Pericyclic reactions in the synthesis of new 5-aryl-5,6-dihydroquinolino[2,1-b]quinazolin-12-ones

Article abstract of DOI:10.1016/j.mencom.2019.03.004

Novel tetracyclic 5-aryl-5,6-dihydroquinolino[2,1-b]quinazolin-12-ones bearing benzo-15-crown-5 ether and dimethoxyphenyl moieties were prepared by one-pot cascade synthesis involving the thermally allowed pericyclic transformations of (E)-2-(2-methoxystyryl)quinazolinones. The pseudocyclic transition state of six-electron electrocyclization has been located and the activation barrier has been estimated by RHF/3-21G and 6-311G* calculation methods. The crystal structure of N-[4-(2,3-dimethoxy-12-oxo-5,6-dihydroquinolino[2,1-b]quinazolin-5-yl)-3-methoxyphenyl]acetamide was determined by X-ray diffraction analysis.

Full text of DOI:10.1016/j.mencom.2019.03.004

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 135–137
Pericyclic reactions in the synthesis of new
5-aryl-5,6-dihydroquinolino[2,1-b]quinazolin-12-ones
Irina G. Ovchinnikova,*a Grigory A. Kim,a Eugeniya G. Matochkina,a Mikhail I. Kodess,a,b
Emiliya V. Nosova,b Gennady L. Rusinova,b and Valery N. Charushina,b
a I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
620990 Ekaterinburg, Russian Federation. Fax: +7 343 369 3058; e-mail: iov@ios.uran.ru
b Ural Federal University, 620002 Ekaterinburg, Russian Federation
DOI: 10.1016/j.mencom.2019.03.004
Novel tetracyclic 5-aryl-5,6-dihydroquinolino[2,1-b]quinazolin-
12-ones bearing benzo-15-crown-5 ether and dimethoxy-
phenyl moieties were prepared by one-pot cascade synthesis
involving the thermally allowed pericyclic transformations
of (E)-2-(2-methoxystyryl)quinazolinones. The pseudocyclic
transition state of six-electron electrocyclization has been
located and the activation barrier has been estimated by
RHF/3-21G and 6-311G* calculation methods. The crystal
structure of N-[4-(2,3-dimethoxy-12-oxo-5,6-dihydroquinolino-
[2,1-b]quinazolin-5-yl)-3-methoxyphenyl]acetamide was deter-
mined by X-ray diffraction analysis.
OR
OR
OR
NHAc
CHO
O
N
OR
+
O
N
N
N
OMe
Me
MeO
NHAc
A six-electron electrocyclization1,2 of aryl polyenes with cis-1,3,5-
triene moiety represents one of the most popular methods for the
synthesis of polycyclic aromatic and heteroaromatic structures.
Diarylethylenes (stilbenes,3 distyrylbenzenes,4,5 2,2'-divinyl-
biphenyls,6 etc.) and related heteroaromatic compounds7–9
demonstrate a photochemical conrotatory electrocyclization.
Natural10 and biomimetic aryl-containing11 hexatrienes are prone
to thermal disrotatory electrocyclization. Usually, these trans-
formations are carried out in tandem with subsequent reactions
of oxidation,3 elimination12 or rearrangement.11,13 Recently, we
reported a convenient synthesis of (E)-2-(2-hydroxystyryl)-
quinazolinones.14 Our research has shown that the incorporation
of hydroxyl group in the styryl fragment of these compounds
promotes a reversible photo/thermal E–Z–E isomerization in
solutions. In the continuation of our studies on influence of
various electron-donating substituents on luminescent properties
of styrylquinazolinones, we explored the interaction of 2-methyl-
quinazolin-4(3H)-ones 1a,b with 4-acetamido-2-methoxybenz-
aldehyde in accordance with the earlier reported protocol14
(Scheme 1).
When heating substrates 1a/1b with the aldehyde for the
first six hours, formation of E-styrylquinazolinone of type A
(Scheme 2) was observed in the reaction mixture, according to
1
UV-TLC monitoring. Moreover, H NMR monitoring of the
reaction mixture revealed doublets of vicinal protons of vinylene
C=C bonds14 in the range of ~7.96 and ~6.56 ppm with the spin–
spin coupling constant of 15.6 Hz (see Online Supplementary
Materials). In the case of substrate 1a, the corresponding olefin A
was isolated and characterized. Further refluxing of the reaction
mixture (up to 180 h) afforded compounds 2a and 2b, whereas
intermediate A disappeared almost completely. The polycyclic
OR
O
OR
i
O
N
ii
O
2a,b
68–73%
51–54%
N
N
Me
1
structures 2 were proven by H and 13C NMR signals assigned
using 2D 1H-1H COSY, 1H-13C HSQC, and HMBC experiments.
In particular, the formation of the dihydropyridine ring was
confirmed by typical ABX spin system of the H6A/H16A, H6B/H16B
Me
1a,b
6
5
O
a R = Me
b R + R = (CH2CH2O)3CH2CH2
O
8
9
3
1
and H5/H15 protons of compounds 2a/2b in H NMR spectra.
2
O
11
Moreover, cross-peaks between H5/H15 or H4/H14 protons and
C4/C14 or C5/C15 carbon atoms were observed in their 2D 1H-13C
HMBC spectra, respectively (see Scheme 1). The structure of 2a
was ultimately proved by X-ray diffraction method (Figure 1).†
O
24a
OMe
2
12
O
OMe
3
1
24
O
O
13a
11
21
14a
13
14
11a
7a
23
N
4
21a
22
12
13a
10
9
13a
6
20
19
N
4a
5
5'
2'
5'
2'
15
7
4'
4'
6a
6'
1'
6'
1'
17a
16a
N
N
16
18
8
†
17
Crystal data for 2a (solvate). C27H25N3O5 ·C2H3N (M = 512.55),
–
3'
3'
MeO
NHAc
triclinic, space group P1, a = 9.441(6), b = 9.858(9) and c = 14.926(15) Å,
MeO
NHAc
a = 96.75(8)°, b = 106.55(7)°, g = 103.20(7)°, V = 1271.3(19) Å3, Z = 2,
m = 0.761 cm–1, dcalc = 1.339 g cm–3; 27546 reflections measured with an
Xcalibur 3 automated diffractometer (MoKa radiation, l = 0.71073 Å,
graphite monochromator, w-scan technique, with a 1° step) at 295(2) K
2b
2a
Scheme 1 Reagents and conditions: i, 3,4-(RO)2C6H3NH2, C5H5N, D;
ii, 2-MeO-4-AcNHC6H3CHO, H3BO3, AcOH, D.
© 2019 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
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Mendeleev Commun., 2019, 29, 135–137
Woodward–Hoffmann rules.1 Quantum mechanical calculations of
OMe
OMe
distance (r) between the terminal carbon atoms in such pseudo-
cycles15 is estimated at ~2.24 Å. Considering the m-symmetry1
of highest occupied molecular orbital (HOMO) for 6p electron
system of intermediate TS, the disrotatory electrocyclization of
E-isomer is to produce the syn configuration of the hydrogen atoms
in intermediate D. The following [1,5]-hydrogen suprafacial shift
allowed by symmetry leads to intermediate E (see Scheme 2).
To identify the geometry of the transition state and to assess
the activation barrier (Ea/kcal mol–1), we carried out a study of
the disrotatory electrocyclization mechanism for the triethoxy-
substituted E-styrylquinazolinone. The stationary points on the
chemical reaction energy curve have been located using Orca 4.0.1
program complex with Restricted Hartree–Fock theory calcula-
tions and the 3-21G and 6-311G* basis sets.16–19 The optimized
structures were proved by the absence of imaginary frequencies in
Hessian, and the TS – by the presence of one imaginary frequency.
The optimized structures of located intermediates B, C, D, E
and transition states TS, TS-D/E and their relative energy values
are given in Table S1 (see Online Supplementary Materials).
Two possible original conformations of E-styrylquinazolinone are
represented by structures B and C (see Table S1). The conformer
C is 7.39 kcal mol–1 higher in energy than the conformer B.
However, the higher-energy conformer C is characterized by a
closer distance (r) between the reaction centers C(b) and C(14),
3.4 Å, and can be considered as the initial coordinate of the
electrocyclization reaction (Figure 2, see Table S1). The transition
state TS was determined through analysis of the reaction
pathway points C®D obtained by the above methods. It was
established that the pseudocyclic 6p electron system becomes
more planar with the reaction coordinate (r) decreasing due to the
disrotatory movement of the terminal bonds C(a)=C(b) and
C(9)=C(14), which is expressed by changing the values of torsion
angles (see Scheme 2, Figure 2, Table S1). The disrotatory
transition structure TS has a boat-like conformation of the
forming six-membered ring and a close interaction distance r
equal to 2.09 Å. A boat-like conformation is characterized by
lower steric repulsions between the inward hydrogen atoms and
provides almost perfect eclipsing between the atoms C(b) and
C(14). However, the inclusion of (hetero)aromatic rings in the
p-system of TS, along with a bulky substituent, leads to the more
significant geometric deformations of pseudocyclic conformation
and subsequently to an increase in the activation energy.15 The
energy barrier required for the formation of the calculated inter-
O
[H+]
[H+]
3 N
1
+
1a,b
ArCHO
H
– H2O
N
Ar
H
Ar = 2-MeO-4-AcNHC6H3
OMe
OMe
A
OMe
OMe
9
OH
N
OH
N
14
r
3
2
N
N
Ar
Ar
B
C
OMe
Ar
OMe
H
OMe
OMe
OH
N
OH
N
H
N
N
Ar
TS
OMe
OMe
OMe
H
OMe
OH
OH
N
4a
N
H
2a,b
H
N
N
6
Ar
H
H
Ar
D
E
Scheme 2
The formation of compounds 2a,b can be explained by thermally
allowed pericyclic transformations of E-styrylquinazolinone A
generated in situ in the reaction medium (see Scheme 2). The
protonation of the keto group of the pyrimidinone ring in AcOH
solution is able to initiate both the formation of the enol form B and
the involvement of the n-orbital2 of the atom N(3) to the p-electron
conjugated system of this heterocycle. As a result, the C=N bond
of the aromatic pyrimidinium tautomer C together with the two
spatially approaching C=C bonds of the terminal vinylene and aryl
groups provide suitable pre-requisites for the emergence of six-
electron pseudocyclic transition state TS in accordance with the
N(1S)
C(1S)
C(2)
O(2)
C(2S)
O(1)
C(3)
C(25)
mediate D through the transition state TS is 66.39–68.36 kcal mol–1
.
C(21)
C(22)
A somewhat larger value of the computed activation barrier at the
highest level of theory employed for conformer C compared to that
for the substituted 1,3,5-hexatrienes is generally consistent with
the previously published quantum chemical studies.15 It should
be noted that the RHF/3-21G and RHF/6-311G* methods that
we applied give the overestimated values of the relative energies
Ea (kcal mol–1) of the transition structures.15 On the contrary, a
significant shortening of the distance r to 2.09 Å against the
postulated 2.24 Å15 can be explained by the involvement of
the p-conjugated system of both (hetero)aromatic rings in the
transition state formation process. The HOMO of intermediates
C(18)
C(27)
C(26)
O(3)
C(19)
C(10)
C(11)
C(12)
N(2)
C(17)
C(15)
C(1)
N(3)
C(23)
C(20)
C(24)
C(8)
C(13)
C(16)
C(4)
O(5)
O(4)
C(9)
C(6)
N(1)
C(14)
C(7)
C(5)
Figure 1 Molecular structure of rac-(15)R*-isomer 2a based on the X-ray
analysis. Thermal ellipsoids are given with 50% probability.
C1–2 and TS shows the localization of the electron density on these
fragments (Table S2). In other words, the pseudocyclic transi-
tion state can be viewed as an 18-electron p-conjugated system.
Moreover, thetransitionstateisadditionallystabilizedby p-stacking
interaction (~3.4 Å) between closely spaced phenyl moieties (see
Tables S1, S2). Cyclization is not accompanied by a decrease in
electron density from intermediates C1–2 to TS, according to the
quantum chemical calculations (see Table S2). This fact may also
be an evidence in favor of stereospecific electrocyclization. In
(3.15 < q < 66.88°), 4448 unique reflections [Rint = 0.0631], R1 = 0.0486,
wR2 = 0.1284 for 2841 reflections with I > 2s(I), R1 = 0.0661, wR2 =
= 0.1326 for all reflections. All calculations were performed using
SHELXS-97 and SHELXL-97.20
CCDC 1890210 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
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Mendeleev Commun., 2019, 29, 135–137
References
TS D/E
TS
75
50
25
0
C3
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[1,5]-hydrogen suprafacial shift is characterized by a distance of
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Ea is 70.49–73.41 kcal mol–1 (see Figure 2, Table S1).
In conclusion, the one-pot cascade synthesis of novel poly-
cyclic 5-aryl-5,6-dihydroquinolino[2,1-b]quinazolin-12-ones
bearing benzo-15-crown-5 ether and dimethoxyphenyl moieties
was developed. The domino process includes the condensation
reaction, electrocyclization and sigmatropic shift. The pyrimidone
ring protonation proved to be the determining pre-requisite for
the passage of six-electron disrotatory cyclization of E-styryl-
quinazolinones forming in situ in the reaction medium. A rare
case of thermally allowed electrocyclization of hetarylethylenes
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Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.03.004.
Received: 7th August 2018; Com. 18/5662
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