Light-induced one-pot synthesis of pyrimidine derivatives from vinyl azides

Article abstract of DOI:10.1039/d0ob00693a

A one-pot procedure for the synthesis of tetrasubstituted dihydropyrimidine and pyrimidine derivatives from α-azidocinnamates was developed. The synthesis is based on the finding that the outcome of LED photolysis of α-azidocinnamates depends on the light wavelength employed. Blue light (455 nm) leads to the formation of 2H-azirines only, but violet light (395 nm), UV-A light (365 nm), or sunlight result in the transformation of the in situ formed 2H-azirines to 1,3-diazabicyclo[3.1.0]hex-3-enes. Under basic catalysis (DBU), the latter were isomerized to 1,6-dihydropyrimidines which were oxidized to pyrimidines using DDQ. A successful use of Cs2CO3 as a base and air as an oxidant was also demonstrated.

Full text of DOI:10.1039/d0ob00693a

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D. Titov, O. V. Khoroshilova, M. A. Kinzhalov and N. V. Rostovskii, Org. Biomol. Chem., 2020, DOI:
10.1039/D0OB00693A.
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DOI: 10.1039/D0OB00693A
ARTICLE
Light-induced one-pot synthesis of pyrimidine derivatives from
vinyl azides
Tuan K. Nguyen, Gleb D. Titov, Olesya V. Khoroshilova, Mikhail A. Kinzhalov,* Nikolai V. Rostovskii*
Received 00th January 20xx,
Accepted 00th January 20xx
A one-pot procedure for the synthesis of tetrasubstituted dihydropyrimidine and pyrimidine derivatives from α-
azidocinnamates was developed. The synthesis is based on the finding that the outcome of LED photolysis of α-
azidocinnamates depends on the light wavelength employed. Blue light (455 nm) leads to the formation of 2H-azirines only,
but violet light (395 nm), UV-A light (365 nm), or sunlight result in the transformation of the in situ formed 2H-azirines to
1,3-diazabicyclo[3.1.0]hex-3-enes. Under basic catalysis (DBU), the latter were isomerized to 1,6-dihydropyrimidines which
were oxidized to pyrimidines using DDQ. A successful use of Cs2CO3 as a base and air as an oxidant was also demonstrated.
DOI: 10.1039/x0xx00000x
substrates and/or reagents11f, 11g, 13 or harsh conditions,11g, 12e,
13d, 14 and only some of them are suitable for the preparation of
functionalized multisubstituted pyrimidine derivatives.
Introduction
Pyrimidine derivatives are one of the most important
biologically active heterocycles.1 In particular, both pyrimidines
and dihydropyrimidines are known to display antibacterial,2
antiviral,3 anticancer,4 anti-HIV,5 antimalarial activities,6 and
others (Figure 1).7 In addition, pyrimidines have found
applications in photophysics8 and polymer chemistry.8g, 9
Known synthetic routes
to pyrimidines
C
This work
C
N
C
N
A
N
N
N
N
C
C
C
C
B
C
C
C
C
F
N
C
N
C
C
C
N
N
C
N
N
N
Et
N
C
Me
Ph
N
Cl
N
MeO2C
Me
MeO2C
Me
N
N
N
F
Ar
X
Ar
i. LED
or sunlight
DDQ
or air
N
NH2
X
N
N
N
NH
Ar
Ar
H
OH
NMe2
F
ii. DBU or
Cs2CO3
N3
X
Ar
X
antibacterial activity
ref. 2a
antiviral activity
ref. 3a
anticancer activity
ref. 4a
X = CO2R
X
4
1
5
Figure 1. Examples of bioactive pyrimidine derivatives.
h
[Ox]
Ar
base
Ar
There are several basic approaches to the construction of a
pyrimidine core (Scheme 1). They include the Pinner-like
condensation of amidines with 1,3-dicarbonyl compounds
(route A), cycloaddition reaction of 1,3-diazadienes (or 1,3,5-
triazines) with alkynes or alkenes (route B), cycloaddition
reaction of 2-azadienes (or 1,2,3-triazines) with nitriles (route
C), and others.10 Due to the demand for pyrimidine derivatives
in various fields, new methods for their synthesis are actively
being developed.11,12 However, they often use specific
X
Ar
N
2
N
h
N
NH
Ar
base
X
N
X
X
X
Ar
3
4
Scheme 1. Synthetic routes to pyrimidines.
In the last decade, vinyl azides, in particular α-azidocinnamates
(Scheme 1, compound 1), have been widely utilized as a key
three-atom synthon for the formation of nitrogen
heterocycles15 such as pyrroles, pyrazines, indoles, etc. Under
thermolysis or photolysis, vinyl azides can produce highly
strained three-membered heterocycles – 2H-azirines (Scheme
1, compound 2),16 which can act as dipolarophiles or source of
highly reactive dipole species – nitrile ylides.16-17 In 1998, Meth-
Cohn and coworkers studied photolysis of α-azidocinnamates
by 300 W Xenon-mercury lamp and mentioned that one of the
a. Saint Petersburg State University, 7/9 Universitetskaya Nab., Saint Petersburg,
199034 Russian Federation; e-mail’s: m.kinzhalov@spbu.ru, n.rostovskiy@spbu.ru
Electronic Supplementary Information (ESI) available: Full details of photochemical
experiments, spectroscopic data for prepared compounds and details of the X-ray
diffraction studies. See DOI: 10.1039/x0xx00000x
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products observed in the complex reaction mixture, namely 1,3- total conversion of 1a to dimers 3a after 2.5 h. The irradiation
View Article Online
DOI: 10.1039/D0OB00693A
diazabicyclo[3.1.0]hex-3-ene derivative (Scheme 1, compound of 1a by UV-A light (LED 365 nm) also led to a quantitative yield
3), can be transformed to a 1,6-dihydropyrimidine derivative of dimers 3a (80% isolated yield). Analogously, the photolysis of
under storage or under treatment with triethylamine.18 Only azidocinnamate 1b gave dimers 3b in 70% isolated yield (for
one example of the 1,6-dihydropyrimidine was described, but details see SI, section S2.3). In order to find out whether azirine
its yield was not reported.
2a is involved in the formation of “dimers” 3a, a control
We assumed that the photolysis of α-azidocinnamates experiment was performed. Pure azirine 2a was irradiated by
followed by the formation of 1,6-dihydropyrimidines and the UV-A light (LED 365 nm) for 2.5 h, which led to complete
aromatization could be a good candidate for the construction of conversion of 2a to dimers 3a. Hence, “dimers” 3 are the
hard-to-synthesize tetrasubstituted pyrimidine derivatives products of photochemical dimerization of azirines 2. The
bearing aryl substituents at the C2 and C4 positions and dimerization probably proceeds through 1,3-dipolar
carbonyl substituents at the C5 and C6 positions. In previous cycloaddition of a nitrile ylide to the C=N bond of the azirine.18
works, a few examples of such pyrimidines were synthesized
LED 455 nm
exclusively
by
the
cycloaddition
of
dimethyl
N
acetylenedicarboxylate with 1,2-dihydro-1,3,5-triazine,19 1,3-
diazabuta-1,3-dienes,20 or 1,2,4-selenodiazoles (Scheme S1).21
Departing from the previous literature, and in connection
with our interests in utilizing 2H-azirines and parent vinyl azides
for the synthesis of important heterocycles22 and in the
progress of new eco-friendly synthetic methods in organic
chemistry,23 we started the development of a new preparative
procedure for the synthesis of tetrasubstituted 1,6-
Ar
CO2Me
(88% 1H NMR)
MeCN, RT
2a
LED 365 nm
or LED 390 nm
N3
N
Ar
CO2Me
Ar
CO2Me
MeCN, RT
LED 365 nm
or LED 390 nm
MeCN, RT
Ar = C6H4-4-Cl
2a
1a
Ir catalyst (5 mol %)
dihydropyrimidines
4
and pyrimidines
5
from α-
CDCl3, RT
LED 365 nm
N
CO2Me
azidocinnamates (Scheme 1).
Ar
2a
CO2Me
Ar
CO2Me
Results and discussion
Ar
3a
(75%)
+
HN
N
Ar
N
Synthesis of intermediates 3 (1,3-diazabicyclo[3.1.0]hex-3-
enes). We suggested that the use of the LED lamps, which emit
high intensity light in a specific region of the spectrum, would
lead to increasing selectivity of α-azidocinnamates photolysis.
As a test of this hypothesis, we investigated the photolysis of
representative azidocinnamate 1a by different LEDs (Figure 2
and Table S1). Indeed, the irradiation of the representative
azidocinnamate 1a by blue light (455 nm) in MeCN during 2.5 h
at RT afforded only azirine 2a (88% yield, hereinafter the H
NMR yields are given unless otherwise stated) (Scheme 2). No
any other reaction was observed even upon prolonged
irradiation of the reaction mixture. An addition of a photoredox
N
N
MeO2C
Ar
Ar
CO2Me
(80%)
MeO2C
6
(5%)
3a
(100% 1H NMR)
dr = 1.5
Scheme 2. Irradiation of α-azidocinnamate 1a with 365–455 nm LED.
Thus, we demonstrated for the first time that the outcome
of the α-azidocinnamates photolysis depends on the light
wavelength employed.27 While the irradiation by blue light (455
nm) leads to the formation of 2H-azirines only, the irradiation
by violet (395 nm) or UV-A light (365 nm) results in the
transformation of the in situ formed 2H-azirines to 1,3-
diazabicyclo[3.1.0]hexenes.
1
24
catalyst, viz. [Ru(bpy)3](BF4)2
or [Ir(ppy)2(CNC6H4-4-
Cl)2](OTf),25 to 1a solution and irradiation also gave azirine 2a as
a single product (Table S2). Analogously, the photolysis of
azidocinnamates 1b–g by blue light resulted in the formation of
azirines 2b–g in 65–88% yield (Table S3). Unfortunately, α-
azidochalcone (Scheme 1, X = Bz, Ar = Tol) and azidocinnamate
bearing p-NO2 group on the phenyl ring (X = CO2Me, Ar = 4-
NO2C6H4) failed to afford the corresponding azirines 2. The
prolonged irradiation of azidocinnamate 1a by 465 nm light did
not lead to any reaction. These data are consistent with Farney
and Yoon results of the absence of a photochemical reaction
upon irradiation of dienyl azides by 465–470 nm light.26
When we carried out irradiation of 1a by a shorter
wavelength LED (425 and 410 nm), the reaction mixture showed
the presence of an equimolar mixture of azirine 2a along with
new products – two diastereomeric “dimers” of azirine – 1,3-
diazabicyclo[3.1.0]hex-3-enes 3a (Figure 2, Scheme 2). A further
decrease of the irradiation wavelength up to 395 nm led to a
2 | J. Name., 2012, 00, 1-3
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In this study, we observed that isomerization of two
View Article Online
DOI: 10.1039/D0OB00693A
diastereomers of 3a into 1,6-dihydropyrimidine 4a in MeCN
“dimers” 3a
azirine 2a
α-azidocinnamate 1a
proceeded slowly in the presence of medium-strength organic
bases, viz. Et3N or DABCO, and almost quantitative yield of 1,6-
dihydropyrimidine 4a was achieved after 2.5 h at RT (Scheme 3,
Table S7). The use of a strong organic base (1,8-diazabicyclo
[5.4.0]undec-7-ene (DBU)) or medium (N-methylmorpholine)
for the isomerization of 3a afforded 4a quantitatively after
15 min; isolated yields were 93%. At the same time, in the
presence of a weak base (pyridine) the isomerization did not
occur. The DBU-catalyzed isomerizations of separated
diastereomers of 3a afforded 4a in nearly quantitative yield in
each case. We also tested inorganic bases (K2CO3 and Cs2CO3)
for the isomerization. The reaction proceeded only with Cs2CO3
(1 h) to give 4a in nearly quantitative yield. From the
mechanistic point of view, the isomerization probably starts
from the removal of more acidic hydrogen atom (H1) of 3a to
form carbanion intermediate A. Further ring opening of
aziridine ring followed by protonation leads to
dihydropyrimidine 4a.
100
80
60
40
20
0
Figure 2. Results of photolysis of α-azidocinnamate 1a by different light sources
for 2.5 h (for details, see Table S1 in SI).
An addition of a photoredox catalyst, viz. [Ir(ppy)2(CNC6H4-
4-Cl)2](OTf)25 (1 mol %), to the solution of α-azidocinnamate 1a
in MeCN and irradiation by UV-A light did not affect the
direction of the reaction and the reaction rate as well and led to
the generation of 3a in a quantitative yield after 2.5 h (Table
S6). At the same time, a change of the solvent from MeCN to
CDCl3 and an increase in the catalyst loading (3 mol %) led to
reduced selectivity of the photolysis. In this case, one more
product, namely tricyclic compound 6 (Scheme 2, Figure 3), was
formed along with dimers 3a (for details see SI, section S2.4).
Ar
H1
N
Ar
N
Base
N
NH
Ar
H2
Ar
MeCN, RT
MeO2C
MeO2C
CO2Me
CO2Me
3a
4a
100% by 1H NMR
– H+
Ar
H+
Ar
N
N
N
N
Ar
CO2Me
MeO2C
Ar
CO2Me
MeO2C
A
B
Scheme 3. Isomerization of 3a into 1,6-dihydropyrimidine 4a.
Then, 1,6-dihydropyrimidines 4a–k were synthesized from α-
azidocinnamates 1a–k without isolation of intermediate 1,3-
diazabicyclo[3.1.0]hex-3-enes 3 (Scheme 4). The exposition of the
solutions of α-azidocinnamates 1a–k in MeCN to UV-A light (LED
365 nm) for 2.5 h and succeeding addition of 0.3 equiv. of DBU in
the reaction mixtures led to 1,6-dihydropyrimidines 4a–k, which
were isolated by column chromatography in 70–97% yields
(Table 1). Dihydropyrimidines 4a–k are previously unknown
compounds, and they were characterized by high-resolution ESI+-
MS, 1H and13C{1H} NMR spectroscopy. It is known that in general
there is an equilibrium of 1,4- and 1,6-dihydropyrimidine
tautomers in solutions.10d The existence of compounds 4 in
Figure 3. Molecular structure of 6 from single crystal X-ray analysis.
Finally, we showed that the synthesis of “dimers” 3 from α-
azidocinnamates 1 can be performed using natural sunlight as a
source of light. Irradiation of the solution of representative α-
azidocinnamate 1a in MeCN under natural sunlight for 2.5 h led
to the desired dimers 3a in 85% overall yield (Figure 2).
In further experiments, we used the UV-A light LED (365 nm)
since the wavelength 365 nm is incorporated in the
commercially available photoreactors,28 which allows to
standardize the method for laboratory and industrial use.
solutions at room temperature in form of
a
1,6-
dihydropyrimidine tautomer was confirmed by the 1H-1H NOESY
NMR spectra of 4d and 4f in DMSO-d6 (Figures S32 and S37). In
addition, the structures of 4d and 4f were confirmed by a single-
crystal X-ray diffraction (Figure 4). In the structures 4d and 4f, the
position of hydrogen atom at the nitrogen atom was determined
from the difference electron density map. Bond length and bond
angle data for 4d and 4f are in the expected range (Tables S12–
Isomerization of 1,3-diazabicyclo[3.1.0]hex-3-enes to 1,6-
dihydropyrimidines. As highlighted in the introduction, the
“dimers” of azirine can isomerize to 1,6-dihydropyrimidines
under Et3N catalysis,18 but, to the best of our knowledge, this
reaction has not been investigated in detail.
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J. Name., 2013, 00, 1-3 | 3
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ARTICLE
S17). The solid state structures are stabilized by N–H···O
Journal Name
In an effort to make the aromatization reaVciteiwoAnrticolefO1n,li6ne-
DOI: 10.1039/D0OB00693A
intramolecular (4d) or intermolecular (4f) hydrogen bonds (Table dihydropyrimidines more suitable for the chemical industry and
S14 and S17).
more environmentally-friendly, several conditions for the
Thereby, both in solution and solid state the 1,6- oxidation of 1,6-dihydropyrimidine 4a to pyrimidine 5a were
dihydropyrimidine tautomeric form was observed for tested (Table S8). Molecular oxygen and air are the most
compounds 4. We also calculated energies of 1,6- and 1,4- abundant and cheapest oxidants available, and accordingly they
dihydropyrimidine tautomers by DFT method. Indeed, the 1,6- are used extensively in organic synthesis.29 The reaction of
isomer turned out to be 4.4 kcal/mol more stable than the 1,4- dihydropyrimidine 5b with [Ru(bpy)3Cl2]⋅6H2O (2 molꢀ%) under
isomer (see SI, Section S6).
air or with bubbling air in MeCN under irradiation with blue LED
gave the desired pyrimidine 6b in 85ꢀ% yield after 10 h. The use
of bubbling air enriched by oxygen (up to 30% O2) allowed to
reduce reaction time to 4 h with the same yield of the product.
In the control experiment, no desired product was observed
without the photoredox catalyst or light, indicating that the
photoredox catalysis is necessary for the oxidation process
(Table S8). In addition, when the reaction was performed under
an argon atmosphere, no product was observed that proved the
participation of molecular oxygen in the reaction (Table S8).
Ar
1. LED 365 nm
MeCN, RT, 2.5 h
N
NH
CO2R
Ar
2. DBU, MeCN,
RT, 15 min
3. AcOH, H2O
RO2C
Ar
CO2R
4a k
N3
1a k
–
–
Scheme 4. One-pot synthesis of 1,6-dihydropyrimidines 4a–k from α-
azidocinnamates 1a–k.
Table 1. Isolated yields of 1,6-dihydropyrimidines 4a–k and pyrimidines 5a–k.
Ar
Ar
Entry Ar
R
Yield of 4,a % Yield of 5,b %
DDQ,
MeCN, RT, 10 min
N
N
N
NH
Ar
1
2
3
4
5
6
7
8
4-ClC6H4
4-BrC6H4
4-IC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
97 (4a)
93 (4b)
70 (4c)
91 (4d)
91 (4e)
91 (4f)
93 (4g)
94 (4h)
95 (4i)
73 (4j)
95 (5a)
95 (5b)
81 (5c)
90 (5d)
85 (5e)
85 (5f)
90 (5g)
90 (5h)
95 (5i)
94 (5j)
89 (5k)
or
RO2C
Ar
CO2R
5a k
RO2C
air, MeCN, RT, LED 455 nm
[Ru(bpy)3Cl2]×6H2O (2 mol %)
CO2R
4a k
2-MeOC6H4
4-MeOC6H4
2,4-Cl2C6H3
4-MeC6H4
4-FC6H4
4-CF3C6H4
naphthalen-2-yl
4-MeOC6H4
–
–
Scheme 5. Aromatization of 1,6-dihydropyrimidines 5a–k to pyrimidines 6a–k.
One-pot synthesis of pyrimidines from α-azidocinnamates.
One-pot reactions are highly valuable in organic synthesis.30 In
this work, a one-pot protocol for the synthesis of pyrimidines 5
from α-azidocinnamates was also developed (Scheme 6). In
particular, it was found that oxidation of dihydropyrimidines 4
to pyrimidines 5 by DDQ can be accomplished without
preliminary removal of DBU. The final one-pot procedure
consisted of photolysis of 1a in acetonitrile, successive
treatment with DBU and DDQ in the same solvent and in the
same vessel, followed by chromatographic purification. The
reaction was carried out on 20 and 850 mg scale and gave
pyrimidine 5a in 81–85% yield.
9
10
11
n-Bu 42 (4k)
a One-pot procedure from α-azidocinnamate 1. b From dihydropyrimidines 4
using DDQ.
Cl
1. LED 365 nm, RT, 2.5 h
2. DBU, RT, 15 min
3. DDQ, RT, 10 min
4. chromatographic
purification
CO2Me
N
N
N3
1a
Cl
MeO2C
MeO2C
Cl
5a,
(0.6 g, 81%)
85%
Figure 4. Molecular structures of 4d and 4f from single crystal X-ray analysis.
Scheme 6. One-pot synthesis of pyrimidine 5a from α-azidocinnamate 1a.
Oxidation of 1,6-dihydropyrimidines to pyrimidines. The
aromatization of 1,6-dihydropyrimidines 4a–k using 1 equiv. of
organic oxidant, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ), proceeded completely in less than ten minutes and led
to pyrimidines 5a–k, which were isolated by column
chromatography in 81–95% yields (Scheme 5, Table 1).
Pyrimidines 5a–k were characterized by high-resolution ESI+-
MS, 1H and 13C{1H} NMR spectroscopy.
Conclusion
The irradiation of α-azidocinnamates by blue light (455 nm)
leads to the formation of 2H-azirines only, while the irradiation
by violet (395 nm) or UV-A light (365 nm) results in the
transformation of the in situ formed 2H-azirines to 1,3-
4 | J. Name., 2012, 00, 1-3
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diazabicyclo[3.1.0]hexenes. Based on these results a one-pot (br s, 1H, NH), 7.27–7.33 (m, 6H, HAr), 7.64 (d, J = 8.5 Hz, 2H, HAr).
View Article Online
procedure
for
the
synthesis
of
tetrasubstituted 13C{1H} NMR (100 MHz, CDCl3, δ): 51.9, 5D2O.7I,: 1502.1.093,91/0D50.O2B,0102689.33A,
dihydropyrimidine and pyrimidine derivatives from α- 128.7, 128.9 (2C), 129.2, 131.2, 134.5, 138.4, 142.0, 149.0,
azidocinnamates was developed. The synthesis consists of the 157.0, 165.0, 168.1. HR ESI+-MS, m/z: [М+H]+ calcd for
+
following stages: (i) LED light induced formation of 1,3- C20H17N235Cl2O4 , 419.0560; found, 419.0581.
diazabicyclo[3.1.0]hex-3-enes, (ii) DBU-catalyzed isomerization
of 1,3-diazabicyclo[3.1.0]hex-3-enes to 1,6-dihydropyrimidines, Dimethyl 2,6-bis(4-bromophenyl)-1,6-dihydropyrimidine-4,5-
(iii) aromatization of 1,6-dihydropyrimidines using DDQ. A dicarboxylate (4b)
successful use of sunlight at the first stage, Cs2CO3 at the second
stage, and air at the third stage was also demonstrated.
Yellow oil (21 mg, yield 93%).1H NMR
(400 MHz, CDCl3, δ): 3.63 (s, 3H, CH3),
3.91 (s, 3H, CH3), 5.57 (s, 1H, CH), 6.72
(br s, 1H, NH), 7.26 (d, J = 8.2 Hz, 2H,
HAr), 7.47 (d, J = 8.2 Hz, 2H, HAr), 7.51 (d,
J = 8.4 Hz, 2H, HAr), 7.59 (d, J = 8.4 Hz,
2H, HAr). 13C{1H} NMR (100 MHz, CDCl3,
Br
N
NH
Experimental
MeO2C
MeO2C
Melting points were determined on a melting point apparatus
Br
1
SMP30. H (400 MHz) and 13C (100 MHz) NMR spectra were
δ): 52.0, 52.7, 53.1, 105.5, 122.9, 127.1, 128.6, 128.8, 131.6,
132.0, 132.3, 142.5, 148.9, 157.1, 164.9, 168.0. HR ESI+-MS, m/z:
recorded on a Bruker AVANCE 400 spectrometer in CDCl3.
Chemical shifts (δ) are reported in ppm downfield from
tetramethylsilane. Electrospray ionization (ESI) mass spectra
were measured on a Bruker MaXis mass spectrometer. Single
crystal X-ray data were collected by means of Agilent
Technologies SuperNova (Single source at offset/far,
HyPix3000), Agilent Technologies SuperNova (Dual, Cu at zero,
Atlas) and Agilent Technologies Xcalibur (Mo, Eos)
diffractometers. Crystallographic data for the structures 4d
(CCDC 1994004), 4f (CCDC 1994005) and 6 (CCDC 1994003)
have been deposited with the Cambridge Crystallographic Data
Centre. Thin-layer chromatography (TLC) was conducted on
aluminum sheets precoated with SiO2 ALUGRAM SIL G/UV254.
Column chromatography was performed on Macherey-Nagel
silica gel 60 M (0.04–0.063 mm). Acetonitrile was distilled from
P2O5 and stored over anhydrous K2CO3. Commercially available
DBU and DDQ were used. 1a,b,d–j were prepared by the
+
[М+H]+ calcd for C20H17N279Br81BrO4 , 508.9530; found,
508.9522.
Dimethyl
2,6-bis(4-iodophenyl)-1,6-dihydropyrimidine-4,5-
dicarboxylate (4c)
Yellow solid (16 mg, yield 70%), mp 170–
171 °C. 1H NMR (400 MHz, CDCl3, δ): 3.63
(s, 3H, CH3), 3.90 (s, 3H, CH3), 5.55 (s, 1H,
CH), 6.71 (br s, 1H, NH), 7.12 (d, J = 8.4
Hz, 2H, HAr), 7.44 (d, J = 8.4 Hz, 2H, HAr),
7.67 (d, J = 8.4 Hz, 2H, HAr), 7.72 (d,
J = 8.4 Hz, 2H, HAr). 13C{1H} NMR (100
I
N
NH
MeO2C
MeO2C
I
MHz, CDCl3, δ): 52.0, 52.7, 53.4, 94.5, 99.3, 105.5, 128.7, 128.8,
132.2, 137.9, 138.2, 143.1, 148.9, 157.2, 165.0, 168.0. HR ESI+-
MS, m/z: [М+H]+ calcd for C20H17I2N2O4 , 602.9273; found,
+
reported procedure.15c Their spectral data matched that
602.9272.
15d, 15g
reported in the literature.15c,
Spectral data for α-
Dimethyl 2,6-bis(2-methoxyphenyl)-1,6-dihydropyrimidine-
4,5-dicarboxylate (4d)
azidocinnamates 1c,k, azirines 2a–g, 1,3-diazabicyclo[3.1.0]hex-
3-enes 3a,b and compound 6 are included in the SI (sections S2
and S7).
Yellow solid (20 mg, yield 91%), mp 190–
191 °C. 1H NMR (400 MHz, CDCl3, δ): 3.65
(s, 3H, CH3), 3.85 (s, 3H, CH3), 3.98 (s, 6H,
CH3), 6.01 (s, 1H, CH), 6.88–7.02 (m, 4H,
HAr), 7.24–7.41 (m, 3H, HAr), 8.32–8.36
(m, 1H, HAr), 8.74 (br s, 1H, NH). 13C{1H}
MeO
General procedure for the synthesis of dihydropyrimidines 4a–k
Azidocinnamate 1 (25 mg, 0.076–0.114 mmol) was dissolved in
MeCN (0.7 mL) in an NMR tube or a Pyrex screw cap tube. The
solution was purged by argon for 5–10 min and then irradiated
with 365 nm LED (3W, the LED was placed opposite to the
solution at a distance of 2 cm from the tube) at RT under stirring
for 2.5–14 h (control by TLC). After that, DBU (2.5 μL, 0.3 equiv)
was added, and the reaction mixture was stirred at RT for 15
min. The reaction mixture was poured into water (3 mL)
acidified with AcOH (3 μL). Product 4 was extracted with EtOAc
(2×2 mL) and dried with Na2SO4. The solvent was removed on a
rotary evaporator, and the product was purified by column
chromatography on silica gel (PE – EtOAc, 3 : 1).
N
NH OMe
MeO2C
MeO2C
NMR (100 MHz, CDCl3, δ): 48.8, 51.6, 52.5, 55.4, 56.0, 99.8,
110.4, 111.6, 120.2, 121.1, 121.4, 127.8, 129.1, 130.0, 132.2,
133.0, 152.2, 156.1, 157.8, 158.0, 165.6, 168.6. HR ESI+-MS, m/z:
[М+H]+ calcd for C22H23N2O6 , 411.1551; found, 411.1551.
+
Dimethyl 2,6-bis(4-methoxyphenyl)-1,6-dihydropyrimidine-
4,5-dicarboxylate (4e)
OMe
Yellow oil (20 mg, yield 91%). 1H NMR
(400 MHz, CDCl3, δ): 3.64 (s, 3H, CH3),
3.79 (s, 3H, CH3), 3.83 (s, 3H, CH3), 3.92
(s, 3H, CH3), 5.56 (s, 1H, CH), 6.35 (br
s, 1H, NH), 6.86 (d, J = 8.7 Hz, 2H, HAr),
6.89 (d, J = 8.9 Hz, 2H, HAr), 7.34 (d,
J = 8.7 Hz, 2H, HAr), 7.72 (d, J = 8.9 Hz,
Dimethyl 2,6-bis(4-chlorophenyl)-1,6-dihydropyrimidine-4,5-
dicarboxylate (4a)
N
NH
MeO2C
MeO2C
1
Yellow oil (21 mg, yield 97%). H NMR
Cl
OMe
(400 MHz, CDCl3, δ): 3.61 (s, 3H, CH3),
3.89 (s, 3H, CH3), 5.56 (s, 1H, CH), 7.04
2H, HAr). 13C{1H} NMR (100 MHz, CDCl3, δ): 51.6, 52.4, 52.9, 55.2,
N
NH
MeO2C
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
MeO2C
Cl
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Journal Name
55.3, 104.9, 113.9, 114.2, 125.3, 128.1, 129.1, 136.5, 149, 157.4, (one signal of CF3 group is not observed). 19F{1H} NMR (377 MHz,
View Article Online
159.6, 162.6, 165.4, 168.3. HR ESI+-MS, m/z: [М+H]+ calcd for CDCl3, δ): –63.10, –62.73. HR ESI+-MS, DmO/I:z1:0[.1М03+9H/D]+0OcaBl0c0d69f3oAr
+
+
C22H23N2O6 , 411.1551; found, 411.1571.
C22H17N2F6O4 , 487.1087; found, 487.1090.
Dimethyl 2,6-bis(2,4-dichlorophenyl)-1,6-dihydropyrimidine- Dimethyl 2,6-bis(naphthalen-2-yl)-1,6-dihydropyrimidine-4,5-
4,5-dicarboxylate (4f)
dicarboxylate (4j)
Yellow solid (21 mg, yield 94%), mp Yellow low-melting solid (16 mg, yield 73%). 1H NMR (400 MHz,
Cl
140–142 °C. 1H NMR (400 MHz, CDCl3,
δ): 3.66 (s, 3H, CH3), 3.94 (s, 3H, CH3),
6.08 (s, 1H, CH), 6.90 (br s, 1H, NH),
7.26–7.34 (m, 3H, HAr), 7.41–7.45 (m,
2H, HAr), 7.66 (d, J = 8.6 Hz, 1H, HAr).
13C{1H} NMR (100 MHz, CDCl3, δ): 49.4,
CDCl3, δ): 3.61 (s, 3H, CH3), 3.96 (s, 3H,
CH3), 5.81 (s, 1H, CH), 6.95 (br s, 1H,
NH), 7.45–7.56 (m, 4H, HAr), 7.61 (d,
J = 8.4 Hz, 1H, HAr), 7.75–7.86 (m, 8H,
HAr), 8.21 (s, 1H, HAr). 13C{1H} NMR
(100 MHz, CDCl3, δ): 51.8, 52.6, 54.0,
105.4, 123.7, 124.8, 125.9, 126.3 (2C),
Cl
N
NH Cl
N
NH
MeO2C
MeO2C
MeO2C
MeO2C
Cl
52.2, 52.8, 103.4, 127.7, 128.3, 129.7, 130.26, 130.34, 130.5,
132.5, 132.7, 132.9, 135.3, 136.5, 138.1, 150.4, 156.8, 164.5, 126.7, 127.6, 127.7, 127.9 (2C), 128.3, 128.5, 128.9, 129.2,
+
167.3. HR ESI+-MS, m/z: [М+H]+ calcd for C20H15N235Cl337ClO4 , 130.2, 132.5, 133.26, 133.30, 134.9, 141.1, 149.3, 158.1, 165.3,
+
488.9751; found, 488.9750.
168.3. HR ESI+-MS, m/z: [М+H]+ calcd for C28H23N2O4 , 451.1652;
found, 451.1647.
Dimethyl 2,6-bis(4-methylphenyl)-1,6-dihydropyrimidine-4,5-
dicarboxylate (4g)
Dibutyl 2,6-bis(4-methoxyphenyl)-1,6-dihydropyrimidine-4,5-
Me
Yellow solid (20 mg, yield 93%), mp 98– dicarboxylate (4k)
1
1
100 °C. H NMR (400 MHz, CDCl3, δ):
OMe
Yellow oil (9 mg, yield 42%). H NMR
(400 MHz, CDCl3, δ): 0.88 (t, J = 7.4 Hz,
3H, Bu), 0.98 (t, J = 7.4 Hz, 3H, Bu),
1.23–1.32 (m, 4H, Bu), 1.42–1.57 (m,
4H, Bu), 1.73–1.80 (m, 2H, Bu), 3.80 (s,
3H, OCH3), 3.84 (s, 3H, OCH3), 3.98–
4.11 (m, 2H, OCH2), 4.26–4.38 (m, 2H,
2.32 (s, 3H, CH3), 2.37 (s, 3H, CH3), 3.62
(s, 3H, CH3), 3.90 (s, 3H, CH3), 5.57 (s,
1H, CH), 6.55 (br s, 1H, NH), 7.13 (d,
J = 8.1 Hz, 2H, HAr), 7.17 (d, J = 8.1 Hz,
2H, HAr), 7.30 (d, J = 8.1 Hz, 2H, HAr),
N
NH
N
NH
MeO2C
MeO2C
BuO2C
BuO2C
Me
7.63 (d, J = 8.1 Hz, 2H, HAr). 13C{1H} NMR (100 MHz, CDCl3, δ):
OMe
21.1, 21.5, 51.7, 52.5, 53.4, 105.5, 126.9, 127.2, 129.4, 129.6, OCH2), 5.57 (s, 1H, CH), 6.36 (br s, 1H, NH), 6.85–6.92 (m, 4H,
130.3, 138.3, 141.1, 142.6, 149.3, 157.9, 165.4, 168.3. HR ESI+- HAr), 7.36 (d, J = 8.3 Hz, 2H, HAr), 7.72 (d, J = 8.7 Hz, 2H, HAr).
MS, m/z: [М+H]+ calcd for C22H23N2O4 , 379.1652; found, 13C{1H} NMR (100 MHz, CDCl3, δ): 13.6, 13.7, 19.0, 19.1, 30.4,
+
379.1677.
30.5, 53.1, 55.2, 55.4, 64.4, 65.5, 105.1, 113.9, 114.2, 125.6,
128.3, 129.1, 136.7, 149.3, 157.0, 159.6, 162.6, 165.1, 168.1. HR
+
Dimethyl 2,6-bis(4-fluorophenyl)-1,6-dihydropyrimidine-4,5- ESI+-MS, m/z: [М+H]+ calcd for C28H35N2O6 , 495.2490; found,
dicarboxylate (4h)
495.2484.
1
F
Yellow oil (20 mg, yield 94%). H NMR
(400 MHz, CDCl3, δ): 3.64 (s, 3H, CH3), General procedure for the synthesis of pyrimidines 5a–k
3.91 (s, 3H, CH3), 5.61 (s, 1H, CH), 6.62 To a solution of 4 (0.018–0.053 mmol) in EtOAc (1 mL) DDQ (1
(br s, 1H, NH), 7.00–7.09 (m, 4H, HAr), equiv.) was added. The reaction mixture was stirred at RT for 10
7.36–7.39 (m, 2H, HAr), 7.73–7.76 (m, 2H, min, EtOAc was evaporated, and the product was purified by
HAr). 13C{1H,19F} NMR (100 MHz, CDCl3, column chromatography on silica gel (PE – EtOAc, 10 : 1).
δ): 51.8, 52.6, 52.8, 105.3, 115.8, 115.9,
N
NH
MeO2C
MeO2C
F
128.6, 129.0, 129.6, 139.6, 149.0, 157.0, 162.7, 165.1 (2C), Dimethyl 2,6-bis(4-chlorophenyl)pyrimidine-4,5-dicarboxylate
+
168.2. HR ESI+-MS, m/z: [М+H]+ calcd for C20H17N2F2O4 , (5a)
387.1151; found, 387.1163.
Cl
Colorless solid (20 mg, yield 95%), mp
125–126 °C. H NMR (400 MHz, CDCl3,
1
Dimethyl
2,6-bis(4-(trifluoromethyl)phenyl)-1,6-
δ): 3.85 (s, 3H, CH3), 4.06 (s, 3H, CH3),
7.47–7.52 (m, 4H, HAr), 7.75 (d, J = 8.7
Hz, 2H, HAr), 8.52 (d, J = 8.7 Hz, 2H, HAr).
13C{1H} NMR (100 MHz, CDCl3, δ): 53.2,
53.6, 123.0, 129.01, 129.04, 130.0,
dihydropyrimidine-4,5-dicarboxylate (4i)
N
N
CF3
Yellow low-melting solid (21 mg, yield
95%). 1H NMR (400 MHz, CDCl3, δ):
3.67 (s, 3H, CH3), 3.94 (s, 3H, CH3), 5.75
MeO2C
MeO2C
Cl
(s, 1H, CH), 6.78 (br s, 1H, NH), 7.55 (d, 130.3, 134.5, 135.3, 137.3, 138.3, 155.2, 156.4, 163.8, 164.4,
N
NH
+
J = 8.1 Hz, 2H, HAr), 7.61–7.69 (m, 4H, 167.0. HR ESI+-MS, m/z: [М+Na]+ calcd for C20H14N235Cl2NaO4 ,
MeO2C
MeO2C
HAr), 7.89 (d, J = 8.3 Hz, 2H, HAr). 439.0223; found, 439.0245.
13C{1H} NMR (100 MHz, CDCl3, δ): 52.1,
CF3
52.8, 53.2, 105.7, 123.5 (q, J = 273 Hz), 125.7, 126.2, 127.3, Dimethyl
2,6-bis(4-bromophenyl)pyrimidine-4,5-
127.7, 133.7, 134.0, 135.9, 146.9, 148.8, 156.8, 164.7, 167.9 dicarboxylate (5b)
6 | J. Name., 2012, 00, 1-3
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Br
Colorless solid (20 mg, yield 95%), mp 3H, HAr), 7.52–7.55 (m, 2H, HAr), 7.88 (d, J = 8.4 VHiezw,A1rtiHcle, OHnAlirn)e.
1
135–136 °C. H NMR (400 MHz, CDCl3, 13C{1H} NMR (100 MHz, CDCl3, δ): 53.D2O, I5: 130..710, 3192/D30.5O,B0102679.34A,
δ): 3.85 (s, 3H, CH3), 4.06 (s, 3H, CH3), 128.8, 129.7, 130.8, 130.9, 131.2, 133.15, 133.24, 134.2, 134.29,
7.64–7.69 (m, 6H, HAr), 8.44 (d, J = 8.6 134.32, 136.6, 137.1, 156.4, 164.4, 164.6, 164.9. HR ESI+-MS,
N
N
+
Hz, 2H, HAr). 13C{1H} NMR (100 MHz, m/z: [М+Na]+ C20H12N235Cl4NaO4 , 508.9414; found, 508.9401.
MeO2C
MeO2C
CDCl3, δ): 53.2, 53.6, 123.1, 125.7,
127.0, 130.2, 130.4, 131.98, 132.00, Dimethyl
Br
2,6-bis(4-methylphenyl)pyrimidine-4,5-
134.9, 135.7, 155.3, 163.9, 164.5, 164.7, 167.0. HR ESI+-MS, m/z: dicarboxylate (5g)
[М+Na]+ calcd for C20H14N279Br81BrNaO4 , 528.9193; found,
528.9191.
+
Me
Yellow solid (18 mg, yield 90%), mp
100–101 °C. 1H NMR (400 MHz, CDCl3,
δ): 2.45 (s, 3H, CH3), 3.84 (s, 3H, CH3),
4.05 (s, 3H, CH3), 7.32 (d, J = 8.1 Hz, 4H,
HAr), 7.72 (d, J = 8.1 Hz, 2H, HAr), 8.48
(d, J = 8.1 Hz, 2H, HAr). 13C{1H} NMR
(100 MHz, CDCl3, δ): 21.5, 21.6, 52.9,
Dimethyl
2,6-bis(4-iodophenyl)-1,6-dihydropyrimidine-4,5-
N
N
dicarboxylate (5c)
I
MeO2C
MeO2C
Yellow solid (13 mg, yield 81%), mp
1
140–141 °C. H NMR (400 MHz, CDCl3,
Me
δ): 3.85 (s, 3H, CH3), 4.05 (s, 3H, CH3), 53.4, 122.4, 128.6, 128.9, 129.4 (2C), 133.6, 134.3, 141.0, 142.2,
7.52 (d, J = 8.4 Hz, 2H, HAr), 7.84–7.89 154.9, 164.6, 165.1, 165.3, 167.6. HR ESI+-MS, m/z: [М+Na]+
(m, 4H, HAr), 8.28 (d, J = 8.4 Hz, 2H, HAr). calcd for C22H20N2NaO4 , 399.1315; found, 399.1331.
13C{1H} NMR (100 MHz, CDCl3, δ): 53.2,
N
N
+
MeO2C
MeO2C
53.6, 97.9, 99.5, 123.1, 130.2, 130.4, Dimethyl 2,6-bis(4-fluorophenyl)pyrimidine-4,5-dicarboxylate
I
135.5, 136.3, 137.95, 137.99, 155.3, 164.1, 164.60, 164.63, (5h)
+
167.0. HR ESI+-MS, m/z: [М+Na]+ calcd for C20H14N2I2NaO4 ,
Colorless solid (18 mg, yield 90%), mp
103–104 °C. H NMR (400 MHz, CDCl3,
F
1
622.8935; found, 622.8964.
δ): 3.85 (s, 3H, CH3), 4.06 (s, 3H, CH3),
7.17–7.24 (m, 4H, HAr), 7.80–7.83 (m,
2H, HAr), 8.58–8.61 (m, 2H, HAr). 13C{1H}
NMR (100 MHz, CDCl3, δ): 53.1, 53.5,
115.8, 115.9, 122.7, 130.9, 131.2, 132.2,
Dimethyl
dicarboxylate (5d)
2,6-bis(2-methoxyphenyl)pyrimidine-4,5-
N
N
MeO2C
MeO2C
Yellow solid (18 mg, yield 90%), mp 140–
141 °C. 1H NMR (400 MHz, CDCl3, δ): 3.74
F
MeO
(s, 3H, CH3), 3.76 (s, 3H, CH3), 3.89 (s, 3H, 133.0, 155.1, 163.7, 164.37, 164.41, 164.8, 165.4, 167.2. HR
N
N
OMe
+
CH3), 4.01 (s, 3H, CH3), 6.93 (d, J = 8.2 Hz, ESI+-MS, m/z: [М+Na]+ calcd for C20H14N2F2NaO4 , 407.0814;
MeO2C
MeO2C
1H, HAr), 7.01–7.14 (m, 3H, HAr), 7.41– found, 407.0816.
7.47 (m, 2H, HAr), 7.67–7.69 (m, 1H, HAr),
7.81–7.83 (m, 1H, HAr). 13C{1H} NMR (100 MHz, CDCl3, δ): 52.4, Dimethyl 2,6-bis(4-(trifluoromethyl)phenyl)pyrimidine-4,5-
53.3, 55.1, 56.1, 110.4, 112.3, 120.7, 121.2, 122.3, 126.5, 127.4, dicarboxylate (5i)
131.2, 131.7, 131.8, 131.9, 156.47, 156.53, 158.1, 164.1, 165.8,
Colorless solid (20 mg, yield 95%),
mp 119–122 °C. 1H NMR (400 MHz,
CDCl3, δ): 3.87 (s, 3H, CH3), 4.10 (s,
3H, CH3), 7.78–7.84 (m, 4H, HAr),
7.93 (d, J = 8.4 Hz, 2H, HAr), 8.71 (d,
J = 8.2 Hz, 2H, HAr). 13C{1H} NMR
(100 MHz, CDCl3, δ): 53.3, 53.7,
123.7 (q, J = 273 Hz), 123.9 (q, J =
CF3
166.1, 166.3. HR ESI+-MS, m/z: [М+Na]+ calcd for
+
C22H20N2NaO6 , 431.1214; found, 431.1213.
Dimethyl
2,6-bis(4-methoxyphenyl)pyrimidine-4,5-
N
N
dicarboxylate (5e)
MeO2C
MeO2C
OMe
Colorless solid (17 mg, yield 85%), mp
162–163 °C. 1H NMR (400 MHz,
CF3
CDCl3, δ): 3.85 (s, 3H, CH3), 3.89 (s, 273 Hz), 123.93, 125.7 (2C), 129.1, 129.3, 132.7 (q, J = 32.9 Hz),
3H, CH3), 3.90 (s, 3H, CH3), 4.04 (s, 3H, 133.5 (q, J = 32.5 Hz), 139.0, 140.1, 155.4, 163.5, 164.44, 164.46,
CH3), 7.00–7.03 (m, 4H, HAr), 7.81 (d, 166.6. 19F{1H} NMR (377 MHz, CDCl3, δ): –62.94, –62.93. HR ESI+-
N
N
MeO2C
MeO2C
+
J = 8.9 Hz, 2H, HAr), 8.54 (d, J = 8.9 Hz, MS, m/z: [М+Na]+ calcd for C22H14N2F6NaO4 , 507.0750; found,
2H, HAr). 13C{1H} NMR (100 MHz, 507.0753.
OMe
CDCl3, δ): 52.9, 53.4, 55.4 (2C), 114.0, 114.1, 121.5, 129.0, 129.5,
130.4, 130.7, 155.0, 161.8, 162.7, 164.2, 164.6, 165.2, 167.9. HR Dimethyl 2,6-bis(napthalen-2-yl)pyrimidine-4,5-dicarboxylate
+
ESI+-MS, m/z: [М+Na]+ calcd for C22H20N2NaO6 , 431.1214; (5j)
found, 431.1224.
Colorless solid (15 mg, yield 94%), mp
111–114 °C. 1H NMR (400 MHz,
CDCl3, δ): 3.86 (s, 3H, CH3), 4.13 (s,
3H, CH3), 7.54–7.66 (m, 4H, HAr),
7.92–8.08 (m, 7H, HAr), 8.39 (s, 1H,
HAr), 8.72 (dd, J = 4.3 Hz, 1.7 Hz, 1H,
HAr), 9.20 (s, 1H, HAr). 13C{1H} NMR
Dimethyl
dicarboxylate (5f)
2,6-bis(2,4-dichlorophenyl)pyrimidine-4,5-
N
N
Yellow low-melting solid (18 mg, yield
85%). 1H NMR (400 MHz, CDCl3, δ): 3.77
(s, 3H, CH3), 4.05 (s, 3H), 7.38–7.44 (m,
Cl
MeO2C
MeO2C
Cl
N
N
Cl
MeO2C
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
MeO2C
Cl
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(100 MHz, CDCl3, δ): 53.0, 53.5, 123.1, 125.3, 125.4, 126.4,
126.8, 127.6, 127.7, 127.8, 128.4, 128.5, 128.9, 129.2, 129.5,
129.8, 133.0, 133.2, 133.6, 134.2, 134.4, 135.2, 155.2, 164.7,
165.1, 165.5, 167.5. HR ESI+-MS, m/z: [М+Na]+ calcd for
Notes and references
View Article Online
1. (a) I. M. Lagoja, Chem. Biodivers.,DO20I:0150.,1023,9/D10–O5B00. 06D9О3IA:
10.1002/cbdv.200490173; (b) S. Kumar and B. Narasimhan,
Chem. Cent. J., 2018, 12, 38. DОI: 10.1186/s13065-018-0406-
5; (c) V. Sharma, N. Chitranshi and A. K. Agarwal, Int. J. Med.
Chem., 2014, 2014, 31. DОI: 10.1155/2014/202784.
+
C28H20N2NaO4 , 471.1315; found, 471.1302.
Di-n-butyl
2,6-bis(4-methoxyphenyl)pyrimidine-4,5-
2. (a) A. R. Gholap, K. S. Toti, F. Shirazi, M. V. Deshpande and K.
V. Srinivasan, Tetrahedron, 2008, 64, 10214–10223. DОI:
10.1016/j.tet.2008.08.033; (b) M. B. Deshmukh, S. M.
Salunkhe, D. R. Patil and P. V. Anbhule, Eur. J. Med. Chem.,
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dicarboxylate (5k)
Colorless solid (8 mg, yield 89%),
mp 49–52 °C. H NMR (400 MHz,
OMe
1
CDCl3, δ): 0.87 (t, J = 7.4 Hz, 3H,
Bu), 1.02 (t, J = 7.4 Hz, 3H, Bu),
1.18–1.26 (m, 2H, Bu), 1.48–1.61
(m, 4H, Bu), 1.79–1.86 (m, 2H, Bu),
3.90 (s, 3H, OCH3), 3.91 (s, 3H,
N
N
BuO2C
BuO2C
OMe
OCH3), 4.24 (t, J = 6.6 Hz, 2H,
OCH2), 4.45 (t, J = 6.7 Hz, 2H, OCH2), 7.02 (d, J = 8.8 Hz, 4H, HAr),
7.80 (d, J = 8.8 Hz, 2H, HAr), 8.56 (d, J = 8.8 Hz, 2H, HAr). 13C{1H}
NMR (100 MHz, CDCl3, δ): 13.6, 13.7, 18.9, 19.1, 30.2, 30.5, 55.4
(2C), 66.0, 66.5, 113.9, 114.0, 121.6, 129.1, 129.8, 130.4, 130.7,
155.7, 161.6, 162.6, 164.0, 164.7, 165.0, 167.4. HR ESI+-MS, m/z:
[М+Na]+ calcd for C28H32N2NaO6 , 515.2153; found, 515.2148.
+
One-pot procedure for the synthesis of pyrimidine 5a
Azidocinnamate 1a (20 mg, 0.084 mmol) was dissolved in MeCN
(0.5 mL) in an NMR tube. The solution was purged with argon
for 10 min and then irradiated with 365 nm LED (3W, the LED
was placed opposite to the solution at a distance of 2 cm from
the tube) at RT under stirring for 2.5 h (control by TLC). Then,
DBU (13 mg of 10% solution in MeCN (8.5 μmol)) was added,
and the reaction mixture was stirred at RT for 15 min. After the
reaction completion (control by TLC), DDQ (9.5 mg, 0.042 mmol)
was added. After 10 min stirring at RT, the reaction mixture was
poured into water (3 mL) acidified with AcOH (3 μL). The
product was extracted with EtOAc (3×2 mL), organic layers were
washed with 5% NaHCO3 (3×1 mL) and dried with Na2SO4. The
drying agent was filtered off, the solvent was removed on a
rotary evaporator, and the product was purified by column
chromatography on silica gel (PE – EtOAc, 3 : 1) to give 5a (15
mg, yield 85%). According to this protocol (LED 395 nm, 30 W,
2.5 h, in a Pyrex tube), using proportional amounts of reagents
and solvents, the reaction of 850 mg of 1a was carried out to
give 605 mg (yield 81%) of pyrimidine 5a.
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Acknowledgements
We gratefully acknowledge the financial support of the Russian
Science Foundation (№ 19-73-10090). This research used
resources of the Magnetic Resonance Research Centre,
Chemical Analysis and Materials Research Centre, Centre for X-
ray Diffraction Studies, and Chemistry Educational Centre of the
Research Park of St. Petersburg State University.
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8 | J. Name., 2012, 00, 1-3
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Page 11 of 11
Organic & Biomolecular Chemistry
one-pot (1. 2. 3.)
View Article Online
DOI: 10.1039/D0OB00693A
1. LED 365 nm
or sunlight
2. base
Ar
Ar
HN
N
3. [Ox]
N
N
N3
Ar
Ar
CO2R
CO2R
Ar
CO2R
CO2R
CO2R
11 examples
11 examples
yields up to 97%
yields up to 97%
A one-pot synthesis of tetrasubstituted dihydropyrimidine and pyrimidine derivatives was developed on
the basis of UV-LED photolysis of α-azidocinnamates as a key stage.