for the preparation.27
O
O
O
O
R
OMe or Ph
OEt
(R = Me, Et)
CO2H
CO2H
NH2
Method A or B
O
N
R1
R
HN
2a–e
OEt
NH
1
(R = COOEt, CN)
Method A
O
2a (R1 = Me): 74% (A), 86% (B)
2b (R1 = Ph): 69% (A), 81% (B)
2c (R1 = Et): 83% (A), 92% (B)
2d (R1 = OH): 71% (A)
2e (R1 = NH2): 72% (A)
Scheme 1 The synthesis of 2-(pyrimidin-2-yl)benzoic acids 2a–e.
Reagents and conditions: Method A: NaOMe (2.2 equiv.), MeOH, reflux,
4–8 h, then AcOH. Method B: NaOH (2 equiv.), EtOH, rt, 2 days, then
AcOH.
Thus, refluxing a mixture of 1 (1 equiv.) with a slight ex-
cess of methyl acetoacetate in anhydrous MeOH in the pres-
ence of 2.2 equivalents of NaOMe (for deprotonation of car-
boxyl group of 1 and activation of 1.2 equiv. dicarbonyl
compound) for 4 hours in a manner similar to the method20
resulted in the formation of the desired 2-(4-methyl-6-oxo-
1,4-dihydro-2-pyrimidinyl)benzoic acid (2a).26 It was iso-
lated in 74% yield as colorless fine needles, poorly soluble in
water, by acidifying with AcOH of an aqueous solution of
the residue after evaporation of the reaction mixture. Under
similar conditions, heterocyclization of the acid 1 was per-
formed with the participation of other mentioned 1,3-di-
carbonyl compounds. It has been found that anhydrous
low-boiling alcohol should be used to complete the reaction
in the desired direction, which means that anhydrous
MeOH is the best suited solvent. This is due to the fact that
strong heating, especially in the presence of traces of water,
led to the decomposition of the starting amidino acid 1
with phthalimide formation and decreasing the yield of the
target compounds.
The synthetic procedure requires a larger amount of
base than conventional methods to deprotonate the carbox-
yl group and activate the corresponding electrophile. At the
same time, this promotes the dissolution of the starting
amidino acid 1, especially in methanol, since under neutral
conditions it is a poorly soluble zwitterion with a reduced
reactivity.
We have found that the reaction of 1 with methyl aceto-
acetate, ethyl benzoylacetate, and methyl propionylacetate
may also occur at room temperature under green chemistry
conditions by adapted method.28 The reaction was per-
formed by stirring the mixture in aqueous EtOH in the pres-
ence of 2 equivalents of NaOH. This required a significant
increase in the reaction time (more than 2 days), but al-
lowed to isolate acids 2a–c in over 80% yields. A five-fold
scale-up of the reagents in the synthesis of acid 2c (by
Method B) did not lead to a decrease in the yield of the reac-
tion product (2.8 g, 92%) (Scheme 1).
CO2H
NH2
CO2H
N
N
F
H
N
O
N
O
N
O
NH
N
R1
2a (R1 = Me)
2b (R1 = Ph)
Filorexant, Merck
2-carbamimidoylbenzoic acid (1)
Figure 1 2-Carbamimidoylbenzoic acid (1), its known pyrimidine de-
rivatives 2a,b, and Filorexant developed by Merck
Some of the main properties of an amidino acid 1 were
studied previously in our lab;24b therefore, it was of interest
to investigate a possibility of its cyclization involving the
amidine function. It was also interesting to find out how
the carboxyl group will behave in these transformations,
since the possibility of its side reactions resulted in
phthalimide formation was previously observed.24b Acid 1
in heterocyclization reactions, which can lead, in particular,
to the formation of pyrimidine derivatives, has a number of
advantages in comparison with previously used synthons.
First of all, it is the simplicity of its non-classical one-step
preparation from commercially available phthalonitrile,24
and, what is important, the stability of this substance
during long-term storage. An important advantage of acid 1
is also its ability to react under green chemistry conditions,
in particular, in lower alcohols and water.
In order to study the heterocyclization of 2-amidino-
benzoic acid 1 leading to a pyrimidine cycle, we investigat-
ed the reaction of the amidinic group of this acid with 1,3-
dielectrophiles – 1,3-dicarbonyl compounds and malonic
acid derivatives. The reaction of acid 1 with methyl acetoac-
etate, methyl propionylacetate, ethyl benzoylacetate, dieth-
yl malonate, and ethyl cyanoacetate allowed to obtain 2-(6-
oxo-1,6-dihydropyrimidin-2-yl)benzoic
(Scheme 1).
acids
2a–e
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 371–382

373
V. A. Tkachuk et al.
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Synthesis
Earlier,
2-(6-oxo-4-phenyl-1,6-dihydro-2-pyrim-
proton signal of 5′-H of the pyrimidine ring at a higher field
at  = 4.98. A broad signal of the carboxylic group and NH or
OH proton with an intensity of about 2 H at  = 12.10 was
observed. A singlet with 2 H intensity at  = 6.38 apparently
corresponded to the amino group of the pyrimidine moiety.
Only a few reactions of [3+3] cyclization of arylamidines
with unsubstituted malononitrile were described in the lit-
erature, which led to the formation of 4,6-diaminopyrimi-
dines.17,18 The conditions used in the case of amidino acid 1
were ineffective primarily because of its insolubility in
most organic solvents and the predominance of a side pro-
cess associated with intramolecular cyclizations, especially
under severe reaction conditions. In order to obtain 2-(4,6-
diamino-2-pyrimidinyl)benzoic acid (2f), an attempt was
made to carry out [3+3] cyclization of amidino acid 1 with
malononitrile, taken in an equimolar ratio, as it was report-
ed for guanidine.30 During the reflux of the reaction mix-
ture for 6 hours, there was an active release of ammonia
gas. After workup similar to those required for the isolation
of compounds 2a–e, a small amount of water insoluble and
slightly soluble in MeOH pale orange precipitate was fil-
tered off. The needles of phthalimide, which was the major
product of the reaction, appeared in the mother liquor after
standing overnight. LC/MS of the precipitate showed mo-
lecular ions at (M + H)+ 165, (M – H)+ 194, and (M + H)+ 294.
The first ion was attributed to unreacted amidino acid 1,
and the other two, given previous studies, probably corre-
sponded to compounds 431,32 and 6 (Scheme 2).32 Attempts
to separate the mixture proved unsuccessful.
idinyl)benzoic acid (2b) was obtained in 30% yield by the
oxidation of 4-phenyl-2H-pyrimido[2,1-a]isoquinolin-2-
one with potassium permanganate in the presence of KOH
in pyridine23b or in 22% yield along with 2-(4-chloro-6-phe-
nyl-2-pyrimidinyl)benzoic acid (45% yield) by oxidation of a
methyl group of 4-chloro-6-phenyl-2-(o-tolyl)pyrimidine
with sodium dichromate.23a Acid 2b was only characterized
by melting point and elemental analysis data.
In the 1H NMR spectrum of compound 2a, there was a 1
H singlet at  = 6.05, which apparently belonged to the 5′-H
proton of the pyrimidine ring, and about 2 H intense broad
signal at  = 12.65, which corresponds to NH or OH protons
and carboxylic group.
The 5′-H pyrimidine proton signal of the product 2b, de-
spite having the same environment as in the 2a and 2c skel-
etons, shifted relative to the corresponding signal of com-
pounds 2a,c to a lower field ( = 6.79), apparently due to the
deshielding effect of an aromatic ring near an adjacent R1
carbon atom.
The acid 2d, which was obtained by the reaction of 1
with diethyl malonate, after separation from the reaction
mixture by workup as described above, in every case was
contaminated with phthalimide (Scheme 1). The only way
to obtain a product containing no phthalimide impurity
was to dissolve the crude product in 25% aqueous ammonia
and then reprecipitate the yellowish small crystals of 2d
with dilute (1 M) hydrochloric acid. In the 1H NMR spec-
trum of 2d, 5′-H proton singlet of the pyrimidine nucleus
was observed at a higher field ( = 5.24) compared to the
similar signal of compounds 2a–c. A broad signal with an
intensity of about 3 H at  = 12.31 was observed. It could be
a result of an overlapping of the carboxylic group, two OH
or OH and NH proton signals from the pyrimidine moiety.
Ethyl cyanoacetate also reacted with amidino acid 1
similar to 1,3-dicarbonyl compounds, and afforded pyrimi-
dine 2e, the yield of which varies from 35 to 72% depending
on the reagents ratio. Under conditions similar to a meth-
od29 when using a four-fold excess of sodium methoxide
and an equivalent ratio of 1:1 of amidine 1 and cyano ester,
the yields of the reaction product 2d were the lowest. The
best yield of 2e was obtained using a double excess cyano-
acetic ester and 3 equivalents of NaOMe. In the 1H NMR
spectrum of 2e, as in the case of 2a–d, there was a single-
That was confirmed by the 1H NMR spectrum of 2f,
which showed a 5′-H signal of pyrimidine ring at  = 5.44, a
4 H intensity signal from protons of two equivalent amino
groups of the pyrimidine moiety ( = 6.33) situated approx-
imately at the same field compared to the amino group sig-
nal of the compound 2e ( = 6.38). The OH signal of the car-
boxylic group was not observed due to the rapid proton ex-
change. Instead of this, the signal of the water protons was
significantly broadened.
The arrangement of the signals of the benzene ring pro-
1
tons in the H NMR spectrum of compound 2f in DMSO-d6
differs from the other synthesized acids 2a–e, and revealed
two doublets together with two doublets of doublets at a
higher field. The 13C NMR spectrum of 2f displayed 10 sig-
nals for 11 carbon atoms due to the coincidence of the
O
CO2H
NC
NC
CO2H
CONH2
CN
CO2H
NH2
CONH2
CN
(a)
1
+
+
NH
N
NH2
CN
+
N
N
NH2
OMe
CN
(3 equiv.)
N
N
CN
NC
6 (49%) NH2
NC
CN
NC
CN
NC
HO2C
3 (17%)
4a
2f (20%)
NH2
5
7
– H2O
Scheme 2 The reaction of acid 1 with malononitrile leading to compounds 2f, 3, and 6. Reagents and conditions: (a) MeOH, NaOMe, reflux, 6 h, then
AcOH; isolated yields are shown. a Detected by LC/MS of initial experiment’s crude product.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 371–382

374
V. A. Tkachuk et al.
Paper
Synthesis
chemical shifts of two pyrimidine carbon atoms associated
with amino groups which resonate at  = 163.5. A signal at
 = 170.1 was attributed to the carboxyl group carbon, in
addition to the signal at  = 164.0 that was assigned to 2′-C
of the pyrimidine, respectively.
Taking into account the basic nature of the diaminopy-
rimidine moiety, it is necessary to consider the presence of
strong intermolecular hydrogen bonds, as well as a signifi-
cant contribution of the zwitterionic structure 2f′ (Scheme
3) as it was observed for the starting amidino acid 1.24a This
assumption is supported by the structure of the salts of 4,6-
diaminopyrimidine with a series of dicarboxylic acids in
the solid state, in which protonation occurs at the pyrimi-
dine nitrogen atom.33
1H and 13C NMR assignments for protonated compound
2f-D were derived from a combination of HMBC and HSQC
experiments that were carried out in DMSO-d6–CF3COOD
solution. The 2D HMBC spectrum of 2f-D showed the ex-
pected intense correlation between the 6-H benzene proton
( = 7.99) and the carbon atom of the carboxyl group ( =
167.1). A significant correlation between 3-H benzene pro-
ton ( = 7.58) and 2′-C pyrimidine carbon atom ( = 159.2)
was also observed. As for the pyrimidine fragment itself,
the HMBC spectrum showed a correlation signal between
5′-H proton signal ( = 5.63) and the equivalent 4′-C and 6′-C
signals of the diazine ring ( = 159.6). The signals of the
latter in the 13C NMR spectrum were overlapped and were
observed as a broadened peak due to proton exchange.
The HMBC spectrum did not exhibit even an insignifi-
cant correlation between pyrimidine 5′-H and the carbon
atom of the carboxyl group. This confirms the absence of a
direct connectivity between them, which would take place
if intramolecular cyclization with the formation of the cor-
responding pyrimidoisoindole occurred during the synthe-
sis of acid 2f.
The major product of the reaction of 1 with a malononi-
trile was 2-(2-amino-3,5-dicyano-6-methoxypyridin-4-
yl)benzamide (6)32 (49% yield) as followed from 1H, 13C
NMR, IR spectra, X-ray diffraction study, and LC/MS where
molecular ions at (M + H)+ = 294 and (M – H)+ = 292 were
detected.
Compound 6 began to precipitate after complete cooling
of the reaction mixture. It was formed, as we believe, by the
sequential condensation of 1 with two malononitrile mole-
cules and the subsequent heterocyclization of an interme-
diate 5 under the action of NaOMe (Scheme 2). This trans-
formation can proceed similarly to that found by us in an
earlier pyridine ring 6 formation by sodium methoxide-cat-
alyzed ring-opening of 1H-isoindol-1-one (4), which was
formed as it could be supposed by cyclization of the acid 332
(Scheme 2). The 1H NMR spectrum of compound 6 was sim-
ilar to that observed previously.32
O
O
OH
N
O
N
NH2
H
NH2
H
N
N
H
NH2
NH2
2f
2f'
CF3COOD
DMSO-d6
7.99H
O
167.1
OH(D)159.6
159.2
N
NH2
7.58H
N
H
H5.63
159.6
NH2
2f–D
Scheme 3 The zwitterionic structure 2f′ and selected HMBC correla-
tions of the protonated/deuterated compound 2f-D in DMSO-d6–
CF3COOD (600 MHz)
A presence of a strong intermolecular hydrogen bonding
interaction between basic 4,6-diaminopyrimidine moiety
and carboxyl group with a formation of a zwitterionic
structure 2f′ is also supported by a low-frequency shift of
an asymmetric C=O stretch vibration to 1655 cm–1
.
In a confirmation of the reaction route, a few days after
separation of the acid 2f, small pale orange needle crystals
of a substance, which was identified as 2-(1-amino-2,2-di-
cyanovinyl)benzoic acid (3) (17% yield) precipitated from
the filtrate. That conclusion was made on the basis of the
absence in the 1H NMR spectrum of the characteristic signal
of the 5′-pyrimidine proton at the region of  = 5–7, the
presence of two closely spaced single-proton singlets at  =
8.62 and 8.72, which may correspond to non-equivalent
protons of NH2 group at a double bond, and a broad single-
proton signal of the COOH group at  = 13.10. The presence
in the IR spectrum of the characteristic bands of two nitrile
groups at 2210, 2224 cm–1 and of ion at (M + H)+ = 214 ac-
cording to LC/MS also supported this supposition.
To confirm this hypothesis, we revised the 1H and 13C
NMR spectra 2f in DMSO-d6 with the addition of one drop
CF3COOD to destroy the zwitterion and restore the carboxyl
function. The positive charge that arises upon protona-
tion/deuteration of 2f can be delocalized between all nitro-
gen atoms.
As a consequence, in the 1H NMR spectrum, the change
in the order of distribution of the benzene protons signals
occurred, and a doublet, two doublets of doublets, and a
doublet were observed in a similar way, as for compounds
2a–e. The signals of the protonated pyrimidine nucleus, to-
gether with the signals of acid protons were observed as a
broadened signal in a wide range at  = 7.50, which was
partially overlapped with the aromatic signals. The 5′-H sig-
nal of the pyrimidine ring was downfield shifted to  = 5.63
(Δ = 0.2 ppm).
Interestingly, using LC/MS analysis in both cases, among
the products, no molecular ion corresponding to 2,2′-(6-
amino-5-cyanopyrimidine-2,4-diyl)dibenzoic acid (7), sim-
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 371–382

375
V. A. Tkachuk et al.
Paper
Synthesis
ilar in structure to pyrimidine obtained from benzamidine
and malononitrile under similar conditions, was detected.34
Pyrimidin-4-ones are characterized by lactam–lactim
tautomerism with predomination of oxo-form,35 which for
the compounds 2a–e can be represented by the following
structures A and B (Figure 2).
dihydropyrimido[2,1-a]isoindole-4,6-diones 8a–c,e with
loss of a water molecule (–18 a.u. according to LC/MS)
(Scheme 4). Their structure could be assigned based on the
most probable a reaction pathway with the participation of
the carboxylic group and the ‘amide’ group of the pyrimidi-
none cycle.23a,36
O
CO2H
N
CO2H
N
(a)
– H2O
CO2H
CO2Me
(b)
O
R1
R1
H
N
N
H
N
O
O
(for 8a)
H2O, rt
(R1 ≠ NH2)
HN
2a–e A
N
N
N
N
R1
2a–e
8a–e
9 (quant.)
O
2a–e B
OH
R1
Me
8a (R1 = Me): 72%(C), 93% (D)
8b (R1 = Ph): 85% (C), 97% (D)
8c (R1 = Et): 78% (C), 95% (D)
8d (R1 = OH): 0% (C)
2c A (R1 = Et)
R
1 = Me (2a), Ph (2b), Et (2c), OH (2d), NH2 (2e)
torsion angle 50.1°
8e (R1 = NH2): quant. (C)
Figure 2 Possible lactam–lactim tautomerism of the compounds 2a–e
and the structure of 2c (R = Et) according to the results of X-ray diffrac-
tion study. Thermal ellipsoids are shown at 50% probability level.
Scheme 4 Conversion of 2-(pyrimidin-2-yl)benzoic acids 2a–e into
4,6-dihydropyrimido[2,1-a]isoindole-4,6-diones 8a–e and methanoly-
sis of 8a into ester 9. Reagents and conditions: (a) Method C: 220–230
°C, oil bath, 15–30 min; Method D: o-xylene, reflux, 8–12 h; (b) For 8a:
MeOH, reflux, 30 min.
In the solid state, 2-(pyrimidin-2-yl)benzoic acid (2c; R1
= Et) exists in the tautomeric form of pyrimidinone 2c A, as
evidenced by X-ray diffraction data (Figure 2). The length of
C=O (C11=O3) bond in the compound 2c is noticeably lon-
ger [1.279 (6) Å] compared to the average C=O bond in lact-
ams (1.240 Å). The NH–C=O (N3–C11) bond also lengthens
[1.410 (6) Å] compared to an average value of 1.334 Å. The
existing intermolecular hydrogen bonds O1···H–N1 and
rather strong intermolecular hydrogen bonds O2–H···O3′
are most likely responsible for this effect. These bonds can
also be present in the DMSO-d6 solution; moreover, in the
solution, it is necessary to take into account the possible
lactam-lactim equilibrium.
Pyrimido[2,1-a]isoindole-4,6-diones 8a–c were ob-
tained similar to the method23a by solvent-free heating the
acids 2a–c in an oil bath at about 220–230 °C for 15 min-
utes (Method C). Under such drastic conditions, heterocy-
clization was accompanied by a partial decomposition of
starting compounds, and the yield of the products 8a–c af-
ter crystallization from hot o-xylene was 72%, 85%, and 78%,
respectively. However, reflux suspensions 2a–c in o-xylene
for 8–12 h with the azeotropic water separation (Method
D) increased the yield of the target compounds to over 90%.
The conversion of 2e (R = NH2) into 8e by heating in an oil
bath at 220–230 °C for 0.5 hour was quantitative, but did
not occur upon reflux in o-xylene similar to the case for the
acid 2d (R = OH). The latter was decomposed almost imme-
diately, when heated solvent-free in an oil bath at a tem-
perature close to the melting point.
Earlier, the similar observation has been made that the
acid 2c upon melting underwent intramolecular cyclization
into a pyrimido[2,1-a]isoindole-4,6-dione derivative 8c,
which melted 50 °C higher than the starting material.23a
The structure of pyrimido[2,1-a]isoindole-4,6-diones
8a–c and 8e was confirmed by their LC/MS and 1H NMR
spectra: the observed in 1H NMR spectra of the starting ac-
ids 2a–c and 2e broad proton signals of pyrimidine ring en-
docyclic carboxamidic group and carboxylic group at  =
12.60, 13.05, and 12.10 were absent in the spectra of the
products 8a–c and 8e. The 3-H proton signals of pyrimi-
do[2,1-a]isoindole-4,6-diones 8a–c were shifted to a lower
field by about 0.1 ppm compared to the corresponding sig-
nals 5′-H of pyrimidine rings 2a–c. When passing to the cy-
clic structures pyrimido[2,1-a]isoindole-4,6-diones 8a–e
from acyclic precursors 2a–e, no tautomeric equilibrium
occurs in the formed ‘imide’ fragment O=C–N–C=O in which
both carbonyl groups can be involved in hydrogen bonding
In the 1H NMR spectra of 2a–e, the intensity of the
broad carboxylic proton signal was much higher than 1 H
and was about 2 H (2a–c, 2e) or 3 H (2d), while OH or NH
proton signals were not observed. This fact did not allow us
to determine a predominant tautomeric form in the solu-
tion. In the IR spectra, among other characteristic bands,
the observed vibrational bands of СОNH groups at 1691–
1698 cm–1, were also in agreement with predomination of
pyrimidinone 2 A form of compounds 2a–e.
According to the data calculated at the m06-2x/cc-pvtz
level, in the gas phase, the 2c A NH tautomer has a lower
energy compared to the OH form 2c B (17.12 kJ/mol) (see
SI). The presence of a carboxyl group promotes a larger
twist angle of aryl rings relative to each other. Upon succes-
sive transition from the OH tautomer with an unsubstitut-
ed phenyl ring to the NH tautomer and then to the 2-car-
boxyphenyl substituted pyrimidinone 2c A, the calculated
torsion angle sequentially increases from 0.8° to 23.6° and
then to 55.3°, which is in good agreement with the experi-
mentally observed value of 50.1° of the angle N1–C8–C1–
C2.
The presence of the form 2 A is also supported by the
fact that acids 2a–c,e under heating above 220 °C under-
went intramolecular cyclization into the corresponding 4,6-
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376
V. A. Tkachuk et al.
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Synthesis
with traces of water in aprotic DMSO-d6. This results in a
more pronounced deshielding effect of the adjacent imide
carbonyl group.
latter was shifted to the lower field compared to the 2-H
proton signal of the starting chromone 10a ( = 8.39) due to
the impact of a neighboring nitrogen atom.
On the contrary, the 3-H proton signal of 8e was shifted
into a higher field by 0.03 ppm compared to the starting
compound 2e. The phenylene proton signals of 8a–c and 8e
were also observed at a lower field (Δ = 0.2–0.4 ppm) com-
pared to a similar signals of the starting materials 2a–c,e.
Compounds 8a–c, unlike 8e, were water sensitive. Thus,
in the 1H NMR spectra of pure lactams 8a–c recorded after a
long-term storage (for several months even in tightly closed
containers), the low-intensity signals of the starting acids
2a–c impurity (10–15% of the major compound) were de-
tected. That indicated a reverse hydrolysis resulted in a pyr-
rolidine cycle opening of 8a–c because of the contact with
atmospheric moisture, similar to that occurred with
2,3,4,6-tetrahydropyrimido[2,1-a]isoindol-6-one under the
action of different nucleophiles.37 A similar effect was also
observed when dissolving compounds 8a–c in non-dried
solvents such as acetone and DCM. In contrast, the hydroly-
sis of 2-aminopyrimidoisoindole-dione 8e did not occur
under working conditions, neither on contact with atmo-
spheric moisture nor when suspended in water. This can be
caused by the stronger donor properties of the 2-amino
group, which reduces the sensitivity of the 6-carbonyl
group to a nucleophilic attack.
During the attempted chromatographic purification of
pyrimidoisoindolone 8a using DCM–MeOH 95:5 as the elu-
ent, methyl ester 9 was isolated instead of the starting 8a.
The latter, as it turned out, upon refluxing its methanolic
solution, underwent methanolysis to 9 in a quantitative
yield.
Recyclization of chromones as masked 1,3-dicarbonyl
compounds with amidines is also known to lead to the for-
mation of pyrimidine derivatives.38–42 The reaction of the
amidino acid 1 with chromone 10a was carried out similar
to the procedure41 in the presence of K2CO3 by heating the
mixture in DMF at 80–90 °C and allowed to obtain 2-[5-(4-
chlorophenyl)-4-(2-hydroxy-4-methoxyphenyl)-2-pyrim-
idinyl]benzoic acid (11a) (Scheme 5).
The proton signals of the phenolic ring formed from the
methoxyphenylene moiety of the chromone system were
shifted to a higher field by Δ = 0.1–0.8 ppm. The same was
observed for two A2B2 doublets of 4 H intensity, corre-
sponding to the protons of the 4-chlorophenyl ring.
The interaction of amidino acid 1 with 3-aryloxychro-
mones 10b–d did not stop at the step of substituted pyrim-
idines 11b–d formation, and gave 2-(benzo[4,5]furo[3,2-
d]pyrimidin-2-yl)benzoic acid derivatives 12a,b (Scheme 6)
similar to the transformation described previously for ami-
notriazole.42
The furan ring closure occurred as a result of intramo-
lecular heteroaromatic nucleophilic substitution of the 5-
aryloxy group of an intermediate pyrimidines 11b–d with
2-(4-methoxy)phenoxy anion and the elimination of sub-
stituted phenolate ArO– leaving group. That conclusion was
made on the 1H NMR spectra analysis of the products 12a,b,
which lacked the proton signals of the aryloxy groups of the
starting chromones 10b–d and proton signals of the pheno-
lic hydroxyl groups from 11b–d. In the 1H NMR spectrum of
compound 12a, the singlet of 4′-CH of the pyrimidine ring
was observed at a lower field ( = 9.23) than the 2-H signal
of the starting chromone 10b ( = 8.54). Such a signal was
not observed in the spectrum of compound 12b. The latter
compound was formed by the reaction of the amidino acid
1 with the chromones 10c,d containing the CF3 group at the
2 position (R = CF3) and differing only in the 3-aryloxy
group (Ar = 4-ClC6H4 or 2-NO2C6H4).
The furan cycle closure occurred by cleavage of aryloxy
group, more probably after the formation of the pyrimidine
ring of 11b–d. That was supported by the LC/MS data of the
crude products 12a,b which showed the presence of a small
number of weak peaks at m/z value (M + H)+ = 449 and (M –
H)+ = 515 (2.5% and 5.6%, respectively) corresponding to the
possible intermediates 11b–d.
Benzoic acid bearing benzofuro[3,2-d]pyrimidin-4(3H)-
one residue at ortho-position was obtained earlier by intra-
molecular condensation of phthalamic acid substituted
with 3-aminobenzofuran-2-carboxamide.43 Previously, it
was found that the formation of 2-benzo[4,5]furo[3,2-d]py-
rimidine occurs during the interaction of benzofuranone
and amidines44 and only a few examples of a transforma-
tion into 2-benzo[4,5]furo[3,2-d]pyrimidine derivatives of
chromones bearing phenoxy,42 tosyl,45a or halogen45b,c leav-
ing groups have recently been described.
Triaryl-substituted pyrimidine 11a was isolated after di-
lution of the reaction mixture with water (1:10 ratio) and
then acidification with AcOH to a slightly acidic pH. In the
1H NMR spectrum of 11a, there were signals from the car-
boxylic group protons ( = 12.80), phenolic hydroxyl ( =
9.85), and 6-H proton of the pyrimidine ring at  = 8.81. The
Ar1
MeO
O
In summary, a simple and straightforward approach to a
novel and previously described 2-(6-oxo-1,6-dihydropy-
rimidin-2-yl)benzoic acids 2a–e using 2-carbamimidoyl-
benzoic acid (1) as a building-block, has been developed.
Along with this derivatives, intermediate 2-(1-amino-2,2-
dicyanovinyl)benzoic acid (3) and substituted 2-(pyridin-4-
yl)benzamide (6) can also be obtained from the acid 1. 2-
CO2H N
(a)
1
+
N
Ar1
O
HO
OMe
10a (Ar1 = 4-ClC6H4)
11a (69%)
Scheme 5 Recyclization of chromone 10a with the amidino acid 1.
Reagents and conditions: (a) 1, K2CO3, DMF, reflux, 6 h, then AcOH.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 371–382

377
V. A. Tkachuk et al.
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Synthesis
KO2C
HN
R4
MeO
MeO
N
N
2 KHCO3
MeO
O
O
NH2
OAr2
– Ar2OH
N
CO2H
N
CO2K
O
O
– 2 K2CO3
Ar2O
R4
R4
K
12a (R4 = H): 82%;
12b (R4 = CF3): 78% from 10c, 73% from 10d
1,4-AdN
MeO
1,4-E
K2CO3, DMF, reflux, 6–8 h,
then AcOH
SNAr
KO2C
HN
MeO
NH CO2K
NH CO2H
O
O
R4
K2CO3
R4
NH2
OAr2
MeO
+
N
H2N
H2N
OAr2
– KHCO3
K
O
Ar2O
N
CO2K
1
O
R4
10b (R4 = H, Ar2 = 4-ClC6H4)
10c (R4 = CF3, Ar2 = 4-ClC6H4)
10d (R4 = CF3, Ar2 = 2-O2NC6H4)
O
i-PT
K2CO3 – KHCO3
OMe
KO2C
HN
KO2C
MeO
OH
N
N
H
R4
NH
HO
K
R4
N
MeO
MeO
K
N
KHCO3
H2CO3
HO
N
CO2K
Ar2O
AdN
then i-PT
OAr2
– H2CO3
N
CO2K
OAr2
– H2O
– KHCO3
Ar2O
R4
11b–d
pKA <10
OH
OH
R4
O
O
i-PT: internal proton transfer
Scheme 6 A plausible mechanism of amidino acid 1 interaction with 3-aryloxychromones 10b–d
(Pyrimidin-2-yl)benzoic acids 2a–e are able to undergo in-
tramolecular cyclization with the formation of pyrimi-
do[2,1-a]isoindole derivatives 8a–e, which can undergo hy-
drolysis and methanolysis. The amidino acid 1 can be used
in the chromone recyclization, which leads to the formation
of triaryl-substituted pyrimidines 11 and 2-(benzo[4,5]fu-
ro[3,2-d]pyrimidin-2-yl)benzoic acid derivatives 12, in
case, if 3-aryloxy group is present at a chromone skeleton.
These transformations make it possible to obtain directly
pyrimidines containing carboxy substituted phenyl group,
which is difficult to introduce into phenylpyrimidines by
other methods.
acid and washing with water, even without the use of chro-
matographic purification and practically without decreas-
ing the yield of the target compound.
2-Carbamimidoylbenzoic acid (1) can serve as an effec-
tive and convenient starting material for the synthesis of
structural diversity of a pyrimidine-based scaffolds with
beneficial properties (pharmacokinetic and physicochemi-
cal parameters, low MW, hydrogen-bond acceptor/donor,
further functionalization, etc.). The developed strategy pro-
vides a fast and efficient access to a number of small mole-
cules containing pyrimidine moiety that will likely be use-
ful in Fragment-Based Drug Discovery.
Carrying out the reactions of 2-carbamimidoylbenzoic
acid 1 in methanolic medium not only simplifies the syn-
thesis of target pyrimidines in high yields, but also increas-
es the yield of the previously described compounds when
used as a starting material. It should be noted that acid 1 is
no less a good amidine donor for a heterocyclization with
less reactive electrophiles under harsh conditions, in partic-
ular, such as refluxing in DMF. Under more severe condi-
tions, this synthon, given the tendency of the amidines
themselves to decompose and the close proximity of the
carboxyl and amidine groups, can lead to the formation of
by-products. However, their number is limited by phtha-
lamic acid and phthalimide, which can be easily removed
during reaction workup upon acidifing with acetic or citric
Further work on transformations of 2-carbamimidoyl-
benzoic acid (1) and obtained 2-(pyrimidin-2-yl)benzoic
acids 2 is under way at our lab.
Melting points were determined on a Boetius microscope hot plate
apparatus. Elemental analyses (C, H, N) were conducted using the
Vario Micro Cube. IR spectra were recorded on a PerkinElmer Spec-
trum BX FTIR spectrophotometer for samples prepared as KBr pellets.
1H and 13C NMR spectra were measured on a Varian 400 Mercury
spectrometer (400 MHz, 100 MHz for 1H, for 13C, respectively) and a
Bruker Avance 500 spectrometer (500, 125 MHz for 1H, 13C, respec-
tively) with TMS as an internal standard, and at 376 MHz for 19F with
CFCl3 as an external standard (20 °C). All signals for protons, carbons
and fluorines are recorded in ppm. HSQC and HMBC spectra were
measured on an Agilent Technologies 600 MHz PremiumCOMPACT+
spectrometer (600, 150 MHz for 1H, 13C, respectively).
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 371–382

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V. A. Tkachuk et al.
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Mass spectra were recorded on an Agilent 1100 LC/MSD SL instru-
ment. The progress of the reaction was monitored by TLC using silica
gel coated aluminum plates (Merck) in DCM–MeOH eluent mixture
and spots were visualized with UV light. Preparative column chroma-
tography was carried out by using silica gel 60, 40–63 m.
2-(4-Methyl-6-oxo-1,6-dihydropyrimidin-2-yl)benzoic Acid (2a)
Yield: 0.426 g (74%, Method A), 0.495 g (86%, Method B); white nee-
dle-shaped crystals; mp 204–206 °С (Lit.26 mp 201–202 °С); Rf = 0.47
(DCM–MeOH 4:1).
IR (KBr): 3448, 3211, 2963, 2918, 2919, 2787, 2630, 2501, 1890, 1691,
1655, 1593, 1567, 1489 сm–1
.
X-ray Diffraction Study of Compound 2c46
1H NMR (500 MHz, DMSO-d6, 25 °C):  = 2.19 (s, 3 H, CH3), 6.14 (s, 1
H), 7.53 (d, J = 7 Hz, 1 H), 7.60–7.67 (m, 2 H), 7.92 (d, J = 7 Hz, 1 H),
12.77 (br s, 2 H).
13C NMR (150 MHz, DMSO-d6):  = 23.8, 111.0, 130.25, 130.27, 130.6,
131.7, 132.1, 135.5, 159.4, 163.3, 164.4, 167.9.
13C NMR (100 MHz, DMSO-d6–CCl4 1:1):  = 23.8, 110.8, 129.9, 130.0,
130.2, 131.3, 132.2, 135.3, 159.1, 163.1, 164.0, 167.7.
ESI-MS: m/z (%) = 231 [100, (M + H)+].
The pyrimidinone and carboaromatic cycles of the molecule 2c are
turned to each other [the N1–C8–C1–C2 torsion angle is 50.1(6)°] due
to steric repulsion between them (the shortest intramolecular con-
tacts are H1N···C2 2.80 Å as compared to van der Waals radii sum47
2.87 Å and C7···N2 3.07 Å as compared to 3.21 Å). The strong steric
repulsion causes also significant non-coplanarity of the carboxyl sub-
stituent in a relation to the aromatic cycle [the C1–C6–C70O1 torsion
angle is 33.0(7)°]. The ethyl group is hardly turned to the pyrimidi-
none cycle [the N2–C9–C12–C13 torsion angle is –17.9(9)°], what is
stabilized by the C13–H···N2 intramolecular hydrogen bond [H···N
2.56 Å, C–H···N 101°].
Anal. Calcd for C12H10N2O3 (230.22): C, 62.60; H, 4.38; N, 12.17.
Found: C, 62.29; H, 4.47; N, 12.43.
In the crystal phase, molecules 2c form the chains along the [001]
crystallographic direction due to the N1–H···O1′ and O2–H···O3′ inter-
molecular hydrogen bonds (1–x, 1–y, 0.5 + z; H···O 2.06 Å, N–H···O
164° and 1–x, 1-y, –0.5 + z; H···O 1.80 Å, O–H···O 170°).
2-(4-Phenyl-6-oxo-1,6-dihydropyrimidin-2-yl)benzoic Acid (2b)
Yield: 0.504 g (69%, Method A), 0.591 g (81%, Method B); white nee-
dle-shaped crystals; mp 226–228 °С (Lit.23a mp 236–238 °С); Rf = 0.77
(DCM–MeOH 4:1).
The colorless crystals of 2c (C13H12N2O3) are orthorhombic. At 293 K, a
IR (KBr): 3449, 3206, 3070, 2992, 2907, 2812, 2640, 2560, 2497, 1698,
= 10.717(4), b = 12.091(8), c = 9.862(4) Å, V = 1277.8(11) Å3, Mr
=
1669, 1645, 1607, 1415, 1385, 1289, 1264 сm–1
.
244.25, Z = 4, space group Pna21, dcalc = 1.270 g/сm3, (MoK) = 0.092
mm–1, F(000) = 512. Intensities of 8240 reflections (2247 indepen-
dent, Rint = 0.060) were measured on the Xcalibur-3 diffractometer
(graphite monochromated MoK radiation, CCD detector, -scanning,
2θmax = 50°). The structure was solved by direct method using SHELX-
TL package.48 Positions of the hydrogen atoms were located from elec-
1H NMR (500 MHz, DMSO-d6):  = 6.87 (s, 1 H), 7.48 (m, 3 H), 7.64–
7.69 (m, 2 H), 7.75 (d, J = 7 Hz, 1 H), 7.89 (d, J = 2 Hz, 1 H), 8.06–8.07
(m, 2 H), 13.17 (br s, 2 H).
13C NMR (125 MHz, DMSO-d6):  = 107.7, 127.5 (2 C), 129.2 (2 C),
130.1, 130.2, 130.8, 130.9, 131.5, 133.6, 134.7, 136.8, 159.6, 161.1,
163.8, 168.8.
tron density difference maps and refined by ‘riding’ model with Uiso
=
nUeq (n = 1.5 for methyl and hydroxyl groups and n = 1.2 for other hy-
drogen atoms) of the carrier atom. Full-matrix least-squares refine-
ment against F2 in anisotropic approximation for non-hydrogen at-
oms using 2247 reflections was converged to wR2 = 0.147 (R1 = 0.058
for 1715 reflections with F>4(F), S = 1.029).
ESI-MS: m/z (%) = 293 [100, (M + H)+].
Anal. Calcd for C17H12N2O3 (292.23): C, 69.86; H, 4.14; N, 9.58. Found:
C, 69.53; H, 4.22; N, 9.75.
2-(4-Ethyl-6-oxo-1,6-dihydropyrimidin-2-yl)benzoic Acid (2c)
2-(Pyrimidin-2-yl)benzoic Acids 2a–e; General Procedure (Scheme
1)
Yield: 0.506 g (83%, Method A), 0.561 g (92%, Method B); colorless
crystals; mp 187–189 °С; Rf = 0.57 (DCM–MeOH 4:1).
IR (KBr): 3065, 2973, 2936, 2868, 2471, 1675, 1604, 1576 сm–1
.
Method A: 2-Carbamimidoylbenzoic acid (1; 0.410 g, 2.5 mmol) and
appropriate 1,3-dielectrophilic compound 3a–e (3 mmol) were added
with stirring to a freshly prepared solution of NaOMe in anhyd MeOH
[prepared by dissolving Na metal (0.127 g, 5.5 mmol) in anhyd MeOH
(25 mL)]. The mixture was refluxed for 4–8 h. Thereafter, the solvent
was removed under reduced pressure and the residue was dissolved
in H2O (15 mL). The solution was acidified with AcOH (2 mL) and the
obtained precipitate was collected by filtration, washed with distilled
H2O, and dried in air.
1H NMR (500 MHz, DMSO-d6):  = 1.15 (t, J = 7.5 Hz, 3 H), 2.47 (q, J =
7.5 Hz, 2 H), 6.13 (s, 1 H), 7.56 (d, J = 7 Hz, 1 H), 7.60–7.67 (m, 2 H),
7.90 (d, J = 7 Hz, 1 H), 12.79 (br s, 2 H).
13C NMR (125 MHz, DMSO-d6):  = 12.7, 30.3, 109.5, 130.1, 130.2,
130.6, 131.9, 132.1, 135.4, 159.3, 163.5, 168.0, 169.2.
ESI-MS: m/z (%) = 245 [100, (M + H)+].
Anal. Calcd for C13H12N2O3 (244.25): C, 63.93; H, 4.95; N, 11.47.
Found: C, 63.58; H, 4.97; N, 11.75.
Method B (for 2a–c): 2-Carbamimidoylbenzoic acid (1; 0.410 g, 2.5
mmol) and methyl acetoacetate (3a; 0.383 g, 3.3 mmol) or ethyl ben-
zoylacetate (3b; 0.634 g, 3.3 mmol) or methyl propionylacetate (3c;
0.430 g, 3.3 mmol) were dissolved with stirring in a solution of NaOH
(0.25 g, 6.25 mmol) in H2O (5 mL) and EtOH (25 mL), and left at rt for
48 h. After evaporation of EtOH under reduced pressure, H2O (30 mL)
was added and the mixture was acidified with AcOH or citric acid.
The precipitated solid was collected by filtration, washed with H2O,
and dried in air.
2-(4-Hydroxy-6-oxo-1,6-dihydropyrimidin-2-yl)benzoic Acid (2d)
The crude product obtained by Method A was dissolved in 25% am-
monia in H2O at pH 9–10 and the resulting cloudy solution was fil-
tered to separate precipitated phthalimide. The filtrate was acidified
with aq 6 N HCl to give a pale yellow crystalline precipitate. This solid
was collected by filtration, washed with H2O, and dried; yield: 0.412 g
(71%); pale yellow crystals; mp 213–215 °С; Rf = 0.13 (DCM–MeOH
4:1).
IR (KBr): 3432, 3137, 3036, 2892, 2846, 2711, 2633, 1880, 1727, 1644,
1543, 1492, 1458, 1406, 1371, 1321, 1260 сm–1
.
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V. A. Tkachuk et al.
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1H NMR (400 MHz, DMSO-d6):  = 5.24 (s, 1 H), 7.54 (d, J = 7.2 Hz, 1
H), 7.62 (dd, J1 = 7.6 Hz, J2 = 7.2 Hz, 1 H), 7.67 (dd, J1 = 7.2 Hz, J2 = 6.8
Hz, 1 H), 7.60–7.69 (m, 2 H), 7.93 (d, J = 7.2 Hz, 1 H), 12.31 (br s, 3 H).
13C NMR (100 MHz, DMSO-d6):  = 88.8, 130.0, 130.4, 130.7, 131.3,
132.2, 135.1, 160.3, 167.3, 167.5 (2 C).
13C NMR (150 MHz, DMSO-d6):  = 88.9, 130.1, 130.5, 130.7, 131.3,
132.3, 135.2, 160.4, 167.3, 167.6 (2 C).
ESI-MS: m/z (%) = 233 [100, (M + H)+].
1H NMR (600 MHz, DMSO-d6–CF3COOD):  = 5.63 (s, 1 H, 5′-Hpyr), 7.58
(d, J = 6 Hz, 1 H, 3-Harom), 7.63 (dd, J1 = 6 Hz, J2 = 6 Hz, 1 H, 4-Harom),
7.69 (dd, J1 = 6 Hz, J2 = 6 Hz, 1 H, 5-Harom), 7.99 (d, J = 6 Hz, 1 H, 6-
Harom).
13C NMR (150 MHz, DMSO-d6–CF3COOD):  = 79.5 (5′-Cpyr), 129.9 (3-
Carom), 130.5 (6-Carom), 130.9 (2-Carom), 131.1 (4-Carom), 132.4 (5-Carom),
134.2 (1-Carom), 159.2 (2′-Cpyr), 159.6 (2 C, 4′,6′-Cpyr), 167.1 (CO2H).
ESI-MS: m/z (%) = 231 [100, (M + H)+].
Anal. Calcd for C11H10N4O2 (230.23): C, 57.39; H, 4.38; N, 24.34.
Found: C, 57.12; H, 4.50; N, 24.66.
Anal. Calcd for C11H8N2O4 (232.12): C, 56.90; H, 3.47; N, 12.06. Found:
C, 56.57; H, 3.60; N, 12.38.
2-(1-Amino-2,2-dicyanovinyl)benzoic Acid (3)
2-(4-Amino-6-oxopyrimidin-2-yl)benzoic Acid (2e)
Yield: 0.145 g (17%); pale orange crystals; mp 240–242 °С; Rf = 0.48
(DCM–MeOH 4:1).
Product 2e was obtained by Method A from acid 1 (1 equiv.) using
ethyl cyanoacetate (2 equiv.) and NaOMe (3 equiv.); yield: 0.416 g
(72%); fine light yellow crystals; mp 295–297 °С; Rf = 0.12 (DCM–
MeOH 4:1).
IR (KBr): 3341, 3221, 3081, 2779, 2224, 2210, 1716, 1663, 1599, 1580,
1518, 1433, 1390, 1296, 1275, 1234, 1183, 1146, 1124, 1077 сm–1
.
IR (KBr): 3481, 3350, 3222, 3082, 2996, 2877, 2773, 2683, 2611, 2487,
1919, 1697, 1636, 1613, 1490, 1466, 1432, 1342, 1287, 1273, 1263,
1H NMR (400 MHz, DMSO-d6):  = 7.46 (d, J = 7.2 Hz, 1 H), 7.65 (dd,
J1 = 7.2 Hz, J2 = 7.6 Hz, 1 H), 7.71 (dd, J1 = 7.6 Hz, J2 = 7.6 Hz, 1 H), 8.01
(d, J = 7.6 Hz, 1 H), 8.86 (s, 1 H, NH2), 8.88 (s, 1 H, NH2), 13.34 (br s, 1
H, COOH).
13C NMR (100 MHz, DMSO-d6):  = 49.6 [C(CN)2], 116.2 (CN), 117.4
(CN), 129.7, 130.2, 131.0, 131.2, 133.0, 134.9, 166.6 (COOH), 174.4
(CNH2).
1244 сm–1
.
1H NMR (500 MHz, DMSO-d6):  = 4.98 (s, 1 H), 6.38 (s, 2 H), 7.49 (d,
J = 7 Hz, 1 H), 7.56–7.63 (m, 2 H), 7.87 (d, J = 7 Hz, 1 H), 11.88 (br s, 1
H), 12.84 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6):  = 84.3, 130.0, 130.20, 130.23, 131.6,
132.0, 135.8, 159.8, 163.8, 164.5, 167.8.
ESI-MS: m/z (%) = 214 [100, (M + H)+].
ESI-MS: m/z (%) = 232 [100 (M + H)+].
Anal. Calcd for C11H7N3O2 (213.19): C, 61.97; H, 3.31; N, 19.71. Found:
C, 61.64; H, 3.39; N, 19.98.
Anal. Calcd for C11H9N3O3 (231.21): C, 57.14; H, 3.92; N, 18.17. Found:
C, 56.88; H, 4.05; N, 18.42.
2-(2-Amino-3,5-dicyano-6-methoxypyridin-4-yl)benzamide (6)
Yield: 0.574 g (49%); pale yellow crystals; mp 262–263 °С (Lit.32 mp
262–263 °С); Rf = 0.60 (DCM–MeOH 9:1).
Reaction of 2-Carbamimidoylbenzoic Acid 1 with Malononitrile;
2-(4,6-Diaminopyrimidin-2-yl)benzoic Acid (2f), 2-(1-Amino-2,2-
dicyanovinyl)benzoic Acid (3), and 2-(2-Amino-3,5-dicyano-6-me-
thoxypyridin-4-yl)benzamide (6) (Scheme 2)
IR (KBr): 3430, 3407, 3340, 3315, 3230, 2218, 1685, 1640, 1616, 1579,
1569, 1546, 1501, 1459, 1370, 1296, 1210 cm–1
.
Acid 1 (0.656 g, 4 mmol) and malononitrile (0.792 g, 12 mmol) were
added with stirring to a freshly prepared solution of NaOMe in MeOH
[prepared by dissolving Na metal (0.368 g, 16 mmol) in anhyd MeOH
(25 mL)]. The mixture was refluxed for 6 h whereupon it turned from
light orange to red-brown in color and was left overnight at rt. The
precipitate of 2-(2-amino-3,5-dicyano-6-methoxypyridin-4-yl)benz-
amide (6)32 was filtered and dried in air. The filtrate was evaporated
to dryness under reduced pressure and dissolved in H2O (15 mL). The
insoluble material (the second crop of 6) was filtered off and the ob-
tained clear solution was acidified with AcOH (pH 5). The resulting
precipitate of 2-(4,6-diaminopyrimidin-2-yl)benzoic acid (2f) was
collected by filtration, washed with H2O, and dried. After a few days
pale orange crystals of 3 precipitated from the filtrate.
1H NMR (500 MHz, DMSO-d6):  = 3.96 (s, 3 H, OCH3), 7.35–7.36 (m, 2
H, CONH2 + 3-Harom), 7.59–7.66 (m, 2 H, 4-Harom + 5-Harom), 7.84 (bs 2
H, NH2), 7.85 (d, J = 7.5 Hz, 1 H), 8.05 (s, 1 H, CONH2).
13C NMR (125 MHz, DMSO-d6):  = 55.0 (Me), 84.38, 84.41, 115.3 (CN),
115.7 (CN), 128.7, 129.9, 130.1, 131.2, 134.8, 134.9, 161.0, 163.8,
165.6, 168.3.
ESI-MS: m/z (%) = 294 [100, (M+H)+].
Anal. Calcd for C15H11N5O2 (293.29): C, 61.43; H, 3.78; N, 23.88.
Found: C, 61.15; H, 3.80; N, 24.09.
2-Substituted 4,6-Dihydropyrimido[2,1-a]isoindole-4,6-diones
8a–c,e; General Procedure (Scheme 4)
Method C: The appropriate 2-(6-oxo-1,6-dihydropyrimidin-2-yl)ben-
zoic acid 2a–c,e (1 mmol) was placed in a vial and heated at 220–230
°С in an oil bath. After 0.5 h, the obtained solid was removed and re-
crystallized from anhyd o-xylene, if necessary.
2-(4,6-Diaminopyrimidin-2-yl)benzoic Acid (2f)
Yield: 0.184 g (20%); beige solid; mp 288–290 °С; Rf = 0.11 (DCM–
MeOH 4:1).
IR (KBr): 3350, 3136, 2936, 2857, 2784, 2723, 2612, 2375, 2347, 2207,
Method D: The respective acid 2a–c (1 mmol) was suspended in an-
hyd o-xylene (10 mL) and heated under reflux with Dean–Stark water
trap for 8–12 h. The insoluble material was filtered and the obtained
clear solution was evaporated to dryness under reduced pressure. The
obtained pale yellow crystals were washed with hexane and dried.
1655, 1617, 1597, 1580, 1546, 1377, 1323, 1269, 927 сm–1
.
1H NMR (500 MHz, DMSO-d6):  = 5.40 (s, 1 H), 6.33 (s, 4 H), 7.46 (dd,
J1 = 7.5 Hz, J2 = 7.5 Hz, 1 H), 7.52 (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1 H), 7.70
(d, J = 7.5 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6):  = 81.4, 129.2, 129.9, 130.2, 130.4,
134.4, 138.4, 163.5 (2 C), 164.0, 170.1.
Compounds 8a–e were not monitored by TLC in the DCM–MeOH sol-
vent system due to the possibility of hydrolysis/methanolysis. When
using aprotic toluene or MeCN as an eluent, the spots for 8a–c re-
mained at the start, 8e ran with a formation of a tailed spot.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 371–382

380
V. A. Tkachuk et al.
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Synthesis
2-Methylpyrimido[2,1-a]isoindole-4,6-dione (8a)
Anal. Calcd for C11H7N3O2 (213.19): C, 61.97; H, 3.31; N, 19.71. Found:
C, 61.67; H, 3.39; N, 20.01.
Yield: 0.153 g (72%, Method C), 0.197 g (93%, Method D); pale yellow
crystals; mp 201–202 °С.
Methyl 2-(4-Methyl-6-oxo-1,6-dihydropyrimidin-2-yl)benzoate
(9)
IR (KBr): 3448, 3067, 2969, 2930, 1798, 1782, 1765, 1696, 1648, 1623,
1578, 1470, 1412, 1382, 1351, 1321, 1282 сm–1
.
Compound 8a (0.212 g, 1 mmol) was dissolved in anhyd MeOH (5
mL). The obtained solution was stirred for 30 min under reflux. The
solvent was removed under reduced pressure to give desired ester 9;
yield: 0.244 g (quant.); white crystalline powder; mp 150–152 °С; Rf =
0.80 (DCM–MeOH 9:1).
1H NMR (500 MHz, DMSO-d6):  = 2.29 (s, 3 H), 6.27 (s, 1 H), 7.80 (dd,
J1= 9 Hz, J2 = 8.5 Hz, 1 H), 7.88 (dd, J1= 8.5 Hz, J2 = 9 Hz, 1 H), 7.96–7.97
(m, 2 H).
13C NMR (125 MHz, DMSO-d6):  = 23.6, 114.8, 123.0, 125.5, 129.0,
133.8, 134.2, 136.2, 154.8, 157.7, 162.8, 164.2.
IR (KBr): 3421, 3023, 2954, 2851, 2753, 1724, 1665, 1656, 1597, 1557
ESI-MS: m/z (%) = 213 [100, (M + H)+].
сm–1
.
Anal. Calcd for C12H8N2O2 (212.21): C, 67.92; H, 3.80; N, 13.20. Found:
C, 67.60; H, 3.87; N, 13.52.
1H NMR (500 MHz, DMSO-d6):  = 2.20 (s, 3 H, CH3), 3.70 (s, 3 H,
OCH3), 6.19 (s, 1 H), 7.63–7.69 (m, 3 H), 7.84 (d, J = 7 Hz, 1 H), 12.68
(br s, 1 H).
2-Phenylpyrimido[2,1-a]isoindole-4,6-dione (8b)
13C NMR (125 MHz, DMSO-d6):  = 23.9, 52.7, 110.7, 129.8, 130.2,
130.8, 131.2, 132.1, 134.9, 158.7, 163.3, 164.7, 167.4.
ESI-MS: m/z (%) = 245 [100, (M + H)+].
Yield: 0.233 g (85%, Method C), 0.265 g (97%, Method D); pale yellow
crystals; mp 239–241 °С (Lit.23a mp 240–241 °С).
IR (KBr): 3754, 3438, 3081, 2930, 1795, 1771, 1696, 1624, 1460, 1354
Anal. Calcd for C13H12N2O3 (244.25): C, 63.93; H, 4.95; N, 11.47.
Found: C, 63.69; H, 4.91; N, 11.73.
сm–1 (Lit.23a 1798, 1696 сm–1).
1H NMR (400 MHz, DMSO-d6):  = 7.02 (s, 1 H), 7.55–7.56 (m, 3 H),
7.84 (dd, J1 = 8 Hz, J2 = 9.5 Hz, 1 H), 7.94 (dd, J1 = 8.5 Hz, J2 = 9 Hz, 1 H),
8.01 (d, J = 9 Hz, 1 H), 8.16 (d, J = 9 Hz, 1 H), 8.22–8.23 (m, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 111.3, 123.3, 125.6, 127.6, 129.26,
129.34, 131.7, 134.1, 134.4, 135.2, 136.3, 155.4, 158.4, 164.3, 167.7.
Reaction 2-Carbamimidoylbenzoic Acid 1 with Chromones 10a–d;
General Procedure (Schemes 5 and 6)
To a mixture of 1 (0.246 g, 1.5 mmol), the corresponding chromone
10a–d (1 mmol), and K2CO3 (0.28 g, 2 mmol) was added anhyd DMF
(5 mL). The obtained suspension was stirred under reflux for 6–9 h
until no starting chromone was observed on TLC. The cooled brown
mixture was poured into H2O (20 mL), acidified with AcOH (pH 5),
and filtered. The obtained light brown product was separated,
washed with H2O, and dried. Compound 11a was purified by column
chromatography with DCM–MeOH (9:1) as an eluent.
ESI-MS: m/z (%) = 275 [100, (M + H)+].
Anal. Calcd for C17H10N2O2 (274.28): C, 74.45; H, 3.67; N, 10.21.
Found: C, 74.15; H, 3.73; N, 10.51.
2-Ethylpyrimido[2,1-a]isoindole-4,6-dione (8c)
Yield: 0.176 g (78%, Method C), 0.202 g (95%, Method D); pale yellow
crystals; mp 167–169 °С.
2-[5-(4-Chlorophenyl)-4-(2-hydroxy-4-methoxyphenyl)pyrimi-
din-2-yl]benzoic Acid (11a)
IR (KBr): 3412, 3052, 2972, 2925, 2872, 1799, 1763, 1699, 1619, 1602,
1562 сm–1
.
Yield: 0.298 g (69%); yellow crystalline powder; mp 197–199 °С; Rf =
0.62 (DCM–MeOH, 9:1).
1H NMR (500 MHz, DMSO-d6):  = 1.21 (t, J = 7.5 Hz, 3 H), 2.29 (q, J =
7.5 Hz, 2 H), 6.23 (s, 1 H), 7.81 (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1 H), 7.89
(dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1 H), 7.97 (d, J = 7.5 Hz, 1 H), 8.00 (d, J = 7.5
Hz, 1 H).
13C NMR (125 MHz, DMSO-d6):  = 12.1, 30.0, 113.2, 123.0, 125.5,
129.1, 133.9, 134.2, 136.2, 155.0, 157.9, 162.2, 167.4.
IR (KBr): 3754, 3441, 3070, 2936, 2840, 2633, 1708, 1611, 1578, 1429,
1289, 1264 сm–1
.
1H NMR (500 MHz, DMSO-d6, 25 °C):  = 3.72 (s, 3 H, CH3), 6.26 (s, 1
H), 6.39 (d, J = 8 Hz, Jm = 1 Hz, Jm = 2 Hz, 1 H), 7.31 (d, J = 8 Hz, 2 H),
7.36 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 8.5 Hz, 2 H), 7.59 (dd, J1 = 7.5 Hz,
J2 = 7.5 Hz, 1 H), 7.65 (dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1 H), 7.69 (d, J = 7.5
Hz, 1 H), 7.99 (d, J = 7.5 Hz, 1 H), 8.81 (s, 1 H), 9.85 (br s, 1 H), 12.63 (br
s, 1 H).
ESI-MS: m/z (%) = 227 [100, (M + H)+].
Anal. Calcd for C12H8N2O2 (226.07): C, 69.02; H, 4.46; N, 12.38. Found:
C, 68.74; H, 4.35; N, 12.60.
13C NMR (125 MHz, DMSO-d6, 20 °C):  = 55.6, 101.5, 106.0, 117.7,
128.9 (2 C), 129.1, 130.0, 130.4 (3 C), 130.9 (2 C), 132.8, 133.0, 134.7,
136.4, 138.0, 156.6, 157.6, 162.1, 162.3, 163.8, 170.5.
2-Aminopyrimido[2,1-a]isoindole-4,6-dione (8e)
Yield: 0.213 g (quant., Method C); fine crystalline orange powder; mp
251–253 °С.
ESI-MS: m/z (%) = 433 [100, (M + H)+].
IR (KBr): 3529, 3361, 3171, 2980, 2711, 1821, 1795, 1775, 1671, 1648,
Anal. Calcd for C24H17ClN2O4 (432.86): C, 66.60; H, 3.96; N, 6.47.
Found: C, 66.26; H, 4.03; N, 6.72.
1610, 1601, 1561, 1411, 1325, 1290, 1242 сm–1
.
1H NMR (500 MHz, DMSO-d6):  = 4.95 (s, 1 H), 7.23 (s, 2 H), 7.79–
7.82 (m, 1 H), 7.86–7.89 (m, 2 H), 7.94 (d, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, DMSO-d6):  = 83.9, 122.8, 125.2, 130.2, 133.7,
134.2, 135.8, 156.7, 158.7, 162.7, 164.4.
ESI-MS: m/z (%) = 214 [100, (M + H)+].
2-(7-Methoxybenzo[4,5]furo[3,2-d]pyrimidin-2-yl)benzoic Acid
(12a)
Yield: 0.263 g (82%); grayish powder; mp 219–221 °С; Rf = 0.60
(DCM–MeOH 9:1).
IR (KBr): 3452, 3068, 2966, 2936, 2913, 2835, 2801, 2627, 2499, 1862,
1690, 1654, 1631, 1603, 1434, 1397, 1319, 1290 сm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2021, 53, 371–382

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V. A. Tkachuk et al.
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Synthesis
1H NMR (500 MHz, DMSO-d6, 25 °C):  = 3.95 (s, 3 H, OCH3), 7.18 (d,
J = 8.5 Hz, 1 H), 7.52 (s, 1 H), 7.58 (dd, J1 = 7 Hz, J2 = 8 Hz, 1 H), 7.65
(dd, J1 = 7.5 Hz, J2 = 7.5 Hz, 1 H), 7.73 (d, J = 7.5 Hz, 1 H), 7.94 (d, J = 8
Hz, 1 H), 8.13 (d, J = 8.5 Hz, 1 H), 9.23 (s, 1 H, 4′-HPyrim), 12.71 (br s, 1
H, COOH).
13C NMR (125 MHz, DMSO-d6, 25 °C):  = 56.7, 97.6, 113.9, 114.5,
123.3, 129.1, 129.5, 130.5, 130.9, 134.4, 138.9, 139.1, 146.6, 150.5,
160.5, 161.2, 164.0, 170.3.
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ESI-MS: m/z (%) = 321 [100, (M + H)+].
Anal. Calcd for C18H12N2O4 (320.30): C, 67.50; H, 3.78; N, 8.75. Found:
C, 67.19; H, 3.86; N, 9.03.
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2-(7-Methoxy-4-trifluoromethylbenzo[4,5]furo[3,2-d]pyrimidin-
2-yl)benzoic Acid (12b)
Yield from chromone 10c: 0.303 g (78%), from chromone 10d: 0.283 g
(73%); fine yellowish crystals; mp 238–240 °С; Rf = 0.66 (DCM–MeOH
9:1).
(11) Krapf, M. K.; Gallus, J.; Wiese, M. J. Med. Chem. 2017, 60, 4474.
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IR (KBr): 3450, 3064, 3020, 2975, 2929, 2857, 2679, 2583, 1696, 1654,
1638, 1610, 1501, 1440, 1387, 1376, 1340, 1288, 1270 сm–1
.
1H NMR (500 MHz, DMSO-d6, 25 °C):  = 3.97 (s, 3 H, CH3), 7.24 (d, J =
9 Hz, 1 H), 7.62–7.72 (m, 3 H), 7.79 (d, J = 7.5 Hz, 1 H), 7.95 (d, J = 7 Hz,
1 H), 8.20 (d, J = 9 Hz, 1 H), 12.88 (br s, 1 H, COOH).
13C NMR (125 MHz, DMSO-d6, 20 °C):  = 56.9, 97.8, 113.0, 115.3,
120.9 (CF3), 123.7, 129.4, 130.2, 130.6, 131.2, 134.4, 134.6, 137.7,
141.9, 154.5, 161.1, 161.5, 165.2, 169.9.
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J.; Tu, M.; Zeng, D.; Liu, S.; Knafels, J. D.; Litchfield, J.; Atkinson,
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19F NMR (376 MHz, DMSO-d6, 25 °C):  = –65.6 (CF3).
ESI-MS: m/z (%) = 389 [100, (M + H)+].
Anal. Calcd for C19H11F3N2O4 (388.30): C, 58.77; H, 2.86; N, 7.21.
Found: C, 58.42; H, 2.91; N, 7.54.
Acknowledgment
The authors thank the reviewers for the insightful mechanistic com-
ments and comments throughout the text, which prompted addition-
al experiments and allowed to make the discussion deeper and more
detailed.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1705941.
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