Hydride transfer reactions of 5-(2-alkohybenzylidene) barbituric acids: Synthesis of 2,4,6-trioxoperhydropyrimidine-5-spiro-3′-chromanes

Article abstract of DOI:10.1016/j.tet.2016.12.045

The thermal cyclization of 5-(2-phenoxymethylphenyl-methylene)barbituric acid and its derivatives affords 2,4,6-trioxoperhydropyrimidine-5-spiro-3′-chromanes. The reactions require no catalysts and proceed at temperatures from 118 to 240?°C depending on the substrate activity. These cyclization reactions are analogous to T-reactions of tertiary amines involving the hydride transfer.

Full text of DOI:10.1016/j.tet.2016.12.045

Accepted Manuscript
Hydride transfer reactions of 5-(2-alkohybenzylidene) barbituric acids: Synthesis of
2,4,6-trioxoperhydropyrimidine-5-spiro-3′-chromanes
Konstantin A. Krasnov, Pavel V. Dorovatovskii, Yan V. Zubavichus, Tatiana V.
Timofeeva, Victor N. Khrustalev
PII:
S0040-4020(16)31332-1
10.1016/j.tet.2016.12.045
TET 28337
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 September 2016
Revised Date: 9 December 2016
Accepted Date: 19 December 2016
Please cite this article as: Krasnov KA, Dorovatovskii PV, Zubavichus YV, Timofeeva TV, Khrustalev
VN, Hydride transfer reactions of 5-(2-alkohybenzylidene) barbituric acids: Synthesis of 2,4,6-
trioxoperhydropyrimidine-5-spiro-3′-chromanes, Tetrahedron (2017), doi: 10.1016/j.tet.2016.12.045.
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ACCEPTED MANUSCRIPT
Graphical Abstract
R2
O
R2
H
O
O
H
R4
R1
R1
O
O
N
R4
N
R3
R3
1,5-hydride
transfer
O
N
R1
O
N
R1
O

ACCEPTED MANUSCRIPT
Hydride transfer reactions of 5-(2-alkohybenzylidene) barbituric
acids: Synthesis of 2,4,6-trioxoperhydropyrimidine-5-spiro-3'-
chromanes
Konstantin A. Krasnov,a* Pavel V. Dorovatovskii,b Yan V. Zubavichus,b
Tatiana V. Timofeevac and Victor N. Khrustalevd,e*
a Institute of Toxicology, St. Petersburg, Russia
E-mail: krasnov_tox@mail.ru
b National Research Center “Kurchatov Institute”, Moscow, Russia
c New Mexico Highlands University, Las Vegas, NM USA
d Peoples’ Friendship University of Russia (RUDN), Moscow, Russia
E-mail: vnkhrustalev@gmail.com
e Nesmeyanov Institute of Organoelement Compounds of RAS, Moscow, Russia
E-mail: vkh@xray.ineos.ac.ru
R2
R2
H
O
O
O
H
R4
R1
O
R1
O
O
N
R4
N
R3
R3
1,5-hydride
transfer
N
R1
O
N
O
R1
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Available online
The thermal cyclization of 5-(2-phenoxymethylphenyl-
methylene)barbituric acid and its derivatives affords
2,4,6-trioxoperhydropyrimidine-5-spiro-3'-chromanes.
The reactions require no catalysts and proceed at
temperatures from 118 to 240 °C depending on the
substrate activity. These cyclization reactions are
analogous to T-reactions of tertiary amines involving
the hydride transfer.
Keywords:
Keyword_1 5-(2-Alkoxyphenylmethylene)-
barbituric acids
Keyword_2 1,5-Hydride shift
Keyword_3 Thermal isomerization
Keyword_4 T-reaction
2016 Elsevier Ltd. All rights reserved.
Keyword_5 Trioxoperhydropyrimidine-5-
spiro-3'-chromane
1

ACCEPTED MANUSCRIPT
1. Introduction
Barbituric acid derivatives attract considerable interest because of their pharmaceutical
importance. A number of 5-alkyl- and aryl barbiturates are used as hypnotic, sedative,
anticonvulsant and antihypertensive drugs.1,2 Many other types of biological activities were also
reported for this class of compounds.3
Furthermore, barbituric acids can be regarded as multifunctional building blocks with interesting
and non-trivial chemistry3,4, which are often used as synthones in the rational design of diverse
fused pyrimidine derivatives including synthetic analogs of a naturally occurring compounds as well
as other systems with promising biological properties.5,6
In this regard the chemistry of barbituric acids experiences rapid development and its toolbox is
being constantly enriched with new unexpected reactions. Among such reactions, the recently
reported radical-radical cyclizations of barbiturates triggered by electron-transfer reduction by
7
SmI2 , and the tert-amino-effect reactions that proceeds by a hydride-transfer mechanism8 are
particular note.
Recently, a series of unusual conversions of ortho-vinylaryl alkyl ethers to dihydrobenzopyran
(chromane) derivatives via a hydride transfer has been reported9,10 (Scheme 1).
LA
LA
-
-
-
-
-
-
-
-
-
-
-
-
O
O
O
O
H
O
C-C
formation
O
O
R
Hydride
transfer
O
O
CO2Me
CO2Me
R
H
H
FG
FG
FG
O+
R
LA
O
Scheme 1. The synthesis of 2-alkyl-3,3-dicarboxymethylchromanes from О-alkyl-substituted
salicylic aldehydes.
The cyclization of such substrates proceeded upon moderate heating in the presence of Lewis
acids, among which Sc(OTf)3 was found to be the most efficient one.9 It was suggested9,10 that the
mechanism of these reactions included the stage of the hydride elimination from the ОСН-moiety to
produce a zwitter-ionic intermediate followed by its cyclization. With this respect, such reactions
resemble cyclization of substituted tert-amines recently surveyed11 within the concept of the t-amino
effect formulated by Meth-Cohn and Suschitsky. That type of processes with tertiary amines are
often referred to as T-reactions in the literature8,12,13,14 (Scheme 2).
R3
R3
R3
R1
N
R4
R1
N
R1
N+
R2
H
R2
R2
H
C
H
R4
X
R4
X
X
2

ACCEPTED MANUSCRIPT
Scheme 2. The thermal isomerization of 2-vinyl-N,N-dialkylanilines into 1,2-annelated
1,2,3,4-tetrahydroquinolines.
Nevertheless, the specific cyclization depicted in Scheme 1 lies beyond the t-amino effect since
the reaction substrates contain no alkylamino groups. On the other hand, these reactions can indeed
be assigned to a common class due to the similarity of their mechanisms involving the hydride
transfer from an aliphatic СН-group to an unsaturated electron-deficient moiety.
2. Results and discussion
It is known that ortho-dialkylaminoarylidene derivatives of 1,3-dicarbonyl compounds, in
particular, 5-arylidene barbituric acids (1), undergo a cyclization into the respective spirocyclic
systems (2)8,15,16 (Scheme 3).
R4
O
R4
R3
O
O
N
N
N
N
R2
R2
O
O
N
H
R3
R2
H
T-reaction
O
N
R2
R1
R1
1
2
Scheme 3. The isomerization of 5-(2-dialkylaminoarylidene)barbituric acids into
5-spirobarbituric 1,2-annelated 1,2,3,4-tetrahydroquinolines.
The rate of the Т-reaction for substrates similar to (1) is surprisingly high, the reaction proceeds
much more readily than for derivatives of acyclic 1,3-dicarbonyl compounds. Indeed, the cyclization
of reactants like (1) starts spontaneously at room temperature. Nevertheless, no cyclization of О-
alkylated cyclic 1,3-dicarbonyl compounds has been reported so far, in contrast to their N,N-
dialkylamino counterparts (1). In the present paper, we report on a newly discovered cyclization of
5-(2-benzyloxybenzylidene)barbituric acids (3) (Scheme 4).
O
R1
N
R1
N
R1
O
R1
O
O
O
O
N
N
H
H
N
O
H
N
R4
1
R1
R4
R
R3
O
O+
R2
R3
O
O
O
R3
R4
R2
R2
3a-g
4a-g
5a-g
Scheme 4. The isomerization of 5-(2-benzyloxybenzylidene)barbituric acids 3a-g into spirocyclic
chromane derivatives. R1 = R2 =R3 = R4 = H (a); R1 = Me, R2 =R3 = R4 = H (b); R1 = R3 =R4 = H,
R2 = OMe (c); R1 = Me, R2 = OMe, R3 = R4 = H (d); R1 = R2 =R3 = H, R4 = Cl (e);
3

ACCEPTED MANUSCRIPT
R1 = R2 =R4 = H, R3 = Cl (f); R1 = R2 = R3 = Н, R4 = ОМе (g)
The starting substrates (3) were synthesized by the Knoevenagel condensation of barbituric
acids with corresponding 2-alkoxybenzaldehydes (see Experimental section). We speculate that this
cyclization follows a mechanism similar to the Т-reaction shown in Scheme 4. Most probably,
compounds 3 experience a hydride transfer giving rise to a zwitter-ionic intermediate (4) followed
by its cyclization into the spirocyclic derivatives (5).
The molecular structure of one of the spirocyclic derivative synthesized via such a reaction is shown
in Figure 1.
Figure 1. Molecular structure of 5d.
The cyclization of 3а into the spirocyclic derivative 5а proceeded at 195 °С for 4 h in the
solvent-free medium (Method A, see Experimental section). Similar conditions were required for
the 1,3-dimethyl derivative 3b. The reaction was facilitated by the presence of weak acids, it was
possible to decrease the reaction temperature to 180 °С by adding succinic acid (Method B, see
Experimental section) (Table 1). Attempts to promote the reaction with Lewis acids (BF3 or AlCl3)
or strong protonic acid (CF3COOH, H2SO4, H3PO4) failed due to the apparent polymerization and
resinification of the reaction mixture yielding no target product 5.
Table 1. Conditions of isomerization for substrates 3a-g, 6с and yields of respective spirocyclic
products 5a-g, 7c
Reactant
R1
R2
R3
R4
Reaction conditions
Product Method of Yield,
synthesis
%
T, °C
Time, h
H
Me
Me
H
H
H
H
OMe
OMe
H
H
H
H
H
H
H
Cl
H
-
H
H
H
H
H
H
Cl
H
OMe
-
195
195
180
180
118
118
240
240
190
180
118
4
5
4
60
45
80
99
97
90
84
35
61
95
80
3a
3b
3b
3c
3c
3d
3e
3f
5a
5b
5b
5c
5c
5d
5e
5f
5g
7
Aa
A
Bb
A
Cc
C
A
A
A
A
C
2
H
12
40
4
4
4
Me OMe
H
H
H
-
H
H
H
-
3g
6c
6c
2
48
-
-
-
-
7
4

ACCEPTED MANUSCRIPT
succinic acid; c Reaction in acetic acid solution under reflux (See Experimental section).
a
b
Reaction by heating of solid substrate; Reaction by heating of solid substrate with admixture of
This means that the hydride elimination from the OCH2-group in compounds 3 as well as
subsequent processes (Scheme 4) require harsher conditions as compared to the initiation of the
Т-reactions involving the alkylamino-group in reactants 1 (Scheme 3). Evidently, this is due to the
lower basicity of the oxygen atom with respect to the amino nitrogen atom, which gives rise to a
lower stability of the intermediate 4. Furthermore, X-ray crystallographic study revealed a distinct
difference between the alkylamine intermediates 113 and their oxygen counterparts 3 (Figure 2).
1a
3b
Figure 2. X-Ray crystal structures of 1a and 3b.
Substrates 1 are characterized by the presence of a close intramolecular C-H…π contact
between the vinyl carbon atom and the hydrogen atom prone to migration.13,16 Meanwhile, no such a
contact is observed in substrates 3.
5-(2-Benzyloxy-3-methoxy-5-benzylidene) barbituric acid derivatives 3с and 3d demonstrate a
higher reactivity as compared to their analogs 3а and 3b. The rearrangement of 3 into respective
spiro-derivatives occurs at 118 °С upon boiling in acetic acid (Method C, see Experimental section)
(Table 1). At first glance, this nearly 100-fold acceleration of the Т-reaction can be assigned to the
donor effect of the methoxy group in the aromatic ring, which stabilizes the zwitter-ionic
intermediate 4. But X-ray crystallographic study of 3d revealed a very unusual molecular structure
with the benzyloxy phenyl ring located nearly above the plane of the ylide double bond with the
shortest intramolecular contact C9…C17 of 3.204(6) Å (Figure 3).
5

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Figure 3. Molecular structure of 3d.
Such a geometry implies rather strong stacking interactions in 3d, which are expected to
become even stronger for the zwitter-ionic intermediate 4d due to the localization of opposite
charges on planes involved into the attractive interactions. This effect is presumably a main reason
for the increased reactivity of substrates 3c,d.
An introduction of σ-acceptor functional groups into the phenyl ring of the benzyloxy group in
reactants 3 gives rise to a pronounced reactivity inhibition. Indeed, the cyclization of 3-chloro- and
2-chloro derivatives 3e and 3f into the respective spiro-products 5е and 5f requires temperatures as
high as 240 °С (Table 1).
The methoxybenzyl-substituted reactant 3g undergoes the cyclization into the respective spiro-
cyclic product 5g nearly as facile as its unsubstituted analog 3a.
The extension of substrate series to other 5-(2-alkoxybenzylidene)barbiturates showed that
methoxy and ethoxy derivatives 6a and 6b do not rearrange even at 270 °С. Meanwhile,
5-(2-isopropyloxybenzylidene) derivative 6с quite readily cyclizes into the respective spirocyclic
product 7 (Scheme 5).
R1
H
O
R2
O
O
O
o
270 C
HN
HN
No reaction
R1 =H;
O
N
H
R1 =R2 = Me
O
N
H
O
H
O
R2 =H, Me
7
6a-c
Scheme 5. The isomerization of 5-(2-alkoxybenzylidene)barbituric acids. R1 = R2 = H (a); R1 = H,
R2 =Me (b); R1 = R2 = Me (c); the yield of 7 is 95% by using of the Method A and 80% by the
Method C (Table 1 and Experimental section)
The rearrangement of 6с into 7c can be realized either in the solvent-free medium or upon
boiling in acetic acid (Table 1). This strongly suggests that a secondary alkoxy group is by far more
reactive towards the Т-reaction than a primary alkoxy group, which is probably due to a higher
stability of the О+СМе2-cationic centre within the zwitter-ionic intermediate generated by the
hydride transfer.
6

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In contrast to aforementioned 5-(2-benzyloxybenzylidene)barbiturates 3a-g (Scheme 4) and 6с
(Scheme 5), the isomerization of 5-(2-allyloxybenzylidene)barbiturates 8a,b follows an alternative
mechanism not involving a hydride transfer and affording cycloaddition products 9a,b (Scheme 6).
R
R
O
O
O
O
O
O
H
R
AcOH
HN
HN
HN
H
118OC, 12 h
O
N
H
O
O
N
O
N
H
O
O
H
8a,b
10
9a,b
Scheme 6. The isomerization of 5-(2-allyloxybenzylidene)barbituric acids; R = H (a); R = OMe (b)
The prevalence of the cycloaddition reaction pathway for derivatives 9a and 9b can be
rationalized taking into account that similar cyclizations were reported for a number of
5-(2-allyloxybenzylidene)barbituriates.17
The Diels-Alder cycloaddition products 9 were isolated as a mixture of two isomers with the
syn- and anti-configurations of protons at asymmetric carbon atoms with the former one being
dominant (approximately 75% of syn-isomer). No traces of anticipated spirocyclic products 10 were
detected, which means that the cycloaddition reaction is much easier initiated than the hydride
transfer. Interestingly, substrates 7 demonstrate totally different reactivity with this respect as
compared to 2-allyloxy derivatives of malonic acid, which undergo cyclization to chromane
derivatives via the hydride transfer (Scheme 1, R = CH=CH2) as reported elsewhere.9
3. Conclusion
Therefore, the experimental evidence outlined above suggests that the reported cyclization of 5-
(2-alkoxybenzylidene)barbituric acids via a hydride transfer is indeed realized in the case of
benzyloxy- or isopropyloxy-derived substrates. This finding unveils new facile routes to the
synthesis of chromane-like spiro-pyrimidine derivatives that can be considered as analogs of
flavonoids and related naturally occurring benzopyran systems.
4. Experimental section
4.1. General
The 1Н and 13C NMR spectra were recorded on a АМ-400 Bruker spectrometer (400 and 100 MHz,
1
respectively). The purity of synthesized compounds was determined by elemental analysis and Н
NMR spectroscopy.
The 5-(2-methoxybenzylidene)barbituric acid (6a) and 5-(2-ethoxybenzylidene)barbituric acid (6b)
are commercially available. The 5-(2-isopropyloxybenzylidene)barbituric acid (6c) and 5-(2-
allyloxybenzylidene)barbituric acid (8a) are presented in catalog of ChemBrige Corporation. Other
5-(2-alkoxybenzylidene)barbituric acids 3а-g, 6c. 7a,b were synthesized from corresponding
barbituric acids and O-alkyl derivatives of salicylic aldehyde (see p.p. 4.3). All of the used
aldehydes are described in the literature, among them 2-benzyloxybenzaldehyde is commercially
7

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available, whereas other derivatives were synthesized by alkylation of salicylic aldehyde or
o-vaniline (see p.p. 4.2).
Crystals of compounds 3b, 3d and 5d suitable for X-ray structural analysis were grown from
chloroform-methanol solutions.
X-ray structure determination. X-ray diffraction data were collected on the ‘Belok’ beamline
of the Kurchatov Synchrotron Radiation Source (National Research Center “Kurchatov Institute”,
Moscow, Russian Federation) in the
compounds 3b and 3d) and on a three-circle Bruker APEX-II CCD diffractometer using
ϕ
scanning mode using a Rayonix SX165 CCD detector (for
and
ϕ
ω
scanning mode (for compound 5d). The reflection intensities measured were corrected for
absorption using the Scala program18 for compounds 3b and 3d and the SADABS program19 for
compound 5d. The data were indexed, integrated and scaled using the utility iMOSFLM in CCP4
program suite20 for compounds 3b and 3d and Bruker APEX2 program21 for compound 5d. For
details, see Supporting Information. The structures were determined by direct methods and refined
by full-matrix least squares technique on F2 with anisotropic displacement parameters for non-
hydrogen atoms. The hydrogen atoms were placed in calculated positions and refined within the
riding model with fixed isotropic displacement parameters [Uiso(H) = 1.5Ueq(C) for the methyl
groups and 1.2Ueq(C) for the other groups]. The calculations were carried out using the SHELXTL
program22.
Crystallographic data for the investigated compounds have been deposited with the Cambridge
Crystallographic Data Center, CCDC 1502465 (3b), CCDC 1502466 (3d), and CCDC 1502467
(5d). Copies of this information may be obtained free of charge from the Director, CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk or
www.ccdc.cam.ac.uk).
4.2. General procedure for synthesis of 2-alkoxy benzaldehydes.
To the stirred solution of salicylic aldehyde (0.1 mol) (or 2-hydroxy-3-methoxybenzaldehyde
(o-vanilin)) in DMF (40 mL), dry K2CO3 (0.12 mol) was added and the mixture was stirred for
15 min at 20 °С. Then corresponding alkyl halide (0.1 mol) was added, and the reaction mixture
was stirred for 12 h at 60 °С. The cooled reaction mixture was poured into water (250 mL) and
extracted by CH2Cl2 (40 mL). An organic layer was separated, washed with NH4OH 5% (5×25 mL)
and water (50 mL), and dried over Na2SO4. A solvent was removed in vacuo and the residue was
crystallized by adding of cyclohexane (in case of the solid compounds, see p.p. 4.2.1-4.2.4), or
distilled in vacuo 1 mm. Hg (in case of liquids, see p.p. 4.2.5-4.2.7).
4.2.1. 2-Benzyloxy-3-methoxybenzaldehyde (Acros Organics, cat. № 42567). It was prepared from
from o-vanilin and benzyl chloride in 77% yield. Colorless crystals, m.p. 48 °С.
4.2.2. 2-(2-Chlorobenzyloxy)benzaldehyde (AK Scientific, cat. № 5081AE). It was prepared from
salicylic aldehyde and 2-chlorobenzyl chloride in 82% yield. Colorless crystals, m.p. 88 °С.
4.2.3. 2-(3-Chlorobenzyloxy)benzaldehyde (AK Scientific, cat. № 2696AE). It was prepared from
salicylic aldehyde and 3-chlorobenzyl chloride in 79% yield. Colorless crystals, m.p. 42 °С.
4.2.4. 2-(3-Methoxybenzyloxy)benzaldehyde (ChemBrige Co cat. № 3014101). It was prepared from
salicylic aldehyde and 2-chlorobenzyl chloride in 85% yield. Colorless crystals, m.p. 73 °С.
4.2.5. 2-Isopropyloxybenzaldehyde (AK Scientific, cat. № 7011AD). It was prepared from salicylic
aldehyde and 2-iodopropane in 66% yield. Сolorless oil.
4.2.6. 2-Allyloxybenzaldehyde (Acros Organics, cat. № 38083). It was prepared from salicylic
aldehyde and allyl bromide in 87% yield. Сolorless oil.
4.2.7. 2-Allyloxy-3-methoxybenzaldehyd (AK Scientific, cat. № 7908AD).. It was prepared from o-
8

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vanilin and allyl bromide in 83% yield. Сolorless oil.
4.3. General procedure for synthesis of 2-alkoxybenzylidene barbiturates 3а-g, 6c, 7a,b.
Barbituric acid (10 mmol) (or 1,3-dimethylbarbituric acid) were dissolved in water (5 mL) under
heating, and the solution of corresponding aldehyde (10 mmol) in ethanol (10 mL) of was added.
The reaction mixture was stirred for 5 min at 75 °С and allowed to stay at room temperature for 2 h.
A precipitate was filtered out, washed with 50% ethanol and dried in air.
4.3.1. 5-(2-Benzyloxybenzylidene)barbituric acid (3a).
It was prepared from barbituric acid and 2-benzyloxybenzaldehyde in 96% yield. Yellow crystals,
m.p. 204−206 °С; [Found: C, 66.87; H, 4.40; N, 8.61. C18H14N2O4 requires C, 67.08; H, 4.38; N,
8.69%]; νmax (KBr) 3062, 2856, 1756, 1664, 1562, 1393, 1294, 1230, 1020, 841, 789, 753, 728,
659, 506 cm-1; δН (400 MHz, DMSO-d6) 11.35 (1 H, s, NH), 11.18 (1 H, s, NH), 8.58 (1 Н, s,
CH=C), 8.01 (1 Н, d, J 8.2 Hz, ArH), 7.29-7.53 (6 Н, m, ArH), 7.19 (1 Н, d, J 8.2 Hz, ArH), 7.00
(1 Н, t, J 8.2 Hz, ArH), 5.22 (2 Н, s, OCH2); δС (100 MHz, DMSO-d6) 163.8, 181.9, 158.6, 150.7,
150.5, 137.1, 134.4, 133.0, 129.0, 128.4, 127.9, 122.5, 120.2, 119.3, 112.9, 70.4.
4.3.2. 1,3-Dimethyl-5-(2-benzyloxybenzylidene)barbituric acid (3b).
It was prepared from 1,3-dimethylbarbituric acid and 2-benzyloxybenzaldehyde in 95% yield.
Yellow crystals, m.p. 160−161 °С. [Found: C, 68.41; H, 5.22; N, 7.93. C20H18N2O4 requires C,
68.56; H, 5.18; N, 8.00%]; νmax (KBr) 3676, 3062, 3031, 1730, 1667, 1587, 1453, 1373, 1253,
1160, 1080, 789, 761, 692, 593, 472 cm-1; δН (400 MHz, CDCl3) 8.97 (1 Н, s, CH=C), 8.03 (1 Н, d,
J 8.2 Hz, ArH), 7.30-7.51 (6 Н, m, ArH), 7.03 (2 Н, m, ArH), 5.20 (2 Н, s, OCH2), 3.41 (3 Н, s,
NMe), 3.24 (3 Н, s, NMe); δС (100 MHz, CDCl3) 162.1, 160.0, 156.8, 149.9, 149.5, 136.0, 133.3,
130.9, 128.1, 127.4, 127.0, 122.1, 119.7, 118.8, 112.5, 71.1, 28.8, 28.1..
4.3.3. 5-(2-Benzyloxy-3-methoxybenzylidene)barbituric acid (3c).
It was prepared from barbituric acid and 2-benzyloxy-3-methoxybenzaldehyde in 95% yield. Yellow
crystals, m.p. 203−204 °С. [Found: C, 64.69; H, 4.60; N, 7.89. C19H16N2O5 requires C, 64.77; H,
4.58; N, 7.95%]; νmax (KBr) 3059, 2841, 1752, 1662, 1548, 1395, 1264, 1230, 1081, 958, 914, 836,
751, 699, 507 cm-1; δН (400 MHz, DMSO-d6) 11.32 (1 H, s, NH), 11.12 (1 H, s, NH), 8.34 (1 Н, s,
CH=C), 7.50 (1 Н, d, J 8.1 Hz, ArH), 7.32 (5 Н, m, ArH), 7.24 (1 Н, d, J 8.1 Hz, ArH), 7.10 (1 Н, t,
J 8.1 Hz, ArH), 5.01 (2 Н, s, OCH2), 3.89 (3 Н, s, OMe); δС (100 MHz, DMSO-d6) 163.6, 161.5,
152.5, 150.9, 150.7, 147.6, 137.2, 129.2, 128.7, 128.5, 128.3, 123.9, 123.6, 120.1, 116.7, 75.4, 56.5.
4.3.4. 1,3-Dimethyl- 5-(2-benzyloxy-3-methoxy-benzylidene)barbituric acid (3d).
It was prepared from 1,3-dimethylbarbituric acid and 2-benzyloxy-3-methoxybenzaldehyde in 95%
yield. Colorless crystals, m.p. 160−161 °С. [Found: C, 66.15; H, 5.33; N, 7.29. C21H20N2O5 requires
C, 66.31; H, 5.30; N, 7.36%]; νmax (KBr) 3006, 2955, 1736, 1667, 1574, 1476, 1379, 1277, 1184,
1107, 788, 749, 703, 610, 470 cm-1; δН (400 MHz, CDCl3) 8.97 (1 Н, s, CH=C), 7.40 (1 Н, d, J 8.1
Hz, ArH),7.28 (5 Н, m, ArH), 7.12 (2 Н, m, ArH), 5.07 (2 Н, s, OCH2), 3.95 (3 Н, s, OMe), 3.40
(3 Н, s, NMe), 3.27 (3 Н, s, NMe); δС (100 MHz, CDCl3) 161.9, 159.8, 155.7, 152.4, 151.3, 147.4,
136.8, 129.3, 128.8, 128.2, 128.0, 123.4, 123.3, 118.3, 115.9, 76.0, 56.0, 28.8, 28.2.
4.3.5. 5-(2-(3-Chlorobenzyloxy)benzylidene)barbituric acid (3e).
It was prepared from barbituric acid and 2-(3-chlorobenzyloxy)benzaldehyde in 97% yield. Yellow
crystals, m.p. 240−241 °С. [Found: C, 60.49; H, 3.74; N 7.80. C18H1335ClN2O4 requires C, 60.60;
H, 3.67; N, 7.85%]; νmax (KBr) 3195, 3066, 1759, 1683, 1582, 1486, 1431, 1381, 1297, 1243, 1122,
935, 828, 746, 704, 551, 505 cm-1; δН (400 MHz, DMSO-d6) 11.36 (1 H, s, NH), 11.17 (1 H, s,
NH), 8.59 (1 Н, s, CH=C), 8.01 (1 Н, d, J 8.2 Hz, ArH), 7.48 (5 Н, m, ArH), 7.21 (1 Н, d, J 8.2 Hz,
ArH), 7.01 (1 Н, t, J 8.2 Hz, ArH), 5.25 (2 Н, s, OCH2); δС (100 MHz, DMSO-d6) 163.8, 161.9,
9

ACCEPTED MANUSCRIPT
158.3, 150.7, 150.2, 139.7, 134.3, 133.7, 133.0, 130.9, 128.3, 127.6, 126.4, 122.5, 120.5, 119.4,
112.9, 69.5.
4.3.6. 5-(2-(2-Chlorobenzyloxy)benzylidene)barbituric acid (3f).
It was prepared from barbituric acid and 2-(2-chlorobenzyloxy)benzaldehyde in 97% yield. Yellow
crystals, m.p. 239−240 °С. [Found: C, 60.64; H, 3.70; N, 7.79. C18H1335ClN2O4 requires C, 60.60;
H, 3.67; N, 7.85%]; νmax (KBr) 3202, 3079, 1760, 1681, 1592, 1486, 1431, 1382, 1298, 1253, 1121,
1035, 935, 788, 744, 540, 505 cm-1; δН (400 MHz, DMSO-d6) 11.33 (1 H, s, NH), 11.17 (1 H, s,
NH), 8.58 (1 Н, s, CH=C), 8.00 (1 Н, d, J 8.2 Hz, ArH), 7.54 (2 Н, m, ArH), 7.40 (2 Н, m, ArH),
7.22 (1 Н, d, J 8.2 Hz, ArH), 7.02 (1 Н, t, J 8.2 Hz, ArH), 5.29 (2 Н, s, OCH2); δС (100 MHz,
DMSO-d6) 163.8, 161.9, 158.2, 150.7, 150.4, 134.4, 134.3, 133.1, 133.0, 130.5 (2C), 130.0, 127.9,
122.7, 120.5, 119.4, 112.9, 68.2.
4.3.7. 5-(2-(3-Methoxybenzyloxy)benzylidene)barbituric acid (3g).
It was prepared from barbituric acid and 2-(3-methoxybenzyloxy)benzaldehyde in 94% yield.
Yellow crystals, m.p. 174−175 °С. [Found: C, 64.65; H, 4.61; N, 7.87. C19H16N2O5 requires C,
64.77; H, 4.58; N 7.95%]; νmax (KBr) 3223, 1746, 1676, 1600, 1452, 1384, 1248, 1031, 932, 783,
758, 692, 503 cm-1; δН (400 MHz, DMSO-d6) 11.37 (1 H, s, NH), 11.17 (1 H, s, NH), 8.61 (1 Н, s,
CH=C), 8.02 (1 Н, d, J 8.2 Hz, ArH), 7.50 (1 Н, t, J 8.2 Hz, ArH), 7.31 (1 Н, t, J 8.2 Hz, ArH),
7.20 (1 Н, d, J 8.2 Hz, ArH), 7.01 (3 Н, m, ArH), 6.90 (1 Н, dd, J 8.2, 2.4 Hz, ArH), 5.27 (2 Н, s,
OCH2), 3.78 (3Н, s, OMe); δС (100 MHz, DMSO-d6) 163.9, 161.9, 159.9, 158.5, 150.7, 150.4,
138.7, 134.4, 133.0, 130.1, 122.5, 120.3, 119.9, 119.3, 114.1, 113.1, 112.9, 70.3, 55.5.
4.3.8. 5-(2-Isopropyloxybenzylidene)barbituric acid (6c) (ChemBrige Co cat. № 5316075).
It was prepared from barbituric acid and 2-isopropyloxybenzaldehyde in 82% yield. Yellow crystals,
m.p. 218−219 °С. [Found: C, 61.29; H, 5.15; N, 10.19. C14H14N2O4 requires C, 61.31; H, 5.14; N,
10.21%]; δН (400 MHz, DMSO-d6) 11.32 (1 H, s, NH), 11.14 (1 H, s, NH), 8.51 (1 Н, s, CH=C),
8.00 (1 Н, dd, J 8.2, 2.2 Hz, ArH), 7.49 (1 Н, dd, J 8.2, 2.2 Hz, ArH), 7.13 (1 Н, d, J 8.0 Hz, ArH),
6.95 (1 Н, t, J 8.0 Hz, ArH), 4.73 (1 Н, m, CHMe2), 1.30 (6 Н, d, J 5.9 Hz, CHMe2).
4.3.9. 5-(2-Allyloxybenzylidene)barbituric acid (8a) (ChemBrige Co cat. № 5567165).
It was prepared from barbituric acid and 2-allyloxybenzaldehyde in 92% yield. Yellow crystals, m.p.
195−196 °С. [Found: C, 61.74; H, 4.47; N, 10.25. C14H12N2O4 requires C, 61.76; H, 4.44;
N, 10.29%]; δН (400 MHz, DMSO-d6) 11.34 (1 H, s, NH). 11.16 (1 H, s, NH), 8.56 (1 Н, s, CH=C),
8.01 (1 Н, dd, J 8.2, 2.1 Hz, ArH), 7.50 (1 Н, t, J 8.2 Hz, ArH), 7.11 (1 Н, d, J 8.2 Hz, ArH), 6.99 (1
Н, t, J 8.2 Hz, ArH), 6.07 (1 Н, m, CH=CH2), 5.43 (1 Н, dd, J 17.1, 1.9 Hz, CH=CHH), 5.30 (1 Н,
dd, J 10.5, 1.8 Hz, CH=CHH), 4.70 (2 Н, d, J 5.1 Hz, OCH2).
4.3.10. 5-(2-Allyloxy-3-methoxybenzylidene)barbituric acid (8b).
It was prepared from barbituric acid and 2-allyloxy-3-methoxybenzaldehyde in 90% yield. Yellow
crystals, m.p. 200−201 °С. [Found: C, 59.56; H, 4.70; N, 9.21. C15H14N2O5 requires C, 59.60; H,
4.67; N, 9.27%]; νmax (KBr) 3199, 3071, 2844, 1743, 1676, 1558, 1444, 1391, 1270, 1223, 1077,
976, 858, 794, 695, 500 cm-1; δН (400 MHz, DMSO-d6) 11.36 (1 H, s, NH), 11.17 (1 H, s, NH),
8.46 (1 Н, s, CH=C), 7.51 (1 Н, d, J 8.2 Hz, ArH), 7.08 (1 Н, t, J 8.2 Hz, ArH), 7.21 (1 Н, d, J 8.2
Hz, ArH), 5.99 (1 Н, m, CH=CH2), 5.33 (1 Н, dd, J 16.1, 2.0 Hz, CH=CHH), 5.20 (1 Н, dd, J 10.6,
1.8 Hz, CH=CHH), 4.53 (2 Н, d, J 5.5 Hz, OCH2), 3.84 (3 Н, s, OMe); δС (100 MHz, DMSO-d6)
163.6, 161.7, 152.3, 150.8, 150.7, 147.9, 134.4, 128.0, 123.8, 123.4, 120.4, 118.4, 116.7, 74.5, 56.4.
4.4. General Method A – the procedure for synthesis of 5-spiro-3’-cromans 5a-q and 7
(Table 1) without solvent
10

ACCEPTED MANUSCRIPT
The derivative of 5-benzylidenebarbituric acid (3a-g, 6c) (2 mmol) of was heated in sealed
ampoule under inert atmosphere. After cooling, the solid product was crushed and washed by hot
aqueous ethanol, filtered out and dried in air to give the 5-spiro-3’-croman derivative (5a-g, 7). The
conditions of reaction (the temperature and time of heating) and yields see in Table 1.
4.4.1. 2,4,6-trioxospiro(perhydropyrimidino-5)-3'-(2-phenylchromane) (5a).
Colorless crystals, m.p. 237−238 °С. [Found: C, 67.05; H, 4.39; N, 8.66. C18H14N2O4 requires C,
67.08; H, 4.38; N, 8.69%]; νmax (KBr) 3197, 3087, 2850, 1692, 1491, 1432, 1367, 1258, 1200,
1101, 1055, 844, 749, 531, 495 cm-1; δН (400 MHz, DMSO-d6) 11.19 (1 H, s, NH), 11.12 (1 H, s,
NH), 7.40 (3 Н, m, ArH), 7.22 (1 Н, d, J 8.0 Hz, ArH), 7.26 (2 Н, m, ArH), 7.13 (1 Н, t, J 8.0 Hz,
ArH), 6.96 (1 Н, t, J 8.4 Hz, ArH), 6.89 (1 Н, d, J 8.2 Hz, ArH), 5.08 (1 Н, s, OCH), 3.24 and 3.62
(1 Н+1 Н, d+d, J 17.0 Hz, АВ-system, CH2Ar); δС (100 MHz, DMSO-d6) 171.2 (O=C), 169.3
(O=C)), 154.4, 149.9 (O=C), 135.4, 129.7, 129.3, 128.7 (2 C), 127.5 (2 C), 126.9, 121.8, 121.6 ,
116.5 , 81.2, 53.1 , 31.6.
4.4.2. 1,3-Dimethyl-2,4,6-trioxospiro(perhydropyrimidino-5)-3'-(2-phenylchromane) (5b)
Colorless crystals, m.p. 161−162 °С. [Found: C, 68.45; H, 5.15; N, 7.94. C20H18N2O4 requires C,
68.56; H, 5.18; N, 8.00%]; νmax (KBr) 3032, 2954, 1667, 1588, 1454, 1383, 1245, 1051, 920, 809,
755, 702, 476 cm-1; δН (400 MHz, CDCl3) 7.40 (3 Н, m, ArH), 7.24 (4 Н, m, ArH), 5.13 (1 Н, s,
OCH), 3.14 and 4.02 (1 Н + 1 Н, d + d, J 17.1 Hz, АВ-system, CH2Ar), 3.09 (3 H, s, NMe), 3.06 (3
H, s, NMe). δС (100 MHz, CDCl3) 169.0 (O=C), 167.1 (O=C), 153.9, 150.0 (O=C), 134.6, 129.9,
128.7 (2 C), 128.4, 127.2, 126.0, 121.9, 120.3, 116.7, 82.0, 54.6, 31.8, 28.6, 28.0.
4.4.3. 2,4,6-Trioxospiro(perhydropyrimidino-5)-3'-(2-phenyl-8-methoxychromane) (5c).
Colorless crystals, m.p. 309−310 °С. [Found: C, 64.74; H, 4.57; N, 7.93. C19H16N2O5 requires C,
64.77; H, 4.58; N, 7.95%]; νmax (KBr) 3242, 1733, 1589, 1488, 1375, 1331, 1265, 1221, 1085, 954,
752, 705, 522, 496 cm-1; δH (400 MHz, DMSO-d6) 11.18 (1 H, s, NH), 11.12 (1 H, s, NH). 7.41
(3Н, m, ArH), 7.26 (2 Н, m, ArH), 6.88 (1 Н, d, J 8.0 Hz, ArH), 6.81 (1 Н, t, J 8.0 Hz, ArH), 5.01
(1 H, s, OCH), 3.73 (3 H, s, OMe), 3.61 + 3.22 (1 H + 1 H, d + d, J 17.1 Hz, АВ-system, CH2Ar);
δC (100 MHz, DMSO-d6) 171.3 (O=C), 169.3 (O=C), 149.9 (O=C), 148.5, 146.0, 135.4, 129.7,
128.7 (2 C), 127.5, 122.4, 121.2, 120.8 (2 C), 109.7, 80.5, 55.9, 53.1, 31.5.
4.4.4.
1,3-Dimethyl-2,4,6-trioxospiro(perhydropyrimidino-5)-3'-(2-phenyl-8-methoxychromane)
(5d).
Colorless crystals, m.p. 170−171 °С. [Found: C, 66.27; H, 5.31; N, 7.31. C21H20N2O5 requires C,
66.31; H, 5.30; N, 7.36%]; νmax (KBr) 3023, 2954, 2836, 1689, 1589, 1451, 1382, 1265, 1220,
1092, 896, 753, 714, 612, 480 cm-1; δH (400 MHz, CDCl3) 7.37 (3 Н, m, ArH), 7.24 (2 Н, m, ArH),
6.97 (1 Н, t, J 8.0 Hz, ArH), 6.81 (1 Н, t, J 8.0 Hz, ArH), 5.01 (1 H, s, OCH), 3.73 (3 H, s, OMe),
3.61 + 3.22 (1 H + 1 H, d + d, J 17.1 Hz, АВ-system, CH2Ar); δC (100 MHz, CDCl3) 171.3 (O=C),
169.3 (O=C4(6), 149.9 (O=C), 148.5, 144.0, 135.4, 129.7, 128.7 (2 C), 127.5, 122.4, 121.2, 120.8,
109.7, 80.5, 55.9, 53.1, 31.5.
4.4.5. 2,4,6-Trioxospiro(perhydropyrimidino-5)-3'-(2-(3-chlorophenyl)chromane) (5e).
Colorless crystals, m.p. 195−196 °С. [Found: C, 60.65; H, 3.70; N, 7.84; C18H1335ClN2O4 requires
C, 60.60; H, 3.67; N, 7.85%]; νmax (KBr) 3222, 3097, 2844, 1726, 1589, 1491, 1428, 1366, 1251,
1055, 757, 692, 528, 500 cm-1; δH (400 MHz, DMSO-d6) 11.25 (2 H, s, NH + N’H), 7.45 (4 Н, m,
ArH), 7.26 (1 Н, d, J 8.0 Hz, ArH), 7.13 (1 Н, t, J 8.0 Hz, ArH), 6.98 (1 Н, t, J 8.1 Hz, ArH), 6.87
(1 Н, d, J 8.1 Hz, ArH), 5.48 (1 H, s, OCH), 3.73 + 3.23 (1 H + 1 H, d + d, J 17.6 Hz, АВ-system,
11

ACCEPTED MANUSCRIPT
CH2Ar); δC (100 MHz, DMSO-d6) 169.6 (O=C), 169.4 (O=C), 154.2, 149.9 (O=C), 142.0, 133.1,
131.4, 129.9, 129.6, 129.3, 127.7, 126.9, 122.0, 121.9, 116.4, 76.8, 52.5, 31.4.
4.4.6. 2,4,6-Trioxospiro(perhydropyrimidino-5)-3'-(2-(2-chlorophenyl)chromane) (5f).
Colorless crystals, m.p. 159−160 °С. [Found: C, 60.71; H, 3.72; N, 7.77. C18H1335ClN2O4 requires
C, 60.60; H, 3.67; N, 7.85%]; νmax (KBr) 3226, 3100, 2846, 1726, 1589, 1492, 1367, 1249, 1113,
754, 504 cm-1; δH (400 MHz, DMSO-d6) 11.31 (1 H, s, NH), 11.22 (1 H, s, NH). 7.50 (1 Н, d, J 7.9
Hz, ArH), 7.45 (1 Н, d, J 7.9 Hz, ArH), 7.28 (1 Н, s, ArH), 7.22 (2 Н, m, ArH), 7.14 (1 Н, t, J 8.0
Hz, ArH), 6.97 (1 Н, t, J 8.2 Hz, ArH), 6.91 (1 Н, t, J 8.2 Hz, ArH), 5.15 (1 H, s, OCH), 3.61 + 3.25
(1 H + 1 H, d + d, J 17.7 Hz, АВ-system, CH2Ar); δC (100 MHz, DMSO-d6) 171.0 (O=C), 169.1
(O=C), 154.1, 149.9 (O=C), 137.8, 130.7, 129.7, 129.2, 127.2, 127.0, 126.2, 121.8, 121.6, 116.6,
116.5, 82.3, 52.9, 31.5.
4.4.7. 2,4,6-Trioxospiro(perhydropyrimidino-5)-3'-(2-(3-methoxyphenyl)chromane) (5g).
Colorless crystals, m.p. 146−147 °С. [Found: C, 64.69; H, 4.60; N, 7.91. C19H16N2O5 requires C,
64.77; H, 4.58; N, 7.95%]; νmax (KBr) 3228, 3106,1728, 1589, 1491, 1368, 1257, 1222, 1114, 1051,
757, 697, 502 cm-1; δH (400 MHz, DMSO-d6) 11.22 (1 H, s, NH), 11.15 (1 H, s, NH). 7.31 (1 Н, t, J
8.0 Hz, ArH), 7.22 (1 Н, d, J 8.0 Hz, ArH), 7.14 (1 Н, t, J 8.0 Hz, ArH), 6.98 (1 Н, d, J 8.0 Hz,
ArH), 6.96 (1 Н, d, J 8.0 Hz, ArH), 6.89 (1 Н, t, J 8.2 Hz, ArH), 6.83 (1 Н, d, J 8.2 Hz, ArH), 6.80
(1 Н, s, Harom), 5.05 (1 H, s, OCH), 3.76 (3 H, s, OMe), 3.61 + 3.23 (1 H + 1 H, d + d, J 17.7 Hz,
АВ-system, CH2Ar); δC (100 MHz, DMSO-d6) 171.2 (O=C), 169.3 (O=C), 159.3, 154.5, 149.9
(O=C), 136.9, 129.9, 129.3, 127.0, 121.7, 121.6, 119.7, 116.5, 115.2, 113.0, 81.1, 55.6, 53.0, 31.6.
4.4.8. 2,4,6-Trioxospiro(perhydropyrimidino-5)-3'-(2,2-dimethylchromane) (7).
Colorless crystals, m.p. 314−315 °С. [Found: C, 61.28; H, 5.13; N, 10.18. C14H14N2O4 requires
C, 61.31; H, 5.14; N, 10.21%]; νmax (KBr) 3201, 3097, 1756, 1696, 1493, 1428, 1342, 1238, 1192,
1144, 1116, 968, 764, 544, 523 cm-1; δH (400 MHz, DMSO-d6) 11.37 (2 H, s, 2 NH), 7.15 (1 Н, d, J
8.0 Hz, ArH), 7.06 (1 Н, d, J 8.0 Hz, ArH), 6.88 (1 Н, t, J 8.0 Hz, ArH), 6.73 (1 Н, d, J 8.0 Hz,
ArH), 3.23 (2 H, s, CH2); 1.31 (6 H, s, CMe2); δC (100 MHz, DMSO-d6) 170.5 (2 O=C), 152.3,
150.8, 128.8, 126.9, 122.4, 122.0, 116.7, 76.7, 54.8, 27.7. 24.1.
4.5. Method
B
–
the procedure for synthesis of 1,3-dimethyl-2,4,6-
trioxospiro(perhydropyrimidino-5)-3'-(2-phenylchromane) (5b) in presence of succinic acid
(Table 1)
1,3-Dimethyl-5-benzylidenebarbituric acid 3b (0.35 g, 1 mmol) was mixed with 0.35 g of
succinic acid and kept under inert atmosphere in a sealed ampoule at 190 oC for 4 h. After cooling,
the product was washed by hot water, dried and extracted by boiling heptane-CH2Cl2 (10:1, 3x15
mL). The combined extract was evaporated, the solid residue was washed by hexane and dried in air
to give the derivative 3b as colorless crystals, m.p. 161−162 °С.
4.6. General Method C – the procedure for synthesis of 5-spiro-3’-chromanes 5c,d and 7
(Table 1) in acetic acid
5-Benzylidene barbituric acid derivative (3c,d, 6c) (2 mmol) was dissolved in acetic acid (10
mL) and heated under reflux. The completion of the reaction was established by TLC. After that the
solvent was removed under reduced pressure, the residue was washed by aqueous methanol and
dried in air. The time of reaction and yield of the obtained 5-spiro-3’-chromane derivatives (5c,d, 7)
see in Table 1.
4.7.
General
procedure
for
synthesis
of
2,3,4,6a,7,12b-hexahydro-1H,6H-
chromeno[4',3':4,5]pyrano[2,3-d]pyrimidine-1,3-diones (9a,b)
12

ACCEPTED MANUSCRIPT
5-(2-Allyloxybenzylidene)barbituric acid (8a) (2 mmol) or its derivative (8b) were dissolved in
acetic acid (15 mL) and heated under reflux for 12 h. The process was monitored by TLC. After
completion of the reaction, the solvent was removed under reduced pressure, the crude residue was
washed by methanol and dried in air.
4.7.1. 2,3,4,6a,7,12b-hexahydro-1H,6H-chromeno[4',3':4,5]pyrano[2,3-d]pyrimidine-1,3-dione
(9a)
Mixture of (R*,S*)- and (S*,S*)-diastereomers (75% and 25%, respectively). Colorless crystals,
m.p. 360 °С (decomp.). [Found: C, 61.72; H, 4.42; N, 10.28. C14H12N2O4 requires C, 61.76; H,
4.44; N, 10.29%]; δH (400 MHz, DMSO-d6) 11.23 (1 H, s, NH (S*,S* + R*,S*)), 10.78 (0.75 H, s,
NH (R*,S*)), 10.40 (0.25 H, s, NH (S*,S*)), 7.37 + 7.29 (0.75 H +0.25 H, d + d, J 8.0 Hz, ArH
(R*,S* + S*,S*)), 7.10 + 7.01 (0.25 H +0.75 H, t + t, J 8.0 Hz, ArH (S*,S* + R*,S*)), 6.99 + 6.78
(0.25 H +0.75 H, t + t, J 8.0 Hz, ArH (S*,S* + R*,S*)), 6.88 + 6.65 (0.25 H +0.75 H, d + d, J 8.0
Hz, ArH (S*,S* + R*,S*)), 4.84 (0.25 Н, s (broad), OCH (S*,S*), 4.54 + 4.03 (0,75 Н + 0.75 H, d +
d, J 11.5 Hz, АВ-system, OCH2 (R*,S*)), 4.49 (0.25 Н, m, OCHH (S*,S*)), 4.30 (1.5 H, OCH2
(R*,S*)), 4.10 (0.75 H, d, J 4.8 Hz, ArCHCH (R*,S*)), 3.75 (0.25 H, d, J 13.2 Hz, ArCHCH
(S*,S*)), 3.74 (0.25 H, m, OCHH (S*,S*)), 2.37 (0.75 H, m, CH (R*,S*)), 2.32 (0.25 H, m, CH
(S*,S*)), 2.11 (0.25 H, m, OCHH (S*,S*)); δС (100 MHz, DMSO-d6) 166.0, 163.7, 158.7, 158.0,
152.4, 150.3, 150.2, 150.0, 136.2, 131.4, 128.3, 128.2, 128.1, 124.8, 124.1, 122.0, 121.3, 116.8,
89.6, 87.9, 75.8, 73.5, 67.1, 65.6, 32.3, 29.3, 29.0, 27.5.
4.7.2. 9-methoxy-2,3,4,6a,7,12b-hexahydro-1H,6H-chromeno[4',3':4,5]pyrano[2,3-d]pyrimidine-
1,3-dione (9b)
Mixture of (R*,S*)- and (S*,S*)-diastereomers (77% and 23%, respectively). Colorless crystals,
m.p. 380 °С (decomp.). [Found: C, 59.57; H, 4.65; N, 9.23. C15H14N2O5 requires C, 59.60; H, 4.67;
N, 9.27%]; δH (400 MHz, DMSO-d6) 11.41 (0.77 H, s, NH (R*,S*)), 11.38 (0.23 H, s, NH (S*,S*)),
10.94 (0.77 H, s, NH (R*,S*)), 10.60 (0.23 H, s, NH (S*,S*)), 6.73-6.98 (3 H, m, ArH (R*,S* +
S*,S*)), 4.85 (0.23 Н, s (broad), OCH (S*,S*), 4.65 (0,77 Н, dd, J 11.5, 4.9 Hz, OCHHCH
(R*,S*)), 4.54 (0.23 Н, dd, J 13.1, 2.8 Hz, OCHHCH (S*,S*)), 4.33 + 4.25 (0,77 Н + 0.77 H, d + d,
J 12.0 Hz, АВ-system, OCH2 (R*,S*)), 4.07 (0.77 H, d, J 5.2 Hz, ArCHCH (R*,S*)), 3.93 (0.77 H,
m, OCHH (R*,S*)), 3.72 (0.23 H, m, OCHH (S*,S*)), 3.70 (3 H, s, OMe (S*,S* + R*,S*)), 3.66
(0.23 H, d, J 13.6 Hz, ArCHCH (S*,S*)), 2.38 (0.77 H, m, CH (R*,S*)), 2.29 (0.23 H, m, CH
(S*,S*)), 2.06 (0.23 H, m, OCHH (S*,S*)); δС (100 MHz, DMSO-d6) 166.0, 163.7, 158.1, 158.0,
152.2, 150.3, 150.2, 148.2, 147.6, 142.0, 137.6, 125.2, 124.0, 122.8, 122.1, 120.6, 111.7, 110.5,
89.6, 87.9, 76.0, 73.3, 67.2, 65.6, 56.1, 55.9, 32.2, 29.2, 28.9, 27.6.
Acknowledgements
This work was supported by the Russian Foundation for Basic Research (grant no. 16-29-10782-
ofi_m), the Ministry of Education and Science of the Russian Federation (the Agreement number
02.a03.21.0008 of June 24, 2016), and the U.S. National Science Foundation (grant PREM DMR-
1523611).
Declaration of interest
The authors of the paper declare no any conflict of interest.
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Highlights
• Thermal cyclization of 5-(2-phenoxymethylphenyl-methylene)barbituric acid is proposed
• Cyclization mechanism via the hydride transfer is supposed based on XRD data
• New facile routes to the synthesis of spiro-pyrimidine derivatives is described